NORD gratefully acknowledges Kaylie Schachter, MDCM Candidate, McGill University School of Medicine and Reem Karmali, MD, MS, Associate Professor of Medicine, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, for assistance in the preparation of this report.
Mantle cell lymphoma (MCL) is a type of non-Hodgkin’s lymphoma, which is a form of cancer that affects the lymphatic system. Lymphomas are cancers that involve white blood cells, and can be divided depending on the type of cell involved, either B-lymphocytes or T-lymphocytes. MCL is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. It affects mostly men who are usually 60 to 70 years old. Approximately one out of 200,000 individuals per year are diagnosed with MCL. The symptoms individuals experience depends on the extent of the disease and the region of the body that is affected. Many affected individuals have widespread disease at diagnosis, with involved regions often including multiple lymph nodes, the spleen, and, potentially, the bone marrow, the liver, and/or regions of the digestive (gastrointestinal) tract. Examples of symptoms include swollen painless lymph nodes, headache, weakness, decreased appetite, and indigestion. Other non-specific symptoms may include fever, weight loss, sweating at night (“night sweats”), fatigue, reduced energy, easy bruising or bleeding. Several treatment options are available. The management selected will be based on a number of patient and disease characteristics. The first-line treatment typically includes chemotherapy combined with immunotherapy, which is a combination of medications that destroy the cancer cells. This approach is meant to cause complete or partial disappearance of the cancer (remission). Following that, patients may be eligible for a stem cell transplant, and/or an extended course of immunotherapy that is meant to prolong cancer remission.
Mantle cell lymphoma belongs to a group of diseases known as non-Hodgkin’s lymphomas, which are related malignancies (cancers) that affect the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.
As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen. Lymphatic tissues also include the thymus, a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty, as well as the bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body, such as the skin, small intestine, liver, and other organs. There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes.
Mantle cell lymphoma and other cancers of the lymphatic system (lymphomas) result from errors in the production of a lymphocyte or transformation of a lymphocyte into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from case to case, depending upon the extent and region(s) of involvement and other factors.
Mantle cell lymphoma is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. As previously mentioned, the signs and symptoms of MCL are dependent on the extent of the region of the body that is affected. Although the exact underlying cause is unknown, researchers have identified several genetic changes (or mutations) in the B-cells, which contribute to the multiplication of the cancer cells. For MCL, a mutation referred to as t(11;14) and denotes the exchange of genetic information between chromosome 11 and 14, leads to the overproduction of a protein called cyclin D1 in the lymphoma cells as will be further explained in the “Causes” section of this report below. These changes are found in more than 90 percent of patients with MCL and are important for diagnosis.
Several disease characteristics are considered when attempting to determine if the cancer will be indolent or aggressive. Indolent lymphomas tend to grow slowly and result in few associated symptoms, whereas more aggressive lymphomas, typically grow rapidly, requiring prompt treatment. There is some debate concerning whether MCL should be categorized as a slow-growing (indolent) or rapidly-growing (aggressive) lymphoma. Although experts have classified MCL as an aggressive lymphoma, it has been shown to have certain characteristics of indolent lymphoma.
Many individuals with mantle cell lymphoma may not have symptoms (asymptomatic) during early stages of the disease. However, affected individuals may eventually seek medical attention due to persistent, usually painless, swelling of certain lymph nodes, particularly nodes within the neck and throat region (e.g., Waldeyer’s ring). Waldeyer’s ring consists of the protective ring of lymphoid tissues near the base of the tongue (lingual tonsils); on either side of the throat (palantine tonsils); and near the back opening of the nasal cavity (pharyngeal tonsils or adenoids). Individuals with non-Hodgkin’s lymphomas (NHLs), including MCL, may also have enlargement of other lymph nodes, such as nodes at the elbows or shoulders; under the arms (axillae); in the chest, abdominal, and/or pelvic regions; and/or in other areas. Lymph node enlargement may be confined to a single region or be present in various areas of the body.
