Primary Cutaneous Marginal Zone B-Cell Lymphoma
Katalin Ferenczi
DEFINITION
Primary cutaneous marginal zone B-cell lymphomas (PCMZLs) are indolent low-grade B-cell lymphomas of the skin. PCMZLs have been regarded as the cutaneous counterpart of marginal zone lymphomas (MZLs) occurring at extranodal sites, in particular the mucosa-associated lymphoid tissue, so-called MALT lymphomas, in light of overlapping morphologic features and indolent clinical behavior. Recent data, however, indicate that primary cutaneous MZL and noncutaneous MZL (so-called MALT lymphoma) have distinct characteristics with respect to eliciting factors, immunoglobulin and chemokine receptor expression pattern, frequency of translocations, and systemic dissemination. In the 2005 World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of primary cutaneous lymphomas, cutaneous marginal zone B-cell lymphomas represent a separate entity.1 However, the distinct features that separate cutaneous MZL from other extranodal marginal zone B-cell lymphomas are not well reflected in the WHO 2008 classification, as PCMZLs are not categorized separately but included in the broad group of extranodal marginal zone B-cell lymphomas of MALT type.2 The term SALT (skin-associated lymphoid tissue) has also formerly been used for these tumors. They incorporate cases previously regarded as primary cutaneous immunocytoma and primary cutaneous plasmacytoma; these entities are now considered plasma cell–rich variants of PCMZL.3 Cutaneous marginal zone B-cell lymphomas also include cases previously designated as cutaneous follicular lymphoid hyperplasia with monotypic plasma cells.4 It remains to be elucidated whether some cases reported as PCMZL characterized by γ light chain restriction, indolent course, and spontaneous remission in children and young individuals represent marginal zone hyperplasia of the skin, a cutaneous counterpart of atypical marginal zone hyperplasia of MALT as found in the appendix and tonsils.5
EPIDEMIOLOGY
Primary cutaneous MZLs account for ∼7% of all primary cutaneous lymphomas and represent between 20% and 40% of all primary cutaneous B-cell lymphomas.1,6,7 The disease affects middle-aged individuals, with the median age at diagnosis of 55 years. Primary cutaneous MZLs with marked plasmacytic differentiation, previously regarded as immunocytomas, tend to be more common in the elderly. PCMZL is rare in children and young adults.8,9 Men are almost twice as frequently affected as women. The incidence rate of cutaneous marginal zone B-cell lymphoma is higher among non-Hispanic whites than in other races.6
ETIOLOGY
The etiology and pathogenesis of PCMZLs are not entirely understood. It has long been thought that the inflammatory microenvironment and host immune response may play a role in the development of extranodal MZLs. MZLs, irrespective of the primary site, originate from B cells in the marginal zone, the portion of the follicle with the highest rate of chronic antigenic exposure that typically function as a first line of defense against microbial pathogens. Chronic antigenic stimulation leading to persistent lymphoid hyperplasia and subsequent development of MZL has been suggested to play a role in the pathogenesis of MALT lymphomas. The pathogenic role of chronic antigenic stimulation, infection, or autoimmunity has been well documented in MALT lymphomas, such as the association between gastric MALT lymphoma and Helicobacter pylori infection, and MALT lymphomas of the salivary gland and thyroid and Sjögren syndrome and Hashimoto thyroiditis, respectively. Extranodal MZLs in general are thought to arise on a background of chronic inflammation characterized by a TH1 cytokine profile, expression of CXCR3, and predominant expression of IgM. In contrast, the vast majority of primary cutaneous MZLs are characterized by a TH2 cytokine profile, absence of CXCR3, and expression of the class-switched immunoglobulins IgG, IgA, and IgE.10 These findings suggest that primary cutaneous MZL may develop in an inflammatory environment that is different from noncutaneous extranodal MZL. However, a small subset of cutaneous MZLs, so-called “non–class-switched” PCMZLs, express CXCR3 and IgM similar to extranodal MZLs.10 Whereas class-switched cases of PCMZLs do not appear to be associated with infectious agents, the small, non–class-switched subset has been linked to Borelia burgdorferi infection.11
Long-term antigenic stimulation caused by B. burgdorferi infection has been hypothesized to play a role in the development of a subset of cutaneous MZL in Europe. Earlier reports from certain endemic areas in Europe documented the development of PCMZL from infiltrates associated with B. Burgdorferi infection, and antibiotic treatment in some cases resulted in regression of the tumors.1,12,13,14 Detection of Borrelia-specific DNA sequences has been reported in 10% to 42% of cutaneous MZL with higher detection rates in certain endemic areas in Europe.12,15,16 These findings, however, were never confirmed in Asian or north American PCMZL patients.17,18 Recent large studies from East Asia, United States, Germany, and Italy similarly failed to show any evidence of Borellia-specific sequences in patients with cutaneous MZL using polymerase chain reaction (PCR).19,20,21
A common antigen, however, may be involved in the antigenic stimulation and development of some cases of cutaneous MZL in the United States as suggested by findings showing the use of similar VH gene segments and conserved complementarity determining region 3 (CDR3) sequences in PCMZL skin lesions.22
Other antigenic, infectious, or inflammatory factors that have been reported in association with the development of PCMZL include tattoos, tick bites, herpes simplex virus type 1 infection, and vaccinations, such as influenza and hepatitis C.23 Chronic inflammation arising in the setting of autoimmune diseases, such as Sjögren syndrome or Hashimoto thyroiditis, and certain medications, such as antidepressants and antihistamines, have also been implicated.24
The clonally restricted response to antigenic triggers in neoplastic transformation and lymphomagenesis is also suggested by reports showing a bias in the IgV repertoire with preferential usage of certain IgVH genes and the pattern of somatic hypermutations.25 Aberrant somatic hypermutation, a mechanism associated with induction of genetic instability, has been described in cutaneous MZL.26 This genetic instability might account for stepwise DNA mutations culminating in the development of MZL.
