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mantle cell lymphoma

An intermediate grade lymphoma. Classification: 1) working formulation category: diffuse small cleaved cell lymphoma 2) Kiel classification: centrocytic lymphoma 3) revised European-American classification: mantle cell lymphoma Epidemiology: 1) older males (median age 60 years) 2) male:female ratio 2.3:1 3) 2-6% of all non-Hodgkin's lymphomas [10] 4) 24% of non-follicular, small B-cell lymphomas Pathology: 1) cells of origin are immature B-cells that leave the bone marrow & form primary lymphoid follicles & mantle zones of secondary lymphoid follicles [6] 2) expansion of the mantle zone area of the lymph node with a homogeneous population of malignant small lymphoid cells with slightly irregular nuclear outlines & scant cytoplasm 3) with disease progression, the germinal centers become destroyed by the neoplastic infiltrate 4) diffuse involvement [10] a) disseminated lymph node involvement b) leukemia is less common c) lymphomatous polyposis of the gastrointestinal tract is clinical variant (reports of uncommon to 15%) d) involvement of the bone marrow is common Microscopic pathology: 1) four histologic patterns a) mantle zone (better prognosis) b) nodular c) diffuse (worse prognosis) d) blastic 2) small to medium sized, irregular, inconspicous nucleolus Immunophenotype: - surface IgM + - surface IgD + - lambda > kappa - CD19, CD20, CD22, CD79a + (B-cell surface antigens) - CD5 + (CD5 is a T-cell marker, but may be found on a small population of B-cells) - CD10 -/+ - CD23 - - CD43 + - CD11c - - CD25 - Genetics: 1) IgH & IgL genes rearranged 2) t(11:14) in > 50% of cases, rearranged bcl-1* gene on chromosome 11 with the Ig heavy chain on chromosome 14 3) t11q13:14q32 involving CCND1 & IgH gene 4) overexpression of CCND1/cyclin D1/PRAD1 mRNA is noted regardless of whether or not bcl-1 gene rearrangements are detected 5) inactivation of p53 in 20% of cases (poor prognosis) 6) inactivation of p16ink4A by deletion, mutation, hypermethylation in 50% of cases with blastic morphology 7) associated with defects in ATM gene 8) ARHGAP29 is down-regulated * also known as CCND1/cyclin D1/PRAD1 Clinical manifestations: 1) generalized lymphadenopathy 2) splenomegaly (may be massive) 3) hepatomegaly 4) patients generally present with stage III/IV disease - involvement of GI tract, bone marrow & bloodstream is common [10] 5) B symptoms* occur in < 50% of patients * B symptoms: weight loss, fever, night sweats. Laboratory: 1) complete blood count (CBC) a) may show lymphocytosis (20-40%) b) mild anemia may be present c) thrombocytopenia is uncommon (< 15%) 2) protein electrophoresis is generally normal 3) renal function tests 4) liver function tests (including serum LDH) 5) serum uric acid 6) serum Ca+2 7) serum beta-2 microglobulin 8) bone marrow biopsy 9) excisional lymph node biopsy Radiology: 1) chest X-ray 2) computed tomography (CT) of abdomen & pelvis Differential diagnosis: 1) Castleman's disease 2) mantle zone hyperplasia Management: 1) prognosis - considered intermediate grade, but may behave as low grade - generally more agressive than small lymphocytic lymphoma, CLL or MALT lymphoma - mantle zone variant: mean survival is 90 months - diffuse variant: mean survival is 30 months 2) treatment has not been shown to result in cure 3) chemotherapy - rituximab-based chemotherapy (R-CHOP, R-CVP) [10] - R-CHOP with less toxicity & better survival than R-CVP [16] - bendamustine plus rituximab with longer progression-free survival & fewer toxic effects than R-CHOP [11] - median survival > 3 years - patients with undetectable minimal residual disease after induction therapy benefit from maintenance rituximab [16] - fludarabine & cladribine may have activity - acalabrutinib (breakthrough therapy designation) Aug 2017 - acalabrutinib (Calquence) FDA-approved in 2022 [14] - ibrutinib + venetoclax may improve outcomes in patients with poor prognosis [13] - ibrutinib alone 86% with 3 year failure-free survival (3yFFS) superior to hematopoietic stem-cell transplantation (72% 3yFFS) [15] - ibrutinib + hematopoietic stem-cell transplantation (86% 3yFFS) [15] 4) radiation therapy is generally not useful, because the disease is often disseminated on presentation 5) alpha-interferon administration after conventional chemotherapy has been used to prolong remission duration 6) allogeneic hematopoietic stem cell transplantation [10] - may produce long-term remission, even in patients in relape - associated with substantial morbidity & mortality

