Gastric NETs (gastric carcinoids)


Neuroendocrine tumors (NETs) originating from the stomach are denoted gastric NETs or gastric carcinoids. An introduction to diagnosis and treatment follows.

Gastric NETs (gastric carcinoids)
Diagnosis and treatment are different due to type of gastric neuroendocrine tumor (type 1-4).

Type 1 gastric NETs (gastric carcinoids).
The type 1 gastric NETs are the most common (70%) and arise in patients having chronic atrophic gastritis with secondary hypergastrinemia. The lack of acid secretion may be measured in the gastric juice (pH usually around 7), but vitamin B12 deficiency and pernicious anemia may also be present. The patients are usually asymptomatic and the diagnosis is most frequently set after upper endoscopy performed due to abdominal discomfort. The ECL cell hyperplasia lead to multicentric tumors, visualized as multiple small polyps of ECL-cells. They are usually benign, and very rarely metastasize (< 2%).

Type 2 gastric NETs (Type 2 gastric carcinoid).
These tumors arise in patients due to hypergastrinemia released from gastrin-producing tumors, most often in association with multiple endocrine neoplasia type 1 (MEN-1) causing the Zollinger-Ellison syndrome (ZES). In 80% of patients with MEN-1 and ZES is ECL-cell hyperplasia present in the stomach, and in 15-30% of these are gastric NETs also present. Differentiation towards type 1 gastric NETs is done by demonstrating ECL-cell hyperplasia, low gastric juice pH (< pH 2). Type 2 gastric NETs are more often malignant than type 1 gastric NETs.

Type 3 gastric NETs (Type 3 gastric carcinoid).
These tumors are more uncommon and develop unrelated to hypergastrinemia usually in association with a solitary tumor. The gastric mucosa is normal. The tumors are usually larger than type 1 and 2 gastric NETs, and the majority are infiltrative into the muscularis layer. Metastases are present in 20-50%, and the Ki67 proliferation index is higher.

Type 4 gastric NETs (Type 4 gastric carcinoids.
Gastric PDEC). Type 4 gastric NETs are more poorly differentiated (PDEC) and have a highly malignant course.
These tumors are highly malignant, and usually beyond being possible for surgical treatment at diagnosis.

Diagnosis of gastric NETs (Gastric carcinoids)
Proper diagnosis is based on establishment of the serum gastrin level. In case of hypergastrinemia (Type 1 or 2), lack of gastric acid secretion and demonstration of atrophic gastric mucosa, and lack of familial history are associated with diagnosis of type 1 gastric NETs. Serum measurements of chromogranin A are usually high in type 1 gastric carcinoids due to the atrophic gastritis, but is useful to follow in the individual patient. In type 2 gastric carcinoids multiple tumors are usually present, as well as low pH and a hyperplastic mucosa.

The endoscopic evaluation includes examination of specific endocrine and proliferative markers (Ki67, chromogranin A) from the biopsies of the tumor itself as well as the mucosa away from the tumor to clarify eventual ECL (enterchromaffin-like) cell hyperplasia and differentiation of chronic atrophic gastritis from the increased oxyntic mucosa thickness seen in MEN-1 with ZES. Differential diagnosis may also include more poorly differentiated sporadic type 3 gastric carcinoids.

Endoscopic ultrasound for evaluation of infiltrative depth and associated lesions in the duodenum and pancreas may be indicated in suspicion of type 2 and 3 gastric NETs. Since differentiation between type 1 and 2 gastric carcinoids sometimes may be difficult, screening for MEN-1 should be performed, including plasma measurements of calcium and parathyroid hormone (PTH), prolactin, growth hormone, insulin-like growth factor type 1 (IGF-1) as well as pancreatic hormones. For all types of gastric NETs computed tomography is indicated to investigate tumor size, location, lymph node and liver metastases. 111In-octreotide scintigraphy (OctreoScan) may also reveal metastatic spread since these tumors usually express somatostatin receptors.

Atypical carcinoid syndrome in gastric NETs
In about 10% of patients with type 3 gastric NETs an atypical carcinoid syndrome may appear with flush, edema, bronchospasm, swelling of salivary glands and lacrimation due to release of histamin. The metabolite MelmAA is raised, but since this is difficult to measure increased levels of 5-HIAA in urine may be used as a biomarker in 20%. H2-blockers may be used to reduce symptoms.

Non-surgical treatment of gastric NETs (gastric carcinoids)
In some cases of type 1 gastric NETs (polyps < 1 cm) endoscopic surveillance is an alternative to polypectomy. Somatostatin analogue treatment may be an alternative, both in Type 1 and 2 gastric NETs to avoid recurrence after surgical treatment. For Type 3 and 4 gastric NETs chemotherapy may be indicated, most often streptocotozin and 5-FU (or doxorubicin), or as an alternative cis-platin and etoposide.

Surgical treatment of
Type 1 gastric NETs (Type 1 gastric carcinoids)
Small, multicentric lesions may be followed with repeated endoscopy. Tumors less than 1 cm have a small risk for being invasive and can be treated by endoscopic polypectomy followed by repeated endoscopy to exclude recurrence. Larger tumors have a higher risk of being invasive and surgical excision is recommended, including possibility to remove regional lymph nodes. Type of surgical excision varies according to tumor location and size. Subtotal or even total gastrectomy may be required. Antrectomy, possibly associated with a Billroth type II repair, reduces antral overproduction of gastrin leading to regression of ECL-cell dysplasia and small type 1 gastric NETs and may be chosen especially for multicentric or recurrent tumors.

Surgical treatment for Type 2 gastric NETs (Type 2 gastric carcinoids)
The MEN-1 related type 2 gastric carcinoids are more malignant than type 1 tumors. Removal of the gastrin-producing tumor(s) as well as the developing secondary gastric tumors is recommended. Therefore, pancreatic resection and duodenotomy may be required, together with a thorough investigation of the remainder of the pancreas for multiple tumors.

Surgical treatment of Type 3 gastric NETs (Type 3 gastric carcinoids)
These tumors, associated with normal serum gastrin levels, are usually highly malignant and require surgical resection with lymph node clearance. In general subtotal or total gastrectomy should be performed. Liver metastases should be treated appropriately with hepatic embolisation, radiofrequency or chemotherapy.

Surgical treatment of Type 4 gastric NETs (Type 4 gastric NETs; gastric PDEC)
These tumours have a comparably short median survival of about 8 months, and are rarely suitable for surgery. In case of mixed populations of tumours cells where also well differentiated cells occur aggressive treatment by surgery and chemotherapy in combination may be beneficial.