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

Molecular and Cytogenetic Features

PMBL demonstrates clonally rearranged and class-switched immunoglobulin genes and a high load of somatic alterations without ongoing alterations.[38] BCL6 is frequently altered.[46] PMBL rarely demonstrates a rearrangement of BCL6 and does not show BCL2 translocations.[47]MYC rearrangements are rare, and alterations or small internal rearrangements are noted occasionally.[48] Copy number gains and losses in PMBL are diverse and notable for amplifications of REL and BCL11A at 2p and for JAK2, PDL1, and PDL2 at 9p.[7,49] Overexpression of JAK2 and constitutive activation of the interleukin (IL)-4 and IL-13 molecules and phosphorylated STAT6 results in upregulation of the JAK/STAT pathway as an important pathogenetic mechanism.[50] FISH studies have demonstrated rearrangements at the PDL locus (9p24.1) that are specific to PMBL compared with other types of B-cell lymphomas and that correlate with overexpression of PDL transcripts.[12] Segmental losses of DNA also occur and affect 1p13.1–1p13.2 at a high frequency as well as areas with implied effect, including 17p (TP53).[8] In several types of B-cell lymphomas, recurrent truncating deletions in the NFKIE gene cause deregulation of the NFĸB pathway. In PMBL, these deletions were found in 22.7% of cases and were associated with inferior outcome.[51] Recently, recurrent alterations of the exportin 1 gene (XPO1), located near the REL 2p16.1 locus, were detected in 24.5% of PMBL cases tested (n = 117) as well as in a similar percentage of CHL. This variant was absent in the MGZL cases and rare in cases of DLBCL NOS.[52]

PMBL has a distinct gene expression signature, with a remarkable overlap of highly expressed genes between PMBL and Hodgkin lymphoma, and these genes were explored in 2 landmark studies of transcriptional profiling.[11,26] The first analysis established a molecular diagnosis of PBML by gene expression profiling (GEP). In this study, Rosenwald et al[26] identified a predictor that classified a distinct clinical group with younger age and favorable overall survival and that established a genetic relationship between PMBL and CHL, with shared signature genes that were more highly expressed in PMBL and CHL than in DLBCL, including MAL, FIG1, TARC, and CD30. PDL2 was identified as the gene that best discriminated PMBL from DLBCL,[26] which was further explored by Savage et al,[11] who developed a classifier to differentiate PMBL from DLBCL. PMBL had low levels of expression of B-cell receptor signaling cascade components and heightened IL-13 receptor and downstream signaling with increased STAT1 and TRAF protein expression.[11] These data strengthen the association between PMBL and the Reed-Sternberg cells of CHL. The gene expression profile of PMBL is distinctive, and using this classifier, it was possible to identify unusual cases with morphologic and immunophenotypic features of PMBL presenting at sites other than the mediastinum.[53]

Another mechanism that contributes to decreased immune surveillance is lower major histocompatibility complex (MHC) class II gene and protein expression in a subset of cases. Although initial data indicated that loss of MHC class II proteins is characteristic of PMBL, a study using GEP, comparative genomic hybridization, and protein expression showed that substantial loss of the MHC II genes by GEP is seen only in about 10% of the cases. When loss of expression does occur, however, those cases have the same extremely poor clinical outcome as MHC II–negative DLBCL.[54] Translocations involving CIITA, a transactivator of MHC class II genes, occur in 40% of PMBL and also represent a mechanism of immune escape.[9]

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