Interactions

disease interactions

Related

2-chlorodeoxyadenosine (2-CdA) [cladribine] (Leustatin) angiofollicular lymph node hyperplasia; Castleman lymphadenopathy cellular tumor antigen p53; tumor suppressor p53, phosphoprotein p53; antigen NY-CO-13 (TP53, p53) chromosomal translocation t11q13.3:14q32 (mantle cell lymphoma) cyclin D1 (parathyroid adenomatosis-1 [PRAD1] protein or bcl-1 proto-oncogene protein, CCND1, BCL1) cyclophosphamide/doxorubicin/vincristine (Oncocin)/prednisone (CHOP) cyclophosphamide/vincristine (Oncocin)/prednisone (CVP, COP) DNA methylation (promoter methylation) fludarabine (Fludara) p16ink4A; cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3; cyclin-dependent kinase 4 inhibitor A; CDK4I; p16-INK4a; p16INK4A; p16-INK4; multiple tumor suppressor 1; MTS-1; p16MTS1 (CDKN2A, CDKN2, MTS1) rituximab (Rituxan, Mabthera, Truxima, Ruxience, Riabni)

General

diffuse small cell lymphoma peripheral B-cell lymphoid neoplasm

References

  1. Chan JK, Banks PM, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Harris NL, Isaacson PG, et al. A revised European-American classification of lymphoid neoplasms proposed by the International Lymphoma Study Group. A summary version. Am J Clin Pathol. 1995 May;103(5):543-60. PMID: 7741099
  2. Williams Hematology, 5th ed, Beutler et al (eds), McGraw Hill, NY, 1995, pg 1054, 1080, 1085
  3. http://pathhsw5m54.ucsf.edu/case11/mcl.html
  4. mantlecell@ucsd.edu
  5. Dalla-Favera & Gaidano, Lymphomas, In: Cancer, Principles & Practice of Oncology, 6th edition, DeVita et al (eds), Lippincott & Williams, Philadelpha, 2001, pg 2220
  6. Weisenberger: Mantle cell lymphoma, In: Neoplastic Hematopathology, Knowles DM (ed), Williams & Wilkins, Baltimore, 1992, pg 617
  7. Yatabe Y, Suzuki R, Tobinai K, Matsuno Y, Ichinohasama R, Okamoto M, Yamaguchi M, Tamaru J, Uike N, Hashimoto Y, Morishima Y, Suchi T, Seto M, Nakamura S. Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma. Blood. 2000 Apr 1;95(7):2253-61. PMID: 10733493
  8. Miranda RN, Briggs RC, Kinney MC, Veno PA, Hammer RD, Cousar JB. Immunohistochemical detection of cyclin D1 using optimized conditions is highly specific for mantle cell lymphoma and hairy cell leukemia. Mod Pathol. 2000 Dec;13(12):1308-14. PMID: 11144927
  9. Aguilera NS, Bijwaard KE, Duncan B, Krafft AE, Chu WS, Abbondanzo SL, Lichy JH, Taubenberger JK. Differential expression of cyclin D1 in mantle cell lymphoma and other non-Hodgkin's lymphomas. Am J Pathol. 1998 Dec;153(6):1969-76. PMID: 9846986
  10. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 18. American College of Physicians, Philadelphia 2009, 2012, 2015, 2018.
  11. Rummel MJ, Niederle N, Maschmeyer G et al Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle- cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10 PMID: 23433739
  12. Hoster E, Dreyling M, Klapper W et al A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008 Jan 15;111(2):558-65. Epub 2007 Oct 25 PMID: 17962512
  13. Tam CS, Anderson MA, Pott C et al Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med 2018; 378:1211-1223. March 29, 2018 PMID: 29590547 http://www.nejm.org/doi/full/10.1056/NEJMoa1715519
  14. Otto MA FDA Approves Tablet Formulation of Acalabrutinib (Calquence) for CLL, SLL, and MCL. Medscape. Aug 5, 2022 https://www.medscape.com/viewarticle/978732
  15. Ingram I Ibrutinib Makes Its Case for First-Line Treatment in Mantle Cell Lymphoma. Standard-of-care autologous transplant fails to prove superior to BTK inhibitor alone. MedPage Today December 11, 2022 https://www.medpagetoday.com/meetingcoverage/ashhematology/102185
  16. Hoster E et al. Predictive value of minimal residual disease for efficacy of rituximab maintenance in mantle cell lymphoma: Results from the European Mantle Cell Lymphoma Elderly Trial. J Clin Oncol 2023 Nov 22; [e-pub]. PMID: 37992261 https://ascopubs.org/doi/10.1200/JCO.23.00899

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