Mantle Cell Lymphoma



Mantle Cell Lymphoma


Roberto N. Miranda, MD





Key Facts


Etiology/Pathogenesis



  • CCND1-IGH/t(11;14)(q13;q32) resulting in Cyclin-D1 overexpression in most cases


Clinical Issues



  • MCL is nodal-based disease but extranodal sites of involvement are common



    • Spleen is common site


  • Splenectomy performed usually for cytopenias, pain, or less commonly, for diagnostic purposes


  • Small subset of MCL patients present with massive splenomegaly and minimal lymphadenopathy


  • Smaller subset of MCL patients have clinical picture that mimics B-PLL



    • Aggressive course and prominent splenomegaly


    • Marked peripheral blood lymphocytosis with many prolymphocytes


Microscopic Pathology



  • Enlarged white pulp nodules with coalescence


  • Red pulp involvement correlates with extent of MCL


  • Typical: MCL cell population is uniform, small to intermediate size, with irregular nuclear contours


  • Other morphologic variants of MCL can involve spleen



    • Pleomorphic, blastoid, prolymphocytoid


Ancillary Tests



  • Surface Ig(+), CD19(+), CD20(+)


  • CD22(+), FMC7(+), Bcl-2(+)


  • CD5(+), Cyclin-D1(+), CD23(−)


  • CCND1-IgH/t(11;14)(q13;q32)


  • Additional chromosomal aberrations are very common







Mantle cell lymphoma involving splenic white pulp image with secondary red pulp involvement present as small aggregates image.






Mantle cell lymphoma involving splenic white pulp as a large nodule image. A uniform cell population is noted.


TERMINOLOGY


Abbreviations



  • Mantle cell lymphoma (MCL)


Synonyms



  • Centrocytic lymphoma


  • Intermediately differentiated lymphocytic lymphoma


  • Intermediate lymphocytic lymphoma


Definitions



  • B-cell lymphoma characterized by CCND1-IGH/t(11;14)(q13;q32)



    • Most cases are composed of monomorphic small to medium-sized lymphocytes with irregular nuclear contours


ETIOLOGY/PATHOGENESIS


Pathogenesis



  • CCND1-IGH/t(11;14)(q13;q32) with Cyclin-D1 overexpression occurs on most cases



    • Dysregulated Cyclin-D1 overexpression accelerates transition from G1 to S phase of cell cycle



      • Overcomes suppressive effects of retinoblastoma (RB1) and p27kip1


    • Other mechanisms are required for lymphomagenesis


  • MCL is thought to arise from an antigen-naive, CD5(+) B cell (pregerminal center) in



    • Peripheral blood


    • Inner zone of mantle zone follicle


CLINICAL ISSUES


Epidemiology



  • Age



    • Median: 7th decade (range: 34-78 years)


  • Gender



    • M:F ratio = 2-3:1


Site



  • Most cases of MCL involve lymph nodes, but extranodal sites are often involved



    • Common extranodal sites



      • Peripheral blood, bone marrow, gastrointestinal tract


      • Liver, spleen, Waldeyer ring


      • ˜ 40% of patients with MCL have splenomegaly


  • In some patients with MCL, splenic involvement is predominant



    • So-called splenomegalic form of MCL


Presentation



  • Splenic involvement by MCL is usually associated with splenomegaly



    • Can be massive


Laboratory Tests



  • Peripheral blood lymphocytosis in ˜ 25% of cases; occasionally > 200 × 109/L


Treatment



  • Surgical approaches



    • Splenectomy performed usually for cytopenias or local symptoms (e.g., pain)



      • Rarely performed to establish diagnosis


  • Adjuvant therapy



    • Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)


    • R-plus-hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone)


    • Other aggressive chemotherapy regimens


Prognosis



  • MCL is currently incurable and usually carries a poor prognosis



    • 27% overall survival at 5 years with R-CHOP



    • 82% overall survival at 3 years with R-hyper-CVAD


    • Blastoid and pleomorphic variants are associated with adverse prognosis


    • Pure (> 90%) mantle zone pattern correlates with better prognosis


IMAGE FINDINGS


Radiographic Findings



  • Splenomegaly can be detected by various imaging modalities


  • MCL is usually fluorodeoxyglucose (FDG) PET negative/low



    • ± blastoid/pleomorphic variants


MACROSCOPIC FEATURES


General Features



  • Median weight: 1.6 kg (range: 0.7-3.8 kg)


