Overview
Mantle cell lymphoma (MCL) is an uncommon and separate subtype of non-Hodgkin lymphomas (NHLs) which is due to a translocation between two different chromosomes located at positions 1 and 14, this triggers the amplification (gene overexpression) of cyclin D (CCND1) gene, and results in aggressive MSL by which the B cells grow rapidly (uncontrolled growth) and disrupts the cell cycle MCL can exist in different forms of morphologic variants during examination which make it competitive for pathologists to confirm its diagnosis.1
Mantle cell lymphoma is one of the most prevalent forms of non-Hodgkin lymphomas (NHLs) that faces challenges in terms of diagnosis and treatment despite advanced treatment that significantly improves prognosis.
Aetiology
Mantle cell lymphoma is considered an occasional disorder, but it may still have a higher incidence among people who have a confirmed history of lymphoid/hematologic aggressive malignancies, other forms of non-Hodgkin's lymphomas, and hereditary or genetic factors that trigger cancer. All these health conditions increase the risk for MCL.1
Epidemiology
Mantle cell lymphoma is a rare subtype of B cell lymphocytes non-Hodgkin lymphoma (NHL) affecting one case in every 200,000 people each year, knowing that MCL accounts for 5% of all non-Hodgkin lymphomas. The median age of patients ranges between 60 and 70 years old with a male predominance of approximately 70% of all cases.1,2
Pathophysiology
Mantle cell lymphoma takes place mainly through the translocation between two different chromosomes which prompts the increased expression of cyclin D1 gene due to the fact that cyclin D1 Gene is located next to the immunoglobulin heavy chain gene. The overexpression of cyclin D1 gene results in the disruption of the cell cycle which stimulates the tumour cells growth by interfering with the mechanism of gene regulation and chromosome stability, despite the presence of exceptional translocations that are linked to cyclin D2 (CCND2) or cyclin D3 (CCND3) instead of cyclin D1 (CCND1). The MCL classification depends on the origin of the B lymphocytes.1
Clinical manifestations
The most prevalent manifestations of MCL are as follows:
- Fevers
- Night Sweats
- Splenomegaly and discomfort
- Lymphadenopathy
- Weight loss
- Blood count abnormalities (because of bone marrow involvement)
- Extranodal involvement that affects not only lymph nodes, but extends to other organs such as the spleen, gastrointestinal tract, and bone marrow. Thus, cancerous cells (lymphomas) originate from lymph nodes, then the tumour spreads to affect the other organs
- Mantle cell lymphoma exhibits a dual mechanistic nature which is indolent and aggressive characterised by slow growth linked to chronic features and fast growth with potential symptoms respectively
Evaluation
Mantle cell lymphoma is diagnosed by excisional biopsy of lymph nodes or the affected organs (extranodal).
In addition to the examination of:
- LDH (lactate dehydrogenase found in several tissues of the body)
- CBC (complete blood count)
- Bone marrows biopsy
- Beta-2 microglobulin (a protein located on the surface of many cells of the body)
- Images such as CT scans (computed tomography scans)
Additional examinations for specific biomarkers that are essential for treatment selection:
- Ki-67 index: It is a measure used to examine the activity of the cell's growth
- P53: this is a protein that has an important role in suppressing tumours and regulating cell growth by preventing abnormal cells from division
- ATM (Ataxia telangiectasia mutated): it is a protein kinase that repairs damaged DNA and controls genetic stability
Patients who complain of neurologic symptoms have elevated Ki-67 index, and blastoid variant (certain morphological features of a lymphoma subtype, they resemble blasts and are immature with distinguished character from typical lymphoblasts) are highly recommended to have CSF (cerebrospinal fluid) examination.
Endoscopic assessment is not a primary requirement for all cases with gastrointestinal involvement. However, it is recommended for patients in their early MCL stages.
Mantle cell lymphoma can be determined by the detection of specific positive biomarkers using immunohistochemistry such as CD19, CD20, CD22, and CD79a which are transmembrane glycoproteins found on B cells (B lymphocytes), in addition to the transcription factor protein SOX11 that regulates the transcription process of the genes, especially in the nervous system. MCL is negative for these biomarkers, CD23, CD10, and BCL6.
MIPI is a term that stands for mantle cell lymphoma international prognostic index, which is a scoring system used to classify the risk of MCL patients and to predict the prognosis of the patient. It depends on:
- Age
- Performance status
- LDH
- Elevated white blood cell count
Treatment and management
The average survival ranges from 1.8 to 9.4 years as MCL is a highly incurable disorder based on its aggressive condition. Treatment options are guided and selected in terms of patient age, MIPI, disease severity, and performance status.
