Mantle cell lymphoma (MCL) belongs to a group of diseases known as non-Hodgkin's lymphomas, which are related malignancies (cancers) that affect the lymphatic system (lymphomas). 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, which filters worn-out red blood cells and produces lymphocytes, and the tonsils, which are masses of lymphoid tissue in the throat region that help to fight infection. 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.
Non-Hodgkin's lymphomas (NHLs) may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) and those derived from abnormal T-lymphocytes (T-cell lymphomas). Mantle cell lymphoma (MCL) is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. NHLs may also be categorized based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, NHLs may be characterized as "low-grade" (or indolent) lymphomas, which tend to grow slowly and result in few associated symptoms, or "intermediate-" or "high-grade" (aggressive) lymphomas, which 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.
According to various estimates, MCL represents approximately 2 to 7 percent of adult NHLs in the United States and Europe. It primarily affects men over the age of 50 years. 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.
Many individuals with mantle cell lymphoma (MCL) may not appear to have symptoms (asymptomatic) during early stages of the disease. (For further information on stages, please see the section entitled “Standard Therapies: Diagnosis” [“Staging”] below.) 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) as well as certain other disorders. 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).
Some individuals with MCL may also develop certain generalized (systemic) symptoms known as “B symptoms.” (For further information, please see the section entitled “Standard Therapies: Diagnosis” [“Stages”] below.) Such symptoms include persistent or repeated fever, unexplained weight loss (i.e., loss of at least 10 percent of normal body weight), and/or sweating, particularly at night (known as “night sweats”). Reports suggest that up to one third of individuals with MCL may develop such “B symptoms.” 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. (As mentioned earlier, 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 (i.e., histologic 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 “Standard Therapies” section of this report below.)
The exact underlying cause of mantle cell lymphoma (MCL) is unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; etc.), diet, stress, and/or other factors may play varying contributing roles in causing specific types of cancer. Investigators at the National Institutes of Health (NIH)/National Cancer Institute, across the United States, and around the world are conducting ongoing basic research to learn more about the many factors that may result in cancer. (The National Cancer Institute is listed in the “Resources” section of this report below.)
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 cause of such changes is 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.
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., deregulation) of a gene (BCL-1) that regulates production of a protein known as cyclin D1. According to researchers, the BCL-1 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). For example, although the specific function of the cyclin D1 protein remains unknown, it belongs to a family of proteins involved in regulating the cell growth cycle. Evidence suggests that deregulation of the BCL-1 gene leads to increased production of the cyclin D1 protein, possibly contributing to malignant transformation of cells and excessive growth of malignant B-lymphocytes. 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.
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. 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. (For further information, please see the section entitled “Standard Therapies: Diagnosis” [“Classification/Grading” and “Staging”].)
Mantle cell lymphoma (MCL) is an uncommon form of non-Hodgkin’s lymphoma (NHL), comprising about 2 to 7 percent of adult NHLs in the United States and Europe. The disease primarily affects older adults, with males representing approximately three-quarters of those with MCL. Many affected individuals are diagnosed in their late 50s or early to mid 60s. Reports suggest that most individuals with MCL have advanced (i.e., stage III or stage IV) disease at diagnosis. (For further information on stages, please see the “Standard Therapies: Diagnosis” [“Stages”] section of this report below.)
Mantle cell lymphoma (MCL) is diagnosed based upon a thorough clinical evaluation, detection of certain symptoms and physical findings, a detailed patient history, and a variety of specialized tests. 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. These may include blood tests, biopsies, specialized imaging tests, bone marrow examination, cerebrospinal fluid (CSF) analysis, and/or other tests.
For example, blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.)
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].)
Various specialized imaging procedures may also be recommended, such as standard x-ray imaging; computed tomography (CT) scanning; magnetic resonance imaging (MRI); gallium scans; lymphangiograms; 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, 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. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. This procedure may be particularly valuable in helping to detect involvement of the brain and spinal cord (central nervous system [CNS]).
Gallium scanning may be used to help assess the extent (stage) of the disease and as a follow-up after treatment. During this procedure, a small dose of radioactive chemical known as gallium is injected. The body is then scanned from various angles and a image is produced, showing where the gallium has collected within the malignancy. Lymphangiography is a procedure in which a substance opaque to x-rays (contrast medium) is injected into lymph vessels, usually through the feet, followed by an x-ray that produces an image of lymph vessels and lymph nodes, particularly within the abdominal and pelvic regions. However, this diagnostic technique is now used less frequently than in the past, since it has been largely replaced by CT scanning of the pelvic and abdominal regions.
A procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. During this procedure, a sample of bone marrow is obtained, usually from the hipbone (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.
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.
