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The three most common primary malignant gastric neoplasms are adenocarcinoma (95%), lymphoma (4%), and malignant GIST (1%) (Table 26-14). Other rare primary malignancies include carcinoid, angiosarcoma, carcinosarcoma, and squamous cell carcinoma. Occasionally the stomach is the site of hematogenous metastasis from other sites (e.g., melanoma or breast). More commonly, malignant tumors from adjacent organs invade the stomach by direct extension (e.g., colon or pancreas) or by peritoneal seeding (e.g., ovary).
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Globally, gastric cancer is the fourth most common cancer type and the second leading cause of cancer death. Over the past several decades, there has been a dramatic decrease in the gastric cancer incidence and death rate in most Western industrialized countries (Fig. 26-49). This decrease has been largely in the so-called intestinal form rather than in the diffuse form of gastric cancer. In Asia and Eastern Europe, gastric cancer remains a leading cause of cancer death. In 2012 in the United States, there were approximately 21,320 new cases of stomach cancer (13,020 in men and 8300 in women), and 10,540 deaths from this disease (6190 men and 4350 women.83 The estimated 5-year survival rate is 27%, up from about 15% in 1975.
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In general, gastric cancer is a disease of the elderly, and it is twice as common in blacks as in whites. In younger patients, tumors are more often of the diffuse variety and tend to be large, aggressive, and more poorly differentiated, sometimes infiltrating the entire stomach (linitis plastic). Gastric cancer has a higher incidence in groups of lower socioeconomic status.
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Gastric cancer is more common in patients with pernicious anemia, blood group A, or a family history of gastric cancer. When patients migrate from a high-incidence region to a low-incidence region, the risk of gastric cancer decreases in the subsequent generations born in the new region. This strongly suggests an environmental influence on the development of gastric cancer. Environmental factors appear to be more related etiologically to the intestinal form of gastric cancer than the more aggressive diffuse form. The commonly accepted risk factors for gastric cancer are listed in Table 26-15.
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Typically, a starchy diet high in pickled, salted, or smoked food is found in many regions of high gastric cancer risk. Dietary nitrates have been impugned as a possible cause of gastric cancer. Gastric bacteria (more common in the achlorhydric stomach of patients with atrophic gastritis, a risk factor for gastric cancer) convert nitrate into nitrite, a proven carcinogen. A diet high in fresh fruits and vegetables and rich in vitamin C and E has been shown to decrease the population’s risk of gastric cancer. The reduced consumption of nitrate-rich preserved foods seen with the growth of refrigeration has been suggested as a cause of the dramatic decrease in gastric cancer seen in North America and Western Europe over the last century. Tobacco use probably increases the risk of stomach cancer, and alcohol use probably has no effect. Regular aspirin use may be protective.
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The risk of gastric cancer in patients with chronic H. pylori infection is increased about threefold. Compared to uninfected patients, patients with a history of gastric ulcer are more likely to develop gastric cancer (incidence ratio 1.8, 95% confidence interval 1.6–2.0), and patients with a history of duodenal ulcer are at decreased risk for gastric cancer (incidence ratio 0.6, 95% confidence interval 0.4–0.7).54,84 As diagrammed in Fig. 26-50, this may be due to the fact that some patients develop antral-predominant disease (predisposing to duodenal ulcer and somehow protecting against gastric cancer), while other patients develop corpus-predominant gastritis, resulting in hypochlorhydria and somehow predisposing to gastric ulcer and gastric cancer.85 The theoretical sequence for development of gastric adenocarcinoma is diagrammed in Fig. 26-51.54,85 Recently, it has been demonstrated that bone marrow-derived stem cells play a key role in the pathogenesis of gastric adenocarcinoma in patients with chronic H. pylori infection.54 However, it must be recognized that gastric adenocarcinoma is a multifactorial disease. Not all patients with gastric cancer have H. pylori, and there are some geographic areas with a high prevalence of chronic H. pylori infection and a low prevalence of gastric cancer (the “African enigma”). Finally, H. pylori-infected patients seem to be at decreased risk for the development of adenocarcinoma of the distal esophagus and cardia region.86 Perhaps the corporeal gastritis decreases acid secretion, creating a less damaging refluxate and thus reducing the risk for Barrett’s esophagus, the precursor lesion for these tumors.
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About 10% of gastric adenocarcinomas carry the EBV virus. Recently it has been suggested that EBV infection is a rather late step in gastric carcinogenesis, since EBV transcripts are present in cancer cells but not in the metaplastic cells of precursor epithelium.87
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A variety of genetic abnormalities have been described in gastric cancer (Table 26-16). Most gastric cancers are aneuploid. The most common genetic abnormalities in sporadic gastric cancer affect the p53 and COX-2 genes. Over two thirds of gastric cancers have deletion or suppression of the important tumor-suppressor gene p53. Additionally, approximately the same proportion have overexpression of COX-2. In the colon, tumors with upregulation of this gene have suppressed apoptosis, more angiogenesis, and higher metastatic potential. Gastric tumors that overexpress COX-2 are more aggressive tumors. Recently, a germline mutation in the CDH1 gene encoding E-cadherin was shown to be associated with hereditary diffuse gastric cancer. Prophylactic total gastrectomy should be considered in patients with these mutations.88
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Recently the role of microRNA abnormalities in gastric cancer have received attention. These are small short sequence molecules (18 to 25 nucleotides) which inhibit the translation or promote the degradation of messenger RNA with complementary sequences. MicroRNAs are important regulators of gene expression, and abnormalities in microRNA have been identified in gastric cancer which effect the cell cycle, apoptosis, and cellular invasiveness and/or metastatic potential.89 It is likely microRNA will have increasing diagnostic, therapeutic, and prognostic significance in gastric cancer as well as other tumors.
