breast pathology cases regional training day april 2017breast pathology cases regional training day...
TRANSCRIPT
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Breast Pathology Cases Regional Training Day
April 2017
Dr Claire Murray
Consultant Histopathologist
Royal Devon and Exeter Hospital
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Case 1(14/604)
• 28 year old female
• Left breast lump
• Well-defined 50 mm mass
• Fatty in texture and easily enucleated at surgery
• Excision specimen
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Case 1 Macro
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Case 1. Diagnosis
Hamartoma (adenolipoma)
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Breast Hamartoma - Clinical
• Occur at any age but most common in premenopausal women
• Present as well circumscribed mass clinically and radiologically
• Vary between 10 and 80mm in size
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Breast Hamartoma - Histology
• Well circumscribed, round or oval mass • Surrounding compressed breast tissue forms
pseudocapsule • Disordered ducts and lobules within lesion are typically
normal • May be associated with fibrocystic change • May contain smooth muscle, fat, cartilage or
pseudoangiomatous stromal hyperplasia (PASH) • Often categorised as B1 due to appearance of normal
tissue on core biopsy – clinical and radiological correlation is essential to avoid over treatment.
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Breast Hamartoma - Variants
• Adenolipoma
• Fibrolipoma
• Adenofibroma
• Chrondrolipoma
• Myoid hamartoma
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Case 2 (16/29962)
• 55 year old female
• Indeterminate 12mm focus, 6 o'clock right breast
• P1/U3
• Right breast core biopsy
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Case 2. Diagnosis
Complex sclerosing lesion and usual epithelial hyperplasia
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Radial Scar/Complex Sclerosing lesion
• Radial Scar • 10mm or less in diamter
• ‘central fibro-elastic zone from which radiate out tubular structures that are two layered and exhibit intraluminal proliferation’
• Immuno panel of myoepithelial markers can be useful to exclude tubular carcinoma or low grade ductal carcinoma
• Complex sclerosing lesion • More than 10mm in diameter
• Exhibit all the features of radial scar
• May be associated with superimposed apocrine metaplasia, papilloma formation and sclerosing adenosis
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Radial Scar/Complex Sclerosing lesion
• Diagnostic core biopsy • Radial scars/CSL should be categorised as B3
• Radial scars/CSL can be associated with epithelial atypia and/or invasive carcinoma in a significant number of cases
• Presence of epithelial atypia within the lesion is important to record as the chance of malignancy in the subsequent excision is much higher
• Vacuum excision biopsy • Recommended technique for full assessment
• If EXCISIONAL VAB has fully assessed lesion and there is no epithelial atypia, it is reasonable to record the RS/CSL as B2 rather than B3
• Upgrading rate for atypia is around 12% and for invasive carcinoma is <2%
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RS/CSL Radiology
• Spiculate lesions which can be misinterpreted as malignant
• Several characteristic features but none are specific and all can be seen in invasive carcinoma
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Case 3 (16/29104)
• 42 year old female
• Indeterminate mass in right breast
• Excised following core biopsy
• Macro: 50mm in maximum dimension, lobulated firm white lesion
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stromal hypercellularlity and atypia
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Frequent mitoses
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Case 3. Diagnosis
Borderline phyllodes tumour
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Phyllodes Tumour (PT)
• Uncommon fibroepithelial neoplasm with biphasic proliferation of both epithelial and stromal components.
• “Phyllodes” - Derived from the Greek word “phyllon” meaning leaf, and “eidos” meaning form.
