Clinicopathological and epigenetic differences between primary neuroendocrine tumors and neuroendocrine metastases in the ovary

Abstract

Currently, the available literature provides insufficient support to differentiate between primary ovarian neuroendocrine tumors (PON) and neuroendocrine ovarian metastases (NOM) in patients. For this reason, patients with a well-differentiated ovarian neuroendocrine tumor (NET) were identified through electronic patient records and a nationwide search between 1991 and 2023. Clinical characteristics were collected from electronic patient files. This resulted in the inclusion of 71 patients with NOM and 17 patients with PON. Histologic material was stained for Ki67, SSTR2a, CDX2, PAX8, TTF1, SATB2, ISLET1, OTP, PDX1, and ARX. DNA methylation analysis was performed on a subset of cases. All PON were unilateral and nine were found within a teratoma (PON-T+). A total of 78% of NOM were bilateral, and none were associated with a teratoma. PON without teratomous components (PON-T-) displayed a similar insular growth pattern and immunohistochemistry as NOM (p > 0.05). When compared with PON-T+, PON-T- more frequently displayed ISLET1 positivity and were larger, and patients were older at diagnosis (p < 0.05). Unsupervised analysis of DNA methylation profiles from tumors of ovarian (n = 16), pancreatic (n = 22), ileal (n = 10), and rectal (n = 7) origin revealed that four of five PON-T- clustered together with NOM and ileal NET, whereas four of five PON-T+ grouped with rectum NET. In conclusion, unilateral ovarian NET within a teratoma should be treated as a PON. Ovarian NET localizations without teratomous components have a molecular profile analogous to midgut NET metastases. For these patients, a thorough review of imaging should be performed to identify a possible undetected midgut NET and a corresponding follow-up strategy may be recommended.

Keywords: DNA methylation; immunohistochemistry; metastasis; neuroendocrine tumor; ovary; primary.

Figure 1

Flow diagram of patient selection. MINEN, mixed neuroendocrine nonneuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; NOM, neuroendocrine ovarian metastasis; SSTR, somatostatin receptor.

Figure 2

Panel of immunohistochemical characteristics that discriminated best between PON and NOM. NOM, neuroendocrine ovarian metastasis; PON‐T−, primary ovarian NET without teratomatous components; PON‐T+, primary ovarian NET within a teratoma.

Figure 3

Two unsupervised analyses, including dimensionality reduction using (A) Uniform Manifold Approximation and Projection (UMAP) and (B) hierarchical clustering, both identifying three clusters: (1) a cluster of pancreatic NET; (2) a cluster of rectal NET and primary ovarian neuroendocrine tumors within a teratoma (PON‐T+), and (3) a cluster of ileal NET with primary ovarian neuroendocrine tumors (PON‐T−) and neuroendocrine ovarian metastases (NOM).