3 Common Syndromes of Gastric Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are rare cancers that can occur anywhere in the body. Those originating from neuroendocrine cells located in the stomach's mucosal lining are called gastric NETs. These specialized cells produce hormones controlling the release of gastric juices and how quickly food moves through the stomach.

Under normal conditions, these cells grow and divide to replace old or damaged cells that eventually die. However, when this process goes awry, abnormal or damaged cells can avoid cell death and continue to grow uncontrollably. This leads to the formation of a mass of cells called a tumor, which becomes malignant (cancerous) when it spreads and invades nearby tissues.

Gastric NETs can be associated with certain syndromes, such as carcinoid syndrome, Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia type 1 (MEN1).

Carcinoid syndrome

Some NETs, including gastric NETs, release various hormones, such as serotonin, histamine, tachykinins and prostaglandins into the bloodstream. When high levels of these substances circulate throughout the body, they can cause a wide range of symptoms collectively known as carcinoid syndrome.

Carcinoid syndrome is typically associated with the oversecretion of the hormone serotonin. However, gastric NETs lack the enzyme that is responsible for converting the precursor molecule of serotonin to its active form. For this reason, the carcinoid syndrome observed in people with metastatic gastric NETs is called atypical carcinoid syndrome, and is primarily mediated by high levels of histamine.

It is more common in people with liver metastatic NETs and is usually seen in NETs originating from the midgut (small intestine, appendix and proximal colon). However, metastatic NETs arising from the foregut (lung, stomach and duodenum) and hindgut (distal colon and rectum) can also cause carcinoid syndrome in rare instances, especially when liver metastasis is present.

The symptoms of atypical carcinoid syndrome include:

• Flushing, which is the development of bright salmon pink or cherry red patches on the skin that feel warm to the touch. It is largely caused by widening or dilation of the blood vessels.
• Telangiectasia, which is the appearance of thread-like, tiny blood vessels close to the surface of skin on the face. Also known as “spider veins”, these show up as fine pink, red or purple lines, usually on the nose and upper lip.
• Wheezing, which is caused by the tightening of the airways.
• Edema, which refers to the face and extremities (feet and legs) becoming hard and swollen due to excess fluid in the body tissues. It is common for cases of metastatic foregut NETs.
• Lacrimation, which is the excessive and abnormal production of tears that often accompanies flushing and facial edema.

Treating or removing the NET itself can help alleviate carcinoid syndrome symptoms. However, there are some methods that are used to control these symptoms directly, such as hormone therapy using somatostatin analogs (SSAs).

Zollinger-Ellison syndrome (ZES)

Zollinger-Ellison syndrome (ZES) is a condition caused by the growth of gastrinomas, which are neuroendocrine tumors that secrete abnormally high levels of the hormone gastrin into the bloodstream (hypergastrinemia). Gastrinomas typically originate from G cells in the pancreas or duodenum, but can sometimes be found in the stomach. They may occur as single tumors or as numerous small tumors.

In normal circumstances, G cells release small amounts of gastrin after eating. This triggers parietal cells in the gastric glands to secrete gastric acid in order to break down food and liquid in the stomach. However, the hypergastrinemia typical of ZES results in increased proliferation of the parietal cells and overproduction of gastric acid. This increase in acidity leads to the formation of multiple and recurrent peptic ulcers – open sores that develop on the lining of the upper gastrointestinal tract, including the stomach and duodenum.

ZES is characterized by the appearance of peptic ulcers and other symptoms such as:

• A dull or burning pain felt in any region between the middle of the chest and navel
• Persistent or chronic diarrhea, including steatorrhea (fatty stools)
• Mild to severe abdominal pain
• Bloating
• Heartburn and acid reflux
• Nausea and vomiting

Peptic ulcers need to be aggressively treated and controlled. This can be achieved with the use of proton pump inhibitors (PPIs), which are drugs used for prolonged reduction of stomach acid. The treatment of choice for ZES is surgical resection of the gastrinoma(s) and metastatic NETs in the body. If there is widespread metastasis and the tumors are unresectable, treatment options include hormone therapy with SSAs, targeted therapies, and liver-directed therapies.

Multiple Endocrine Neoplasia Type 1 (MEN1)

Roughly 70-75% of ZES cases are caused by gastrinomas that occur sporadically. However, the remaining 25-30% of cases occur as part of an inherited tumor syndrome called multiple endocrine neoplasia type 1 (MEN1), also known as Werner syndrome. MEN1 is characterized by the development of multiple tumors, including parathyroid adenomas and gastroenteropancreatic NETs that are gastrinomas.

Up to 30-50% of people with MEN1-associated gastrinomas develop gastric NETs, especially if ZES is present. These stomach tumors are typically Type II gastric NETs, and occur due to proliferation of enterochromaffin-like (ECL) cells in the stomach lining stimulated by hypergastrinemia.

The condition is caused by germline mutations in the MEN1 gene, which encodes menin, a tumor suppressor protein. These mutations lead to the inactivation of the gene and no tumor suppressor activity, thereby paving the way for uncontrolled cell proliferation and tumorigenesis.

The clinical symptoms of MEN1-associated gastrinomas/ZES are similar to those caused by sporadic cases of ZES. However, the onset of symptoms in people with MEN1 generally present at an earlier age (32–35 years) compared to people with sporadic gastrinomas (48–55 years). Furthermore, while the frequency of most symptoms is similar, diarrhea is not as common in people with MEN1 syndrome.

To control ZES in MEN1-associated gastrinomas, PPIs are used to inhibit acid secretion and relieve symptoms of peptic ulcer disease. However, unlike sporadic cases of ZES, surgery may not be the treatment of choice. Studies have found that surgical resection of the primary gastrinoma(s) in MEN1 is unlikely to result in cure. Combined with the multiplicity of tumors and the fact that MEN1 is usually accompanied by metastatic disease, medical therapy, such as hormone therapy with SSAs and targeted therapy, is the current standard of care for most people with MEN1-associated gastrinomas/ZES.