Lineage-Specific Alterations in Gynecologic Neoplasms with Choriocarcinomatous Differentiation: Implications for Origin and Therapeutics

Abstract

Purpose: Choriocarcinoma is most commonly gestational (androgenetic or biparental) but can be of germ cell origin or can develop as a component of a somatic neoplasm (genetically related to the patient). The latter type are aggressive neoplasms for which the underlying genetic alterations are not well characterized. Experimental Design: To investigate the relationship between the different components of somatic neoplasms with choriocarcinomatous elements, the genetic differences between gestational and nongestational tumors, and identify potential targetable alterations, we analyzed 23 samples from 11 tumors, including five gynecologic-type somatic neoplasms with choriocarcinomatous differentiation (two to three different components each) and six pure choriocarcinomas, for somatic mutations, single-nucleotide polymorphisms, and PD-L1 expression. Results: In mixed tumors, gynecologic-type carcinoma components demonstrated lineage-characteristic and line-age-specific alterations, with choriocarcinomatous components sharing some of these as well as demonstrating novel alterations, supporting a clonal relationship with divergent differentiation of the choriocarcinoma from the somatic carcinoma. TP53 mutation only occurred in nongestational tumors. Diffuse PD-L1 expression was characteristic of choriocarcinoma in both pure and mixed tumors but not seen in the gynecologic-type carcinoma components. Conclusions: Given that the somatic carcinomatous and choriocarcinomatous components of mixed tumors have distinct genetic alterations and biomarker expression, separate analysis of these components is required to guide targeted therapy. High PD-L1 expression suggests a role for checkpoint inhibitor-based immunotherapy in tumors with a choriocarcinoma component. The underlying mechanisms by which cancer stem cells reprogram and initiate trophoblastic retrodifferentiation in some somatic tumors warrant further investigation.

Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability

“…Recently, Xing et al demonstrated that tumours with malignant somatic epithelial elements and choriocarcinoma show similar mutations in both components, which are different from the variants seen in gestational choriocarcinoma. 19 The results of this study also suggest that the epithelial and choriocarcinoma components of these tumours have a common (clonal) origin and that, unlike gestational trophoblastic neoplasms, choriocarcinoma occurring in this context harbours a large number of CNVs. 19 The data presented herein support the concept that the different components of MMGC/T have a clonal origin, given their almost identical mutational profiles.…”

“…19 The results of this study also suggest that the epithelial and choriocarcinoma components of these tumours have a common (clonal) origin and that, unlike gestational trophoblastic neoplasms, choriocarcinoma occurring in this context harbours a large number of CNVs. 19 The data presented herein support the concept that the different components of MMGC/T have a clonal origin, given their almost identical mutational profiles. Interestingly, the oncogenic drivers identified in YST and trophoblastic components are those expected in the Mullerian components of the tumour.…”

“…Consistent with previously published data, the present study shows that non-gestational trophoblastic tumor and YST associated with somatic malignancies harbor a large number of CNVs. 19 Therefore, the presence of YST or trophoblastic tumour components might be a marker of underlying genomic instability in somatic Mullerian malignancies.…”

Ovarian Intermediate Trophoblastic Tumors

“…In women, trophoblastic neoplasms include both gestational (common) and nongestational (uncommon) types. Those involving the ovary are rather uncommon and include gestational tumors that are metastatic from the uterus or ectopic, and nongestational tumors, which include those of germ cell type/origin and somatic tumors with trophoblastic differentiation 1,2 ; in all these types, most are pure choriocarcinoma. Intermediate trophoblastic tumors, which include placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT), are rare in the ovary.…”

Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients

“…Each case had duplicate tissue cores. IHC staining for FH (J13, sc‐100743; Santa Cruz Biotechnology, Santa Cruz, CA, USA; 1:200 dilution) was performed on TMA tissue sections with the previously described staining protocol for routine IHC …”