mantle cell lymphoma (MCL)

Introduction

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
- this chromosomal translocation drags a powerful regulatory element into a new area of the human genome, where its new position allows it to boost the activity of not just one but 50 genes at once
  - a gene regulatory element called the IGH enhancer, which normally boosts the activity of antibody production in healthy B cells, lands right beside CCND1, a gene which helps cells divide. The enhancer treats CCND1 as if it were a gene encoding for antibodies, boosting its activity and fuelling the disease. Over fifty genes along the entire chromosome 11 are much more active after the translocation took place, but only genes which were already active are boosted¹⁾

Aetiology

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

Types of MCL

2 main types of MCL²⁾:
- 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)

Clinical presentation

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)

General behaviour

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 ³⁾
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

Diagnosis

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)

Staging workup

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−)

Staging:

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

Prognosis

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. ⁴⁾
prognosis for the blastoid variant of MCL is poor, this type of MCL typically progresses after chemotherapy⁵⁾
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 months⁶⁾