Neuroendocrine neoplasm (NEN) refers to a relatively rare and highly heterogeneous group of tumors originating from neuroendocrine cells or peptidergic neurons. These tumors exhibit neuroendocrine functional characteristics and express specific markers. NEN can occur in various parts of the body, primarily in neuroendocrine organs (such as the pituitary gland, thymus, and adrenal glands) and non-neuroendocrine organs containing scattered neuroendocrine cells, such as the gastrointestinal tract and lungs. Among these, the digestive organs, including the stomach, intestines, and pancreas, are the most commonly affected, accounting for approximately two-thirds of all NEN cases.
Based on their proliferative and differentiation potential, the World Health Organization (WHO) currently classifies NEN into well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Most neuroendocrine tumors are sporadic, and their precise etiology remains unclear. A small proportion of cases show familial clustering, which may be closely related to genetic factors, such as multiple endocrine neoplasia type 1 (MEN1).
Pathogenesis
The pathogenesis of NEN is not fully understood. Unlike non-endocrine tumors, oncogenes (e.g., RAS, FOS, and MYC) and tumor suppressor genes (e.g., TP53 and RB1) frequently observed in other cancers rarely undergo mutations in NEN. Current research suggests that the mechanisms underlying pancreatic neuroendocrine tumors (pNEN) differ from those of gastrointestinal neuroendocrine tumors. Common allelic loss sites in pNEN include chromosomal regions 1p, 1q, 3p, 11p, and 22p, whereas those in gastrointestinal NEN are 18q, 18p, 9p, and 16q.
Epigenetic dysregulation is considered to play a significant role in the pathogenesis of NEN. Approximately 5–10% of NEN cases are significantly associated with genetic factors, including conditions such as MEN1 (associated with pNEN in over 80% of cases), MEN2, von Hippel-Lindau disease, and neurofibromatosis type 1 (NF1). Additionally, some rare genetic mutations, such as germline mutations in genes like CDKN1A, CDKN2B, and CDKN2C, have also been closely linked to NEN.
Pathology and Classification
Neuroendocrine cells are widely distributed in various organs and tissues, and most commonly arise from the endoderm during embryonic development. Central nervous system cells, gastrointestinal tract cells, pancreatic cells, and endocrine tissue cells are the most commonly involved. Neuroendocrine cells have the ability to secrete a variety of hormones and amines, including gastrin, insulin, glucagon, somatostatin, enkephalins, vasoactive intestinal peptide, cholecystokinin, and substance P. However, these hormones and their analogs often have a short half-life (less than 3 minutes) in the bloodstream, preventing them from functioning as effective circulating hormones. Instead, they primarily act as neurotransmitters or paracrine hormones in endocrine and digestive systems.
NEN originates from the neuroendocrine system and is widely distributed throughout the body. At the ultrastructural level, these cells contain dense-core granules, which may include peptides/amines, neuron-specific enolase, synaptophysin, and chromogranins. Histologically, NEN cells are small, exhibit uniform nuclei, and have a low mitotic index.
Currently, NEN is categorized into functional neuroendocrine tumors (F-NEN), accounting for approximately 20% of cases, and nonfunctional neuroendocrine tumors (NF-NEN), accounting for around 80% of cases, based on whether the tumor secretes hormones that produce typical clinical symptoms. F-NEN refers to tumors that release active hormones or their products into the bloodstream, resulting in characteristic clinical manifestations. By contrast, NF-NEN refers to tumors without evident hormone production or hormone-related symptoms. Some NF-NENs secrete large amounts of hormone precursors that cannot be converted into biologically active hormones. Additionally, as the disease progresses, a small proportion of NF-NENs may evolve into F-NENs, highlighting the importance of hormone level assessment and dynamic monitoring.
F-NENs primarily occur in the pancreas, small intestine, lungs, and thymus. Examples include insulinomas, glucagonomas, gastrinomas, vasoactive intestinal peptide (VIP)-secreting tumors, and somatostatinomas, with the pancreas being the most frequently affected site. Small intestine and lung NENs often manifest as carcinoid syndrome.
Clinical Presentation
The clinical manifestations of neuroendocrine neoplasms (NEN) largely depend on the tumor's location, the type of hormones secreted, and the rate of disease progression. Nonfunctional NENs (NF-NENs) typically present with nonspecific gastrointestinal symptoms, tumor mass effects, or symptoms related to metastasis and infiltration, such as progressive dysphagia, abdominal pain, diarrhea, abdominal masses, jaundice, melena, and weight loss. In contrast, functional NENs (F-NENs) often have more specific manifestations related to biologically active substances secreted by the tumor, including recurrent refractory peptic ulcers, hypoglycemia, diabetes mellitus, and hypercalcemia, which serve as important diagnostic clues.
Certain NENs may also exhibit clinical features resembling “carcinoid syndrome,” which can include flushing, wheezing, tachycardia, diarrhea, abdominal pain, gastrointestinal bleeding, and even bronchospasms. NENs with no obvious symptoms, such as pulmonary carcinoid tumors, are often incidentally discovered during imaging studies like chest X-rays. Some pulmonary carcinoid tumors may secrete hormones such as CRH or ACTH, leading to Cushing syndrome-like manifestations.
