merkel cell carcinoma & skin-associated polyomavirus€¦ · insulinoma‐associated 1: a novel...
TRANSCRIPT
Merkel Cell Carcinoma amp Skin-Associated Polyomavirus
Rosalie Elenitsas MD
Professor of Dermatology
Director Dermatopathology
University of Pennsylvania
Merkel Cell Carcinoma and Polyomavirus
bull Merkel Cell Carcinomabull Epidemiology
bull Pathogenesis
bull Clinical Presentation
bull PathologySerology
bull Staging and Prognosis
bull Other skin-associated polyomavirus
Case 1
bull 75 year old man
bull Neck
bull Rule out basal cell carcinoma
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
Merkel Cell Carcinoma Epidemiology
bull SEER data incidence is increasingbull 5-fold increase over past 30 years
bull More common in men 21
bull 94 Caucasians
bull Age 7th -9th decade
bull Head and neck most common sites
Merkel Cell Carcinoma Risk Factors
bull Sun exposurebull Age fair skin cumulative actinic damage
bull Polyomavirus infection
bull Immunosuppressionbull Hematologic malignancy
bull Organ transplant
bull Treatment for autoimmune disease
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma and Polyomavirus
bull Merkel Cell Carcinomabull Epidemiology
bull Pathogenesis
bull Clinical Presentation
bull PathologySerology
bull Staging and Prognosis
bull Other skin-associated polyomavirus
Case 1
bull 75 year old man
bull Neck
bull Rule out basal cell carcinoma
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
Merkel Cell Carcinoma Epidemiology
bull SEER data incidence is increasingbull 5-fold increase over past 30 years
bull More common in men 21
bull 94 Caucasians
bull Age 7th -9th decade
bull Head and neck most common sites
Merkel Cell Carcinoma Risk Factors
bull Sun exposurebull Age fair skin cumulative actinic damage
bull Polyomavirus infection
bull Immunosuppressionbull Hematologic malignancy
bull Organ transplant
bull Treatment for autoimmune disease
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Case 1
bull 75 year old man
bull Neck
bull Rule out basal cell carcinoma
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
Merkel Cell Carcinoma Epidemiology
bull SEER data incidence is increasingbull 5-fold increase over past 30 years
bull More common in men 21
bull 94 Caucasians
bull Age 7th -9th decade
bull Head and neck most common sites
Merkel Cell Carcinoma Risk Factors
bull Sun exposurebull Age fair skin cumulative actinic damage
bull Polyomavirus infection
bull Immunosuppressionbull Hematologic malignancy
bull Organ transplant
bull Treatment for autoimmune disease
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
Merkel Cell Carcinoma Epidemiology
bull SEER data incidence is increasingbull 5-fold increase over past 30 years
bull More common in men 21
bull 94 Caucasians
bull Age 7th -9th decade
bull Head and neck most common sites
Merkel Cell Carcinoma Risk Factors
bull Sun exposurebull Age fair skin cumulative actinic damage
bull Polyomavirus infection
bull Immunosuppressionbull Hematologic malignancy
bull Organ transplant
bull Treatment for autoimmune disease
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
Merkel Cell Carcinoma Epidemiology
bull SEER data incidence is increasingbull 5-fold increase over past 30 years
bull More common in men 21
bull 94 Caucasians
bull Age 7th -9th decade
bull Head and neck most common sites
Merkel Cell Carcinoma Risk Factors
bull Sun exposurebull Age fair skin cumulative actinic damage
bull Polyomavirus infection
bull Immunosuppressionbull Hematologic malignancy
bull Organ transplant
bull Treatment for autoimmune disease
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Epidemiology
bull SEER data incidence is increasingbull 5-fold increase over past 30 years
bull More common in men 21
bull 94 Caucasians
bull Age 7th -9th decade
bull Head and neck most common sites
Merkel Cell Carcinoma Risk Factors
bull Sun exposurebull Age fair skin cumulative actinic damage
bull Polyomavirus infection
bull Immunosuppressionbull Hematologic malignancy
bull Organ transplant
bull Treatment for autoimmune disease
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Risk Factors
bull Sun exposurebull Age fair skin cumulative actinic damage
bull Polyomavirus infection
bull Immunosuppressionbull Hematologic malignancy
bull Organ transplant
