Classic Hodgkin lymphoma with marked granulomatous reaction: A clinicopathologic study of 20 cases

Granulomatous reactions can be associated with various types of lymphoma, most commonly classic Hodgkin lymphoma (CHL). In some cases, the granulomatous reaction is extensive, obscuring the presence of neoplastic cells and potentially leading to delayed diagnosis and treatment. It is unknown if this subgroup of CHL has any unique clinicopathologic features. Here, we assessed the clinical and pathological features of 20 cases of CHL with a marked granulomatous reaction, defined in this study as granulomas representing ≥50% of the total cellularity/space of the specimen. This cohort of patients showed a male predominance (M:F ratio = 1.9:1) and 75% of patients were older than 40 years. Nineteen (95%) patients presented with lymphadenopathy with the neck/supraclavicular areas being most commonly involved (11/19; 58%). Advanced stage (III-IV) disease and B symptoms were present in 69% and 64% of patients, respectively. The morphologic features of these neoplasms fit best with mixed cellularity type. The Hodgkin and Reed-Sternberg (HRS) cells were positive for CD30, PAX5 (weak), pSTAT3 (80%), CD15 (70%), PD-L1 (67%), EBV-encoded small RNA (EBER)/LMP1 (50%) and CD20 (42%), and were negative for CD3, CD5, CD45, ALK and pERK. The histiocytes of the granulomas were positive for PD-L1 (67%), pSTAT3 (50%), and were negative for pERK and cyclin D1. Next generation sequencing using a 162-gene panel was negative for mutations in 4 cases. With a median follow-up of 58.9 months (range, 3.4-199.2 months), the median overall survival was 111 months and the 5-year overall survival was 78%. In summary, patients with CHL and a marked granulomatous reaction can present a diagnostic challenge and the pathologist must be alert to the possible presence of CHL to avert potential misdiagnosis. The histiocytes in the granulomas frequently express PD-L1, likely through the activation of the JAK/STAT pathway, suggesting a potential role for PD-1 blockade therapy in these patients.