ORIGINAL ARTICLE Mediastinal Gray Zone Lymphoma The Missing Link Between Classic Hodgkin’s Lymphoma and Mediastinal Large B-Cell Lymphoma Alexandra Traverse-Glehen, MD,* Stefania Pittaluga, MD, PhD,* Philippe Gaulard, MD,† Lynn Sorbara, PhD,* Miguel A. Alonso, PhD,‡ Mark Raffeld, MD,* and Elaine S. Jaffe, MD Abstract: In recent years, overlap in biologic and morphologic features has been identified between classic Hodgkin lymphoma (cHL) and B-cell non-Hodgkin lymphoma. Nevertheless, the thera- peutic approaches for these diseases remain different. We undertook a study of ‘‘mediastinal gray zone lymphomas’’ (MGZL), with features transitional between cHL nodular sclerosis (NS) and primary mediastinal large B-cell lymphoma (MLBCL) to better understand the morphologic and immunophenotypic spectrum of such cases. Twenty-one MGZL cases were identified over a 20-year period. We also studied 6 cases of composite or synchronous lymphoma with two distinct components at the same time (cHL-NS and MLBCL) and 9 sequential cases with MLBCL and cHL-NS at different times. All patients had a large mediastinal mass. Immunohistochemical stud- ies focused on markers known to discriminate between cHL and MLBCL, including B-cell transcription factors. VJ-PCR was per- formed in 8 cases to look at clonality of the immunoglobulin heavy chain gene (IgH). Of the gray zone cases, 11 had morphology reminiscent of cHL-NS, but with unusual features, including a large number of mononuclear variants, diminished inflammatory back- ground, absence of classic Hodgkin phenotype, and strong CD20 expression (11 of 11). Ten cases had morphology of MLBCL, but with admixed Hodgkin/Reed-Sternberg and lacunar cells, absent (3 of 10) or weak (7 of 10) CD20 expression, and positivity for CD15 in 7 cases. B-cell transcription factor expression in the gray zone cases more closely resembled MLBCL than cHL with expression of Pax5, Oct2, and BOB.1 in all but 1 case studied (14 of 15). MAL staining was found in 7 of 10 MGZL, and in at least one component of 6 of 7 evaluable composite or sequential MLBCL/cHL cases. Two cases of sequential lymphoma showed rearrangements of the IgH gene of identical size: one in which MLBCL was the first diagnosis and one in which MLBCL was diagnosed at relapse, indicating clonal identity for the two components of cHL and MLBCL. There is accumulating evidence that MLBCL and cHL are related entities. Further support for a relationship between MLBCL and cHL-NS is provided by composite and metachronous lymphomas in the same patient, as well as the existence of MGZL with transitional morphology and phenotype. Key Words: gray zone lymphoma, composite lymphoma, primary mediastinal large B-cell lymphoma, classic Hodgkin’s disease, nodular sclerosis Hodgkin’s lymphoma, transcription factor, mor- phology, immunohistochemistry (Am J Surg Pathol 2005;29:1411–1421) C onsiderable progress has been made regarding the origin of the neoplastic cell in classic Hodgkin lymphoma (cHL). Recent data suggest that the malignant cell of cHL is a B-cell in all, or nearly all, cases. 20 If cHL is derived from an altered B-lymphocyte, it is not surprising that areas of overlap with B-cell non-Hodgkin lymphomas (NHLs) should occur both biologically and clinically. The association of primary mediastinal large B-cell lymphoma (MLBCL) and cHL- nodular sclerosis (NS) has been reported sporadically, either as composite or metachronous lymphomas in the same patient. 12,35,57 cHL-NS and MLBCL share a number of common features. They both show a female predominance, and present in young adults, with the median age of presentation for MLBCL being slightly older than that of cHL-NS. The clinical presentation is frequently that of an anterior mediastinal mass with involvement of the thymus gland and involvement of supraclavicular lymph nodes. Both cHL and MLBCL lack Ig expression and functional expression of HLA class I antigens. An additional link between cHL and MLBCL has been demonstrated by the identification of amplifications of the REL locus on chromosome 2p and the JAK2 locus on 9p in both lymphoma subtypes. 2,18,19 Most recently, two groups using gene profiling have suggested shared patterns of gene expression in MLBCL and the neoplastic cells of cHL. 42,46 However, because the therapeutic approach to cHL and MLBCL historically has been different, there is pressure on pathologists to distinguish cHL from cases of morphologically similar NHL. 4 The term ‘‘gray zone lymphoma’’ to refer to From the *Hematopathology Section, Laboratory of Pathology, National Institutes of Health, Bethesda, MD; †Departement de Pathologie, Ho ˆ pital Henri Mondor, Cre ´teil, France; and ‡Centro de Biologı ´a Molecular ‘‘Severo Ochoa,’’ Universidad Auto ´noma de Madrid, Madrid, Spain. The current address for Dr. Traverse-Glehen is Laboratory of Anatomic Pathology, Centre Hospitalier Lyon-Sud, Lyon, France. Presented in part at the meeting of the United States and Canadian Academy of Pathology, Vancouver, British Columbia, Canada, March 2004; and the 6th International Congress on Hodgkin’s Lymphoma, Cologne, Germany, September 2004. Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Reprints: Elaine S. Jaffe, MD, Building 10, Room 2N202, 10 Center Drive, MSC-1500, Bethesda, MD 20892 (e-mail: elainejaffe@nih.gov). Copyright Ó 2005 by Lippincott Williams & Wilkins Am J Surg Pathol  Volume 29, Number 11, November 2005 1411