bull Treatment for autoimmune disease
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Cell of origin
bull NOT YET IDENTIFIED
bull Thought to be Merkel cells but these reside in epidermis and most tumors in the dermis now unlike to be Merkel cells
bull Candidatesbull Primitive B cells tumors express PAX5 and TdTbull Stem cellsbull Fibroblastsbull Epithelial cells (possible only in the UV-induced tumors)
bull MCV+ tumors possibly virus integrates into another cell (B cell fibroblast) and induces a Merkel-like phenotype
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Polyomavirus
bull Discovered in 2008
bull Detected in 60-80 of MCC
bull Detected using PCR
bull Higher percentage in US compared to Australia
bull Rates can vary dependent on quality of tissuefixation
bull Immunohistochemical stain CM2B4bull Nuclear variable cytoplasmic stainbull Sensitivity 39-90
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Clinical Presentation
bull Erythematous or violaceous nodule
bull Sun-exposed skin
bull Elderly patients
bull Head and Neck
bull Rapidly growing
bull 23 patients present with local disease onlybull 26 nodal disease
bull 8 distant disease
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Clinical Presentation
bull AEIOU acronym developed to help recognize MCC
J Am Acad Dermatol 200858375-81
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Clinical Presentation
A = asymptomaticE = expandingI = immune suppressionO = Older than 50 yearsU = Ultraviolet exposed skin
90 of patients have at least 3 features
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Histopathology
bull Nodular tumor of small blue cells
bull Epidermal dermal or subcutaneous
bull Sheets nests or trabeculae
bull Scant cytoplasm high nuclearcytoplasm ratio
bull Stippled nuclei
bull Mitoses and apoptotic cells are abundant
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Histopathology variations
bull Intraepidermal only
bull Areas of squamous eccrine or sarcomatous differentiation
bull Association with other cutaneous malignancybull SCC most common usually SCCIS
bull Called ldquocombinedrdquo
bull Combined MCC are negative for the polyomavirus (small series)
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Immunohistochemistry
bull CK20bull gt90 positive
bull Perinuclear dot pattern or cytoplasmic
bull Other keratins same patternbull AE1AE3
bull Cam52
bull Neuroendocrine markersbull CD56 chromogranin synaptopysin neurofilament
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
CK-20
CK20
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
CK20
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Immunohistochemistry
bull MCPyVbull 70-80 positive
bull Negativebull Melanocytic Markers
bull Lymphoid markers
bull TTF1
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Case 1
bull You suspect merkel cell carcinoma so you order CK20
bull What other stains should you order to confirm the diagnosis
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Case 1
A No other stains are needed
B TTF1
C TTF1 SOX10 PAX5
D TTF1 SOX10 CD3
E TTF1 SOX10 CD45
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
INSM1
bull Insulinoma-associated protein 1
bull Neuroendocrine differentiation
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
ORIGINAL ARTICLEInsulinoma‐associated 1 A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)Patrick S Rush et al
INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell CarcinomaLilo Mohammed T MDdagger Chen Youdinghuan BS MSDagger LeBlanc Robert E MDdagger
The American Journal of Surgical Pathology November 2018 -Volume 42 - Issue 11 - p 1541ndash1548
INSM1 A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and NeuroepithelialNeoplasmsJason N Rosenbaum MD et alAmerican Journal of Clinical Pathology Vol 144 Issue 4 October 2015 Pages 579-591 httpsdoiorg101309AJCPGZWXXBSNL4VD
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Insulinoma-associated protein 1INSM1
bull Nuclear marker
bull Neuroendocrine differentiation
bull (+) in Merkel cell carcinoma and other neuroendocrine tumors
bull Negative in other ldquobasaloidrdquo skin tumors BCC sebaceous carcinoma lymphoma melanoma basaloid SCC
cannot differentiate from metastatic neuroendocrine CA