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Premalignant Conditions of the Stomach
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Figure 26-52 shows the prevalence of some premalignant conditions associated with the development of early gastric cancer in a series of 1900 cases from Tokyo. By far the most common precancerous lesion is atrophic gastritis. There is a growing appreciation of the important influence of the chronic inflammatory milieu on the genome of mucosal cells. Chronic inflammation leads to both genetic and epigenetic changes in mucosal cells which in the stomach leads to the development of gastritis associated cancer.90
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Benign gastric polyps are classified as neoplastic (adenoma and fundic gland polyps) or nonneoplastic (hyperplastic polyp, inflammatory polyp, hamartomatous polyp).90A In general, inflammatory and hamartomatous polyps have little or no malignant potential. Fundic gland polyps, commonly seen in patients on long term proton pump inhibitor therapy, are not premalignant but in patients with familial adenomatous polyposis, dysplasia in these lesions is not uncommon. Hyperplastic polyps usually occur in the setting of chronic inflammation. Large hyperplastic polyps (>2cm) may harbor dysplasia or carcinoma in situ, and gastric cancer may develop remote from the hyperplastic polyp in an area of associated chronic inflammation. Gastric adenomas are premalignant, similar to colon adenomas. Patients with familial adenomatous polyposis (FAP) have a high prevalence of gastric adenomatous polyps (about 50%), and are 10 times more likely to develop adenocarcinoma of the stomach than the general population.91 Screening EGD is indicated in these families. Patients with hereditary nonpolyposis colorectal cancer may also be at risk for gastric cancer.92
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Gastric polyps greater than 1cm should be removed to confirm the diagnosis and to eliminate any risk of malignant degeneration. Patients with gastric adenomatous polyps and FAP should have periodic upper endoscopy, which may also be considered in selected patients with hyperplastic polyps and chronic gastric inflammation.
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Chronic atrophic gastritis (Fig. 26-53) is by far the most common precursor for gastric cancer, particularly the intestinal subtype (see Fig. 26-52). The prevalence of atrophic gastritis is higher in older age groups, but it is also common in younger people in areas with a high incidence of gastric cancer. In many patients, it is likely that H. pylori is involved in the pathogenesis of atrophic gastritis. Correa described three distinct patterns of chronic atrophic gastritis: autoimmune (involves the acid-secreting proximal stomach), hypersecretory (involving the distal stomach), and environmental (involving multiple random areas at the junction of the oxyntic and antral mucosa).84
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Intestinal Metaplasia
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Gastric carcinoma often occurs in an area of intestinal metaplasia. Furthermore, an individual’s risk of gastric cancer is proportional to the extent of intestinal metaplasia of the gastric mucosa. These observations strongly suggest that intestinal metaplasia is a precursor lesion to gastric cancer. There are different pathologic subtypes of intestinal metaplasia in the stomach, based upon the histologic and biochemical characteristics of the changed mucosal glands. In the complete type of intestinal metaplasia, the glands are completely lined with goblet cells and intestinal absorptive cells (Fig. 26-54). These cells are indistinguishable histologically and biochemically from their small bowel counterparts, and are not seen in the normal stomach. There is evidence that eradication of H. pylori infection leads to significant regression of intestinal metaplasia and improvement in atrophic gastritis. Therefore, treatment of H. pylori infection is a reasonable recommendation for patients with these pathologic diagnoses and H. pylori infection.
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Although once considered a premalignant condition, it is likely that the older literature was confounded by mistakenly labeling inadequately biopsied ulcers and healing ulcers as “benign,” when, in fact, they were malignant to begin with. It is now generally recognized that all gastric ulcers are cancer until proven otherwise with adequate biopsy and follow-up. Even today, carcinomas are occasionally found when adequately biopsied “benign” ulcers are resected for nonhealing. It is more than likely that the factors previously discussed are more significant etiologically in the development of gastric cancer than the history of a benign gastric ulcer.
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Gastric Remnant Cancer
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It has long been recognized that stomach cancer can develop in the gastric remnant, usually years following distal gastrectomy for PUD. The risk is controversial, but the phenomenon is real. Most tumors develop >10 years following the initial operation, and they usually arise in an area of chronic gastritis, metaplasia, and dysplasia. This is often near the stoma, but many of these tumors are quite large at presentation, and are equally divided between intestinal and diffuse subtypes. Most cases have been reported following Billroth II gastroenterostomy, but there also have been cases following Billroth I gastroduodenostomy. Whether simple loop gastrojejunostomy increases a patient’s risk of gastric cancer, and whether a Roux-en-Y anastomosis following gastric resection lowers their risk of gastric cancer is unknown. Stage for stage, the prognosis for gastric stump cancer is similar to proximal gastric cancer.93
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Other Premalignant States
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A mutated E-cadherin gene is associated with hereditary diffuse gastric cancer. Prophylactic total gastrectomy should be considered.88 Obviously, a myriad of genetic and environmental factors will affect members of the same family, and up to 10% of gastric cancer cases appear to be familial without a clear-cut genetic diagnosis. First-degree relatives of patients with gastric cancer have a two- to threefold increased risk of developing the disease. Patients with hereditary nonpolyposis colorectal cancer have a 10% risk of developing gastric cancer, predominantly the intestinal subtype. The mucous cell hyperplasia of Ménétrier’s disease is generally considered to carry a 5% to 10% risk of adenocarcinoma. Periodic surveillance EGD is prudent in all the above conditions. The glandular hyperplasia associated with gastrinoma is not premalignant, but ECL hyperplasia and/or carcinoid tumors can occur.
