Clinicopathologic and molecular characterization of primitive neuroectodermal tumors (PNET) in the female genital tract: a retrospective study of 8 cases.

Aims: This study aimed to investigate the molecular alterations in primitive neuroectodermal tumors (PNET) of the female genital tract.

Methods: We retrospectively analyzed the clinicopathologic and immunohistochemical features of 8 gynecologic PNET cases (3 cervical, 1 vaginal, and 4 ovarian). Fluorescence in situ hybridization and targeted next-generation sequencing (NGS) were performed to identify molecular alterations in these tumors.

Results: The cohort included 5 FIGO stage I, 1 stage III, and 2 stage IV tumors. Two patients with stage IV disease died at 8 and 12 months. The cervical/vaginal tumors consisted of small round blue cells arranged in sheets, with EWSR1 rearrangements and concurrent diffuse expression of membranous CD99 and nuclear FLI1. The ovarian tumors displayed diverse morphologic features resembling central nervous system (CNS) tumors, including embryonal tumor with multilayered rosettes (case 5), medulloblastoma (case 6), glioblastoma (case 7), and ependymoma (case 8). Three ovarian tumors were associated with teratomas. None of the ovarian tumors exhibited EWSR1 rearrangements or i(12p)/12p overrepresentation. NGS identified an EWSR1::exon11∼FLI1::exon6 fusion in one cervical PNET, with no additional molecular alterations. In contrast, three ovarian tumors lacked common genetic changes seen in CNS tumors but harbored several significant variants, including NTRK2 exon11 c.1019C > T (p.T340 M) (case 6), INPP4B exon23 c.2221G > A (p.V741 M) (case 7), and FANCG exon7 c.882_883insA (p.D295Rfs∗14) with MET 7q31 polysomy (case 8).

Conclusions: Our findings confirm that cervical/vaginal and ovarian PNET represent two distinct tumor types. Ovarian PNET have different pathogenetic pathways from their CNS and testicular counterparts most likely.