eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Gastric Cancer

Author: Elwyn C Cabebe, MD, Postdoctoral Fellow, Department of Internal Medicine, Division of Medical Oncology, Stanford University School of Medicine
Coauthor(s): Vivek K Mehta, MD, Radiation Oncologist, Director, Center for Advanced Targeted Radiotherapies, Department of Radiation Oncology, Swedish Cancer Institute, Seattle, Washington; George Fisher, MD, PhD, Associate Professor, Department of Internal Medicine, Division of Medical Oncology, Stanford University School of Medicine
Contributor Information and Disclosures

Updated: Jul 21, 2008

Introduction

Background

Gastric cancer is the second most common cause of cancer-related death in the world. Many Asian countries, including Korea, China, Taiwan, and Japan, have very high rates of gastric cancer. Gastric cancer was the leading cause of cancer deaths in men and the third leading cause of cancer deaths in women in the early 1940s. In 2007, 21,260 new cases of gastric cancer (13,000 men; 8,260 women) will be diagnosed with stomach cancer in the United States, and 11,210 persons (6,610 men; 4,600 women) will die of the disease, making gastric cancer the 14th most common cancer in this country. The median age for gastric cancer in the United States is 70 years for males and 74 years for females. Also in the United States, Asian and Pacific Islander males and females have the highest incidence of stomach cancer, followed by black, Hispanic, white, American Indian, and Inuit populations.

Gastric cancer remains a difficult disease to cure in Western countries, primarily because most patients present with advanced disease. Even patients who present in the most favorable condition and who undergo curative surgical resection often die of recurrent disease. Two recent studies have demonstrated improved survival with adjuvant therapy; a US study using postoperative chemoradiation¹ and a European study using preoperative and postoperative chemotherapy.²

The molecular biology responsible for carcinogenesis, tumor biology, and response to therapy are active areas of investigation but are not addressed in this review. Instead, this article focuses on clinical management, which first requires a thorough understanding of gastric anatomy.

The stomach begins at the gastroesophageal junction and ends at the duodenum. The stomach has 3 parts. The uppermost part of the stomach is the cardia, and the largest and middle part is called the body. The distal portion of the stomach, the pylorus, connects to the duodenum. These anatomic zones have distinct histologic features. The cardia contains predominantly mucin-secreting cells. The fundus (ie, body) contains mucoid cells, chief cells, and parietal cells, while the pylorus is composed of mucus-producing cells and endocrine cells.

The stomach wall is made up of 5 layers. From the lumen out, the layers include the mucosa, the submucosa, the muscularis layer, the subserosal layer, and the serosal layer. The peritoneum of the greater sac covers the anterior surface of the stomach. A portion of the lesser sac drapes posteriorly over the stomach. The gastroesophageal junction has limited or no serosal covering. The right portion of the anterior gastric surface is adjacent to the left lobe of the liver and the anterior abdominal wall. The left portion of the stomach is adjacent to the spleen, the left adrenal gland, the superior portion of the left kidney, the ventral portion of the pancreas, and the transverse colon.

The site of the cancer is classified on the basis of its relationship to the long axis of the stomach. Approximately 40% of cancers develop in the lower part, 40% in the middle part, and 15% in the upper part, and 10% involve more than one part of the organ. Over the past half century or so, there has been a steady decline in gastric cancer incidence and gastric cancer deaths in men and women in the United States. Most of this decrease has occurred in the intestinal type of gastric cancer. In addition, the incidence of gastric cardia adenocarcinoma has actually gradually increased.

The decrease in gastric cancer incidence may be attributed in part to the adoption of diets high in vegetables and fruit. The widespread use of refrigeration contributes to the decline in incidence by reducing the intake of salt, which had been used as a food preservative, and decreasing the contamination of food by carcinogenic compounds arising from the decay of unrefrigerated meat products. Salt and salted foods may cause damage to the gastric mucosa with resultant inflammation associated with increase in DNA synthesis and cell proliferation.

