Primary Nodal Marginal Zone Research Articles

The B Lymphocyte Predominance: Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) denominates a category of indolent B lymphocytic lymphomas engendered from the marginal zone of lymphoid follicles. Marginal zone lymphomas comprise of an estimated (8%) of non-Hodgkin’s lymphomas with a median age of disease emergence at 60 years and a slight female preponderance. Marginal zone lymphomas display identical morphological and immune phenotypic features across the subcategories. The world health organization (WHO) designates marginal zone lymphoma into three distinct subtypes as extra nodal marginal zone lymphoma (mucosa associated lymphoid tissue - MALT lymphoma), nodal marginal zone lymphoma and splenic marginal zone lymphoma. Primary nodal marginal zone lymphoma remains an exceptional entity and necessitates a demarcation from secondary nodal marginal zone lymphoma on account of metastasis from extra nodal or splenic marginal zone lymphoma. Nodal marginal zone lymphoma constitutes an estimated 2.4% and splenic marginal zone lymphoma around 0.7% of the B lymphocytic lymphomas.

The bendamustine plus rituximab regimen is active against primary nodal marginal zone B-cell lymphoma.

Primary nodal marginal zone lymphoma (NMZL) is a rare disease. There is no current consensus on how to treat it. The bendamustine plus rituximab (BR) regimen is effective for the treatment of follicular and other indolent lymphomas, but its efficacy in NMZL is not known. We analyzed the outcome of 14 patients diagnosed with NMZL (median age 67years) who were treated with 375mg/m2 of rituximab on day 1 and 90mg/m2 of bendamustine on days 1 and 2. The overall and complete response rates were 93% and 71%, respectively. Major toxicity (grade 3/4 neutropenia) occurred in 5% of treatment courses. After a median follow-up of 22months (range: 18-55), the overall survival and the free survival rates were 100% and 93%, respectively. None of the patients showing a complete or partial response developed secondary myelodysplastic syndrome/acute myeloid leukemia. Bendamustine plus rituximab was found to be an active and well-tolerated regimen leading to the rapid control of disease.

Primary nodal marginal zone B‐cell lymphoma: clinical features and prognostic assessment of a rare disease

This study defined the clinical features and assessed the prognosis of 47 patients (17 males, 30 females, median age 63 years) with primary nodal marginal zone B-cell lymphoma. Forty-five per cent had stage IV disease. Hepatitis C virus serology was positive in 24%. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 33% were classified as low-risk, 34% as intermediate-risk, and 33% as high-risk. The 5-year overall survival (OS) was 69%. In univariate analysis worse OS was associated with: FLIPI (P = 0.02), age > 60 years (P = 0.05) and raised lactate dehydrogenase (P = 0.05). In multivariate analysis, only FLIPI predicted a worse OS (P = 0.02).

Clinical Features and Prognostic Assessment of Nodal Marginal Zone B-Cell Lymphoma, a Rare Disease with Follicular-Like Behaviour.

Background. Primary nodal marginal zone B-cell lymphoma (MZL) is a rare entity recognized by the WHO classification. Diagnosis requires a lymph node localization in the absence of prior or concurrent involvement of extranodal sites. Most studies reported so far focus mainly on histopathology, while the clinical features and outcome of this uncommon lymphoma remains less defined.Aim. To define the clinical features and to assess prognosis of primary nodal marginal zone B-cell lymphoma. Methods. We studied a series of 47 newly diagnosed patients with primary nodal marginal zone B-cell lymphoma. Diagnosis was made on histologic examination of lesional tissues integrated with immunohistochemical data. No patient showed MALT or splenic localisation of lymphoma at diagnosis.Results. Patients: 17 males and 30 females, median age 63 years (25–79) with 64% aged more than 60 years. 13% of patients had stage I disease, 10% stage II, 32% stage III, 45% stage IV (bone marrow involvement). 11% had peripheral blood involvement, 11% had bulky disease, 15% B symptoms, 6% ECOG score ≥ 2. 23% had hemoglobin <12 g/dl. LDH was above normal in 15% and β2-microglobulin in 45%. 11% had an autoimmune background. HCV serology was positive in 24% (9/38). With the IPI score 37% ranked in the low risk, 22% in the low-intermediate, 35% in the intermediate-high, and 7% in the high risk category. Using the FLIPI score, 33% were classified as low risk, 34% as intermediate risk, and 33% as high risk. After treatment, 57% achieved a complete response and 24% a partial response, for an overall response rate of 81%. At a median follow-up of 2.6 years, no patient developed splenic or MALT involvement. 5-years and 10-years OS is 69% (95% CI 52–86%). Death occurred in 10 pts (related to NHL in 9, to another neoplasm in one). In univariate analysis the following factors were associated with shorter event-free survival (EFS): B symptoms (p=0.001), high vs intermediate vs low risk FLIPI score (p=0.009). The following factors were associated with worse overall survival: high vs intermediate vs low risk FLIPI score (p=0.02), age > 60 years (p=0.05), LDH above normal (p=0.05). HCV positivity was of borderline significance (p=0.06). In multivariate analysis hemoglobin < 12 g/dl (p=0.02, HR 14.3) was predictive of shorter EFS. Concerning overall survival, only the FLIPI retained statistical significance in predicting a worse outcome (p=0.02, HR 3.5). Positive HCV serology was of borderline significance (p=0.06, HR 4.4).Conclusions: among marginal zone neoplasms, primary nodal marginal zone lymphoma appears a distinct disorder with an indolent behaviour. The association with HCV infection (25%) is particularly high in comparison with non-marginal zone lymphomas. Considering the prognostic assessment of this rare disease, the FLIPI score is effective in detecting patients at worse prognosis with the same power as in follicular lymphoma. Thus, the application of the FLIPI may be of clinical value for treatment decision also in primary nodal marginal zone lymphoma.

