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    Mantle Cell Lymphoma

    Definition

    • Lymphoma composed of small to medium sized cells with mild to moderate nuclear irregularities, with a predilection for involving and expanding mantle zones

    Alternate/Historical Names

    • Mantle zone lymphoma
    • Intermediate lymphocytic lymphoma
    • Centrocytic lymphoma
    • Diffuse small cleaved lymphoma
    • Multiple lymphomatous polyposis

    Diagnostic Criteria

    • Predilection for involving and expanding mantle zones around compressed germinal centers
      • Germinal centers may be obliterated yielding vague follicular pattern or diffuse pattern
      • Pseudofollicular proliferation centers not seen
      • Pericapillary hyaline deposits frequent
      • Earlier studies described two types: diffuse and mantle zone
        • These types not currently distinguished
    • Uniform population of small to medium sized cells
      • Mild to moderate nuclear irrregularites
        • Generally less irregular than follicular center cells
        • Some cases with mixture of regular and irregular cells
      • Mitotic rate variable
      • Plasmacytoid differentiation infrequent but may be seen
    • Separation from other small B cell lymphomas may require immunologic study
      • bcl1 expression definitional, seen in 85%
        • BCL1-negative cases may have cyclinD2 (CCND2) or cyclin D3 (CCND3) expression
    • Scattered histiocytes frequent
      • Non-phagocytic, no tingible bodies
    • May undergo blastic transformation
      • Uniform, medium sized nuclei
      • Dispersed, fine chromatin
      • Numerous mitotic figures
      • Same phenotype as non-blastic mantle cell lymphoma
    • Multiple lymphomatous polyposis
      • Mantle cell lymphoma involving intestines

    Yasodha Natkunam MD PhD
    Robert V Rouse MD
    Department of Pathology
    Stanford University School of Medicine
    Stanford CA 94305-5342

    Original posting:: October 11, 2006
    Last update: October 8, 2007

    Supplemental studies

    Immunohistology and Flow Cytometry

    B lineage 100%
    Immunoglobulins Variably detectable
    bcl1 (cyclinD1) 85%
    CD5 80%
    CD43 85%
    CD23 2%
    bcl2 95%
    CD10 2%
    bcl1 negative cases may have cyclinD2 (CCND2) or cyclinD3 (CCND3) expression detectable by immunohistochemistry

    Ki67 should be performed and reported in every case as the % positive is related to survival
    Ki67 rate 5 year survival
    5-20% 47%
    21-40% 32%
    41-60% 31%
    61-90% 25%
    Katzenberger 2006

     

    Genetic Analysis

    • bcl1 (cyclinD1) negative cases may have cyclinD2 (CCND2) or cyclinD3 (CCND3) expression
    • FISH for t(11;14) detects nearly 100% of cases
      • Karyotype detects 65% of cases
      • PCR for major translocation cluster detects 30-40% of cases

    Differential Diagnosis

    Small B Cell Lymphomas
      SLL/CLL Mantle Marginal Zone Lymphoplasmacytic Follicular
    CD23 85% 2% 8% 0-30% on immunohistology but up to 60% weak positive on flow 0-25%
    CD5 80% 80% 0% 5% 0%
    bcl1 2% 85% 0% 0% 0%
    CD10 0% 2% 2% 3% 85%
    CD43 80% 85% 35% 10-30% 7%
    bcl2 95% 95% 65-90% >50% 90%
    • CD23 staining refers to lymphoid staining
      • Follicular dendritic cells stain in many processes
    • bcl1
      • Blastic mantle cell lymphoma 100%
      • Hairy cell leukemia 41%
    • CD43 stains only 2% of splenic marginal zone lymphoma

     

    Mantle Cell Lymphoma SLL/CLL
    Irregular nuclear membranes Round nuclei
    Residual germinal centers may be prominent Proliferation centers present
    Expanded mantle zone around germinal centers variably present No mantle zone pattern
    Scattered histiocytes Histiocytes not prominent
    bcl1 85% bcl1 2%
    CD23 2% CD23 85%
    Blastic transformation Large cell transformation
    Some mantle cell lymphomas have been reported to have proliferation centers; these are better considered as SLL/CLL