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Phyllodes Tumour (PT)
‘Fibroepithelial architecture shows exaggerated intracanalicular pattern with leaf-like frond protruding into cystically dilated spaces accompanied by stromal hypercellularity’
Histopathology 2016, 68, 5-21 Phyllodes tumours of the breast: a consensus review
Arch Pathol Lab Med. 2016;140:665-671 Phyllodes Tumor of the Breast
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WHO 2012 Classification of PT
Histologic Features Benign Borderline Malignant
Stromal cellularity Mild Moderate Marked
Stromal atypia Mild Moderate Marked
Mitoses per 10 hpf (x 40)
<5 5 – 9 >10
Stromal Overgrowth *
Absent Absent or focal Present
Tumour Margin Well defined Well defined or focal infiltrative
Infiltrative
Malignant heterologous element
Absent Absent May be present
Proportion of all phyllodes tumours
60 – 75% 15 – 20 % 10 – 20%
* Stromal overgrowth defined as presence of stroma without epithelium in at least one low-power field (x4 objective or x10 in a core biopsy)
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Stromal cellularity and atypia
• No objective criteria for assessment which confounds grading attempts
• Practical advice is to centre on the most cellular/atypical zones of lesion
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Stromal cellularity
• Mild hypercellularity • Slight increase in stromal cells compared with normal
perilobular stroma ( some suggest twice cellularity of normal stroma)
• Evenly spaced nuclei; no touching or overlapping
• Marked hypercellularity • Confluent areas of densely overlapping nuclei
• Moderate hypercellularity • Intermediate findings with some overlapping
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Stromal atypia
• Mild atypia • Nuclei with little variantion in size; inconspicuous nucleoli
• Smooth nuclear contours
• Moderate atypia • Some variation in nuclear size
• Wrinkled nuclear membranes
• Marked atypia • Marked variation in nuclear size
• Coarse chromatin
• Irregular nuclear membranes with discernible nucleoli
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Practical Application of WHO classification
• Guidelines ambiguous
• ‘A practical approach is to grade a phyllodes tumour as malignant when it shows ALL the histological changes of malignancy, and as borderline when not all the malignant characteristics are present’
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Differential Diagnosis of malignant PT
• Metaplastic carcinoma • Malignant epithelial and stromal element
• Use a panel of cytokeratins and myoepithelial markers ( these can also be positive in some malignant PT)
• CD34 + ve favours PT but can also be + ve in metaplastic carcinoma
• Primary sarcoma of breast • Extremely rare
• Most sarcomas arising as a component of malignant PT
• Extensive sampling to exclude an epithelial component
• Clinical management is similar
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PT practical management
• Benign phyllodes that have been enucleated without margins can be managed conservatively
• Borderline phyllodes should be completely excised but there is no agreement on ideal margin width
• Recurrent and malignant phyllodes tumours should be excised with clear margins
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Case 4 (16/19862)
• 46 year old female
• Presented with left breast lump
• M4/U5
• Left breast excision at RD&E following biopsy in NDDH
• Macro: Irregular greyish lesion 22 x 15mm
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ASMA
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Desmin
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β catenin
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Immuno Profile
Positive Negative
Β catenin AE1/AE3
ASMA S100
Desmin CD34
Bcl2
Caldesmon
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Case 4. Diagnosis
Mammary Fibromatosis
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Mammary Fibromatosis
• Rare (< 0.2 % primary breast tumours)
• Typically women of reproductive age
• May arise within breast or chest wall fascia
• Benign and non-metastasising
• Infiltrative and locally recurrent if not completely excised
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Fibromatosis – clinical features
• Usually solitary
• Non-tender
• Ill-defined mass
• May be spiculate on mammography mimiking malignancy
• Ultrasound and MRI more accurate at defining the lesion
• Can be associated with trauma and implants
• May arising in FAP, Gardener’s syndrome
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Fibromatosis – Macro
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Fibromatosis – Micro
• Irregular, non-encapsulated proliferation of spindle cells (fibroblasts and myofibroblasts)
• Formation of sweeping, interlacing fascicles
• Extension into surrounding parenchyma with entrapment of lobules and fat
• No epithelial component
• Evenly spaced nuclei with smooth membranes and delicate nucleoli
• Uniformaly distributed collagen (can be keloid –like)
• Small but conspicuous blood vessels
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Fibromatosis – Immuno
Antibody Reactivity Staining pattern Coment
β catenin Positive Nuclear Correlates with β catenin and APC gene mutations
ASMA Positive Cytoplasmic Reflects myofibroblastic differentiation
Desmin Focally positive Cytoplasmic
CD34 Negative Excludes phyllodes
Pan cytokeratins
Negative Excludes metaplastic carcinoma
S100 Negative Excludes melanoma
ER/PR/AR Negative
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Fibromatosis – Genetics
• Mutations in β catenin gene (CTNNB1) associated with nuclear staining in >80% of cases
• Nuclear expression of β catenin also seen in • 23% of metaplastic breast carcinoma • 94% of benign phyllodes tumour • 57% of malignant phyllodes tumour
• Mutations in exon 3 of CTNNB1 more frequent in breast fibromatosis
• * CTNNB1 mutations not present in MBC or PT • Association with FAP and germline mutations in
APC gene which regulates β catenin.
