Cutaneous B-cell Lymphomas

Youn H Kim, MDDirector, Multidisciplinary Cutaneous Lymphoma Group

Department of DermatologyStanford Cancer Center

Handout will be available at the AAD website

Disclosure statement

Youn Kim, MD• Advisory board

– Merck, Therakos, Eisai

• Consultant – Allos, Celgene, Gloucester, Kyowa Kirin, Seattle Genetics, Millennium

• Investigator – Merck, Gloucester, BioCryst, Allos, Kyowa Kirin, Yaupon, Celgene

Primary Cutaneous B-cell Lymphomas

Indolent

IntermediateAggressive

New WHO-EORTC Classification

Marginal zone B-cell lymphoma

Follicle center lymphoma

Diffuse large B-cell lymphoma, leg-type

Diffuse large B-cell lymphoma, other

Most primary cutaneous CBCL are “good” except DLBCL, leg-type/other

Blood 2005;105: 3768-85

WHO monogram, 4th Ed, 2008

DSS, n = 280 Dutch patientsWillemze, Curr Op Oncol, 2006

Differential gene expression patterns, PCFCL vs. DLBCL leg-type Hoefnagel et al, Blood 2005

PCBCL, Stanford Experience, n = 198

Follicle Center Lymphoma

(n=103)

Marginal Zone Lymphoma

(n=85)

Diffuse Large Cell Lymphoma-leg type

(n=10)Age median 51 (17-88) 49 (15 -80) 71 (41-90)

% Male/Female 70/30 63/37 60/40

% Generalized 33 20 40

OS, 5-year 95% 100% 33%

RFS, 5-year 44% 38% 17%

Sites for localized disease

H/N 55%

Arm 10%

Torso 27%

H/N 30%

Arms 36%

Torso 26%

Leg 100%

In indolent CBCL (MZL/FCL), when relapse occurs, majority are limited to skin and respond well to salvage therapy

PC Marginal-Zone B-cell Lymphoma• Indolent BCL of mature small B-cells including MZ

(centrocyte-like) cells, lymphoplasmacytoid cells, plasma cells– “immunocytoma”, part of extranodal MZL of MALT (GI tract,

salivary gland, lung, H/N, ocular adnexa, skin, thyroid, breast)– MZ B-cells: CD20+, CD79a+, Bcl-2+, CD5-, CD10-, Bcl-6-– Plasma cells: CD138+, CD79a+, freq. CD20-– Molecular/Genetic

• 40-60% clonal IgH gene rearrangement • t(11;18)(q21;q21) => GI tract, lung – rare in skin MZL• t(14;18)(q32;q21) => ocular, salivary gland MZL• t(3;14)(p14.1;q32) => thyroid > ocular, skin MZL

• Red-violaceous plaques or tumor nodules commonly on extremities (esp. arms) or trunk; solitary or multifocal– 5-yr OS near 100%

Precursor lesions of MALT lymphomas

• Pre-existing chronic inflammatory d/o resulting in accumulation of extranodal lymphoid tissue

• Infectious cause– H pylori (gastric MALT lymphoma)– Chlamydia psittaci (ocular adnexal MALT)– Campylobacter jejuni (IPSID- small intestine)– Borrelia burgdorferi (cutaneous- geographic diversity)

• Autoimmune based inflammation– Sjögren’s (salivary gland MALT lymphoma)– Hashiomoto’s thyroiditis (thyroid gland MALT)

PCMZL

CBCL mimicking CTCL clinically and histologically-Widespread patches/plaques with epidermotropism

Chui CT, Hoppe RT, Kohler S, Kim YH: J Am Acad Dermatol, 41:271-274, 1999

PC Follicle-Center Lymphoma• Tumor of neoplastic follicle center cells, mix of

centrocytes and centroblasts (not in sheets), w/ a follicular, follicular and diffuse, or diffuse growth pattern– CD20+, CD79a+, +/- monotypic light chain expression– Bcl-6+, HGAL+, LMO2+, IRF4/MUM1-, CD10+/-, Bcl-2-/+– Molecular/Genetic

• 50-70% clonal IgH rearrangement by PCR• Lack t(14:18) IgH/bcl-2 fusion, minority of positive reports• Inactivation of p15, p16 tumor suppressor genes in 10%, 30%

• Solitary, grouped, or multifocal plaques or tumor nodules, preferentially on scalp, forehead/face, trunk– 5-yr OS 95%