Common Types of Functional Neuroendocrine Tumors
Insulinoma
Insulinoma is one of the most common types of functional NENs affecting the gastrointestinal tract and pancreas. It is primarily located within the pancreas and is predominantly benign. Approximately 95% of insulinomas are sporadic and solitary, but about 90% of cases in patients with MEN1 are associated with tumors in other locations. Some pancreatic NENs (pNENs) may also secrete peptides (e.g., chromogranin and pancreatic polypeptides), though these rarely result in noticeable clinical syndromes. Outside of insulinomas, most other pNENs tend to be malignant.
Gastrinoma
Gastrinoma is a type of secretory NEN located in the pancreas or duodenum, which leads to excessive secretion of gastric acid. This results in various clinical symptoms, including diarrhea, esophageal reflux, and recurrent refractory peptic ulcers, collectively referred to as Zollinger-Ellison syndrome (ZES). Gastrinoma typically affects individuals aged 35–65 years and most frequently occurs in the duodenum (49%), pancreas (24%), or surrounding lymph nodes (11%).
Sporadic gastrinoma can be difficult to diagnose due to atypical symptoms, and approximately 22% of gastrinomas are seen in patients with MEN1. Patients with MEN1-associated gastrinomas usually develop symptoms at a younger age and often have multiple tumors. In rare cases, gastrinoma may co-occur with other endocrine tumors, such as thyroid or adrenal tumors. The exact etiology of gastrinoma remains unclear, but recurrent abdominal pain secondary to peptic ulcer disease is often the most common presenting symptom. Most ulcers occur in the duodenum, although rarely in the jejunum. Early-stage gastrinoma symptoms may resemble typical peptic ulcer disease, but as the condition progresses, persistent abdominal pain poorly responsive to standard treatments may develop. In advanced stages, symptoms related to metastasis or tumor invasion may occur, with approximately 50% of malignant gastrinoma cases presenting with liver metastases at the time of diagnosis. Additionally, about 5% of gastrinomas can secrete ACTH, resulting in Cushing syndrome-like features.
Glucagonoma
Glucagonoma is characterized by excessive secretion of glucagon, leading to clinical symptoms such as dermatitis (necrolytic migratory erythema), diabetes or impaired glucose tolerance, weight loss, anemia, and fatigue. Patients often exhibit markedly elevated plasma glucagon levels (>1,000 pg/mL), while the normal plasma glucagon concentration in healthy individuals ranges from 150–200 pg/mL. Conditions such as renal insufficiency, acute pancreatitis, liver disease, celiac disease, severe stress, and prolonged fasting may, however, result in elevated glucagon levels without significant clinical manifestations.
Vasoactive Intestinal Peptide Tumor (VIPoma)
VIPoma is primarily found in the pancreas and results from ectopic secretion of large amounts of vasoactive intestinal peptide (VIP), causing its characteristic symptoms. In adults, 80–90% of VIPomas occur in the pancreas, with a small proportion arising from the intestines, esophagus, or nerve ganglia. In children and adolescents under age 10, most VIPomas manifest as extrapancreatic ganglioneuromas or neuroblastomas.
VIPomas are typically large, solitary tumors, with 50–75% located in the pancreatic tail. At the time of diagnosis, 40–70% of VIPomas already present with metastases. VIP released by the tumors acts as a strong stimulant for intestinal secretion, resulting in profuse watery diarrhea (>1L/day), which does not improve with fasting and is often accompanied by significant electrolyte imbalance. Plasma VIP concentrations are useful for differentiating between VIPoma and other causes of diarrhea, such as gastrinoma or pseudo-VIPoma. In healthy individuals, plasma VIP levels are typically less than 190 pg/mL, whereas over 90% of VIPoma patients have levels well above normal.
Somatostatinoma
Somatostatinomas primarily occur in the pancreas or proximal small intestine, and ectopic secretion of somatostatin can inhibit gastric acid and pancreatic enzyme secretion, reduce amino acid absorption in the intestine, and suppress the release of hormones such as cholecystokinin and gastrin. Somatostatinomas are often challenging to diagnose and may only be incidentally discovered during abdominal exploration, cholecystectomy, endoscopy, or imaging studies. Tumors tend to be large (average diameter 5 cm) and solitary at the time of diagnosis, with 60–80% of pancreatic somatostatinomas located in the head of the pancreas and many already exhibiting metastases.
Approximately 10% of duodenal somatostatinoma patients have associated neurofibromatosis type I (NF1), though often without obvious symptoms. Somatostatinoma syndrome features diabetes, gallbladder disease, diarrhea (steatorrhea), and weight loss, and is more commonly observed in patients with pancreatic somatostatinomas than in those with duodenal or intestinal tumors. In addition to the pancreas and intestines, other tumors—including small cell lung cancer, medullary thyroid carcinoma, pheochromocytoma, and paraganglioma—can secrete somatostatin-like substances, which can be detected via imaging studies or somatostatin receptor scans to localize the tumor.