Some affected individuals may develop additional symptoms and signs that are “non-specific” in nature, meaning that they may be associated with any number of underlying disorders, including other forms of lymphoma (other non-Hodgkin’s lymphomas and Hodgkin’s disease). For example, some individuals may have lack of appetite (anorexia), nausea, vomiting, and indigestion. Additional symptoms may include a sense of “fullness” (satiety), abdominal swelling (distension) or bloating, and abdominal pain or discomfort. Such findings may be due to enlargement of abdominal lymph nodes and/or of the spleen (splenomegaly) or liver (hepatomegaly) or involvement of the gastrointestinal tract.
Some individuals with MCL may also develop certain generalized (systemic) symptoms known as “B symptoms.” Such symptoms include persistent or repeated fever, unexplained weight loss (i.e., loss of at least 10 percent of normal body weight in the 6 months prior to diagnosis), and/or sweating, particularly at night (known as “night sweats”). It is suggested that up to one third of individuals with MCL may have “B symptoms” by the time they present to their doctor. However, such findings more commonly occur in individuals with Hodgkin’s disease as compared to those with different forms of NHL. (For further information on Hodgkin’s disease, please see the “Related Disorders” section below.)
Depending upon the extent and region(s) of involvement, some individuals with MCL may develop other or additional symptoms and findings due to infiltration by proliferating lymphoma cells within and impaired functioning or failure of certain organs and tissues. If MCL has spread to involve the bone marrow, for example, malignant lymphocytes may essentially crowd the bone marrow, resulting in decreased manufacture of certain blood cells. (The bone marrow is the soft, spongy tissue located within the cavities of bones that produces blood cells. More specifically, immature cells known as stem cells within the bone marrow develop into the three cellular components of the blood: i.e., red blood cells, which contain the oxygen-carrying pigment hemoglobin; white blood cells, which help to fight infection; and platelets, which play an essential role in blood clotting [coagulation].) Some individuals with bone marrow involvement may develop anemia or abnormally low levels of the oxygen-transporting component of red blood cells. Associated symptoms may include fatigue, listlessness and lack of energy (lethargy), paleness of the skin (pallor), headaches, and/or other symptoms. Affected individuals may also become susceptible to certain infections, easy bruising and excessive bleeding, and/or other findings.
In some individuals with MCL, there may be involvement of the digestive (gastrointestinal [GI]) tract. In some of these cases, GI involvement may be associated with the development of multiple polyps within the intestines (lymphomatous polyposis). Intestinal polyps are growths of tissue that project, often on a stalk, from the intestinal wall. In addition, in some rare cases, MCL may also spread to involve the brain and spinal cord (central nervous system [CNS]), potentially resulting in certain neurologic signs. Although such symptoms may be variable, they may include lethargy, headaches, weakness, confusion, personality changes, sudden episodes of uncontrolled electrical activity in the brain (seizures), and/or other findings.
Depending on MCL subtype, sites and extent of involvement, disease management, and other factors, disease progression may eventually lead to life-threatening complications. (For further information on subtypes, disease staging, treatment options, etc., please see the “Classification,” “Staging,” and “Standard Therapies” section of this report below.)
The exact underlying cause of mantle cell lymphoma is unknown. As with numerous types of cancer, there are many possible factors that may contribute to its development. These factors include genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; etc.), diet, stress and others. Current investigations are researching the possibility of an association between family history, inflammation, infection and the development of MCL.
In individuals with cancer, including MCL, malignancies may develop due to abnormal changes in the structure and orientation of certain cells (e.g., lymphocytes). As mentioned above, the specific factors that cause such changes are unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically), such as due to exposure to certain environmental factors, or, more rarely, may be inherited. Specifically, for MCL, several genetic abnormalities have been identified.
Evidence suggests that many individuals with MCL have a specific, acquired genetic change in which there was an exchange of chromosomal material (translocation) between certain regions of the long arms of chromosomes 11 and 14 (11q13 and 14q32). Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 11q13” refers to band 13 on the long arm of chromosome 11.
This specific chromosomal translocation–t(11;14)(q13;q32)–has been shown to lead to impaired functioning (i.e., dysregulation) of a gene (CCND1) that regulates production of a protein known as cyclin D1. According to researchers, the CCND1 gene, located at chromosome 11q13, may function as an oncogene. In other words, when functioning normally, the gene is thought to have some role in controlling cellular growth and multiplication; however, if it is altered in some way (e.g., by exposure to certain environmental factors), it may cause the cell to be converted to a malignant state (malignant transformation).
