Mantle Cell Lymphoma

Updated May 2024

Simeon Lauer, MD

Establishing the diagnosis

Etiology

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s B-cell lymphoma.
- Originates from mantle zone pre-germinal center.
In majority of cases, characterized by a unique chromosomal translocation, t(11;14)(q13;q32).
- Initiating oncogenetic event.
- Results in overexpression of cyclin D1 and deregulation of the cell cycle (Oka, 1996).
Secondary oncogenetic events complete the transformation and lymphomagenesis (Orchard, 2003):
- In 20-30% of cases there are hypermutated IgH-V genes – immunoglobulin heavy chain variable region.
- NFκB – nuclear factor kappa light chain enhancer of activated B-cells, controls DNA transcription, involved in cell survival and cytokine production.
- PI3K – phosphor inositide 3-kinase, a tumor suppressor involved in cell growth and differentiation. INK4a – another tumor suppressor involved in cell cycle regulation.
- CDK4 – inhibitor of cyclin dependent kinase, also tumor suppressor.
- RB1 – retinoblastoma protein, tumor suppressor.
- MDM2 – mouse double minute 2 homolog, a ubiquitin ligase.
- P53 – tumor suppressor.
Periocular presentation may represent initial evidence of nodal MCL, or may represent non-nodal disease.
- Non-nodal MCL can have disease in spleen and/or bone marrow but does not reside primarily in lymph nodes.
- Blood involvement in non-nodal MCL is common and does not have a negative impact on prognosis
  - In contrast to nodal MCL where leukemic variant has a poorer prognosis (Matutes, 2004).
- Overall survival for non-nodal MCL is about two years longer than nodal MCL (Orchard, 2003).
- Patients may have “composite histologic findings”, meaning their tumor is consistent with more than one lymphoma type.
  - In the Vancouver series (Looi, 2005), one had evidence of MCL and follicular lymphoma, another had MCL and a plasma cell tumor.
  - The MCL tumor component in those patients had the t(11;14) transformation.

Epidemiology

Overall accounts for 9% of non-Hodgkin’s lymphoma.
Annual incidence 1-2 per year per 100,000 persons.
Multicenter study of ocular adnexal mantle cell lymphoma, among 55 patients, 62% (n=34) had disseminated disease at presentation (Knudsen, 2017).
- Mean age 70 years (range 34-90 years)
- 76% (n=42) were male
- 90% were white
Among 21 patients with ocular adnexal MCL in the Danish Ocular Lymphoma Database 1980-2005, 67% had a primary periocular presentation (Rasmussen, 2009)
- Age range was 60-90 years, median 75 years.
- 18 were males (86%).
Among 10 patients with ocular adnexal MCL treated in Vancouver, 80% had primary periocular presentation (Looi, 2005).
- 60% had atypical cells in the peripheral blood smear
- 70% had bone marrow involvement on presentation.
- Age range was 32-84 years, median 73 years.
- Nine were males (90%).
Among 211 ocular adnexal lymphomas treated in Berlin, Germany, 136 were MALT tumors, 31 diffuse large B-cell lymphomas, 27 follicular lymphomas, 9 plasma cell tumors, and 8 MCLs (Coupland, 2004).
Among 106 ocular adnexal lymphomas treated in Seoul, South Korea, 96 were MALT lymphomas, 6 diffuse large B-cell lymphomas, 4 mantle cell lymphomas (Oh, 2007).
Among 43 ocular adnexal lymphomas treated at MD Anderson in Houston, there were 19 MALT tumors, 9 diffuse large B-cell lymphomas, 9 follicular lymphomas, 3 mantle cell lymphomas, and 3 others (Hatef, 2007).
Among 27 lacrimal gland lymphomas recorded in the Danish Registry of Pathology from 1975-2009, there were 10 MALT lymphomas, 4 diffuse large B-cell lymphomas, 5 follicular lymphomas, 3 mantle cell lymphomas, and 5 others (Rasmussen, 2011).

History

Most common presenting symptoms are tumor, swelling and irritation (Knudsen, 2017).
Other presenting symptoms
- Pain
- Epiphora
- Chemosis
- Lacrimal gland enlargemen
- Ptosis
- Diplopia

Clinical features

Among ten patients with ocular adnexal MCL treated in Vancouver, 90% had lymphoma present at 2 or more periocular sites.
Orbit was most commonly involved (90%) followed by lacrimal gland (50%), and lid (50%).
Can present as conjunctival salmon patch lesion (Choi, 2016).

