Overview

Mantle cell lymphoma (MCL) is an aggressive blood cancer that affects B cells. These cells are key players in your immune system and help to fight infections. There is no exact cause of MCL, yet it can be easily diagnosed by detecting specific genetic mutations within individuals. It is more common in people assigned male at birth (AMAB) than people assigned female at birth (AFAB), and those above the age of 60, although the reasons for this are unclear. MCL is known for its aggressiveness and challenging treatment plans, allowing individuals to enter remission; however, the remission periods are often temporary.

Understanding MCL

MCL is a subtype of non-Hodgkin lymphoma (NHL), a cancer characterised by abnormal proliferation of B cells or lymphocytes. A lymphocyte is a type of white blood cell whose role within the body is to protect against infection. Regular functioning B cells produce antibodies that help to fight off infections by attaching to foreign particles and leading them to destruction. ‘Mantle’ refers to the mantle zone of lymphoid follicles within lymph nodes, where the cancer first begins to develop. The cancer is then able to travel through the lymphatic system around the body.

MCL symptoms

Symptoms of MCL can present similarly to symptoms of being generally ‘unwell’ or other less serious illnesses. Because of this, MCL is often diagnosed late and after the cancer has already begun to spread. It is also commonly detected after multiple lymph nodes around the body are made cancerous. As a result, swollen lymph nodes are a common symptom. Other symptoms include:

• Weight and appetite loss
• Fever 
• Night sweats
• Nausea/vomiting
• Heartburn or belly pain
• Pressure in the lower back
• Fatigue

Diagnosis

Getting an MCL diagnosis involves a series of questions from a healthcare professional and a physical examination. There are tests that follow to definitively diagnose MCL.

Blood tests

These will involve blood counts and checking whether organ function is normal.

Imaging

Your doctor may request imaging to be performed, including, CT, X-ray or PET scans. These will help them see the lymphatic systems and organs.

Biopsy

During a biopsy, a small sample of tissue will be removed from the body and tested for cancer. Multiple biopsies may be taken from different places around the body, suspected to be cancerous.

Antigen testing

Antigens are small proteins on cells which help scientists to identify a particular cell type. Samples from the biopsy will be tested for specific antigens associated with MCL (e.g., CD5, CD19, and CD20).

Genetic screening

Using the biopsy samples, scientists can detect genetic changes. There are genetic factors that influence MCL presentation, as listed in the section below. For example, a genetic translocation, specific to the CCND gene, that is heavily associated with MCL will be tested for.

Treatment

There is currently no cure for MCL. Current treatments allow many patients to enter remission, which is usually only temporary. 

Treatment will depend on the individual and will be discussed with your healthcare professional. As with many cancer treatments, it will be dependent on age, stage, and any other underlying health conditions present. The effects of the drugs used can cause negative symptoms in individuals, often affecting their quality of life. Common treatment plans involve:

Chemotherapy 

Chemotherapy works by targeting cells that are rapidly dividing, a trait of all cancerous cells. It can be taken either orally or intravenously. It is commonly used in combination with other forms of therapy. Side effects are negative and often affect an individual's quality of life. These include but are not limited to:

• Hair loss
• Fatigue
• Appetite changes
• Changes to blood
• Infertility

Immunotherapy

This involves drugs that specifically target the CD20 antigens (proteins) that are on the outside of MCL cells. For example, rituximab.

Stem cell therapy

This involves either taking your own stem cells or a transplant from a donor to help restore and rebuild your immune system following chemotherapy.

Maintenance immunotherapy

Maintenance therapy has been shown by research to sustain remission, typically for many years, extending the lives of those with MCL.¹

Causes and risk factors of MCL

There is not one direct cause of MCL. As with symptoms, factors influencing the disease are specific to individuals.

