Gene expression profiling of gray zone lymphoma

Abstract

Gray zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classic Hodgkin lymphoma (cHL), is a rare and poorly defined entity. Alongside GZL, a subset of Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL) has been described with polymorphic/GZL-like morphology (polymorphic-EBV-L). To fill the important gap in our understanding of the pathogenic process underlying these entities, we performed a gene expression study of a large international cohort of GZL and polymorphic-EBV-L, combined with cHL and primary mediastinal large B-cell lymphoma (PMBCL) cases. In an unsupervised principal component analysis, GZL cases presented with intermediate scores in a spectrum between cHL and PMBCL, whereas polymorphic-EBV-L clustered distinctly. The main biological pathways underlying the GZL spectrum were related to cell cycle, reflecting tumor cell content, and extracellular matrix signatures related to the cellular tumor microenvironment. Differential expression analysis and phenotypic characterization of the tumor microenvironment highlighted the predominance of regulatory macrophages in GZL compared with cHL and PMBCL. Two distinct subtypes of GZL were distinguishable that were phenotypically reminiscent of PMBCL and DLBCL, and we observed an association of PMBCL-type GZL with clinical presentation in the “thymic” anatomic niche. In summary, gene expression profiling (GEP) enabled us to add precision to the GZL spectrum, describe the biological distinction compared with polymorphic-EBV-L, and distinguish cases with and without thymic involvement as 2 subgroups of GZL, namely PMBCL-like and DLBCL-like GZL.

Clinical genomic profiling of novel grey zone lymphoma paired lesions with sequential central nervous system involvement in two adolescent patients

“…Recent molecular characterization of GZL supports the classification of two distinct subtypes of GZL: a "thymic" subtype that occurs in the anterior mediastinum and resembles Epstein-Barr virus (EBV)-negative cHL and PMBCL, and a “non-thymic” subtype which occurs outside the thymus and harbors TP53 mutations in a subset of cases. 9 , 10 In our two patients, the CNS location and mutations in TP53 (case #2) and other associated genes (e.g., CREBBP, RELN , and KMT2D ) support a “nonthymic” GZL classification. The presence of complex genomic profiles is also consistent with dysregulated TP53 signaling, and both CNS LBCL harbored complex cytogenomic arrays with copy number abnormalities previously reported in GZL 11-13 and frequently reported in cHL and PMBCL.…”

Hodgkin Lymphoma: Biology and Differential Diagnostic Problem

“…Non-mediastinal (systemic) GZL poses a more challenging diagnostic problem, and is characterized by onset in elderly patients, and more advanced disease than MGZL, without a bulky mass [ 126 ]. Recent studies reveal similar gene expression patterns between MGZL and CHL, as well as between non-mediastinal GZL and DLBCL [ 127 , 128 ]. Notably, non-mediastinal GZLs are characterized by a relatively low frequency of PD-L1 aberrations (up to 50%) [ 129 ], and by enrichment of TP53 and BCL2 mutations, and translocations of BCL2 and/or BCL6 , which are frequently detected in high-grade B-cell lymphomas transformed from low-grade B-cell lymphomas [ 130 , 131 ].…”

Clinicopathological features and survival in EBV-positive diffuse large B-cell lymphoma not otherwise specified

“…Of note, 50 patients (71%) underwent an excisional biopsy and 20 patients (29%) a core needle biopsy at diagnosis, and these latter patients were significantly older and had more frequently extranodal 44,45 ), the lymph node architecture was erased by a prominent and rich inflammatory background, in which a variable number (from 2% to 40% of the cellular infiltrate) of large neoplastic cells were embedded (Figure 2). The large neoplastic B-cells resembled Hodgkin/Reed-Sternberg cells or lymphocyte predominant cells and were scattered either singly or in loose clusters (n 5 41), rarely forming sheets (n 5 5).…”