Incidence and Epidemiology
For unclear reasons, the incidence and mortality rates for gastric cancer have decreased in the United States during the past 80 years, although the disease remains the second most frequent cause of worldwide cancer-related death. The mortality rate from gastric cancer in the United States has dropped in men from 28 to 5.8 per 100,000 persons, whereas in women, the rate has decreased from 27 to 2.8 per 100,000. Nonetheless, in 2014, 22,220 new cases of stomach cancer were diagnosed in the United States, and 10,990 Americans died of the disease. Although the incidence of gastric cancer has decreased worldwide, it remains high in such disparate geographic regions as Japan, China, Chile, and Ireland.
The risk of gastric cancer is greater among lower socioeconomic classes. Migrants from high- to low-incidence nations maintain their susceptibility to gastric cancer, whereas the risk for their offspring approximates that of the new homeland. These findings suggest that an environmental exposure, probably beginning early in life, is related to the development of gastric cancer, with dietary carcinogens considered the most likely factor(s).
About 85% of stomach cancers are adenocarcinomas, with 15% due to lymphomas, gastrointestinal stromal tumors (GISTs), and leiomyosarcomas. Gastric adenocarcinomas may be subdivided into two categories: a diffuse type, in which cell cohesion is absent, so that individual cells infiltrate and thicken the stomach wall without forming a discrete mass; and an intestinal type, characterized by cohesive neoplastic cells that form glandlike tubular structures. The diffuse carcinomas occur more often in younger patients, develop throughout the stomach (including the cardia), result in a loss of distensibility of the gastric wall (so-called linitis plastica, or “leather bottle” appearance), and carry a poorer prognosis. Diffuse cancers have defective intercellular adhesion, mainly as a consequence of loss of expression of E-cadherin. Intestinal-type lesions are frequently ulcerative, more commonly appear in the antrum and lesser curvature of the stomach, and are often preceded by a prolonged precancerous process, often initiated by H. pylori infection. Although the incidence of diffuse carcinomas is similar in most populations, the intestinal type tends to predominate in the high-risk geographic regions and is less likely to be found in areas where the frequency of gastric cancer is declining. Thus, different etiologic factor(s) are likely involved in these two subtypes. In the United States, ~30% of gastric cancers originate in the distal stomach, ~20% arise in the midportion of the stomach, and ~40% originate in the proximal third of the stomach. The remaining 10% involve the entire stomach.
The long-term ingestion of high concentrations of nitrates found in dried, smoked, and salted foods appears to be associated with a higher risk. The nitrates are thought to be converted to carcinogenic nitrites by bacteria (Table 39-3). Such bacteria may be introduced exogenously through the ingestion of partially decayed foods, which are consumed in abundance worldwide by the lower socioeconomic classes. Bacteria such as H. pylori may also contribute to this effect by causing chronic inflammatory atrophic gastritis, loss of gastric acidity, and bacterial growth in the stomach. Although the risk for developing gastric cancer is thought to be sixfold higher in people infected with H. pylori, it remains uncertain whether eradicating the bacteria after infection has already occurred actually reduces this risk. Loss of acidity may occur when acid-producing cells of the gastric antrum have been removed surgically to control benign peptic ulcer disease or when achlorhydria, atrophic gastritis, and even pernicious anemia develop in the elderly. Serial endoscopic examinations of the stomach in patients with atrophic gastritis have documented replacement of the usual gastric mucosa by intestinal-type cells. This process of intestinal metaplasia may lead to cellular atypia and eventual neoplasia. Because the declining incidence of gastric cancer in the United States primarily reflects a decline in distal, ulcerating, intestinal-type lesions, it is conceivable that better food preservation and the availability of refrigeration for all socioeconomic classes have decreased the dietary ingestion of exogenous bacteria. H. pylori has not been associated with the diffuse, more proximal form of gastric carcinoma or with cancers arising at the gastroesophageal junction or in the distal esophagus. Approximately 10–15% of adenocarcinomas appearing in the proximal stomach, the gastroesophageal junction, and the distal esophagus overexpress the HER2/neu gene; individuals whose tumors demonstrate this overexpression benefit from treatment directed against this target (i.e., trastuzumab [Herceptin]).
TABLE 39-3Nitrate-Converting Bacteria as a Factor in the Causation of Gastric Carcinomaa ||Download (.pdf) TABLE 39-3 Nitrate-Converting Bacteria as a Factor in the Causation of Gastric Carcinomaa
|Exogenous sources of nitrate-converting bacteria: |
| Bacterially contaminated food (common in lower socioeconomic classes, who have a higher incidence of the disease; diminished by improved food preservation and refrigeration) |
| Helicobacter pylori infection |
|Endogenous factors favoring growth of nitrate-converting bacteria in the stomach: |
| Decreased gastric acidity |
| Prior gastric surgery (antrectomy) (15- to 20-year latency period) |
| Atrophic gastritis and/or pernicious anemia |
| ? Prolonged exposure to histamine H2-receptor antagonists |
Several additional etiologic factors have been associated with gastric carcinoma. Gastric ulcers and adenomatous polyps have occasionally been linked, but data on a cause-and-effect relationship are unconvincing. The inadequate clinical distinction between benign gastric ulcers and small ulcerating carcinomas may, in part, account for this presumed association. The presence of extreme hypertrophy of gastric rugal folds (i.e., Ménétrier’s disease), giving the impression of polypoid lesions, has been associated with a striking frequency of malignant transformation; such hypertrophy, however, does not represent the presence of true adenomatous polyps. Individuals with blood group A have a higher incidence of gastric cancer than persons with blood group O; this observation may be related to differences in the mucous secretion, leading to altered mucosal protection from carcinogens. A germline mutation in the E-cadherin gene (CDH1), inherited in an autosomal dominant pattern and coding for a cell adhesion protein, has been linked to a high incidence of occult diffuse-type gastric cancers in young asymptomatic carriers. Duodenal ulcers are not associated with gastric cancer.