Mantle cell lymphoma arising within primary nodal marginal zone lymphoma: a unique presentation of two uncommon B-cell lymphoproliferative disorders

Mantle cell lymphoma and primary nodal marginal zone lymphoma are uncommon tumors thought to arise within discrete anatomic compartments of the B-cell follicle. We report an unusual composite lymphoma comprised of these two neoplasms within an isolated lymph node in a 72-year-old woman. Strikingly, both tumors were completely confined to the respective microanatomic sites of their proposed nonneoplastic lymphoid counterparts, in keeping with early detection of these lesions. The tumors were distinguished by a combination of morphologic, phenotypic, and cytogenetic findings, and the presence of dual, unrelated neoplasms was confirmed by molecular diagnostic studies. After local radiation treatment, there was no recurrence or evidence of systemic disease over more than 2 years. These findings underscore the unique characteristics of these B-cell tumors and support the notion that early in disease development both neoplasms are confined to the distinct anatomic compartments of their postulated normal B-cell counterparts.

A clinicopathological study of nodal marginal zone B‐cell lymphoma. A report on 21 cases

To report the clinicopathological findings of 21 cases of primary nodal marginal zone B-cell lymphoma (NMZL). NMZL is a recently characterized lymphoma and few series have been published. The clinical data were characteristic of a disseminated disease at presentation: presence of peripheral and abdominal lymph nodes, bone marrow involvement (62%), disease stage III and IV (76%), elevated lactate dehydrogenase (LDH) (48%). Other features included peripheral blood involvement (23%), anaemia (24%), thrombocytopenia (10%) and presence of serum M component (33%), while the previously reported association with hepatitis C virus and cryoglobulinaemia was not found. Relapses were frequent but the majority of patients receiving chemotherapy had a good initial response. Morphological features were heterogeneous and there were some differences compared with other marginal zone B-cell lymphomas (MZL). Pure monocytoid B-cell lymphomas were rare (10%) but a minor component of monocytoid B cell was observed more frequently (23%). Plasmacytoid or plasmacytic differentiation was a very common feature (61%). Large cells and a high mitotic count were also frequent (57%). NMZL can be distinguished from splenic MZL and extranodal MZL by its aggressive morphology and disseminated disease at presentation.

Primary Splenic and Nodal Marginal Zone Lymphoma:

Primary splenic and nodal marginal zone (MZ) lymphomas are rare small B cell lymphomas presenting with similar histopathologic features. The neoplastic cell population mostly consists of monocytoid B cells organized in a MZ pattern, associated with centrocytoid cells colonizing follicles. About 50% of cases have a monotypic plasma cell component. The different histopathologic patterns and differential diagnosis are discussed here. Both diseases share a similar immunophenotype, with the expression of B-cell associated antigens and restriction of immunoglobulin light chain. The only difference is the more frequent expression of IgD in splenic than in nodal lymphomas. The most recent findings in genetics and molecular biology are presented and discussed. The main clinical and biological symptoms are described and the similarity of some cases with Waldenstroms macroglobulinemia is stressed. Both lymphomas present with the same type of bone marrow involvement with a high frequency of intravascular infiltrates, which can be associated with interstitial and nodular infiltrates. Transformation into diffuse large B cell lymphoma occurs in about 10 to 15% of the cases. The outcome in many splenic MZ lymphomas is characterized by a lengthy survival after splenectomy (9 to 13 years or longer), despite the absence of a consensus on the optimal treatment. Nodal MZ lymphoma has a more aggressive evolution and seems to only be curable at an early stage. Further studies are needed of both lymphomas to improve treatment and prognosis.