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It is generally accepted that gastric dysplasia is the universal precursor to gastric adenocarcinoma. Patients with severe dysplasia should be considered for gastric resection if the abnormality is widespread or multifocal, or EMR if the severe dysplasia is localized. Patients with mild dysplasia should be followed with endoscopic biopsy surveillance, and Helicobacter eradication.
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Early gastric cancer is defined as adenocarcinoma limited to the mucosa and submucosa of the stomach, regardless of lymph node status. The entity is common in the Orient, where gastric cancer is a common cause of cancer death, and where aggressive surveillance programs have therefore been established. Approximately 10% of patients with early gastric cancer will have lymph node metastases. There are several types and subtypes of early gastric cancer (Table 26-17 and Fig. 26-55). Approximately 70% of early gastric cancers are well differentiated, and 30% are poorly differentiated. The overall cure rate with adequate gastric resection and lymphadenectomy is 95%. In some Japanese centers, 50% of the gastric cancers treated are early gastric cancer. In the United States, less than 20% of resected gastric adenocarcinomas are early gastric cancer. Small intramucosal lesions can be treated with EMR.94
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Gross Morphology and Histologic Subtypes
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There are four gross forms of gastric cancer: polypoid, fungating, ulcerative, and scirrhous. In the first two, the bulk of the tumor mass is intraluminal. Polypoid tumors are not ulcerated; fungating tumors are elevated intraluminally, but also ulcerated. In the latter two gross subtypes, the bulk of the tumor mass is in the wall of the stomach. Ulcerative tumors are self-descriptive; scirrhous tumors infiltrate the entire thickness of the stomach and cover a very large surface area. Scirrhous tumors (linitis plastica) have a particularly poor prognosis, and commonly involve the entire stomach. Although these latter lesions may be technically resectable with total gastrectomy, it is common for both the esophageal and duodenal margins of resection to show microscopic evidence of tumor infiltration, and death from recurrent disease within 6 months is common. Palliative chemotherapy may prolong median survival94A.
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The location of the primary tumor in the stomach is important in planning the operation. Several decades ago, the large majority of gastric cancers were in the distal stomach. Recently, there has been a proximal migration of tumors, so that currently, the distribution is closer to 40% distal, 30% middle, and 30% proximal.
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The most important prognostic indicators in gastric cancer are both histologic: lymph node involvement and depth of tumor invasion. Tumor grade (degree of differentiation: well, moderately, or poorly) is also important prognostically.
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There are several histologic classifications of gastric cancer. The World Health Organization recognizes several histologic types (Table 26-18). The Japanese classification is similar but more detailed. The commonly used Lauren classification separates gastric cancers into intestinal type (53%), diffuse type (33%), and unclassified (14%). The intestinal type is associated with chronic atrophic gastritis, severe intestinal metaplasia, and dysplasia, and tends to be less aggressive than the diffuse type. The diffuse type of gastric cancer is more likely to be poorly differentiated and is associated with younger patients and proximal tumors. The Ming classification also is useful and easy to remember, with only two types—expanding (67%) and infiltrative (33%).
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Recently, the significance of human epidermal growth factor receptor-2 (HER2) was reported in patients with gastric cancer. In breast cancer, overexpression of HER2 has been reported in 15% to 25% and is well recognized as one of the unfavorable prognostic factors. However, the development of molecular targeted agents such as trastuzumab has improved the survival of HER2 positive patients. Likewise, recently in gastric cancer, HER2 overexpression has been reported in 13% to 30% of patients. According to the result of large clinical trial, Immunohistochemistry (IHC) staining of HER2 has become the important examination for recurrent or metastatic gastric cancer to decide the treatment strategy.94B
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Ultimately, prognosis is related to pathologic stage. The most widespread system for staging of gastric cancer is the tumor-node-metastasis (TNM) staging system based on depth of tumor invasion, extent of lymph node metastases, and presence of distant metastases. This system was developed by the American Joint Committee on Cancer and the International Union Against Cancer, and has under gone several modifications since it was originally conceived (Table 26-19).
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Clinical Manifestations
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Most patients who are diagnosed with gastric cancer in the United States have advanced stage III or IV disease at the time of diagnosis. The most common symptoms are weight loss and decreased food intake due to anorexia and early satiety. Abdominal pain (usually not severe and often ignored) also is common. Other symptoms include nausea, vomiting, and bloating. Acute GI bleeding is somewhat unusual (5%), but chronic occult blood loss is common and manifests as iron deficiency anemia and heme-positive stool. Dysphagia is common if the tumor involves the cardia of the stomach. Paraneoplastic syndromes such as Trousseau’s syndrome (thrombophlebitis), acanthosis nigricans (hyperpigmentation of the axilla and groin), or peripheral neuropathy are rarely present.
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Physical examination typically is normal. Other than signs of weight loss, specific physical findings usually indicate incurability. A focused examination in a patient in whom gastric cancer is a likely part of the differential diagnosis should include an examination of the neck, chest, abdomen, rectum, and pelvis. Cervical, supraclavicular (on the left referred to as Virchow’s node), and axillary lymph nodes may be enlarged, and today can be sampled in the office with fine-needle aspiration cytology. There may be a metastatic pleural effusion, or aspiration pneumonitis in a patient with vomiting and/or obstruction. An abdominal mass could indicate a large (usually T4 incurable) primary tumor, liver metastases, or carcinomatosis (including Krukenberg’s tumor of the ovary). A palpable umbilical nodule (Sister Joseph’s nodule) is pathognomonic of advanced disease, or there may be evidence on exam of malignant ascites. Rectal exam may reveal heme-positive stool and hard nodularity extraluminally and anteriorly, indicating so-called drop metastases, or rectal shelf of Blumer in the pouch of Douglas.