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Fibromatosis - Differentials
• Low grade, fibromatosis-like, metaplastic breast carcinoma
– Express cytokeratins
– Minority of cases can also show some nuclear expression of beta catenin
• Myofibroblastoma
• Stromal component of phyllodes tumour
• Nodular fasciitis
• Solitary fibrous tumour
• Scar
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Case 5 (14/26001)
• 82 year old female
• Left breast carcinoma in 2010.
• ER positive, on tamoxifen
• Recurrent lesion left breast in region of previous surgery
• Left mastectomy
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p63 p63
CK5/6 SMM
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Case 5. Diagnosis
Encapsulated (encysted/intracystic) papillary
carcinoma
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Encapsulated papillary carcinoma (EPC)
• Controversy as to whether this is an in-situ or invasive lesion
• Pure forms categorised as B5a on core biopsy and staged as Tis
• Biopsy report should clearly document the nature of the lesion so that it is not confused with conventional DCIS
• Goal is to avoid over treatment • Exception: high grade nuclear morphology and/or
triple negative phenotype should be classified as invasive (B5b)
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EPC – Histological features
• Central and solitary
• Thick fibrous capsule
• Monotonous neoplastic cells arranged in solid and cribriform patterns
• Delicate fibrovascular cores
• Mostly low or intermediate nuclear grade
• Lack of myoepithelial cells around periphery of tumours and around fibrovascular cores
• Typically strongly ER positive , HER2 negative
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EPC- invasive components
• Small number of EPC associated with invasion
• Invasion characterised by tumour cells extending beyond the fibrous capsule and inducing stromal reaction
• Invasive component can be papillary or IDC NST
• Staging should only follow the invasive component and not include the EPC component
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EPC –Differentials
• Papillary DCIS – Maintains myoepithelial layer around periphery
• Solid papillary carcinoma – Predominantly solid growth pattern
– Often lacks peripheral fibrous capsule
– More often multinodular
– Frequent neuroendocrine and mucinous differentiation
– Indolent behaviour
– Staged as Tis
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EPC – behaviour and management
• > 80% have indolent invasive pattern
• Lymphovascular invasion (3%)
• Nodal metastases (3%)
• Local recurrence (7%) – in those lacking conventional invasive components
• Should be managed as in-situ disease
• High grade and micropapillary patterns can be considered as invasive
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Case 6 (13/30811)
• 83 year old female
• 18mm mass left breast
• P1/M3/U4
• Left breast WLE
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ER strongly and diffusely positive
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Case 6. Diagnosis
Mucinous carcinoma
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Mucinous (colloid) carcinoma
• 0.5 – 3 % of all invasive breast carcinoma
• Rare in younger women (mean age 71)
• Nodal metastases rare
• 10 year survival for pure form is better than invasive carcinoma (NST)
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Mucinous (colloid) carcinoma - Micro
• Clusters of small uniform cells floating in lakes of extracellular mucin
• Tumour nests may be solid, acinar, cribriform
• Typically ER positive and HER2 negative
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Mucinous (colloid) carcinoma - Micro
• Type A: paucicellular/ no neuroendocrine diff
• Type B: hypercellular/ neuroendocrine differentiation in 10-15%
• Type AB: intermediate
Classification based on molecular studies but has no clinical significance
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Mucinous (colloid) carcinoma - Micro
• Type A: paucicellular/ no neuroendocrine diff
• Type B: hypercellular/ neuroendocrine differentiation in 10-15%
• Type AB: intermediate
Classification based on molecular studies but has no clinical significance
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Mucinous (colloid) carcinoma - Micro
• Type A: paucicellular/ no neuroendocrine diff
• Type B: hypercellular/ neuroendocrine differentiation in 10-15%
• Type AB: intermediate
Classification based on molecular studies but has no clinical significance
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Invasive Carcinoma – tumour typing categories
