Gastric Cancer

Synonyms and related keywords: adenocarcinoma of the stomach, gastric adenocarcinoma, gastric carcinoma, stomach cancer, Helicobacter pylori infection, H pylori infection, pernicious anemia, adenomatous polyps, chronic atrophic gastritis



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. More than 22,000 new cases will be diagnosed this year in the United States, making gastric cancer the fourteenth most common cancer in this country.

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. A recent randomized study demonstrates a survival benefit with postoperative chemoradiotherapy.

Tumor biology and carcinogenesis are active areas of research investigation. The management of gastric cancer 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 last part of the stomach, the pylorus, connects to the duodenum. These semidistinct 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. The pyloric part 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, a muscular layer, a subserosal layer, and serosal layers. 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 lesion 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. Recently, the number of lesions discovered in the proximal aspect of the stomach and approaching or involving the gastroesophageal junction has increased. An increase in the diffuse type of gastric cancer also has been observed recently.

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:

• In the US: Gastric cancer is the seventh leading cause of cancer deaths. More than 22,000 new cases are diagnosed each year, and more than 14,000 deaths occur each year.

• Internationally: Adenocarcinoma of the stomach is the second most common cancer worldwide. Tremendous geographic variation exists in the incidence of this disease around the world. The highest death rates are recorded in Chile, Japan, 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 countries than in the United States. Japan 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 between the disease as it manifests in Asia and in Western countries.

Sex: Gastric cancer afflicts slightly more men than women.

Age: Most patients are elderly at diagnosis. The median age at diagnosis is 65 years (range 40-70 y). The gastric cancers that occur in younger patients may represent a more aggressive variant.

CLINICAL

History:

• 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, postprandial fullness, loss of appetite, 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; primary mass (rare); and enlarged liver, Virchow nodes (ie, left supraclavicular), Sister Mary Joseph node, and Blumer shelf. Some patients have signs of weight loss. Other patients may have pallor from bleeding and 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, genetic factors, and previous radiation therapy. Gastric cancer most likely represents the result of multiple events occurring in an appropriate environment.

• Diet

• Certain diets are implicated in the pathogenesis of this disease process.

• A diet rich in pickled vegetables, salted fish, excessive dietary salt, and smoked meats correlates with an increased incidence of gastric cancer.

• A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.

• Helicobacter pylori infection

• Infection with this organism is implicated as a precursor of gastric cancer.

• 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.

• Previous gastric surgery

• Previous surgery is implicated as a risk factor. The rationale is that surgery alters the normal pH of the stomach.

• 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

• Genetic factors involved in gastric cancer remain poorly understood.

• Certainly some familial aggregation exists.

DIFFERENTIALS
Esophageal Cancer
Esophageal Stricture
Esophagitis
Gastric Ulcers
Gastritis, Acute
Gastritis, Atrophic
Gastritis, Chronic
Gastroenteritis, Bacterial
Gastroenteritis, Viral
Lymphoma, Non-Hodgkin
Malignant Neoplasms of the Small Intestine


WORKUP

Lab Studies:

• The goal of obtaining laboratory studies is to assist in determining optimal therapy.

• A complete blood cell count can identify anemia, which may be caused by bleeding, liver dysfunction, or poor nutrition. Approximately 30% of patients have anemia.

• Electrolyte panels and liver function tests also are essential to better characterize the patient's clinical state.

Imaging Studies:

• Esophagogastroduodenoscopy

• This relatively safe and simple procedure provides a permanent color photographic record of the lesion.

• This procedure also is the primary method for obtaining a tissue diagnosis of suspected lesions.

• Double-contrast upper GI series

• An upper gastrointestinal barium swallow detects large primary tumors but only occasionally detects their spread to the esophagus and duodenum (particularly if the tumor is small and submucosal).

• The smaller the primary lesion, the more important is the use of double-contrast and cineradiography.

• Chest radiograph: This is done to evaluate for metastatic lesions.