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Diagnostic Evaluation
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Distinguishing between peptic ulcer and gastric cancer on clinical grounds alone is usually impossible. Patients over the age of 45 years old who have new-onset dyspepsia, as well as all patients with dyspepsia and alarm symptoms (weight loss, recurrent vomiting, dysphagia, evidence of GI bleeding, or anemia) or with a family history of gastric cancer should have prompt upper endoscopy and biopsy if a mucosal lesion is noted. Essentially, all patients in whom gastric cancer is part of the differential diagnosis should have endoscopy and biopsy. If suspicion for cancer is high and the biopsy is negative, the patient should be re-endoscoped and more aggressively biopsied. In some patients with gastric tumors, upper GI series can be helpful in planning treatment. Although a good double-contrast barium upper GI examination is sensitive for gastric tumors (up to 75% sensitive), in most centers, endoscopy has become the gold standard for the diagnosis of gastric malignancy.
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In addition, recent advances in endoscopy have contributed to the earlier diagnosis of gastric cancer. Magnifying endoscopy with narrow-band imaging (NBI) has undergone technological improvements and can observe the microvascular architecture of the mucosa and microsurface pattern of the lesion. Magnifying endoscopy with NBI has been reported to be accurate and reliable in the diagnosis of early gastric cancer.94C Furthermore, endocytoscopy, a technique allowing microscopic visualization of the mucosal surface, has been developed and has the potential for pathological diagnosis.94D Another diagnostic innovation is virtual endoscopy which is an imaging examination of the gastrointestinal tract reconstructed by multidetector-row computed tomography. The image of virtual endoscopy is now quite similar to that of upper endoscopy. In the near future, this novel technology may play a role in the screening of the stomach.
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Preoperative staging of gastric cancer is best accomplished with abdominal/pelvic CT scanning with IV and oral contrast. MRI is probably comparable. The best way to stage the tumor locally is via EUS, which gives fairly accurate (80%) information about the depth of tumor penetration into the gastric wall, and can usually show enlarged (>5 mm) perigastric and celiac lymph nodes. In some centers, if the tumor is transmural (T3) or involves lymph nodes (enlarged nodes can usually be needled under endoscopic ultrasound guidance), preoperative (neoadjuvant) chemotherapy is given. However, there are limitations to tumor staging with EUS. It largely is operator dependent and may underestimate lymph node involvement because normal-sized nodes (<5 mm) can harbor metastases. EUS is most accurate in distinguishing early gastric cancer (T1) from more advanced tumors.
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Positron Emission Tomography Scanning
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Whole-body PET scanning uses the principle that tumor cells preferentially accumulate positron-emitting 18F-fluorodeoxy glucose. This modality is most useful in the evaluation of distant metastasis in gastric cancer but can also be useful in locoregional staging. PET scan is accurate when combined with spiral CT (PET-CT)95 and should be considered before major surgery in patients with particularly high-risk tumors or multiple medical comorbidities.
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Staging Laparoscopy and Peritoneal Cytology
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To some extent, the usefulness of these modalities depends on the individual patient’s situation as well as the treatment philosophy of the cancer team. The fundamental question is “will it make a difference to this patient’s management?” Patients with gastric cancer who undergo R0 resection (i.e., no gross residual disease) and are found to have positive peritoneal cytology (no gross carcinomatosis) have a much worse prognosis than the cytology negative group (median survival 14.8 months vs. 98.5 months).96 It is controversial how much this information adds prognostically to that of pathologic staging (TNM). Whether this poor prognosis can be improved postresection with aggressive adjuvant treatment (systemic, or local intraperitoneal hyperthermic chemotherapy) is unknown. Unfortunately, it is also unclear how much these patients benefit from gastric resection. Currently peritoneal cytology information is unlikely to change the treatment of patients with gastric cancer, and most patients without detectable distant metastases will have (and should have) gastric resection regardless of the peritoneal cytology results. A quick laparoscopic examination can occasionally reveal small peritoneal implants or liver metastases that were not detected on preoperative imaging studies and, in some patients (e.g., high risk for surgery or impressive carcinomatosis), this will change the operative plan and avoid a major but futile surgical procedure. Laparoscopy may be most useful in patients with proximal tumors or with adenopathy on spiral CT scan.97 An extensive laparoscopic staging procedure, although quite accurate, has not been widely adopted.
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Surgical resection is the only curative treatment for gastric cancer98,99 and most patients with clinically resectable locoregional disease should have gastric resection. Obvious exceptions include patients who cannot tolerate an abdominal operation, and patients with overwhelming metastatic disease.
