Brief report Malignant mesothelioma after radiation treatment for Hodgkin lymphoma

Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the disease may be associated with radiation exposure. Recently, increased risks for second primary mesothelioma after radiation for lymphoma have been reported. Because these findings are based on small numbers of patients, they need to be confirmed. We examined mesothelioma risk in 2567 5-year survivors of Hodgkin lymphoma. The risk was almost 30-fold increased in Hodgkin lymphoma patients treated with irradiation compared with the general population. Although histology and survival of the mesothelioma cases were comparable with cases from the general population, asbestos exposure and the proportion of males were lower than expected. The evidence for radiotherapy as cause for mesothelioma independent of exposure to asbestos is expanding, and the diagnosis of mesothelioma should be kept in mind whenever related symptoms arise in patients who had previous irradiation.


Introduction
Malignant mesothelioma is a relatively uncommon malignancy. The pathogenesis is primarily related to asbestos, typically with a lag time of 10 to 40 years between exposure to asbestos and time of diagnosis. 1 In approximately 15% of mesothelioma patients, no overt exposure to asbestos can be identified, 2 and the disease may be related to other causes, such as irradiation, man-made mineral fibers, organic chemicals, viruses, and chronic inflammation. 3,4 Recently, several epidemiologic studies have reported increased risk of second primary mesothelioma after treatment for testicular cancer 5 and lymphoma. [6][7][8] However, absolute numbers of reported mesothelioma cases were small, leaving the need for confirmation of the previous results and description of additional features. We therefore assessed the long-term risk of malignant mesothelioma in a cohort of 2567 patients treated for Hodgkin lymphoma (HL) in The Netherlands.

Methods
We performed a cohort study in all patients who had been treated for HL at 5 cancer centers/university hospitals in The Netherlands (The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital in Amsterdam, Erasmus MC/Daniel den Hoed Kliniek in Rotterdam, VU Medical Center in Amsterdam, Leiden University Medical Center in Leiden, and the Emma Children's Hospital/ Academic Medical Center in Amsterdam) and in the affiliated hospitals of the Eindhoven Cancer Registry. Patient selection and methods of data collection have been described in detail previously. [9][10][11][12] Patients were younger than 51 years of age at the time of treatment for HL  with radiotherapy and/or chemotherapy and survived at least 5 years.
Follow-up started 5 years after first treatment for HL and ended at the date of diagnosis of mesothelioma, date of death, or date of most recent medical information on second malignancies, whichever came first. Follow-up was complete for 94% of the cohort. Mesothelioma was defined as a malignant tumor of the pleura (code C38.4) of malignant mesothelial morphology (code 9050/3, 9051/3, 9052/3, or 9054/3) according to the International Classification of Diseases for Oncology, 3rd Ed. 13 Pathology of all our cases had been reviewed by the national pathology expert panel, which had verified all diagnoses by directly reexamining the original biopsies on which the diagnosis of mesothelioma had been made. Medical records were screened, and general practitioners were contacted to identify previous exposure to asbestos. Radiotherapy charts were reviewed to assess whether the mesothelioma had developed in the radiation field; in addition, the radiation dose was recorded.
We compared the incidence of mesothelioma in our cohort with the general population, using incidence rates from the Eindhoven Cancer Registry 14 up to 1988 and from The Netherlands Cancer Registry 15 for the period 1989 to 2003. We calculated standardized incidence ratios (SIRs) and absolute excess rates, taking into account person-years of the patients in the HL cohort, according to methods previously described. 11

Results and conclusions
After a median follow-up of 18.1 years, 8 men and 5 women of the 2567 patients experienced mesothelioma at least 5 years after being treated for HL. General characteristics of the study population are given in Table 1. Median age of the cohort members at first treatment for HL was 27.4 years, with a range of 3 to 50 years. Median time from treatment for HL to mesothelioma was 27.7 years, which was diagnosed at a median age of 56.4 years ( Table 2). We found that 5-year survivors of HL experience an almost 26-fold increased risk for mesothelioma The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 Table 1). The absolute excess number of mesothelioma was 3.5 cases per 10 000 patients per year. The risk of mesothelioma was much more pronounced among women (SIR, 85.2; range, 27.6-199) compared with men (SIR, 17.9; range, 7.7-35.3), among patients treated at young ages (age at first treatment Ͻ 31 years), and after prolonged follow-up (Ͼ 25 years after treatment). Among patients treated with radiotherapy, the risk was almost 30-fold increased (SIR, 29.4; range, 15.7-50.4). Although none of the 232 patients treated with chemotherapy only developed mesothelioma, the SIR for mesothelioma among patients treated with a combination of radiotherapy and chemotherapy was much higher (SIR, 44.8; range, 23.2-78.3) compared with patients treated with radiotherapy alone (SIR, 5.8; range, 0.2-32.1). This suggests a potential synergistic effect between chemotherapy and radiotherapy. High cumulative doses of alkylating chemotherapy have been linked previously to an increased risk lung cancer among HL patients. 16,17 Diagnoses of all 13 cases were confirmed by the national pathology expert panel. The epithelial type was most prevalent (Table 2). Twelve tumors developed within the radiation field. In 3 patients, mesothelioma was their third primary tumor. All 13 mesothelioma patients were primarily treated in the 2 hospitals where HL patients from the highly industrialized areas were treated (The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital; Erasmus MC/Daniel den Hoed Kliniek). In the other hospitals, no mesothelioma cases were identified, although with a relative risk of 26 for mesothelioma among HL patients, we would have expected to observe 4 cases in these hospitals.
In this patient population, the characteristics of the mesotheliomas were similar to those seen after overt asbestos exposure. The majority had an epithelial subtype, and survival was limited (median, 10.2 months). However, our cases do not represent the general population of mesothelioma patients. Compared with all cases of mesothelioma newly diagnosed between 1989 and 2005 in The Netherlands, 15 our cases were younger (69% vs 23% younger than 60 years old) and more often female (38% vs 13%). In addition, exposure to asbestos was established in fewer patients than the expected 85%. 2 Our data on asbestos exposure revealed that only 7 of the 13 patients had previous exposure to asbestos (6 occupational, 1 environmental). Because we assume that less than 50% of the Dutch inhabitants have been exposed to asbestos, the exposure among our mesothelioma cases is higher than expected in the general population. 18 This might add to the scarce preclinical evidence for the synergistic action of asbestos and radiation in the pathogenesis of mesotheliomas. 19,20  SIR indicates standardized incidence ratio; AER, absolute excess rate; CI, confidence interval; and HL, Hodgkin lymphoma. *Including primary/salvage treatment for HL and treatment for second malignancies other than mesothelioma. †Indicates radiotherapy with or without chemotherapy. Patients treated with radiation for HL (especially in combination with chemotherapy) experience a dramatically increased risk for mesothelioma, which manifests particularly 25 years or more after treatment. Our study confirms the high risks previously reported among other groups of patients treated with high-dose radiation to the chest. 6-8 Furthermore, our results suggest a potential interaction with chemotherapy or asbestos.
In conclusion, the evidence for radiotherapy as cause for mesothelioma independent of exposure to asbestos is expanding, but the absolute number of patients who are involved is low. Nevertheless, the diagnosis of mesothelioma should be kept in mind whenever new symptoms arise in patients who had previous irradiation.