Gastrointestinal neuroendocrine tumors

Definition

Gastrointestinal neuroendocrine tumors are a heterogeneous group of epithelial neoplasms originating from APUD cells of the gastrointestinal tract. Most patients with neuroendocrine tumors develop a carcinoid syndrome that includes flushes, abdominal pain, diarrhea, respiratory disturbances, heart valve damage, and telangiectasia. Hypoglycemia, hunger, disorders of consciousness, seizures, peptic ulcers, weight loss, diabetes, dermatitis, thrombosis, and thromboembolism are also possible. Diagnosis is made based on symptoms, laboratory, and instrumental findings. Treatment – surgery, chemotherapy, symptomatic therapy.

General information

Neuroendocrine tumors (NETs) are a group of neoplasms of varying degrees of malignancy originating from cells of the diffuse neuroendocrine system capable of producing peptide hormones and biogenic amines. Neuroendocrine tumors are among the rare cancers. Usually, it affects the digestive and respiratory systems, but it can be detected in other organs. They occur sporadically or are the result of one of several hereditary syndromes accompanied by the development of multiple neuroendocrine tumors in various organs.

Statistical indicators of morbidity are 2-3 people per 100,000 population, but experts point out that during autopsy, neuroendocrine tumors are found in 8-9 people per 100,000 population, which indicates a low level of lifetime diagnosis. They are usually detected in adults; men are affected more often than women. Treatment is provided by specialists in oncology, gastroenterology, pulmonology, endocrinology, and other areas of medicine (depending on the localization of the neoplasm).

Classification of neuroendocrine tumors

Taking into account the peculiarities of embryogenesis, three groups of neuroendocrine tumors are distinguished:

• A neoplasm originating from the upper part of the primary embryonic intestine giving rise to the lungs, bronchi, esophagus, stomach, and upper part of the duodenum.
• Neuroendocrine tumors originating from the middle section of the primary embryonic colon, which is the precursor to the lower duodenum, jejunum, and upper sections of the large intestine, including the appendix, cecum, ileum, and ascending colon.
• Neuroendocrine tumors originating from the lower primary embryonic intestine giving rise to the lower colon andrectum.

Considering the localization, bronchopulmonary neuroendocrine tumors and neoplasms of the digestive system are distinguished. Bronchial and pulmonary NETs account for about 3% of all cancers of the respiratory system and about 25% of the total number of neuroendocrine tumors. NETs of the digestive system account for about 2% of all oncological processes of this localization and more than 60% of the total number of neuroendocrine tumors. 

According to the WHO classification, all neuroendocrine tumors of the digestive system, regardless of their type and localization, are divided into three categories:

• Highly differentiated neoplasms with benign course or indeterminate malignancy.
• Highly differentiated neuroendocrine tumors with low malignancy potential.
• Low-differentiated neoplasms with high malignancy potential.

Along with the above “generalized” classifications, there are WHO classifications for neuroendocrine tumors of various localizations, created taking into account the diameter of the primary neoplasm, the depth of penetration of the underlying tissues, the degree of involvement of nerves, lymphatic and blood vessels, the presence or absence of metastases and some other factors that affect the course and prognosis of the disease.

Symptoms of neuroendocrine tumors

Neuroendocrine tumors of the GI tract (endocrine carcinomas, carcinoid tumors of the GI tract) are most often detected in the appendix region. Neoplasia of the small intestine is the second most common. Neuroendocrine tumors of the large intestine and rectum account for 1-2% of the total number of oncological processes in this anatomical zone. Gastric and duodenal neoplasms are relatively rare. A genetic predisposition to the occurrence of multiple neuroendocrine tumors is detected in 10% of patients.

All endocrine carcinomas secrete peptides and biogenic amines, but the list of biologically active compounds and the level of activity of secretory cells of neoplasms can vary significantly, which determines possible differences in the clinical picture of the disease. The most characteristic sign of neuroendocrine tumors of the GI tract is carcinoid syndrome, usually occurring after the appearance of metastases in the liver and accompanied by flushes, diarrhea, and abdominal pain. Heart valve lesions, respiratory disorders, and telangiectasias are less common in this syndrome.

Flushes are observed in 90% of patients with neuroendocrine tumors. The release of large amounts of serotonin and prostaglandins into the bloodstream is considered to be the main cause of the attacks. Flushes develop spontaneously, against the background of alcohol consumption, emotional stress, or physical activity, and last from a few minutes to several hours. During hot flashes, patients with neuroendocrine tumors show hyperemia of the face or upper half of the trunk in combination with hypotension (rarely hypertension), tachycardia, and dizziness.

Diarrhea can be noted both against the background of attacks and in their absence and is detected in 75% of patients with neuroendocrine tumors. Heart valve damage develops gradually and occurs in 45% of patients. Pathology is due to cardiac fibrosis resulting from prolonged exposure to serotonin. In 5% of patients with carcinoid syndrome, pellagra is observed, manifested by weakness, sleep disorders, increased aggressiveness, neuritis, dermatitis, glossitis, photodermatosis, cardiomyopathy, and cognitive disorders.

In 5% of patients with neuroendocrine tumors, there is an atypical course of carcinoid syndrome due to the release of histamine and 5-hydroxytryptophan into the blood. Usually, this variant is detected in the NET of the stomach and upper part of the duodenum. Atypical carcinoid syndrome in neuroendocrine tumors is manifested by headache, hot flashes, bronchospasm, and lacrimation. During the tides, a brief hyperemia of the face and upper half of the trunk is detected, accompanied by fever, sweating, and skin itching. At the end of the flushes, numerous telangiectasias form in the area of redness.

Carcinoid crisis is a dangerous complication of neuroendocrine tumors. Usually, such a crisis develops against the background of surgical intervention, invasive procedures (e.g., biopsy), or severe stress, but it can occur without visible external causes. The condition is accompanied by a sharp drop in blood pressure, marked tachycardia, and severe bronchospasm. It is life-threatening and requires emergency treatment.

Diagnosis and treatment of neuroendocrine tumors

Diagnosis is established based on clinical symptoms and laboratory and instrumental tests. In addition, the plan of examination of patients with suspected neuroendocrine tumors includes ultrasound of abdominal organs, CT and MRI of abdominal organs, PET, scintigraphy, and endoscopic studies. If malignancy is suspected, a biopsy is performed.

The radical method of treating neuroendocrine tumors is surgical excision within healthy tissues. Due to the multiplicity of neoplasms, difficulties in determining the location of small nodules, and a high incidence of metastasis, complete removal of neuroendocrine tumors in a significant proportion of patients is not possible. To reduce the clinical manifestations of the disease, symptomatic treatment with the use of somatostatin analogs is prescribed. In case of rapid growth of malignant neoplasms, chemotherapy is indicated.

All these treatment options are available in more than 800 hospitals worldwide (https://doctor.global/results/diseases/gastrointestinal-neuroendocrine-tumor). For example, Gastric endoscopic submucosal dissection (ESD) can be performed in these countries at following approximate prices:

Turkey$2,029 in 22 clinics

China$4,784 in 6 clinics

Israel$5,945 in 11 clinics

Germany$6,100 in 36 clinics

United States$8,677 in 12 clinics.

Prognosis in neuroendocrine tumors

The prognosis depends on the type, degree of malignancy, and extent of neoplasia. The average five-year survival rate of patients with endocrine carcinoma is 50%. In patients with carcinoid syndrome, this indicator decreases to 30-47%. In the presence of metastases, the five-year survival rate of patients with such a neuroendocrine tumor decreases to 30%.