Clinicopathologic and Molecular Analysis of Malignant Neoplasms With Yolk Sac Tumor Differentiation in Women 40 Years of Age and Older

Gynecologic yolk sac tumors (YSTs) are more commonly encountered in children and young women as pure or mixed germ cell tumors and are rarely observed in older women. YSTs in older women are sometimes accompanied by a Müllerian-type carcinoma component, indicating a likely somatic rather than germ-cell origin. Studies of YSTs of germ cell and somatic types in this age group are limited. Analysis of additional pure and mixed tumors with YST differentiation could elucidate differences between these tumor subtypes and the relationship between components in mixed tumors. Clinicopathologic features of 32 malignant neoplasms with YST differentiation in women aged 40+ were analyzed. There were 11 pure YSTs, 7 mixed germ cell tumors, and 14 YSTs with a malignant non-germ cell tumor component (somatically derived yolk sac tumor [SDYST]). Targeted next-generation sequencing (NGS) was performed in 4/11 pure YSTs, 0/7 mixed germ cell tumors, and 4/14 SDYSTs. For the pure YSTs, alterations in DICER1 (1/4), PIK3R1 and PTPRT (1/4), PMS1 (1/4) , and TP53 (2/4) were identified. One other pure YST had alterations in PTEN , ARID1A , ARID1B , FGFR2 , and CTNNB1 (alterations common in endometrioid carcinoma). SDYSTs demonstrated shared alterations between both components including TP53 , KRAS , FBXW7, and KMT2C , suggesting a common origin. The findings in the pure YSTs in older women suggest that for some, the origin could be germ cell as they harbor similar alterations as those described in pure YSTs in young women, whereas in other “pure” YSTs, the molecular profile aligns with previously described SDYSTs, which suggests a SDYST with an unsampled Müllerian carcinoma component rather than a germ cell origin. In SDYSTs, shared alterations are consistent with prior studies and suggest a somatic rather than germ-cell origin.