Diagnostics

Mantle Cell Lymphoma (MCL)

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Cytomorphology
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Immunophenotyping
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Chromosome analysis
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FISH
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Molecular genetics
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Classification
Diagnostic methods
Prognosis
Therapy
Recommendation

Based on the current guidelines and the current state of research, there are different diagnostic recommendations for patients with mantle cell lymphoma. We have summarized the most important information on classification and diagnostic methods at the MLL. In addition, we provide further links on prognosis and therapy in mantle cell lymphoma, so that you can inform yourself in more detail.

Mantle cell lymphoma: Classification

Mantle cell lymphoma (MCL) is classically a mature B-cell neoplasia with indolent to aggressive courses. Characteristic is the chromosomal translocation t(11;14)(q13;q32) (IGH::CCND1) with overexpression of cyclin D1, which is present in more than 95% of cases. According to WHO, mantle cell lymphoma (MCL) is subdivided into the following subtypes depending on clinicopathologic features and underlying pathogenic pathways, as shown in Figure 1 (WHO 2022):

In situ mantle cell neoplasm (ISMCN)
Mantle cell lymphoma (MCL)
Leukaemic non-nodal mantle cell lymphoma (nnMCL)

Figure 1: Schematic representation of the defined mantle cell lymphoma subtypes (modeled after WHO 2022)

ISMCN are mostly indolent and usually incidental findings in lymph nodes. B cells are present in the mantle zone of the lymphoid follicle and show CCND1 overexpression due to the IGH::CCND1 fusion. ISMCN rarely develop into MCL (<10%) (WHO 2022).

Classic MCL derives from naive-like mature B cells. The IGH::CCND1 fusion is present in >95% of MCL. MCL typically show high SOX11 expression, mutations of the genes ATM and TP53, copy number gains of 3q, and copy number losses of 13q and 1p. Patients usually have generalized lymphadenopathy and an unfavorable course (Nadeu et al. 2020, WHO 2022).

IGH::CCND1 fusion is also present in nnMCL arising from memory-like B cells. They are characterized by involvement of peripheral blood, bone marrow, and spleen with little or no lymphadenopathy and a usually asymptomatic clinical presentation. nnMCL typically show no or low SOX11 expression and fewer genetic aberrations than classic MCL (Nadeu et al. 2020, WHO 2022). SOX11-negative MCL are the much rarer variant and account for approximately 14%-32% of MCL (Cheah et al. 2016).

Mantle cell lymphoma: Diagnostic methods

In diagnostics, assessment of the blood and bone marrow smear provides an initial landmark statement as to whether lymphoma washout exists or is possible. In addition, cytomorphology and histology are useful for assessing the degree of maturity of mantle cell lymphomas.

According to the WHO classification of 2022, there are clinically aggressive morphologic variants of MCL, which include the blastic and pleomorphic variants. High proliferation rates are characteristic of both variants. The lymphoma cells of the pleomorphic variant are larger than those of classic MCL, and the shape of the nucleus and chromatin structure resemble those of diffuse large B-cell lymphoma (DLBCL). In addition, the cytoplasm is usually pale and the nucleus contours are irregular. The blastic variant resembles lymphoblasts and shows roundish nuclei, a high mitotic rate, a narrow cytoplasmic rim, and scattered chromatin (Dreyling et al. 2018, WHO 2022).

In addition, cytomorphology reveals small-cell MCL and marginal zone-like MCL as further variants (WHO 2022).

In the case of lymphomas, such as mantle cell lymphoma, immunophenotyping allows clear determination of lineage affiliation to the T or B lineage, or precise differentiation of lymphomas. Furthermore, multiparametric flow cytometry is often indispensable for differentiating a reactive change from a lymphoid neoplasia, e.g. in EBV infections.

Mantle cell lymphomas express CD5 and are usually negative for CD23 in contrast to B-CLL. Table 1 shows characteristic findings in mantle cell lymphoma.

