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1 New Haven, Connecticut
2 Yale University Main Campus
3 Yale mascot: Handsome Dan
4
5 Cutaneous Lymphomas Tony Subtil, MD, MBA Associate Professor Yale University
6 Cutaneous Lymphomas: 1. Intro 2. CTCL/NK 3. CBCL 4. Systemic/Nodal 5. Cases Antonio Subtil, MD, MBA Associate Professor, Yale University
7 If there are no secrets, why is there so much confusion? Lymphoma classifications Frequent updates WHO-EORTC 2005, WHO 2008, WHO 2016
8 Skin Lymphoma is a Clinical Pathologic Diagnosis
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10 Clinical pathologic correlation is essential for proper classification We frequently found it impossible to unequivocally classify single cases on (histo)morphologic grounds alone. Santucci M et al. Cytotoxic/ Natural Killer Cell Cutaneous Lymphomas. Cancer 2003
11 Challenge: Lack of Clinical Information for the Pathologist
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13 Multidisciplinary Knowledge Gaps (blind spots & fear of the unknown) Clinical Dermatology Hematopathology Dermatopathology Hematology/ Radiation Oncology
14 Clinical Pathologic Correlation is very important!
15 Skin Lymphomas: B vs T
16 Histopathology 1994:24:
17 Relative Frequency CTCL CD4+ SMPTCL 3% SPTCL 1% PTCL, unspecified 3% NKTCL, nasaltype 1% LyP 15% C-ALCL 10% MF 57% SS 4% MF variants 6% 1476 patients with a primary CTCL registered at the Dutch and Austrian Cutaneous Lymphoma Group and classified according to WHO-EORTC. Blood ;105(10):
18 Folliculotropic Mycosis Fungoides Follicle center lymphoma CD4+ small/medium CTCL Classic Mycosis Fungoides Marginal Zone lymphoma Follicle center lymphoma Pagetoid Reticulosis (Woringer- Kolopp) Diffuse large B-cell, leg type Subcutaneous panniculitis-like TCL Erythroderma: Sezary syndrome Location is important
19 - Classic MF - Marginal zone B-cell lymphoma - Follicle center lymphoma (Crosti) Surg Pathol Clin Jun 2014; Bolognia JL et al Dermatology
20 - Folliculotropic Mycosis Fungoides * - Follicle center lymphoma - CD4+ small/medium pleomorphic T-cell lymphoproliferative disorder * Gerami et al. Arch Dermatol 2008 Jun;144(6):738-46
21 - Diffuse large B-cell lymphoma, leg type - Subcutaneous panniculitis-like T-cell lymphoma
22 - Folliculotropic Mycosis Fungoides - Follicle center lymphoma - CD4+ small/medium pleomorphic T-cell lymphoma - Classic Mycosis Fungoides - Marginal zone lymphoma - Follicle center lymphoma Pagetoid Reticulosis (Localized Woringer- Kolopp) - Diffuse large B-cell lymphoma, leg type - Subcutaneous panniculitis-like T-cell lymphoma Surg Pathol Clin Jun 2014; JCAD 2010 Oct;3(10):46-9
23 Erythroderma: Sézary syndrome
24 Small self-regressing: Lymphomatoid papulosis (LyP) Multiple ulcerated lesions Progressive/persistent: Aggressive cytotoxic lymphomas
25 - Folliculotropic Mycosis Fungoides - Follicle center lymphoma - CD4+ small/medium pleomorphic T-cell lymphoma - Classic Mycosis Fungoides - Marginal zone lymphoma - Follicle center lymphoma Pagetoid Reticulosis - Diffuse large B-cell lymphoma, leg type - Subcutaneous panniculitis-like T-cell lymphoma Erythroderma: Sézary syndrome Multiple ulcerated lesions Small self-regressing: Lymphomatoid papulosis (LyP) Progressive/persistent: Aggressive cytotoxic lymphomas
26 Challenge: Everything is Atypical Syndrome
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31 Morphologic evaluation of cutaneous lymphoid infiltrates Density: mild, moderate, dense Pattern (s): Nodular Diffuse Interstitial Perivascular Periadnexal Perineural Angiocentric Intravascular Epithelial involvement? (Y / N) Epidermis Hair follicles Sweat glands Lymphoid follicles? (Y / N) Composition of the infiltrate: Other findings? Lymphocytes Size: small/medium large Morphology Plasma /-cytoid cells Macrophages Eosinophils Neutrophils Dendritic cells