45M with 1 yr h/o slowly enlarging tumors on scalp/forehead

25 yrslater

PCFCLLocalized T1, 2

PCFCLMultifocal/generalized, T3

72 yo M initially noted R ankle swelling, then 5 mo h/o rapidly progressive tumor nodules along the R lower leg

CD20

Bcl-2

Bcl-6

MUM-1

PC Diffuse Large B-cell Lymphoma, Leg-Type• PCLBCL w/ predominance or confluent sheets of

centroblasts and immunoblasts– CD20+, CD79a+, monotypic light chain expression– Bcl-2+ (strong), Bcl-6+/-, CD10-, IRF4/MUM1+, FOXP1+, IgM+,

IgD+/-– Lack t(14;18) despite strong Bcl-2; lack IRF4 rearrangement– Inactivation of p15, p16 in 11%, 44%; chromosomal imbalances

in 85% w/ gains of 18q, 7p, loss of 6q; translocations of myc, bcl-6, IgH

– Frequent clonal IgH gene rearrangement by PCR• Rapidly growing red-violaceous tumor(s), most

commonly on leg(s), but can affect non-leg sites– Common in elderly– Less favorable prognosis w/ increased risk of development of

extracutaneous disease => 5-yr OS 35-50%

Am J Surg Pathol 2010;34:1043-48

• 100% (40/40) of DLBCL leg type => cytoplasmic IgM+; 18/40 IgD+• 10% (5/53) of FCL are IgM+ and/or IgD+

IHC for IgM, IgD can be very helpful in distinguishing FCL vs. DLBCL leg type

DLBCL leg-type

DLBCL leg-type,

leg or non-leg location

Cutaneous B-cell LymphomaDiagnosis• Clinical suspicion• Adequate tissue sampling with biopsy

– Adequately wide and deep– Incisional/excisional biopsy or > 6 mm punch

== Avoid small punch or shave biopsy• How to distinguish cutaneous lymphoid hyperplasia (CLH,

pseudolymphoma, lymphocytoma cutis) vs. CBCL (lymphoma cutis)?• Important role of immunohistochemistry and/or

molecular/genetic studies– Assessing clonality using the newer BIOMED-2 PCR methods

can increase sensitivity and specificity, Morales et al, Am J Dermatopathol 2008;30:425-30. Felcht et al, J Am Acad Dermatol 2011;64:135-43.

Clinical suspicion of CBCL

Morphology/immunophenotye

Not diagnostic of CBCL, clinical suspicion highCBCL

IGH and IGK BIOMED-2 PCR, preferably on > 1 site

Follow clinically, periodic biopsies as indicatedCBCL

Utility of BIOMED-2 PCR Clonality Assays in CBCL Diagnosis

classic morphology +/-light chain restriction

PCR+ PCR-

Skin biopsy (wide/deep)

Morales et al, Am J Dermatopathol 2008;30:425-30

Is CBCL associated with borrelia infection?

• NO in the US, YES in subset of cases in Europe

• European reports of B burgdorferi in B-cell lymphoproliferative disorders – “lymphocytoma cutis, pseudolymphoma” (cutaneous

lymphoid hyperplasia) === low-grade CBCL, esp. MZL/immunocytomaGarbe et al, J Am Acad Dermatol 1991;24:584, Cerroni et al. J Cutan Pathol 1997;24:457, Goodlad et al. Am J Surg Pathol 2000;24:1279, Kutting et al. J Am Acad Dermatol 1997;36:311, Colli et al. J Cutan Pathol 2004;31:232

• Link NOT demonstrated in US cases– Wood et al, J Cutan Pathol 2001;28:502 (includes Stanford’s cases)

Acrodermatitis chronica atrophicans, B-cell LPDs in Europe is primarily caused by B afzelii

B afzelli is NOT found in the US

=> CBCL a/w borrelia is most likely a European phenomenon as B burgdorferi sensu lato, either B burgdorferi or B afzelli, has NOT been demonstrated by PCR in affected tissue in the US cases

Aberer et al. Lancet 2011;377:178

Borrelia-associated cutaneous lymphoproliferative disorders:

“Pseudolymphoma” to low-grade CBCL

Colli et al. J Cutan Pathol 2004;31:232

US Treatment Guidelines in PCBCL

• NCCN practice guidelines for available since 2009=> www. nccn. org => NHL => PCBCL

– First available standard of care treatment guideline in cutaneous lymphoma

– Help with insurance auth and reimbursement

ISCL/EORTC Recommendations for Staging Evaluation in Cutaneous Lymphomas other than MF/SS, Blood 2007;110:479-484