• CT scan or MRI of the chest, abdomen, and pelvis

• These imaging studies assess the local disease process as well as evaluate potential areas of spread (ie, enlarged lymph nodes, possible liver metastases).

• Some patients' tumors are judged surgically unresectable on the basis of radiographic criteria.

• Endoscopic ultrasound

• This study allows for a more precise preoperative assessment of the tumor stage.

• Endoscopic sonography is becoming increasingly useful as a staging tool when the CT scan fails to find evidence of T3, T4, or metastatic disease.

• Institutions that favor neoadjuvant chemoradiotherapy for patients with locally advanced disease rely on endoscopic ultrasound data to improve patient stratification.

Histologic Findings: Adenocarcinoma of the stomach constitutes between 90% and 95% of all gastric malignancies. The second most common gastric malignancies are lymphomas. Leiomyosarcomas (2%), carcinoids (1%), adenoacanthomas (1%), and squamous cell carcinomas (1%) are the remaining tumor histologic types.

• Adenocarcinoma of the stomach is classified according to microscopic criteria. Classification is based on the most unfavorable microscopic element present, which are, in order of increasing danger, tubular, papillary, mucinous, or signet-ring cells, and undifferentiated lesions.
• Pathology specimens also are classified by gross appearance. In general, researchers consider gastric cancers ulcerative, polypoid, scirrhous (ie, diffuse linitis plastica), superficial spreading, multicentric, or Barrett ectopic adenocarcinoma.
• Researchers also employ a variety of other classification schemes.
  • The Borrmann system has 5 categories: type I tumors are polypoid or fungating; type II are ulcerating lesions surrounded by elevated borders; type III have ulceration with invasion of the gastric wall; type IV are diffusely infiltrating (ie, linitis plastica); and type V cannot be classified.
  • Another classification system, the Lauren system, classifies gastric cancer pathology as either an epidemic form or an endemic form. An appealing feature of classifying patients according to the Lauren system is that the descriptive pathologic entities have clinically relevant differences. The intestinal, expansive, epidemic-type gastric cancer is associated with chronic atrophic gastritis, retained glandular structure, little invasiveness, and a sharp margin. This type also is classified as Borrmann I or II.
  • The pathologic presentation classified as epidemic by the Lauren system or Borrmann I or II is associated with most environmental risk factors, carries a better prognosis, and shows no familial history.
  • The second type, the diffuse, infiltrative, endemic cancer, consists of scattered cell clusters with poor differentiation and dangerously deceptive margins. Margins that appear clear to the operating surgeon and examining pathologist often are determined retrospectively to be involved. The endemic-type tumor invades large areas of the stomach. This type of tumor also is not recognizably influenced by environment or diet, is more virulent in women, and occurs more often in relatively young patients. This pathologic entity is associated with genetic factors, blood groups, and a family history of gastric cancer.

Staging: The 1997 American Joint Committee on Cancer (AJCC) Cancer Staging Manual presents the following TNM classification system for staging gastric carcinoma:

• Primary tumor

• TX = primary tumor (T) cannot be assessed
• T0 = no evidence of primary tumor
• Tis = carcinoma in situ, intraepithelial tumor without invasion of lamina propria
• T1 = tumor invades lamina propria or submucosa
• T2 = tumor invades muscularis propria or subserosa
• T3 = tumor penetrates serosa (ie, visceral peritoneum) without invasion of adjacent structures
• T4 = tumor invades adjacent structures

• Regional lymph nodes

• NX = regional lymph nodes (N) cannot be assessed
• N0 = no regional lymph node metastases
• N1 = metastasis in 1-6 regional lymph nodes
• N2 = metastasis in 7-15 regional lymph nodes
• N3 = metastasis in more than 15 regional lymph nodes

• Distant metastasis

• MX = distant metastasis (M) cannot be assessed
• M0 = no distant metastasis
• M1 = distant metastasis

• Prognostic features

• Two important factors influencing survival in resectable gastric cancer are depth of cancer invasion through the gastric wall and presence or absence of regional lymph node involvement.
• The greater the number of involved lymph nodes, the more likely the patient is to develop local and systemic failure after surgery.
• In a study by Shen and colleagues, the depth of tumor invasion and gross appearance, size, and location of the tumor were 4 pathological factors independently correlated with the number of metastatic lymph nodes associated with gastric cancer.

