Abstract
Initially, carcinoid tumors were a curiosity for physicians and were so named because of their relatively benign behavior as compared to the more common adenocarcinomas. As medicine has evolved, our understanding and management have greatly improved. Our classification system has also become more specific. Gastric carcinoid tumors are unique in that three types have been described based upon each one's pathophysiology. In general, none of these give rise to the typical carcinoid syndrome as seen with metastatic ileal carcinoids.
Type 1 gastric carcinoids represent 70% to 80% and are characterized by multiple small lesions and their association with hypergastrinemia secondary to chronic atrophic gastritis and pernicious anemia, and are less likely to metastasize. Type 2 is a rare entity, representing 5%, and is characterized by multiple small lesions, hypergastrinemia secondary to Zollinger-Ellison syndrome, and multiple endocrine neoplasia (MEN) type 1. The risk for metastasis is slightly higher than for type 1; however, overall prognosis is dependent upon the gastrinoma prognosis. Accounting for 20%, type 3 is known as sporadic gastric carcinoids in that there is no association with hypergastrinemia, chronic atrophic gastritis, or Zollinger-Ellison syndrome. These present as large solitary lesions and are often metastatic upon diagnosis. A unique feature of type 3 is its association with an atypical carcinoid syndrome that is thought to be mediated by histamine.
The treatment—including medical, endoscopic, and surgical—of gastric carcinoids is dictated by the type, size, and presence of metastasis.
- chronic atrophic gastritis
- Gastric carcinoid
- GEP-NETs
- hypergastrinemia
- multiple endocrine neoplasia (MEN) type 1
- pernicious anemia
- somatostatin
- somatostatin receptor scintigraphy
- Zollinger-Ellison syndrome
Case
An 83-year-old female presented to the emergency department for worsening weakness and fatigue over a few weeks' duration. Her only significant medical history was hypertension. She reported that her stools had become loose and black for the last couple of weeks. Her complaints included dyspnea on exertion, but she denied symptoms of orthopnea or paroxysmal nocturnal dyspnea. She denied nausea, vomiting, heartburn, odynophagia, dysphagia, abdominal pain, appetite changes, weight loss, constipation, or nonsteroidal anti-inflammatory drug use. Her review of systems was unremarkable except for increased falling for 1 month.
The vital signs at presentation included a blood pressure of 91/49 mmHg, pulse 80 beats per minute, temperature 97.0°F, and respiration 18 breaths per minute. On physical examination, she was alert and oriented, breath sounds were normal, skin was warm, dry, with normal skin turgor, and mucous membranes were moist. Her abdomen was soft, nontender, nondistended, and had no evidence of hernias, masses, ascites, or scars. A rectal examination revealed frank melena without masses. Her hemoglobin was 8.8 gm/dL (normal 12.0 to 16 gm/dL) and hematocrit was 27.3% (normal 37.0 to 48.5%). Her blood urea nitrogen was 37 mg/dL (normal 5 to 23 mg/dL). Results of all other laboratory tests were essentially within normal limits, including creatinine, electrolytes, liver function tests, and coagulation factors.
She was admitted to the internal medicine service for resuscitation and consultation by the gastroenterology service. She did well with basic resuscitative support. Later that afternoon, an esophagoduodenoscopy was performed. Hematin (altered blood) was found in the gastric fundus. One non-bleeding cratered gastric ulcer with a visible vessel was found on the lesser curvature of the stomach. The lesion was 30 mm in largest diameter (Figure 1). Coagulation of the exposed vessel using a bipolar probe was successful. She was placed on a proton pump inhibitor daily and scheduled for a repeat esophagoduodenoscopy to prove ulcer healing 8 weeks later. In the interim, she was found to be positive for serum H. pylori immunoglobulin and treated with a course of amoxicillin, clarithromycin, and proton pump inhibitors for 14 days. Repeat endoscopy revealed a healing cratered gastric ulcer, which was 10 mm in largest dimension (Figure 2). Routine biopsy specimens were obtained. Histology revealed an increase in fibrous tissue with moderate chronic inflammation of the lamina propria. Goblet cells and Paneth cells were present, indicating intestinalization. In addition, there were clusters of relatively innocuous-appearing, homogeneous cells with small round nuclei consistent with a carcinoid tumor. There was positive staining with chromogranin and synaptophysin. The carcinoid tumor did not have particularly aggressive morphologic features (Figure 3, pathology slides).
An abdominal and pelvic computed tomography (CT) scan revealed no evidence of a gastric mass or metastasis. A third esophagoduodenoscopy was performed in order to tattoo the carcinoid tumor to assist in surgical resection. A laparoscopic wedge resection of the carcinoid mass was uncomplicated and successful. Currently, at 3 years post-surgery, she is doing well.
Introduction
Originating from enterochromaffin-like (ECL) cells, gastric carcinoid tumors are rare tumors that develop within the gastric mucosa. They can present as an isolated lesion or there can be multiple lesions. The tumor can invade locally into deeper structures of the gastrointestinal (GI) tract wall. Solitary gastric carcinoids have a greater chance for the development of malignancy and metastasis as compared to multiple gastric carcinoids due to hypergastrinemia.1 This difference in the biologic behavior has challenged physicians for years.