     

    Lymphoplasmacytic Lymphoma / Immunocytoma Mantle Cell Lymphoma
    Round nuclear membranes Variably irregular nuclear membranes
    bcl1 negative bcl1 85%
    CD5 5% CD5 80%
    Large cell transformation Blastic transformation
    Plasmacytoid diffrentiation may be prominent in mantle cell lymphoma

     

    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Mantle Cell Lymphoma
    Enlarged marginal and mantle zones Enlarged mantle zone frequent
    Polymorphous population Uniform small lymphocytes
    bcl1 negative bcl1 85%
    CD25 negative CD25 30%
    CD5 negative CD5 80%
    CD43 35% (Splenic 2%) CD43 85%
    • Both may involve the GI tract and other mucosal sites in extranodal cases.
    • Enlarged marginal and mantle zones may be hard to distinguish

     

    Follicular Lymphoma Mantle Cell Lymphoma
    Distinct nodules composed of cleaved cells Residual germinal centers may simulate nodules
    Mantle pattern surrounding germinal center rare Mantle pattern frequent
    bcl1 negative bcl1 85%
    CD5 negative CD5 80%
    CD43 7% CD43 85%
    CD10 85% CD10 2%
    Follicular dendritic network intact FDC network disrupted or confined to germinal centers
    bcl2 92% bcl2 95%
    Floral variant of follicular lymphoma surrounds and invades follicles resulting in a lobulated follicle rather than the more even obliteration by mantle cell lymphoma

     

    Lymphoblastic Lymphoma, T or B Blastic Mantle Cell Lymphoma
    Median age 17-20 years Rare under 30 years
    Histiocytes infrequent (tingible body macrophages frequent) Scattered histiocytes frequent
    No prior diagnosis of mantle zone lymphoma Frequent diagnosis of mantle zone lymphoma
    T lineage 90%, B lineage 10% B lineage markers positive
    bcl1 negative bcl1 85%
    CD5 negative if B lineage CD5 80%

     

    Burkitt Lymphoma Blastic Mantle Cell Lymphoma
    Median age 30 years Rare under 30 years
    Histiocytes infrequent (tingible body macrophages frequent) Scattered histiocytes in most cases
    No prior diagnosis of mantle zone lymphoma May have prior diagnosis of mantle zone lymphoma
    bcl1 negative bcl1 100%
    CD5 negative CD5 80%
    CD10 99% CD10 negative
    Translocation involving myc gene No myc translocation

    Mantle Cell Lymphoma Reactive Hyperplasia
    Uniform moderately atypical population Mixed population, small round cells
    Light chain monotypia variably demonstrable No monotypia
    Clonal Ig gene rearrangement No clonal rearrangement
    Coexpression of CD43 by B cells 84% No CD43 coexpression
    Coexpression of CD5 by B cells 80% No CD5 coexpression

    Clinical

    • Mean age 60 years, rare before 30
    • More frequent involvement of GI tract, Waldeyer ring and spleen than SLL/CLL
    • High mitotic rate and blastic morphology are adverse prognostic features
      KI67 rate 5 year survival
      5-20% 47%
      21-40% 32%
      41-60% 31%
      61-90% 25%
      Katzenberger 2006

    Grading / Staging / Report

    • While staging is linked to prognosis, it does not generally determine therapy
      • Therapy generally determined by clinical signs and symptoms
    • Pathologic staging is usually limited to bone marrow biopsy and biopsies of other sites to confirm clinical evidence of involvement