Evidence suggests that dysregulation of the CCND1 gene leads to increased production of the cyclin D1 protein. Cyclin D1 protein belongs to a family of proteins involved in regulating cell cycle progression and therefore, cell proliferation. Therefore, overexpression of cyclin D1 likely contributes to malignant transformation of cells and excessive growth of malignant B-lymphocytes. However, increased expression of cyclin D1 is not sufficient to cause MCL on its own. Investigators also indicate that abnormalities in the expression of other genes (e.g., the p53 gene, which normally functions as a tumor suppressor gene) may play some role in leading to MCL.
The cancerous cells often express another gene, which is known as SOX11. SOX11 is not typically found in B-cells; however, it may be found in the malignant B-cells of MCL. In cells that have undergone malignant transformation, there is typically reversion to a less specialized, more primitive form (i.e., loss of “differentiation” or anaplasia), meaning that the cells do not perform their “intended,” specialized functions within the tissue in question. SOX11 is believed to block the differentiation of B cells so that they remain in their more primitive form. Malignant cells pass their abnormal changes on to all their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body’s natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm).
In individuals with MCL, lymphocytic malignant transformation and uncontrolled cellular growth may lead to abnormal expansion of a region of the lymph node known as the mantle zone; eventual destruction of the region with loss of the mantle zone boundaries; and potentially widespread growth of malignant lymphocytes throughout the node (i.e., diffuse lymphoma). Disease progression may be characterized by involvement of additional lymph node regions and/or other lymphatic tissues and spread of the malignancy to other bodily tissues and organs. The rate of malignant cell growth, resulting symptoms and findings, and overall disease course may vary, depending upon various factors.
Mantle cell lymphoma is an uncommon form of non-Hodgkin’s lymphoma (NHL), accounting for 5% to 7% of all cases of NHL. Approximately one out of 200,000 individuals is diagnosed each year with MCL. The disease primarily affects older adults, with males representing approximately three-quarters of those with MCL. Many affected individuals are diagnosed at approximately 60 to 70 years old. Reports suggest that most individuals with MCL have advanced (i.e., stage III or stage IV) disease at diagnosis.
Mantle cell lymphoma is diagnosed based upon a detailed patient history, thorough clinical evaluation and a variety of specialized tests, including a biopsy of an affected lymph node or the bone marrow. Such testing is necessary to confirm the specific type (and subtype) of NHL present, to assess the nature and extent of the disease, and to determine the most appropriate treatments.
During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck, tonsil, and adenoidal region, under the arms, and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen and liver, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.
For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. In order to confirm the diagnosis, a biopsy of an affected lymph node or of the bone marrow must be done. Such evaluation is necessary to help differentiate MCL from other malignancies, including different forms of NHL and Hodgkin’s disease, as well as other diseases that may affect the lymph nodes. (For further information, please see the “Related Disorders” section of this report above.)
Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Depending upon the specific type of biopsy performed, the procedure may be conducted under local or whole body (general) anesthesia. In addition, in some cases, such as when involvement appears to be restricted to the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. (Biopsy samples are examined by physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis [pathologists].)
For individuals with MCL, microscopic evaluation of biopsy samples may reveal abnormalities of the normal structure (architecture) of the lymph nodes, such as expansion of the region of the lymph node known as the mantle zone. More specifically, there may be abnormal infiltration and expansion of the mantle zone around germinal centers* of the lymph node, eventual loss of mantle zone boundaries, and potentially widespread growth of malignant lymphocytes throughout the node. (*Lymph nodes are comprised of a fibrous outer capsule and an inner mass of lymphatic tissue. The outer region or cortex includes groups of lymphocytes known as follicles; regions known as germinal centers are at the center of the follicles. Germinal cells are primarily B-lymphocytes.)
