Mantle cell lymphoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

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 4–8% of all adult non-Hodgkin’s 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.

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

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.

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.

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

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.

Mantle cell lymphoma accounts for 4–8% of all adult non-Hodgkin’s 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.

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 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.

There are no ECG findings associated with mantle cell lymphoma.

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

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.

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

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.

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

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

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 δ (PI3K δ) 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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2]

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

• In 1964, Lennert first described the disease as ‘centrocytic’ lymphoma.
• In 1982, Weisenburger first proposed the concept of ‘mantle-zone lymphoma’.^[1]
• In 1985, Pileri et al. reported on 18 cases of small B-cell lymphomas which displayed a mantle-fashion growth around reactive germinal centers.^[2]
• In 1992, Banks first coined the term mantle cell lymphoma (MCL).^[3]
• 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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2]

According to the revised 2016 World Health Organization classification of lymphoid neoplasms, mantle cell lymphoma (MCL) can be broadly classified into two types include 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.

• Classical MCL typically develops from immunoglobulin heavy-chain variable region gene(IGHV)-unmutated or minimally mutated B cells that usually express SOX11 (SRY-Box 11 gene).^[1][2][3]
• Classical MCL usually involves the lymph nodes and other extranodal sites.
• However, these cells can acquire further molecular and cytogenetic abnormalities leading to the more aggressive:^[4][5]
  • Blastoid MCL
  • Pleomorphic MCL

• Leukemic nonnodal MCL typically develops from immunoglobulin heavy-chain variable region gene(IGHV)-mutated B cells that do not express SOX11 (SRY-Box 11 gene).^[1][2]
• Leukemic nonnodal MCL involve the peripheral blood (PB), bone marrow and the spleen.
• Although these are commonly clinically indolent in nature further mutations ,especially of TP53, can lead to more aggressive disease.

• It is characterized by the presence of cyclin D1 positive cells mostly in the inner mantle zones of follicles in lymphoid tissues that do not otherwise suggest the diagnosis of a MCL.^[6]
• The in situ lesion stage may be a common step in both SOX11-negative and positive subtypes of MCL as some in situ lesions express SOX11, whereas others are SOX11 negative.^[7]
• ISMCN is often found incidentally, occasionally in association with other types of lymphomas.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

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.

• The translocation t(11;14)(q13;q32) is considered the precipitating oncogenic event that induces cell cycle deregulation due to overexpression of cyclin D1.
• This translocation juxtaposes the CCDN1 gene encoding cyclin D1 to the immunoglobulin heavy chain (IgH) leading to its overexpression. However, less commonly, mutations in CCDN2 and CCDN3 have also been identified in cases of mantle cell lymphoma lacking the t(11;14) translocation.^[1]
• 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.^[2]
• These secondary genetic alterations and dysregulated signaling pathways are as follows:
  • Deregulation of cell cycle:^[3]
    • INK4a/CDK4/RB1 pathway
    • ARF/MDM2/p53 pathway
  • Deregulation of DNA damage repair:^[4]
    • Mutation in ATM gene
    • Mutation in p53 gene
  • Deregulation of apoptosis:^[5][6][7]
    • BCL2 amplifications
    • BCL2L11 deletions
    • FBXO10 deficiency
    • MCL1 overexpression
  • Deregulation of chromatin modifiers:^[8]
    • WHSC1 mutations
    • MLL2 mutations
    • MEF2B mutations
  • Constitutive activation of oncogenic pathways:^{[9][10][11][12]}
    • Classical NF-kB pathway
    • Alternate NF-kB pathway
    • PI3K/AKT/mTOR pathway
    • NOTCH pathway
    • JAK/STAT3 pathway
    • WNT pathway
• SOX11, a SOX family transcription factor, has recently been identified as an important molecular feature of MCL regardless of cyclin D1 status.^[13]

Genes involved in the pathogenesis of mantle cell lymphoma include:

• CCDN1 (primarily)
• CCDN2
• CCDN3
• CDK4
• MDM2
• BMI1
• P53
• ATM
• BCL2
• BCL2L11
• FBXO10
• MCL1
• WHSC1
• MLL2
• MEF2B

• The typical (classical) morphology of mantle cell lymphoma is seen in about 90% of cases:^[14]
  • Cells are slightly larger than lymphocytes.
  • The nucleus is indented or bean-shaped.
  • Prominent nucleoli are missing.
  • The chromatin structure is less condensed and not as bright as in blasts like centroblasts.
  • The cytoplasmic rim is narrow and not basophilic.