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36 Morphology 101 Small noncleaved Small cleaved (centrocyte) Large noncleaved (centroblast) Follicular dendritic cell (FDC) Immunoblast
37 Special stains ANTIBODY PREDOMINANT CELLS LABELED CD1a Langerhans cells, precursor T-cells CD2 T-cells CD3 T-cells CD4 T-helper cells CD5 T-cells, B-CLL (chronic lymphocytic leukemia/small lymphocytic lymphoma), Mantle cell lymphoma CD7 T-cells CD8 T-cytotoxic cells CD10 (CALLA, common acute lymphoblastic leukemia antigen); germinal center B-cells, follicular lymphoma, B-ALL (acute lymphoblastic leukemia/lymphoma), Burkitt lymphoma CD15 Neutrophils, Reed-Sternberg cells (classical Hodgk in lymphoma) CD20 B-cells CD21 Follicular dendritic cells CD30 Activated lymphocytes, ALCL, LyP (types A and C), Reed-Sternberg cells (classical Hodgkin lymphoma) CD34 Endothelial cells, precursor cells CD43 T-cells, myeloid cells, mast cells, T-cell lymphomas, some B-cell lymphomas CD45 (LCA; Leukocyte common antigen); hematolymphoid cells, most B - and T-cell lymphomas CD45RO T-cells CD56 (NCAM; neural cell adhesion molecule); NK cells, NK-cell lymphomas, some T-cell lymphomas, gamma-delta T-cell lymphoma, neuroendocrine tumors CD68 Histiocytes/macrophages, mast cells CD79a Immature and mature B-cells, plasma cells CD117 (c-kit); mast cells CD138 Plasma cells TIA-1 T-cytotoxic cells, cytotoxic T/NK-cell lymphomas Granzyme B T-cytotoxic cells, cytotoxic T/NK-cell lymphomas Perforin T-cytotoxic cells, cytotoxic T/NK-cell lymphomas BCL-2 T-cells, non-germinal center B-cells, sub set of follicular lymphomas BCL-6 Germinal center B-cells, B-cell lymphomas of germinal center origin Myeloperoxidase Myeloid cells TdT Precursor cells, B- and T-ALL (acute lymphoblastic leukemia/lymphoma)
38 Immunohistochemistry secret It is much easier to interpret immunostains if you know the diagnosis.
39 Special Stains: Interpretation and Technical Issues
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42 Marginal Zone B-cell Lymphoma Kappa Lambda
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44 Emperipolesis S-100 (+)
45 Repeat light chain stains Kappa Lambda
46 Rosai-Dorfman misdiagnosed Lesson: as Marginal Zone B-cell Lymphoma Consider other differential diagnoses Watch out for technical problems with immunostains
47 Molecular challenge: PCR false positives and false negatives
48 PCR PCR results should not be interpreted in isolation (+) or (-) PCR must always be correlated with the clinical and histopathologic findings Certain benign dermatoses may frequently demonstrate T-cell monoclonality
49 Clonal PCR (T-cell receptor) May be seen in benign conditions Lichen planus (25%) PLEVA (65%) PLC (50%) Lichen sclerosus (49%) Pigmented purpuric dermatoses Lymphomatoid lichenoid keratosis Consider PCR at 2 different sites Identical clone with dual PCR: high specificity (95.7%, JAAD 2007;57:782)
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52 Biopsy issues: topical treatment and adequate sampling
53 Topical Rx alters histologic appearance Rx
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55 Classification challenge: Different types of skin lymphoma can resemble each other
56 4-yr hx of plaques on trunk, outside dx: Mycosis fungoides/ctcl
57 CD3 Kappa CD20 Lambda Marginal Zone B-cell Lymphoma
58 Challenge: Benign skin diseases can mimic cutaneous lymphoma
