Mantle cell lymphoma

What is mantle cell lymphoma?

Non-Hodgkin’s lymphomas are a set of related malignancies (cancers) that affect the lymphatic system, and mantle cell lymphoma is one of them. The lymphatic system, which is part of the immune system, helps to protect the body against infection and disease. It is made up of a network of tubular channels (lymph vessels) that drain a thin watery fluid called lymph into the bloodstream from various parts of the body. Lymph is a fluid that collects in the microscopic crevices between tissue cells and contains proteins, lipids, and lymphocytes, which are white blood cells.

Lymph is filtered as it travels through the lymphatic system by a network of small structures known as lymph nodes, which help to eliminate germs (such as viruses, bacteria, and other foreign bodies) and other foreign bodies. Lymph nodes can be found in the neck, beneath the arms (axillae), at the elbows, and in the chest, belly, and groyne, among other places. Lymphocytes are present in lymph nodes and other lymphatic tissues and are preserved there. The lymphatic system also includes the spleen in addition to the lymph nodes. The thymus, a tiny organ beneath the breastbone that is thought to play a significant role in the immune system until adolescence, and bone marrow, the spongy tissue inside the cavities of bones that creates blood cells, are both lymphatic tissues. Other parts of the body, such as the skin, small intestine, liver, and other organs, may have lymphatic tissue or circulating lymphocytes. B-cells, which may create specialised antibodies to “neutralise” certain invading pathogens, and T-lymphocytes, which may directly eliminate bacteria or aid other lymphocytes in their activities, are the two primary types of lymphocytes.

Mantle cell lymphoma and other lymphatic system malignancies (lymphoma) are caused by mistakes in lymphocyte production or the transformation of a lymphocyte into a malignant cell. Malignant lymphocytes’ abnormal, uncontrolled growth and multiplication (proliferation) can result in lymph node enlargement, involvement of other lymphatic tissues like the spleen and bone marrow, and spread to other bodily tissues and organs, all of which can result in life-threatening complications. Depending on the intensity and region(s) of involvement, as well as other circumstances, the particular symptoms and physical findings may vary from case to case.

Mantle cell lymphoma is a type of B-cell lymphoma that originates from malignant B-lymphocytes in the mantle zone of the lymph node. As previously said, the signs and symptoms of MCL are determined by the extent of the affected body region. Although the specific cause is uncertain, researchers have discovered a number of genetic abnormalities (or mutations) in B-cells that lead to cancer cell proliferation. For MCL, a mutation known as t(11;14), which signals the exchange of genetic material between chromosomes 11 and 14, causes the lymphoma cells to overproduce a protein called cyclin D1, as discussed in the “Causes” section of this article. These alterations are present in more than 90% of MCL patients and are crucial for diagnosis.

When determining whether a cancer will be indolent or aggressive, certain disease characteristics are taken into account. More aggressive lymphomas grow quickly and have few symptoms, whereas indolent lymphomas grow slowly and cause few symptoms. MCL is classified as either a slow-growing (indolent) or a fast-growing (aggressive) lymphoma, however experts disagree. Despite the fact that MCL is classed as an aggressive lymphoma, it has been proven to have some indolent lymphoma characteristics.

Signs & symptoms of mantle cell lymphoma

Many people with mantle cell lymphoma are asymptomatic (without symptoms) in the early stages of the disease. However, persistent, typically painless enlargement of some lymph nodes, particularly those in the neck and throat region (e.g., Waldeyer’s ring), may prompt affected persons to seek medical attention. The protective ring of lymphoid tissues at the base of the tongue (lingual tonsils), on each side of the throat (palantine tonsils), and near the back aperture of the nasal cavity is known as Waldeyer’s ring (pharyngeal tonsils or adenoids). Other lymph nodes, such as those in the elbows or shoulders; beneath the arms (axillae); in the chest, stomach, and/or pelvic regions; and/or in other places, may increase in people with non-lymphomas Hodgkin’s (NHLs), including MCL. Lymph node enlargement might be limited to a specific place or can occur across the body.

