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Diagnosis, Staging, and Risk in MCL

Published Online: Mar 14,2018
Epidemiology and Risk Factors

MCL has a reported incidence of approximately 0.5 to 2 per 100,000 individuals.7-9 Most patients with MCL are older: Their median age at diagnosis is between 60 and 70 years.2 The 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.2 An 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.12,13 Classical MCL is usually composed of IGHV-unmutated B cells and SOX11 expression and involves lymph nodes and extranodal sites.14 Leukemic 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.7 In 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.7 A study by Ommoleila Molavi, MD, and colleagues correlated the expression of SOCS3 and OS in 33 randomly chosen patients with MCL.16 Patients 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.7,17,18 A study by Mohand-Akli Boukhiar, MD, and colleagues19 on 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.5,7,20,21 A review of 214 MCL cases showed that t(11;14)(q13;q32) was identified in 53 of 78 cases submitted for cytogenetic analysis.22 In 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.24 MCL 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.10,24,25 The diagnosis of MCL is confirmed with the detection of cyclin D1 overexpression by immunohistochemistry (IHC), as seen in 98% of cases,24 or with detection of the t(11;14) (q13;32) translocation by molecular or cytogenetic methods.


 

Immunophenotypic Variants

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




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Diagnosis, Staging, and Risk in MCL
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