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Nodal marginal zone lymphoma with increased large cells: myth versus entity.

To the Editor.--Nodal marginal zone B-cell lymphoma (NMZL) has recently been recognized in the World Health Organization (WHO) lymphoma classification (1) as a separate clinical and pathologic entity. Nodal marginal zone lymphomas are considered indolent lymphomas by the WHO monogram. (1,2) Yet, the 7 or 8 large studies (3-10) describing the clinical features of this entity (as defined by the 2008 WHO monogram (2))describe a significant subset of cases that display an aggressive morphology with a corresponding aggressive clinical course. The cases with numerous large lymphocytes do not fulfill criteria for diagnosis as large B-cell lymphoma. Furthermore, it has been reported (3-10) that those patients were treated with anthracyclin-based therapies, usually reserved for aggressive lymphomas, such as diffuse large B-cell lymphoma (DLBCL). There is, however, no consensus definition on the histologic criteria for the diagnosis of progression to large B-cell lymphoma. Clearly, this subgroup needs to be better defined in larger studies and, perhaps, be delineated with a grading system, similar to follicular lymphoma. This letter presents an example of this morphologically aggressive subtype with a brief review of the literature addressing this issue.

Nodal marginal zone lymphoma is a rare, biologically and clinically heterogeneous entity (2) that shares morphologic and immunophenotypic characteristics with extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue type and with splenic marginal zone lymphomas. Nodal marginal zone lymphoma can be diagnosed only in the absence of clinical evidence of extranodal or splenic disease. The relationship among nodal, splenic, and extranodal marginal zone lymphomas is difficult to delineate; however there are studies (3-6) that report differences in disease distribution and clinical outcome, findings that argue for consideration of NMZL as a distinct clinical entity. Although NMZL was considered a provisional subtype in the Revised European-American Lymphoma classification, it was finally designated as a distinct entity in the WHO classification in 2001 (1) and retained as such in the WHO 2008 classification. (2)

The NMZL has various different patterns, including nodular, "marginal zonelike," or perifollicular, interfollicular, and diffuse. (2,7) These patterns may be seen in combination. In the nodular pattern, the neoplastic nodules are well demarcated from uninvolved, interfollicular areas and contain a monotonous population of small, neoplastic cells without evidence of germinal centers. In the perifollicular pattern, the lymphoma cells surround reactive, secondary follicles and can colonize the follicles. The pale monocytoid cells may expand between the reactive germinal centers and an attenuated mantle cuff. The neoplastic cells in the interfollicular pattern are limited to the interfollicular areas. The nodal architecture is effaced in the diffuse pattern. The cellular distribution is polymorphous and includes small lymphocytes with irregular or cleaved nuclei (centrocytelike), medium-sized monocytoid cells with round to slightly irregular nuclear contours, ample cytoplasm, and large, transformed cells with vesicular nuclear chromatin and prominent single-to-multiple nucleoli (centroblast-like or immunoblast-like cells). The number of large cells may increase ("sometimes >20%," (2)) and, by definition, are interspersed among the small- and intermediate-sized lymphocytes. There may also be plasmacytic differentiation, and NMZL can transform into large B-cell lymphoma.

The NMZLs with increased, transformed lymphocytes are not considered to have been transformed into large B-cell lymphoma because there are no sheets of large lymphocytes. (2) However, those lymphomas often present with more large, transformed lymphocytes (ranging from 20% to >50%, (3-8) interspersed among smalland intermediate-sized lymphocytes, with increased proliferation as delineated by Ki-67 staining. An example of this morphologic subtype is presented in Figures 1, A and B, and 2, A through D. Some of these NMZLs with aggressive morphology may portend a more aggressive clinical course. There is no consensus definition, to my knowledge, on the histologic criteria for the diagnosis of progression to large B-cell lymphoma or high-grade lymphoma.



Nathwani et al (3) delineated the lymphoma as "transformed when it had more than 20% large lymphocytes. By that definition, they found that 20% of their NMZL cases (5 out of 25) were transformed. (3,8) Berger et al (5) classified the lymphoma as transformed to large cell lymphoma when the large cell component was at 50%. Sixty-two percent (23 of 37) of the patients described in their series were described with a high percentage of large cells and were treated with the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOPlike regimens. In the series of NMZL cases described by Camacho et al, (9) 7 of 28 cases (25%) showed a focal increase in large, transformed cells, without further delineation. Twelve of 24 cases (50%) received multiagent chemotherapy. (9) Kojima et al, (4) likewise, classified the lymphoma as transformed to large cell lymphoma if there were more than 50% large cells or there were sheets of large cells. In their series of 65 cases, 20 (30.8%) had transformed to DLBCL. (4) Eleven of 20 cases (55%) were treated with a CHOP-like regimen; 9 of 20 (45%) were treated with surgery, radiation, or a single agent with radiation. Interestingly, their series (4) reports differences in the treatment modalities within the transformed lymphoma group. The 5-year overall survival rate was 85% for NMZL but was 77% for the large cell-rich variant. (4) In the series reported by TraverseGlehen et al, (6) 57% (13 of 21) had greater than 20% large cells and 6 of those 13 cases (46.2%) had 50% large cells. Of the 21 cases, 17 (81%) were treated with multidrug regimens (either CHOP or the combination of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone). (2,6) They note that the percentage of large cells was not associated with an increased risk of progression. (2,6) However, it appears that most of the patients, irrespective of the quantity of large cells, were treated with polychemotherapy (anthracyclin-based therapies, which are usually given to patients with DLBCLs). The aggressive treatment given to most of these patients may have precluded the authors (6) from assessing the effect of large cells on prognosis. Petit et al (10) showed that survival of patients with greater than 20% of tumor cells staining positive for Ki-67 had a markedly reduced overall survival.

