Endometrial Carcinomas With a Somatically Derived Yolk Sac Tumor Component Share Molecular Similarities to...

Primary endometrial carcinomas with somatically derived yolk sac tumor (YST) components are rare. We analyzed 23 such cases using detailed clinicopathologic, immunohistochemical, and molecular methods. The median patient age was 68 years. Elevated serum alpha-fetoprotein (AFP) was detected in 76.9% (10/13) of tested cases. International Federation of Gynecology and Obstetrics (FIGO) 2009 stages were I (n = 12, 55%), II (n = 1, 5%), III (n = 5, 23%), IV (n = 4, 18%), and unknown in one. Histologic YST patterns included glandular (87%), papillary (52%), solid (48%), endodermal sinus (17%), hepatoid (17%), and reticular (13%) architectures. The associated Müllerian-type neoplasms were endometrioid carcinoma (n = 17), carcinosarcoma (n = 3), serous carcinoma (n = 2), and clear cell carcinoma (n = 1). Immunohistochemically, 17 cases (74%) exhibited mutation-type p53 staining, and 2 (9%) were mismatch repair-deficient (MMRd). YST components uniformly expressed glypican-3 and spalt-like transcription factor 4 (SALL4), whereas 17 (74%) also expressed AFP. HER2 positivity was seen in 13 of 21 tested (62%; four 3+, three 2+, and six 1+). Molecular analysis revealed TP53 variants in 16 of 22 cases (73%) without POLE hotspot mutations. According to The Cancer Genome Atlas molecular classification, 17 tumors were p53-abnormal (74%), 2 (9%) MMRd, 4 (17%) were no specific molecular profile, and none was POLE-ultramutated. Recurrent copy number gains involved CCNE1 (9/22, 41%), 1q44 (12/14, 86%), and 3q26.32 (8/14, 57%). Features reminiscent of germ cell tumors included amplifications at 7p21.2 (8/14, 57%) and 9p21.3 (11/14, 79%), polysomy or amplification of chromosome 12p (6/22, 27%), deletion at 11q24.3 (8/14, 57%), and a high frequency of T>C nucleotide substitutions. Follow-up showed 15 patients (75%) had died of disease or were alive with disease; 12 of these 15 cases were p53-abnormal. Overall survival was significantly poorer than in other molecular subtypes of endometrial carcinoma. These tumors should therefore be regarded as high grade (grade 3) by definition. In summary, endometrial carcinomas with a somatically derived YST component are highly aggressive, predominantly p53-abnormal, with smaller subsets classified as MMRd or no specific molecular profile. Recognition of the YST component is crucial, and biomarker profiling may reveal therapeutic targets.