Microscopic analysis also enables pathologists to determine additional histologic features that may be important in the malignancy’s classification, such as size of malignant lymphocytes, appearance of the nucleus within a lymphoma cell, distribution or pattern of the abnormal cells, etc. (For further information, please see “Classification/Grading” below). In addition, specialized studies are conducted to help determine the malignancy’s specific cell type of origin. For example, MCL cells–and the normal cells from which the malignancy develops– have specific antigens located on their cell surface that can be identified using specialized tests, such as immunohistochemistry. Examples of some of the antigens that should be identified to diagnose MCL include CD5, CD19, CD20, and CD22. Thus, testing to identify such markers assists in differentiating normal cells from malignant cells, and helping to distinguish MCL from other B-cell lymphomas to aid in disease management decisions.
Additional specialized tests may also be conducted on biopsy samples to assist in a diagnosis of MCL. These may include studies to detect the presence of the chromosome 11;14 translocation in malignant lymphocytes and the cyclin D1 protein. Immunohistochemistry may also be used to identify the expression of gene SOX11, which may be helpful in rare cases that do not express cyclin D1. (For further information, please see the “Causes” section of this report above.)
In a specific subtype of MCL (“leukemic non-nodal subtype”), a procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. (For further information on subtypes, please see “Classification” below). During this procedure, a sample of bone marrow is obtained, usually from the hip bone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.
Although the lymph node biopsy is the crucial test in diagnosing MCL, there are several other tests that must be done in order to evaluate the extent and the effects of the illness. Several of these tests may occur prior to the biopsy.
Blood tests will be done to evaluate the number and appearance of white blood cells, red blood cells, and platelets, liver enzyme studies, renal function tests, tests to measure levels of the enzyme lactate dehydrogenase (LDH), calcium, uric acid and/or other studies.
Various specialized imaging procedures may also be recommended, such as standard x-ray imaging; computed tomography (CT) scanning; magnetic resonance imaging (MRI); positron emission tomography scans (PET); and/or other studies. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed NHL including MCL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs. This helps to assess the extent (stage) of the disease. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. This may be particularly valuable in helping to detect involvement of the brain and spinal cord (central nervous system [CNS]).
PET scans may also be used stage the disease and as a follow-up after treatment to assess response to therapy (mostly used in clinical trials). During this procedure, a small dose of radioactive chemical is injected. The body is then scanned from various angles and an image is produced, showing where the radioactive chemical has collected within the body. This helps to identify areas of active disease.
As mentioned earlier, NHL, including MCL, may sometimes spread to the brain and spinal cord. In such cases, analysis of cerebrospinal fluid (CSF) may reveal certain abnormalities of chemical content as well as the presence of cancerous cells. CSF is a watery fluid that flows through and protects the cavities (ventricles) of the brain; the space (i.e., subarachnoid space) 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). CSF is obtained for analysis by a procedure known as a lumbar puncture. During the procedure, skin and overlying tissue at the base of the spine is numbed with local anesthetic; a needle is then inserted between certain bones in the lower back and a sample of CSF is removed.
As the gastrointestinal tract may develop polyps (lymphomatous polyposis), individuals with early stages of MCL or those with specific symptoms should undergo an endoscopy. An endoscopy is a procedure where a physician will put a camera in the esophagus to look for polyps, while the patient is given medication that keeps him/her comfortable.
In some cases, physicians may recommend other testing procedures to help assess the extent of disease and to follow treatment. In addition, tests may be required to help evaluate the health and functioning of certain organs that may potentially be adversely affected due to certain treatments (e.g., particular anticancer [chemotherapeutic] drugs]). For example, such tests may include certain procedures to evaluate functioning of the heart and lungs.
As discussed above, non-Hodgkin’s lymphomas (NHLs) may be broadly classified into B-cell and T-cell lymphomas based upon the cell type of origin. In addition, the NHLs may be categorized according to how quickly the malignancy is growing; the growth pattern and appearance of malignant cells; genetic findings; and/or a combination of such factors. Several systems of identification have been proposed based upon certain or all of these elements. These include the Rappaport classification (no longer used), the National Cancer Institute’s (NCI’s) International Working Formulation (IWF), which consolidated terms from past systems of classification; the Revised European-American Lymphoma (REAL) Classification, and the World Health Organization (WHO) classification. The WHO classification originated as a modification to the REAL classification in 2001, and has undergone several updates, most recently in 2018. These classification systems have been developed in order to describe and define diseases, to help with diagnoses and plan management.
