Mantle cell lymphoma overview

# Overview
Mantle cell lymphoma is a subtype of B-cell lymphoma characterized by the presence of CD5 positive antigen-naive, pregerminal center, B-cells within the mantle zone that surrounds normal germinal center follicles. Mantle cell lymphoma accounts for 48% of all adult non-Hodgkins lymphomas (NHL). It has an incidence of approximately 1-2/100000 and tends to occur more in males, Caucasian race, with a median age of about 60 years.The translocation t(11;14)(q13;q32) is considered the precipitating oncogenic event that induces cell cycle deregulation in mantle cell lymphoma due to overexpression of cyclin D1. In addition to the pathogonomic translocation, MCL progression is controlled by secondary genetic abberations and dysregulated signaling pathways involved in DNA damage repair, proliferation, and apoptosis. According to the revised 2016 World Health Organization classification of lymphoid neoplasms, mantle cell lymphoma (MCL) can be broadly classified into classical MCL and leukemic nonnodal MCL. In-situ mantle cell neoplasia (ISMCN) is considered a separate entity, often as a precursor lesion, to the mantle cell lymphoma. The causes of mantle cell lymphoma have not been clearly identified. There are no established risk factors for mantle cell lymphoma. However, recently weak associations have been observed in the development of mantle cell lymphoma with the exposure to European strains of Borellia burgdoferi, family history of hematologic malignancy and Genetic polymorphisms in the pro-inflammatory cytokine IL-10. Mantle cell lymphoma must be differentiated from other diseases that present similarly with B symptoms (fever, night sweats and unexplained weight loss), lymphocytosis, lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. Mantle cell lymphoma must be differentiated from other diseases such as diffuse large B cell lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, lymphoplasmacytoid lymphoma/Immunocytoma, marginal zone lymphoma, lymphoblastic lymphoma, burkitt lymphoma and reactive hyperplasia. Screening for mantle cell lymphoma is not recommended. The prognosis of mantle cell lymphoma has historically been very poor. However, recently improvements have been made and the median survival has increased from 3-4 years to 5-7 years. It is very important to stratify the patients according to their biological risk to better direct the therapeutic approaches. Tissue biopsy (nodal or extranodal) is the gold standard test for the diagnosis of mantle cell lymphoma. The most common symptoms of mantle cell lymphoma include fever, weight loss, night sweats, fatigue, skin rash, abdominal pain, bone pain, loss of appetite, and painless swelling in the neck, axilla, groin, thorax and abdomen. Common physical examination findings of mantle cell lymphoma include fever, rash, splenomegaly, hepatomegaly, peripheral lymphadenopathy, and central lymphadenopathy. Laboratory tests for mantle cell lymphoma include complete blood count (CBC), comprehensive metabolic panel, LDH levels, Hepatitis B testing if treatment with rituximab is planned, uric acid levels, beta-2-microglobulin, pregnancy testing in woman of child-bearing age, flow cytometry, immunohistochemistry, genetic testing and FISH. Ultrasound may be helpful in the diagnosis of mantle cell lymphoma. Findings on an ultrasound helpful in the diagnosis of mantle cell lymphoma include lymphadenopathy, splenomegaly and hepatomegaly. There are no echocardiography findings associated with mantle cell lymphoma. However, an echocardiography may be helpful in following patients who might be at risk of anthracycline-induced cardiotoxicity due to chemotherapy. CT scan may be helpful in the diagnosis of mantle cell lymphoma. CT scans of the chest, abdominal and pelvic are done to check for lymphadenopathy and is helpful in the staging the disease. MRI may be helpful in the diagnosis of mantle cell lymphoma involving the CNS. PET scan (positron emission tomography) integrated with CT scan may be helpful in the staging and treatment response assessment of mantle cell lymphoma. Other diagnostic studies for the diagnosis of mantle cell lymphoma include bone marrow aspiration, lumbar puncture, colonoscopy, upper endoscopy, laparoscopy, and laparotomy.The mainstay of treatment for mantle cell lymphoma is chemotherapy. However, immunotherapy, radioimmunotherapy, targeted therapy using newer biologic agents and stem cell transplantation are also used along with chemotherapy to treat the disease. Mantle cell lymphoma shows a heterogeneous clinical behavior, with some patients having indolent disease whereas a vast majority show aggressive presentation. Most of the patients eventually relapse and have disease progression after treatment. Hence, mantle cell lymphoma is still considered an incurable disease and there is no consensus among oncologists about its optimal treatment. It is therefore recommended that mantle cell lymphoma patients are seen by physicians having extensive experience in dealing with mantle cell lymphoma and they are also encouraged to participate in clinical trials to get the latest treatments. Recent advances in the understanding of the pathogenesis of mantle cell lymphoma have led to the development of targeted therapies which have shown potential promise as effective therapeutic approaches in the future.

