PMLBCL : Escape from Immuno-surveillance

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Image Description

Escape from Immunosurveillance: The tumor microenvironment in primary mediastinal large B-cell lymphomas (PMLBCL) causes dysregulated immune response which allows the tumor cells to escape immunosurveillance.

Expression of major histocompatibility complex (MHC) genes and proteins is regulated by MHC class II transactivator CIITA at 16p13.13 locus. Rearrangements or mutations in CIITA gene with downregulation of MHC class II proteins have been found in approximately 53% of PMLBCL.

Translocations involving CIITA also impact PDL1 and PDL2 resulting in their overexpression. About 63% of PMLBCL show amplification of 9p24.1 containing PDL1 and PDL2 further causing their amplification. PDL1 and PDL2 interact with PD1 on T-lymphocytes and cause T-cell anergy (functional inactivation following encounter with antigen). This allows tumor cells to evade immunosurveillance. The combination of CIITA alterations and amplification of the PDL locus is unique to PMLBCL among large B-cell lymphomas but is also seen in classic Hodgkin lymphoma.

Image source: Lees, Charlotte & Keane, Colm & Gunawardana, Jay. (2019). Biology and therapy of primary mediastinal B‐cell lymphoma: current status and future directions. British Journal of Haematology. 185. 10.1111/bjh.15778; used under Creative Commons Attribution-noncommercial 4.0 International License.

About the Disease

Primary mediastinal large B-cell lymphoma (PMLBCL) is a rare, aggressive, distinct subtype of large B-cell lymphoma localized in anterosuperior mediastinum. It shares clinical, morphologic, and molecular genetic features with nodular sclerosing Hodgkin lymphoma. It makes up 2-3% of non-Hodgkin lymphomas and affects young adults with a female predilection. Patients develop compressive symptoms, such as cough and dyspnea, from the rapidly growing mediastinal mass. About 20-30% have superior vena cava syndrome. Pleural and pericardial effusion develop in 30-50%. Surrounding thoracic structures may be invaded. Bone marrow is rarely involved. Extranodal sites may be invaded in advanced stages. The tumor cells are highly variable, medium-to-large size, with irregular or multilobated nuclei and pale or clear cytoplasm in a sclerotic stroma. Reed-Sternberg-like cells may be present. Immunophenotype: positive for pan B-cell antigens (CD19, CD20, CD22, CD79a), no surface or cytoplasmic immunoglobulins, PDL1+, PDL2+, PAX5%, CD30+ (variable, heterogenous), IRF4/MUM1+, BCL2, BCL6, PU.1, OCT2; variable positivity for CD15, CD10, CD11c, CD23, MYC; negative for EBV. MAL gene (chromosome 2q) is + in 70%. Ig heavy and light chain genes are clonally rearranged. TCR genes are germline. Rearrangements of CCND1, BCL2, BCL6, and MYC are rare/absent. Three molecular pathways are implicated in the pathogenesis - NF-κB signaling pathway, JAK-STAT signaling cascade, and immune privilege. References:Dabrowska-Iwanicka A & Walewski J. Primary Mediastinal Large B-cell Lymphoma. Curr Hematol Malig Rep (2014) 9:273-283. Lees, C. et al. Biology and therapy of primary mediastinal B-cell lymphoma : current status and future directions. British Journal of Haematology, 2019, 185, 25-41. Jaffe, E. S. et al (2017). Hematopathology - Second Edition. Philadelphia, PA. Elsevier. Swerdlow, S. H. et al (2017). WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Revised 4th Edition; IARC, Lyon, France.

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