• Spread patterns

• Cancer of the stomach can spread directly, via lymphatics, or hematogenously.
• Direct extension into the omenta, pancreas, diaphragm, transverse colon or mesocolon, and duodenum is common.
• If the lesion extends beyond the gastric wall to a free peritoneal (ie, serosal) surface, then peritoneal involvement is frequent.
• The visible gross lesion frequently underestimates the true extent of the disease.
• The abundant lymphatic channels within the submucosal and subserosal layers of the gastric wall allow for easy microscopic spread.
• The submucosal plexus is prominent in the esophagus and the subserosal plexus is prominent in the duodenum, allowing proximal and distal spread.
• Lymphatic drainage is through numerous pathways and can involve multiple nodal groups (eg, gastric, gastroepiploic, celiac, porta hepatic, splenic, suprapancreatic, pancreaticoduodenal, paraesophageal, and paraaortic lymph nodes).
• The cancer also spreads hematogenously, and liver metastases are common.

TREATMENT

Surgical Care:

• Type of surgery

• In general, most surgeons in the United States perform a total gastrectomy (if required for negative margins), an esophagogastrectomy for tumors of the cardia and gastroesophageal junction, and a subtotal gastrectomy for tumors of the distal stomach.
• A randomized trial comparing subtotal with total gastrectomy for distal gastric cancer revealed similar morbidity, mortality, and 5-year survival rates.
• Because of the extensive lymphatic network around the stomach and the propensity for this tumor to extend microscopically, traditional teaching is to attempt to maintain a 5-cm surgical margin proximally and distally to the primary lesion.

• Lymph node dissection

• The extent of the lymph node dissection is somewhat controversial.

• Many studies demonstrate that nodal involvement indicates a poor prognosis, and more aggressive surgical approaches to attempt to remove involved lymph nodes are gaining popularity.

• Two large ongoing trials in Europe are investigating the efficacy of this new aggressive approach.

• In a recently completed trial, patients were randomized to an R1 or a R2 nodal dissection. The endpoints of local regional recurrence and overall survival were similar.

• Critics of extended nodal dissections argue that the apparent benefit associated with extended lymph node dissection reflects stage migration (ie, more lymph nodes are dissected, and each pathologic specimen is reviewed more carefully).

• Outcome

• The 5-year survival rate for a 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 recent Intergroup 0116 randomized study offers evidence of a survival benefit associated with postoperative chemoradiotherapy.

Consultations: Specialists recommend obtaining consultations freely in the management of most malignancies, and gastric carcinoma is no exception. The gastroenterologist, surgical oncologist, radiation oncologist, and medical oncologist work closely as a team.

FOLLOW-UP

Deterrence/Prevention:

• A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.

Complications:

• Direct mortality rate within 30 days after a surgical procedure for gastric cancer has been reduced substantially over the last 40 years. Most major centers report a direct mortality rate of 1-2%.

• Early postoperative complications include anastomotic failure, bleeding, ileus, transit failure at the anastomosis, cholecystitis (often occult sepsis without localizing signs), pancreatitis, pulmonary infections, and thromboembolism. Further surgery may be required for anastomotic leaks.

• Late mechanicophysiologic complications include dumping syndrome, vitamin B-12 deficiency, reflux esophagitis, and bone disorders, especially osteoporosis.

• Postgastrectomy patients often are immunologically deficient as measured by blastogenic and delayed cutaneous hypersensitivity responses.

Prognosis:

• Unfortunately, most patients with gastric cancer who undergo a surgical resection will experience a tumor recurrence and die.