    Ann Arbor Staging System

    • Stage I
      • I if involvement of a single lymph node region
      • IE if involvement of a single extralymphatic organ or site
    • Stage II
      • II if two or more lymph node regions on same side of diaphragm
      • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
    • Stage III
      • III if Involvement of lymph node regions on both sides of the diphragm
      • IIIS if spleen involved
      • IIIE if extralymphatic site involved
    • Stage IV
      • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
    • Systemic Symptoms in 6 months preceding admission
      • Fever, night sweats, 10% weight loss
      • A = absent
      • B = present
    • Extranodal sites are also designated
      • M+ = marrow
      • L+ = lung
      • H+ = liver
      • P+ = pleura
      • O+ = bone
      • D+ = skin and subcutaneous tissue
    • Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

    The pathology report should contain the following information:

    • Diagnosis in the World Health Organization (WHO) classification
      • Equivalent diagnosis in other classifications used by relevant clinicians
    • Results of supplementary studies if performed
    • Relationship to other specimens from the same patient
    • Information relevant to staging if available

    Lists

    Types of small B cell lymphoma

    Blastic lymphomas

    Bibliography

    • Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
    • Jaffe ES, Harris NL Stein H, Vardiman JW . Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
    • Banks PM, Chan J, Cleary ML, Delsol G, De Wolf-Peeters C, Gatter K, Grogan TM, Harris NL, Isaacson PG, Jaffe ES, et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol. 1992 Jul;16(7):637-40.
    • Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. French-American-British (FAB) Cooperative Group. J Clin Pathol. 1989 Jun;42(6):56
    • Schlette E, Lai R, Onciu M, Doherty D, Bueso-Ramos C, Medeiros LJ. Leukemic mantle cell lymphoma: clinical and pathologic spectrum of twenty-three cases. Mod Pathol. 2001 Nov;14(11):1133-40.
    • Dunphy CH, Wheaton SE, Perkins SL. CD23 expression in transformed small lymphocytic lymphomas/chronic lymphocytic leukemias and blastic transformations of mantle cell lymphoma. Mod Pathol. 1997 Aug;10(8):818-22.
    • Domizio P, Owen RA, Shepherd NA, Talbot IC, Norton AJ. Primary lymphoma of the small intestine. A clinicopathological study of 119 cases. Am J Surg Pathol. 1993 May;17(5):429-42.
    • Isaacson PG, MacLennan KA, Subbuswamy SG. Multiple lymphomatous polyposis of the gastrointestinal tract. Histopathology. 1984 Jul;8(4):641-56.
    • Moynihan MJ, Bast MA, Chan WC, Delabie Jan, Wickert RS, Wu G, Weisenburger DD. Lymphomatous polyposis. A neoplasm of either follicular mantle or germinal center cell origin. Am J Surg Pathol. 1996 Apr;20(4):442-52.
    • Katzenberger T, Petzoldt C, Holler S, Mader U, Kalla J, Adam P, Ott MM, Muller-Hermelink HK, Rosenwald A, Ott G. The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood. 2006 Apr 15;107(8):3407.
    • Fu K, Weisenburger DD, Greiner TC, Dave S, Wright G, Rosenwald A, Chiorazzi M, Iqbal J, Gesk S, Siebert R, De Jong D, Jaffe ES, Wilson WH, Delabie J, Ott G, Dave BJ, Sanger WG, Smith LM, Rimsza L, Braziel RM, Muller-Hermelink HK, Campo E, Gascoyne RD, Staudt LM, Chan WC; Lymphoma/Leukemia Molecular Profiling Project. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood. 2005 Dec 15;106(13):4315-21.
    • Tiemann M, Schrader C, Klapper W, Dreyling MH, Campo E, Norton A, Berger F, Kluin
      P, Ott G, Pileri S, Pedrinis E, Feller AC, Merz H, Janssen D, Hansmann ML,
      Krieken H, Möller P, Stein H, Unterhalt M, Hiddemann W, Parwaresch R; European
      MCL Network. Histopathology, cell proliferation indices and clinical outcome in 304 patients
      with mantle cell lymphoma (MCL): a clinicopathological study from the European
      MCL Network. Br J Haematol. 2005 Oct;131(1):29-38.
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