The diagnostic value of cytoplasmic expression of the transcription factor Oct4 in neuroendocrine tumors

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Background: The transcription factor Oct4 plays an important role in tumor progression; however, it has not been adequately studied in neuroendocrine neoplasms. Its impact on the differentiation, functional activity of neuroendocrine cells and mechanisms of neurosecretory granule formation remains unclear. Aim: To evaluate the diagnostic value of the qualitative and quantitative determination of the transcription factor Oct4 cytoplasmic expression in neuroendocrine tumors (NETs) of various localizations, hormonal activity, and grade. Methods: In this single-center observational cross-sectional comparative two-sample study we analyzed the Oct4 expression in primary and metastatic NETs in tumor samples from 257 patients (243 with NETs and 14 with other tumor types) who were followed up or consulted at Moscow Regional Research and Clinical Institute (MONIKI) from 2000 to 2025. Tissue samples of tumors obtained during surgery or biopsy, as well as samples of unaffected NET-adjacent mucosa of the small intestine, colon and rectum, stomach, pancreatic islets and adrenal medullaries were examined. The Oct4 expression was assessed by immunohistochemistry with anti-Oct4 monoclonal antibodies (MRQ-10, RTU). A positive result was an intensive and even cytoplasmatic reaction in most tumor cells scored as 3+ if 90 to 100% cells were stained and 2+ if 50 to 89% cells were stained. A negative result for the expression looked as mild cytoplasmatic staining or focal reaction in cytoplasm of some tumor cells (1+) or complete absence of staining (0). Results: Oct4 expression was present in 181 epithelial NETs of various locations and functional activities (56 bronchopulmonary, 7 thymus / mediastinum, 33 pancreas, 45 stomach, 32 intestine, 4 kidneys and 4 Merkel cell carcinomas), in 62 non-epithelial NETs (54 adrenal pheochromocytomas and 8 extra-adrenal paragangliomas), and in 14 non-neuroendocrine tumors. There were 135 low-grade (LG) NETs and 44 high-grade (HG) neuroendocrine carcinomas (22 small cell and 22 large cell). Positive (2+/3+) Oct4 cytoplasmatic staining was found in 100% of LG ECL- and EC-cell NETs of the stomach, small intestine, and appendix + colon (32/32, 20/20, and 4/4, respectively), 98.1% (53/54) of adrenal pheochromocytomas, 51.4% (18/35) of lung carcinoids, 40% (2/5) of thymus/mediastinum, and 24.5% (8/33) of pancreatic NETs. The highest Oct4 expression (3+) was detected in total (100%) of LG NETs of the small intestine (20/20) and appendix + colon (4/4), 90.6% (29/32) of the stomach, 75.4% (41/54) of adrenal pheochromocytomas (41/54), 22.8% (8/35) of lung carcinoids, 20% (1/5) of thymus / mediastinum, 62.5% (3/8) of extra-adrenal paragangliomas, and in none of pancreatic NETs. The highest Oct4 expression (3+) was found in 2 of 11 pheochromocytomas with increased metastatic potential, compared to 41 of 42 those with low metastatic potential. All NETs of the kidneys (4/4) and rectum (5/5), gastrinomas and somatostatinomas of the pancreas (3/3 and 2/2, respectively), 1 oncocytic pheochromocytoma (1.8%), 62.5% (5/8) of extra-adrenal paragangliomas and all tumors without neuroendocrine differentiation (100%, 14/14) were negative for Oct4. Positive Oct4 expression was observed significantly more frequent in functionally active NETs than in functionally inactive ones (67.4% vs 40.6%, respectively, odds ratio (OR) 3.03, 95% confidence interval (CI) 1.47 to 6.25, p = 0.003), and in well-differentiated NETs compared with neuroendocrine carcinomas (60.6% vs 6.8%, OR 21.01, 95% CI 6.19 to 71.25; p 0.001). Positive cytoplasmic expression of Oct4 with a high specificity of 94.83% and sensitivity of 60.58% is a marker of well-differentiated NETs. The predictive value of positive cytoplasmic expression of Oct4 in the diagnosis of well-differentiated NETs is 96.51%. Conclusion: The maximal Oct4 expression was found in the cytoplasm of EC- and ECL-cell of well-differentiated NETs of the gastrointestinal tract, as well as in adrenal pheochromocytomas and their normal cell counterparts. Positive cytoplasmic expression of Oct4 was a highly specific marker of well-differentiated NETs with possible hormonal activity. The specificity of Oct4 expression in various NETs could be used for the development of new individuated approaches to their diagnosis and therapy.

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