Neuroendocrine neoplasms (NENs) are relatively rare tumors, given that they account for approximately 2% of all neoplasms.1 Their annual incidence is 5.25 per 100,000 inhabitants, and most cases (62–70%) originate in the gastrointestinal tract and pancreas.2,3 In recent years, the incidence of NENs has been on the rise due to greater knowledge about them, as well as to the advent of new technologies that facilitate their diagnosis.4

NENs originate in cells with a neural/endocrine hybrid phenotype. Their neural component characteristics include the presence of dense-core granules, similar to those of serotonergic cells that store monoamines, but they lack synapses. Because of their endocrine nature, these cells are capable of synthesizing amines, peptides, and hormones and secreting them into the circulation, generating metabolic effects and systemic clinical manifestations.1,5–7

The neuroendocrine cells may agglomerate at specific anatomic sites, such as the pancreatic islets of Langerhans, or scatter throughout the gastrointestinal tract, lung, thyroid, and pituitary gland, among other organs. The neuroendocrine cells make up the so-called diffuse endocrine system or amine precursor uptake and decarboxylation (APUD) system and are in charge of relevant physiologic functions.5

The clinical presentation of NENs depends on their anatomic location and capacity to secrete amines or biologically active peptides. Patients may present with a specific syndrome, such as fasting hypoglycemia due to insulinoma, recurrent peptic ulcer, atypical location of tumors that secrete gastrin (Zollinger-Ellison syndrome), the development of diabetes mellitus, migratory necrolytic erythema associated with glucagon-producing tumors, and “carcinoid syndrome” characterized by chronic diarrhea, abdominal discomfort, fecal urgency, flushing, hypotension, and bronchospasm associated with the episodic release of serotonin.4,6,8 Chronic diarrhea may be diagnosed when stool weight is above 240 g per day, with at least 3 daily bowel movements for more than 4 weeks.9 However, a large percentage of NENs are not secretory, and so are discovered incidentally during surgery, endoscopy, or in imaging studies due to the presence of metastasis, bowel obstruction, or in appendectomy specimens.10

Many NENs are indolent and produce nonspecific symptoms, and as a result, are confused with disorders of gut-brain interaction (DGBIs) (irritable colon, spastic colon, functional gastrointestinal disorders), considerably delaying diagnosis. Between 21 and 69% of cases are detected in advanced stages, presenting with metastatic disease, worsening prognosis and reducing the life expectancy of the affected patients.5,10

Chromogranin A, gastrin, and serotonin blood tests are used as markers for neuroendocrine cells that can identify NENs, enabling early diagnosis. The most widely used immunohistochemical markers for identifying neuroendocrine tumor (NET) differentiation are chromogranin A and synaptophysin.10,11

The present work is a detailed review of 48 cases of NENs diagnosed at the Hospital Ángeles del Pedregal (HAP) within the time frame of 2018 and 2024. Our review is limited to gastroenteropancreatic tumors that correspond to the most frequent locations of said tumors and are a greater diagnostic challenge. All the cases were confirmed by the pathology department of the HAP, and most were complemented with immunohistochemistry studies. The data from patient hospital charts were carefully analyzed and additional information from the attending physicians was collected to clarify the clinical characteristics of the patients and their progression.

The results of our case series were compared with those in national and international publications. We believe it is very important to know the clinical-pathologic characteristics of NENs to improve the diagnostic process, having greater suspicion of them for early diagnosis, and consequently achieving better therapeutic results.

The aims of our study were to know the incidence of gastroenteropancreatic NETs at the HAP over a 6-year period, compare the epidemiologic data of our hospital with those reported in Mexico and internationally, describe the clinical presentation of the gastroenteropancreatic NENs and the probability of their metastatic spread, and review the auxiliary diagnostic methods for diagnosing said tumors at the HAP.

The protocol planning began in November 2023, together with the bibliographic review of the most recent articles on NETs. Once we had the approval of the ethics committee (January 2024), we began to collect the clinical and pathologic information, and in April 2024, started the analyses of the data collected.

Our case series is a retrospective, cross-sectional, observational, descriptive study on patients with a confirmed diagnosis of NEN, treated at the HAP within the time frame of 2018 and 2024. The study was structured according to the strengthening the reporting of observational studies in epidemiology (STROBE) checklist. Given the cross-sectional and observational nature of our analysis, defining outcomes, predictors, potential confounders, or effect modifiers was not necessary. The diagnostic criteria were those following the World Health Organization (WHO) norms that establish both the diagnostic and classification criteria of NENs.