• Patterns of failure

• Several studies have investigated the patterns of failure after surgical resection alone. Studies that depend solely on the physical examination, laboratory studies, and imaging studies may overestimate the percentage of patients with distant failure and underestimate the incidence of local failure, which is more difficult to detect.

• A reoperation series from the University of Minnesota may offer a more accurate understanding of the biology of the disease. In this series of patients, researchers surgically reexplored patients 6 months after the initial surgery and meticulously recorded the patterns of disease spread. The total local-regional failure rate approached 67%. The gastric bed was the site of failure in 54% of these cases, and the regional lymph nodes were the site of failure in 42%. Approximately 22% of patients had evidence of distant failure. The patterns of failure included local tumor regrowth, tumor bed recurrences, regional lymph node failures, and distant failures (ie, hematogenous failures and peritoneal spread). Primary tumors involving the gastroesophageal junction tended to fail in the liver and the lungs. Lesions involving the esophagus failed in the liver.

• Adjuvant therapy

• The pattern of failure prompted a number of investigations into adjuvant therapy. The rationale behind radiotherapy is to provide additional local-regional tumor control. Adjuvant chemotherapy is used either as a radiosensitizer or as definitive treatment for presumed systemic metastases.

• Results of INT-0116
  • In this study, patients underwent an en bloc resection.
  • Patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive bolus 5-fluorouracil (5-FU) and leucovorin (LV) and radiotherapy or observation.
  • Patients who received the adjuvant chemoradiotherapy demonstrated improved disease free-survival and improved overall survival rates.
• Adjuvant radiotherapy
  • Moertel and colleagues randomized postoperative patients with advanced gastric cancer to receive 40 Gy of radiotherapy or 40 Gy of radiotherapy with 5-FU as a radiosensitizer, and demonstrated improved survival associated with the combined modality therapy.
  • The British Stomach Cancer Group reported lower rates of local recurrence in patients who received postoperative radiotherapy than in those who underwent surgery alone.
  • The update of the initial Gastrointestinal Tumor Study Group series revealed higher 4-year survival rates in patients with unresectable gastric cancer who received combined modality therapy than in those who received chemotherapy alone (18% vs 6%).
  • A series from the Mayo Clinic randomized patients to receive postoperative radiotherapy with 5-FU or surgery alone and demonstrated improved survival in the patients receiving adjuvant therapy (23% vs 4%).

• Intraoperative radiotherapy
  • Some authors suggest that intraoperative radiotherapy (IORT) shows promising results.
  • This alternative method of delivering radiotherapy allows for a high dose to be given in a single fraction while in the operating room so that other critical structures can be avoided.
  • The National Cancer Institute randomized patients with grossly resected stage III/IV gastric cancer to receive either 20 Gy of IORT or 50 Gy of postoperative external beam. Local failure was delayed in the patients treated with IORT (21 mo vs 8 mo). Although the median survival duration also was higher (21 mo vs 10 mo), this figure did not reach statistical significance.
• Chemotherapy
  • Numerous randomized clinical trials comparing combination chemotherapy in the adjuvant setting to surgery alone did not demonstrate a consistent survival benefit.
  • The most widely studied regimen is 5-FU, doxorubicin, and mitomycin-C. The addition of methyl-CCNUR, leucovorin, or triazinade did not increase response rates.

• Advanced unresectable disease

• Many patients present with distant metastases, carcinomatosis, unresectable hepatic metastases, pulmonary metastases, or direct infiltration into organs that cannot be resected completely.
• In the palliative setting, radiotherapy provides relief from bleeding, obstruction, and pain in 50-75% of patients. The median duration of palliation is 4-18 months.
• Surgical procedures such as wide local excision, partial gastrectomy, total gastrectomy, simple laparotomy, gastrointestinal anastomosis, and bypass also are performed with palliative intent, with a goal of allowing oral intake of food and alleviating pain.

Patient Education:

• For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education article, Stomach Cancer.