Indolent types that include low MIPI scores, negative SOX11, uncomplicated karyotypes, and hypermutated IGH (immunoglobulin heavy chains, these genes which encode HIGH exhibits an abnormally high rate of mutation) may be monitored closely without the need to initiate any treatment. Early stages of MCL/non-bulky stage II can be guided to be treated by radiation therapies or non-complicated regimens.
Patients with severe MCL(stage II bulky, III, or IV) or those who are symptomatic are categorised into two groups, the group eligible for transplant and the ineligible group, this depends on their complications and performance status. The used chemotherapy regimens include R-DHAP, BR, R-CHOP, and hyper-CVAD.
Relapsed MCL relies on complicated treatment approaches that use stem cell transplantation and high doses of chemotherapy. FDA-approved target therapeutics are zanubrutinib, venetoclax, ibrutinib, acalabrutinib, and others are indicated along with other therapies that are in clinical trials, in addition to emerging treatments such as CAR-T cell therapy (Chimeric Antigen Receptor T-cell therapy) which acts by potentiates the patient immune system to fight cancerous cells.
All these treatment strategies mainly aim to improve the patient’s quality of life, prognosis, and survival expectations. Additionally, it can manage the symptoms of MCL and reduce the risk of comorbidities.
Complications
The complications that are linked to the disease itself include:
- Gastrointestinal bleeding/obstruction
- Splenic rupture due to enlarged spleen
- Tumour lysis syndrome (cancer cells release their contents to the bloodstream)
Treatment-related complications:
- Neutropenic sepsis (low neutrophils count due to infection can lead to a systemic response that can lead to tissue damage)
- Severe infections
- The need for blood transfusions because of cytopenias (low count of blood cells)
Side effects of certain therapeutics such as ibrutinib:
- Arrhythmias (irregular heart rhythm)
- Hypertension (high blood pressure)
- Bleeding
- Skin Rashes
- Diarrhoea
- Tumour lysis syndrome (venetoclax and BCL-2 inhibitor therapy)
- Blood clot risk and oedema (lenalidomide therapy)
- Encephalopathy that affects brain function, cytopenias, and cytokine release syndrome (CAR-T cell therapy)
Consultations
Mantle cell lymphoma is an aggressive disease that requires a multidisciplinary approach that involves a bone marrow transplant team, medical oncologist, and clinical trials team.
Improving outcomes by the healthcare team
The MCL disorder can be directly and easily diagnosed, but the diversity in morphologic variants can resemble other lymphoid disorders and malignancies which hinders the proper diagnosis (misdiagnosis). In order to avoid this, additional examinations should be conducted such as SOX11 immunohistochemistry and cyclin D1. Moreover, to achieve a positive outcome, a multispeciality healthcare team is required including oncologists, internists, radiologists, haematologists, bone marrow specialists, experienced and specialised nurses, and a clinical trial team.
Summary
- Mantle cell lymphoma (MCL) is an uncommon and separate subtype of non-Hodgkin lymphomas (NHLs) which results in abnormal growth of B lymphocytes
- Mantle cell lymphoma is considered a rare disorder, but it may still have a higher incidence among people who have a confirmed history of lymphoid/hematologic aggressive malignancies
- MCL is affecting one case in every 200,000 people each year, knowing that MCL. It predominates in men
- The median age of patients ranges between 60 and 70 years
- Mantle cell lymphoma occurs through the translocation between two different chromosomes which prompts the increased expression of cyclin D1 gene
- The most common symptoms are fevers, night Sweats, splenomegaly, lymphadenopathy, weight loss, and blood count abnormalities
- Mantle cell lymphoma is diagnosed by excisional biopsy of lymph nodes or the affected organs (extranodal) along with other specific positive biomarkers. CSF is examined in the presence of neurologic symptoms
- The average survival ranging from 1.8 to 9.4 years as MCL is a highly incurable disorder based on its aggressive condition. Treatment options are guided and selected in terms of patient age, MIPI, disease severity, and performance status
References
- Adams, Molly. ‘What to Know about Mantle Cell Lymphoma’. MD Anderson Cancer Center, https://www.mdanderson.org/cancerwise/what-to-know-about-mantle-cell-lymphoma-symptoms-diagnosis-and-treatment.h00-159385101.html. Accessed 28 June 2024.
- Armitage, James O., and Dan L. Longo. ‘Mantle-Cell Lymphoma’. New England Journal of Medicine, edited by C. Corey Hardin, vol. 386, no. 26, June 2022, pp. 2495–506. DOI.org (Crossref), https://doi.org/10.1056/NEJMra2202672.
- Lynch, David T., et al. ‘Mantle Cell Lymphoma’. StatPearls, StatPearls Publishing, 2024. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK536985/.