Revealing neuroendocrine transformation in gynecological cancers through genomic analysis

Abstract

Neuroendocrine transformation (NT) in cancers, typically observed under the selective pressure of targeted therapies, involves lineage plasticity where adenocarcinomas adopt neuroendocrine characteristics while retaining the molecular alterations of their original histology. This phenomenon, well-documented in prostate and lung cancers, has not been observed in gynecological malignancies until now. We present two pivotal cases involving primary ovarian and uterine cancers that developed neuroendocrine carcinomas post-treatment. Initially presumed to be independent primaries, comprehensive next-generation sequencing technologies, including UW-OncoPlex and BROCA panels, were used to establish a clonal relationship between the primary tumors and their respective neuroendocrine metastases. This report provides the first documented instances of NT in gynecological cancers, indicating that it may be a more widespread resistance mechanism than previously recognized. Routine re-biopsy and early integration of advanced molecular diagnostics into clinical practice will identify NT and provide insights into pathogenesis and eventual therapeutic options.

Fig. 1. Comparison of primary and metastatic lesions in Patient 1.

A Histologic examination of the primary ovarian neoplasm (top panel) demonstrates complex branching glands composed of the pseudostratified back-to-back columnar epithelium (shown at 10X and 40X magnification) positive for ER and PAX8 (shown at 20X magnification) consistent with low-grade endometrioid carcinoma, while the spinal metastasis (middle panel) consists of sheets of poorly differentiated cells with high nuclear-to-cytoplasmic ratio and nuclear molding (10 and 40X magnification), negative for ER and PAX8 and (lower panel) with variable positivity for CK7, chromogranin, synaptophysin, and INSM1 indicating neuroendocrine differentiation (all at 20X magnification). B Next-generation sequencing demonstrates the overlap of several copy alterations with a notable divergence between the specimens, consistent with tumor heterogeneity and/or clonal evolution. C Comparison of the single nucleotide variants and indels (and their variant allele fractions, VAFs) between the primary ovarian neoplasm, pelvic recurrence, and neuroendocrine spinal metastasis reveals multiple shared somatic findings, confirming their clonal relationship (shared variants are highlighted in yellow).

Fig. 2. Comparison of primary and metastatic lesions in Patient 2.

A Histologic examination of the primary uterine neoplasm (top panel) shows complex branching glands composed of pseudostratified back-to-back columnar epithelium (shown at 10X and 40X magnification) consistent with low-grade endometrioid carcinoma. Histologic examination of the lung neoplasm (middle panel) demonstrates sheets of cells with a high nuclear-to-cytoplasmic ratio and nuclear molding (shown at 10X and 40X magnification). Lung tumor cells are negative for PAX8, but positive for chromogranin (lower panel), indicating neuroendocrine differentiation (shown at 20X). B Comparison of the single nucleotide variants and indels (and their variant allele fractions, VAFs) between the uterine neoplasm and neuroendocrine metastasis revealed multiple shared somatic findings, confirming their clonal relationship (shared variants are highlighted in yellow).