Approach to the Diagnosis of Cutaneous B-Cell Lymphomas



Approach to the Diagnosis of Cutaneous B-Cell Lymphomas


Alejandro A. Gru

Elaine S. Jaffe



INTRODUCTION

The diagnosis of cutaneous B-cell lymphomas (CBCLs) requires a careful evaluation of the clinical features, as well as a comprehensive histologic and immunophenotypic analysis. It is important that oncologists, dermatologists, and pathologists speak a common language. While many cutaneous lymphomas have distinctive features, there is also overlap with other nodal and extranodal lymphomas, so that cutaneous lymphomas must be viewed in a broader context.1,2,3

Several factors can affect the way one approaches a diagnosis of CBCL: (1) the same disease can have different names in different sites; (2) “organ-specific diagnoses” may impede understanding of diseases common to diverse anatomic sites (e.g., extranodal marginal zone lymphoma vs. cutaneous immunocytoma); (3) some primary “cutaneous lymphomas” may be systemic, and the skin may be the first clinical presentation of the disease (e.g., intravascular large B-cell lymphoma, EBV+ diffuse large B-cell lymphoma [DLBCL]); (4) a diagnosis of large B-cell lymphoma on the skin might not reflect the true clinical behavior of the disease (e.g., many cutaneous follicle center lymphomas show a significant component of large cells, and that does not correlate with the clinical behavior or need for systemic therapy). Nevertheless, the site of presentation of a lymphoproliferative disorder is a signpost for some of the underlying biologic features of the disease.


APPROACH TO THE DIAGNOSIS OF CUTANEOUS B-CELL LYMPHOMAS—HISTOLOGIC CLUES

Table 25-1 summarizes the more common primary and secondary CBCLs. The diagnosis of B-cell lymphomas in the skin should always start with the question of: is the infiltrate in question a reactive condition or neoplastic? We now understand that some instances of cutaneous lymphoid hyperplasia represent examples of primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL)4,5 and vice versa. Molecular studies can be useful ancillary techniques for the detection of a clonal B-cell expansion, but should not be used to define an infiltrate as neoplastic.6 Cutaneous findings in Lyme disease can be typically confused with PCMZL. In fact, many of the cases of PCMZL in Europe have been linked to the infection by B. burgdorferi,7,8,9 a feature that has not been seen in the United States. In Lyme disease, there is typically a superficial and deep perivascular and interstitial lymphoplasmacytic infiltrate with the formation of germinal centers.10 Other causes of B-pseudolymphomatous reactions occur in the setting of contact dermatitis, arthropod-bite reactions, cutaneous adverse manifestations to specific medications, tattoos, vaccinations, and infections, among other causes.11 The histology in those pseudolymphomas revealed dermal lymphoid, follicle-like structures with predominantly CD20+ cells, and variable number of germinal centers12,13,14 (Fig. 25-1). The presence of follicular aggregates of B cells, under these circumstances, is referred to as cutaneous lymphoid hyperplasias or “lymphocytoma cutis” and many of them are idiopathic in nature.






FIGURE 25-1. A–D. Angiolymphoid hyperplasia with eosinophilia (ALHE). Nodular aggregates of lymphocytes with the presence of germinal center formation (more common in Kimura disease). Increased vascularity and endothelial swelling is typical (20×, 100×, and 200×). E and F. Cutaneous idiopathic lymphoid hyperplasia with focal germinal center formation (40× and 200×). G. CD20 is positive in follicles of B cells. H. Ki67 is very high in the germinal centers.








Table 25-1 Primary Cutaneous B-Cell Lymphomas and Systemic B-Cell Lymphomas With Cutaneous Dissemination



































PRIMARY CUTANEOUS B-CELL LYMPHOMASAND LYMPHOPROLIFERATIVE CONDITIONS

SYSTEMIC B-CELL LYMPHOMAS WITH CUTANEOUS DISSEMINATION


Primary cutaneous follicle center lymphoma

Chronic lymphocytic leukemia


Diffuse large B-cell lymphoma, leg-type

Mantle cell lymphoma


Marginal zone lymphoma

Follicular lymphoma


EBV+ diffuse large B-cell lymphoma

Plasmablastic lymphoma


Plasmablastic lymphoma

Multiple myeloma


EBV+ mucocutaneous ulcer

Primary effusion lymphoma


Methotrexate-related B-lymphoproliferative disorders

Diffuse large B-cell lymphoma


Lymphomatoid granulomatosis


Burkitt lymphoma


Intravascular B-cell lymphoma


Classical Hodgkin lymphoma


The presence of normal-appearing germinal centers should not be used as an excuse to define something as reactive. Marginal zone lymphoma (MZL) frequently has germinal centers admixed with the neoplastic infiltrate.15,16,17 More characteristically, the germinal centers show a more atrophic pattern in well-established lesions of PCMZL.18 Furthermore, the abundance of B cells in a mixed infiltrate might not necessarily imply a diagnosis of a B-cell lymphoma.19,20 For example, subsets of T-cell lymphomas with a follicular T-helper (TFH) phenotype can be accompanied by a large number of B cells and plasma cells, and potentially mimic B-cell lymphomas. T-cell lymphomas with prominent B-cell infiltrates include CD4+ small- to medium-sized lymphoproliferative disorder, mycosis fungoides with a TFH phenotype, and angioimmunoblastic T-cell lymphoma (Fig. 25-2).21






FIGURE 25-2. Small to medium size CD4+ lymphoproliferative disorder. A and B. Diffuse and vaguely nodular infiltrate that spares the epidermis (40× and 100×). C. The infiltrate contains scattered medium and large cells with irregular nuclear borders (400×). The infiltrate shows a mixture of CD3+ T cells (D) and numerous background CD20+ B cells (E) which can raise the diagnostic possibility of a B-cell lymphoma. CD4 is diffusely positive in most of the cells (not shown), which also stain for the follicular T-helper marker PD-1 (F).