Pure special type: 90% or more of tumour shows classical histological features
Invasive carcinoma, no special type (NST): < 50% special type morphology
Mixed carcinoma: special type areas >50% but < 90%
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Case 7 (17/4440)
• 72 year old female
• Previous lesion excised from left breast 2015
• M3, U4 lesion at surgical site ?recurrence
• Left breast core biopsy
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CK7 p63
SMM MIB1
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Case 7. Diagnosis
Recurrent adenomyoepithelioma
(Low Grade malignant adenomyoepithelioma previously
excised in 2015)
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Adenomyoepithelioma (AME)
• Rare breast tumour
• Biphasic, neoplastic proliferation of luminal and myoepithelial cells
• Most tumours have a benign clinical course but local recurrences, malignant transformations and distant metastases are reported
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Benign AME – clinical features
• Occurs in adults at any age (mean age 59)
• Presents as solitary palpable nodule
• Can occur in any location but most common in periphery
• Mammogram: rounded or lobulated mass, dense, sometimes indistinct margins
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Benign AME – Gross Features
• Size range: 3 – 70 mm (average 25mm)
• Round to lobulated with firm texture
• Pink-white to grey-tan cut surface
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Benign AME – Histology
• Biphasic tumour composed of epithelial-lined tubules surrounded by myoepithelial cells
• Dual population highlighted using immunostains • Varying patterns described:
• Tubular - proliferation of tubules and hyperplastic myoepithelial cells
• Spindle cell – predominantly composed of spindled myoepithelial cells with a few tubules
• Lobular - solid nests of myoepithelial cells proliferating around comporessed tubules
• Catergorised as B3 on core biopsy • Complete excision with clear margins recommended to
prevent recurrence
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Atypical AME – Histology
• Features of atypia are subjective and poorly defined
– Increase in mitotic figures
– Cytonuclear atypia in the proliferating myoepithelial cell population
– Infiltrative borders
• Uncertain metastatic behaviour
• Lymph node metastases have been seen subsequent to diagnosis of atypical AME
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Malignant AME – Histology
• Locally invasive borders
• High mitotic rate
• High grade nuclear pleomorphism
• Lymphovascular invasion
• Epithelial or myoepithelial components of AME can give rise to invasive carcinoma
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Case 8 (16/24107; 16/26640)
• 56 year old female
• Left sided breast pain and lumpiness
• Mammogram and ultrasound scan normal (M1/U1)
• Follow-up MRI scan detect MRI3 lesion
• Patient proceeded to core biopsy (16/24107)
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p63
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CK5/6
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S100 CD10
SMM ER
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Summary
• Tubular/glandular and focally cribriform proliferation
• Dual population of cells with some basal/myoepithelial expression although not confined to the periphery of the tubules
• Eosinophilic luminal secretions
• S100 and ER negative
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Provisional Diagnosis
• Atypical microglandular adenosis
• B3
• Further vacuum biopsy recommended at MDT
• Vacuum biopsy (16/26640)
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ABDPAS
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p63 ASMA
Collagen IV CK7
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ER PgR
CD117 MIB-1 very low
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Summary of vacuum biopsy findings
• Infiltrative lesion composed of tubular and prominent cribriform areas
• Dual luminal and basal cell population highlighted by immuno
• ER, PgR, S100 and CD117 negative
• DD: Adenoid cystic carcinoma; collagenous spherulosis
• Slides of core and vacuum biopsy sent to Professor Sarah Pinder for an expert opinion
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Expert Diagnosis
• In keeping with ADENOID CYSTIC CARCINOMA
• Immuno panel not entirely typical (CD117 negative and only scant luminal cells)
• Tissue sent for molecular genetic testing (interphase FISH analysis)
• MYB (6q23) gene rearrangement present consistent with adenoid cystic carcinoma
