see also:

• lymphoma
• Fact sheet (pdf)
• LLS Fact sheet (pdf)
• Int J Molecular Sciences 2019 review article (pdf)

• accounts for ~7% of non-Hodgkin lymphoma (NHL) cases
• most patients are aged over 50yrs (men have 2-7x risk)
• so-called because the tumour cells originally come from the “mantle zone” (the outer edge) of the lymph node
• 85% have a characteristic chromosomal translocation in the B-cells where two chromosomes 11 and 14 break and join together with each other resulting in over-expression of cyclin D1 and the dysregulation of the cell cycle

• increased risk of MCL is associated with:
  • certain autoimmune disorders
  • FH of haematopoietic malignancy
  • Borrelia burgdorferi infection (Lyme disease)

• 2 main types of MCL¹⁾:
  • classical nodal MCL
    • 80-90% of cases
    • usually composed of IGHV-unmutated B cells and SOX11 expression and involves lymph nodes and extranodal sites
    • high degree of genomic instability and generally aggressive behaviour
    • the cell of origin is believed to be a naïve, pre-germinal B-cell with the t(11;14) translocation which then is thought to sequentially undergo further mutations of ATM deletion (in 40-50%), then de novo SOX11 expression (this is the main factor preventing these cells from entering into germinal centre reactions), then secondary lesions (eg. TP53).
      • development of nodal MCL aggressiveness dependent upon further oncogenic mutations (eg. MYC, CDKN2A, NSD2) which add to the cyclin D1 over-expression mediated cell cycle deregulation
      • virtually all MCL primary cells over-express B-cell lymphoma 2 (BCL2) protein which has important anti-apoptotic properties
  • leukaemic non-nodal MCL
    • 10-20% of cases
    • generally composed of IGHV-mutated genes without SOX11 expression and involves the bone marrow, peripheral blood, and spleen;
    • typically has an indolent presentation
    • cell of origin is thought to be a memory B-cell with germinal center experience
• 3 main histologic types
  • classical
  • pleomorphic
  • blastoid
• transformations
  • classical type may transform into blastoid type
  • chronic lymphocytic leukemia (CLL) may transform into blastoid type MCL (MCL-variant Richter transformation)

• asymptomatic with incidental lymphadenopathy found on CXR or CT scans
• splenomegaly (30-50% of cases at presentation)
• peripheral blood leukemization (B cells entering the circulation)
• extranodal involvement - especially GIT (40-50% at diagnosis)
• CNS involvement, usually leptomeningeal disease (<5% at diagnosis)

• clinical behavior directly or indirectly correlates with the genetic background of the disease (see under types)
• some are indolent, but most are fast growing and have the worst prognosis of the B-cell lymphomas
• aggressiveness may be determined by degree of circulating levels of LDH and beta-2 microglobulin
• 5% to 10% have NOTCH1/2 mutations, which are associated with aggressive clinical behavior, including an association with poor OS
• patients with indolent MCL were characterized by non-nodal disease, splenomegaly, leukocytosis, and lower Ki-67 in addition to SOX11 negativity ²⁾
• majority of people with MCL have stage IV disease at diagnosis
• often causes splenomegaly and may spread to other organs in the body, including the bone marrow, spleen, liver, stomach and bowel as well as CNS.
• may cause B symptoms

• often found as incidental lymphadenopathy on CT scans but may present in advanced stages with or without B symptoms
• diagnosis is confirmed by LN excision and biopsy
  • fine needle biopsy is often done first but may give false negative or erroneous NHL types
  • confirmation of overexpression of cyclin D1 and translocation t (11,14) by fluorescence in situ hybridization (FISH)

• full body CT and PET scans
  • CT scans may show lymphadenopathy of other causes
  • PET scan is required to confirm lymphoma involvement - 2-deoxy-2-fluoro-D-glucose (FDG)-avid lymphoma is revealed in the vast majority of cases
• echocardiogram
• colonoscopy to exclude bowel involvement
• general blood workup including lactic dehydrogenase (LDH) to help assess tumour load
• specific lymphoma analysis workup to determine genetic types etc.
  • flow cytometry usually confirms the presence of MCL clone with typical immunophenotype (CD20+, CD5+, CD22+, CD79b+, FMC-7+, CD23−, CD200−)

• Stage 1: single LN region or lymphoid structure (eg spleen, thymus)
• Stage 2: more than 1 LN region on the same side of the diaphragm
• Stage 3: both sides of diaphragm involved
• Stage 4: extranodal sites beyond sites that are contiguous with or proximal to the LN region involved
• Presence of B symptoms adds to the stage category

• cures are still rare although advances in Rx have significantly improved survival duration
• indolent non-nodal MCL without B symptoms, cytopenia, etc may not require Rx for years
• most though are aggressive and require Rx
• treatment is partly based upon whether patient is fit enough to tolerate high-dose therapy (HDT eg. MAXI-CHOP) and marrow transplant (ASCT), or not fit enough, and are thus given lower dose therapy
• recommendations seem to be all patients should be treated with rituximab maintenance (RM), usually every 2–3 months for 2–3 years
• median progression-free period for patients with MCL is 20 months and the median overall survival is between 5 and 7 years.
• median progression-free survival (PFS) of the elderly patients who start RM is >5 years
• median overall survival (OS) of younger patients who finish the induction therapy and HDT-ASCT consolidation and start RM is more than 12 years. Relapses in the low-risk mantle cell lymphoma prognostic index (MIPI) patients are rare, indicating potential cure at least in some of these patients. ³⁾
• prognosis for the blastoid variant of MCL is poor, this type of MCL typically progresses after chemotherapy⁴⁾
• relapse/refractory (R/R) MCL is an incurable disease with median overall survival of 1–2 years
  • BTK inhibitors ibrutinib and acalabrutinib have revolutionized the therapy of R/R MCL with significant improvement in PFS but virtually all will relapse and median OS after ibrutinib seems to range between 3 and 10 months⁵⁾

• see https://www.thecalculator.co/health/Mantle-Cell-Lymphoma-Prognostic-Index-(MIPI)-Score-Calculator-1093.html
• based upon:
  • age
  • lactic dehydrogenase (LDH)
  • ECOG performance status (0 = active, 1 = sedentery, 4 = bedbound)
  • WCC
  • Ki67 if known