Gastric Neuroendocrine Neoplasms

Overview

Gastric neuroendocrine neoplasms are rare lesions found in the stomach. They grow slowly and are often divided into four types based on their clinical characteristics. Type I lesions are found in the stomach and are linked with autoimmune chronic atrophic gastritis. Type II lesions are often caused by gastrin-producing tumors. Type III are characterized by its sporadic nature and has the greatest potential to generate metastasis. Type IV are often multiple small lesions and are characterized by hypertrophy and hyperplasia of parietal cells with vacuolated cytoplasm.

Neuroendocrine Neoplasms (NENS)

Neuroendocrine neoplasms (NENs) were previously considered carcinoids. They have historically been very rare, but now, according to the Surveillance, Epidemiology and End Results (SEER) program in the United States, patients with these tumors are increasing.

In 2010, the World Health Organization (WHO) classified neuroendocrine neoplasms (NENs) in three grades based on their Ki-67 proliferation index and mitotic activity. This was changed seven years later as NENs were divided into NET and neuroendocrine carcinoma (NEC) according to tumor grade, independently where the tumor arises. One of the rarest types of NENs is the mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN). These types of neoplasms include both neuroendocrine tumor and non-neuroendocrine tumor components.

Epidemiology

Gastric NENs often develop from the digestive tract and the pancreas. They are rare disorders that affect 5% to 23% of all digestive NENs in various trials. The incidence of g-NENs increases nearly 15-fold with time, probably because of the expanding use of upper gastrointestinal endoscopy. There are also studies that show the incidence of g-NENs increasing with time. One such study noted from 0.309 to 6.149 per 1000000 persons in the last 40 years. Another recorded as high as 4.82 per 100000 population had NENs. Studies have also found that the incidence of g-NENs is increasing overtime at a rate higher than any other cancer.

Pathogenesis

Elevated gastrin levels have always been linked with hyperplasia, dysplasia, and neoplasia development in ECL cells. Researchers also found that gastrin levels are correlated with hyperplasia severity. Elevated serum gastrin levels are linked with both the type 1 and 2 g-NENs, with different mechanisms for hypergastrinemia. Elevated gastrin levels also are the ones responsible for waking up ECL cells which produce histamine, and histamine—which also stimulates parietal cells to produce acid. Thus, chronic atrophic gastritis is involved in the pathogenesis of type 1 g-NEN. If chronic atrophic gastritis is associated with a parietal cell or intrinsic factor antibodies the condition is named pernicious anemia, and this is commonly present in patients with type 1 g-NEN.

Type 2 g-NEN is similar to Type I due to hypergastrinemia. On the contrary, hypergastrinemia and excess acid production are due to an ectopic gastrin-producing G cell neoplasia (gastrinoma).

The exact pathogenesis of type 3 g-NEN is not very well established. Experts believe that mutations of the p53 gene may have caused type 3 g-NEN. Also, the fact that g-NEN develops only in a minority of patients with chronic atrophic gastritis suggests that other pathogenic factors other than hypergastrinemia are involved in the development of g-NENs.

The discrimination between g-NEN types is of great importance because the therapy and follow-up differ among types. Serum gastrin levels are elevated in type 1 and 2 g-NENs, whereas it is normal in patients with type 3 and 4 g-NENs.

For differential diagnosis of type 1 and 2 g-NENs, biopsy samples outside the lesions should be investigated to detect whether atrophy is present. Atrophic mucosa indicates type-1 gNENs, whereas normal mucosa is detected in patients with type 2 g-NEN. Another tool for differential diagnosis may be the gastric acid measurement. In cases with hypergastrinemia, gastric pH is generally above 4 in type-1 g-NEN, while it is less than 2 in type 2 g-NEN. If type 2 g-NEN is detected, additional testing for MEN-1 syndrome should be performed.

Treatment

The treatment for g-NENs is based on the tumor type, lesion size, lesion severity, and disease extent. Treatment is often by endoscopic resection, surgical resection, and different kinds of therapies for g-NENs.

Type 1

Type 1 g-NEN has a low metastasis risk. Conservative management strategies are the best mode of treatment for small lesions. Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) may be used for endoscopic resection. ESD has the advantage of en bloc resection for complete histological analysis. Preferably EUS should be performed for lesions greater than 10 mm to assess tumor invasion, and endoscopic resection should be done when it is possible. Surgical treatment is the option for lesions that are predicted to be T2 or lesions with positive margins.

Type 2

The widely used treatment for type 2 g-NEN is local excision. Endoscopic treatment for noninvasive tumors and surgical resection for invasive or metastatic lesions should be chosen. When performing surgical resection, it’s also important to search for gastrinoma lesions.

Type 3 and type 4

For types 3 and 4, the optimal treatment strategy is surgical treatment. Although some authors cited that endoscopic resection would be sufficient in small lesions without invasion, this is not a widely accepted approach. Similarly, the treatment of localized type 4 g-NEN is gastrectomy and lymph node dissection.

Metastatic disease

Surgery, local methods, and systemic treatment are included in the treatment options of liver metastasis due to g-NENs. Treatment options for patients with metastases of g-NENs are not specific for gastric lesions, and the options are based on recommendations for liver metastases of NETs. The treatment method for liver metastases of grade 1 and 2 g-NENs is the surgical removal of the metastatic lesions. Although surgery is not commonly recommended for grade 3 tumors, single and suitable lesions may be surgically removed. Primary tumor resection is suggested in patients with advanced resectable disease, but the role of primary tumor resection in patients with unresectable metastases is debated.

Carcinoid syndrome

Carcinoid syndrome is rare for patients with g-NENS. It is more commonly seen in patients with liver metastasis. If carcinoid syndrome is present, it should be treated with SSAs, along with symptomatic treatment if indicated. In addition, SSAs should be given for prophylaxis before surgical and local treatment methods.

Conclusion

G-NENs are tumors with increasing incidence. The pathogenesis, clinical characteristics, prognosis, and treatment options differ apparently between subgroups of g-NENS. Type 1 and 2 are gastrin dependent, whereas type 3 and 4 are considered sporadic. It is very important to differentiate tumors between these subgroups for further management and treatment. Treatment options for g-NENs include endoscopic resection, surgical resection with or without antrectomy, medical treatment with somatostatin analogs, netazepide, or chemotherapy regimens.

Gastric Neuroendocrine Neoplasms