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Differential Diagnosis
bull Basal cell carcinomabull CK20
bull Malignant melanomabull SOX10 MART1 MelanA HMB45 MiTF
bull S100 rarely + in MCC
bull Lymphomaleukemiabull PAX5 and TdT can be + in MCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Panse G McNiff JM Ko CJ Basal cell carcinoma CD56 and cytokeratin 56 staining patterns in the differential diagnosis with Merkel cell carcinoma J Cutan Pathol 201744553ndash556 httpsdoiorg101111cup12950
MCC
vs
BCC
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Differential Diagnosis
bull Metastatic small cell lung carcinoma (SCLC)
bull CK20bull About 7 + in SCLC
bull TTF1bull 80 SCLCbull 1-2 MCC
bull MASH1bull 70-80 SCLCbull 3 MCC
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Histopathology 2018 Sep 21 doi 101111his13758
Neurofilament is Superior to Cytokeratin 20 in Supporting Cutaneous Origin for Neuroendocrine CarcinomaStanoszek LM1 Chan MP12 Palanisamy N3 Carskadon S3 Siddiqui J1 Patel RM12 Harms KL2 Lowe L12 Fullen DR12 Harms PW12
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
bull 55 MCC specimens including 9 CK20-negative MCC tumors
bull Neurofilament expression was observed in 4255 (764) MCC cases including 79 CK20-negative MCC cases
bull Neurofilament was also positive in 25 of 61 extracutaneousSmCCbull primary sites lung (27) bladder (18) cervix (3)
gastrointestinal (3) sinonasal (2) and other (7)
bull CK20 in 2561 (410) non-cutaneous SmCC cases
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Pathology of MCV+ vs MCV- tumorsKervarrec et al Modern Pathol 321605-1616 2019
bull MCV ndashbull Larger cell size
bull More cytoplasm
bull Prominent nucleoli
bull Neurofilament (-)
bull (+) TTF1 And CK7
bull MCV+bull CK818 +
bull CD99 + in dot pattern (vs diffuse pattern) may be helpful
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
CD99 staining in MCC
MCPyV neg n=21
5
10
85
MCPyV pos n=80
15
81
4
Negative
Dot pattern
Diffuse pattern
Kervarrec et al Modern Pathol 321605-1616 2019
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Serology
bull Antibodies to MCPyV capsid proteinsbull Mark viral exposure
bull Present in 90 of patients with MCC
bull Present in 60 of healthy adults
bull Indicates prior exposure
bull Antibodies to MCPyV oncoprotein (DNA)bull 50 of patients with MCC
bull Rare in healthy adults (lt1)
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
bull Antibody level correlates with tumor burden
bull Seronegative patients with MCC have higher risk of recurrence
Cancer Res 70(21) 8388ndash97
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC antibodies to oncoprotein
bull Available testingbull httpswwwmerkelcellorgsero
bull Useful only for patients with high titersbull Levels drop after treatment
bull Levels increase with recurrence
Cancer Res 70(21) 8388ndash97
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma
bull Staging and Prognosis
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma
Presentation 5 year survival
Local disease 65 51
Nodal disease 26 35
Distant mets 8 14
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Staging
bull Two most important variables
bull Utilized in AJCC 8th Edition
bull Tumor size (clinical diameter)bull Depth of invasion (ldquoClark levelrdquo)
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Tumor Size
bull pT1 lt 2cm
bull pT2 2-5cm
bull pT3 gt 5cm
bull pT4 invasion of fascia bone cartilage or muscle
bull 56 survival
bull 41
bull 41
bull 32
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Other variables
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Tumor thickness
bull Increasing thickness associated with poor survival outcomes
bull Measure from granular layer (similar to melanoma)
bull Report in millimeters
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Mitotic rate
bull More than 10 mitosesHPF associated with poor prognosis
bull Can report per HPF or per mm2
bull MIB-1 index greater than 50 associated with poor prognosis
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Tumor Infiltrating Lymphocytes
bull CD8+ TILs associated with better prognosis
bull TILs in thick tumors (gt5mm) have worse prognosis
bull Conflicting data
bull Similar to melanoma reportingbull Brisk diffusely infiltrating the base of tumor
