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Splenectomy and second malignancies in patients with Hodgkin lymphoma

Splenectomy is part of treatment for hematological diseases and its long-term sequelae are varied and still under investigation [1,2]. Until the 1990s, many patients with Hodgkin lymphoma underwent splenectomy as a part of staging procedures. During follow-up, a number of patients splenectomized or not developed second malignan­ cies. Whether splenectomy might also increase the risk of malignancies due to impaired immune surveillance is still a matter of debate. In some studies, splenectomy appeared to be a significant risk factor for the development of second malignancies [3-5], but others found no such association [6,7]. We analyzed the risk of second malignancies after splenectomy in a consecutive cohort of long-term survivors of Hodgkin lymphoma. Between 1970 and 1996, 179 patients, all registered in a database, were treated for Hodgkin lymphoma at the University Medical Center Groningen (UMCG), The Netherlands. We selected all patients with a follow-up > 2 years (170 patients, 95%). Subsequently, four patients were excluded because of a solid tumor before or within 2 years of follow-up. Given the time course, these malignancies were probably not related to the effects of splenectomy. Clinical data were retrieved from patients' files. Treatment characteristics were based on primary and salvage Hodgkin lymphoma therapy. Splenectomy was defined as total or partial surgical removal of the spleen. Second malignancies were defined as any malignancy confirmed by a patholo­ gist or registered as a discharge diagnosis after hospital admission, including melanoma, but excluding all other skin cancers. To verify and complete second malignancy data, a questionnaire was sent to the general practitioner, and a link was made with the population-based registry of the Comprehensive Cancer Center North East Netherlands. This registry is based on all diagnoses made by pathologists and discharge diagnoses from hospitals in the north east of The Netherlands. The follow-up started at treatment initiation and ended at date of death, date of most recent medical information or date of diagnosis of a second malignancy, whichever came first. To assess whether splenectomy was related to second malignancies, a Cox regression analysis with forward step­ wise confounder selection was performed, including sex, age, radiotherapy, mediastinal irradiation, chemotherapy, alkylating agents, smoking and relapse. In addition, the incidence of second malignancies was calculated using a cumulative incidence analysis that accounts for competing risk, with death as competing event [8]. We evaluated the Cox proportional hazards assumption by assessing log minus log curves. This assumption was satisfied for all variables. Out of the 166 patients, 90 (54%) underwent a splenec­ tomy. Patient characteristics, treatment characteristics (pri­ mary and salvage treatment) and second malignancies are presented in Table I. The median follow-up of splenectomized and non-splenectomized patients was 21 years (range: 3-40) and 17 years (range: 3-37), respectively. Twenty-one percent of the splenectomized and 17% of the non-splenectomized patients developed one or more second malignancies. Of the splenectomized patients, 13 (14%) developed a solid tumor and nine (10%) a hematological malignancy, compared to nine patients (12%) with a solid tumor and five patients (7%) with a hematological malignancy in the non-splenectomized group (Table I). Median time interval between the start of Hodgkin treatment and diagnosis of hematological malig­ nancies and solid tumors was 18 years (range: 10-30) and 18 years (range: 4-34), respectively. In the splenectomized group 10 patients (11%) and in the non-splenectomized group 12 patients (16%) died. The cumulative incidence of second malignancies at 25 years of follow-up was 18% for patients with and 22% for patients without splenectomy (see also Figure 1). The esti­ mated risk for splenectomized patients was not different from that of non-splenectomized patients (hazard ratio [HR]