  • Usually diffuse/miliary growth pattern



    • Occasionally large fleshy nodules


MICROSCOPIC PATHOLOGY


Histologic Features



  • Enlarged white pulp nodules with frequent coalescence



    • Massive white pulp expansion in some cases


    • ± small residual germinal centers or marginal zone pattern


  • Red pulp involvement correlates with extent of disease



    • Lesser disease: Small aggregates of MCL cells in cords and sinuses


    • Extensive disease: Diffuse infiltration of red pulp


  • Scattered or clusters of histiocytes are common


  • Tumor cell population is uniform and typically of small to intermediate size



    • Round to irregular nuclear contours


    • Clumped chromatin and occasionally distinct nucleoli


    • Mitotic rate is variable



      • High in blastoid/pleomorphic variants


  • Morphologic variants of MCL



    • Small round: Round nuclear contours and low mitotic rate



      • Mimics chronic lymphocytic leukemia/small lymphocytic lymphoma


    • Pleomorphic: Large cells with pale cytoplasm, more prominent nucleoli, and increased mitoses



      • Mimics diffuse large B-cell lymphoma


    • Blastoid: Medium-sized cells with immature chromatin



      • Mimics lymphoblastic lymphoma


    • Prolymphocytoid: Intermediate to large cells with prominent nucleoli



      • More easily recognized in touch imprints than in histologic sections


      • Mimics prolymphocytic leukemia


    • Monocytoid: Small cells with abundant pale cytoplasm



      • Mimics marginal zone B-cell lymphoma


  • Examination of splenic hilar lymph nodes is helpful for diagnosis



    • Can assess pattern more reliably than in spleen



      • Diffuse, nodular, or mantle zone


      • Pure (> 90%) mantle zone pattern correlates with better prognosis


    • Cytologic features of MCL can be assessed more reliably



      • Environment of spleen or other extranodal sites alters cytologic features


ANCILLARY TESTS


Immunohistochemistry



  • Pan-B-cell antigens(+), CD5(+)


  • Bcl-2(+), CD43(+/−)


  • CD3(−), CD23(−)


  • CD10(−), Bcl-6(−)


  • Cyclin-D1(+) with nuclear pattern



  • Proliferation index as determined by Ki-67 is variable and has prognostic significance



    • > 40% correlates with poorer survival in R-CHOP-treated patients


Flow Cytometry



  • Monotypic surface Ig(+), intermediate to strong


  • IgM(+), IgD(+)


  • CD19(+), CD20(+), CD22(+), CD79a(+)


  • CD79b(+), FMC7(+)


  • CD5(+), CD10(−), Bcl-6(−)



    • Occasional cases are CD5(−), CD10(+), or Bcl-6(+)



      • More often pleomorphic/blastoid variants


  • CD23 usually negative but dimly positive in ˜ 10% of MCL cases


  • Cyclin-D1 is technically difficult to assess by flow cytometry


Cytogenetics



  • t(11;14)(q13;q32) is present in ˜ 70-80% of cases



    • Possible explanations for cases (−) by conventional cytogenetics



      • Poor growth of tumor cells in culture


      • Sampling error: e.g., only (−) BM assessed by conventional cytogenetics


      • Rare cases of of so-called Cyclin-D1(−) MCL


  • Additional nonrandom chromosomal aberrations are very common in MCL



    • Detected by conventional cytogenetics or comparative genomic hybridization


    • Gains of 3q26, 7p21, 8q24, or trisomy 12


    • Losses of 1p13-q31, 6q23-q27, 9p21, 11q22-q23, 13q11-q13, and 17p13-pter


  • Blastoid/pleomorphic variants of MCL



    • High frequency of additional chromosomal abnormalities


    • Tetraploid clones are more frequent


    • Higher frequency of abnormalities of 17p/P53, 9q/P16, and 8q24/MYC


  • Prolymphocytoid variant of MCL



    • High frequency of chromosome 17p/P53 abnormalities


In Situ Hybridization



  • FISH demonstrates the CCND1/IgH gene rearrangement in ˜ 95% of cases


Molecular Genetics



  • CCND1–IgH fusion gene can be shown by PCR in 30-40% of cases



    • Commonly used primers detect only major translocation cluster (MTC)


  • Southern blotting shows BCL1 locus rearrangements in 60-70% of cases



    • Multiple probes required for this detection rate


  • Additional genetic changes in MCL



    • Inactivating mutations of ATM gene at 11q22-23 in ˜ 50% of cases


    • P53 mutations, P15/16 deletions, P18 deletion


    • Loss of p16 and p21 expression


    • MYC rearrangements or amplification


  • Monoclonal IgH and lg Iight chain gene rearrangements


  • No evidence of monoclonal T-cell receptor gene rearrangements


  • Somatic hypermutation of Ig variable region genes uncommon (˜ 20%)

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Mantle Cell Lymphoma

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