Mantle cell lymphoma has been called by various terms according to different classifications, including diffuse small-cleaved cell lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation. However, in 1992, an international consensus conference of experts proposed the name mantle cell lymphoma to help distinguish it more appropriately from other NHLs.
The WHO classification system divides NHL according to the cell which the cancer started from and how the malignant cells look under the microscope. This classification system provides information about the genetic components of the disease and the organs which are commonly involved. Non-Hodgkin’s lymphomas have been divided into two categories. These categories depend on whether the NHL starts from a precursor cell or from a more mature version of the cell. Well over 50 subtypes of NHL have been identified with this classification system.
In the WHO classification, mantle cell lymphoma has been classified into the mature cell group. MCL is described as a mature B-cell neoplasm. Microscopic evaluation of biopsy samples usually reveals small to medium sized lymphocytes with irregular nuclei.
MCL has been divided into two subtypes as they have been found to have different clinical presentations, different histological findings when evaluated under the microscope, and various molecular pathways involved. The first subtype, known as “Classical MCL” has limited mutations in a gene called IGHV and expresses the gene SOX11. It develops outside the germinal center of lymph nodes. In addition to lymph node involvement, other extranodal sites are often involved. If this subtype acquires additional genetic abnormalities in cell cycle regulation, it could lead to a more aggressive form known as blastoid or pleomorphic MCL.
The second subtype, known as “leukemic non-nodal MCL” develops in the germinal center of lymph nodes. This subtype has mutations in the IGHV gene and does not express SOX11. There is no or minimal enlargement of lymph nodes (lymphadenopathy). It involves peripheral blood, bone marrow and possibly leads to enlargement of the spleen (splenomegaly). It is known to be a more indolent subtype, meaning it may grow relatively slowly. However, if secondary genetic abnormalities do occur, (i.e., TP53 mutation), it could lead to a more aggressive disease.
Accordingly, experts disagree whether mantle cell lymphoma as a whole is more appropriately classified as indolent or aggressive. Although the National Cancer Institute (NCI) has categorized MCL as an aggressive lymphoma, the malignancy is known to have certain features associated with indolent lymphomas in some cases.
When an individual is diagnosed with a NHL such as MCL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests described above may be used in staging NHL (e.g., blood tests, CT scanning, PET scanning, bone marrow biopsy). In addition, in some cases, additional biopsies may be obtained to assist in lymphoma staging.
The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)
Although various staging systems have been described, a system commonly used for adult NHLs (i.e., the Ann Arbor staging system or Lugano staging system) includes the following stages:
Stage I indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extra-lymphatic organ or site).
Stage II refers to locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extra-lymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).
Stage III indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extra-lymphatic organ or site.
Stage IV indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extra-lymphatic organs or sites with or without associated lymph node involvement.
Each stage of NHL may be further divided into categories A, B, E, S and X based upon whether or not affected individuals have symptoms. More specifically:
A indicates that no generalized (systemic) symptoms are present upon diagnosis.
B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). Thus, individuals with such features may be said to have “B symptoms.”
E indicates that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ.
S indicates the lymphoma has spread to the spleen.
X indicates there are large masses of lymphoma, known as bulky disease. To classify the mass as bulky, it needs to meet specific criteria, such as being larger than 10 cm across.
Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors.
As discussed above, many individuals with MCL may not appear to have symptoms during the early stages of the disease. As a result, the disease is most often diagnosed in later, advanced stages (i.e., Stage III or Stage IV). Accordingly, at diagnosis, the malignancy may have spread beyond lymph nodes and may often affect the spleen, the bone marrow, and organs outside the lymphatic system, such as the liver or regions of the digestive (gastrointestinal [GI]) tract.
The diagnosis and therapeutic management of MCL may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other professionals.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage (see “Stages” above); tumor size; subtype of MCL (i.e., classical vs leukemic non-nodal); the presence or absence of certain symptoms; individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Certain factors can be measured to determine if the MCL is more indolent or more aggressive. When individuals are diagnosed with a more indolent form, with no apparent symptoms, physicians may recommend a short period of waiting before implementing treatment. In such cases, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watchful waiting.”
