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Discussion

CARCINOID TUMORS and the STOMACH

The incidence of carcinoid tumors in the United States is 1 to 2 cases per 100,000 people. The vast majority of these tumors arise in the appendix, rectum and small intestine. These three locations account for 95 % of all GI carcinoid tumors ‚ in contrast to gastric carcinoids, which account for 2%. The incidence may actually be higher as many of these tumors are clinically silent. The tumors originate from well-differentiated serotonin producing intraepithelial cells, sometimes referred to as enterochromaffin-like (ECL) cells. These cells can produce numerous peptides, which include serotonin, gastrin, somatostatin, kinins and catecholamines. Carcinoid tumors are always considered neoplastic but they often have a prolonged course. Carcinoids involving the ileum are more likely to be symptomatic and metastatic at diagnosis unlike jejunal, duodenal or gastric carcinoids that tend to remain local and silent. At surgery approximately 20% of gastric carcinoids are reported to be metastatic.

Of gastric tumors, carcinoids account for approximately 0.3%. Most of these tumors (~80%) are clinically silent and the patients remain asymptomatic unless they develop hepatic metastasis. Most of the tumors are small and submucosal making endoscopic biopsy difficult and unreliable. Endoscopic ultrasound (EUS) has showed great promise in the detection of these lesions. In a Japanese study involving 15 patients Yoshikane showed that the diagnostic accuracy of EUS compared to resected specimens approached 88%. Five of these patients had gastric carcinoid lesions. By ultrasound the tumors appear homogenous and hypoechoic with sharp borders and can be characterized according to their depth of invasion into the submucosa.

An association between gastric carcinoid tumors and hypergastrinemic states exists. Patients with Zollinger-Ellison syndrome associated with MEN-1 and atrophic gastritis with hypochlorydria have an increased risk of developing carcinoids. Both of these conditions are associated with hypergastrinemic states. Serum gastrin has a trophic effect on ECL cells in the gastric mucosa. A significant concern about the safety of long term therapy with proton pump inhibitors has been raised. In rats subjected to high dose omeprazole or lansoprazole, with serum gastrin levels exceeding 1000 pg/ml, a high frequency of carcinoid tumors was reported. However, this association was not seen in dogs and mice similarly treated. Furthermore, in humans on antisecretory therapy serum gastrin levels exceed 500 pg/ml in only 1-2 % of patients. Only 32 humans on prolonged proton pump therapy are known to have developed carcinoid tumors. Interestingly an association between crohn's disease and neurofibromatosis with carcinoid tumors also exists.

Patients with distal small bowel carcinoids involving the ileum are more likely to be symptomatic than patients with duodenal, jejunal or gastric carcinoids in which the tumors can be silent. Only a small percentage of patients develop the carcinoid syndrome. Diarrhea is the most common symptom experienced in carcinoid syndrome followed by flushing. The flushing is often described as a faint pink discoloration of the face and trunk, usually transient and sometimes associated with the ingestion of alcohol and tyramine containing products. Other manifestations may include asthma, valvular heart disease, cyanosis, pellagra and facial telangiectasias in a malar distribution. A rare but feared entity is the carcinoid crisis in which patients have intense and unremitting flushing, severe diarrhea, abdominal pain and central nervous system compromise.

The flushing in carcinoid syndrome is quite characteristic. The most common type is the 'midgut flush' which is usually seen in carcinoids of the ileum. Jejunoileal carcinoids are more likely to express serotonin than duodenal or foregut carcinoids. In contrast, the 'foregut flush' is more intense and often associated with conjunctival injection and facial edema. This flush is often more associated with stomach carcinoids. In addition a 'histamine' variant flush exists in which patients develop pruritic erythematous blotches and wheals. This also is associated with gastric carcinoid tumors, though much more rare.

It is important to note that the carcinoid syndrome usually heralds late-stage disease and is often associated with tumor bulk and distant metastasis. Patients with hepatic metastasis will usually develop the syndrome and should be expected to have elevated levels of urine 5-HIAA, a serotonin metabolite. The urine 5-HIAA test is a 24 hour collection that has high sensitivity and specificity for carcinoid syndrome and its levels may correlate with the degree of tumor burden. A patient with facial flushing but an otherwise normal physical exam, a negative CT of the abdomen/liver and a normal urine 5-HIAA probably does not have carcinoid syndrome.

Surgical resection is generally the treatment of choice. Tumor size appears to be a major prognostic indicator though not necessarily a reliable one. In general, patients with tumors less than 2 cm tend to do quite well, although metastatic spread of tumors even less than 0.5 cm has been documented. For gastric carcinoids a tumor size of greater than 2 cm usually requires a subtotal or complete gastrectomy. Smaller tumors can sometimes be removed endoscopically. Twenty percent of gastric carcinoids may be metastatic at the time of surgery and these patients may benefit from palliative chemotherapy with 5-FU or steptozocin. The overall survival in patients with localized disease is 65 % at 5 years and 36 % for those with distant metastatic disease. Tumor debulking and treatment with octreotide, a somatostatin analog, can offer significant palliation to patients with metastatic disease and the presence of carcinoid syndrome. One final caveat for physicians to be aware of is that up to 20% of patients with carcinoid tumors may have other occult malignant tumors.