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Diagnosis, Staging, and Risk in MCL

Published Online: Mar 14,2018

The Ann Arbor staging classification remains the optimal available method for anatomic staging of NHL and has been universally adopted.30 Divided into 4 stages of disease, this approach reflects both the number of sites of involvement and the presence of disease above and/or below the diaphragm.10 Extended definitions were later added by the Cotswold modi cations (Table 1).30


Risk Assessments

In 2008, the Mantle Cell Lymphoma International Prognostic Index (MIPI) was created by the European Mantle Cell Lymphoma Network to stratify risk in patients with advanced-stage MCL.31 The MIPI is used to predict survival outcomes for patients with MCL and attempts to account for the heterogeneity of the disease by considering several patient characteristics. The MIPI incorporates measures of chemotherapy tolerance (eg, age and Eastern Cooperative Oncology Group performance status) and indirect measures of disease activity (eg, serum lactate dehydrogenase and white blood cell count) to stratify patients into low-risk, intermediate-risk, and high-risk groups.5,6 The MIPI has been validated in patients receiving frontline therapy with or without autologous stem cell transplant.1

“[To] effectively tailor the therapeutic approach according to the individual patient’s risk profile, reliable prognostic tools applicable in clinical routine are mandatory. The ideal prognosticator should integrate clinical and biological features, taking into account the recent knowledge of molecular pathogenesis,” commented Martin Dreyling, MD, PhD, and Simone Ferrero, MD, on behalf of the European MCL Network, in a review article in Haematologica.32 To address the biological heterogeneity of MCL, a modi cation of the MIPI score, known as MIPI-c (MIPC-combined), adds the Ki-67 proliferative index, when available (Table 2).33 Encoded by the MKI67 gene, Ki-67 is a nuclear antigen expressed by dividing cells. Immunohistochemistry staining for Ki-67 is highly recommended as a strong prognostic indicator of long-term outcomes in patients with MCL.6,25

In additional to Ki-67, other prognostic factors have been identified, including cell type and beta-2 microglobulin.7 Several morphologic variants of MCL have been described, including small round (resembling chronic lymphocytic leukemia), marginal zone‒like, blastoid, and pleomorphic cells.9 The blastoid and pleomorphic variants are associated with more aggressive clinical behavior.20

Serum beta-2 microglobulin has also been suggested as a potential prognostic factor for MCL.34 Beta-2 microglobulin is necessary for the cell surface expression of major histocompatibility complex (MHC) class I and the stability of the peptide-binding groove.7 Although elevated beta-2 microglobulin has been associated with poor OS,34 the prognostic value of this biomarker and others remains controversial.35 According to Chan Yoon Cheah, MBBS, and colleagues, “Established prognostic factors will evolve as molecular analyses move into routine diagnostic laboratories and targeted agents are incorporated into frontline treatment strategies.”6



Response Criteria

First published in 1999 and revised in 2007, the International Working Group response criteria for malignant lymphoma incorporated PET, IHC, and ow cytometry to standardize de nitions of response (Table 3).36 The standardization of the response criteria aimed to provide uniform endpoints for clinical trials, allow for comparisons between studies, facilitate the identification of more effective therapies, and aid in the approval process for new agents by regulatory agencies.

Originally established in 2011 and revised in 2014, the Lugano classification provides recommendations for the initial evaluation, staging, and response assessment of Hodgkin lymphoma and NHLs.37 The overarching goals identified for the 2014 revision were to improve the evaluation of patients with lymphoma and enhance the ability to compare outcomes of clinical trials. The Lugano classification was most recently updated in 2016 to modify response criteria in the context of lymphoma immunomodulatory therapies (Table 4).38
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  2. Bhatt VR, Valdes RF, Vose JM. Chapter 81: mantle cell lymphoma. In: Hoffman R, Benz Jr EJ, Silberstein LE, et al, eds. Hematology: Basic Principles and Practice. Philadelphia, PA: Elsevier; 2018.
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  9. Dreyling M, Campo E, Hermine O, et al; ESMO Guidelines Committee. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv62-iv71. doi: 10.1093/annonc/mdx223.
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  12. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. doi: 10.1182/blood-2016-01-643569.
  13. Fakhri B, Kahl B. Current and emerging treatment options for mantle cell lymphoma. Ther Adv Hematol. 2017;8(8):223-234. doi: 10.1177/2040620717719616.
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  15. Fernandez V, Salamero O, Espinet B, et al. Genomic and gene expression pro ling de nes indolent forms of mantle cell lymphoma. Cancer Res. 2010;70(4):1408-1418. doi: 10.1158/0008-5472.CAN-09-3419.
  16. Molavi O, Wang P, Zak Z, Gelebart P, Belch A, Lai R. Gene methylation and silencing of SOCS3 in mantle cell lymphoma. Br J Haematol. 2013;161(3):348-356.doi: 10.1111/bjh.12262.
  17. Bernard S, Danglade D, Gardano L, et al. Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma. Int J Cancer. 2015;136(12):2761-2774. doi: 10.1002/ijc.29326.
  18. Fichtner M, Dreyling M, Binder M, Trepel M. The role of B cell antigen receptors in mantle cell lymphoma. J Hematol Oncol. 2017;10(1):164.doi: 10.1186/s13045-017-0533-9.
  19. Boukhiar MA, Roger C, Tran J, et al. Targeting early B-cell receptor signaling induces apoptosis in leukemic mantle cell lymphoma. Exp Hematol Oncol. 2013;2(1):4. doi: 10.1186/2162-3619-2-4.
  20. Gao J, Peterson L, Nelson B, Goolsby C, Chen YH. Immunophenotypic variations in mantle cell lymphoma. Am J Clin Pathol. 2009;132(5):699-706. doi: 10.1309/AJCPV8LN5ENMZOVY.
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  22. Au WY, Gascoyne RD, Viswanatha DS, Connors JM, Klasa RJ, Horsman DE. Cytogenetic analysis in mantle cell lymphoma: a review of 214 cases. Leuk Lymphoma. 2002;43(4):783-791. doi: 10.1080/10428190290016890.
  23. Vorobyev V, Gretsov E, Obukhova T, et al. T(11;14)(q13;q32) in mantle cell lymphoma patients is present only on mature malignant cells. Fluorescence-activated cell sorting and uorescence in situ hybridization analysis. Blood. 2011;118(12; abstr 4405). bloodjournal.org/content/101/12/4975?sso-checked=true.
  24. Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-strati cation, and clinical management. Am J Hematol. 2017;92(8):806-813. doi: 10.1002/ajh.24797.
  25. Dreyling M, Ferrero S, Hermine O. How to manage mantle cell lymphoma. Leukemia. 2014;28(11):2117-2130. doi: 10.1038/leu.2014.171.
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  27. Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). B-cell Lymphomas. Version 7.2017. www.nccn.org/ professionals/physician_gls/pdf/b-cell.pdf. Published December 5, 2017. Accessed February 12, 2018.
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  33. Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results rrom randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34(12):1386-1394. doi: 10.1200/JCO.2015.63.8387.
  34. Yoo C, Yoon DH, Kim S, et al. Serum beta-2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma. Hematol Oncol. 2016;34(1):22-27. doi: 10.1002/hon.2188.
  35. Wang XL, Wang XL, He S, Zhai HL. Association of beta2-microglobulin with the prognosis of non-Hodgkin’s lymphoma: a meta analysis. Int J Clin Exp Med. 2015;8(3):3992-3999.
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Diagnosis, Staging, and Risk in MCL
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