Individuals who are diagnosed with a more aggressive form will often need to start treatment near the time of diagnosis. The physicians may recommend combination therapy with multiple anticancer drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. The most common types of anticancer agents used in MCL for initial therapy are chemotherapy and immunotherapy. Chemotherapy refers to anticancer medications that have a direct toxic effect on cancer cell replication. Immunotherapy refers to anticancer medications that use the body’s own immune system to fight cancer cells. An example of immunotherapy is the monoclonal antibody rituximab. Rituximab binds to a specific target on tumor cells that express CD20 causing the immune system to attack and lyse (break apart) the tumor cells.
Although most anticancer medications are provided via a vein (intravenously [IV]), some may be administered by mouth (orally). Chemotherapy and/or immunotherapy is typically provided at regular intervals or “cycles” on an outpatient basis, such as at a physician’s office, at the hospital, and/or at home. However, it may sometimes be necessary to receive such therapy on an inpatient basis. The number of treatment cycles may depend upon several factors, including the specific drug regimen(s), response to treatment, patient’s overall health, etc.
Most of the management options start with an induction phase, meaning the goal of that treatment is to put the lymphoma into remission. This may include chemotherapy and immunotherapy. Remission refers to the partial or complete disappearance of symptoms and physical signs of cancer. Following the induction, another treatment is given with the goal of keeping the cancer in remission. This treatment is often referred to as “consolidation.” In MCL, an extended course of treatment referred to as “maintenance” is used to prolong cancer remission as well.
At the time of diagnosis, if the illness is in stage 1 or 2, without bulky disease, patients may first be treated with chemotherapy and immunotherapy induction followed by consolidation radiation therapy to the affected site. During radiotherapy, radiation (via x-rays or other sources of radioactivity) is passed through selected regions of the body to destroy cancer cells and shrink tumors. Radiotherapy is provided in carefully determined dosages to help minimize damage to normal body cells. The total amount of radiation is typically provided on an outpatient basis over several weeks. For those with bulky disease or adverse prognostic factors, they will be treated similarly to patients in the later stages.
If MCL is determined to be more advanced in stage (stage 3 or 4), physicians must consider patient characteristics and preferences as well as clinical and disease factors when determining which treatment to provide. For younger patients (usually less than 65 years old) old and fit patients, it is recommended for them to receive an intensive treatment course with induction therapy followed by autologous stem cell transplant (ASCT) and immunotherapy maintenance. ASCT is a procedure that involves collecting healthy blood stem cells from the patient, and following chemotherapy, the stem cells are put back into the patient after high-dose chemotherapy is used.
There are various combinations of medications that can be used for induction therapy but typically incorporate the monoclonal antibody rituximab and a combination chemotherapy regimen that includes cytarabine as a drug. Examples include R-hyperCVAD, which represents a combination of the following medications – rituximab with cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine), or R-DHAP, which represents rituximab with dexamethasone, cytarabine and cisplatin. After induction, ASCT consolidation is administered to those in remission. This is followed with rituximab as a maintenance therapy for several years with the goal of prolonging remission.
Elderly patients will also receive immunochemotherapeutic medications to induce remission. There are several combinations of medications that can be given. Examples of possible combinations are R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), BR (bendamustine and rituximab) and rituximab, bendamustine and cytarabine (R-BAC). The induction would be followed with rituximab as the maintenance medication.
In frail patients, a less toxic medication regimen may be prescribed, usually with the goal of palliation. An example of a medication used in this circumstance is rituximab alone.
If a patient were to experience a relapse in their illness following initial therapy, there are several treatment options available. Similarly to determining the initial therapy, the relapse therapy will be dependent on patient characteristic and preferences, as well as disease factors. In the relapsed setting, chemotherapy, immunotherapy, immunomodulatory agents, targeted therapies and cellular therapies are available.
Immunomodulatory agents refer to drugs that alter the functioning of the immune system and include Revlamid (lenalidomide). Targeted therapies are agents that target a specific protein and stop signals in cancer cells responsible for growth and survival. Examples of targeted agents approved by the Food and Drug Administration (FDA) in relapsed MCL include Bruton tyrosine kinase inhibitors (BTKi), Imbruvica (ibrutinib) Calquence (acalabrutinib), and Brukinsa (zanubrutinib). Most recently, in 2020, the FDA also approved a cellular therapy Tecartus (Brexucabtagene) for treatment of adults with MCL who have received at least one prior therapy. This treatment utilizes the patient’s own T-cells and reprograms them to better detect and destroy cancer cells.
