Endocrine Pathology

Mixed Sparsely Granulated Lactotroph and Densely Granulated Somatotroph Pituitary Neuroendocrine Tumor Expands the Spectrum of Neuroendocrine Neoplasms in Ovarian Teratomas: the Role of Pituitary Neuroendocrine Cell Lineage Biomarkers

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

AbstractPrimary 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.

Immunohistochemical Profile and 47-Gene Next-Generation Sequencing (NGS) Solid Tumor Panel Analysis of a Series of 13 Strumal Carcinoids

AbstractStrumal carcinoid is an extraordinary rare tumor of the ovary consisting of thyroid tissue intermixed with neuroendocrine tumor component. The cellular origin of strumal carcinoids has been an area of debate. There is also little data on detailed immunohistochemical and molecular characteristics of these neoplasms. For this reason, this series investigated the characteristics of a series of 13 strumal carcinoids using immunohistochemical markers and a 47-gene next-generation sequencing (NGS) solid tumor panel analysis. Both cellular components showed thyroglobulin expression in all tumors. TTF-1 expression was noted in both cellular components of 11 cases. Chromogranin A was positive in both components of most tumors (n = 12, 92.3% in the neuroendocrine component and n = 10, 76.9% in the thyroid follicular component). Synaptophysin stained the neuroendocrine component of all cases, and it was also identified in the follicular thyroid component of a single case. All tumors were negative for CDX2 and calcitonin. ISLET1 was positive in the neuroendocrine component of 8 cases (6.5%). With the exception of one case, all tumors were positive for SSTR2a. The tumors were associated with a low Ki67 labeling index. All cases were microsatellite stable and no pathogenic mutations were identified using a 47-gene NGS solid tumor analysis. This series underscored that strumal carcinoids are distinct neuroendocrine tumors. The synchronous expression for thyroid follicular epithelial and neuroendocrine differentiation biomarkers may suggest a precursor cell origin displaying mixed-amphicrine differentiation. While strumal carcinoids can be diagnosed by their typical morphology and immunohistochemical profile, frequent SSTR expression may serve as a potential theranostic biomarker in the management of affected patients. In addition, the absence of common driver mutations in the NGS solid tumor panel may suggest that these neoplasms seem to be genetically unrelated to follicular epithelial–derived thyroid tumors and potentially different than other commonly identified well-differentiated neuroendocrine neoplasms. Therefore, further studies focusing on molecular characteristics of this entity are still needed.

Exploring Intratumoral Heterogeneity in Mixed Neuroendocrine-Nonneuroendocrine Neoplasms with Spatial Transcriptomics: Even More Diverse Than Anticipated

Abstract Mixed neuroendocrine–nonneuroendocrine neoplasms (MiNEN) are usually highly aggressive tumors characterized by marked histological heterogeneity, most commonly represented by mixed adenocarcinoma and poorly differentiated neuroendocrine carcinoma (NEC). However, beyond morphological observations, the biological basis and implications of this heterogeneity remain incompletely understood. In this study, we combined component-specific next-generation sequencing and spatial transcriptomics to investigate three mixed adenocarcinoma-NEC cases from different anatomical sites (ileocecal, ovarian, gastric), tracing tumor progression from precursor lesions to invasive NEC. Genomic analyses revealed a shared trunk of driver mutations across all tumor compartments, confirming their clonal origin, while also uncovering additional compartment-specific alterations. Spatial transcriptomics, together with gene set enrichment analysis (GSEA), revealed distinct transcriptional profiles aligned with histologically annotated compartments (e.g., adenocarcinoma, NEC, precursor). In NECs, GSEA consistently showed downregulation of immune-related pathways and upregulation of proliferation-associated pathways compared to non-neuroendocrine tumor areas. Moreover, distinct transcriptomic subclusters were identified within morphologically homogeneous NEC regions in two of the three cases. These subclusters exhibited significant differences in immune regulation, proliferation signaling, and cell-cycle control, and were associated with divergent predicted chemotherapy-response signatures, suggesting clinically relevant implications for treatment sensitivity and resistance. In summary, our findings indicate that despite a shared clonal origin, MiNEN develop distinct genetic and transcriptomic features across tumor compartments. The inconsistent presence of transcriptomic subclusters within morphologically similar regions underscores the complexity of intratumoral heterogeneity in these aggressive neoplasms. By connecting morphological and molecular layers of tumor architecture, spatial profiling may aid in translating biological complexity into more targeted clinical strategies.