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The goal of curative surgical treatment is resection of all tumor (i.e., R0 resection). Thus, all margins (proximal, distal, and radial) should be negative and an adequate lymphadenectomy performed. Generally, the surgeon strives for a grossly negative margin of at least 5 cm. Some gastric tumors, particularly the diffuse variety, are quite infiltrative and tumor cells can extend well beyond the tumor mass; thus, gross margins beyond 5 cm may be desirable. Frozen section confirmation of negative margins is important when performing operation for cure, but it is less important in patients with nodal metastases beyond the N1 nodal basin. It should be strongly emphasized that many patients with positive lymph nodes are cured by adequate surgery. It should also be stressed that often lymph nodes that appear to be grossly involved with tumor turn out to be benign or reactive on pathologic examination. More than 15 resected lymph nodes are required for adequate staging.100 Therapeutic nihilism should be avoided and, in the low-risk patient, an aggressive attempt to resect all tumor should be made. The primary tumor may be resected en bloc with adjacent involved organs (e.g., distal pancreas, transverse colon, or spleen) during the course of curative gastrectomy. Palliative gastrectomy may be indicated in some patients with obviously incurable disease, but most patients presenting with stage IV gastric cancer can be managed without major operation.99,101
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Extent of Gastrectomy
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The standard operation for gastric cancer is radical subtotal gastrectomy. Unless required for R0 resection, total gastrectomy confers no additional survival benefit and may have adverse nutritional or quality-of-life consequences, and higher peri-operative morbidity and mortality.98,99 Subtotal gastric resection typically entails ligation of the left and right gastric and gastroepiploic arteries at the origin, as well as the en bloc removal of the distal 75% of the stomach, including the pylorus and 2 cm of duodenum, the greater and lesser omentum, and all associated lymphatic tissue (Fig. 26-56). Reconstruction is usually by Billroth II gastrojejunostomy, but if a small gastric remnant is left, a Roux-en-Y reconstruction is considered. In East Asia especially in Japan, Billroth-I gastroduodenostomy was usually performed after distal gastrectomy. Billroth-I gastroduodenostomy consists of one anastomosis (which is usually straightforward and keeps the duodenum in the food stream). In the United States, traditional surgical teaching eschews gastroduodenostomy following gastric cancer resection because of the possibility of anastomotic recurrence and obstruction. The operative mortality is around 2% to 5%. Radical subtotal gastrectomy is generally deemed to be an adequate cancer operation in most Western countries, provided that tumor-free margins are obtained, >15 lymph nodes are removed, and all gross tumor is resected. In the absence of involvement by direct extension, the spleen and pancreatic tail are not removed.
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Total gastrectomy with Roux-en-Y esophagojejunostomy may be required for R0 resection (Fig. 26-57), and may be the best operation for patients with proximal gastric adenocarcinoma. The construction of a jejunal pouch can be beneficial nutritionally, particularly for those patients with a good prognosis.102 Proximal subtotal gastric resection, a technically feasible alternative to total gastrectomy for some proximal gastric tumors, requires an esophagogastrostomy to a vagotomized distal gastric remnant, and the functional outcome is poor. Pyloroplasty in this setting virtually guarantees bile esophagitis, and if the pylorus is left intact, gastric emptying may be problematic. An isoperistaltic jejunal interosition (Henley loop) between the esophagus and antrum could be considered an alternative reconstruction, but, all things considered, total gastrectomy usually results in superior functional, if not oncologic, results for most patients with proximal gastric cancer.
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Extent of Lymphadenectomy
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According to the 3rd edition of Japanese classification of gastric carcinoma, lymph node stations are numbered by anatomical definition. Lymph node stations from 1 to 12, and 14V are classified as regional lymph nodes and metastasis of any other lymph node is classified as distant metastasis (M1) (see Fig. 26-4). According to the type of gastrectomy, the definition of extent of lymphadectomy is different. D1 lymphadenectomy in distal gastrectomy requires the dissection of the stations 1, 3, 4sb, 4d, 5, 6, 7. Furthermore, additional resection of stations 8a, 9, 11p and 12a is needed for D2 lymphadenectomy. D1 lymphadenectomy in total gastrectomy requires dissection of stations 1 through 7 and in D2, from 8a to 12a too. The operation described above (radical subtotal gastrectomy in the Extent of Gastrectomy section), which is by far the most commonly performed procedure in the United States for gastric cancer, is called a D1 resection because it removes the tumor and the perigastric D1 nodes. The standard operation for gastric cancer in Asia and specialized U.S. centers is the D2 gastrectomy, which involves a more extensive lymphadenectomy (removal of the D1 and D2 nodes). In addition to the tissue removed in a D1 resection, the standard D2 gastrectomy removes the peritoneal layer over the anterior mesocolon and selectively over the pancreas, along with nodes along the hepatic and splenic arteries, and the crural nodes. Splenectomy and distal pancreatectomy are not routinely performed, because this clearly has been shown to increase the morbidity of the operation. The purported survival advantage of D2 gastrectomy in gastric cancer is shown in Table 26-20, which shows the 5-year survival rates for gastric cancer stratified by pathologic stage for the United States and Japan. Unfortunately, the randomized prospective trials that have been performed have not confirmed this survival advantage, but the morbidity and mortality in the D2 group was higher (Table 26-21).103,104,104A This was mostly attributable to the splenectomy and distal pancreatectomy, which are no longer routinely done as part of the D2 gastrectomy in the United States. However, since D2 lymphadenectomy in total gastrectomy requires the dissection of station 10 which is splenic hilar lymph node as described above, splenectomy is recommended to fulfill the criteria of D2. In Japan, pancreas-preserving splenectomy is generally performed to avoid the severe postoperative complications such as pancreas fistula in patients with advanced upper gastric cancer who underwent total gastrectomy. Some experts have argued that the D2 operation is simply a better staging procedure, and that the apparent improved survival with this more extensive dissection is simply an epiphenomenon of improved pathologic