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 mentioned above, the diagnosis of different forms of NHL requires the removal (biopsy) and microscopic (histologic) examination of tissue cells from lymph nodes or other tissues suspected of being cancerous. 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.)
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–produce distinctive proteins (antigens) that may promote an antibody response (e.g., antigens known as CD5, CD19, CD20, and CD22). They also may express certain antibodies on their outer surfaces (e.g., immunoglobulin D and M [IgD, IgM]). Thus, testing to identify such markers assists in determining the normal cells from which the malignancy derived, helping to distinguish MCL from other B-cell lymphomas and aiding in diagnosis and 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. (For further information, please see the "Causes" section of this report above.)
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 commonly used National Cancer Institute's (NCI's) International Working Formulation (IWF), which consolidates terms from past systems of classification; the Revised European-American Lymphoma (REAL) Classification, a new system that is increasing in popularity (and that includes MCL as a distinct entity); and a new World Health Organization (WHO) classification that is similar to the REAL Classification.
For example, NHLs may be divided into two major categories based upon growth pattern of a malignancy within a lymph node. In so-called follicular (or "nodular") lymphomas, cells appear clustered together within the lymph node into distinctive nodules or follicles. In diffuse lymphomas, there is widespread infiltration of the malignancy throughout the lymph node in an unorganized pattern.
NHLs may also be categorized based upon malignant cell size as well as the appearance of a malignant cell's nucleus. (The nucleus is the round, membrane-bound structure of the center of the cell containing the chromosomes.. For example, in some lymphomas, there may an abnormal indentation in a malignant cell's nucleus; such cells are called "cleaved cells.". Thus, according to certain classifications, certain follicular or diffuse lymphomas may be further characterized as small or large cleaved or "noncleaved" lymphomas.
In addition, NHL is commonly classified according to a "grading" system (e.g., within the NCI's widely used International Working Formulation). It is based upon how quickly the malignancy may tend to grow and spread as determined by certain characteristics of the malignancy upon microscopic examination and natural history of the specific disease. The grading of NHLs is important in determining potential disease course and appropriate treatment approaches.
Generally, malignancies comprised of small cells are classified as low grade (slow growing). Those consisting of larger cells are generally categorized as intermediate grade or high grade (i.e., rapidly or extremely rapidly growing).
Low-grade lymphomas are often called "indolent" lymphomas, since they typically grow relatively slowly and may have few apparent symptoms. Such lymphomas may tend to be widespread at diagnosis. In addition, in some instances, indolent lymphomas may gradually transform into a combination of indolent and aggressive lymphoma, requiring more aggressive treatment approaches. Evidence indicates that, although indolent lymphomas are rarely completely "cured," affected individuals may have the disease over long periods with a relatively good quality of life.
Intermediate- or high-grade lymphomas are generally categorized as "aggressive lymphomas" since they typically grow quickly and require prompt treatment. With immediate, aggressive treatment, such as intensive combination chemotherapy and other therapies (e.g., stem cell/bone marrow transplantation), certain aggressive lymphomas may sometimes be cured or go into remission. (In this context, remission indicates the complete or partial disappearance of symptoms and physical signs of cancer or the period during which this occurs. Remissions may be temporary or permanent. Relapse indicates the return of the disease following apparent recovery.)
Mantle cell lymphoma (MCL) 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.
In individuals with MCL, microscopic evaluation of biopsy samples usually reveals small- to medium-sized lymphocytes that may have slightly irregular or irregular (i.e., cleaved) nuclei. Such analysis may also reveal different patterns of malignant cell distribution. Thus, MCL may be further subdivided based upon these distinct growth patterns (or "histologic subtypes"), including a so-called mantle-zone pattern, in which malignant cells grow in expanding nodules around germinal centers; a relatively nodular pattern or diffuse pattern of growth throughout the node characterized by small malignant cells with somewhat irregular or "cleaved" nuclei; or a distinctive variant (i.e., blastic [blastic transformation]) in which medium- and large-sized lymphocytes are apparent with round or irregular nuclei. It has been suggested that the mantle-zone subtype may tend to have features of a low-grade (indolent) lymphoma, whereas the other subtypes may be more aggressive and are appropriately classified as intermediate-grade lymphomas. In addition, evidence suggests that the blastic variant may be most resistant to treatment.
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 non-Hodgkin's lymphoma (NHL) such as mantle cell lymphoma (MCL), assessment is also required to determine the extent or "stage" of the disease. As is the case with NHL grading, staging is important to help characterize the potential disease course and determine appropriate treatment approaches. Certain of the same diagnostic tests described above may be used in staging NHL (e.g., blood tests, CT scanning, gallium 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) 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 (extralymphatic 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 extralymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).
