Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare malignancies which originate from neoplastic proliferation of neuroendocrine cells and neuroendocrine-differentiated gastrointestinal epithelium. As the name indicates, we conclude that these neoplastic cells have features of both endocrine and nerve cells [1].

NENs are rare and can occur in almost every organ in the body. The highest incidence is within the gastrointestinal tract, with > 40% involving the small intestine [2].

These tumors have various and unpredictable clinical behavior and are slow-growing and often asymptomatic in most cases. Some clinical and pathological characteristics depend on the organ characteristics in which they occur, while other features are the same for all NENs [3], [4].

Gastrointestinal NENs are mostly intramural or submucosal masses that create small polypoid lesions, rarely > 3.5 cm. These neoplasms are usually yellowish or brown and some can cause a conspicuous desmoplastic reaction, leading to intestinal obstruction. The desmoplastic reaction is mostly restricted to a subset of ileal carcinoids. Well-differentiated NENs are composed of islands, trabeculae, or plaques of uniform cells with scarce acidophilic, granular cytoplasm, and round or oval nuclei on histological examination. The appearance of the nucleus is often described as “salt and pepper” because they contain granulated chromatin, typically without a prominent nucleolus, except for large cell neuroendocrine carcinomas (NECS), which have one conspicuous nucleolus that shows minimal or no pleomorphism. Mitoses are rare. Cytological characteristics do not depend on the cell origin; thus, determining the primary origin of the tumor in metastasis is difficult [5].

The highest incidence of NENs is in the seventh decade, but they occur at all ages [6]. The symptoms in clinically manifested disease depend on the hormones produced by these tumors. Neuroendocrine cells are characterized by the secretion of amines and neuropeptide hormones, which can cause carcinoid syndrome. The released vasoactive substances are metabolized and inactivated in the liver when NENs are located in the gastrointestinal tract. Therefore, carcinoid syndrome is present in < 10% of patients with gastrointestinal tract NENs [7].

These tumors mainly grow and expand predictably. Diagnosing metastatic disease, especially liver metastases, is the most important aim. Larger lesions usually metastasize to both liver and regional lymph nodes, as well as distant organs, such as skin and bones [8], [9]. These tumors grow slowly, and metastases can persist for years before they lead to a deadly outcome. The survival depends on the presence of distant metastases, mitotic index, carcinoid syndrome, depth of intestinal wall invasion, tumor size of > 2 cm, and blood vessel invasion [10], [11].

The 2020 World Health Organization recommendations divided gastroenteropancreatic tract NEN (GEP-NEN) into G1 (well-differentiated neuroendocrine tumors [NETs]), G2 (well-differentiated NETs), and G3 (well-differentiated NETs and poorly differentiated NECs). The histological grade is based on the mitotic activity and the percentage of Ki67 positive cells (G1: Ki67 index of < 3%, G2: Ki67 index of 3%–20%, and G3: Ki67 index of > 20%) [12].

The most important prognostic factor for gastrointestinal NENs is their localization in the gastrointestinal tract. Neoplasms proximal of the Treitz ligament, such as the esophagus, stomach, or duodenum, rarely metastasize and these patients most often end up disease-free after surgical resection. Jejunal and ileal NENs are often multiple and aggressive, characterized by deeper local invasion, more intense growth, presence of necrosis, and pathological mitoses that are also associated with worse outcomes. Appendix and rectal NENs are most commonly accidentally found. Appendix NENs can occur at any age and are almost always benign. Rectal NENs are frequent, unlike the colon NENs, which are very rare [13].

Several tumor markers are usually used to diagnose and monitor these tumors. Currently, Chromogranin A (CgA) is the most important of these markers, and measuring the serum value of CgA is recommended. It consists of a polypeptide located in the secretory granules of neuroendocrine cells. Plasma CgA is elevated (60%–100%) in patients with NENs, whether they are symptomatic or not [14]. However, this marker has been reported to show false elevations in patients using proton pump inhibitors for chronic gastritis or liver or kidney failure. Synaptophysin is recommended as a minimal panel for GEP-NENs diagnosis in addition to CgA. Other markers used are plasma neuron-specific enolase, urinary 5-hydroxyindoleacetic acid (5-HIAA, as a marker of carcinoid tumors), and many other amines, such as chromogranin B and C, substance P, neurotensin, and others [15], [16].

This study aimed to determine the frequency of NENs in the gastrointestinal tract, the average age, and sex of patients with gastrointestinal tract NENs, the anatomical regions that are more commonly affected by these tumors, the differentiation of NENs in the gastrointestinal tract, and evaluate the correlation between lymph node status and Ki67 proliferative index.