• Complete history/ROS and physical examination• Laboratory studies

– CBC, comprehensive serum chemistries, serum LDH– flow cytometric studies if indicated

• Imaging studies– CT neck, chest, abdomen & pelvis w/ contrast alone or with

whole body FDG-PET– Whole body integrated PET/CT (alternative to contrast-

enhanced CT)

LNs > 1.0 cm in short axis and /or have significantly increased PET activity should be sampled for tissue examination (an excisional bx is preferable whenever possible)

ISCL/EORTC Recommendations for Staging Evaluation in Cutaneous Lymphomas other than MF/SS, Blood 2007;110:479-484

• Bone marrow biopsy and aspirate– Required in CLs with intermediate to aggressive clinical

behavior as categorized in the WHO-EORTC classification– Should be considered in CLs with indolent clinical behavior but

not required unless indicated by other staging assessments

• Additional studies as clinically indicated

Blood 2008;112:1600-1609

EORTC-ISCL CBCL Consensus document,

Blood 2008;112: 1600-1609

Morales et al, Stanford series, J Am Acad Dermatol 2008;59:953-7

Indolent(MZL/FCL)

Aggressive(DLBCL leg-type)

Solitary / Regional(T1-2)

Generalized(T3)

Solitary(T1)

Multiple(T2-3)

• RT• Excision• Observation• Topical tx

-NM, imiq, retinoid

• IL steroids

• Observation• RT for sx+ lesions• Topical tx

- NM, imiq, retinoid• IL steroids• Biologics

- Rituximab• Chemotherapy + R

Single or Combination• Clinical Trials

• RT (caution)• R-CHOP + IFRT• Clinical Trials

• R-CHOP + IFRT• Clinical Trials

Management of PCBCL

www.nccn.org => NHL => PCBCL Blood 2008;112:1600-1609

Intralesional rituximab in indolent CBCLs more common in Europe

PCFCLLocalized T1, 2

Local RT

PCFCLMultifocal/generalized, T3

Rituximab

Local RT

72 yo M initially noted R ankle swelling, then 5 mo h/o rapidly progressive tumor nodules along the R lower leg

R-CHOP +/-IFRT

Beyond rituximab, new Mabs and mab-conjugates in clinical studies

• Novel anti-CD20 MAbs– Higher affinity for FcgRIIIa– Lower immunogenecity (fully human or humanized)

– Reduced-fucose technology to enhance ADCC

• Targets other than CD20– Anti-CD22 MAb (epratuzumab)– Anti-CD40 MAb (SGN40, HCD122)– Anti-CD80 MAb (galiximab)

• Radio-immunoconjugates– I-131 tositumomab, Y-90 ibritumomab tiuxetan

• Antibody-drug conjugates– SGN19A, SGN75, CMC-544

B-cell LymphomaOther emerging new/novel therapies• Gene delivery-based immunotherapy

– Adenovirus-interferon-γ gene transfer (TG1042, Transgene)

• Vaccination strategies– In situ vaccination, immunotransplantation

• Inhibition of signal transduction & activation pathways– Tyrosine kinase inhibitors (Syk inhibitors; PI-32765 -

Btk inhibitor)– Protein kinase C inhibitors (enzastaurin – PkCβ/Akt

inhibitor)– PI3K/Akt/mTOR inhibitors

• Bcl-2 inhibitors and more

PC CBCL - Take Home Summary

• Indolent (FCL/MZL) vs. aggressive (DLBCL leg-type)• Do not over treat the indolent cases

– Management driven by symptom– Local tx for localized disease– Rituximab only if symptom+ generalized dz– 40-60% relapse rate post initial therapy, regardless of

tx type• Do not under treat aggressive cases (age appropriate)• Utilize NCCN practice guidelines

– NCCN.org => NHL => CBCL• Numerous exciting new targeted therapies under

development => lots to look forward to!

Stanford Multidisciplinary Cutaneous Lymphoma Clinic/ProgramYoun Kim, Director, Cutaneous Oncology/DermatologyRichard Hoppe, Co-Director, Radiation OncologyRanjana Advani, Sunil Reddy, Medical OncologyUma Sundram, DermatopathologyCameron Harrison, Cutaneous Lymphoma FellowKatherine Sutherland, Physician AssistantCarol Bruce, Michelle Callejas, Chris Suk, Leon Xing, Clinical Research & Database Administrators Laura Morris, RN CoordinatorDermatology, Radiation Oncology Residents URL: Cutaneouslymphoma. stanford. edu

Session handout will be available for 1 mo at AAD website

younkim@stanford.edu