In those with Stage III or advanced disease, 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 extralymphatic organ or site.
In Stage IV or widespread (disseminated) disease, the malignancy is diffusely spread throughout one or more extralymphatic organs or sites with or without associated lymph node involvement.
Each stage of NHL may be further divided into categories A or B, 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."
In addition, category E may indicate that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ.
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 (histologic subtype, e.g., mantle-zone, nodular, diffuse, or blastic); 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.
In selected individuals with low-grade (indolent) NHL without apparent symptoms, physicians may recommend waiting before implementing treatment until the disease leads to certain symptoms. 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.”
However, as discussed above, MCL is typically considered intermediate-grade (aggressive) NHL. Therefore, for individuals with MCL, physicians may recommend combination therapy with multiple anticancer (chemotherapeutic) drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. For example, recommended treatment may include three medications, such as cyclophosphamide (Cytoxan), vincristine (Oncovin), and prednisone (Deltasone), which is known as “CVP,” or addition of a fourth medication–i.e., cyclophosphamide, doxorubicin or hydroxydaunorubicin (Adriamycin or Rubex), vincristine, and prednisone, known as “CHOP.”. In other cases, other drugs and drug combinations may be recommended. Although most chemotherapeutic medications are provided via a vein (intravenously [IV]), some may be administered by mouth (orally). Chemotherapy 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.
The standard treatment provided is often the CHOP regimen, possibly in association with other therapies. These may include localized radiation (radiotherapy) for selected individuals with early stage (stage I or II) lymphoma or various treatments for selected patients with advanced stage (stage III or IV) lymphoma. 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 affected individuals with involvement of the brain and spinal cord (central nervous system [CNS]), certain chemotherapeutic drugs may be administered directly into the cerebrospinal fluid (CSF) in the spinal canal (intrathecally), such as via lumbar puncture. Such administration directly into the spinal canal may be necessary since many drugs are unable to effectively penetrate the so-called “blood-brain barrier.” (This barrier prevents or slows the passage of certain foreign agents, including harmful chemicals, microorganisms, particular medications, etc., from the bloodstream into the CNS. In addition, in some individuals with aggressive NHL who have disease involvement of certain body regions, such therapy may also be recommended in an effort to help prevent proliferation of the malignancy within the CNS (CNS prophylaxis). Such treatment may include intrathecal chemotherapy as described above and/or, in some cases, high-dose intravenous treatment with certain chemotherapeutic drugs (e.g., methotrexate) that may effectively cross the blood-brain barrier.
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.
Although response to such treatments may vary widely, many individuals with MCL may have insufficient response to standard chemotherapeutic regimens or may experience relapses, and the disease often becomes resistant (refractory) to treatment, potentially leading to life-threatening complications. Therefore, researchers are exploring the potential effectiveness of differing combinations of various chemotherapeutic drugs, high-dose chemotherapy regimens followed by stem cell/bone marrow transplantation, and/or other investigational therapies that may be warranted for selected individuals, possibly at the time of diagnosis, following certain standard therapies, and/or for those with refractory disease or relapse. They are also investigating appropriate ways in which to combine various therapies and to reduce potential side effects.
In 2017, Calquence (acalabrutinib) was approved by the FDA for treatment of adults with MCL who have received at least one prior therapy. Calquence is manufactured by AstraZeneca Pharmaceuticals LP.
Other standard therapies for individuals with MCL include symptomatic and supportive measures as required.
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
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.
Argatoff LH, et al. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood. 1997;89:2067-2078.
Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Seminars in Hematology. 1999;36:115-127.
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.
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.
Finsterer J, et al. Recovery from coma caused by primary CNS mantle cell lymphoma presenting as encephalitis. Neurology. 1996;46:824-826.
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.
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.
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.
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.
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.
Hinds PW, et al. Function of a human cyclin gene as an oncogene. Proc Nat Acad Sci. 1994;91:709-713.
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.
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.
Korin HW, et al. Optimized cyclin D1 immunoperoxidase staining in mantle cell lymphoma. Appl Immunohistochem Molecul Morphol. 2000;8:57-60.
Lardelli P, et al. Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunophenotypic spectrum and clinical correlations. Am J Surg Pathol. 1990;14:752-763.
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.
Montserrat E, et al. CNS involvement in mantle-cell lymphoma. J Clin Oncol. 1996;14:941-944.
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.
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.
Oinonen R, et al. Central nervous system involvement in patients with mantle cell lymphoma. Ann Hematol 1999;78:145-149.
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.
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.
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.
Velders GA, et al. Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol. 1996;14:1269-1274.
FROM THE INTERNET
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 168461; 7/8/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?168461.
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