Table 1: Immunophenotyping in mantle cell lymphoma (Béné et al. 2011)

Antigen	Finding
CD19	+
CD20	+
CD22	+
CD23	-
CD25	-
FMC7	+(-)
CD79b	+
CD5	+
sIg	+
CD10	-
CD11c	-
CD103	-
CD43	+

Characteristic in mantle cell lymphoma is the translocation t(11;14)(q13;q32) leading to an IGH::CyclinD1 (CCND1) rearrangement. Instead of an IGH::CCND1 rearrangement, variants also occur in which the light chains of the immunoglobulins IGK or IGL are involved in a rearrangement with CCND1. Beyond that, rearrangements involving CCND2 (12p13) or CCND3 (6p21) occur very rarely. Frequently, additional, sometimes complex cytogenetic aberrations are found (Espinet et al. 2010, Cohen 2017, WHO 2022):

Balanced translocations: t(11;14)(q13;q32)/IGH::CCND1, t(2;11)(p11;q13)/IGK, t(11;22)(q13;q11)/IGL
rarer: t(8;14)(q24;q32)/IGH::MYC, 3q27/BCL6 rearrangements

Gains: 3q, 7p, 8q, 11q, trisomy 12, 13q, 15q, 18q, tetraploid sets of chromosomes

Losses: 1p, 2q, 6q, 8p, 9p, 9q, 10p, 11q, 13q, 17p, 19p, Y

With the help of FISH analysis, chromosomal regions with genetic alterations can be detected, such as the characteristic IGH::CCND1 translocation, whereby FISH analysis can help to confirm the diagnosis (Espinet et al. 2010). Additional alterations can often be detected in chromosomal regions where the genes ATM (11q22-q23), CDKN2A (9p21), or TP53 (17p13), among others, are located (Sander et al. 2008). TP53 and CDKN2A deletions are associated with an unfavorable prognosis, with an additive prognostically unfavorable effect when both deletions occur (Delfau-Larue et al. 2015).

At the molecular level using an RNA-based assay, mantle cell lymphoma is best confirmed by measuring cyclinD1 (CCND1) overexpression. In addition, at the genomic DNA level, detection of the IGH::CCND1 rearrangement (also IGH::BCL1 rearrangement) is possible. However, due to the heterogeneity of breakpoints, only about 40% of all IGH::CCND1 rearrangements can be detected by PCR (Belaud-Rotureau et al. 2002).

Analysis of SOX11 overexpression is a factor to differentiate conventional MCL (SOX11+) from non-nodal MCL (SOX11-). The prognostic relevance of SOX11 overexpression is currently controversial (Wang et al. 2008, Fernàndez et al. 2010, Nygren et al. 2012, Meggendorfer et al. 2013).

Some patients have clinically relevant mutations in the genes ATM, TP53, or NOTCH1/2. ATM (40-75%) and CCND1 (35%) represent the most frequently affected gene loci (Beà et al. 2013, WHO 2022). In 18% of patients with mantle cell lymphoma, a mutation in exon 58 of the UBR5 gene is additionally detected (Meissner et al. 2013). MYC translocations and TP53 mutations are frequently associated with disease progression (WHO 2022).

Mantle cell lymphoma: Prognosis

Prognostically unfavorable markers include TP53 deletions and mutations, CDKN2A deletions, NOTCH1/2 mutations, and Ki-67. TP53 mutations have an even worse impact on prognosis compared to TP53 deletions (Rubio-Moscardo et al. 2005, Salaverria et al. 2007, Sander et al. 2008, Cheah et al. 2016, Hoster et al. 2016, Eskelund et al. 2017). Age, poor general health, advanced disease stage (Ann Arbor stage III or IV), splenomegaly and anemia, serum levels of β2-microgloblulin and LDH, blastoid cytology, extranodal presentation, and constitutional symptoms are among important clinical and serologic factors associated with an unfavorable course (Silkenstedt & Dreyling 2023).

The MIPI (MCL International Prognostic Index) is established as a clinical risk score. In combination, the MIPI and Ki-67 index form the MIPI-c (combined MIPI) for risk assessment (Hoster et al. 2008, Hoster et al. 2016). Click here for the prognosis calculation of the MIPI and the MIPI/MIPI-c.

