Mixed Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) of the Ovary Arising from Endometriosis: Molecular Pathology Analysis in Support of a Pathogenetic Paradigm

Abstract

Primary ovarian neuroendocrine neoplasms (Ov-NENs) are infrequent and mainly represented by well-differentiated forms (neuroendocrine tumors — NETs — or carcinoids). Poorly differentiated neuroendocrine carcinomas (Ov-NECs) are exceedingly rare and only few cases have been reported in the literature. A subset of Ov-NECs are admixed with non-neuroendocrine carcinomas, as it occurs in other female genital organs, as well (mostly endometrium and uterine cervix), and may be assimilated to mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs) described in digestive and extra-digestive sites. Here, we present a case of large cell Ov-NEC admixed with an endometrioid carcinoma of the ovary, arising in the context of ovarian endometriosis, associated with a uterine endometrial atypical hyperplasia (EAH). We performed targeted next-generation sequencing analysis, along with a comprehensive immunohistochemical study and FISH analysis for TP53 locus, separately on the four morphologically distinct lesions (Ov-NEC, endometrioid carcinoma, endometriosis, and EAH). The results of our study identified molecular alterations of cancer-related genes (PIK3CA, CTNNB1, TP53, RB1, ARID1A, and p16), which were present with an increasing gradient from preneoplastic lesions to malignant proliferations, both neuroendocrine and non-neuroendocrine components. In conclusion, our findings underscored that the two neoplastic components of this Ov-MiNEN share a substantially identical molecular profile and they progress from a preexisting ovarian endometriotic lesion, in a patient with a coexisting preneoplastic proliferation of the endometrium, genotypically and phenotypically related to the ovarian neoplasm. Moreover, this study supports the inclusion of MiNEN in the spectrum ovarian and, possibly, of all gynecological NENs, among which they are currently not classified.

Mixed neuroendocrine/Non-neuroendocrine neoplasm (MiNEN) of gastrointestinal lineage arising in an ovarian mature cystic teratoma

“…This case calls for the inclusion of the concept of MiNEN in the spectrum of gynecological neuroendocrine neoplasia analogous to its counterparts in the digestive and extra digestive locations. To the best of our knowledge, the term MiNEN was employed in the gynecologic pathology literature once earlier, in a report of a mixed ovarian carcinoma composed of high grade endometrioid carcinoma and large cell neuroendocrine carcinoma arising in the background of endometriosis ( Maragliano et al, 2022 ). Another case was reported in the literature by Pavithra et al ( Ayyanar et al, 2021 ) as synchronous colonic adenocarcinoma and well differentiated neuroendocrine tumor arising in a mature cystic teratoma of the ovary in a postmenopausal woman.…”

Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract

“…Both small cell and large cell ovarian neuroendocrine carcinomas are frequently associated with non-neuroendocrine carcinoma components and may be defined as mixed neuroendocrine/non-neuroendocrine (MiNENs), similar to those arising in the gastrointestinal or urogenital tract [82].…”