Molecular characterization of neuroendocrine neoplasms - PhDData

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Molecular characterization of neuroendocrine neoplasms

The thesis was published by Turkevi-Nagy Sándor, in December 2023, University of Szeged.

Abstract:

Neuroendocrine neoplasms (NENs) comprise approximately 1% of malignant tumors. They can arise in any organ throughout the body, the most common sites of origin are the gastrointestinal (GI) tract and the lower respiratory tract. Because of the unique therapy of NENs, an accurate diagnosis is vital, and relies on histomorphology as well as immunohistochemistry (IHC). Numerous IHC markers are applied to confirm neuroendocrine differentiation, suggesting that none of the currently available molecules is completely reliable. There is a diagnostic need to identify novel (more specific and sensitive) neuroendocrine marker candidates.
We aimed to examine the expression of two such markers, syntaxin 1 (STX1) and insulinoma associated protein 1 (INSM1) by IHC in various non- neuroendocrine tumors as well as NENs and non-tumorous conditions. We compared the sensitivity and specificity of STX1 and INSM1 with those of the traditional NE differentiation markers, such as CD56, chromogranin A (CHGA) and synaptophysin (SYP).
The sensitivity of STX1 was assessed on a diverse cohort of benign and malignant tumors as well as non-neoplastic tissues. Consistent STX1 immunoreactivity was observed in all NENs and non-tumorous NE lesions, regardless of the anatomical site, grade or subtype; with a sensitivity of 99% and 100% concerning neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), respectively. Except for neuronal tumors, all included non-NE neoplasms were negative for STX1, proving its excellent specificity.
Subsequently, we evaluated the utility of STX1 and INSM1 as NE markers in pulmonary tumors. The overall sensitivity of STX1 and INSM1 was proven to be 96,5% and 97,6%, respectively. Regarding pulmonary carcinoids and large cell NECs, the sensitivity of STX1 was 100%, and it exceeded 90% even in the case of small cell NECs, which often constitute a diagnostic pitfall. Overall, the specificity of STX1 has been found to be excellent (99,4%), even somewhat better than that of INSM1 (96,3%). The combined application of STX1 and INSM1 outperformed the panel of CD56, CHGA and SYP regarding both their sensitivity and specificity.
Regarding breast lesions exhibiting NE features, STX1 proved to be a reliable marker for their diagnosis with a sensitivity of 84.7%. Depending on the applied threshold, the sensitivity of INSM1 proved to be 89,6% and 86,4, respectively. Additionally to exhibiting great sensitivity, STX1 was also characterized by an excellent specificity (98.1%). Concerning INSM1, if the more permissive threshold was applied, its specificity was found to be 57.4%; however, when the more strict definition was used, it increased to 88.9%.
Based on our observations, the strong and easy-to-read membranous labeling pattern of STX1 and the nuclear staining of INSM1 was more convenient to interpret than the cytoplasmic expression pattern of other markers. Therefore, along with INSM1, we strongly recommend STX1 to be included in the routine diagnostic IHC panel of NE differentiation.



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