# Integrative Genomic and Clinicopathologic Characterization of Pure Primary Ovarian Large Cell Neuroendocrine Carcinoma: A Case Report and Molecular Insight

## TL;DR

This case study explores a rare ovarian cancer with genomic profiling, revealing features that suggest potential targeted therapies like PARP inhibitors and immunotherapy.

## Contribution

The study provides the first comprehensive genomic characterization of pure primary ovarian large cell neuroendocrine carcinoma.

## Key findings

- The tumor showed a BRCA2 mutation, HRD, MSI-H, and high TMB, similar to other gynecologic neuroendocrine carcinomas.
- Genomic profiling identified potential therapeutic targets, including PARP inhibitors and immune checkpoint blockade.
- The findings suggest a shared genomic profile among gynecologic neuroendocrine carcinomas.

## Abstract

Primary ovarian large cell neuroendocrine carcinoma (LCNEC) is a very rare and aggressive cancer, with no established treatment guidelines. We report a case in a postmenopausal woman treated with complete surgical resection followed by platinum-based chemotherapy. Comprehensive genomic profiling revealed a BRCA2 mutation, homologous recombination deficiency (HRD), microsatellite instability-high (MSI-H), and a very high tumor mutational burden (TMB). These features resemble those seen in other gynecologic neuroendocrine carcinomas and suggest possible benefit from targeted therapies such as PARP inhibitors or immune checkpoint blockade. This case highlights the value of genomic analysis in rare gynecologic cancers to guide personalized treatment.

Primary ovarian large cell neuroendocrine carcinoma is an extremely rare and aggressive gynecologic malignancy with poorly defined molecular characteristics and no standard treatment protocols. We present a case of pure ovarian LCNEC in a postmenopausal woman who underwent optimal cytoreductive surgery followed by platinum-based chemotherapy. Histopathologic and immunohistochemical analyses confirmed the diagnosis. Next-generation sequencing (NGS) revealed a pathogenic BRCA2 frameshift mutation (c.7177dupA), an ATM nonsense mutation, and Tier II mutations in TP53 and PTEN. The tumor exhibited homologous recombination deficiency (HRD), microsatellite instability-high (MSI-H), and an exceptionally high tumor mutational burden (TMB) of 277.49 mutations/Mb. These molecular alterations closely resemble those observed in high-grade neuroendocrine carcinomas of cervical and endometrial origin, suggesting a convergent genomic profile across gynecologic neuroendocrine carcinomas (NECs). Our findings underscore the potential of comprehensive genomic profiling in rare tumors such as ovarian LCNEC to refine diagnosis and identify candidates for biomarker-driven therapies, including PARP inhibitors and immune checkpoint inhibitors. This case supports the integration of molecular diagnostics into clinical practice and highlights the need for prospective studies incorporating molecular stratification to inform treatment strategies for rare and aggressive neuroendocrine tumors.