Mantle Cell Lymphoma (MCL)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    facultative
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative

Mantle cell lymphomas (MCL) account for approximately 3-10% of all non-Hodgkin lymphomas. The median age at diagnosis is about 60 years. Men develop the disease more than twice as often as women. The MIPI (MCL International Prognostic Index) has been established as a clinical risk score. The MIPI is based on parameters such as general health, age of the patient, LDH and leukocyte values. By using the MIPI, patients with mantle cell lymphoma can be divided into three risk groups: low, intermediate and high. As an additional parameter, the index of the proliferation marker Ki-67 can be used, which is considered a risk factor in its own right. In combination, the MIPI and Ki-67 index form the MIPI-c (combined MIPI) for risk assessment. Genetically, mantle cell lymphoma can be characterized by CCND1 translocations, classically t(11;14)(q13;32), leading to overexpression of cyclin D1 (CCND1) (Hoster et al. 2008, Hoster et al. 2016, Swerdlow et al. 2017).

Classification of mantle cell lymphoma

Mantle cell lymphoma (MCL) is classically a B-cell neoplasm with indolent to aggressive courses that develops linearly from naïve B cells. Indolent variants include leukemic non-nodal mantle cell lymphoma and in situ mantle cell neoplasia (ISMCN).  According to the new 2017 WHO classification (Swerdlow et al. 2017), mantle cell lymphoma (MCL) is divided into two subtypes according to clinicopathologic features and underlying pathogenic pathways:

  • Classical mantle cell lymphoma with unmutated/minimally mutated IGHV and SOX11-positive.

  • Non-nodal mantle cell lymphoma with mutated IGHV and SOX11- negative 

SOX11-negative mantle cell lymphoma is the much rarer variant and accounts for approximately 14%-32% of mantle cell lymphoma. Genetically, this form of mantle cell lymphoma is more stable than SOX11-positive MCL. The SOX11 gene encodes the transcription factor SOX11, which is not expressed in normal B cells and in mantle cell lymphoma influences B cell differentiation, proliferation, and apoptosis, among other functions (Cheah et al. 2016, Martin 2018, Puente et al. 2018).


Classical vs. non-nodal mantle cell lymphoma

In the pathogenesis of classical mantle cell lymphoma, progenitor B cells, in which a CCND1 rearrangement is usually present, mature into naïve B cells with genetic abnormalities that initially settle in the inner region of the mantle zone of lymphoid tissue and usually have no or minimal IGHV mutations and are SOX11-positive. Without transit through the germinal center, classic  mantle cell lymphoma affects both lymph nodes and extranodal sites. During progression, blastic and pleomorphic variants of mantle cell lymphoma may develop (see Cytomorphology). A commonly aberrant gene is TP53 (localized to 17p13), which encodes a tumor suppressor protein and is involved in a number of processes including apoptosis and cell differentiation. Abnormalities of this gene are typical of genetically unstable diseases. Reduced expression of wild-type TP53 and expression of mutant TP53 result in loss of growth-limiting function of the gene. Abnormalities of TP53 are associated with lower response to therapies as well as shortened overall survival, with mutations having even greater relevance here than deletions (Greiner et al. 1996, Dreyling et al. 1997, Greiner et al. 2006, Halldórsdóttir et al. 2011, Eskelund et al. 2017, Swerdlow et al. 2017).

17p deletions leading to TP53 gene loss and TP53 mutations are found in both classical and non-nodal mantle cell lymphoma. Biallelic inactivation can occur when mutation and deletion are present simultaneously; this is also observed in both subtypes (Clot et al. 2018, Nadeu et al. 2020).

Leukemic non-nodal mantle cell lymphoma differs from classical mantle cell lymphoma in the absence of significant adenopathy. The neoplastic cells of non-nodal MCL are usually small, resemble those of chronic lymphocytic leukemia (CLL), are SOX11 negative, and have somatic IG hypermutations that presumably arise during germinal center transit. Non-nodal mantle cell lymphoma often involve the peripheral blood, bone marrow, or spleen. They are genetically more stable and have few additional aberrations to the CCND1 translocation, del(17p), and TP53 mutations. Prognosis for overall survival is generally better than for classic mantle cell lymphoma (median survival 68 months), with a median survival of 79 months, and the time to initial therapy is also longer. However, non-nodal mantle cell lymphoma can also evolve into aggressive disease, which is often associated with the presence of TP53 mutations or other oncogenic abnormalities (Swerdlow et al. 2017, Clot et al. 2018, Maddocks 2018, Sander 2020). In clinical practice, distinguishing between the two subtypes is challenging despite the different abnormalities (Martin 2018).

