Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was

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... irmed in 25/54 patients. In six of these, subsequent lymphoma concerned primary mediastinal B-cell lymphoma/mediastinal grey zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), EBV+ diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and EBV-association were identified as markers to alert for CHL mimickers. Based on these data, risk to develop NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; CI 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for individual patient care, interpretation of trials and epidemiological assessments.