# Historical Perspective
In 1982, Weisenburger first proposed the concept of 'mantle-zone lymphoma' and in 1992, Banks first coined the term mantle cell lymphoma (MCL). In 1994, MCL was included into the Revised European-American Classification of Lymphoid Neoplasms (REAL) classification, and later also in the World Health Organization (WHO) Classification of Tumors of Haematopoietic and Lymphoid Tissues

# Classification
According to the revised 2016 World Health Organization classification of lymphoid neoplasms, mantle cell lymphoma (MCL) can be broadly classified into two types:
- Classical MCL.
- Leukemic nonnodal MCL.
In-situ mantle cell neoplasia (ISMCN) is considered a separate entity, often as a precursor lesion, to the mantle cell lymphoma.

# Pathophysiology
The translocation t(11;14)(q13;q32) is considered the precipitating oncogenic event that induces cell cycle deregulation in mantle cell lymphoma due to overexpression of cyclin D1. In addition to the pathogonomic translocation, MCL progression is controlled by secondary genetic abberations and dysregulated signaling pathways involved in DNA damage repair, proliferation, and apoptosis.

# Causes
The causes of mantle cell lymphoma have not been clearly identified.

# Differentiating Mantle Cell Lymphoma from Other Diseases
Mantle cell lymphoma must be differentiated from other diseases that present similarly with B symptoms (fever, night sweats and unexplained weight loss), lymphocytosis, lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. Mantle cell lymphoma must be differentiated from other diseases such as diffuse large B cell lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, lymphoplasmacytoid lymphoma/Immunocytoma, marginal zone lymphoma, lymphoblastic lymphoma, burkitt lymphoma and reactive hyperplasia.

# Epidemiology and Demographics
Mantle cell lymphoma accounts for 48% of all adult non-Hodgkins lymphomas (NHL). It has an incidence of approximately 1-2/100000 and tends to occur more in males, Caucasian race, with a median age of about 60 years.

# Risk Factors
There are no established risk factors for mantle cell lymphoma. However, recently weak associations have been observed in the development of mantle cell lymphoma with the exposure to European strains of Borellia burgdoferi., family history of hematologic malignancy and Genetic polymorphisms in the pro-inflammatory cytokine IL-10.

# Screening
Screening for mantle cell lymphoma is not recommended.

# Natural History, Complications, and Prognosis
The prognosis of mantle cell lymphoma has historically been very poor. However, recently improvements have been made and the median survival has increased from 3-4 years to 5-7 years. It is very important to stratify the patients according to their biological risk to better direct the therapeutic approaches.

# Diagnosis

## Diagnostic Study of Choice
Tissue biopsy (nodal or extranodal) is the gold standard test for the diagnosis of mantle cell lymphoma.

## History and Symptoms
The most common symptoms of mantle cell lymphoma include fever, weight loss, night sweats, fatigue, skin rash, abdominal pain, bone pain, loss of appetite, and painless swelling in the neck, axilla, groin, thorax and abdomen.