bull Non-brisk infiltrating less than entire base
bull Absent no lymphocytes infiltrating the tumor
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Tumor Growth Pattern
bull Nodular pattern associated with better survival
bull Nodular relatively well circumscribed interface with surrounding tissue
bull Infiltrative single cells trabeculae infiltrating between collagen
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Nodular pattern
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Infiltrative pattern
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Nodal Disease
bull Worse outcomes with more extensive nodal disease
bull Patients with Pathology Proven negative nodes do the best
bull SLNB recommended for primary MCC in ldquorelatively healthyrdquo patients
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Prognostic Markers
bull Should the pathologist perform any biomarkers to aid in prognosis
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Prognostic biomarker
bull p63 is the most studiedbull (+) p63 associated with worse prognosis
bull Not confirmed by all studies
bull More work needed
bull Ckitbull (+) Ckit tends to worse prognosis
bull MCPyVbull (+) has better prognosis than if (-) for the virus
bull Viral (-) tumors may have higher mutation burden (UV mutations)
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
D2-40
evaluate for
lymphatic invasion
MCC
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Prognostic markers
bull Chronic immunosuppressionbull Lower survival
bull MCC higher incidence in AIDS and solid organ transplant patients
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Treatment
bull Surgical excision mainstaybull Traditional wide excision
bull Mohs micrographic surgery
bull Adjuvant XRT to primary skin site (hi risk tumor) vs observation
bull Consideration for Sentinel Lymph Node Biopsy in almost all patients
NCCN Guidelines Volume 16 Number 6 June 2018
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Merkel Cell Carcinoma Treatment
bull (-) lymph node bull consider adjuvant XRT to nodal basin (hi risk) vs bull Observation
bull (+) lymph node bull Systemic therapy clinical trial if availablebull XRT to nodal basin orbull Observation
NCCN Guidelines Volume 16 Number 6 June 2018
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Metastatic Merkel Cell Carcinoma
bull Cytotoxic chemotherapybull Cisplatinetoposide
bull Immune checkpoint inhibitorsbull Avelumab
bull Pembrolizumab
bull Nivolumab
bull Talimogen laherparepvec (T-VEC)
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Talimogene laherparepvec (T-VEC)
bull Modified oncolytic herpes simplex virus
bull Replicates in the tumor
bull Expresses GMCSF
bull Promotes local and systemic antitumor response
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Talimogene laherparepvec (T-VEC)
bull Intralesional injection
bull Used for advanced melanoma
bull MCC used in locally recurrent or advanced diseasebull Induces both partial and complete remissionbull Most gt 2 years
Westbrook BC et al JAAD 20195782-786
Chesney J et al J Clin Oncol 201836(17)1658-1667
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
CAP Protocol for Merkel Cell Carcinoma
bull Not all items requiredbull June 2017 most recent
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Pathology Report recommended
bull Thickness (Breslow)bull Tumor sizebull Clark levelbull Growth patternbull Lymphovascular invasionbull Tumor Infiltrating Lymphocytesbull Margin statusbull Extracutaneous involvementbull Mitotic count (per mm2)bull Presence of second malignancy
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
MCC Template
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Case 2
bull 72 year old man
bull Idiopathic pulmonary fibrosis
bull sp double lung transplant 5 years ago
bull Immunosuppression prednisone tacrolimus mycophenolic acid
bull 2 years severely itchy rash
bull No gastrointestinal symptoms
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Case 2 Clinical
bull Thin velvety plaques with hyperpigmentation
bull Neck back chest axillae buttocks legs
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Skin Biopsy
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Site L upper armDate 2217