Some people with lymphoma may experience additional symptoms and signs that are “non-specific,” meaning they could be caused by a variety of underlying conditions, including other types of lymphoma (including non-lymphomas Hodgkin’s and Hodgkin’s disease). Some people may have anorexia (a lack of appetite), nausea, vomiting, and indigestion. A feeling of “fullness” (satiety), stomach swelling (distension) or bloating, and abdominal pain or discomfort are all possible symptoms. Enlargement of the abdominal lymph nodes and/or the spleen (splenomegaly) or liver (hepatomegaly) or involvement of the gastrointestinal tract may cause such abnormalities.

Some people with MCL may experience “B symptoms,” which are broad (systemic) symptoms. Persistent or recurrent fever, unexplained weight loss (i.e., a loss of at least 10% of normal body weight in the 6 months preceding to diagnosis), and/or sweating, especially at night (known as “night sweats”) are examples of such symptoms. It’s estimated that up to a third of people with MCL will have “B symptoms” by the time they see a doctor. However, such findings are more common in people with Hodgkin’s disease than in those with other types of NHL. (See the “Related Disorders” section below for further information on Hodgkin’s disease.)

Due to infiltration by growing lymphoma cells within and reduced functioning or failure of some organs and tissues, some people with MCL may have other or additional symptoms and findings, depending on the extent and region(s) of involvement. Malignant lymphocytes may effectively overload the bone marrow if MCL has migrated to the bone marrow, resulting in decreased production of specific blood cells. (Bone marrow is the soft, spongy substance that creates blood cells within the cavities of bones.) In the bone marrow, immature cells called stem cells develop into the three cellular components of blood: red blood cells, which contain the oxygen-carrying pigment haemoglobin; white blood cells, which help fight infection; and platelets, which play an important role in blood clotting [coagulation].) Anemia or abnormally low levels of the oxygen-transporting component of red blood cells can occur in some people with bone marrow involvement. Fatigue, listlessness, and lack of energy (lethargy), paleness of the skin (pallor), headaches, and/or other symptoms may be present. Certain infections, easy bruising and heavy bleeding, and/or other symptoms may develop in affected persons.

The digestive (gastrointestinal [GI]) system may be involved in some people who have MCL. GI involvement may be linked to the formation of numerous polyps within the intestines in some of these patients (lymphomatous polyposis). Gut polyps are tissue growths that protrude from the intestinal wall on a stalk. MCL can also expand to the brain and spinal cord (central nervous system [CNS]) in rare cases, causing neurologic symptoms. Lethargy, headaches, weakness, disorientation, personality changes, abrupt episodes of uncontrolled electrical activity in the brain (seizures), and/or other abnormalities may be among the symptoms.

Disease progression may potentially lead to life-threatening consequences, depending on MCL subtype, sites and amount of involvement, disease management, and other factors. (See the “Classification,” “Staging,” and “Standard Therapies” sections of this study for more information on subtypes, illness staging, and therapy options, among other things.)

Diagnosis of mantle cell lymphoma

A detailed patient history, extensive clinical evaluation, and a variety of specialist tests, including a biopsy of an afflicted lymph node or bone marrow, are used to identify mantle cell lymphoma. Such testing is required to confirm the kind (and subtype) of NHL present, assess the nature and degree of the disease, and establish the best treatment options.

Physicians may feel (i.e., palpate) lymph nodes in certain areas during a comprehensive physical examination to detect any enlargement, such as the neck, tonsil, and adenoidal region, under the arms, and in the groyne. They may also look at other areas to see whether specific internal organs, such as the spleen and liver, are enlarging, as well as to look for swelling and abnormal fluid accumulation that could indicate lymphatic system disease.

Various diagnostic tests may be indicated for patients with lymphoma suspicion based on a thorough patient history and clinical examination. A biopsy of an afflicted lymph node or of the bone marrow is required to confirm the diagnosis. This type of testing is required to distinguish MCL from other cancers, such as other types of NHL and Hodgkin’s disease, as well as other disorders that affect the lymph nodes. (Please consult the “Related Disorders” section of this report for more information.)