Genetic and molecular factors

Genetic predisposition plays a significant role in the development of MCL. Specific chromosomal abnormalities and mutations have been identified as contributing factors. These include:

Genetic translocation

This genetic abnormality is the hallmark of MCL, meaning this is used to detect MCL. A genetic translocation is a phenomenon whereby a chromosome breaks and is reattached to another chromosome. In MCL, it is the translocation of the CCND1 gene which codes for a protein, cyclin-D1, onto chromosome 14. This results in overexpression of the protein which results in uncontrolled cell cycle progression.²

SOX11 expression

Transcription factors are proteins that assist with turning certain genes ‘on’ or ‘off’. MCL is characterised by the expression of a transcription factor, SOX11, which is involved in cell differentiation and development. SOX11 expression is usually absent in normal B cells but consistently present in MCL cells, contributing to disease progression.

TP53 mutations

TP53 is a tumour suppressor gene which helps control cell multiplication and proliferation. Mutations in TP53 have been identified in a subset of MCL cases, leading to impaired DNA repair mechanisms and increased genomic instability.

Immunological factors

The immune system plays a critical role in detecting and eliminating abnormal cells, including the B cells affected by MCL. Disruptions in immune function and chronic antigenic stimulation are linked to an increased risk of developing malignancies within the lymph nodes:

Chronic antigenic stimulation

Prolonged exposure to antigens from infections or environmental factors can trigger chronic B-cell activation and proliferation, predisposing to genetic alterations and lymphomagenesis (growth and development of a lymphoma).

Immune suppression

Immunosuppressive conditions or therapies (e.g., post-organ transplantation, HIV/AIDS) weaken the immune system and therefore the surveillance of the immune cells. This allows for the unchecked proliferation of malignant B cells.

Environmental and lifestyle factors

While genetic predisposition plays a dominant role in MCL development, environmental and lifestyle factors may also contribute to the risk of disease:

Pesticide exposure

Some studies suggest a possible association between exposure to certain pesticides and an increased risk of lymphomas, including MCL. The exact mechanisms linking pesticides to lymphomas are still under investigation.

Ionising radiation

High-dose ionising radiation, such as that used in cancer treatment or occupational exposure (e.g., nuclear industry workers), is a known risk factor for various cancers, including non-Hodgkin lymphoma (NHL). The specific impact on MCL risk requires further research.

Age and gender

MCL primarily affects older adults, with a median age at diagnosis of around 70 years. The incidence is slightly higher in people AMAB compared to people AFAB. The reasons for this gender disparity are not fully understood without further research.³

Viral infections

Viral infections have been implicated in the development of certain lymphomas, although direct causality remains unclear for MCL.

Hepatitis C Virus (HCV)

Chronic infection with HCV has been associated with an increased risk of NHL, including marginal zone lymphoma and diffuse large B-cell lymphoma. The role of HCV in MCL development requires further investigation.

Human T-lymphotropic Virus (HTLV-1)

HTLV-1 infection is linked to adult T-cell leukaemia/lymphoma (ATLL) but has not been definitively associated with MCL.

Familial predisposition

While most cases of MCL occur sporadically, familial clustering has been observed in a small percentage of cases.

Familial aggregation

Rare instances of familial MCL suggest a potential genetic predisposition or shared environmental exposures within families. Studies exploring inherited genetic variants and familial cancer syndromes (e.g., ataxia-telangiectasia) may shed light on familial MCL risk factors.⁴

Summary

MCL is a complex blood cancer influenced by genetic, immunological, environmental, and possibly viral factors. The translocation of the CCND1 gene and subsequent cyclin D1 overexpression represents a defining and seemingly sporadic genetic abnormality in MCL, while immunological disruptions and environmental exposures contribute to disease susceptibility.

Further research is needed to uncover the interplay between these factors and to develop targeted prevention strategies and improved therapeutic approaches. Enhanced understanding of MCL’s causes and risk factors will facilitate earlier detection and personalised treatment strategies, ultimately improving patient outcomes and quality of life.