Primary nodal marginal zone B-cell lymphoma arising from more than one clonal neoplastic population.

Primary nodal marginal zone B-cell lymphoma is an uncommon monoclonal B-cell lymphoproliferative disorder. We report a case of a 79-year-old woman who presented with generalized lymphadenopathy. Histologic and immunohistochemical examinations of biopsy sections from an axillary lymph node were consistent with nodal marginal zone B-cell lymphoma. Flow cytometry analysis showed 2 distinct clonal B-cell populations expressing lambda or kappa light chain restriction. Subsequently, genomic deoxyribonucleic acid (DNA) isolated from a paraffin-embedded lymph node section was analyzed for the presence of gene rearrangements. Polymerase chain reaction (PCR) analysis of immunoglobulin heavy chain genes revealed 3 rearranged DNA bands, confirming the presence of more than one clonal B-cell population. These immunophenotypic and genotypic findings have not been previously described in association with this type of lymphoma. To our knowledge, this represents the first reported case of biclonal nodal marginal zone B-cell lymphoma.

Incidence and Subtype Specificity of API2-MALT1 Fusion Translocations in Extranodal, Nodal, and Splenic Marginal Zone Lymphomas

The t(11;18)(q21;q21) is thought to represent an important primary event in the development of marginal zone lymphomas, although an accurate estimation of the frequency and distribution of this genetic alteration among nodal, splenic, and extranodal marginal zone lymphoma types has yet to be determined. Recently, molecular genetic studies have shown that this translocation results in the fusion of the API2 gene on chromosome 11 and a novel gene termed MALT1 on chromosome 18. To investigate the incidence of API2-MALT1 fusion transcripts among marginal zone lymphomas and to determine possible marginal zone lymphoma subtype associations, we used reverse transcriptase-polymerase chain reaction to analyze RNAs extracted from frozen tissue samples of 99 marginal zone lymphomas. Fifty-seven involved diverse extranodal sites including 14 stomach, 11 lung, 7 orbit, 7 parotid, 5 thyroid, 5 lacrimal gland, 3 small intestine, 2 large intestine, 1 kidney, 1 paraspinal region and 1 skin. Twenty-one primary splenic and twenty-one primary nodal marginal zone lymphomas were also studied. API2-MALT1 fusion transcripts were detected in 12 of 57 extranodal marginal zone lymphomas (21%), but in none of the nodal or splenic cases. The cDNA sequences of the fusion transcripts were determined, revealing variation in the coding sequence fusion point for both API2 and MALT1. The findings suggest that t(11;18)(q21;q21) is restricted to extranodal marginal zone lymphomas and that these tumors have distinct genetic etiologies in comparison with their splenic and nodal counterparts.

Primary Nodal Marginal Zone Lymphomas of Splenic and MALT Type

The existence of primary nodal marginal zone lymphomas (MZL) is controversial, as is their relationship to putative extranodal counterparts. Most nodal lymphomas with monocytoid B cell/marginal zone differentiation exhibit the morphologic and immunophenotypical characteristics of extranodal MALT-lymphomas. Splenic marginal zone lymphoma (SMZL) is also of putative marginal zone derivation, but it differs immunophenotypically from MALT lymphoma. To clarify the relationship between nodal and extranodal MZLs and to investigate the possible existence of a nodal variant of SMZL, 36 MZL initially considered to be primary nodal neoplasms were examined. Other low-grade lymphomas with marginal zone differentiation were excluded (small lymphocytic lymphoma/chronic lymphocytic leukemia [SLL/CLL], follicular lymphoma, and mantle cell lymphoma). Six nodal MZLs showed morphologic and phenotypic characteristics similar to those of SMZL, whereas 30 tumors were more similar to MALT-type lymphomas. The six tumors with SMZL features showed a polymorphic infiltrate surrounding residual germinal centers with absent or very attenuated mantle cuffs. These lymphomas were IgD positive (6/6) but cyclin D1 (0/5), CD5 (0/6), and CD23 (0/6) negative. Five of these patients came for treatment in stage I or II. No patient manifested splenomegaly, peripheral blood, and/or bone marrow infiltration either at diagnosis or during follow-up. Lymph nodes from 30 patients with MALT-type features showed a perisinusoidal and perivascular infiltration of monocytoid/centrocytoid cells and residual germinal centers with a relatively well-preserved mantle cuff. The neoplastic cells were negative for IgD (0/17), cyclin D1 (0/8), and CD5 (0/12). Seven of 16 (44%) patients with a detailed history and clinical follow-up had evidence of extranodal lymphoma. These observations suggest that most nodal B cell lymphomas with marginal zone differentiation are of the MALT type and that they are frequently associated with an extranodal component. In addition, a primary nodal counterpart of splenic MZL also exists, and may occur in the absence of splenomegaly.