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Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6YE361immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6YE361immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6YE361[46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6YE361staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6YE361was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6YE361was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1,and ITPKBas well CISHP213L(in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6YE361although no underlying STAT6mutations were observed in either sample examined. STAT6YE361nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.

Nodal follicular helper T-cell-derived lymphoproliferations (specifically the less common peripheral T-cell lymphomas of follicular type) exhibit a spectrum of histologic features that may mimic reactive hyperplasia or Hodgkin lymphoma. Even though angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma of follicular type share a common biologic origin from follicular helper T-cells and their morphology has been well characterized, flow cytometry of peripheral T-cell lymphomas of follicular type has not been widely discussed as a tool for identifying this reactive hyperplasia/Hodgkin lymphoma mimic. We identified 10 peripheral T-cell lymphomas of follicular type with available flow cytometry data from five different institutions, including two cases with peripheral blood evaluation. For comparison, we examined flow cytometry data for 8 classical Hodgkin lymphomas (including 1 lymphocyte-rich classical Hodgkin lymphoma), 15 nodular lymphocyte predominant Hodgkin lymphomas, 15 angioimmunoblastic T-cell lymphomas, and 26 reactive nodes. Lymph node histology and flow cytometry data were reviewed, specifically for the presence of a CD3−/dimCD4+aberrant T-cell population (described in angioimmunoblastic T-cell lymphomas), besides other T-cell aberrancies. Nine of 10 (90%) peripheral T-cell lymphomas of follicular type showed a CD3−/dimCD4+T-cell population constituting 29.3% (range 7.9–62%) of all lymphocytes. Five of 10 (50%) had nodular lymphocyte predominant Hodgkin lymphoma or lymphocyte-rich classical Hodgkin lymphoma-like morphology with scattered Hodgkin-like cells that expressed CD20, CD30, CD15, and MUM1. Three cases had a nodular growth pattern and three others exhibited a perifollicular growth pattern without Hodgkin-like cells. Epstein–Barr virus was positive in 1 of 10 cases (10%). PCR analysis showed clonal T-cell receptor gamma gene rearrangement in all 10 peripheral T-cell lymphomas of follicular type. By flow cytometry, 11 of 15 (73.3%) angioimmunoblastic T-cell lymphomas showed the CD3−/dimCD4+population (mean: 19.5%, range: 3–71.8%). Using a threshold of 3% for CD3−/dimCD4+T cells, all 15 nodular lymphocyte predominant Hodgkin lymphoma controls and 8 classical Hodgkin lymphomas were negative (Mann–Whitney P=0.01, F-PTCL vsHodgkin lymphomas), as were 25 of 26 reactive lymph nodes. The high frequency of CD3−/dimCD4+aberrant T cells is similar in angioimmunoblastic T-cell lymphomas and peripheral T-cell lymphomas of follicular type, and is a useful feature in distinguishing peripheral T-cell lymphomas of follicular type from morphologic mimics such as reactive hyperplasia or Hodgkin lymphoma.

Plasmablastic lymphoma, which is considered a subtype of diffuse large B-cell lymphoma, shares many similar morphological and immunophenotypic features with plasmablastic transformation of plasma cell myeloma. In the setting of human immunodeficiency virus (HIV) infection, both types of neoplasms can be associated with Epstein–Barr virus (EBV), thus making their distinction challenging. Moreover, the biological relationship between these entities remains unclear. We report four unique cases of plasmablastic lymphoma occurring in the setting of HIV infection that had overlapping clinical and genetic features with plasma cell myeloma. We reviewed the clinical, morphological, and cytogenetic findings and performed immunohistochemistry, in situhybridization for EBV, chromosome analysis, and fluorescent in situhybridization (FISH) using the MYCbreak-apart rearrangement probe. All patients were males with a median age of 45 years. In addition to extra-nodal disease, plasmablastic morphology, and phenotype typical of plasmablastic lymphoma, three of the four cases also showed clinical findings overlapping with plasma cell myeloma, that is, monoclonal serum immunoglobulin and lytic bone lesions. Furthermore, these cases showed complex cytogenetic changes that are more commonly observed in plasma cell myeloma. A unique feature was the presence of MYC(8q24.1) rearrangement confirmed by FISH in all four cases. MYCtranslocation has been associated with tumor progression in multiple myeloma but has only rarely been previously reported in plasmablastic lymphoma. These cases show a clinical and biological relationship between plasmablastic lymphoma and the plasmablastic variant of plasma cell myeloma. Dysregulation of MYCmay be a common genetic mechanism that imparts plasmablastic morphology and aggressive clinical course to B-cell neoplasms at a later stage of differentiation.