The most common clinical scenario is that these lesions are found incidentally on endoscopy. However, some patients present with nonspecific symptoms such as nausea, vomiting, dyspepsia, abdominal discomfort, and early satiety, or with complications such as gastrointestinal bleeding. In addition, a small percentage of patients present with the classic carcinoid syndrome, which is characterized by flushing, diarrhea, and right-sided heart failure. Carcinoids typically appear as polypoid lesions or nodules with normal-appearing overlying mucosa on endoscopy. An endoscopic ultrasound of the lesion reveals a hypoechoic lesion which usually originates from the deep mucosa or submucosa (second or third endoscopic ultrasound layer.) This procedure is helpful in determining the depth of invasion as well as assessing lymph nodes for metastatic involvement.1
In the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute database from 1973 to 1997, 11,427 cases reviewed revealed 55% of carcinoids were within the GI tract and 30% within the bronchopulmonary system. Within the GI tract, 45% arose in the small intestine (most commonly distal ileum), 20% rectum, 16% appendix, 11% colon, and 7% stomach.2 According to these data, the stomach is the least common site of gastrointestinal carcinoids; however, this likely represents underreporting as many incidental small gastric nodules in elderly patients are often not pursued.
Pathology/history
In 1888, Lubarsch gave the first microscopic description of a carcinoid tumor involving a patient with multiple ileal carcinoids. He described carcinoids as originating in the intestinal crypts of Lieberkuhn.3 Two years later, Ransom described the classical symptoms of carcinoid syndrome in a patient with ileal carcinoid complicated by liver metastasis.4 In 1907, Oberndorfer coined the term karzinoide (carcinoma-like) to describe these tumors which were thought to have a more benign course in comparison to adenocarcinomas.5 The first recognition of carcinoids as being endocrine-related tumors was by Gosset and Masson in 1914.6 In 1963, Williams and Sandler classified carcinoids according to their embryologic site of origin as foregut (bronchopulmonary, stomach, duodenum, biliary, and pancreas), midgut (jejunum, ileum, appendix, and proximal colon), and hindgut (distal colon and rectum).7 As our understanding of the difference between carcinoid tumors has improved, our classification system has changed. In 2004, the World Health Organization (WHO) suggested a more generic term, neuroendocrine tumor (NET) which has replaced the older catch-all term carcinoid; therefore, these tumors are currently referred to as gastroenteropancreatic (GEP) NETs (GEP-NETs). In this system, the term carcinoid is reserved for describing a somatostatinoma.8
Three Types of Gastric Carcinoids
Once thought to be extremely rare lesions, gastric carcinoids have been reported to comprise up to 8.7% to 30% of all carcinoids in more recent studies.2,9,10 There is an increased incidence of gastric carcinoids in patients with chronic atrophic gastritis, pernicious anemia, auto-immune diseases, and multiple endocrine neoplasia (MEN)-1-associated gastrinomas.11 As our understanding of the pathophysiology has improved, we have recognized that there are distinct differences between gastric carcinoids. Therefore, three types of gastric carcinoids varying by tumor characteristics, histology, association with hypergastrinemia, as well as their biological behavior have been described.
The most frequent type, representing 70% to 80%, of gastric carcinoids is type 1.12–14 These generally present as multiple small lesions (< 1 cm) which are nodular or polypoid in nature and can have a small central ulceration. Histologically, the tumors are derived from ECL cells. The most likely hypothesis is that ECL cells develop into carcinoids after chronic stimulation by high gastrin levels, as seen in patients with achlorhydria associated with chronic atrophic gastritis. The sequence involves the transformation from ECL cell hyperplasia, to dysplasia, and finally to neoplasia.15 Interestingly, rats treated with a proton pump inhibitor have been shown to develop carcinoid tumors, but this has not been seen in humans.16 Thus, factors other than hypergastinemia are likely involved. The mechanism of hyperproliferation may be related to mutations in the Regl alpha gene, which may normally function as an autocrine or paracrine suppressor of gastrin stimulation of ECL proliferation.17 Patients with gastric carcinoids associated with longstanding atrophic gastritis generally have a benign course. The biological behavior is one of slow growth. Fortunately, regional as well as distant metastases are rare (< 5%).15 However, all carcinoids have a potential for metastasis. For lesions less than 2 cm, the risk for metastatic disease is less than 10%, and this increases to almost 20% for larger lesions. These tumors do not cause the carcinoid syndrome.18 The 5-year survival is > 95%.15
