Simultaneous osteosarcoma and renal cell carcinoma with BRCA1 mutation in a young male adult with prior oligodendroglioma

Abstract

Secondary malignant neoplasms (SMN) are a rare but serious complication in childhood cancer survivors.1 The data on underlying genetic predisposition contributing to SMNs are limited. We present a case of two simultaneous SMNs posing a diagnostic dilemma with an unexpected finding of a BRCA1 germlinemutation. An 18-year-old male presented with headache and scalp swelling. History was notable for WHO grade III anaplastic oligodendroglioma at two years of age, with recurrence at age five, treated with resection, radiation (54 Gy), and chemotherapy. Antineoplastic exposures included lomustine, procarbazine, temozolomide (TMZ), and vincristine. Family historywas negative formalignancies. Imaging demonstrated a left parietal mass (5.8 × 5.3 × 5.0 cm) arising from the bone with soft-tissue extension in the prior radiation field (Figure 1A and 1B). The patient underwent subtotal resection of the mass. Persistent hypertension was noted, and workup revealed a solid mass (4.1 × 4.2 × 3.6 cm) in the left kidney with multiple small lesions on bilateral kidneys (Figure 1C). Further imaging revealed a 1 cm nodule in the right upper lobe of the lung (Figure 1D and 1E). Initial histology from the intracranial lesion was suggestive of gliosarcoma. However, secondary pathology review was concerning for osteosarcoma (Supporting Information Figure S1). Pathology from the kidney mass was consistent with unclassified, grade 2 renal cell carcinoma (RCC; Supporting Information Figure S2). Lung nodule was not resected. Genomic sequencing (FoundationMedicine, Cambridge, MA) from the intracranial lesion demonstrated loss of TP53 and RB1, pathogenic variant in BRCA1 (splice site 213-11T>G) and MLL2, and significant aneuploidy. Based on these results and immunoreactivity for SATB2, the final pathology was determined to be osteosarcoma. Testing from the RCC revealed mutations in BRCA1, TSC2, PBRM1, and a high mutation burden (33 Mut/Mb). Germline testing confirmed a pathogenic variant in BRCA1 (c.213-11T>G). Initial treatment included methotrexate, doxorubicin, cisplatin (MAP), and everolimus for RCC given TSC2 mutation. The latter was withheld after the first cycle due to toxicity. Given the more indolent nature of RCC, treatment for this was deferred until the completion of osteosarcoma treatment. Treatment was complicated by recurrent acute kidney injurywith slowworsening of his kidney function, limiting