Prognostic Impact of Extranodal Organ Burden in Classical Hodgkin Lymphoma with Extranodal Involvement: A...

Background: The prognostic significance of extranodal disease in classical Hodgkin lymphoma remains incompletely defined. Although contemporary models such as the Advanced Hodgkin International Prognostic Index (A-HIPI) improve systemic risk stratification, it remains unclear whether outcomes are more closely associated with specific extranodal organ involvement or with the overall burden of extranodal dissemination. Methods: This retrospective single-center study included 89 patients with predominantly advanced-stage classical Hodgkin lymphoma, including a minority of high-risk stage II bulky cases, and documented extranodal involvement at diagnosis. Extranodal disease was evaluated according to both organ-specific involvement and extranodal organ burden (EOB), defined as single extranodal organ involvement (single EO) versus involvement of two or more extranodal organs (≥2 EO). Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier analysis and Cox proportional hazard models. Risk stratification was examined using both the International Prognostic Score (IPS) and A-HIPI. Results: Patients with ≥2 EO had significantly inferior OS compared with those with single EO involvement (5-year OS, 66.8% vs. 96.7%; log-rank p = 0.018), whereas the difference in PFS did not reach statistical significance (5-year PFS, 49.6% vs. 73.5%; log-rank p = 0.108). A-HIPI-based stratification significantly discriminated OS (5-year OS, 92.2% vs. 78.2%; p = 0.001) and showed borderline discrimination for PFS (5-year PFS, 71.5% vs. 57.2%; p = 0.053). In the combined analysis, patients with high A-HIPI risk and ≥2 EO had the poorest outcomes, with a 5-year PFS of 34.1% and a 5-year OS of 25.0%. In a parsimonious multivariable Cox model including EOB and A-HIPI-predicted 5-year risk as a continuous variable, ≥2 EO remained associated with inferior OS (HR 3.83, 95% CI 1.34-10.97; p = 0.013), while its association with PFS was adverse but not statistically significant (HR 1.83, 95% CI 0.86-3.88; p = 0.114). Organ-specific extranodal involvement showed limited and inconsistent associations with survival across A-HIPI- and IPS-defined subgroups. Conclusions: In this retrospective single-center cohort, involvement of multiple extranodal organs was associated with inferior OS after adjustment for continuous A-HIPI-predicted risk, whereas its association with PFS did not reach statistical significance. Individual extranodal sites showed no consistent prognostic associations. These exploratory and hypothesis-generating findings suggest that quantitative assessment of extranodal organ burden may complement existing clinical risk measures; however, confirmation in larger, contemporary, externally validated cohorts is required before clinical application.