(P 158) RECURRENT RADIATION-INDUCED SARCOMA IN A PATIENT WITH HEREDITARY RETINOBLASTOMA: PRESENTATION AND OUTCOME

Objective: Patients with hereditary retinoblastoma (Rb), a rare pediatric ocular tumor resulting from a germline mutation and a second acquired somatic mutation in the RB1 tumor suppressor gene, have a significantly higher risk of developing subsequent malignant neoplasms, primarily bone and soft tissue sarcomas. This risk appears to increase with the use of ionizing radiation in some therapeutic approaches commonly used to treat Rb during childhood. Following the “two-hit” hypothesis observed in Rb, the development of most tumors requires the inactivation of both alleles of tumor suppressor genes. We describe a hereditary Rb patient who developed three malignancies, including a radiation-associated sarcoma that harbored a single-allele somatic BRCA2 deletion. The significance of this finding will be explored.

Methods: We report the case of a 68-year-old female patient with a history of germline Rb, with enucleation of the right eye and radiation to the left eye, who developed radiation-induced high-grade sarcoma with myoid differentiation of the left nasal cavity more than 50 years after completion of radiation. Prior to this diagnosis, the patient developed two other separate tumors, including a renal cell carcinoma that was resected and an ovarian serous carcinoma, for which the patient underwent surgery and received adjuvant chemotherapy with carboplatin/Taxol. The high-grade sarcoma was seen two months after the ovarian tumor was resected. The patient’s sarcoma was treated with surgical resection and adjuvant pazopanib, but the tumor recurred in the nasal cavity four years later. Molecular profiling of this tumor showed a single-allele BRCA2 deletion that appeared to be a somatic mutation. Although the literature supports the use of PARP inhibitors for patients with germline BRCA1/BRCA2 mutated tumors, we treated this patient empirically with olaparib 150mg twice a day given the high risk for recurrence.

To further investigate the occurrence of single-allelic somatic mutations/deletions resulting in clinically significant secondary malignancies in patients with germline Rb treated with radiation, we pursued molecular profiling by next-generation sequencing (NGS) of the patient’s other tumors whose fields of tumor development did not receive prior radiation. Direct sequence analysis was performed on genomic DNA isolated from each tumor, with driver mutations and clinically relevant gene mutations analyzed.

Results: While NGS demonstrated a single allele BRCA2 deletion in the patient’s recurrent nasal cavity sarcoma, no other somatic mutations have been identified yet in the other tumors. The patient’s ovarian carcinoma showed a TP53 mutation, and the renal cell carcinoma showed a pathogenic variant in exon 2 of VHL, but both were otherwise negative for BRCA1/2 mutations or deletions. After these tumors were submitted for NGS, the patient was found to have a left lingula lung nodule on routine computed tomography scan of the thorax. The patient underwent resection of the nodule, with pathology results confirming metastatic high-grade sarcoma. The histomorphology of the metastatic tumor, similar to the patient’s prior nasal cavity sarcoma, is demonstrated in Figure 1. The patient is currently alive and free of disease now almost seven years after her original sarcoma diagnosis.

Conclusion: Sarcomas account for approximately 40-60% of subsequent malignant neoplasms in hereditary Rb survivors. Our case suggests that certain single allelic somatic mutations may be associated with sarcoma developments in hereditary Rb patients who received prior radiotherapy. Future molecular studies involving a larger cohort of hereditary Rb patients may better characterize the significance of single copy somatic mutations in sarcoma development.


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