The nodularity and presence of T-cell rosettes surrounding the neoplastic cells has been described as a defining feature of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We have explored the potential diagnostic value of a new marker (NAT105) that recognizes the antigen PD-1 in a series of 152 cases diagnosed as nodular sclerosis Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte-rich classic Hodgkin lymphoma, NLPHL, and T-cell/histiocyte-rich B-cell lymphoma (T/HRBCL). All the cases were immunostained with a panel of antibodies against CD10, bcl-6, CXCL13, CD57, and PD-1 (NAT-105). The series includes a set of cases diagnosed as NLPHL with diffuse areas, and a group of borderline cases with features between those of NLPHL and T/HRBCL. Results show that PD-1 (NAT-105) is an excellent immunomarker not only of follicular T-cell rosettes in NLPHL, but also of a subset of lymphocyte-rich classic Hodgkin lymphomas. However, it is not a unique and defining feature of NLPHL. The presence of PD-1-positive (NAT-105) T-cell rosettes seems to be an additional useful feature in the differential diagnosis of NLPHL and T/HRBCL, which is normally a controversial and difficult task. The standard T/HRBCL cases lack follicular T-cell rosettes, whereas most of the borderline cases between the 2 entities have follicular T-cell rosettes, thus suggesting a closer relation with NLPHL.

The existence, diagnostic features, and the biological and clinical relevance of lymphocyte-rich classical Hodgkin's lymphoma remain controversial. A comparative marker analysis of lymphocyte-rich classical Hodgkin's lymphoma, nodular lymphocyte-predominance Hodgkin's lymphoma, and of other subtypes of classical Hodgkin's lymphoma was carried out. Markers were selected focusing on B-cell lineage and transcription program (OCT.1, OCT.2, BOB.1, BCL6, PAX-5, GCET1, KLHL6, and BLIMP1), the NF-jB signaling pathway (REL-B, C-REL, TRAF-1, p-50, and MUM-1) and the T-cell microenvironment (CD3, CD57, PD-1, CXCL-13, and CD10, BCL-6, CD23). Lymphocyte-rich classical Hodgkin's lymphoma cases displayed features intermediate between those of classical Hodgkin's lymphoma and nodular lymphocyte-predominance Hodgkin's lymphoma. The expression of B-cell transcription factors such as OCT.1, OCT.2, BOB.1, and BCL6 was more frequent in lymphocyte-rich classical Hodgkin's lymphoma than in classical Hodgkin's lymphoma. A follicular T-cell microenvironment was also identified in 50% of lymphocyte-rich classical Hodgkin's lymphoma cases. NF-kB markers were expressed at frequencies comparable with those observed in classical Hodgkin's lymphoma. The neoplastic cell immunophenotype and microenvironment in lymphocyte-rich classical Hodgkin's lymphoma closely mimic that which are observed in the outer zone of the germinal center, where B-cell blasts with germinal-center markers co-express CD30 and the B-cell transcription program, surrounded by follicular T-cell rosettes. Lymphocyte-rich classical Hodgkin's lymphoma seems to be characterized by a stronger expression of the B-cell transcription program by the neoplastic cells and by a follicular T-cell background, occupying an intermediate position between classical Hodgkin's lymphoma and nodular lymphocyte-predominance Hodgkin's lymphoma.

These findings may be a manifestation of an underlying disorder in the regulation of the immune response, or an exaggeration of the germinal centre oligoclonal nature. This should be taken into account in the differential diagnosis of follicular hyperplasia.