Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.
MCL is a subtype of B-cell lymphoma, due to CD5 positive antigen-naive pregerminal center B-cell within the mantle zone that surrounds normal germinal center follicles. MCL cells generally over-express cyclin D1 due to the t(11:14) translocation, a chromosomal translocation in the DNA.
Signs and symptoms People with mantle cell lymphoma typically present with symptoms later in life, with a median age of onset between 60 and 70 years of age. In Western countries MCL accounts for around 7% of adult non-Hodgkin's lymphomas, with between 4 and 8 per cases per million diagnosed each year. The incidence of MCL increases with age. In the United States, the median age for its diagnosis is 68 years. Three-quarters of patients are men. In addition, patients are more likely to be Caucasian.
People commonly present with a non-localizing lymphadenopathy (enlarged lymph nodes) with B symptoms including fevers, chills and night sweats sometimes being present. 80% of patients present with stage 3 or 4 disease (advanced disease) at the time of diagnosis, with involvement of the bone marrow, liver or gastrointestinal tract. 25% of patients present with a bulky lymphadenopathy characterized by lymph nodes greater than 10 cm in size. Other patients may present with central nervous system (CNS) involvement, which is associated with a very poor prognosis. However, CNS involvement is rare at diagnosis.
A rare subtype, known as non-nodal mantle cell lymphoma, presents without lymph node swelling (non-nodal) with circulating lymphoma cells (leukemic presentation). This type of mantle cell lymphoma is associated with a more indolent, asymptomatic and slowly progressive course, however malignant transformation to aggressive forms is possible.
Mantle cell lymphoma has been reported in rare cases to be associated with severe allergic reactions to mosquito bites. These reactions involve extensive allergic reactions to mosquito bites which range from greatly enlarged bite sites that may be painful and involve necrosis to systemic symptoms (e.g. fever, swollen lymph nodes, abdominal pain, and diarrhea), or, in extremely rare cases, to life-threatening anaphylaxis. In several of these cases, the mosquito bite allergy reaction occurred prior to the diagnosis of MCL suggesting that mosquito bite allergy can be a manifestation of early-developing mantle cell lymphoma.
Pathogenesis
MCL, like most cancers, results from the acquisition of a combination of (non-inherited) genetic mutations in somatic cells. This leads to a clonal expansion of malignant B lymphocytes. The factors that initiate the genetic alterations are typically not identifiable, and usually occur in people with no particular risk factors for lymphoma development. Because it is an acquired genetic disorder, MCL is neither communicable nor inheritable.
A defining characteristic of MCL is mutation and overexpression of cyclin D1, a cell cycle gene, that contributes to the abnormal proliferation of the malignant cells. MCL cells may also be resistant to drug-induced apoptosis, making them harder to cure with chemotherapy or radiation. Cells affected by MCL proliferate in a nodular or diffuse pattern with two main cytologic variants, typical or blastic. Typical cases are small to intermediate-sized cells with irregular nuclei. Blastic (aka blastoid) variants have intermediate to large-sized cells with finely dispersed chromatin, and are more aggressive in nature. The tumor cells accumulate in the lymphoid system, including lymph nodes and the spleen, with non-useful cells eventually rendering the system dysfunctional. MCL may also replace normal cells in the bone marrow, which impairs normal blood cell production.
Diagnosis
The history and physical examination may reveal some of the signs and symptoms consistent with Mantle Cell Lymphoma. Biopsy of the involved tissues (such as the lymph nodes, bone marrow, gastrointestinal tract, spleen or other areas) shows the characteristic histopathologic changes of MCL. There are distinct growth patterns of MCL seen on biopsy; these include the diffuse type, nodular type, mantle zone lymphoma and in situ mantle cell lymphoma. In the diffuse growth pattern, there is a diffuse growth of lymphoma cells throughout the lymph node resulting in effacement of the architecture of the lymph node. In the nodular type, there are large nodules of MCL cells in the lymph node with no germinal centers observed. In MCL with expansion of the mantle zone, the lymphoma cells cause expansion of the mantle zone around normal germinal centers. And in MCL in situ, the lymphoma cells are contained within the mantle zone without expansion. Histologically, the lymphoma cells in classic MCL are characterized as small to medium lymphocytes with scant cytoplasm and clumped chromatin with prominent nuclear clefts and the nucleoli are not visible. There are cytologic subtypes; the blastoid subtype, is characterized by round nuclei, fine chromatin with some distinct nucleoli. The pleomorphic subtype is characterized by nuclei that vary in size and shape with some having a cleaved form. The blastoid and pleomorphic subtypes of MCL are associated with a more aggressive course.
The most common B-cell type seen in MCL is a pre-germinal center cell (that has not yet undergone the germinal center reaction), that is CD5, CD20, CD19 positive with expression of IgM and IgD with monoclonal kappa and gamma light chains. CD23 and CD200 are usually negative and cyclin-D1 (a cell cycle regulatory protein controlling transition from the G1 phase to the S phase in the cell cycle) is classically overexpressed in MCL. SOX11 (a transcription factor controlling genes involved in cell survival) is characteristically over-expressed in MCL as well. Ki-67, a marker of cell proliferation, if elevated (greater than 30% expression) is associated with an aggressive course of MCL.