Biopsies usually entail the removal and microscopic (i.e., histologic) inspection of small samples of tissue cells from a lymph node suspected of being cancerous–or, in some cases, the excision of an entire, larger lymph node. The technique may be performed under local or whole body (general) anaesthesia, depending on the type of biopsy performed. Furthermore, laparoscopy or laparotomy may be required to obtain biopsy samples in some circumstances, such as when involvement appears to be limited to the abdomen or pelvic region. An illuminated viewing tube (laparoscope) implanted through incisions in the abdominal wall is used to examine the abdominal cavity. Laparotomy is a surgical operation that involves opening the abdomen, carefully inspecting the organs for signs of disease, and removing tissue samples for microscopic inspection. (Biopsy samples are evaluated by pathologists, who are doctors who specialise in studying cells and tissues to aid in proper diagnosis.)

Microscopic examination of biopsy samples from people with MCL may indicate anomalies in the typical structure (architecture) of the lymph nodes, such as enlargement of the lymph node’s mantle zone. More precisely, aberrant infiltration and enlargement of the mantle zone around the lymph node’s germinal centres*, ultimate loss of mantle zone boundaries, and potentially extensive proliferation of malignant cells throughout the node are all possibilities. (*Lymph nodes are made up of a fibrous outer capsule and a lymphatic tissue mass inside.) The outside region, or cortex, contains follicles, which are groupings of lymphocytes; at the centre of the follicles are germinal centres. B-lymphocytes make up the majority of germinal cells.)

Pathologists can also use microscopic analysis to determine other histologic features that may be important in the classification of the malignancy, such as the size of malignant lymphocytes, the appearance of the nucleus within a lymphoma cell, the distribution or pattern of abnormal cells, and so on. (Please see “Classification/Grading” below for more information.) In addition, specialist examinations are carried out to help pinpoint the cell type of origin of the cancer. MCL cells, as well as the normal cells from which the malignancy arises, have antigens on their cell surfaces that may be recognised using specialist procedures like immunohistochemistry. CD5, CD19, CD20, and CD22 are some of the antigens that should be detected to identify MCL. As a result, identifying such markers can help separate normal cells from malignant cells, as well as distinguish MCL from other B-cell lymphomas, which can help with disease treatment decisions.

Additional specialist testing on biopsy samples may be performed to aid in the diagnosis of MCL. These could include tests to see if the chromosomal 11;14 translocation and the cyclin D1 protein are present in malignant cells. Immunohistochemistry can also be used to detect the expression of the SOX11 gene, which can be useful in circumstances when cyclin D1 is not expressed. (Please consult the “Causes” section of this report for more details.)

A bone marrow biopsy may be advised in a specific subtype of MCL called “leukemic non-nodal subtype” to detect whether the malignancy has spread to the bone marrow. (Please read “Classification” below for further information on subtypes.) A sample of bone marrow is taken during this surgery, usually from the hip bone (iliac crest). A local anaesthetic is used to numb the skin and tissue over the bone before a needle is introduced into the bone and a bone marrow sample is taken. A pathologist examines the sample under a microscope after that. Because a bone marrow biopsy might be uncomfortable, a modest sedative (calming) drug may be prescribed prior to the surgery.

Although a lymph node biopsy is the most important test for identifying MCL, several other procedures are required to determine the severity and impact of the disease. A number of these tests may be performed prior to the biopsy.

Blood tests will be performed to assess the amount and appearance of white blood cells, red blood cells, and platelets, as well as liver enzyme testing, renal function tests, tests to detect lactate dehydrogenase (LDH) levels, calcium, uric acid, and/or other studies.

