Due to the diversity of disease presentation, together with new iterations of guidelines for MCL diagnosis, staging, and risk, there is no standardized therapeutic approach. Treatment decisions are currently guided by several factors, including patient age, level of fitness, presence of symptoms, risk category, proliferative index, and cell variant, which means it is important to accurately diagnose, stage, and assess risk in patients with MCL
Epidemiology and Risk Factors
MCL has a reported incidence of approximately 0.5 to 2 per 100,000 individuals.7-9Most patients with MCL are older: Their median age at diagnosis is between 60 and 70 years.2The disease is 2 to 7 times more common in men than in women and is 2 times more common in Caucasians than in African Americans.2An increased risk of MCL is associated with certain autoimmune disorders, family history of hematopoietic malignancy, and Borrelia burgdorferi infection.7,10,11
In 2016, the World Health Organization revised the classification of lymphoid neoplasms, recognizing 2 types of MCL: classical MCL and leukemic non-nodal MCL.12,13Classical MCL is usually composed of IGHV-unmutated B cells and SOX11 expression and involves lymph nodes and extranodal sites.14Leukemic non-nodal MCL is generally composed of IGHV-mutated genes without SOX11 expression and involves the bone marrow, peripheral blood, and spleen; leukemic non-nodal MCL also typically has an indolent presentation.
Several molecular risk factors, including SOX11, SOCS3, and defects in the B-cell receptor (BCR) signaling pathway, have been implicated in the etiology and prognosis of MCL.7In a study by Fernandez et al,15 patients with SOX11-negative tumors had significantly improved outcomes compared with SOX11-positive tumors (5-year overall survival [OS], 78% vs 36%, respectively; P = .001). However, the authors noted that SOX11 expression alone should not be used to assess risk because most patients with MCL have SOX11-positive tumors. In the study, patients with indolent MCL were characterized by non-nodal disease, splenomegaly, leukocytosis, and lower Ki-67 in addition to SOX11 negativity, identifying a subset of patients who could be observed.
SOCS3 suppresses cytokine signaling pathways, including those of STAT3 and NF-kB.7A study by Ommoleila Molavi, MD, and colleagues correlated the expression of SOCS3 and OS in 33 randomly chosen patients with MCL.16Patients with SOCS3-negative tumors showed a trend toward a borderline signi cantly worse outcome (P = .1).
Genetic alterations in the BCR signaling pathway are thought to also play a role in the pathogenesis of MCL and have become an important target in therapeutic development.7,17,18A study by Mohand-Akli Boukhiar, MD, and colleagues19on MCL lymphocytes provides evidence for the role of the BCR signaling pathway in MCL cell survival. These study findings are consistent with the substantial progress achieved in MCL treatment through therapies targeting the BCR-associated kinases.17
Cytogenetics of MCL
MCL is characterized genetically by the chromosomal translocation t(11;14)(q13;q32), which is found to be present in most cases of MCL and leads to overexpression of cyclin D1 and deregulation of the cell cycle.5,7,20,21A review of 214 MCL cases showed that t(11;14)(q13;q32) was identified in 53 of 78 cases submitted for cytogenetic analysis.22In an evaluation of mature malignant MCL cells, including different hematopoietic lineages, t(11;14(q13;q32) was present in 97% (range, 84%-100%) of sorted MCL cells.23
Diagnostic Testing in MCL
The differential diagnosis of MCL includes small lymphocytic leukemia, marginal zone lymphoma, and follicular lymphoma.24MCL is typically diagnosed by blood phenotype or biopsy of a lymph node, tissue, or bone marrow demonstrating the classical cytologic appearance of a monomorphic proliferation of small to medium lymphoid cells with irregular nuclear contours and unapparent nucleoli.10,24,25The diagnosis of MCL is confirmed with the detection of cyclin D1 overexpression by immunohistochemistry (IHC), as seen in 98% of cases,24or with detection of the t(11;14) (q13;32) translocation by molecular or cytogenetic methods.
The immunophenotype of MCL, which is characterized by the detection of cyclin D1+, CD5+, CD19+, CD20+, CD22+, CD23-/+, and CD10-/+, helps to establish diagnosis and differentiate MCL from other NHL subtypes.25-27 Other speci c markers for MCL include SOX11, NOTCH1/2, and ATM, among others.2,28,29 NOTCH1/2 mutations, which are present in 5% to 10% of patients with MCL, are associated with aggressive clinical behavior, including an association with poor OS.6
The Ann Arbor staging classification remains the optimal available method for anatomic staging of NHL and has been universally adopted.30Divided 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.10Extended definitions were later added by the Cotswold modi cations (Table 1).30
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.31The 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.5,6The 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.32To 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).33Encoded 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.7Several morphologic variants of MCL have been described, including small round (resembling chronic lymphocytic leukemia), marginal zone‒like, blastoid, and pleomorphic cells.9The 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.34Beta-2 microglobulin is necessary for the cell surface expression of major histocompatibility complex (MHC) class I and the stability of the peptide-binding groove.7Although elevated beta-2 microglobulin has been associated with poor OS,34the prognostic value of this biomarker and others remains controversial.35According 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
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).36The 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.37The 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