Original ArticlesVulvar Yolk Sac Tumors Are Somatically Derived SMARCB1 (INI-1)-Deficient NeoplasmsKolin, David L. MD, PhD*; Konstantinopoulos, Panagiotis A. MD, PhD†; Campos, Susana M. MD, MPH†; Toumi, Gisele MD‡; Kolahi, Kevin A. MD, PhD‡; Gars, Eric J. MD‡; Howitt, Brooke E. MD‡ Author Information *Department of Pathology, Division of Women’s and Perinatal Pathology, Brigham and Women’s Hospital †Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA ‡Department of Pathology, Stanford University Medical Center, Stanford, CA Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: David L. Kolin, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115 (e-mail: [email protected]). The American Journal of Surgical Pathology 46(2):p 169-178, February 2022. | DOI: 10.1097/PAS.0000000000001777 Buy Metrics Abstract So-called primary yolk sac tumors of the vulva are very rare and often have an aggressive disease course. Their molecular features have not been previously characterized. There is also a well-documented group of SMARCB1 (INI-1)-deficient vulvar neoplasms, which includes proximal-type epithelioid sarcoma and myoepithelial carcinoma. Until now, “vulvar yolk sac tumors” and SMARCB1-deficient neoplasms were considered unrelated diseases. After reviewing an index case of a vulvar yolk sac tumor with loss of SMARCB1 by immunohistochemistry, we retrospectively identified 2 additional cases diagnosed as vulvar yolk sac tumors. Patient ages were 34, 32, and 25 years old, and 2 tumors were associated with a pregnancy. All 3 cases showed morphology typical of a yolk sac tumor, and by immunohistochemistry all were positive for SALL4, glypican-3, keratins, and lacked CD34 positivity. All tumors also demonstrated loss of SMARCB1 in tumor cells. Targeted molecular profiling was performed in 2 cases and identified 2 copy deletion of SMARCB1, without genomic alterations typically seen in gonadal yolk sac tumors. In the third case, isochromosome 12p was not identified by fluorescence in situ hybridization. All 3 patients had either local recurrences or distant metastases, and 2 died of disease. One patient had progressive disease while receiving the enhancer of zeste homolog 2 inhibitor tazemetostat. Overall, these findings suggest that vulvar tumors with pure yolk sac-like morphology may represent morphologic variants of SMARCB1-deficient tumors and not veritable germ cell neoplasia. This potential reclassification may have both prognostic and treatment implications and warrants study of additional extragonadal yolk sac tumors. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.