Testing and establishing the diagnosis

The typical immunohistochemical profile is:
- CD5 positive – encoded on the long arm of chromosome 11, usually a marker for T-cells, responds to strong antigenic stimulation such as bacterial infection.
- CD20 positive – a B-lymphocyte surface molecule that mediates transformation to plasma cells.
- bcl-2 positive – prevents apoptosis in B-lymphocytes, also plays a role in follicular lymphoma, and other cancers such as melanoma, breast and prostate.
- CD23 negative – low affinity receptor for IgE, a sign of B-cell differentiation.
- CD10 negative – a surface zinc metalloprotein expressed in normally differentiated lymphoid tissue.
- CD11c negative – integrin, involved in normal processing and destruction of antigenic protein.
- CD25 negative – the alpha chain of the IL-2 receptor, a transmembrane protein found on normal activated B- and T-lymphocytes.
11:14 translocation can be diagnosed by fluorescent in situ hydbridization (Coffee, 2005)

Testing and staging

The commonly available cell proliferation index Ki67 is among the most powerful indicators of overall survival.
- Ki67 index of <10% is associated with three year survival of 93%; 10-30% with 74%; >30% with 66% (Hoster, 2008).
Blastoid features indicate poor prognosis (Rubio-Moscardo, 2005).
Central nervous system involvement indicates poor prognosis (Cheah, 2013).
PET scan with F-18 fluorodeoxyglucose (FDG-PET) is highly sensitive for staging MCL (Brepoels, 2008).

Risk factors

Not known

Differential diagnosis

Benign lymphoid hyperplasia
Orbital inflammation
Chronic orbital infection
MALT lymphoma
Follicular cell lymphoma
Diffuse large cell lymphoma

Patient management

Natural history

Mantle cell lymphoma is more heterogeneous than originally recognized (Hsi, 2014).

A less aggressive subgroup has been termed “indolent mantle cell lymphoma”.
The absence of sox11 mutations, which otherwise is typical of MCL, seems to indicate indolent MCL.
Indolent MCL patients have less lyphocytosis, minimal bone marrow involvement, no splenomegaly, no lymphadenopathy and are otherwise asymptomatic.
Indolent MCL has a marked female predominance and predominance of kappa light chain restriction, in contrast to typical MCL.
Periocular MCL in the absence of substantial systemic disease may represent indolent MCL.

Medical therapy

Palliative therapy with anthracycline based chemotherapy was the approach until more effective regimens were developed.
R-CHOP (rituximab, vincristine, cyclophosphamide, doxorubicin, prednisone) is current standard for intensive induction therapy with some variation.

Example may be rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with rituximab, high dose methotrexate and cytarabine (R-hyper-CVAD/R-MA regimen) (Romaguera, 2015).
There are treatment related deaths from toxicity with more intensive regimens.
Therapy related acute myelogenous leukemia can develop with intense induction regimens.
Intense induction regimens are suggested for younger patients (i.e. age 65 or younger).

Improved survival is achieved with autologous or allogeneic stem cell transplantation after first remission with induction immunochemotherapy.

Patients who undergo stem cell transplant have better survival than additional chemotherapy (Dreyling, 2013).

Radiation therapy

MCL limited to the orbit, with no systemic evidence of disease, is rare.

Systemic treatment is primary.

For indolent MCL, if observation is recommended, orbital radiotherapy may limit regional morbidity.
In the Danish series of 21 patients with periocular MCL, one patient had no evidence of extraocular disease (stage I), treated with orbital radiotherapy alone, had disease in the brain four months later (Rasmussen, 2009).

Surgery

There are limited surgical options for this infiltrative tumor.
After reduction chemotherapy, resection of residual disease may be reasonable, if accessible, to limit regional morbidity.

Response to treatment

In Knudsen study (2017) the five year disease specific survival was 38%.

Recurrence or progression was observed in 84% after primary treatment
Median progression free survival was 2.3 years.
Overall survival was 65% at 3 years and 34% at 5 years.
Patients who received rituximab in addition to chemotherapy had a better five year survival than chemotherapy alone.

In the Vancouver series, median progression free survival was only twelve months.

Five year overall survival was 39%, a more favorable prognosis than nodal MCL.
Median overall survival was 57 months (Looi, 2005).

Among the 21 Danish patients with periocular MCL, including 7 with previously known systemic MCL, 13 died of the disease, and one from other causes (Rasmussen, 2009).

Historical perspective

The term “mantle cell lymphoma” was introduced in 1992 by the International Lymphoma Study Group (Swerdlow, 2002).
The earlier term was “diffuse germinocytoma” suggested by Lennert in 1973 (Looi, 2005).
Under the Kiel classification it is called “centrocytic lymphoma”, cleaved cells without follicular centers (Anderson, 1982).

References

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