Pathophysiology

Understanding the vascular supply of the stomach allows understanding of the routes of hematogenous spread. The vascular supply of the stomach is derived from the celiac artery. The left gastric artery, a branch of the celiac artery, supplies the upper right portion of the stomach. The common hepatic artery branches into the right gastric artery, which supplies the lower portion of the stomach, and the right gastroepiploic branch, which supplies the lower portion of the greater curvature.

Understanding the lymphatic drainage can clarify the areas at risk for nodal involvement by cancer. The lymphatic drainage of the stomach is complex. Primary lymphatic drainage is along the celiac axis. Minor drainage occurs along the splenic hilum, suprapancreatic nodal groups, porta hepatis, and gastroduodenal areas.

Frequency

United States

Gastric cancer is the seventh leading cause of cancer deaths. More than 22,000 new cases are diagnosed each year, of which 11,430 are expected to die. In 2007, 21,260 new cases of gastric cancer (13,000 men; 8,260 women) will be diagnosed with stomach cancer in the United States, and 11,210 persons (6,610 men; 4,600 women) will die of the disease.

International

Adenocarcinoma of the stomach is the second most common cancer worldwide. In 2001, stomach cancer affected 850,000 people, of which 522,000 men and 328,000 women died of stomach cancer. According to data collected by the World Health Organization, the most common forms of cancer worldwide (excluding nonmelanoma skin cancers) are lung (12.3%), breast (10.4%), and colorectum (9.4%), while the top 3 causes of death from cancer are lung (17.8%), gastric (10.4%), and liver (8.8%). Tremendous geographic variation exists in the incidence of this disease around the world. The highest death rates are recorded in Chile, Japan, South America, and the former Soviet Union.

Mortality/Morbidity

The 5-year survival rate for curative surgical resection ranges from 30-50% for patients with stage II disease and from 10-25% for patients with stage III disease. Because these patients have a high likelihood of local and systemic relapse, some physicians offer them adjuvant therapy. The operative mortality rate for patients undergoing curative surgical resection at major academic centers is less than 3%.

Race

The rates of gastric cancer are higher in Asian and South American countries than in the United States. Japan, Chile, and Venezuela have developed a very rigorous early screening program that detects patients with early stage disease (ie, low tumor burden). These patients appear to do quite well. In fact, in many Asian studies, patients with resected stage II and III disease tend to have better outcomes than similarly staged patients treated in Western countries. Some researchers suggest that this reflects a fundamental biologic difference in the disease as it manifests in Western countries.

In the United States, Asian and Pacific Islander males and females have the highest incidence of stomach cancer, followed by black, Hispanic, white, American Indian, and Inuit populations.

Sex

Gastric cancer affects slightly more men than women.

Age

Most patients are elderly at diagnosis. The median age for gastric cancer in the United States is 70 years for males and 74 years for females. The gastric cancers that occur in younger patients may represent a more aggressive variant.

Clinical

History

• In the United States, about 25% of stomach cancer cases present with localized disease, 31% present with regional disease, and 32% present with distant metastatic disease; the remainder of cases surveyed were listed as unstaged.
• Early disease has no associated symptoms; however, some patients with incidental complaints are diagnosed with early gastric cancer. Most symptoms of gastric cancer reflect advanced disease. Patients may complain of indigestion, nausea or vomiting, dysphagia (see related CME at Diagnostic Evaluation of Dysphagia), postprandial fullness, loss of appetite, melena, hematemesis, and weight loss.
• Late complications include pathologic peritoneal and pleural effusions; obstruction of the gastric outlet, gastroesophageal junction, or small bowel; bleeding in the stomach from esophageal varices or at the anastomosis after surgery; intrahepatic jaundice caused by hepatomegaly; extrahepatic jaundice; and inanition resulting from starvation or cachexia of tumor origin.

