What is the pathophysiology of primary mediastinal B-cell lymphoma (PMBCL)?

Answer

The tumor cells resemble immunoblasts or centroblasts, and, in many cases, sclerosis and fibrosis can be identified. Flow cytometry studies identify a unique immunophenotype profile for primary mediastinal B-cell lymphoma (PMBCL). Malignant cells express B-cell antigens (CD20, CD19, CD22, and CD79a), and, in some patients, weak CD30 expression is noted. The weak CD30 expression can aid in differentiating PMBCL from anaplastic large cell lymphoma and classic Hodgkin lymphoma. This is critical, as Reed-Sternberg–like cells can be present in patients with PMBCL. Additionally, the malignant cells also lack CD15 expression but have frequent positivity of the transcriptional regulators BCL6, PAX5, and BOB1.

PMBCL is hypothesized to originate from the germinal or postgerminal centers; however, surface immunoglobulin expression is frequently absent.

Several studies have explored the underlying genetic and molecular features that lead to the evolution of primary mediastinal B-cell lymphoma (PMBCL). Gene expression profiling has clearly demonstrated that this disease entity is different from diffuse large B-cell lymphoma (DLBCL) and has identified several deregulated pathways involved in the pathogenesis of PMBCL. Steidl and Gascoyne eloquently summarized the recurrent gene alterations involved in the pathogenesis of PMBCL.^[9]

Gene expression profiling has demonstrated overexpression of genes encoding the NF-kappa-B pathway, suggesting its involvement in the pathogenesis of PMBCL. Further, inhibiting I-kappa-B, which activates NF-kappa-B signaling, was shown to induce cell kill in vitro in PMBCL cell-lines.

Chromosomal gains and amplifications of the REL gene locus on band 2p16.1 have been found in 50% of cases.^{[9, 10, 11]} Other chromosomal aberrations that affect NF-kappa-B pathways include BCL-10 (1p22) and MALT-1 (18q21).

Song et al identified a tumor suppressor gene that encodes the A-20 protein, which acts as an inhibitor to the NF-kappa-B pathway downstream from the tumor necrosis factor (TNF) receptor.^[12] Mutations in that gene have been found in over 30% of PMBCL cases, but it has also been described in other lymphoid malignancies.^{[13, 14]} Another mutated tumor suppressor gene is SOCS1 (suppressor of cytokine signaling). SOCS1 usually acts as an inhibitor to the JAK-STAT6 pathway, preventing continued activation and proliferation.^[15] In fact, Mottok et al suggested that SOCS1 deletion mutations were present in 45% of 20 studied patients.^[16]

More recent studies have also shown a role of immune deregulation in PMBCL pathogenesis. Specifically, the reduced expression of major histocompatibility II complex genes led to decreased infiltrating cytotoxic T-cells, and some investigators have suggested this can lead to inferior outcomes, arguing that more studies exploring the role of immune escape in PMBCL are warranted. Another mechanism by which PMBCL cells escape immune surveillance has been by overexpressing certain surface molecules such as PD-1 ligands and receptors, which, in turn, leads to inactivating infiltrating effector T cells.^[17]

