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Lymphoma - B cell neoplasms

B cell lymphoma subtypes

Mantle cell lymphoma


Reviewer: Nikhil Sangle, M.D., University of Utah and ARUP Laboratories (see Reviewers page)
Revised: 27 February 2011, last major update February 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● Intermediate grade B cell lymphoma characterized by CD5+ CD23-, cyclin D1+ and t(11;14)(q13;q32)

Terminology
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● Formerly known as centrocytic lymphoma (Hum Pathol 2002;33:7)

Etiology
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● Cell of origin appears to be naïve pregerminal center B lymphocyte present in primary lymphoid follicles and mantle zones of secondary follicles with nonmutated Vh region genes

Clinical features
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● 3-10% of non-Hodgkin lymphomas in Western countries
● Usually 60+ years with stage III/IV disease; 80% men
● Lymphadenopathy, bone marrow involvement in 2/3 (lymphoid aggregates, often paratrabecular), splenomegaly in 50% with white pulp involvement, periportal hepatic infiltration, lymphomatoid polyposis of small bowel and other extranodal involvement
● CNS involvement in 10% (Mod Pathol 2002;15:1073)
● B symptoms (fever, night sweaters, weight loss) in 30%
● Peripheral blood involvement (leukemic phase) in 20-60% at diagnosis; usually <20,000 absolute lymphocytes, associated with worse outcome
● More aggressive than SLL/CLL or marginal zone lymphoma
● Median survival 3 years, may transform to blastoid variant, but blastic transformation is uncommon
● Does not transform to large cell lymphoma
● Most patients relapse
● Complete remission in less than 35%
● Cutaneous cases associated with disseminated disease at diagnosis or shortly thereafter

Prognostic features
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● Longer survival: nodular or mantle zone pattern (5 years)
● Shorter survival: blastic variant (3 years), high mitotic count, high proportion of Ki67+ cells, trisomy 12, 3q+, 9q-, p53 mutation/overexpression/loss
● International Prognostic Index not useful because most patients present with high stage disease with multiple foci of extranodal involvement

Case reports
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● Chronic indolent tumors with mutated immunoglobulin genes (Hum Pathol 2003;34:1030, Hum Pathol 2005;36:1232)
● Two cases with prominent intrasinusoidal bone marrow infiltrate (Hum Pathol 2003;34:789)
● Cases with composite Hodgkin lymphoma (Am J Surg Pathol 2003;27:1577, Am J Surg Pathol 2003;27:1483)
● Multiple lymphomatous polyposis throughout GI tract (Arch Pathol Lab Med 2003;127:1028)
● Colonic tumor with synchronous adenocarcinoma (Arch Pathol Lab Med 2003;127:E64)
● Presenting as breast mass (J Clin Pathol 2001;54:883)
● Prolymphocytoid variant with leukostasis (Mod Pathol 2004;17:879)

Treatment
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● No standard or curative treatment - various chemotherapy regimens are used, with rituximab
● Proteasome inhibitor bortezomib may be helpful

Micro description
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● Three patterns of tumor infiltration: (1) diffuse replacement of entire lymph node, (2) infiltration into expanded mantle zone, or (3) vague nodular pattern
● Tumor cells are monotonous small lymphocytes resembling centrocytes / mantle cells with scant cytoplasm, cleaved, slightly irregular or round nuclei; condensed chromatin
● Tumor cells have no nucleoli; no large cells, no proliferation centers
● May have prominent hyalinized vessels or scattered epithelioid histiocytes
● Rarely platelet satellitism around atypical lymphocytes (Am J Clin Path 2001;115:567)
● Cases with prominent nucleoli resemble AML-M3 (Am J Clin Path 2002;117:246)
● Bone marrow involvement: most of these patients relapse - only 35% attain complete remission; focal paratrabecular and nonparatrabecular patterns; may have benign germinal centers; cells are pleomorphic with variation in size and irregular nuclear contours
● Cutaneous: dermal and subcutaneous aggregates of small to medium lymphocytes, often perivascular or periadnexal; Grenz zone present with sparing of the epidermis; often blastoid (Am J Surg Pathol 2002;26:1312)

