DIFFUSE INTRINSIC PONTINE GLIOMA AS A SECONDARY MALIGNANCY: A REPORT FROM THE DIPG REGISTRY AND REVIEW OF THE LITERATURE

Exposure to cranial radiation in childhood increases the risk of subsequent CNS malignancies, an important cause of late mortality. Studies have shown a linear relationship between radiation dose and risk of secondary meningiomas and gliomas. However no studies have specifically examined the development of diffuse intrinsic pontine glioma (DIPG) after childhood craniospinal radiation. Given the frequent brainstem irradiation and growing number of pediatric brain tumor survivors, we sought to investigate the risk of DIPG as a secondary malignancy in childhood cancer survivors. We performed a retrospective analysis of the DIPG Registry and Repository for cases of DIPG occurring after radiation therapy for primary pediatric CNS malignancies. We identified four cases of secondary DIPG confirmed by neuroimaging, three after primary medulloblastoma and one after ependymoma. Additionally, we performed an extensive literature search for secondary DIPG cases after radiation therapy for any primary childhood CNS malignancy. This search identified seven additional cases of brainstem glioma occurring after CNS radiation for primary medulloblastoma (n=5), pituitary macroadenoma (n=1), and pleomorphic xanthoastrocytoma (n=1). We were unable to confirm DIPG diagnosis by neuroimaging for these patients. For patients with available treatment and outcome data, DIPG occurred an average of 7.8 years (10.3 months-15 years) after completion of therapy. For patients with radiation details available, all received photon radiation to the brainstem (range 50-56.1 Gy) during primary tumor treatment. Patients died of disease an average of 6.5 months (4-10 months) after diagnosis. One patient has stable disease 13 months from diagnosis on adjuvant experimental treatment with panobinostat, a pan-HDAC inhibitor. In summary, secondary DIPG is a rare, but increasingly common, secondary malignancy in children who have received CNS radiation. A better understanding of the impact of radiation dose, field, and modality on the risk of secondary malignancies is necessary to guide future treatment of childhood CNS cancer.