Various specialised imaging procedures, such as normal x-ray imaging, computed tomography (CT) scanning, magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and/or other tests, may also be indicated. A computer and x-rays are used to make a film that shows cross-sectional views of inside structures during CT scanning. CT scans of the neck, chest, abdominal, and/or pelvic regions may be used to detect enlargement of particular lymph nodes or spread of the malignancy to certain organs in those who have suspected or been diagnosed with NHL, including MCL. This aids in determining the disease’s severity (stage). MRI creates comprehensive cross-sectional pictures of organs and tissues using a magnetic field and radio waves. This could be particularly useful in detecting brain and spinal cord involvement (central nervous system [CNS]).

PET scans can also be used to diagnose the condition and to monitor the patient’s response to treatment after treatment (mostly used in clinical trials). A modest dosage of radioactive substance is administered during this process. After that, the body is scanned from various angles to create an image that shows where the radioactive substance has accumulated within the body. This aids in the detection of active disease regions.

NHL, including MCL, can sometimes expand to the brain and spinal cord, as previously stated. In such circumstances, cerebrospinal fluid (CSF) investigation may indicate chemical anomalies as well as the presence of malignant cells. CSF is a watery fluid that runs through and protects the brain’s cavities (ventricles), the gap between the brain and spinal cord and their protective membranes (meninges), and the cavity within the spinal column that contains the spinal cord (spinal canal). A procedure known as a lumbar puncture is used to acquire CSF for analysis. During the process, local anaesthesia is used to numb the skin and underlying tissue at the base of the spine; a needle is then placed between particular bones in the lower back, and a sample of CSF is taken.

Individuals with early stages of MCL or specific symptoms should have an endoscopy since the gastrointestinal tract can develop polyps (lymphomatous polyposis). An endoscopy is a technique in which a physician inserts a camera into the oesophagus to check for polyps while the patient is given pain medication.

Other testing procedures may be recommended by physicians in some circumstances to help identify the extent of disease and monitor treatment. Additionally, tests may be required to assess the health and function of certain organs that may be harmed as a result of certain treatments (e.g., particular anticancer [chemotherapeutic] drugs]). Certain treatments to check the heart and lungs, for example, may be included in such testing.

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Treatment of mantle cell lymphoma

Physicians who specialise in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (haematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other professionals may be required for the diagnosis and therapeutic management of MCL.

Specific therapeutic procedures and interventions may differ depending on a variety of factors, including disease stage (see “Stages” above), tumour size, MCL subtype (classical vs. leukemic non-nodal), the presence or absence of certain symptoms, the patient’s age and general health, and/or other factors. Physicians and other members of the health care team should make decisions about the use of specific drug regimens and/or other treatments based on the specifics of the patient’s case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.

To identify whether the MCL is more indolent or aggressive, some parameters can be examined. When people are diagnosed with a more indolent form of cancer that has no symptoms, doctors may advise waiting a few weeks before starting therapy. In such circumstances, regular, thorough checks are essential to ensure that suitable therapies are initiated as the condition progresses. “Watchful waiting” is a term used to describe this approach to disease care.

Individuals who are diagnosed with a more aggressive type of the disease may typically need to begin treatment right away. Combination therapy using numerous anticancer medications with diverse mechanisms of action in eliminating tumour cells and/or preventing them from growing may be recommended by the doctors. Chemotherapy and immunotherapy are the most prevalent forms of anticancer drugs utilised in MCL for initial treatment. Chemotherapy is a term used to describe anticancer drugs that have a direct harmful effect on the reproduction of cancer cells. Anticancer drugs that use the body’s own immune system to fight cancer cells are referred to as immunotherapy. Rituximab, a monoclonal antibody, is an example of immunotherapy. Rituximab binds to a specific target on CD20-expressing tumour cells, triggering the immune system to attack and lyse (break up) the tumour cells.

Although most anticancer drugs are given through a vein (intravenously [IV]), others can be taken by mouth (orally). Chemotherapy and/or immunotherapy are usually given in outpatient settings, such as a doctor’s office, a hospital, or at home, at regular intervals or “cycles.” However, it may be important to undergo such treatment in a hospital setting on occasion. The number of treatment cycles is determined by a variety of criteria, including the drug regimen(s), the patient’s reaction to treatment, and the patient’s overall health.

