In the last lymphoma classifications, three types of marginal zone lymphoma (MZL) were delineated: extranodal mucosa-associated lymphatic tissue (MALT) lymphoma, splenic MZL, and nodal MZL (NMZL). While MALT lymphoma is already well characterized and has been extensively studied, the pathogenesis of the other two types, especially that of NMZL, remains incompletely understood. The tumor is rather uncommon, although it shares morphologic and immunophenotypic similarities with the other MZLs. Few series have been published, and the description is quite heterogeneous, reflecting the lack of consensus criteria for its diagnosis; the ability to develop such criteria is impeded by the absence of specific immunological or molecular abnormalities. The disease develops from peripheral (mostly cervical) and abdominal lymph nodes, with or without bone marrow and blood involvement. How to differentiate NMZL from lymphoplasmacytic lymphoma remains a key point of debate. NMZL also represents a therapeutic dilemma, given the absence of published large or prospective series. The 5-year overall survival as well as the failure-free survival of patients appear to be lower than those of patients with extranodal MZL. The aim of this review is twofold: to summarize descriptions of the clinical presentation provided in published series in order to help clinicians recognize and treat patients, and to discuss diagnostic difficulties faced by hematopathologists when dealing with these lesions and others in the differential diagnosis that must be distinguished from one another.
Nodal marginal zone B-cell lymphoma (NMZL) is a primary nodal B-cell lymphoma that shares morphologic, immunophenotypic, and genetic characteristics with extranodal marginal zone lymphoma (MZL) and splenic MZL, but without those specific localizations at presentation. NMZL was first described as “nodal monocytoid B-cell lymphoma” in 1986 by Sheibani et al. In 1987, Cousar et al described it as “parafollicular B-cell lymphoma.”The relationship with marginal zone B cells was established by Piris et al in 1988. Nodal monocytoid B-cell lymphoma was introduced in the Revised Kiel classification by Lennert and Fellerin 1990. NMZL, either with or without monocytoid B cells, was considered as a provisional subtype in the Revised European-American Lymphoma Classification in 2001. In 2008, NMZL was finally admitted as a distinct entity in the World Health Organization (WHO) classification. However, few series have been published, and discrepancies remain about the morphologic, biologic, and clinical characteristics of this disease.[7-20] There are also disagreements regarding therapeutic recommendations. In addition, the recent update of the WHO Lymphoma Classification has included a pediatric variant of NMZL, which has some distinguishing morphologic and clinical features.
Frequency and Epidemiology
Compared to other lymphomas, NMZL is rare; of the cases analysed in an international study, NMZL represented 1.5%, and in a single-center series, NMZL represented 1.8%. Two-thirds of the cases of the Southwest Oncology Group study were described as “composite lymphomas” with concomitant follicular lymphoma, which might include follicular lymphomas with marginal zone differentiation. Other series probably include cases corresponding to nodal spread of extranodal marginal zone lymphoma or cases disseminated at diagnosis, with peripheral lymph nodes associated and/or extranodal or splenic involvement. The association of hepatitis C virus (HCV) infection with NMZL has been reported for the most part only in the Italian and Spanish series and appears rather rare in other settings.
Given the recent identification of NMZL, few reports present detailed clinical and outcome data from affected patients. Only 10 series are available, and these have relatively small numbers of patients (Table). The median age is 50 to 64 years; the sex ratio differs from one series to the next. The disease is localized in peripheral lymph nodes, mostly cervical and inguinal, with frequent involvement of other thoracic or abdominal nodes. The clinical stage at diagnosis varies among the series, but the majority of patients usually present with advanced clinical stage III or IV disease. Only two series reported patients with stage I or II disease.[16,23] Bone marrow infiltration is observed in 19% to 62% of cases, and peripheral blood involvement is very rare. The presence of B symptoms is infrequent. Elevated levels of β2-microglobulin are found in one-third of patients. An M component is detected in 5% to 33% of cases. A few cases have been reported to be associated with HCV infection (HCV seroprevalence was reported in 24% of patients in a series from Italy, in 20% of patients from Spain, and in 5% from Korea), but no such cases have been seen in our experience in France. Cryoglobulins may be present when associated with HCV infection. In contrast to the other MZL entities, there is no history of autoimmune disease in most patients with NMZL (although autoimmune hemolytic anemia has been reported in a subset of patients). Nodal involvement of other MZLs must be strictly excluded for diagnosis. Therefore, a careful clinical history is important when evaluating these cases.