Chromosomal assessment using fluorescence in situ hybridization shows the characteristic chromosomal translocation t(11;14)(q13;q32) which is present in 90–95% of cases of MCL. Imaging using computed tomography (CT) or positron emission tomography–computed tomography is required to assess for any extra-nodal or distal involvement.
MRI of the brain and the spine are performed in cases of MCL with suspected central nervous system involvement. And, since 40-80% of MCL presents with gastrointestinal involvement at the time of diagnosis, endoscopy (colonoscopy and esophagogastroduodenoscopy (EGD)) with biopsies may also aid in the diagnosis, but they are not always required for the diagnosis of MCL.
The diagnosis may be complicated as a minority of cases of multiple myeloma, chronic lymphocytic leukemia and plasma cell leukemia may also present with the t(11;14)(q13;q32) translocation. The diagnosis may be complicated further as some cases of MCL present atypically; these rare subtypes include CD10-positive MCL, CD5-negative MCL, cyclin D1-negative MCL, CD200-positive MCL, SOX-11-negative MCL, and CD23-positive MCL. The cyclin-D1-negative MCL subtypes usually result in lymphomagenesis via over-expression of cyclin D2, cyclin D3 or cyclin E, which also lead to cell cycle hyperactivity and have a similar prognosis to the main cyclin-D1 variant of MCL.
The Lugano and Ann Arbor Staging systems are two commonly used clinical staging criteria used to stage the disease, allowing decisions to be made with respect to treatment, prognosis and salvage therapy.
TP53 Overexpression of the p53 protein is a reliable immunohistochemical (IHC) surrogate marker that strongly correlates with an underlying missense mutation in the TP53 gene, which can be examined using next-generation sequencing (NGS). TP53 mutations in MCL patients have been consistently associated with primary refractoriness to chemoimmunotherapy and significantly reduced overall survival.
Treatments There are no proven standards of treatment for MCL, and there is no consensus among specialists on how to treat it optimally. Many regimens are available and often get good response rates, but patients almost always get disease progression after chemotherapy. Each relapse is typically more difficult to treat, and relapse is generally faster. As of 2023 it is incurable though some patients can live many years after their initial diagnosis. Regimens are available that treat relapses, and new approaches are under test. Because of the aforementioned factors, many MCL patients enroll in clinical trials to get the latest treatments – a survey at a specialist treatment centre in the UK showed that In total 58.7% of patients treated at the hospital were enrolled on at least one clinical trial. Indeed, this might well be a recommendation by the patient's care team in the hope it will give them access to the latest advances.
There are four classes of treatments in general use: chemotherapy, immunotherapy, radioimmunotherapy and biologic agents. The phases of treatment are generally: frontline, following diagnosis, consolidation, after frontline response (to prolong remissions), and relapse. Relapse is usually experienced multiple times.
Chemotherapy Chemotherapy is widely used as frontline treatment, and often is not repeated in relapse due to side effects. Alternate chemotherapy is sometimes used at first relapse. For frontline treatment, CHOP with rituximab is the most common chemotherapy, and often given as outpatient by IV. A stronger chemotherapy with greater side effects (mostly hematologic) is HyperCVAD, often given in the hospital setting, with rituximab and generally to fitter patients (some of which are over 65). HyperCVAD is becoming popular and showing promising results, especially with rituximab. It can be used on some elderly (over 65) patients, but seems only beneficial when the baseline Beta-2-MG blood test was normal. It is showing better complete remissions (CR) and progression-free survival (PFS) than CHOP regimens. A less intensive option is bendamustine with rituximab.
Second line treatment may include fludarabine, combined with cyclophosphamide and/or mitoxantrone, usually with rituximab. Cladribine and clofarabine are two other medications being investigated in MCL. A relatively new regimen that uses old medications is PEP-C, which includes relatively small, daily doses of prednisone, etoposide, procarbazine, and cyclophosphamide, taken orally, has proven effective for relapsed patients. According to Dr. John Leonard, PEP-C may have anti-angiogenetic properties, something that he and his colleagues are testing through an ongoing drug trial.
Another approach involves using very high doses of chemotherapy, sometimes combined with total body irradiation (TBI), in an attempt to destroy all evidence of the disease. The downside to this is the destruction of the patient's entire immune system as well, requiring rescue by transplantation of a new immune system (hematopoietic stem cell transplantation), using either autologous stem cell transplantation, or those from a matched donor (an allogeneic stem cell transplant). A presentation at the December 2007 American Society of Hematology (ASH) conference by Christian Geisler, chairman of the Nordic Lymphoma Group claimed that according to trial results, mantle cell lymphoma is potentially curable with very intensive chemo-immunotherapy followed by a stem cell transplant, when treated upon first presentation of the disease.