Mantle cell lymphoma: Therapy

The choice of therapy should be made in the context of the mutation status (Martin et al. 2017). According to the current Onkopedia guideline on mantle cell lymphoma, which also provides detailed information on therapeutic strategies, patients with MCL should be treated in the context of clinical trials whenever possible. This is especially true for patients with a high burden of copy number alterations (Martin 2018).

Mantle cell lymphoma: Recommendation

According to the current Onkopedia guideline on mantle cell lymphoma, besides the collection of clinical and laboratory parameters from peripheral blood, cytological and histological examination of bone marrow is recommended, and in case of leukemic course, immunophenotyping of surface markers from peripheral blood is also recommended.

Beà S et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc. Natl. Acad. Sci. U S. A 2013;110(45):18250-18255.

Belaud-Rotureau MA et al. A comparative analysis of FISH, RT-PCR, PCR, and immunohistochemistry for the diagnosis of mantle cell lymphomas. Mod. Pathol 2002;15(5):517-525.

Béné MC et al. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10. Leukemia 2011;25(4):567-574.

Cheah CY et al. Mantle Cell Lymphoma. J Clin Oncol 2016;34(11):1256-1269.

Cohen JB. TP53 mutations in MCL: more therapy is not better. Blood 2017;130(17):1876-1877.

Delfau-Larue MH et al. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood 2015;126(5):604-611.

Dreyling M et al. Blastoid and pleomorphic mantle cell lymphoma: still a diagnostic and therapeutic challenge! Blood 2018;132(26):2722-2729.

Eskelund CW et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood 2017;130(17):1903-1910.

Espinet B et al. Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma. Genes Chromosomes Cancer 2010;49(5):439-451.

Fernàndez V et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 2010;70(4):1408-1418.

Hoster E et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 2008;111(2):558-565.

Hoster E et al. Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network. J Clin Oncol 2016;34(12):1386-1394.

Martin P. A tale of two mantle cell lymphomas. Blood 2018;132(4):347-348.

Martin P et al. The potential for chemotherapy-free strategies in mantle cell lymphoma. Blood 2017;130(17):1881-1888.

Meggendorfer M et al. SOX11 overexpression is a specific marker for mantle cell lymphoma and correlates with t(11;14) translocation, CCND1 expression and an adverse prognosis. Leukemia 2013;27(12):2388-2391.

Meissner B et al. The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma. Blood 2013;121(16):3161-3164.

Nadeu F et al. Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes. Blood 2020;136(12):1419-1432.

Nygren L et al. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood 2012;119(18):4215-4223.

Onkopedia Leitlinie „Mantelzell-Lymphom“ 2023; DGHO 2023.

Rubio-Moscardo F et al. Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood 2005;105(11):4445-4454.

Salaverria I et al. Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature. J Clin Oncol 2007;25(10):1216-1222.

Sander S et al. Genomic aberrations in mantle cell lymphoma detected by interphase fluorescence in situ hybridization. Incidence and clinicopathological correlations. Haematologica 2008;93(5):680-687.

Silkenstedt E, Dreyling M. Mantle cell lymphoma-Update on molecular biology, prognostication and treatment approaches. Hematol Oncol 2023;41 Suppl 1(36-42).

Wang X et al. The subcellular Sox11 distribution pattern identifies subsets of mantle cell lymphoma: correlation to overall survival. Br J Haematol 2008;143(2):248-252.

WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chapters/63.

Status: September 2023

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Mantle Cell Lymphoma (MCL)

Mantle cell lymphoma: Classification

Mantle cell lymphoma: Diagnostic methods

Cytomorphology

Immunophenotyping

Table 1: Immunophenotyping in mantle cell lymphoma (Béné et al. 2011)

Chromosome analysis

Fluorescence in situ hybridisation (FISH)

Molecular genetics

Mantle cell lymphoma: Prognosis

Mantle cell lymphoma: Therapy

Mantle cell lymphoma: Recommendation

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