The spectrum of non-Hodgkin lymphomas presenting in patients treated for classic Hodgkin lymphoma; the consequences of Hodgkin mimickers
Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk to subsequently develop non-Hodgkin lymphoma (NHL). This is hypothesized to result from treatment-related (late) toxicity, genetic predisposition and co-incidental findings during follow-up. More recently, the problem of CHL mimickers has gained attention, concerning NHL that may be mistakenly diagnosed as CHL. In these cases, relapse of NHL may impact the epidemiological risk of NHL after CHL. Based on pathology review of a nationwide cohort of patients with reported NHL after CHL, we investigated primary and subsequent lymphoma diagnoses to re-assess the epidemiological risk and provide diagnostic clues to avoid misdiagnosis.
All patients diagnosed and treated for CHL in the Netherlands from 2006-2013 were identified in the Netherlands Cancer Registry. Of these, all pathology reports concerning lymphoma were obtained from the Dutch Pathology Registry (PALGA). CHL patients with subsequent NHL were identified and biopsy material of both diagnoses was obtained from the original laboratories to perform in-depth pathology review according to current WHO criteria.
We identified 2669 patients with biopsy-proven CHL diagnosis, 54/2669 patients (2.0%) reportedly developed subsequent NHL. After pathology review, in 19/54 patients primary CHL diagnosis was retrospectively recognized unequivocally as NHL. In 12/54 patients, primary CHL diagnosis was highly suspicious for NHL while lacking unequivocal criteria. Misdiagnosis concerned lymphomas with secondary Hodgkin-like, mostly EBV+ cells (angio-immunoblastic T-cell lymphoma (AITL; n=12), other peripheral T-cell lymphomas (PTCL; n=5), immunodeficiency-related lymphoproliferative disease (ID-BLPD; n=8)), CD30+ T-cell lymphomas (n=3) and other indolent B-cell proliferations (n=3).
In 23/54 patients, primary CHL diagnoses was confirmed. Subsequent NHL were in the primary mediastinal B-cell lymphoma–CHL spectrum (n=6) or consisted of various B-cell lymphomas (diffuse large B-cell lymphoma (n=6), B-cell acute lymphoblastic leukemia (n=1), indolent B-cell NHL (n=10)). CD20 expression on Hodgkin(-like) cells was more common in ID-LPD and AITL/PTCL than in confirmed CHL (75%, 40% and 9% of cases respectively), CD15 expression was less common in mimickers (27%, 25% and 86% respectively).
Based on pathology review of a nationwide, unbiased cohort of CHL patients, risk of subsequent NHL is far lower than previously thought, resulting from recurring NHL initially misdiagnosed as CHL. Most of these are T-cell lymphomas with secondary, mostly EBV+ Hodgkin-like cells or ID-BLPD. This impacts epidemiology of subsequent NHL after CHL, but more importantly, mistaken CHL diagnoses have consequences regarding treatment of individual patients and affect outcome and relapse rates in clinical trials. Diagnostic clues to recognize CHL mimickers include EBV-positivity, CD20 expression and CD15 negativity on Hodgkin(-like) cells. Furthermore, clinicopathologic correlation regarding disease distribution and especially immunodeficiency status is paramount when facing the complex differential diagnostic problems surrounding CHL.