Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with classical Hodgkin lymphoma like Richter transformation (cHL-RT) is rare (<1%). cHL-RT is associated with a shorter overall survival and poor clinical prognosis compared to either CLL/SLL alone or de novo Hodgkin lymphoma, even when treated with standard ABVD-based regimens. Two histological subtypes have been accepted by the International Consensus Classification, although they have not yet been adopted by the WHO 5th edition: Type I, featuring scattered Hodgkin and Reed–Sternberg (HRS)-like cells within a CLL/SLL background without a mixed inflammatory infiltrate; and Type II, resembling de novo cHL with a polymorphous inflammatory background. A recent study further supports a biological continuum between type 1 and type 2 cHL-RT, suggesting that even patients with type 1 cHL-RT may benefit from Hodgkin-directed therapy.

Constitutive activation of the JAK/STAT signaling pathway and mechanisms of immune evasion are key drivers in the pathogenesis of de novo cHL. HRS cells in cHL commonly exhibit elevated expression of STAT6 and its activated form, phosphorylated STAT6 (pSTAT6). In parallel, both genetic alterations and the surrounding tumor microenvironment contribute to the upregulation of PD-L1 on HRS cells, facilitating their immune escape. Therapeutically, the combination of JAK inhibitors and immune checkpoint blockade has demonstrated promising efficacy in patients with relapsed or refractory cHL. Although the immunophenotypic profile of HRS-like cells in type 1 and type 2 cHL-RT appears similar to that of de novo cHL, the expression patterns of these key markers have not been systematically characterized in the setting of cHL-RT.

To assess the frequency of STAT6 and PD-L1 expression by immunohistochemistry (IHC), we conducted aretrospective analysis of 19 cases of cHL-RT diagnosed at Brigham and Women's Hospital between 2010 and 2025. Clinical characteristics, histomorphology, immunophenotype, EBV status, molecular and cytogenetic data, treatment details, and outcomes were collected. Six cases were classified as Type I, and 13 cases as Type II. No cases in our cohort demonstrated progression from type I to type II. The cohort showed a male predominance, with a male to female ratio of 3:1 (15 males, 4 females). The median age at diagnosis was 63 years (range, 50-75 years) in Type I cases, and 75 years (range, 55-85 years) in Type II cases. A prior history of CLL/SLL was present in 89% of patients (17/19 patients), with a mean interval of 86 months (range, 21-168 months) in Type I cases and 58 months (range, 3-240 months) in Type II cases from initial CLL/SLL diagnosis to transformation into cHL-RT. The cHL-RT diagnosis was made in biopsy sites from bone marrow in 6 cases (32%), and from lymph node and extranodal sites in 13 cases (68%). EBV status was assessed in all cases: 8 of 19 (42%) were positive by in situ hybridization for EBV-encoded small RNAs (EBER-ISH), while 11 of 19 (58%) were negative for both EBER-ISH or Latent Membrane Protein 1 (LMP1) by IHC. Although EBV was more frequently detected in type II cases (54%; 7 of 13 cases) compared to type I cases (17%; 1 of 6 cases), this difference was not statistically significant (p = 0.17). All evaluable cases of both type I and type II cHL-RT were negative for STAT6 (0/18), while the majority demonstrated PD-L1 expression, observed in 13 of 17 cases (76%), including 4 of 6 type I cases (67%) and 9 of 11 type II cases (82%). Treatment modalities were available for 16 of 19 cases (84%). Among these, 12 (75%) received ABVD/AVD-based chemotherapy and 4 (25%) received PD-1 immunotherapy combined with ABVD/AVD-based chemotherapy. Two patients (13%) in the overall cohort underwent allogeneic stem cell transplantation. Follow-up data were available for 18 of 19 patients (95%). With a median follow-up of 44 months (range, 1-148 months), 28% (5/18) died of disease within three years, 5% (1/18) died of unrelated causes, and 67% (12/18) were alive. Our findings suggest that cHL-RT may arise through distinct pathogenic pathways compared to de novo cHL, highlighted by the lack of STAT6 expression. Nevertheless, further comprehensive analyses, including gene expression profiling, are essential to confirm these observations. Moreover, the frequent upregulation of PD-L1 in HRS cells of cHL-RT underscores the potential efficacy of PD-L1–targeted immunotherapies in this setting.

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2025
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