Table 2.

Features of mediastinal gray zone lymphoma compared to cHL and primary mediastinal large B-cell lymphoma.

	Classical Hodgkin lymphoma (cHL)	Primary mediastinal large B-cell lymphoma (PMLBCL)	Mediastinal gray zone lymphoma (MGZL)
Clinical features	• Bimodal age distribution • Slight female predominance in nodular sclerosis • Frequent mediastinal involvement in nodular sclerosis • Most cases in stage I/II, in nodular sclerosis	• Young adults with female predominance (2:1) • Bulky mediastinal presentation (about 50%) • Rare involvement at unusual sites (kidneys, adrenals, CNS)	• Young adults with slight male predominance • Frequent mediastinal involvement with bulky disease • Primary extra-mediastinal presentation is better classified as DLBCL, NOS
Morphology	• Infrequent H-RS cells embedded in the typical cellular background (lymphocytes, eosinophils, histiocytes, plasma cells) • Collagen bands delimiting cellular nodules in nodular sclerosis • Syncytial variant of nodular sclerosis (rich in H-RS cells)	• Medium to large tumor cells with clear cytoplasm • Increase of reticular fibrosis leading to “compartmental” growth of tumor cells • Occasional H-RS like cells	• About 70% of cases shows a “cHL like morphology” resembling nodular sclerosis • About 30% mimic PMLBCL (monomorphic proliferation of medium-large neoplastic cells, pauci-cellular inflammatory infiltrate)
Immunophenotype	CD20− (rarely positive in a percentage or in most tumor cells), CD19−, CD79a−, CD79b−, PAX5+ (weak), CD30+ (strong), CD15+/−, MUM1/IRF4+, BCL6−, EBV −/+	CD20+, CD19+, CD79a+, CD79b+, PAX5+, BCL6+/−, CD30+ (weak/partial expression), CD23+ (>50%), MUM1/IRF4+/−, EBV−	Uniform and strong expression of >1 B-cell marker (CD20, CD19, CD79a, CD79b), PAX5+ (strong), CD30+, MUM1/IRF4+, BCL6+, EBV− (rarely positive)
Genetics and molecular features	• JAK/STAT and NF-kB activation • Mutations in NF-kB inhibitors (TNFAIP3, NFKBIE, NFKB1A) • CN gains of REL, JAK2 and PD-L1/2 (9p24 amplification) • Mutations of JAK1/3, STAT3/5B/6, SOCS1 • CIITA translocation	• JAK/STAT, NF-kB activation • CN gains of REL, PD-L1/2 and JAK2 (amplifications of 2p16 and 9p24) • Loss of TNFAIP3, NFKBIE, EZH2, IL4R, GNA13 • STAT6 mutations	• JAK/STAT and NF-kB activation • CN gains of REL, PD-L1/2 and JAK2 • Mutations in SOCS1, TNFAIP3, NFKBIE, GNA13, XPO1 and B2M with loss of MHC-1 and MHC-2 expression • Lack of BCL2 and BCL6 translocations

H-RS Hodgkin and Reed-Sternberg cells.