## Physical Examination
Common physical examination findings of mantle cell lymphoma include fever, rash, splenomegaly, hepatomegaly, peripheral lymphadenopathy, and central lymphadenopathy.

## Laboratory Findings
Laboratory tests for mantle cell lymphoma include complete blood count (CBC), comprehensive metabolic panel, LDH levels, Hepatitis B testing if treatment with rituximab is planned, uric acid levels, beta-2-microglobulin, pregnancy testing in woman of child-bearing age, flow cytometry, immunohistochemistry, genetic testing and FISH.

## Electrocardiogram
There are no ECG findings associated with mantle cell lymphoma.

## X-ray
Presence of nodules and pleural effusion on chest x ray may be suggestive of mantle cell lymphoma.

## Echocardiography and Ultrasound
Ultrasound may be helpful in the diagnosis of mantle cell lymphoma. Findings on an ultrasound helpful in the diagnosis of mantle cell lymphoma include lymphadenopathy, splenomegaly and hepatomegaly. There are no echocardiography findings associated with mantle cell lymphoma. However, an echocardiography may be helpful in following patients who might be at risk of anthracycline-induced cardiotoxicity due to chemotherapy.

## CT scan
CT scan may be helpful in the diagnosis of mantle cell lymphoma. CT scans of the chest, abdominal and pelvic are done to check for lymphadenopathy and is helpful in the staging the disease.

## MRI
MRI may be helpful in the diagnosis of mantle cell lymphoma involving the CNS.

## Other Imaging Findings
PET scan (positron emission tomography) integrated with CT scan may be helpful in the staging and treatment response assessment of mantle cell lymphoma.

## Other Diagnostic Studies
Other diagnostic studies for the diagnosis of mantle cell lymphoma include bone marrow aspiration, lumbar puncture, colonoscopy, upper endoscopy, laparoscopy, and laparotomy.

# Treatment

## Medical Therapy
The mainstay of treatment for mantle cell lymphoma is chemotherapy. However, immunotherapy, radioimmunotherapy, targeted therapy using newer biologic agents and stem cell transplantation are also used along with chemotherapy to treat the disease. Mantle cell lymphoma shows a heterogeneous clinical behavior, with some patients having indolent disease whereas a vast majority show aggressive presentation. Most of the patients eventually relapse and have disease progression after treatment. Hence, mantle cell lymphoma is still considered an incurable disease and there is no consensus among oncologists about its optimal treatment. It is therefore recommended that mantle cell lymphoma patients are seen by physicians having extensive experience in dealing with mantle cell lymphoma and they are also encouraged to participate in clinical trials to get the latest treatments.

## Interventions
The mainstay of treatment for mantle cell lymphoma is medical therapy.

## Surgery
The mainstay of treatment for mantle cell lymphoma is medical therapy. However, surgical therapy has proven curative in a case of MCL with a single protruding lesion presenting as intussusception.

## Primary Prevention
There are no established measures for the primary prevention of mantle cell lymphoma.

## Secondary Prevention
There are no established measures for the secondary prevention of mantle cell lymphoma.

## Future or investigational therapies:
Recent advances in the understanding of the pathogenesis of mantle cell lymphoma have led to the development of targeted therapies which have shown potential promise as effective therapeutic approaches in the future. In addition to the ongoing assessment of new monoclonal antibody-based therapies, the continued development of targeted molecular signaling inhibitors based on the underlying biology of MCL is an approach that will potentially yield fruitful results in this disease. Some of the current therapies under clinical investigation are the BCL-2 inhibitor venetoclax (ABT-199), the phosphatydilinosytol 3-kinase  (PI3K ) inhibitor idelalisib, chimeric antigen receptor T-cell (CAR-T) therapy in relapsed MCL, androgen receptor (AR) blockers like enzalutamide as means of decreasing MCL cell proliferation and a few next-generation proteasome inhibitors (carfilzomib, oprozomib, ixazomib) in bortezomib-resistant MCL patients.