Micro images
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Presenting as breast mass

       
Axillary node: tumor cells have scant cytoplasm, irregular nuclei, small nucleoli


With synchronous colonic adenocarcinoma

       
CD20+                         Cyclin D1+                 CD43+ (cytoplasmic staining)

H&E and cyclin D1

Virtual slides
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Lymph node: H&E (left) and Cyclin D1 (right)

Cytology images
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CSF with lymphoid cells with moderate cytoplasm and irregular nuclear contours #1, #2, #3-with prominent cytoplasmic granules

Peripheral smear
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● Cells (if present) have scant cytoplasm and cleaved nuclei; confirm neoplastic with flow cytometry
● Differential diagnosis is SLL/CLL, prolymphocytic leukemia, follicular lymphoma

Positive stains
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● CD5, CD19 (strong), CD20 (strong), cyclin D1/bcl1 (variable nuclear staining since cells are at different stages of cell cycle); also CD22, CD43, CD79a, FMC7, surface IgM or IgD, kappa or lambda, bcl2
● In-situ hybridization for cyclin D1/bcl-1 is more sensitive/specific than immunostains (Mod Pathol 2001; 14:62)
● Cyclin D1 helpful to identify ‘in-situ MCL’, when the involvement is restricted to the inner mantle zones
● Rare cases have all morphologic features of MCL but are negative for cyclin D1, may be positive for cyclin D2/D3 (great caution required for diagnosis, Blood 2005;106:4315, Blood 2006;108:1109)

Negative stains
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● CD23, usually CD10; also bcl6, CD11c, TdT, T cell antigens
● Usually p27(kip1) negative (note that B-CLL, follicular lymphoma and marginal zone lymphomas are p27 positive; hairy cell leukemia is p27 weak/negative, Mod Pathol 2001;14:1022)
● May have dim CD23 expression by flow cytometry (Am J Clin Pathol 2001;116:893, Am J Clin Pathol 2003;120:760)
● Occasionally is discordance between results in peripheral blood and bone marrow (Am J Clin Pathol 2002;118:758)

Molecular
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● t(11;14)(q13;q32): fusion of cyclin D1 (also called bcl-1, PRAD1, CCND1) and IgH in 90% (same translocation present in some B cell prolymphocytic leukemia, myeloma and CLL)
● Cyclin D1 regulates G1 to S phase transition, but the cell cycle suppressive effect of RB1 & p27Kip1 is overcome by deregulated expression of cyclin D1, leading to development of mantle cell lymphoma
● t(11;14) is not specific for mantle cells - it is also found in normal patients
● Leukemic cases often have chromosome 17 abnormalities associated with p53; also additional cytogenetic breakpoints at 8q24, 9p22-24 and 16q24 (Am J Clin Pathol 2001;116:886)
● Clonal IgH rearrangements are present in 100% of cases by PCR
● Real time RT-PCR for quantifying cyclin D1 may be useful for diagnosis (Mod Pathol 2002;15:556)
● Insertion of CCDN1 gene at IgH locus may be microscopic, causing fusion gene with bcl1 overexpression on an apparently normal chromosome 14 (J Clin Pathol 2003;56:798)
● FISH: 57%-90% of interphase nuclei have 3 or more 11q13 signals (Am J Clin Path 2000;114:248); may be more sensitive than immunostains (Mod Pathol 2002;15:517)

Molecular images
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Left: PCR/Southern blot image; Right: peripheral blood single and double fusion of cyclin D1-IgH cells

ISH for cyclin D1

Differential diagnosis
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SLL/CLL: CD5+, CD23+, cyclin D1- (Am J Surg Pathol 2004;28:801), weak CD19 and CD20 staining, usually no atypical nuclei, p27 negative
Follicular lymphoma: CD5-, CD10+, cyclin D1-
Marginal zone lymphoma: CD5-, CD10-, cyclin D1-
● Note: hairy cell leukemia and myeloma can also be cyclin D1+

End of Lymphoma - B cell neoplasms > B cell lymphoma subtypes > Mantle cell lymphoma


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