staging. This stage shift suggests that many patients in the U.S. series treated with D1 gastrectomy really had metastatic nodes at the D2 level that went unresected and undetected. Therefore, in the U.S. series, there were patients classified as stage I, who, if they had undergone a D2 gastrectomy, would be classified as stage II; and there were patients classified as stage II, who, if they had undergone a D2 gastrectomy, would be classified as stage III. The stage I survival in the United States would then actually be closer to the (more accurately staged) stage II survival in Japan, because this group includes some patients who really are stage II, but the nodes were not found in the D1 resection. All experts would agree that to avoid understaging of gastric cancer, a minimum of 15 nodes should be resected with the gastrectomy specimen. Despite the lack of strong data from RCTs supporting a survival advantage of D2 gastrectomy for gastric cancer, this has become standard practice in Asia and has been adopted by an increasing number of large Western centers. Reasons for this are safety of operation in experienced hands as well as data from observational studies and subgroup analysis of RCTs suggesting a survival benefit.104B
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Chemotherapy and Radiation for Gastric Cancer
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In general, the actuarial 5-year survival for resected gastric adenocarcinoma stages I, II, and III is about 75%, 50%, and 25%, respectively. Because most surgical patients have stage II disease or greater, it is common to refer gastric cancer patients postoperatively to a medical and/or radiation oncologist. Unfortunately, the existing data suggest that the incremental survival benefit attendant to adjuvant treatment is marginal, particularly in those patients who have had an adequate resection.98,99 In one prospective randomized study, adjuvant treatment with chemotherapy (5-fluorouracil and leucovorin) and radiation (4500 cGy) has demonstrated a survival benefit in resected patients with stage II and III adenocarcinoma of the stomach.105 Unfortunately, only 10% of patients entered in the study actually had D2 gastrectomy, and most (54%) had less than an adequate D1 gastrectomy. Because adequacy of lymphadenectomy has clearly been shown to impact survival, particularly in patients with stage III gastric cancer,99,100 it has been suggested that the benefits of adjuvant chemoradiation shown in this study would be vitiated by an adequate operation. Recent clinical trials suggest the potential importance of adjuvant chemotherapy after D2 lymphadenectomy in patients with advanced gastric cancer. These trials compared surgery alone and surgery plus adjuvant chemotherapy including oral fluoropyrimidines for curatively resected advanced gastric cancer. After D2 lymphadenectomy, the benefit of adjuvant chemotherapy has also been established and further improvement in prognosis is expected.105A,105B A recently published study from the Japan Clinical Oncology Group showed a 69% overall 5-year survival rate in patients with clinically curable T2b, T3, and T4 gastric cancer, treated with D2 gastrectomy alone (no chemotherapy).106 There was no incremental benefit from para-aortic lymph node dissection. There is no indication for the routine use of radiation alone in (D3) the adjuvant setting, but in certain patients, it can be effective palliation for bleeding or pain. Although the prognosis of metastatic or recurrent gastric cancer is poor, systemic chemotherapy provides a significant survival benefit over the best supportive care.106A Agents that have shown activity against gastric cancer include 5-fluorouracil (5-FU), cisplatin, doxorubicin, methotrexate, taxanes, and camptothecin. Until recently, 5-FU based chemotherapy especially in combination with platinums played a key role in the treatment for the unresectable gastric cancer as well as several types of cancer, such as colon and lung. In the 1990s, the introduction of novel anticancer agents such as camptothecin, taxanes, third-generation platinums, and new oral fluoropyrimidines, improved the prognosis of unresectable gastric cancer. Recently, although the risk of the toxicities is increased, triple combination chemotherapy is associated with better prognosis than double agent therapy. In the United States, triple chemotherapy consists of 5-FU, cisplatin and docetaxel and is now recognized as a standard first-line regimen. In Europe, triple therapy is more often epirubicin, cisplatin, and 5-FU. Sometimes 5-FU may be replaced by capecitabine which is an oral fluoropyrimidine, and cisplatin can be replaced by oxaliplatin which does not require hydration, respectively. Neoadjuvant treatment of gastric adenocarcinoma is being evaluated, particularly in patients with clinical T3 or N1 disease. It is likely that targeted molecular agents will have an increasing role in treating gastric cancer. Recently, Trastuzumab, a humanized molecular antibody reactive against the extracellular domain of HER2, increased the effectiveness of cytotoxic chemotherapy in patients with advanced gastric cancer.94B Other large trials are ongoing. Determination of HER2 gene amplification status may have prognostic significance.106B
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It has been demonstrated initially at numerous East Asian centers that some patients with early gastric cancer can be adequately treated by an endoscopic mucosal resection (EMR).106C EMR is a minimally invasive procedure that provides curative resection and has dramatically changed the treatment of early gastric cancer. EMR is indicated for patients in whom the probability of lymph node metastasis is low. According to the Japanese treatment guidelines for gastric cancer, EMR is a standard treatment for differentiated mucosal gastric cancer measuring less than 2 cm and without signs of ulceration, which has almost no risk of lymph node metastasis. En bloc resection is required to evaluate the surgical margin for confirmation of curative resection. Furthermore, the development of endoscopic submucosal dissection (ESD) allows en bloc resection of larger tumors. Therefore, the indications for endoscopic treatment of patients with gastric cancer may be broadened. New indications for minimally invasive treatment will require evaluation before implementation. Small tumors (<3 cm) confined to the mucosa have an extremely low chance of lymph node metastasis (3%), which approaches the operative mortality rate for gastrectomy. If the resected specimen demonstrates no ulceration, no penetration of the muscularis mucosae, no lymphatic invasion, and size <3 cm, then the risk of lymph node metastases is less than 1%. Thus, some patients with early gastric cancer might be better treated with the endoscopic technique. Currently, this should be limited to patients with tumors <2 cm in size that are node negative and confined to the mucosa on EUS, in the absence of other gastriclesions. The addition of laparoscopic lymph node sampling may be considered in selected patients.
