PMLBCL : Differential Diagnosis

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Differential Diagnosis of Primary Mediastinal Large B-cell Lymphoma (PMLBCL): The list includes - classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, NOS (DLBCL-NOS), anaplastic large cell lymphoma (ALCL), mediastinal seminoma, thymic carcinoma, and thymic carcinoid.

PMLBCL and cHL have a lot of common clinical and morphologic features, including young patient age, origin from thymic B-cells, location primarily in anterior mediastinum, large tumor cells, and sclerosis. CD30 positive tumor cells (a feature of cHL) may be found in PMLBCL and pan-B-cell marker expression (a feature of PMLBCL) may be seen in cHL.

Features favoring cHL over PMLBCL:

polymorphous infiltrate in the background with numerous eosinophils
tumor cells positive for CD30 and CD15 but negative for CD45
B-cell markers, when present, are heterogenous and not uniformly strongly positive
negative for immunoglobulin transactivating factors OCT-2 and BOB-1
EBV positive
Grb2 positive in only 10% (vs 98% for PMLBCL)
cyclin E positive (79% in cHL vs 0% in PMLBCL)

Some cases may consist of both PMLBCL and cHL (Composite lymphoma) and show same clone of tumor cells in both components. Others may be PMLBCL to start with but relapse as cHL (Mediastinal sequential lymphoma).

Differential diagnosis continues in the next slide.

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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