Because certain therapies directed against destroying cancer cells may also damage healthy cells, many of these therapies may be associated with various side effects. Therefore, patients should ask their physicians about the specific effects that may be associated with certain treatments. In addition, physicians and other members of the health care team may be able to take certain steps during and following treatment and may advise patients to take particular precautions during therapy that may help to alleviate or prevent certain side effects. Other standard therapies for individuals with MCL include symptomatic and supportive measures as required.
Currently, there are several clinical trials under way with the goal of identifying drugs that can cure or increase the remission rate of mantle cell lymphoma. Some of these ongoing studies are focusing on the initial treatment of MCL at the time of diagnosis, whereas other studies are investigating drugs which could be used for individuals with relapsed or refractory disease. Many of these drugs can be classified as either chemotherapeutic agents, immunotherapies like rituximab, targeted agents, cellular therapies or immunomodulators. Research of these drugs and several others either alone or in combination is ongoing and necessary in order to determine long term safety and efficacy.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies, Inc.; 1998:700-706.
DeVita Jr. VT, et al., eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1997:2135, 2185, 2202-2203.
Veloza L, Ribera-Cortada I, Campo E. Mantle cell lymphoma pathology update 2016 WHO classification. Ann Lymphoma. 2019;3:3.. http://aol.amegroups.com/article/view/5078/html.
McKay P, Leach M, Jackson B, et al. Guideline for the management of mantle cell lymphoma. British Jounal of Haematology. 2018;182:46-62. https://pubmed.ncbi.nlm.nih.gov/29767454/.
Schieber M, Gordon LI, Karmali R. Current overview and treatment of mantle cell lymphoma. F1000Res. 2018;7:F1000 Faculty Rev-1136. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069726/.
Quintanilla-Martinez L. The 2016 updated WHO classification of lymphoid neoplasias. Hematol Oncol. 2017;35:37-45. https://pubmed.ncbi.nlm.nih.gov/28591427/.
Dreyling M, Campo E, Hermine O, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow up. Ann Oncol. 2017;28:iv62-iv71. https://pubmed.ncbi.nlm.nih.gov/28881919/
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.. https://pubmed.ncbi.nlm.nih.gov/26980727/.
Sander B. Mantle cell lymphoma: recent insights into pathogenesis, clinical variability, and new diagnostic markers. Semin Diagn Pathol. 2011;28:245-55. https://pubmed.ncbi.nlm.nih.gov/21850989/.
Good DJ, Gascoyne RD. Classification of non-Hodgkin’s lymphoma. Hematology/Oncology clinics of North America. 2008;22:781-805. https://www.sciencedirect.com/science/article/pii/S0889858808001007?via%3Dihub.
Chen CC, et al. Classification of small B-cell lymphoid neoplasms using a paraffin section immunohistochemical panel. Appl Immunohistochem Molecul Morphol. 2000;8:1-11.
Coupland SE, et al. Small cell B-cell lymphomas: guidelines for differential diagnosis. Pathologe. 2000;21:147-161.
Foran JM, et al. Treatment of mantle-cell lymphoma with Rituximab (chimeric monoclonal anti-CD20 antibody): analysis of factors associated with response. Ann Oncol. 2000;11:117-121.
Katz RL, et al. Detection of chromosome 11q13 breakpoints by interphase fluorescence in situ hybridization. A useful ancillary method for the diagnosis of mantle cell lymphoma. Am J Clin Pathol. 2000;114:248-257.
Korin HW, et al. Optimized cyclin D1 immunoperoxidase staining in mantle cell lymphoma. Appl Immunohistochem Molecul Morphol. 2000;8:57-60.
Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Seminars in Hematology. 1999;36:115-127.
Oinonen R, et al. Central nervous system involvement in patients with mantle cell lymphoma. Ann Hematol 1999;78:145-149.
Freedman AS, et al. High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantle-cell lymphoma: no evidence for long-term remission. J Clin Oncol. 1998;16:13-18.