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Lisenko K, Dingeldein G, Cremer M, Kriegsmann M, Ho AD, Rieger M, et al. Addition of rituximab to CHOP-like chemotherapy in first line treatment of primary mediastinal B-cell lymphoma. BMC Cancer. 2017 May 22. 17 (1):359. [Medline]. [Full Text].
Miles RR, Mankey CC, Seiler CE 3rd, Smith LB, Teruya-Feldstein J, Hsi ED, et al. Expression of Grb2 distinguishes classical Hodgkin lymphomas from primary mediastinal B-cell lymphomas and other diffuse large B-cell lymphomas. Hum Pathol. 2009 Dec. 40(12):1731-7. [Medline].
Feuerhake F, Kutok JL, Monti S, Chen W, LaCasce AS, Cattoretti G, et al. NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood. 2005 Aug 15. 106(4):1392-9. [Medline].
Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. 2003 Dec 1. 102(12):3871-9. [Medline].
Savage KJ, Al-Rajhi N, Voss N, Paltiel C, Klasa R, Gascoyne RD. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Ann Oncol. 2006 Jan. 17(1):123-30. [Medline].
Rieger M, Osterborg A, Pettengell R, White D, Gill D, Walewski J. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 2011 Mar. 22(3):664-70. [Medline].
Dubashi B, Cyriac S, Tenali SG. Clinicopathological analysis and outcome of primary mediastinal malignancies - A report of 91 cases from a single institute. Ann Thorac Med. 2009 Jul. 4(3):140-2. [Medline]. [Full Text].
van Besien K, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma: a review of pathology and management. J Clin Oncol. 2001 Mar 15. 19(6):1855-64. [Medline].
Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood. 2011 Sep 8. 118(10):2659-69. [Medline].
Bea S, Zettl A, Wright G, Salaverria I, Jehn P, Moreno V. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood. 2005 Nov 1. 106(9):3183-90. [Medline].
Weniger MA, Gesk S, Ehrlich S, Martin-Subero JI, Dyer MJ, Siebert R. Gains of REL in primary mediastinal B-cell lymphoma coincide with nuclear accumulation of REL protein. Genes Chromosomes Cancer. 2007 Apr. 46(4):406-15. [Medline].
Song HY, Rothe M, Goeddel DV. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci U S A. 1996 Jun 25. 93(13):6721-5. [Medline].
Honma K, Tsuzuki S, Nakagawa M, Tagawa H, Nakamura S, Morishima Y, et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood. 2009 Sep 17. 114(12):2467-75. [Medline].
Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009 Jun 4. 459(7247):712-6. [Medline].
Davey GM, Heath WR, Starr R. SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation. Tissue Antigens. 2006 Jan. 67(1):1-9. [Medline].
Mottok A, Renné C, Seifert M, Oppermann E, Bechstein W, Hansmann ML. Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities. Blood. 2009 Nov 12. 114(20):4503-6. [Medline].
Mottok A, Woolcock B, Chan FC, Tong KM, Chong L, Farinha P, et al. Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell Rep. 2015 Nov 17. 13 (7):1418-31. [Medline].
Lazzarino M, Orlandi E, Paulli M, Sträter J, Klersy C, Gianelli U, et al. Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: a multicenter study of 106 patients. J Clin Oncol. 1997 Apr. 15(4):1646-53. [Medline].
Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, et al. Mediastinal gray zone lymphoma: the missing link between classic Hodgkin's lymphoma and mediastinal large B-cell lymphoma. Am J Surg Pathol. 2005 Nov. 29(11):1411-21. [Medline].
[Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. NCCN.org. Available at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Version 4.2019 — June 18, 2019; Accessed: September 14, 2019.
Song HN, Kim SJ, Ko YH, Kim WS. Mediastinal Gray Zone Lymphoma with Features Intermediate between Classical Hodgkin Lymphoma and Primary Mediastinal B-Cell Lymphoma. Acta Haematol. 2016. 136 (3):186-90. [Medline].
Sun W, Song K, Zervos M, Pass H, Cangiarella J, Bizekis C, et al. The diagnostic value of endobronchial ultrasound-guided needle biopsy in lung cancer and mediastinal adenopathy. Diagn Cytopathol. 2010 May. 38(5):337-42. [Medline].
Jackson MW, Rusthoven CG, Jones BL, Kamdar M, Rabinovitch R. Improved Survival With Radiation Therapy in Stage I-II Primary Mediastinal B Cell Lymphoma: A Surveillance, Epidemiology, and End Results Database Analysis. Int J Radiat Oncol Biol Phys. 2015 Sep 25. [Medline].
Zinzani PL, Stefoni V, Finolezzi E, Brusamolino E, Cabras MG, Chiappella A, et al. Rituximab combined with MACOP-B or VACOP-B and radiation therapy in primary mediastinal large B-cell lymphoma: a retrospective study. Clin Lymphoma Myeloma. 2009 Oct. 9(5):381-5. [Medline].
Savage KJ, Al-Rajhi N, Voss N, Paltiel C, Klasa R, Gascoyne RD, et al. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Ann Oncol. 2006 Jan. 17(1):123-30. [Medline].
Zinzani PL, Martelli M, Magagnoli M, Pescarmona E, Scaramucci L, Palombi F, et al. Treatment and clinical management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients. Blood. 1999 Nov 15. 94(10):3289-93. [Medline].
Dunleavy K, Pittaluga S, Maeda LS, Advani R, Chen CC, Hessler J. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013 Apr 11. 368(15):1408-16. [Medline].
Witzens-Harig M, Ho AD, Kuhnt E, Trneny M, Rieger M, Österborg A, et al. Primary Mediastinal B Cell Lymphoma Treated with CHOP-Like Chemotherapy with or without Rituximab: 5-Year Results of the Mabthera International Trial Group (MInT) Study. Blood (ASH Annual Meeting Abstracts). 2012. 120:Abstract 1612.
Jackson MW, Rusthoven CG, Jones BL, Kamdar M, Rabinovitch R. Improved survival with combined modality therapy in the modern era for primary mediastinal B-cell lymphoma. Am J Hematol. 2016 May. 91 (5):476-80. [Medline]. [Full Text].
Spaepen K, Stroobants S, Dupont P, Van Steenweghen S, Thomas J, Vandenberghe P. Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-Hodgkin's lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic methods?. J Clin Oncol. 2001 Jan 15. 19(2):414-9. [Medline].
Jerusalem G, Beguin Y, Fassotte MF, Najjar F, Paulus P, Rigo P. Persistent tumor 18F-FDG uptake after a few cycles of polychemotherapy is predictive of treatment failure in non-Hodgkin's lymphoma. Haematologica. 2000 Jun. 85(6):613-8. [Medline].
Haioun C, Itti E, Rahmouni A, Brice P, Rain JD, Belhadj K. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. Blood. 2005 Aug 15. 106(4):1376-81. [Medline].
Moskowitz CH, Schöder H, Teruya-Feldstein J, Sima C, Iasonos A, Portlock CS. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol. 2010 Apr 10. 28(11):1896-903. [Medline].
Savage KJ, Yenson PR, Shenkier T, Klasa R, Villa D, Goktepe O, et al. The Outcome of Primary Mediastinal Large B-Cell Lymphoma (PMBCL) in the R-CHOP Treatment Era. Blood (ASH Annual Meeting Abstracts). 2012. 120:Abstract 303.
Popat U, Przepiork D, Champlin R, Pugh W, Amin K, Mehra R, et al. High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma: mediastinal localization predicts for a favorable outcome. J Clin Oncol. 1998 Jan. 16(1):63-9. [Medline].
[Guideline] Vitolo U, Seymour JF, Martelli M, Illerhaus G, Illidge T, Zucca E, et al. Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep. 27 (suppl 5):v91-v102. [Medline]. [Full Text].
Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017 Jul 20. 130 (3):267-270. [Medline]. [Full Text].