The majority of treatment methods begin with an induction phase, in which the goal is to bring the lymphoma into remission. Chemotherapy and immunotherapy are two examples. The partial or total absence of cancer symptoms and physical evidence is referred to as remission. Another treatment is provided after the induction with the goal of keeping the malignancy in remission. “Consolidation” is a term used to describe this procedure. An longer course of treatment known as “maintenance” is also employed in MCL to sustain cancer remission.

Patients may be treated with chemotherapy and immunotherapy induction followed by consolidation radiation therapy to the afflicted spot if the sickness is in stage 1 or 2 at the time of diagnosis and there is no bulky disease. Radiation (through x-rays or other sources of radioactivity) is sent through certain areas of the body during radiotherapy to destroy cancer cells and shrink tumours. To assist reduce damage to normal body cells, radiotherapy is given in carefully calculated doses. The complete dose of radiation is usually given as an outpatient treatment over a period of several weeks. People with advanced disease or poor prognosis will be treated similarly to patients in the later stages.

If MCL is found to be in a later stage (stage 3 or 4), doctors must consider patient qualities and preferences, as well as clinical and illness aspects, while deciding which treatment to provide. It is advised that younger (less than 65 years old) and fit patients undertake a rigorous treatment course that includes induction therapy, autologous stem cell transplant (ASCT), and immunotherapy maintenance. ASCT is a treatment that includes harvesting healthy blood stem cells from the patient and then re-injecting the stem cells into the patient after high-dose chemotherapy.

Induction therapy can comprise a variety of drugs, but it usually includes the monoclonal antibody rituximab and a combined chemotherapy regimen that includes the drug cytarabine. R-hyperCVAD (rituximab with cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine) and R-DHAP (rituximab with dexamethasone, cytarabine, and cisplatin) are two examples. Those in remission are given ASCT consolidation after induction. Following that, rituximab is used as a maintenance medication for several years in order to prolong remission.

Immunochemotherapeutic drugs will also be given to elderly people in order to achieve remission. There are a variety of pharmaceutical combinations that can be used. R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone), BR (bendamustine and rituximab), and rituximab, bendamustine, and cytarabine are examples of potential combinations (R-BAC). The induction would be followed by a maintenance dose of rituximab.

A less toxic pharmaceutical regimen may be administered for frail patients, usually with the purpose of palliation. Rituximab alone is an example of a drug used in this situation.

There are numerous therapeutic options available if a patient’s sickness recurs after first therapy. The relapse therapy, like the original therapy, will be determined by patient characteristics and preferences, as well as disease criteria. Chemotherapy, immunotherapy, immunomodulatory drugs, targeted treatments, and cellular therapies are all options for relapsed cancer patients.

Revlamid is an immunomodulatory agent, which means it affects the immune system’s activity (lenalidomide). Agents that target a specific protein and inhibit the development and survival of cancer cells are known as targeted treatments. Bruton tyrosine kinase inhibitors (BTKi), Imbruvica (ibrutinib), Calquence (acalabrutinib), and Brukinsa are examples of targeted treatments approved by the Food and Drug Administration (FDA) for relapsed MCL (zanubrutinib). In 2020, the FDA authorised Tecartus (Brexucabtagene), a cellular therapy, for the treatment of people with MCL who have had at least one prior therapy. The patient’s own T-cells are reprogrammed to better recognise and destroy cancer cells in this treatment.

Many of these medicines may be associated with various adverse effects since many medications aimed at killing cancer cells may also harm healthy cells. As a result, patients should inquire about the specific side effects that may be associated with certain treatments from their doctors. Furthermore, physicians and other members of the health-care team may be able to take specific steps before and after treatment, as well as urge patients to take specific precautions during therapy, to assist reduce or prevent certain adverse effects. Symptomatic and supportive interventions, where needed, are also typical therapies for people with MCL.

Brukinsa (Zanubrutinib) is a medication used for the treatment of mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma. Zanubrutinib is classified as a Bruton’s tyrosine kinase inhibitor. It is given by mouth.