Primary Cutaneous B-Cell Lymphomas

Concept of Primary Cutaneous Lymphomas

The history of CBCL started in the 1980s after the introduction of immunohistochemistry in the diagnosis and classification of malignant lymphomas. Before that time, reports on cutaneous lymphomas other than mycosis fungoides (MF) and Sézary syndrome (SS) were few, and it was firmly believed that these represented skin manifestations of a systemic lymphoma, even if staging procedures failed to demonstrate extracutaneous disease. The development of monoclonal antibodies that could detect T-cell–associated and B-cell–associated antigens on tissue sections had a major impact on the diagnosis and classification of cutaneous lymphomas. It allowed a distinction between CTCL and CBCL, and demonstration of monotypic light chain expression became the most important criterion to differentiate between benign and malignant B-cell proliferations. In the 1980s, several European groups, using these new immunohistochemical methods, started to classify cutaneous lymphomas according to the criteria of the Kiel classification. In contrast to earlier thinking, these studies demonstrated that malignant lymphoma other than MF/SS can present in the skin without any evidence of extracutaneous disease at the time of diagnosis. These studies also resulted in the recognition of several new types of CTCL and CBCL, which appeared to have highly characteristic clinical and histologic features, a different clinical behavior, and often a much better prognosis compared with histologically similar nodal lymphomas involving the skin secondarily. Subsequent studies demonstrating differences in the presence of specific translocations, and the expression of oncogenes and adhesion receptors between primary cutaneous lymphomas and their nodal counterparts provided further support for the view that primary cutaneous lymphomas should be considered as distinct disease entities. Because these primary cutaneous lymphomas other than MF/SS were not recognized in classification systems used by hematopathologists for nodal lymphomas at that time and therefore treated as systemic lymphomas, the European Organization for the Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group formulated in 1997 a separate classification for primary cutaneous lymphomas, which simply listed the different types of CTCL and CBCL, that had been defined as separate entities in the decade before. The EORTC classification included three main types of CBCL: primary cutaneous immunocytoma (later renamed primary cutaneous marginal-zone B-cell lymphoma ), the group of primary cutaneous follicle-center cell lymphomas (PCFCCLs), and primary cutaneous large B-cell lymphoma of the leg.

WHO-EORTC, WHO 2008, and Revised WHO 2016 Classification

The third edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, published in 2001, included most types of CTCL, but differences in the definition and terminology of the different types of CBCL resulted in considerable debate and confusion. In the EORTC classification, the term PCFCCL was used for CBCL that is composed of cells with the morphology of follicle-center cells, which could have a (partly) follicular growth pattern, but more often show a diffuse infiltrate with a predominance of large B cells, particularly large cleaved or multilobated cells. In the 2001 WHO classification, this well-defined disease entity was not recognized. PCFCCL with a (partly) follicular growth pattern was included as a variant of follicular lymphoma and designated cutaneous follicle-center lymphoma, but cases with a diffuse growth pattern were classified as diffuse large B-cell lymphoma (DLBCL), which in daily practice resulted in overtreatment with multi-agent chemotherapy ( Table 20-1 ).

In 2005, the WHO and EORTC reached consensus on a new classification: the WHO-EORTC classification for cutaneous lymphomas. In this classification, three main types of CBCL are recognized: primary cutaneous marginal-zone lymphoma (PCMZL), primary cutaneous follicle-center lymphoma (PCFCL), and primary cutaneous large B-cell lymphoma, leg type (PCDLBCL, LT). It was recognized that PCFCL represents a spectrum of disease and includes lymphomas with a follicular pattern, a follicular and diffuse pattern, and a diffuse growth pattern. Whereas PCDLBC, LT was recognized as a distinct disease entity, lymphomas with a similar morphology and phenotype presenting at sites other than the leg were included in this category. In addition, a category PCDLBCL, other was introduced for rare PCDLBCL other than PCDLBCL, LT and PCFCL. Several large studies have validated the clinical significance of this new classification.

