Post-Radiation Grade 3 Neuroendocrine Carcinoma: A New Entity?

BACKGROUND: Cancer survivors have a 14% increased risk of developing a malignancy compared with the general population. Second radiation-induced malignancies with different histologies have been described in different organs. Based on individual observations, we hypothesized that neuroendocrine carcinoma (NEC) could arise in irradiated organs. METHODS: In a retrospective analysis of Gustave Roussy database of NEC patients (small cell lung cancer excluded) diagnosed as a second cancer, we looked for the frequency of grade 3 NEC that arose in patients who had received previous radiation therapy for a first cancer. Radiation therapy for the first cancer, dose, location of radiation therapy, pathological characteristics, overall survival, and response to treatment of secondary NEC were analyzed. RESULTS: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) patients had a history of previous malignancy of which 36 (4%) had been treated with radiation therapy. Out of these 36 patients, 12 (1.4% of all NEC patients) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36-67.5). Most frequent first cancers were breast cancer (n = 4) and Hodgkin lymphoma (n = 3). NEC arose within a median time of 21.7 years (range 5.1-36.4) from radiation in the thorax (n = 5), digestive tract (n = 3), and other sites. Five large cell NEC, 3 small cell NEC, 1 mixed neuroendocrine neoplasm and 3 not otherwise specified NEC were diagnosed. Ten patients had stage IV disease at diagnosis; median overall survival was 37.8 months (95% CI [17.6 to NA]). Three patients (25%) achieved complete response with multimodal treatment. CONCLUSIONS: NEC can arise from previously irradiated organs and may have a better outcome in this setting. Other risk factors should be investigated to explain the high rate of previous cancer in this population of neuroendocrine neoplasm.