CLINICAL PRESENTATION AND PROGNOSIS
PCMZLs clinically present as solitary or multiple red to violaceous papules, nodules (<3 cm), or plaques most often localized on the trunk (Fig. 27-1) and upper extremities or, less frequently, the head and neck. Rare, unusual clinical variants, such as anetodermic27 or agminated form resembling rosacea, have been described.28 The anetodermic form of PCMZL may be associated with antiphospholipid antibodies.29
 FIGURE 27-1. Primary cutaneous marginal zone lymphoma. Red nodule on the arm. |
Primary cutaneous MZL is an indolent but persistent disease and ∼50% of PCMZL cases will show cutaneous relapses.30 Patients with multifocal disease have shorter disease-free survival than those with single or localized lesions.30 The disease typically remains confined to the skin; rarely, extracutaneous disease with systemic involvement by marginal zone B-cell lymphoma can occur. Extracutaneous spread is seen in less than 10% of the patients, and it is more commonly seen in the non–class-switched subtype of the disease. Significant association with gastrointestinal tract disorders, certain autoimmune conditions, and systemic malignancies has been reported.31 Although relapses are common, prognosis is excellent with a 5-year disease-specific survival rate of over 98%.1,32,33,34
HISTOLOGY
Histology shows nodular or diffuse mononuclear cell infiltrate centered in the dermis, which may extend into the subcutaneous fat (Figs. 27-2 and 27-3). The epidermis is spared, and a zone of uninvolved dermis (grenz zone) is often present (Fig. 27-4). Periadnexal tracking by neoplastic cells surrounding eccrine glands and hair follicles is frequently seen35 (Fig. 27-5). It has been suggested that the presence of infiltration of the follicular epithelium or eccrine ducts could provide a helpful clue for MZL.24 Subcutaneous extension and involvement in MZL is more commonly seen in secondary cutaneous MZL.36 Reactive germinal centers with distinct surrounding mantle zones are frequently seen (Fig. 27-2), but as the disease progresses the follicles can become colonized by neoplastic B cells and the distinct germinal center–mantle zone demarcation will be absent.
 FIGURE 27-2. Primary cutaneous marginal zone lymphoma. Dense nodular lymphoid infiltrate involving the dermis and extending into subcutaneous tissue. Note the presence of a reactive germinal center in the reticular dermis (H&E, 4×). |
 FIGURE 27-3. Primary cutaneous marginal zone lymphoma. Diffuse dermal mononuclear infiltrate showing perifollicular accentuation (H&E, 4×). |
 FIGURE 27-4. Primary cutaneous marginal zone lymphoma. The dermal infiltrate is separated from the epidermis by a grenz zone in the superficial dermis (H&E, 20×). |
 FIGURE 27-5. Primary cutaneous marginal zone lymphoma. Periadnexal distribution of the neoplastic cells is often seen (H&E, 20×). |
The infiltrate is polymorphous, composed of small-to-medium–sized lymphocytes, plasma cells, lymphoplasmacytoid cells, and often considerable numbers of reactive T cells (Fig. 27-6). Marginal zone B cells or centrocyte-like cells are small-to-medium–sized lymphocytes with indented nuclei, inconspicuous nucleoli, and abundant pale cytoplasm (Fig. 27-7). The number of neoplastic B cells within the infiltrate can be variable, but at times is very low.2 Admixed T cells are numerous, often comprising 50% to 70% of the infiltrate. Fewer reactive T cells may be seen in the rare, non–class-switched IgM+ subtype of PCMZL. Prominent plasmacytic differentiation is not uncommon. Plasma cells and lymphoplasmacytoid cells are often found in the superficial dermis and at the periphery of the infiltrates (Fig. 27-8A,B). Plasma cells may demonstrate atypia or binucleation (Fig. 27-9A). Periodic acid–Schiff (PAS)-positive immunoglobulin-containing intranuclear inclusions (Dutcher bodies) may be present in cases with predominance of lymphoplasmacytoid cells (Fig. 27-9B). Eosinophilic, immunoglobulin-containing intracytoplasmic inclusions (Russell bodies) may occasionally be seen in cases with abundant plasma cells. Occasionally, a predominance of monocytoid B cells instead of lymphoplasmacytic cells or plasma cells is seen.37 Within the infiltrate, occasional centroblasts and a few eosinophils can be seen (Fig. 27-10A,B). Whereas the presence of eosinophils is not unusual, moderate-to-marked increase in the number of eosinophils was reported as a feature of Asian but not European or US cutaneous MZL cases.19
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