59 SKIN LYMPHOMAS Mycosis Fungoides MF variants Sezary Syndrome Adult T-cell Leukemia/Lymphoma Primary Cutaneous CD30+ LPDs (C-ALCL and LyP) Subcutaneous Panniculitis-like T-cell Lymphoma (alpha-beta) Extranodal NK/T-cell Lymphoma, Nasal Type Cutaneous gamma-delta / T-cell Lymphoma Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma Primary Cutaneous CD4+ small/medium-sized Pleomorphic T-cell Lymphoma Primary Cutaneous Marginal Zone B-cell Lymphoma Primary Cutaneous Follicle Center Lymphoma Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type Primary Cutaneous Diffuse Large B-cell Lymphoma, Other
60 SKIN LYMPHOMAS Mycosis Fungoides MF variants Sezary Syndrome Adult T-cell Leukemia/Lymphoma Primary Cutaneous CD30+ LPDs (C-ALCL and LyP) Subcutaneous Panniculitis-like T-cell Lymphoma (alpha-beta) Extranodal NK/T-cell Lymphoma, Nasal Type Cutaneous gamma-delta / T-cell Lymphoma Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma Primary Cutaneous CD4+ small/medium-sized Pleomorphic T-cell Lymphoma Primary Cutaneous Marginal Zone B-cell Lymphoma Primary Cutaneous Follicle Center Lymphoma Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type Primary Cutaneous Diffuse Large B-cell Lymphoma, Other PSEUDOLYMPHOMAS Lymphomatoid drug eruption Cutaneous reactive lymphoid hyperplasia in the setting of viral infection (herpes folliculitis, inflamed molluscum contagiosum, orf, milker s nodule) Cutaneous Leishmaniasis Syphilis Borrelia infection Persistent nodular scabies Persistent arthropod bite reactions Exaggerated bite-like reactions in the setting of systemic hematologic disorders Pseudolymphomatous tattoo reaction Reactive lymphoid hyperplasia at sites of vaccination Inflammatory stage of vitiligo Early stage of lichen sclerosus et atrophicus Inflammatory stage of morphea Lymphomatoid lichenoid keratosis Pigmented purpuric dermatoses Pityriasis lichenoides Lupus panniculitis Pseudolymphomatous variant of cutaneous angiosarcoma Lymphoepithelioma-like carcinoma of the skin Merkel cell carcinoma Acral pseudolymphomatous angiokeratoma in children (APACHE) Pseudolymphomatous folliculitis Cutaneous plasmacytosis CD8-positive infiltrates in the setting of advanced AIDS
61 Challenge: Lymphoma can mimic benign skin diseases
62 MF Inflammatory Patterns (222 Biopsies - Shapiro PE, Pinto FJ. AJSP 1994;18:645) Sup perivasc 7 Sup PV + I 14 Vacuolar 13 Lichenoid 42 Spongiotic 3 Spong/pso 5 Spong/pso/lich 14 Psoriasiform 47 Pso/lich 32 S+D PV+/- I 8 Nodular 12 Diffuse 12 Folliculitis 9 Vasculitis 1 Vesicular 1 Panniculitis 1 LSA-like MF. Br J Derm 2007;157:411 Anetodermic MF. Br J Derm 2008;158:157
63 Bad Psoriasis
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65 MZBCL misdiagnosed as leprosy
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67 Marginal zone B-cell lymphoma Lesson: misdiagnosed as leprosy Perineural and periadnexal accentuation often seen in MZBCL
68 Ways to help the pathologist >1 bx Bx area without recent topical Rx/ sun exposure Provide some hx/short clinical description Mention if previous hx/dx CTCL Mention any specific requests (e.g., CD25) Contact us if path findings don t seem to fit clinical findings
69 Ways to help the clinician Keep lines of communication open Be careful not to over/undercall dx (mimics) Review of prior bxs may be helpful Look for any unexpected findings Fungal/bacterial infection 2nd malignancy Know %s CD30+: >75% LCT: >25% Non-MF CD30- CTCL large vs small/medium-sized: 30% % CD25 expression (Ontak)
70 Patterns that may require more careful clinical correlation for correct diagnosis CD8+ Indolent CD8+ Mycosis Fungoides Aggressive Epidermotropic CD8+ cytotoxic T-cell lymphoma Ulceration Lymphomatoid papulosis Aggressive variant of T-cell Lymphoma Marked epidermotropism Pagetoid reticulosis 2y cutaneous involvement by nodal PTCL
71 Skin Lymphomas: B vs T
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