DICER1-Related Primitive Polyphenotypic Neoplasm

Somatic or germline pathogenic/likely pathogenic variants in DICER1 have known associations with certain neoplasms in the gynecologic tract, including Sertoli-Leydig cell tumors, embryonal rhabdomyosarcoma, and adenosarcoma. However, recent studies have highlighted DICER1-related malignant neoplasms with complex admixtures of sarcomatous, primitive glandular, and/or neuroectodermal elements, which are underrecognized and lack consistent nomenclature. We report the largest series of these primitive polyphenotypic DICER1-related neoplasms arising in the gynecologic tract or peritoneum. The 15 patients were aged 10 to 77 (median: 37) years. Tumors involved the endometrium (n=6), cervix (n=3), endometrium and cervix (n=2), ovary (n=2), or pelvic peritoneum (n=2). Twelve were organ-confined and 3 were at an advanced stage at presentation. All contained sarcomatous elements composed of sheets and aggregates of ovoid/spindled cells with rhabdomyoblastic differentiation in 13. Periglandular condensation (n=13), cambium layer (n=12), fetal-type cartilage (n=11), and anaplasia (n=4) were also identified. Primitive glands were present in 14 (abundant in 8) and comprised single or clustered simple (n=14) or variably dilated/elongated glands resembling those seen in adenosarcoma (n=9). The epithelium had a primitive appearance with frequent subnuclear vacuoles (n=14), intracytoplasmic granules (n=7), or minimal amphophilic cytoplasm (n=3), and frequently stained for SALL4, glypican-3, and AFP. Neuroectodermal elements were seen in 12, composed of compact small round blue cells punctuated by neuroepithelial tubules. DICER1 alterations were present in all tumors. DICER1-related primitive polyphenotypic neoplasms present significant diagnostic difficulty due to their varied appearances and lack of consistent nomenclature in the rare reports to date. Recognition of the morphologic features of these unusual neoplasms should prompt confirmatory DICER1 testing and consideration of germline evaluation, particularly in young patients.