Fig. 1: Distinction between classical and non-nodal mantle cell lymphomas (modeled after Sander 2020).

Classical MCL typically show high SOX11 expression, mutations of the ATM and TP53 genes, copy number gains of 3q, and copy number losses of 13q and 1p. Non-nodal MCL typically show no or low SOX11 expression, mutations of the CCND1 and TP53 genes, and copy number losses of 17p.


In Situ Mantle Cell Neoplasms

In addition to classic and non-nodal MCL, there are in situ mantle cell neoplasms characterized by the presence of CCND1-positive lymphoma cells, with the presence of CCND1 rearrangements restricted to cells in the mantle zone of otherwise hyperplastic lymphoid tissue. CCND1-positive cells are typically found in the inner mantle zone. Compared with classic MCL, in situ mantle cell neoplasms are more often CD5-negative. Both SOX11-positive and SOX11-negative cases have been reported, with the latter being much less common. In situ mantle cell neoplasms often show an indolent course, but in rare cases can also develop into mantle cell lymphomas (Swerdlow et al. 2017).

Diagnostics of mantle cell lymphoma

Prognosis

Patients with a TP53 deletion (17p deletion) or a CDKN2A deletion (9p deletion) have a less favorable prognosis independent of the proliferation marker Ki-67 and the risk score MIPI (Rubio-Moscardo et al. 2005, Salaverria et al. 2007, Sander et al. 2008). Eskelund et al. demonstrated that patients with age less than 65 years and TP53 mutation have significantly reduced overall survival and progression-free survival compared with patients with TP53 deletion or without TP53 abnormalities, as well as a significantly increased risk of recurrence. In addition, TP53 mutations appear to be frequently associated with blastoid morphology, Ki67 scores of > 30%, high MIPI score, and high MIPI-c risk (Eskelund et al. 2017). When TP53 and CDKN2A deletion occur simultaneously, there is an additive prognostically unfavorable effect. The prognosis of patients with heterozygous CDKN2A deletion does not differ from patients with homozygous CDKN2A deletion (Delfau-Larue et al. 2015).

Mutations of NOTCH1/2 are associated with an aggressive clinical course and occur in approximately 5-10% of mantle cell lymphoma (Cheah et al. 2016).

The proliferation marker Ki-67 also serves as an independent prognostic marker. An increased rate of Ki-67-positive tumor cells is associated with shorter overall survival and progression-free survival (Hoster et al. 2016).

While non-nodal mantle cell lymphoma generally has a more favorable prognosis than classical mantle cell lymphoma (see also Classification), the survival benefit was found to be strongly dependent on the number of copy number alterations (CNA). Here, more than 6 CNA in both classical and non-noda mantle cell lymphoma lead to significantly shorter overall survival compared to a number of 0-5 CNA (Clot et al. 2018). This may also have relevance for the treatment of patients in the future (Martin 2018).


Calculation of prognosis

Click here for the prognosis calculation of the MIPI score.

Therapy

Response to standard chemotherapy and autologous stem cell therapy may be influenced by molecular mutations. Patients with an age below 65 years and TP53 mutation were less likely to achieve complete remission after induction chemotherapy or autologous stem cell therapy in a study by Eskelund et al. Therefore, mutation status may play a role in treatment decisions (Eskelund et al. 2017). When choosing therapy, both chemotherapies and non-chemotherapies or combinations may be considered, and their respective benefits should be assessed in context with mutation status (Martin et al. 2017). According to the current Onkopedia guideline on mantle cell lymphoma, patients with indolent lymphomas should be treated in the setting of clinical trials whenever possible. This is especially true for patients with a high burden of copy number alterations (Martin 2018).

Recommendation

According to the current Onkopedia guideline on mantle cell lymphoma, in addition to the collection of clinical and laboratory parameters from peripheral blood (cell count, differential blood count, reticulocyte ESR, electrophoresis, total protein, GOT, GPT, AP, γ-GT, bilirubin, creatinine, uric acid, blood glucose, LDH, β²-microglobulin, Quick value, PTT) a cytological and histological examination of the bone marrow is recommended, in case of leukemic course also FACS analysis of surface markers from peripheral blood.

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