LAUSR

Hodgkin lymphoma (HL) has been classified into 2 categories: classic Hodgkin lymphoma (CHL), which accounts for 95% of all HL cases, and the less common nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). CHL is a distinct neoplastic entity with typical clinical and epidemiological characteristics and unique pathological, genetic, and virological features. On the basis of the morphological characteristics of the Hodgkin Reed-Sternberg cells (lacunar cells, multinucleated giant cells, and pseudosarcomatous cells) and the composition of the reactive infiltrate, 4 histological subtypes have been distinguished: lymphocyte-rich classic Hodgkin lymphoma (LRCHL), nodular-sclerosis CHL, mixedcellularity CHL, and lymphocyte-depleted CHL. The HL classification has not changed over the last 2 decades; however, updates concerning NLPHL and LRCHL have incorporated information with significant clinical and biological implications. A considerable body of evidence indicates that so-called NLPHL exhibits features of a B-cell lymphoma with a typical antigen profile and characteristic clinical behavior. Tumor cells are antigen-selected, mutating germinal-center B cells; the germinal center B-cell origin is also supported by the expression of BCL6 and CD40, the gene expression profile, the rearranged, clonal, and mutated (ongoing) immunoglobulin (Ig) genes of tumor cells, the presence of CD4 1 and PD1 1 T cells surrounding the tumor cells, and the presence of a follicular dendritic cell meshwork within the tumor nodules. Interestingly, molecular studies have shown similarities between NLPHL and T-cell or histiocyte-rich large B-cell lymphoma (THCRLBCL). Moreover, clinical and pathological observations have demonstrated that NLPHL may evolve into a completely diffuse T cell–rich proliferation resembling THCRLBCL. The 2016 revision of the World Health Organization classification recommends that these cases be designated as THCRLBCL-like transformation of NLPHL (Fig. 1). So-called LRCHL morphologically resembles NLPHL in terms of nodular growth and lymphocyte richness. However, the tumor cell phenotype of LRCHL is similar to that of other CHL subtypes with co-expression of CD30 and CD15 and an Epstein-Barr virus infection. Furthermore, the tumor cells of NLPHL, which consistently lack expression of CD30 and CD15, appear not to be permissive for an Epstein-Barr virus infection (Fig. 1). Curiously, the tumor cell phenotype of LRCHL and NLPHL exhibits the B-cell transcriptional program (Fig. 1). Importantly, the 2016 World Health Organization revision also acknowledges that LRCHL exhibits features intermediate between those of other subtypes of CHL and NLPHL (Fig. 1). Clinically, patients with NLPHL and patients with LRCHL differ in the frequency of multiple relapses and in the prognosis after relapse. Taken together, these data confirm the view that NLPHL should be separated from the CHL subtypes. Furthermore, on the basis of the putative cell of origin, the presence of a translocation involving the BCL6 proto-oncogene, the expression of the B-cell phenotype, and the propensity to progress toward large B-cell lymphoma, NLPHL should be designated as a special type of B-cell lymphoma with a follicular center cell origin and should be pulled out from the HL classification. To achieve clinicians’ acknowledgment of this change, in the pathological report, the prior designation of NLPHL for this lymphoma should be mentioned. To guarantee the appropriate management of patients, information on the nodular growth patterns, the amount (the number and the size) of diffuse areas, and the tumor cell richness should be reported because of the clinical associations of these features.