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Case 8. Diagnosis
Adenoid cystic carcinoma (AdCC)
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Adenoid cystic carcinoma (AdCC)
• Uncommon; <0.1% of all breast carcinomas
• A salivary gland-type breast carcinoma
• Better prognosis than salivary AdCC
• Age distribution similar to other invasive breast cancers
• Mean size is 30mm (range 7 – 120mm)
• Radiologically non-specific features; can be misdiagnosed as benign
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AdCC - Histology
• Typical dual population of luminal and myoepithelial-basal cells
• 3 architectural patterns: • Tubular/trabecular
• Cribriform
• Solid basaloid
• True glandular spaces and pseudolumina
• Luminal spaces contain PAS +ve neutral mucin
• Nottingham histological grading applies
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AdCC – Immunohistochemistry
Myoepithelial –basal cells Luminal cells Hormone receptors
CK5/6 CK7 Triple negative
CK17 CK8/18 ER and PgR positive in a small minority
P63 EMA HER2 typically negative
Actin CD117 (positive in 90%)
Calponin
S100
Collagen IV – highlights pseudolumina
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AdCC - Differentials
• Cribriform/tubular carcinoma • Monomorphic population of neoplastic cells • Typically ER and PgR positive • Rarely express p63 or CD117
• Collagenous spherulosis • Collagenous spherules are irregular and mostly observed at the
periphery of lesions • No mucosubstance within lumina • Typically CD117 negative and Calponin/SMM positive
• DD of solid variant of AdCC includes: • Small cell carcinoma • Solid papillary carcinoma • Metaplastic carcinoma • Lymphoma
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AdCC – Molecular pathology
• T (6;9)(q22-23; p23-24) chromosomal translocation which generates fusion transcripts of the oncogene MYB and the transcription factor NFIB
• Translocation present in 90% of AdCC
• Next generation sequencing shows breast AdCC have basal phenotype
• No association found with BRCA1 mutations
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AdCC – Prognosis
• Excellent prognosis – 10 year survival rate 90-100%)
• Lymph node metastasis (10-15%)
• Distant mets typically affect visceral organs
• Solid pattern associated with more aggressive behaviour
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Case 9 (14/16598)
• 50 year old female
• Bleeding and crusting of left nipple with area of redness
• Nipple biopsy
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CK7
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CK5/6
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p63
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S100
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ER
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Case 9. Diagnosis
Paget’s disease of nipple
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Paget’s disease of Nipple
• First described by James Paget in 1874
• Present in 1-2% of breast cancers
• Almost all cases associated with HG DCIS +/- invasive ductal carcinoma
• Excludes direct invasion of the skin by an invasive carcinoma
• Clinical features: red, weaping, crusting
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Paget’s histology
• Adenocarcinoma cells within epidermis
• Cells either singly dispersed or efface the entire epidermis
• Large nuclei; prominent nucleoli
• Abundant pale cytoplasm
• Shrinkage artefact may leave space around cells
• Upper dermal telangiectasia and chronic inflammation
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Paget’s differentials
Normal nipple skin Mammary Paget’s Pagetoid Bowen’s Melanoma
Toker cells = clear cells that occur in the epidermis of nipple skin
Described above No maturation and individual cell keratinisation
Pigmentation; dermal invasion can be present
CK5/6 +ve; CK7, CAM5.2 can be +ve
EMA, CAM5.2, CEA, CK7 +ve; HER2 +ve in 80-90% S100 +ve in 20% Mucin may be present
CK5/6; p63 +ve in epidermal cells and Bowen’s
HMB45; Melan A most specific S100 can be positive in Paget’s
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References
• Histopathology Vol 68(1); Jan 2016: Annual Review Issue: Breast Pathology
• RCPath: Guidelines for non-operative diagnostic procedures and reporting in breast cancer screening (June 2016)
• RCPath: Pathology reporting of breast disease in surgical excision specimens incorporating the dataset for histological reporting of breast cancer (June 2016)
• World J Clin Cases 2014 December 16; 2(12):732-742: Adenoid cystic carcinoma of the breast: recent advances