The prognosis of these patients may be predicted using the Follicular Lymphoma International Prognostic Index. (11) According to that index, patients with a good prognosis have a 10-year overall survival rate of 70%, and therefore, conservative treatment like radiotherapy may be applicable. In contrast patients with high-risk disease may be treated with polychemotherapy along with an anti-CD20 monoclonal antibody. In NMZL, along with clinical parameters, treatment decisions are influenced by the morphologic description of an increased number of large cells or a high proliferative index rank. Some authors (5,12) allude to anthracycline-based polychemotherapy, in cases with a high percentage of large cells.

In summary, NMZL, despite being an indolent disorder, is often seen with an aggressive morphology and also presents as a high-stage disease with a more aggressive clinical course. In most series, a significant subset was treated with polychemotherapy. There is a clear need for larger collaborative studies that can delineate the significance of large cells in NMZL, analogous to the Mann and Berard grading system in follicular lymphoma. (13) Of note, the case shown in Figures 1, A and B, and 2, A through D, was presented at the 2009 Society for Hematopathology and European Association for Haematopathology Workshop at Cleveland Clinic (Cleveland, Ohio), and the panel concurred with the diagnosis of NMZL with increased large cells. Presently, there are no guidelines; therefore, it is important to be aware of this entity.

(1.) Jaffe ES, Harris NL, Stein H, and Vardiman JW, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. World Health Organization Classification of Tumours.

(2.) Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC Press, 2008. World Health Organization Classification of Tumours; vol 2.

(3.) Nathwani BN, Anderson JR, Armitage JO, et al; for the Non-Hodgkin's Lymphoma Classification Project. Marginal zone B-cell lymphoma: a clinical comparison of nodal and mucosa-associated lymphoid tissue types. J Clin Oncol. 1999;17(8):2486-2492.

(4.) Kojima M, Inagaki H, Motoori T, et al. Clinical implications of nodal marginal zone B-cell lymphoma among Japanese: study of 65 cases. Cancer Sci. 2007;98(1):44-49.

(5.) Berger F, Felman P, Thieblemont C, et al. Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients. Blood. 2000;95(6):1950-1956.

(6.) Traverse-Glehen A, Felman P, Callet-Bauchu E, et al. A clinicopathological study of nodal marginal zone B-cell lymphoma: a report on 21 cases. Histopathology. 2006;48(2):162-173.

(7.) Salama ME, Lossos IS, Warnke RA, Natkunam Y. Immunoarchitectural patterns in nodal marginal zone B-cell lymphoma: a study of 51 cases. Am J Clin Pathol. 2009;132(1):39-49.

(8.) Nathwani BN, Mohrmann RL, Brynes RK, et al. Monocytoid B-cell lymphomas: an assessment of diagnostic criteria and a perspective on histogenesis. Hum Pathol. 1992;23(9):1061-1071.

(9.) Camacho FI, Algara P, Mollejo M, Garcia JF, et al. Nodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases. Am J Surg Pathol. 2003;27(6):762-771.

(10.) Petit B, Chaury MP, Le Clorennec C, et al. Indolent lymphoplasmacytic and marginal zone B-cell lymphomas: absence of both IRF4 and Ki-67 expression identifies a better prognosis subgroup. Haematologica. 2005;90(2):200-206.

(11.) Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma International Prognostic Index. Blood. 2004;104(5):1258-1265.

(12.) Arcaini L, Lucioni M, Boveri E, et al. Nodal marginal zone lymphoma: current knowledge and future directions of an heterogeneous disease. Eur J Haematol. 2009;83(3):165-174.

(13.) Nathwani BN, Metter GE, Miller TP, et al. What should be the morphologic criteria for the subdivision of follicular lymphomas? Blood. 1986;68(4):837-845.

The author has no relevant financial interest in the products or companies described in this article.

Prabhjot Kaur, MD

Department of Pathology

Dartmouth-Hitchcock Medical Center

Lebanon, NH 03756
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Title Annotation:Letters to the Editor
Author:Kaur, Prabhjot
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Aug 1, 2011
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