The database of the pathology service of the HAP covering the period from 2018 to 2024 was reviewed. Forty-eight cases with a histopathologic diagnosis of a NET of the pancreas, liver, or any segment of the gastrointestinal tract were included in the study. To establish a clinical-pathologic correlation, only cases treated at the HAP were included that had clinical and laboratory information, as well as an available hospital chart with the NET diagnosis confirmed by immunohistochemistry or histopathology report.

Given the low incidence of NETs, the decision was made to exclude those outside of the gastrointestinal tract, liver, or pancreas, from our analysis. The data are presented through simple descriptive statistics, like those utilized in similar studies found in the literature.

The clinical-pathologic data of 48 cases diagnosed with gastroenteropancreatic NENs, treated at the HAP in Mexico City within the time frame of 2018 and 2024, are presented. This is the first case series on NENs describing patients from a private hospital in Mexico.

Our retrospective design was similar to that used in 3 other Mexican studies conducted in Mexico City1,16 and Guadalajara, Jalisco.2 The cases were identified through the diagnoses of NENs made from surgical specimens received at the anatomic pathology service. The large majority of cases were classified by histopathologic grade, according to the Ki-67-based cell replication rate (42/48 or 87.5%) or the number of mitoses per field, and were confirmed by immunohistochemical markers (75%).

Table 5 shows a comparison of the data obtained in the present study with those of other Mexican studies,1,2,16 revealing great demographic similarity. The median patient age was between the fifth and sixth decades of life, with a wide range of presentation ages and no clear predominance of sex. The most frequent sites of tumor origin were the stomach and pancreas. The NENs were not frequently associated with hormone or peptide secretory syndromes and most patients had a history of long-term abdominal pain, gastrointestinal bleeding, or recurrent ulcer disease.

Table 6 shows the main case series of NENs published internationally. Once again, the data were similar to ours. The largest study is a multicenter case series conducted in 20 states of the United States.17–20 Our data coincide in presentation age, the incidence of affected organs, and clinical presentation.

NENs are relatively rare, compared with other types of malignant neoplasms. Nevertheless, their incidence appears to have risen, perhaps due to improved diagnostic methods through circulating markers, imaging studies, and endoscopy. Endoscopy enables the detection of localized lesions, and CT and magnetic resonance imaging have similar diagnostic yields, albeit tomography is more efficacious in NETs of the small bowel. Endoscopic ultrasound is a very useful technique, given that it can diagnose up to 26% of pancreatic NETs at early stages, whereas CT or other radiologic alternatives are less efficacious.21

There is no doubt that NENs are a diagnostic challenge because only a small percentage of them (10.4% in our series) present with a clinical syndrome associated with the hypersecretion of hormones or vasoactive substances. In our study, we found 3 cases of insulinoma, 2 of which had severe hypoglycemia and neuroglycopenia. One case expressed immunohistochemical markers corresponding to insulinoma, but the patient had not presented with significant episodes of hypoglycemia. Two of our cases had gastrinomas with recurrent ulcers in the gastrointestinal tract. The remaining patients (89.5%) had no specific associated symptoms. Only 5/48 patients (10.4%) presented with specific syndromes that could be clinically related to the presence of a NEN. None of our cases presented with clinical or laboratory data consistent with carcinoid syndrome, such as diarrhea, flushing, or bronchospasm. Carcinoid syndrome is more frequent in NENs of the respiratory tract, which were excluded from our study. In gastrointestinal NENs, carcinoid syndrome is present only in patients with extensive liver metastases capable of releasing serotonin directly into the systemic circulation, preventing its inactivation during its passage through the liver by the monoamine oxidase enzyme.

One of the relatively frequent (16%) clinical presentations in our series was upper abdominal pain, with a progression of several months, misdiagnosed and treated as a DGBI. Importantly, the possibility of NEN should be considered in patients with nonspecific abdominal pain. In that sense, ordering chromogranin A and serotonin (or its urinary metabolite, 5-hydroxyindolacetic acid) tests could be useful, given that elevated levels of those markers in blood could facilitate the early diagnosis of a NEN.

