We herein present an overview of the upcoming 5^thedition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4^thedition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5^thedition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis.

Background Cytogenetic analysis of classical Hodgkin’s lymphoma is limited by the low content of the neoplastic Hodgkin-Reed-Sternberg cells in the affected tissues. However, available cytogenetic data point to an extreme karyotype complexity. To obtain insights into chromosomal imbalances in classical Hodgkin’s lymphoma, we applied array-based comparative genomic hybridization (array comparative genomic hybridization) using DNA from microdissected Hodgkin-Reed-Sternberg cells. Design and Methods To avoid biases introduced by DNA amplification for array comparative genomic hybridization, cHL cases rich in Hodgkin-Reed-Sternberg cells were selected. DNA obtained from approximately 100,000 microdissected Hodgkin-Reed-Sternberg cells of each of ten classical Hodgkin’s lymphoma cases was hybridized onto commercial 105 K oligonucleotide comparative genomic hybridization microarrays. Selected imbalances were confirmed by interphase cytogenetics and quantitative polymerase chain reaction analysis and further studied in an independent series of classical Hodgkin’s lymphoma. Results Gains identified in at least five cHL affected 2p12-16, 5q15-23, 6p22, 8q13, 8q24, 9p21-24, 9q34, 12q13-14, 17q12, 19p13, 19q13 and 20q11 whereas losses recurrent in at least five cases involved Xp21, 6q23-24 and 13q22. Copy number changes of selected genes and a small deletion (156 kb) of the CDKN2B (p15) gene were confirmed by interphase cytogenetics and polymerase chain reaction analysis, respectively. Several gained regions included genes constitutively expressed in cHL. Among these, gains of STAT6 (12q13), NOTCH1 (9q34) and JUNB (19p13) were present in additional cHL with the usual low Hodgkin-Reed-Sternberg cell content. Conclusions The present study demonstrates that array comparative genomic hybridization of microdissected Hodgkin-Reed-Sternberg cells is suitable for identifying and characterizing chromosomal imbalances. Regions affected by genomic changes in Hodgkin-Reed-Sternberg cells recurrently include genes constitutively expressed in cHL.

T-cell/histiocyte-rich large B-cell lymphoma is a rare aggressive lymphoma showing histopathological overlap with nodular lymphocyte-predominant Hodgkin lymphoma. Despite differences in tumor microenvironment and clinical behavior, the tumor cells of both entities show remarkable similarities, suggesting that both lymphomas might represent a spectrum of the same disease. To address this issue, we investigated whether these entities share mutations. Ultra-deep targeted resequencing of six typical and 11 histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma, and nine cases of T-cell/histiocyte-rich large B-cell lymphoma revealed that genes recurrently mutated in nodular lymphocyte-predominant Hodgkin lymphoma are affected by mutations at similar frequencies in T-cell/histiocyte-rich large B-cell lymphoma. The most recurrently mutated genes were JUNB, DUSP2, SGK1, SOCS1 and CREBBP, which harbored mutations more frequently in T-cell/histiocyte-rich large B-cell lymphoma and the histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma than in its typical form. Mutations in JUNB, DUSP2, SGK1 and SOCS1 were highly enriched for somatic hypermutation hotspot sites, suggesting an important role of aberrant somatic hypermutation in the generation of these somatic mutations and thus in the pathogenesis of both lymphoma entities. Mutations in JUNB are generally rarely observed in malignant lymphomas and thus are relatively specific for nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma at such high frequencies (5/17 and 5/9 cases with JUNB mutations, respectively). Taken together, the findings of the present study further support a close relationship between T-cell/histiocyte-rich large B-cell lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma by showing that they share highly recurrent genetic lesions.