DICER1-associated malignancies mimicking germ cell neoplasms: Report of two cases and review of the literature

Abstract DICER1 syndrome is characterized by a unique combination of features and a growing list of associated rare tumors. Traditionally, gonadal or extra-gonadal teratomas have not been considered part of this spectrum, with only rare DICER1-related teratoid neoplasms recently reported. Besides, their methylation profiles remain elusive. We report two DICER1-associated malignancies involving the lumbar spine of a 22-year-old man (case 1) and the pelvic cavity of a 14-year-old girl (case 2). Both tumors exhibited teratoma-like features with a high-grade malignant somatic component, including rhabdomyosarcomatous elements for case 1 and a malignant neuroectodermal neoplasm with features of an embryonal tumor with multilayered rosettes (ETMR) for case 2. Both tumors showed strong SALL4 expression and H3K27me3 loss by immunohistochemistry. Next-generation sequencing studies confirmed biallelic DICER1 mutations with additional pathogenic missense mutations in KRAS (case 1) and CTNNB1 (case 2). The methylation profile of case 1 clustered with DICER1-associated sarcomas, whereas case 2 classified as an ETMR (albeit low raw and calibrated score). In conclusion, we report two DICER1-related malignancies with teratoma-like features, further expanding their morphologic spectrum and highlighting the multipotentiality of their presumed cell of origin. Notably, we describe the first ETMR identified outside the CNS with a documented DICER1 biallelic inactivation. Our findings also highlight the potential role of other molecular alterations such as KRAS and CTNNB1 mutations in defining the phenotype of embryonal and primitive DICER1-associated neoplasms, a notion that deserves further studies.