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.

原发性卵巢神经内分泌肿瘤 (Ov-NEN) 并不常见，主要表现为分化良好的形式（神经内分泌肿瘤 - NETs - 或类癌）。低分化神经内分泌癌 (Ov-NECs) 极为罕见，文献中仅报道了少数病例。一部分 Ov-NEC 与非神经内分泌癌混合，因为它也发生在其他女性生殖器官（主要是子宫内膜和子宫颈）中，并且可能同化为混合神经内分泌/非神经内分泌肿瘤 (MiNEN)，见消化道和消化道外的部位。在这里，我们提出一例大细胞 Ov-NEC 与卵巢子宫内膜样癌混合，在卵巢子宫内膜异位症的背景下出现，与子宫内膜非典型增生 (EAH) 相关。TP53基因座，分别位于四种形态不同的病变（Ov-NEC、子宫内膜样癌、子宫内膜异位症和 EAH）上。我们的研究结果确定了癌症相关基因（PIK3CA、CTNNB1、TP53、RB1、ARID1A和p16 ）的分子改变)，从肿瘤前病变到恶性增殖的梯度逐渐增加，包括神经内分泌和非神经内分泌成分。总之，我们的研究结果强调了这种 Ov-MiNEN 的两个肿瘤成分具有基本相同的分子谱，并且它们从预先存在的卵巢子宫内膜异位病变进展而来，在一个同时存在子宫内膜癌前增殖的患者中，基因型和表型与卵巢肿瘤。此外，本研究支持将 MiNEN 纳入卵巢谱，并可能纳入所有妇科 NEN，目前尚未将其分类。