• The remaining 10% are the morphological variants:^[15]
  • Small cell type: They resemble CLL cytologically but the prolymphocytes and paraimmunoblasts are usually missing. This variant usually shows a very low proliferative activity.
  • Pleomorphic and blastic type(together known as the blastoid variant): The pleomorphic type are similar to diffuse large B-cell lymphoma (DLBCL). The blastic type resemble lymphoblastic lymphoma or leukemia and have monomorphic roundish blasts. The blastoid variant usually have numerous mitotic figures and are very highly proliferative.
• Scattered non-granumloma forming epithelioid macrophages, hyalinized vessels and a few reactive T cells or mast cells are seen along with the lymphoma cells in MCL. Follicular dendritic cells (FDC) are a hallmark of mantle cell lymphoma and may also be involved in its pathogenesis.^[16]
• Three types of growth pattern are observed in mantle cell lymphoma:^[17]
  • Mantle zone: Nodular with germinal centers
  • Nodular: >50% nodular growth
  • Diffuse: <50% nodular growth

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• 
  Intermediate magnification micrograph of mantle cell lymphoma of the terminal ileum. Endoscopic biopsy. H&E stain. Histomorphologic features: Monomorphic small lymphoid cells less than twice the size of a resting lymphocyte. Abundant mitoses. Sclerosed blood vessels. Scattered epithelioid histiocytes.
• 
  Mantle cell lymphoma. Notice the irregular nuclear contours of the medium-sized lymphoma cells and the presence of a pink histiocyte. By immunohistochemistry the lymphoma cells expressed CD20, CD5 and Cyclin D1 (high power view, H&E).
• 
  Lymph node with mantle cell lymphoma (low power view, H&E).
• 
  Micrograph of terminal ileum with mantle cell lymphoma (bottom of image). H&E stain.
• 
  Micrograph of terminal ileum with mantle cell lymphoma (bottom of image – brown colour). Cyclin D1 immunostain.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

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

• Mantle cell lymphoma is thought to be caused when the somatic cells acquire non-inherited genetic mutations.
• The typical mutation occurring in mantle cell lymphoma due to the “reciprocal translocation” between chromosome 11 and chromosome 14 t(11;14) causes the over expression of cyclin D1 which results in uncontrolled growth of B cells leading to lymphoma development.
• However, the initiating factors of these genetic alterations are generally not identifiable. People with no particular risk factors for lymphoma development are commonly affected by these alterations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

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 should be differentiated from other conditions presenting with fever, fatigue, lymphadenopathy, abdominal pain, rash and soft tissue swelling. The differentials include the following:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]}

Mantle cell lymphoma must be differentiated from other diseases such as:^[26][27][28]

Based on the expression of cell surface markers, the table below differentiates mantle cell lymphoma from other diseases that cause similar clinical presentations:^[29]

• 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
• Reactive hyperplasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2]

Mantle cell lymphoma accounts for 4–8% of all adult non-Hodgkin lymphoma (NHL). It has an incidence of approximately 1-2 per 100,000 individuals worldwide. The male to female ratio is approximately 4 to 1 and the median age is about 60 years.

• The annual incidence of mantle cell lymphoma has increased during recent decades to 1–2 per 100,000 individuals worldwide.^[1]

• The median age at diagnosis for mantle cell lymphoma is about 60 years.^[2]

• Mantle cell lymphoma tends to affect Caucasians more than African-Americans.^[3]

• Males are more commonly affected by mantle cell lymphoma than females. The male to female ratio is approximately 4 to 1.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

There are no established risk factors for mantle cell lymphoma. However, recently weak associations have been observed in the development of mantle cell lymphoma such as the exposure to European strains of Borrelia burgdorferi, family history of hematologic malignancy, and genetic polymorphisms in the pro-inflammatory cytokine IL-10.

• There are no established risk factors for mantle cell lymphoma. Although, the pathogenesis of mantle cell lymphoma at the cellular level is well understood now, there is not enough information on the risk factors that precipitate the cellular events.
• However, recently weak associations have been observed in the development of mantle cell lymphoma include following:^[1][2][3]
  • Exposure to European strains of Borrelia burgdorferi
  • Family history of hematologic malignancy
  • Genetic polymorphisms in the pro-inflammatory cytokine IL-10

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

There is insufficient evidence to recommend routine screening for Mantle cell lymphoma.

There is insufficient evidence to recommend routine screening for Mantle cell lymphoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

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.^[1] It is very important to stratify the patients according to their biological risk to better direct the therapeutic approaches.

• Mantle cell lymphoma is generally considered to be an aggressive disease with patients having early relapses and poor long-term survival rates.
• However, rare forms of the disease which show an indolent behavior, have better outcomes. ^[2]

• The evolution of disease in mantle cell lymphoma is highly heterogeneous. Therefore, it is very important to stratify the patients according to their biological risk to better direct the therapeutic approaches.
• The Mantle Cell Lymphoma International Prognostic Index (MIPI) is now widely used as a prognostic model in MCL patients. It uses the following four parameters to assess the prognosis (Age, ECOG performance, LDH levels, WBC Count):

• The tumor proliferation marker, Ki-67, is also an important prognostic marker for mantle cell lymphoma. Values of >30% are associated with a poor progression free survival.^[3]
• Presence of blastoid or pleomorphic morphologic characteristics have also shown to have poor outcomes.^[4]

• Other markers which have shown to adversely affect prognosis are as follows:^{[5][6][7][8][9][10][11][12]}
  • High expression of eukaryotic initiation factor 4E
  • Myc overexpression
  • Increased expression of SOX11
  • Low TCL1 expression
  • TP53 deletion
  • Lack of hypermutated heavy chain immunoglobulin variable regions
  • Increased absolute levels of the following in the serum:
    • Monocytes
    • Beta-2 microglobulin
    • Monoclonal and polyclonal immunoglobulin free light chain
    • IL-2Rα
    • IL-8
    • MIP-1β.

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