Most of the WHO-EORTC classification has been incorporated in the fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, published in 2008. In this 2008 WHO classification and in the revised WHO 2016 classification, PCFCL and PCDLBCL, LT are included as separate entities, as defined in the WHO-EORTC classification. However, a category of PCDLBCL, other was no longer included, and PCMZL was not categorized separately, but as in the WHO 2001 classification, was included in the broad group of extranodal marginal-zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma). While similarities in morphology and indolent clinical behavior are well acknowledged, extranodal marginal-zone lymphomas arising at different extranodal sites differ in the type and frequency of translocations, (potential) eliciting factors (different site-related infectious organisms and autoimmune diseases), response to antibiotic treatment, and frequency of blastic transformation and systemic dissemination. Lumping together all cases arising at different sites may hamper further elucidation of site-specific pathogenetic mechanisms. In this chapter, the term PCMZL is therefore preferred.

Definition

PCMZL is an indolent lymphoma composed of small B cells including marginal-zone (centrocyte-like) cells, lymphoplasmacytoid cells, and plasma cells. It includes cases previously designated as primary cutaneous immunocytoma, cutaneous follicular lymphoid hyperplasia with monotypic plasma cells, and primary cutaneous plasmacytoma without underlying multiple myeloma (extramedullary plasmacytoma of the skin). In the 2008 and in the revised 2016 WHO classification, PCMZL is not listed separately, but is included in the broad group of MALT lymphomas.

Epidemiology

PCMZL make up about 7% of all cutaneous lymphomas and about 30% of primary CBCLs. They affect most commonly (young) adults, and a male predominance has been reported.

Etiology

PCMZL has been described in relation to tattoo pigments, tick bites, and antigen injection, suggesting that they may develop from chronic antigenic stimulation by intradermally applied antigens. However, in most cases the cause is unknown. An association with Borrelia burgdorferi infection has been reported in a minority of European cases of PCMZL, but not in cases from Asia or the United States. Associated autoimmune diseases are uncommon in PCMZL, but rather suggest secondary cutaneous involvement of a systemic lymphoma.

Clinical Features

PCMZL presents with red to violaceous papules, plaques, or nodules localized preferentially on the trunk and arms ( Fig. 20-1, A ). In contrast to PCFCL, presentation with multifocal skin lesions is frequent ( Table 20-2 ). Ulceration is uncommon. Cutaneous relapses are common, particularly in patients presenting with multifocal skin lesions. Extracutaneous dissemination is uncommon, however, and is reported in 4% to 8% of patients. Bone marrow involvement is exceedingly rare, and a bone marrow biopsy is therefore not required unless indicated by other staging procedures.

Histopathology

These lymphomas show patchy, nodular, or diffuse infiltrates with sparing of the epidermis ( Fig. 20-1, B ). The infiltrates are composed of small lymphocytes, marginal-zone cells, lymphoplasmacytoid cells, and plasma cells, admixed with small numbers of centroblast-like or immunoblast-like cells and many reactive T cells. Reactive germinal centers are frequently observed. They may be surrounded by a population of small to medium-sized cells with irregular nuclei, inconspicuous nucleoli, and abundant pale cytoplasm (marginal-zone cells). Monotypic plasma cells are often located at the periphery of the infiltrates and in the superficial dermis beneath the epidermis. Unlike MZL occurring at other sites, PCMZL does not or rarely shows colonization of reactive germinal centers by neoplastic B cells, lymphoepithelial lesions, or transformation into a diffuse large B-cell lymphoma, but a relative increase in large transformed cells can be seen in some cases. In most PCMZLs, neoplastic B cells represent a minority of the infiltrate, and diffuse infiltrates of small cells with a monocytoid appearance should raise suspicion of a systemic lymphoma. In rare cases, a pure population of neoplastic plasma cells, formerly classified as primary cutaneous plasmacytoma, can be observed. In cases with a predominance of lymphoplasmacytoid cells or plasma cells, PAS-positive intranuclear inclusions (Dutcher bodies) can be found.

