How I Diagnose Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Sarah L. Ondrejka, DO; German Ott, MD

Disclosures

Am J Clin Pathol. 2021;156(4):497-512. 

In This Article

Abstract and Introduction

Abstract

Objectives: Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is an uncommon large B-cell neoplasm recognized by the World Health Organization as a distinct entity on the basis of its unique clinical features, histogenesis, phenotype, and pathogenetic mechanisms. The diagnosis of PMBL can be challenging because of features that may overlap with other (Hodgkin and non-Hodgkin) lymphoma types. This review describes our approach to the diagnosis of PMBL.

Methods: Two cases are presented to illustrate how we diagnose PMBL and separate PMBL from related histologic and biological mimickers, such as Hodgkin lymphoma and gray zone lymphoma.

Results: A diagnosis of PMBL requires correlation of morphology and immunophenotype with clinical and staging data. Gene expression analysis is not typically performed in clinical labs but has expanded our understanding of the functional pathways underlying this disease and helped identify biomarkers that can be translated to diagnostic practice and possibly to future therapeutic options.

Conclusions: PMBL and closely related entities can pose diagnostic challenges. It is important to understand the borders between PMBL and other closely related lymphoma types so that patients receive successful primary treatment with curative intent.

Introduction

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is an aggressive, locally invasive neoplasm that arises in the thymus, presumably of thymic medullary B-cell origin. Non-Hodgkin lymphomas with a primary mediastinal location were beginning to be identified and tracked in the late 1970s,[1] but the first description is attributable to Lichtenstein et al[2] in a 1980 series of 17 patients whose tumors shared features that were derived from review of 184 non-Hodgkin lymphoma specimens. These cases were unified by rapid onset, low-stage disease, and compression of intrathoracic structures, with vascular and cardiac complications and diffuse aggressive histology.[2] PMBL was recognized as a distinct entity among diffuse large B-cell lymphomas by the International Lymphoma Study Group and thereafter incorporated into World Health Organization (WHO) classification schemata; it is currently recognized by both the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues[3] and the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.[4] Although in many aspects PMBL resembles diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), PMBL has distinctive morphologic, immunophenotypic, and molecular genetic features, with a characteristic presentation in the upper anterior mediastinum.

PMBL presents with rapid onset of symptoms related to the bulky mediastinal mass, including dyspnea, dysphagia, cough, and superior vena cava obstruction. The disease occurs in women more commonly than in men, in the third or fourth decade of life compared with DLBCL NOS, which has a higher incidence in older populations. The disease can spread to regional lymph nodes but typically presents with low Ann Arbor stage (I/II); as such, bone marrow involvement at presentation is uncommon. Relapses of PMBL may involve extranodal sites.[5,6] The lymphoma is composed of diffuse aggregates of large or intermediate-sized cells with varying degrees of pleomorphism, with clear cytoplasm and compartmentalizing fibrosis. Hodgkin and Reed-Sternberg–like cells can be present. PMBL has a strong B-cell immunophenotype and rearranged immunoglobulin (Ig) genes but frequently absent surface light chain expression.[3] A variety of genetic alterations underlie its pathogenesis, including regions of genomic gains and losses,[7,8] translocations of CIITA,[9] activation of the nuclear factor κ B (NFκB) and JAK-STAT pathways,[10,11] and expression of programmed death ligands that imbue it with an immunosuppressive microenvironment.[12] For the past 2 decades, it has been recognized that there is some overlap in phenotypic attributes and pathobiology of PMBL and classic Hodgkin lymphoma (CHL); as such, a category of neoplasms intermediate between these entities exists, also referred to as mediastinal gray zone lymphoma (MGZL).[13]

Diagnosis of PMBL is based on the assimilation of clinical presentation with morphology, immunophenotype, and genetic data. Knowledge of staging information can be helpful but is not always available to the consulting pathologist at the time of diagnosis. The differential diagnosis includes CHL, MGZL, and other subtypes of DLBCL, including DLBCL NOS presenting in mediastinal lymph nodes. The differential diagnosis of mediastinal masses identified by imaging is broader and includes T-lymphoblastic lymphoma, thymic mucosa-associated lymphoid tissue (MALT) lymphoma, thymic neoplasms, and nonhematopoietic tumors Table 1. In this review, we discuss the clinical and pathologic features of PMBL and the pathobiology of this neoplasm and relatedness to other mediastinal lymphomas by describing 2 case examples. This discussion includes areas of diagnostic complexity in mediastinal lymphoma and how pathologists might use the available data to generate a report that will guide their oncology colleagues to the most appropriate therapy for this relatively uncommon entity.

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