Physical

• All physical signs are late events, and almost invariably the signs develop too late for curative procedures.
• Signs may include a palpable enlarged stomach with succussion splash; hepatomegaly; periumbilical metastasis (Sister Mary Joseph nodule); and enlarged lymph nodes such as the following: Virchow nodes (ie, left supraclavicular) and Irish node (anterior axillary). Blumer shelf (ie, shelflike tumor of the anterior rectal wall) may also be present. Some patients experience weight loss and others may present with melena or pallor from anemia.
• Paraneoplastic syndromes such as dermatomyositis, acanthosis nigricans, and circinate erythemas are poor prognostic features.
• Other associated abnormalities also include peripheral thrombophlebitis and microangiopathic hemolytic anemia.

Causes

Several factors are implicated in the development of gastric cancer, including diet, Helicobacter pylori infection, previous gastric surgery, pernicious anemia, adenomatous polyps, chronic atrophic gastritis, prior radiation exposure or inherited syndromes. Gastric cancer may often be multifactorial involving both inherited predisposition and environmental factors.³

• Diet
  • A diet rich in pickled vegetables, salted fish, excessive dietary salt, and smoked meats correlates with an increased incidence of gastric cancer.³
  • A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.⁴
• Smoking
  • Smoking is associated with an increased incidence of stomach cancer in a dose-dependent manner, both for number of cigarettes and duration of smoking.
  • Smoking increases the risk of cardiac and noncardiac forms of stomach cancer. Cessation of smoking reduces the risk.
  • A meta-analysis of 40 studies estimated that the risk was increased by approximately 1.5- to 1.6-fold and was higher in men.⁵
• Helicobacter pylori infection
  • Chronic bacterial infection with H pylori is the strongest risk factor for stomach cancer.
  • H pylori may infect 50% of the world's population, but much less than 5% of infected individuals develop cancer. It may be that only a particular strain of H pylori, one of which is capable of producing the greatest amount of inflammation, is especially associated with the risk of malignancy. The full malignant transformation of affected parts of the stomach may require that the human host have a particular genotype of interleukin-Iβ to cause the increased inflammation and an increased suppression of gastric acid secretion.
  • H pylori infection is associated with chronic atrophic gastritis, and patients with a history of prolonged gastritis have a 6-fold increase in their risk of developing gastric cancer. Interestingly, this association is particularly strong for tumors located in the antrum, body, and fundus of the stomach but does not seem to hold for tumors originating in the cardia.⁶
• Previous gastric surgery
  • Previous surgery is implicated as a risk factor. The rationale is that surgery alters the normal pH of the stomach, which may in turn lead to metaplastic and dysplastic changes in luminal cells.⁷
  • Retrospective studies demonstrate that a small percentage of patients who undergo gastric polyp removal have evidence of invasive carcinoma within the polyp. This discovery has led some researchers to conclude that polyps might represent premalignant conditions.
• Genetic factors
  • Some 10% of stomach cancer cases are familial in origin.
  • Genetic factors involved in gastric cancer remain poorly understood, though specific mutations have been identified in a subset of gastric cancer patients. For example, germ-line truncating mutations of the E-cadherin gene are detected in 50% of diffuse-type gastric cancers and families that harbor these mutations have an autosomal dominant pattern of inheritance with a very high penetrance.⁸
  • Other hereditary syndromes with a predisposition for stomach cancer include hereditary nonpolyposis colorectal cancer, Li-Fraumeni syndrome, familial adenomatous polyposis, and Peutz-Jeghers syndrome. 
  • Ebstein-Barr virus: The Epstein-Barr virus may be associated with an unusual form of stomach cancer (<1%), lymphoepitheliomalike carcinoma.
  • Pernicious anemia: Pernicious anemia associated with advanced atrophic gastritis and intrinsic factor deficiency is a risk factor for gastric carcinoma.
• Gastric ulcers
  • Gastric cancer may develop in the remaining portion of the stomach following a partial gastrectomy for gastric ulcer.
  • Benign gastric ulcers may themselves develop into malignancy.
• Obesity: Obesity increases the risk of gastric cardiac cancer.
• Radiation exposure: Atomic bomb survivors exposed to radiation have had an increased risk of stomach cancer. Other populations exposed to radiation may also have an increased risk of stomach cancer.

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