Diagnostic utility of STAT6YE361 expression in classical Hodgkin lymphoma and related entities

Abstract

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, STAT6YE361 immunostaining 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 STAT6YE361 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway 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 STAT6YE361 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6YE361 was 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-L1 gene 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 STAT6YE361 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6YE361 although no underlying STAT6 mutations were observed in either sample examined. STAT6YE361 nuclear 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.

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Fig. 1: Typical STAT6YE361 staining pattern in reactive nodal tissues: STAT6YE361.
Fig. 2: Typical STAT6YE361 staining patterns in classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma.
Fig. 3: Examples of challenging cases mimicking classical Hodgkin lymphoma.
Fig. 4: Comparison of STAT6YE361 and p-STAT6YE641 in a case of coexisting and clonally identical classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma.
Fig. 5: PD-L1 IHC and FISH in diagnostic classical Hodgkin lymphoma tissue and relapsed gray zone lymphoma tissue.

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The study was in part funded by the Hoogland lymphoma biobank at the University of Chicago.

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Correspondence to Girish Venkataraman.

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Van Slambrouck, C., Huh, J., Suh, C. et al. Diagnostic utility of STAT6YE361 expression in classical Hodgkin lymphoma and related entities. Mod Pathol 33, 834–845 (2020). https://doi.org/10.1038/s41379-019-0428-0

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