The less common type 2 gastric carcinoids account for 5% and are associated with gastrinomas (Zollinger-Ellison syndrome). Carcinoids associated with Zollinger-Ellison syndrome occur almost exclusively in patients with MEN type 1. These lesions are generally small (< 1 cm) and multiple. Histologically, these tumors are also derived from ECL cells secondary to a hypergastrinemic state. Thus, both type 1 and type 2 are associated with marked elevations of serum gastrin. In type 1, it is the lack of stomach acid that leads to a secondary secretion of gastrin, whereas patients with type 2 have a marked increase in gastric acid production which is responsible for the clinical presentation of Zollinger-Ellison syndrome. In contrast to that of type 1 gastric carcinoids, the pathogenesis of type 2 tumors is often associated with the inactivation of the MEN 1 gene, a tumor suppressor gene located on chromosome 11q13.19 The biological behavior is one of slow growth. Metastasis is more often seen (7% to 12%) as compared to chronic atrophic gastritis associated lesions. The 5-year survival is 70% to 90% but is dependent upon gastrinoma prognosis.15
Finally, type 3 gastric carcinoids, accounting for about 20%, are known as sporadic carcinoids because they are not associated with atrophic gastritis, gastrinomas, or the MEN 1 syndromes.20,21 These are generally solitary lesions and are often large (> 1 cm). They evolve in normal gastric mucosa with normal plasma gastrin levels. Histologically, the tumors are thought to be derived from ECL cells, enterochromaffin cells, or X cells. In contrast to the other two types, the sequence involves tumor formation without evidence of hyperplasia or pre-carcinoid dysplasia in adjacent mucosa.15 Type 3 gastric carcinoids often contain a variety of endocrine cells and may be associated with an atypical carcinoid syndrome.22 They often produce 5-hydroxy-tryptophan in contrast to type 1 and 2 tumors, which more often produce serotonin. Atypical carcinoid syndrome is primarily manifested by flushing and is thought to be mediated by histamine.23 In contrast to typical carcinoid syndrome, the flush seen in patients with atypical carcinoid syndrome is cherry red, patchy, sharply demarcated, serpiginous, and intensely pruritic.24 The biological behavior is one of relatively aggressive growth with frequent metastases to regional nodes (55%) and liver (24%). The 5-year survival is < 35%.15
Diagnosis/treatment
Gastric carcinoid management is dictated by the specific type involved. Endoscopic resection can be safely accomplished and is the treatment of choice for type 1 gastric carcinoids less than 1 cm.12,25 Periodic endoscopic surveillance is recommended every 6 to 12 months in order to exclude the formation of new lesions given the persistent hypergastrinemia. Antrectomy is recommended for type 1 gastric carcinoids when there are more than 5 lesions or any lesion is greater than 1 cm.12 Plasma gastrin levels decrease due to the removal of the source of gastrin production (G-cells). This in turn usually leads to tumor regression.12,14,26,27 Rarely, more extensive surgical resection may be required for extensive tumor involvement, bleeding, or recurrence.28,29 Medical treatment should be reserved for patients who are not surgical candidates. This entails anti-gastrin therapies (acidification by diet or dilute oral hydrochloric acid) or somatostatin therapy. There is controversy about the medical role given gastrin levels may or may not decrease. Continued endoscopic surveillance is required.24
Small lesions (< 1 cm) in type 2 are best removed with endoscopic resection.12,25 Patients with larger lesions or recurrent tumors may require more extensive surgical resection.29 In patients with gastrinomas, somatostatin analogs have resulted in tumor regression.30
Unfortunately, most type 3 (sporadic) carcinoids are metastatic at the time of presentation. Death attributable to the underlying disease is frequent.29 They are treated by partial or total gastrectomy with local lymph node resection.21
The liver is the most common site for carcinoid metastasis. Unfortunately, liver function tests are often normal and therefore unreliable to rule out disease. Of note, the serum alkaline phosphatase is frequently normal despite extensive liver involvement. Therefore, an abdominal CT scan should be performed when metastasis is suspected. The lesions are often hypervascular and may become isodense relative to the liver when intravenous contrast is administered. Therefore, CT scans should be performed before and after intravenous contrast is given.
Somatostatin receptor scintigraphy is a very useful modality for the detection of metastasis based on the fact that more than 90% of GEP-NETs contain high concentrations of somatostatin receptors. The one exception is insulinomas in which only 50% express type 2 somatostatin receptors. Radiolabeled octreotide (indium-111 pentetreotide, OctreoScan), a somatostatin analog, is used as an imaging modality to evaluate for metastasis.31–33 In addition to localization, the uptake of octreotide is predictive of a clinical response to the somatostatin analogs.34
Magnetic resonance imaging (MRI) is sometimes helpful when the CT findings are unclear.35,36 MRI has been shown in one prospective trial to have a greater sensitivity than CT imaging and somatostatin receptor scintigraphy in patients with well-differentiated GEP-NETs (sensitivities for MRI, CT, and planar scintigraphy were 95%, 49%, and 79%, respectively).37 This has led many authorities to believe that MRI is the diagnostic procedure of choice for the detection of metastatic NETs.37,38
Acknowledgments
The authors thank Nancy K. Davis for her help with the pathology slides.
- Academic Division of Ochsner Clinic Foundation