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The 5-year survival for gastric adenocarcinoma has increased from 15% to 22% in the United States over the past 25 years. Survival is dependent on pathologic stage (TNM stage) and degree of tumor differentiation. Other important prognostic factors are sex, age, primary gastric tumor site, tumor size, and tumor depth.
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Palliative gastrectomy may be indicated in some patients with obviously incurable disease, but most patients presenting with stage IV gastric cancer can be managed without major operation.99,101
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Screening for Gastric Cancer
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In Japan, it clearly has been shown that patients participating in gastric cancer screening programs have a significantly decreased risk of dying from gastric cancer. Thus, screening is effective in a high-risk population. Screening the general population in the United States (a low-risk country) does not make sense, but patients clearly at risk for gastric cancer probably should have periodic endoscopy and biopsy. This includes patients with familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, gastric adenomas, Ménétrier’s disease, intestinal metaplasia or dysplasia, and remote gastrectomy or gastrojejunostomy.
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Gastric lymphomas generally account for about 4% of gastric malignancies. Over half of patients with non-Hodgkin’s lymphoma have involvement of the GI tract. The stomach is the most common site of primary GI lymphoma, and over 95% are non-Hodgkin’s type. Most are B-cell type, thought to arise in mucosa associated lymphoid tissue (MALT), although most high-grade gastric lymphomas are without any characteristics of the low-grade MALT neoplasm.107 About half of gastric lymphomas are histologically low grade, and about half are high grade. Interestingly, the normal stomach is relatively devoid of lymphoid tissue. However, in the setting of chronic gastritis, the stomach acquires MALT, which can undergo malignant degeneration. Again, H. pylori is thought to be the culprit. In populations with a high incidence of gastric lymphoma, there is a high incidence of H. pylori infection; patients with gastric lymphoma also usually have H. pylori infection.107A
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Low-grade MALT lymphoma, essentially a monoclonal proliferation of B cells, presumably arises from a background of chronic gastritis associated with H. pylori. These relatively innocuous tumors then undergo degeneration to high-grade lymphoma, which is the usual variety seen by the surgeon. Remarkably, when the H. pylori is eradicated and the gastritis improves, the low-grade MALT lymphoma often disappears. Thus, low-grade MALT lymphoma is not a surgical lesion. Careful follow-up is necessary particularly in those lesions with a t(11:18) translocation, thought to be a risk factor for a more aggressive MALT lesion. If low-grade lymphoma persists after H. pylori eradication, radiation should be considered for disease clinically confined to the stomach (stage I), while chemotherapy with or without radiation is used for more advanced lesions (Fig. 26-58).
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Patients with high-grade gastric lymphoma require aggressive oncologic treatment for cure and present with many of the same symptoms as gastric cancer patients. However, systemic symptoms such as fever, weight loss, and night sweats occur in about 50% of patients with gastric lymphoma. The tumors may bleed and/or obstruct. Lymphadenopathy and/or organomegaly suggest systemic disease. Diagnosis is by endoscopy and biopsy. Much of the tumor may be submucosal, and an assiduous attempt at biopsy is necessary. Primary lymphoma is usually nodular with enlarged gastric folds. A diffusely infiltrative process akin to linitis plastica is more suggestive of secondary gastric involvement by lymphoma. A diligent search for extragastric disease is necessary before the diagnosis of localized primary gastric lymphoma is made. This includes EUS; CT scanning of the chest, abdomen, and pelvis; and bone marrow biopsy. Most patients with high-grade gastric lymphoma are currently treated with chemotherapy and radiation, without surgical resection. Treatment-related perforation or bleeding is unusual but recognized. For disease limited to the stomach and regional nodes, radical subtotal D2 gastrectomy may be performed, especially for bulky tumors with bleeding and/or obstruction. Palliative gastrectomy for tumor complications also has a role. Certainly, a multidisciplinary team should be involved with the treatment plan for patients with primary gastric lymphoma.
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Gastrointestinal Stromal Tumor
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GISTs arise from interstitial cells of Cajal (ICC) and are distinct from leiomyoma and leiomyosarcoma, which arise from smooth muscle.108,109 Prognosis in patients with GIST tumors depends mostly on tumor size and mitotic count, and metastasis, when it occurs, is typically by the hematogenous route. Any lesion >1 cm can behave in a malignant fashion and may recur. Thus, all GISTs are best resected along with a margin of normal tissue. Almost all GISTs (and almost no smooth muscle tumors) express c-KIT (CD117) or the related PDGF receptor A, as well as CD34; almost all smooth muscle tumors (and almost no GISTs) express actin and desmin. These markers can often be detected on specimens obtained by fine-needle aspiration110 and are useful in differentiating between GIST and smooth muscle tumor histopathologically. Lesions that are definitively leiomyoma by current histopathologic criteria are adequately treated by enucleation. Lesions that are definitively GIST or leiomyosarcoma are best treated by resection with negative margins. Most equivocal lesions should be resected provided that the patient is a reasonable operative risk.
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Two-thirds of all GISTs occur in the stomach. Epithelial cell stromal GIST is the most common cell type arising in the stomach, and cellular spindle type is the next most common. The glomus tumor type is seen only in the stomach.
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GISTs are submucosal tumors that are slow growing. Smaller lesions are usually found incidentally, although they occasionally may ulcerate and cause impressive bleeding. Larger lesions generally produce symptoms of weight loss, abdominal pain, fullness, early satiety, and bleeding. An abdominal mass may be palpable. Metastasis is by the hematogenous route, often to liver and/or lung, although positive lymph nodes are occasionally seen in resected specimens.