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
What is the most likely etiology
A Infectious agent
B Medication
C Neoplasia (hematopoietic malignancy)
D Contactant
E Autoimmune (connective tissue disease)
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Differential
bull Graft vs host disease
bull Chronic eczematous dermatitis
bull Sezary Syndrome
bull Dermatomyositis
bull Other
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Patient
ldquoThey told me I had a rare viral infection of the skinrdquo
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Human Polyomavirus 7 associated rash
bull Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant Recipients
bull Jonhan Ho Jaroslaw J Jedrych Huichen Feng et albull The Journal of Infectious Diseases Volume 211 Issue
10 15 May 2015 Pages 1560ndash1565
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Diagnosis
bull Immunoperoxidase stain to HPyV7 antigenbull (+) epidermal keratinocytes weaker in stratum corneum
bull Electron microscopybull 39-46 nm icosahedral virions cw polyomavirus
bull Quantitative PCRbull High HPyV-7 viral genome copy number
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Human Polyomavirus 7ndashAssociated Pruritic Rash and Viremia in Transplant RecipientsJonhan Ho Jaroslaw J Jedrych Huichen Feng et alThe Journal of Infectious Diseases Volume 211 Issue 10 15 May 2015 Pages 1560ndash1565
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Human papillomavirus-7 skin rash
bull Resembles peacock plumage
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
J Am Acad Dermatol 201776932-40
3 additional patients with similar clinical and histopathology
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
JAAD 201776932-40
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Human Polyomavirus
bull Family Polyomaviridaebull 77 species of virus
bull 13 known to be infectious to humans
bull Icosahedral virus
bull Double stranded circular DNA
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Polyomavirus History
bull First polyomavirus described in 1952bull Caused adenocarcinoma and leukemia when injected into micebull 1971 became known as BK virus (patient BK)
bull Same year JC virus isolated from patient JC with Hodgkinrsquos lymphoma and progressive multifocal leukoencephalopathy (PML)
bull 2008 Merkel cell polyomavirusbull 2010 trichodysplasia spinulosa virus
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Polyomavirus
bull JC virus progressive multifocal leukoencephalopathy
bull BK virus nephropathybull BK and JC virus affect immunosuppressed patients not known to
cause skin disease
bull Merkel cell polyomavirus MC carcinoma
bull Polyomavirus 8 trichodysplasia spinuloma
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Arch Dermatol 2012148(2)219-223
Viral Associated Trichodysplasia
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Viral Associated TrichodysplasiaTrichodysplasia Spinulosa
JAAD Case Reports 20162307-9
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Viral Associated Trichodysplasia
bull Folliculocentric papules with keratotic spiculations
bull Mid face and ears
bull Less common on trunk and extremities
bull Variable alopecia of eyelashes and eyebrows
bull Path dysmorphic follicles with enlarged trichohyalingranules
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Dysmorphic hair follicles
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Dysmorphic hair follicles
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Prominent and enlarged trichohyalin
granules
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Prominent and enlarged trichohyalin
granules
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
VAT HPyV 7
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
HPyV 7Verruca vulgaris
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Dermatopathology201521ndash8
DDX Wong-Type Dermatomyositis
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
HPyV 7Wong-type Dermatomyositis
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Take home
bull Polyomaviruses are ubiquitous and asymptomatic in most humans
bull Immunosuppression may lead to skin manifestions of viral infection
Thank you
rosalieelenitsaspennmedicineupennedu
Thank you
rosalieelenitsaspennmedicineupennedu