The morphologic features of NMZL are very heterogeneous (Figure 1), in terms of both architecture and cytology.[12,15,18] Different patterns of lymph node infiltration have been reported: marginal zone–like/perifollicular or “inverse follicular,” interfollicular, perisinusoidal, follicular via colonization of reactive follicles (less frequent than in MALT lymphomas), or diffuse. A combination of different patterns in a single case is a common finding. The morphologic evolution of the disease could be described as a perifollicular pattern characterized by enlargement of the marginal zone; followed by expansion into the interfollicular areas, follicular colonization, and formation of large nodules; and ending, in advanced cases, with total effacement of the lymph node architecture and a diffuse pattern. Residual atrophic follicles, which rarely are hyperplasic, are usually seen.
Unlike with splenic MZL, few data about bone marrow histology are available for NMZL.[18,24] A nodular and interstitial pattern has been reported. The sinusoidal localization that is more typical of splenic MZL is also frequently described in NMZL. As in splenic MZL, histology seems to be more sensitive than flow cytometry for the detection of bone marrow infiltration.
Several cell types may be encountered in varying proportions: small cells with irregular nuclei, clumped chromatin, and clear cytoplasm; cells resembling small lymphocytes; small cells with a plasmacytoid differentiation; plasma cells; and a variable content of medium to large cells that are centro-blast- or immunoblast-like. Follicular dendritic cells, usually arranged in a nodular meshwork or restricted to the perifollicular area (marginal zone pattern), are always present. “Monocytoid” B cells, which have more abundant and clear cytoplasm, are not usually predominant, and pure monocytoid B-cell lymphomas are less frequent than cases with plasmacytoid or plasmacytic differentiation. Unlike in MALT lymphoma and splenic MZL, the proportion of large cells is often relatively high (more than 20%), and the mitotic index is frequently elevated as well. These findings throw into question the classification of NMZL as a low-grade lymphoma. However, the component of large cells is always admixed with a small B-cell component without sheets of large cells, and the component of large cells sometimes colonizes the follicle. Those cases with a high proportion of large cells should not be considered as de novo diffuse large B-cell lymphoma because they retain the morphology previously described as characteristic of NMZL. In our experience, it seems that marginal zone B-cell lymphoma with a component composed purely of small cells is rarely seen at diagnosis; this is probably because biopsies are more often done for symptomatic patients and advanced-stage disease, which suggests a very indolent progression at the beginning of the disease. The high proportion of large cells and number of mitoses may explain the more aggressive clinical course reported in our previous series and those of others. However, in our experience, the number of large cells does not seem to influence the outcome in patients treated with polychemotherapy (Figure 2).
The phenotype, usually identical to that of extranodal MZL, is an important diagnostic feature that can help distinguish cases of NMZLs from other small B-cell lymphomas: typically the lymphoma cells are sIgM±D/G+, cIg±, CD19+, CD20+, CD79a+, Oct2+, Pax5+, CD5-, CD10-, CD23-, BCL2+, CyclinD1-. Few cases have been reported with expression of CD5 and/or CD23. CD43 is reported in up to 50% of cases. The expression of IgD has been reported by Campo, who described a “splenic type” and a “MALT type” of NMZL. The splenic type (in the absence of splenic involvement) shows a nodular pattern with IgD positivity. In contrast, the MALT type shows a perivascular/perisinusoidal and parafollicular pattern, without expression of IgD. However, this subtyping is still debatable, and IgD expression has not been confirmed in a recent series of 51 cases. The plasmacytic differentiation is usually associated with the expression of CD38, CD138, and MUM1. In the largest series, the CD138 expression reflected an increase in plasma cell numbers in about half of the cases (24 of 51). In cases with follicle colonization, the benign reactive follicle center cells express CD10 and Bcl-6 and are negative for Bcl-2 and MUM1. In contrast, the colonizing MZL cells express Bcl-2 and often MUM1 and are negative for Bcl-6 and CD10. Partially colonized follicles have exhibited a “moth-eaten” appearance on CD10, Bcl-2, Bcl-6, and MUM1 immunohistochemistry. In most cases, Ki67 expression is much higher among the residual benign/reactive follicle center cells than in the lymphoma cells themselves.
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