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Diagnosis is by endoscopy and biopsy, although the interpretation of the latter may be problematic. EUS may be helpful, but symptomatic tumors and tumors >1 cm in size should be removed. Metastatic work-up entails CT of the chest, abdomen, and pelvis (chest X-ray may suffice in lieu of CT of the chest). Most gastric GISTs occur in the body of the stomach, but they also can occur in the fundus or antrum. They are almost always solitary. Wedge resection with clear margins is adequate surgical treatment. True invasion of adjacent structures by the primary tumor is evidence of malignancy. If safe, en bloc resection of involved surrounding organs is appropriate to remove all tumor when the primary is large and invasive. Five-year survival following resection for GIST is about 50%. Most patients with low-grade lesions are cured (80% 5-year survival), but most patients with high-grade lesions are not (30% 5-year survival).
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According to the tumor size and mitotic count,110A the risk of aggressive behavior was classified into four groups. Very low risk was defined as <2 cm and <5/50 HPF (high-power field) and low risk was defined as 2 to 5cm and <5/50 cm. Intermediate risk was defined as <5 cm and 6 to 10/50 HPF or 5 to 10cm and >5/50 HPF. And high risk was defined as >5 cm and >5/50HPF, >10cm with any mitotic rate or >10/50/ HPF with any size. It was known that the risk of recurrence differs by the primary site of the tumor. Recently, new classification based on tumor location, size, and mitotic rate has been used to evaluate the risk of recurrence and metastasis.110B
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GISTs are usually positive for the protooncogene, c-kit, a characteristic shared with the ICC. Imatinib (Gleevec), a chemotherapeutic agent that blocks the activity of the tyrosine kinase product of c-kit, yields excellent results in many patients with metastatic or unresectable GIST. Up to 50% of treated patients develop resistance to imatinib by 2 years, and several newer agents show promise for patients with refractory disease. The efficacy of imatinib as adjuvant therapy for high risk patients has been demonstrated in large clinical trials.110C,110D According to the NCCN guidelines for soft tissue sarcoma (version 2, 2012), the administration of imatinib was recommended in high risk groups as an adjuvant therapy.110E An algorithm for the treatment of patients with GIST is shown in Fig. 26-59.
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Gastric Carcinoid Tumors
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Compared to midgut and hindgut locations, carcinoid tumors of the stomach are rather unusual.111,112,113 Gastric carcinoids comprise about 1% of all carcinoid tumors and less than 2% of gastric neoplasms. They arise from gastric enterochromaffin-like (ECL) cells and some have malignant potential. The apparent incidence of gastric carcinoids is increasing, perhaps related to the more common use of upper endoscopy and/or the increasing use of acid suppressive medication. The latter may cause hypergastrinemia, and gastrin has a recognized trophic effect on gastric ECL cells. Gastric carcinoid is equivalent to neuroendocrine tumor (NET) or well-differentiated neuroendocrine tumor/carcinoma according to WHO classification.
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Gastric carcinoids are classified into one of three different types. Type I is the most common type of gastric carcinoid, accounting for about 75% of patients. Type I carcinoids occur in patients with chronic hypergastrinemia secondary to pernicious anemia or chronic atrophic gastritis. These lesions occur more frequently in women, are often multiple and small, and have low malignant potential (<5% metastasize). The role of long-term acid suppression with resultant hypergastrinemia in the pathogenesis of type I gastric carcinoids is unclear.
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Type II gastric carcinoids are associated with MEN1 and ZES. These lesions also tend to be small and multiple, but have a somewhat higher malignant potential than type I lesions (10% metastasize). Type II gastric carcinoids are more strongly associated with MEN1; they are quite uncommon in patients with sporadic ZES without MEN1. Gastric acid hypersecretion, hypergastrinemia, and gastric carcinoid imply gastrinoma until proven otherwise.
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Type III gastric carcinoids are sporadic tumors. They are most often solitary (usually >2 cm) and occur more commonly in men. They are not associated with hypergastrinemia and biopsy shows a heterogeneous cell population. Most patients have nodal or distant metastases at the time of diagnosis, and some present with symptoms of carcinoid syndrome.
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Gastric carcinoids are usually diagnosed with endoscopy and biopsy. Some tumors are submucosal and may be quite small. They are often confused with heterotopic pancreas or small leiomyomas. Biopsy may be difficult because of the submucosal location, and EUS can be helpful in defining the size and depth of the lesion. Plasma chromogranin A levels are elevated in patients with gastric carcinoid. CT scan and octreotide scan are useful for staging.
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Gastric carcinoids should be resected. Small lesions confined to the mucosa (typically type I or type II lesions) may be treated endoscopically with EMR if there are only a few lesions (<5) and if margins are histologically negative. Careful follow-up is necessary. Larger lesions should be removed by D1 or D2 gastrectomy. Survival is excellent for node-negative patients (>90% 5-year survival); node-positive patients have a 50% 5-year survival. Gastrinoma should be resected if located in patients with type II carcinoid. The 5-year survival for patients with type I gastric carcinoid is close to 100%; for patients with type III lesions, the 5-year survival is less than 50%. Somatostatin analogue treatment is useful in controlling the symptoms of carcinoid syndrome but apparently does not prolong survival in patients with metastatic gastric carcinoid. Surgical debulking may have a role in selected patients with metastatic disease. Because somatostatin has an antiproliferative effect on gastric ECL cells, there may be a possible primary treatment role for octreotide in poor-risk surgical patients with gastric carcinoid.