Media Gallery

Example of mediastinal lymphoma at diagnosis. A large tumor mass is present in the anterior mediastinum, and an associated pleural effusion can also be seen.
Isolated CNS relapse of primary mediastinal B-cell lymphoma.

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Author

Sonali M Smith, MD Associate Professor, Section of Hematology/Oncology, Director, Lymphoma Program, The University of Chicago Pritzker School of Medicine

Sonali M Smith, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Received consulting fee from Genentech/BiogenIdec for speaking and teaching; Received consulting fee from Lilly for speaking and teaching; Received consulting fee from Cephalon for consulting; Received consulting fee from Allos for speaking and teaching; Received consulting fee from Spectrum Pharmaceuticals for consulting; Received consulting fee from GlaxoSmithKline for consulting; Received consulting fee from Novartis for consulting; Received consulting fee from Celgene for consulting.

Coauthor(s)

Koen W Van Besien, MD Director of Stem Cell Transplantation and Lymphoma, Associate Professor, Department of Internal Medicine, Section of Hematology/Oncology, The University of Chicago Pritzker School of Medicine

Koen W Van Besien, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Andrew S Artz, MD, MS Associate Professor, Department of Medicine, Section of Hematology/Oncology, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine

Andrew S Artz, MD, MS is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Hematology, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Chadi Nabhan, MD, FACP Associate Professor of Medicine, Department of Medicine, Section of Hematology and Oncology, Medical Director, Ambulatory Clinical Cancer Care Services, The University of Chicago Comprehensive Cancer Center

Chadi Nabhan, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology

Disclosure: Received grant/research funds from Genentech for other; Received honoraria from Genentech for speaking and teaching.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MBBCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Koyamangalath Krishnan, MD, FRCP, FACP Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

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