Several of our patients were diagnosed during surgery for acute abdomen; 2 with bowel obstruction due to the mechanical effect of the tumor and 5 were associated with acute appendicitis. Cases of NEN-associated acute appendicitis cover a wide range of ages, and so there are no data for suspecting the neoplasm in those patients. Because they are malignant tumors, once the abdominal emergency is resolved, the patient should receive postoperative surveillance and treatment of possible tumor-related complications. When the tumor in the appendicular area is smaller than 1 cm, resection of colonic segments is not recommended, but in tumors larger than 2 cm, hemicolectomy of the ascending colon may be considered.22

One-third of our cases (16/48) were detected incidentally in endoscopy or imaging studies, signifying that measuring circulating markers for NENs could be of great utility in cases that are difficult to diagnose.23

It is important to define the histopathologic grade of each case of NEN, according to the WHO classification, because tumor grade is correlated with prognosis. NENs should also be classified according to cell differentiation grade, cell proliferation index and/or the number of mitoses per high power field. In cases of grade 3 disease, the well-differentiated tumors are called NETs. Poorly differentiated tumors are called neuroendocrine carcinomas (NECs) and they have a worse prognosis. NECs are divided into small cell or large cell tumors. Not only do the subclassifications have prognostic implications, but they are also useful for selecting specific chemotherapeutic agents.

Even though the majority of NENs are sporadic, a small percentage are associated with type I and II multiple endocrine neoplasms that possibly have a hereditary transmission pattern.

Cases of high-grade NENs (poorly differentiated) have poor prognosis. According to international case series, survival is 16.2 years for grade 1, 8.3 years for grade 2, and 10 months for grade 3.18 However, long-term clinical follow-up is necessary in all cases because even well-differentiated and low-grade NENs occasionally have aggressive biologic behavior and can produce distant metastases. High-grade tumors require systemic management with combined chemotherapeutic agents (etoposide/cis-platin). Sunitinib and everolimus are also being used.23–25 In 2018, therapy with radionuclides targeted at peptide receptors was approved for gastroenteropancreatic tumors that express somatostatin receptors. Receptor expression can be demonstrated through PET before the patient receives therapy, especially in grade 1 and 2 tumors.7,26

Well-differentiated NENs generally respond well to treatment with somatostatin analogues, with favorable effects on symptomatology and possible antiproliferative effects,27 but one of their main adverse effects is uncontrollable diarrhea due to the suppression of the release of hormones and the biologically active substances that inhibit pancreatic enzyme secretion and gastrointestinal motility.9 Resection is indicated for NENs, whenever possible, and radiofrequency ablation and transarterial chemoembolization may also be used for liver metastases. In cases that are surgically unresectable, platin-derived chemotherapy is usually indicated,28 especially in grade 2 or 3 tumors.18,25

Serum chromogranin A measurement is useful for monitoring progression, for prognosis, and for treatment response. Its utility in immunohistochemistry lies in its capacity to evaluate NEN extension and differentiation.

Other markers, such as secreted phosphoprotein 1 (SPP1), have been shown to be efficient for NEN diagnosis, given that they are more sensitive than even chromogranin A, even though chromogranin A has better correlation with tumor aggressiveness.21,29,30 Immunohistochemical markers, such as INSM1, have recently acquired importance; INSM1 may be more specific than conventional markers.31

One of the new genetic tests is the NETest. It is a “liquid biopsy” for NETs that improves molecular diagnostic accuracy by assessing the expression of certain genes, such as Ki-67, SSTR1, and SSTR2, in blood, through reverse transcription polymerase chain reaction.21

The diagnosis of gastroenteropancreatic NENs was made in 48 patients treated at the HAP in Mexico City over the 6-year study period. Our cases showed very similar demographic data and clinical presentations to those published nationally and internationally. The diagnosis of NENs is a great challenge for the clinician, due to the variety of their clinical manifestations, as well as to their incidental presence in asymptomatic patients. The use of biomarkers may facilitate early diagnosis and should be ordered in patients with a wide range of chronic issues, such as abdominal pain, diarrhea, gastrointestinal bleeding, bowel occlusion or subocclusion, and weight loss. The review of the hospital charts of our patients showed that circulating biomarker measurement was hardly ever ordered before the histopathologic diagnosis; said quantifications could also be very useful in the postoperative surveillance of patients. New circulating biomarkers for improving the diagnostic process in NENs are being developed, based on the genetic expression of the tumor cells (liquid biopsy).

No financial support was received in relation to this study/article.