Immunophenotype

Tumor cells express CD20, CD79a, and BCL2, but are negative for CD5, CD10, and BCL6, which may be useful in distinction from PCFCL ( Table 20-3 ). Reactive germinal centers are typically BCL6 positive, CD10 positive, and BCL2 negative. Plasma cells express CD138, IRF-4/MUM1, and CD79a, but generally not CD20, and show monotypic cytoplasmic immunoglobulin light chain expression on paraffin sections (see Fig. 20-1, C-E ). In some cases, biclonal expression of kappa and lambda light chain–restricted B cells has been reported. Recent studies suggest the existence of two types of PCMZL. Unlike most other MALT lymphomas, the vast majority of PCMZL express class-switched immunoglobulins including immunoglobulin G (IgG), IgA, and IgE; do not express the chemokine receptor CXCR3, which has been suggested to play a role in the homing of the malignant B cells to mucosa-associated malignant tissue; and have a Th2 inflammatory background. These cases show a predominance of T cells and often contain reactive follicles and only a small proportion of neoplastic B cells. A small subset of (P)CMZL shows a diffuse proliferation of large nodules or neoplastic B cells, which express IgM and often CXCR3. These cases contain a much lower number of admixed T cells and more likely have extracutaneous disease. It has been suggested that B. burgdorferi– associated PCMZL belongs to this second group. A recent study reported IgG4 expression in approximately 40% of PCMZL with plasmacytic differentiation, whereas IgG4 was rarely expressed in non-cutaneous MZL. There was no evidence of systemic IgG4 disease in any of these patients, pointing to a localized immunologic IgG4-driven process.

Genetic Features

Clonal rearrangements of the immunoglobulin heavy chain (IGH) gene are found in approximately 80% of cases. It is a matter of debate whether skin lesions showing clonal IGH gene rearrangement, but no monotypic Ig light chain expression should be labeled CBCL or still considered as a benign condition (clonal cutaneous lymphoid hyperplasia). The presence of the t(14;18)(q32;q21) translocation involving the IGH gene on chromosome 14 and the MLT gene on chromosome 18, and the t(3;14)(p14.1;q32) translocation involving the IGH and FOXP1 genes, has been reported in a proportion of PCMZLs. In one of these studies, the t(14;18)(q32;q21) translocation was only found in cases with a (partly) monocytoid appearance, as often seen in MZL in other organs. Other translocations observed in MALT lymphomas at other sites, such as t(11;18)(q21;q21) and t(1;14)(p22;q32), are not found or are rarely found in PCMZL.

Differential Diagnosis

The differential diagnosis of PCMZL includes pseudo–B-cell lymphoma (lymphocytoma cutis; cutaneous lymphoid hyperplasia), PCFCL with a follicular growth pattern, and skin localizations of systemic small B-cell lymphomas/leukemias.

Differentiation between PCMZL and pseudo–B-cell lymphoma can be challenging. Apart from clinical and histologic similarities, clonal B-cell receptor rearrangements have not only been found in approximately 80% of PCMZLs, but also in a small subset of pseudo–B-cell lymphomas, as defined by immunohistochemical criteria. Demonstration of monotypic plasma cells expressing either kappa or lambda light chain by immunohistochemistry or in situ hybridization on paraffin sections is generally used as a decisive criterion for PCMZL. However, monotypic plasma cells may be minimal, and when evaluating recurrent lesions, they can be undetectable in some of these lesions. The observation that both PCMZLs and pseudo–B-cell lymphomas may develop from chronic stimulation by intradermally applied antigens (e.g., tattoo pigments, tick bites, antigen injections) suggests that they represent a continuous spectrum of cutaneous B-cell proliferations with a stepwise progression from a reactive to a neoplastic state. These observations have also resulted in discussions about whether PCMZL, or at least a major subset of PCMZL, should be considered as an overt malignant lymphoma.

The clinical and histologic features of systemic MZL involving the skin secondarily may resemble those of PCMZL. Histologic features suggesting secondary cutaneous involvement include the presence of a predominant B-cell infiltrate and expression of IgM by the neoplastic B cells. Colonization of follicular structures by neoplastic marginal-zone cells and the presence of lymphoepithelial lesions are common in MALT lymphomas at other sites, but are rarely seen in PCMZL and should therefore raise suspicion of secondary cutaneous involvement. In particular, in such cases staging is necessary to rule out extracutaneous disease. Differentiation between PCMZL and skin localizations of other systemic small B-cell lymphomas (mantle cell lymphoma, B-cell lymphocytic leukemia) may sometimes be difficult based upon histology alone. Staining for CD5 and cyclin D1 may be useful to differentiate PCMZL (CD5 negative, cyclin D1 negative) from mantle cell lymphoma (CD5 positive, cyclin D1 positive) and skin localizations of B-cell lymphocytic leukemia (CD5 positive, cyclin D1 negative) (see Table 20-3 ). In cases with a predominance of plasma cells, multiple myeloma should be excluded by appropriate staging, which should include a bone marrow biopsy and serum electrophoresis. Differentiation between PCMZL and PCFCL is discussed in the section on PCFCL later in the chapter.