Hiddemann W, et al. Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol. 1998;16:1922-1930.
Khouri IF, et al. Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol. 1998;16:3803-3809.
Pileri SA, et al. From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities? Ann Oncol. 1998;9:607-612.
Argatoff LH, et al. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood. 1997;89:2067-2078.
de Boer CJ, et al. Bcl-1/cyclin D1 in malignant lymphoma. Ann Oncol. 1997;8:109-117.
Dreger P, et al. Sequential high-dose therapy and autologous stem cell transplantation for treatment of mantle cell lymphoma. Ann Oncol. 1997;8:401-403.
Majlis A, et al. Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants. J Clin Oncol. 1997;15:1664-1671.
Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89:3909-3918.
Finsterer J, et al. Recovery from coma caused by primary CNS mantle cell lymphoma presenting as encephalitis. Neurology. 1996;46:824-826.
Montserrat E, et al. CNS involvement in mantle-cell lymphoma. J Clin Oncol. 1996;14:941-944.
Velders GA, et al. Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol. 1996;14:1269-1274.
Fisher RI, et al. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood. 1995;85:1075-1082.
Stewart DA, et al. The role of high-dose therapy and autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Ann Oncol. 1995;6:263-266.
Teodorovic I, et al. Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin’s lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol. 1995;13:2819-2826.
Harris NL, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84:1361-1392.
Hinds PW, et al. Function of a human cyclin gene as an oncogene. Proc Nat Acad Sci. 1994;91:709-713.
Shivdasani RA, et al. Intermediate lymphocytic lymphoma: clinical and pathologic features of a recently characterized subtype of non-Hodgkin’s lymphoma. J Clin Oncol. 1993;11:802-811.
Lardelli P, et al. Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunophenotypic spectrum and clinical correlations. Am J Surg Pathol. 1990;14:752-763.
Non-Hodgkin’s Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. Cancer. 1982;49:2112-2135.
FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. US Food and Drug Administration. Updated July 27, 2020. https://www.fda.gov/drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma. Accessed August 28, 2020.
PDQ Adult Treatment Editorial Board. Adult Non-Hodgkin Lymphoma Treatment (PDQ®): Health Professional Version. National Cancer Institute. Updated June 26, 2020. https://pubmed.ncbi.nlm.nih.gov/26389492/ Accessed August 28, 2020.
Lynch DT, Acharya U. Cancer, Mantle Cell Lymphoma. StatPearls. Updated June 7, 2020. https://www.ncbi.nlm.nih.gov/books/NBK536985/ Accessed: August 28, 2020.
Lymphoma- Non-Hodgkin: Subtypes. Cancer.net. Published August 2019. https://www.cancer.net/cancer-types/lymphoma-non-hodgkin/subtypes Accessed August 28, 2020.
Freedman AS, Aster JC. Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma. UpToDate, Inc. Updated August 5, 2019. https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-mantle-cell-lymphoma?search=mantle%20cell%20lymphoma&source=search_result&selectedTitle=1~86&usage_type=default&display_rank=1 Accessed August 28, 2020.
Freedman AS, Friedberg JW. Initial treatment of mantle cell lymphoma. UpToDate, Inc. Updated November 14, 2019. https://www.uptodate.com/contents/initial-treatment-of-mantle-cell-lymphoma?search=mantle%20cell%20lymphoma&source=search_result&selectedTitle=2~69&usage_type=default&display_rank=2 Accessed August 28, 2020.
Patel PP, Hernandez-Ilizaliturri FJ. Non-Hodgkin Lymphoma Guidelines. Medscape. Updated June 12, 2019. https://emedicine.medscape.com/article/2500022-overview#a7 Accessed August 28, 2020.
Köhler S, Carmody L,Vasilevsky N, et al. Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic Acids Research. Published 2018. https://hpo.jax.org/app/browse/disease/ORPHA:52416 Accessed August 28, 2020.
Current NHL research and clinical trials. Leukemia & lymphoma society of Canada https://www.llscanada.org/lymphoma/non-hodgkin-lymphoma/treatment/clinical-trials#. Accessed August 28, 2020.
Non-Hodgkin Lymphoma. Canadian Cancer Society. https://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/?region=on. Accessed August 28, 2020.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100