Tables 25-2 and 25-3 summarize a concise clinical, histologic, and molecular approach to common primary cutaneous and secondary cutaneous B-cell lymphomas, respectively.








TABLE 25-2 Common Primary Cutaneous B-Cell Lymphomas




















































SUBTYPE

LOCATION/CLINICAL

AGE

MORPHOLOGY

IMMUNOPHENOTYPE

MOLECULAR


Primary cutaneous follicle center lymphoma (PCFCL)

Head and neck, trunk (plaques, papules, nodules, and tumors)

55 median

Nodular, diffuse, nodular and diffuse.


Centrocytes, centroblasts, and spindle cells

CD20+, BCL6+, CD10−/+ (+ in nodular pattern more frequently), BCL2−/+


MUM1−, p63−


CD21+ in follicles

t(14;18) IGH-BCL2 (10%–20%)


1p36del


Diffuse large B-cell lymphoma, leg type (DLBCL-LT)

Legs (10%–20%) outside this location; nodules and tumors +/− ulceration

76 median

Diffuse


Immunoblasts

CD20+, BCL-6+, MUM1+, p63+, CD10−

MYD88 mutations


BCL6 translocations; BCL2 amplifications


9p21.3 deletion (loss of CDKN2A and CDKN2B)


Primary cutaneous marginal zone lymphoma (PCZML)

Trunk and extremities (papulonodular rash)

55 median

Nodular or diffuse.


Presence of GCs, monocytoid cells, plasma cells, centrocyte-like cells

CD20+, CD10−, BCL-6−, CD43−, IgG or IgM, CD5−, intact or disrupted FDC, CD138 (if PCs), IgG4+

t(14;18) IGH–MALT1


Intravascular large B-cell lymphoma (IVLBCL)

Trunk and extremities (macules, nodules, and plaques)

67 median

Intravascular immunoblasts.


Western variant (++ skin) vs. Asian variant (++ hemophagocytosis)

CD20+, MUM1+, BCL6+/−, CD5+/−, BCL-2+

None specific


Plasmablastic lymphoma (PBL)

Oral cavity (tumor) and skin

30–40 (in HIV), second peak 70–80 (no HIV)

Plasmablasts

CD20 and CD19−, CD138+, CD79a+, EMA+, CD30+, CD10−/+, CD56−/+

MYC rearrangements (30%–40%)


EBER+


EBV-mucocutaneous ulcer (EBV-MCU)

Oropharyngeal mucosa, perianal skin (ulcers)

77 median

Diffuse


Immunoblasts, RS cells, RS variants, necrosis.

PAX5+, OCT2+, MUM1+, CD45+/−, CD30+, CD15+/−, CD20+/−

EBER+









TABLE 25-3 Systemic B-Cell Lymphomas With Frequent Cutaneous Dissemination













































SUBTYPE

LOCATION/CLINICAL

AGE

MORPHOLOGY

IMMUNOPHENOTYPE

MOLECULAR


Chronic lymphocytic leukemia (CLL)

Head and neck (papules, plaques, nodules, and tumors)

60 median

Perivascular and periadnexal nodular and diffuse infiltrate of small lymphocytes. Rare Richter transformation

CD19+, CD20+, CD5+, CD23+, BCL-1−, CD43+

Trisomy 12 (30%), deletion 13q14 (25%–50%), deletion 11q23 (10%–20%)


Mantle cell lymphoma

Trunk, head and neck, extremities (nodules and tumors)

60

Nodular or nodular and diffuse. Small- to medium-sized lymphocytes. Blastoid and pleomorphic variants more frequent

CD19+, CD20+, CD5+, CD43+, BCL1+, SOX11+, CD23−, MUM1+

t(11;14) IGH-CCND1


Diffuse large B-cell lymphoma

Variable, trunk and extremities more common (nodules and tumors, +/− ulceration)

Variable, typically 50–70


EBV-DLBCL 80–90

Diffuse infiltrate of large cells. Geographic necrosis (EBV-associated)


Immunoblasts; Hodgkin-like cells (EBV); plasmablasts

CD19+, CD20+, CD5+/− (association with extranodal disease); CD30+/−


Different groups ABC (MUM1+) vs. GCT(CD10+ or BCL6+/MUM1−)

Variable MYC, BCL2, and BCL6 translocations


EBER: plasmablastic and EBV-DLBCL


HHV8: primary effusion lymphoma


ALK rearrangements


Lymphomatoid granulomatosis

Variable, trunk and extremities (nodules and tumors, −/+ ulceration)

40–60

Angiocentric +/− angiodestruction, lymphohistiocytic panniculitis


Immunoblasts, Hodgkin-like cells

CD19+, CD20+, CD30+, EBER used for grading,CD15−

EBER


Plasma cell myeloma

Trunk and extremities (nodules, tumors, and plaques)—very advanced stage

59 median

Diffuse; +/− amyloid


Malignant plasma cells and plasmablasts more frequent

CD20, CD138+, CD38+, EMA+/−,CD56+, BCL1+/−

Deletion of 13q, 17p−/p53 deletion or translocations t(4;14) and t(14;16)

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Nov 8, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Approach to the Diagnosis of Cutaneous B-Cell Lymphomas

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