Development of high-grade glioma as a second malignant neoplasm in patients treated for primary brain tumors.
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PURPOSE: Second malignant neoplasms (SMNs) represent a devastating late complication of central nervous system (CNS) tumor, particularly in pediatric and young adult populations. While improved treatments have increased survival rates, the risk and characteristics of SMNs in contemporary cohorts remain poorly characterized. The purpose of this study is to characterize the clinicopathological and molecular features of therapy-related high-grade gliomas(t-HGGs), and to explore their multifactorial etiology involving radiation, chemotherapy, and potential genetic susceptibility. METHODS: We analyzed seven cases of histologically confirmed SMNs developing after treatment for primary CNS tumors. We collected and analyzed key clinical information from patients, including gender, age, time to second tumor onset (latency), treatment modalities, and outcomes. Additionally, we examined imaging findings, histopathological features using hematoxylin-eosin (H&E) staining and immunohistochemistry, as well as molecular marker characteristics. RESULTS: The cohort consisted of seven patients (5 males, 2 females). The median age at primary tumor diagnosis was 5 years (range: 3-21 years), and at SMN diagnosis was 12 years (range: 7-27 years), with a median latency of 6 years (range: 2-9 years). All patients received radiotherapy. Exploratory analysis revealed no significant relationship between radiation dose and latency period. Histological transformation was universal, most commonly from medulloblastoma to high-grade glioma (3/7 cases) and germ cell tumors (3/7 cases, including 2 germinomas and 1 non-germinomatous germ cell tumor (NGGCT)). Molecular analysis in sequenced cases revealed distinct profiles, including NF1/PDGFRA alterations. Outcomes were poor. CONCLUSION: This study delineates a rare yet distinct clinicopathological entity-therapy-related high-grade glioma, which may arise from the complex interplay of prior radiotherapy, chemotherapy, and underlying genetic susceptibility. Recognition of this multifactorial etiology is critical for risk stratification and long-term surveillance.