Laboratory Tests and Diagnosis
The diagnosis of neuroendocrine neoplasms (NEN) primarily relies on clinical presentation, hormone measurements, imaging studies, and pathological examinations. Among these, dynamic monitoring of hormone levels through laboratory tests holds significant value in assessing the effectiveness of antitumor therapies and prognosis.
Hormone Measurements
In functional neuroendocrine neoplasms (F-NENs), clinical diagnosis places emphasis on detecting specific hormones, such as gastrin, vasoactive intestinal peptide (VIP), insulin, glucagon, ACTH, somatostatin, and serotonin (5-HT). Additionally, various hormone receptors, such as somatostatin receptors (SSTR), are present in the tumor tissues of some gastrointestinal and pancreatic NENs. Receptor imaging techniques could aid differential diagnosis and provide guidance for the treatment of tumors that secrete somatostatin-like substances. Percutaneous liver biopsy and splenic vein blood sampling can also improve the accuracy of localization diagnoses, although these methods are less commonly used in clinical practice due to their complexity and invasiveness. Hormone stimulation or suppression tests are also useful in diagnosing gastrointestinal and pancreatic F-NENs. For example, the fasting test may assist in diagnosing insulinoma, while secretin and calcium stimulation tests could help confirm gastrinoma. However, diagnosing nonfunctional NENs (NF-NENs) remains challenging due to the lack of specific symptoms.
Specific Biomarker Testing
The measurement of serum biomarkers holds high specificity for diagnosing NEN. These biomarkers include chromogranin A (CgA), synaptophysin, neuron-specific enolase (NSE), and pancreatic polypeptide. Chromogranin A (CgA), chromogranin B, and secretogranin II (SgII) are members of the acidic secretory protein family in the diffuse neuroendocrine system and play essential roles in the formation and secretion of hormone granules. CgA is valuable in distinguishing between benign and malignant neuroendocrine tumors. NSE, an isoform of the glycolytic enzyme enolase found in neuroendocrine cells and neurons, is present in approximately 90% of NENs and carries strong diagnostic significance. Mutational analysis, including evaluations of DNA copy numbers, gene expression, or mutations, also provides a precise method for confirming the diagnosis.
Imaging Studies
Accurate tumor localization is critical for surgical decisions and guiding treatment, and imaging studies play a pivotal role in localizing the tumor and evaluating treatment efficacy over time. For gastrointestinal and pancreatic NENs, imaging modalities such as ultrasonography (B-mode), CT, or MRI are commonly employed for localization, while CT is the first choice for NENs in the lung or thymus. Additionally, for patients receiving antiangiogenic therapies, CT also aids in assessing the tumor’s blood supply. Somatostatin receptor imaging (SRS) and positron emission tomography (PET) are useful for further localizing NENs and identifying metastatic lesions. Over 90% of well-differentiated NENs exhibit overexpression of somatostatin receptors (SST1–SST5), with SST2 having the highest expression rate (approximately 80%). SRS imaging uses radiolabeled somatostatin analogs with high affinity for SST2 receptors.
Endoscopy and Endoscopic Ultrasound
Endoscopy is an important method for localizing and characterizing NENs, particularly for those in the gastrointestinal tract. Endoscopy combined with pathological biopsy facilitates diagnosis and classification of gastrointestinal NENs. Endoscopic ultrasound (EUS) is widely used for the localization of gastrointestinal and pancreatic NENs and for evaluating the depth of gastric or rectal NEN infiltration. Modern electronic endoscopy and EUS have become crucial tools in diagnosing digestive system NENs.
Pathological Examination
Pathological examinations, including histological staining and immunohistochemical analysis of tumor markers, are of paramount importance in diagnosing NENs. Histological staining determines tumor size, vascular or nerve infiltration, and mitotic activity under high magnification, which aids in differentiating the malignancy grade of the tumor. Immunohistochemical staining for specific markers in tumor cells, such as silver staining for neuroendocrine cells, also helps in classifying the type of NEN.
Treatment and Prognosis
The management of NENs commonly involves a multidisciplinary approach. Treatment modalities primarily include surgical intervention, pharmacological therapy, and supportive care. The main objectives of treatment are to manage clinical symptoms caused by excessive hormone or biologically active substance secretion and to suppress tumor growth and spread. Surgical resection of the primary tumor remains the only curative option. In patients diagnosed with resectable NENs and fit for surgery, resection of the primary tumor should be considered as early as possible after evaluating the disease.
For patients presenting with metastatic disease or those unable to tolerate surgery at the time of diagnosis, pharmacological therapies may be used for disease control. These therapies are also applicable during preoperative preparation or postoperative management. In cases of hormone overproduction, hormone secretion inhibitors or receptor antagonists may be administered. For highly malignant neuroendocrine tumors, therapies such as radiotherapy, chemotherapy, immunotherapy, or combination treatments might also achieve certain efficacy.
Lifelong follow-up is necessary for all NEN patients and typically includes monitoring clinical symptoms, biochemical markers, and imaging studies. Due to the high heterogeneity of NENs, clinical prognosis depends on factors such as tumor location, functional status, pathological differentiation, tumor grading and staging, as well as the treatment approach adopted.