Gastric cancers, when superficial and surgically curable, usually produce no symptoms. As the tumor becomes more extensive, patients may complain of an insidious upper abdominal discomfort varying in intensity from a vague, postprandial fullness to a severe, steady pain. Anorexia, often with slight nausea, is very common but is not the usual presenting complaint. Weight loss may eventually be observed, and nausea and vomiting are particularly prominent in patients whose tumors involve the pylorus; dysphagia and early satiety may be the major symptoms caused by diffuse lesions originating in the cardia. There may be no early physical signs. A palpable abdominal mass indicates long-standing growth and predicts regional extension.
Gastric carcinomas spread by direct extension through the gastric wall to the perigastric tissues, occasionally adhering to adjacent organs such as the pancreas, colon, or liver. The disease also spreads via lymphatics or by seeding of peritoneal surfaces. Metastases to intraabdominal and supraclavicular lymph nodes occur frequently, as do metastatic nodules to the ovary (Krukenberg’s tumor), periumbilical region (“Sister Mary Joseph node”), or peritoneal cul-de-sac (Blumer’s shelf palpable on rectal or vaginal examination); malignant ascites may also develop. The liver is the most common site for hematogenous spread of tumor.
The presence of iron-deficiency anemia in men and of occult blood in the stool in both sexes mandates a search for an occult gastrointestinal tract lesion. A careful assessment is of particular importance in patients with atrophic gastritis or pernicious anemia. Unusual clinical features associated with gastric adenocarcinomas include migratory thrombophlebitis, microangiopathic hemolytic anemia, diffuse seborrheic keratoses (so-called Leser-Trélat sign), and acanthosis nigricans.
The use of double-contrast radiographic examinations has been supplanted by esophagogastroscopy and CT scanning for the evaluation of patients with epigastric complaints.
Gastric ulcers identified at the time of such endoscopic procedure may appear benign but merit biopsy in order to exclude a malignancy. Malignant gastric ulcers must be recognized before they penetrate into surrounding tissues, because the rate of cure of early lesions limited to the mucosa or submucosa is >80%. Because gastric carcinomas are difficult to distinguish clinically or endoscopically from gastric lymphomas, endoscopic biopsies should be made as deeply as possible, due to the submucosal location of lymphoid tumors.
The staging system for gastric carcinoma is shown in Table 39-4.
TABLE 39-4Staging System for Gastric Carcinoma ||Download (.pdf) TABLE 39-4 Staging System for Gastric Carcinoma
|Stage ||TNM ||Features ||Data from ACS in the United States |
|No. of Cases, % ||5-Year Survival, % |
|0 ||TisN0M0 ||Node negative; limited to mucosa ||1 ||90 |
|IA ||T1N0M0 ||Node negative; invasion of lamina propria or submucosa ||7 ||59 |
|IB || |
|Node negative; invasion of muscularis propria ||10 ||44 |
|II || |
|Node positive; invasion beyond mucosa but within wall or ||17 ||29 |
| ||T3N0M0 ||Node negative; extension through wall || || |
|IIIA || |
|Node positive; invasion of muscularis propria or through wall ||21 ||15 |
|IIIB ||T4N0-1M0 ||Node negative; adherence to surrounding tissue ||14 ||9 |
|IIIC ||T4N2-3M0 ||>3 nodes positive; invasion of serosa or adjacent structures || || |
| ||T3N3M0 ||7 or more positive nodes; penetrates wall without invading serosa or adjacent structures || || |
|IV ||T4N2M0 ||Node positive; adherence to surrounding tissue ||30 ||3 |
| || ||or || || |
| ||T1-4N0-2-M1 ||Distant metastases || |
Complete surgical removal of the tumor with resection of adjacent lymph nodes offers the only chance for cure. However, this is possible in less than a third of patients. A subtotal gastrectomy is the treatment of choice for patients with distal carcinomas, whereas total or near-total gastrectomies are required for more proximal tumors. The inclusion of extended lymph node dissection in these procedures appears to confer an added risk for complications without providing a meaningful enhancement in survival. The prognosis following complete surgical resection depends on the degree of tumor penetration into the stomach wall and is adversely influenced by regional lymph node involvement and vascular invasion, characteristics found in the vast majority of American patients. As a result, the probability of survival after 5 years for the 25–30% of patients able to undergo complete resection is ~20% for distal tumors and <10% for proximal tumors, with recurrences continuing for at least 8 years after surgery. In the absence of ascites or extensive hepatic or peritoneal metastases, even patients whose disease is believed to be incurable by surgery should be offered resection of the primary lesion. Reduction of tumor bulk is the best form of palliation and may enhance the probability of benefit from subsequent therapy. In high-incidence regions such as Japan and Korea, where the use of endoscopic screening programs has identified patients with superficial tumors, the use of laparoscopic gastrectomy has gained popularity. In the United States and western Europe, the use of this less invasive surgical approach remains investigational.
Gastric adenocarcinoma is a relatively radioresistant tumor, and the adequate control of the primary tumor requires doses of external-beam irradiation that exceed the tolerance of surrounding structures, such as bowel mucosa and spinal cord. As a result, the major role of radiation therapy in patients has been palliation of pain. Radiation therapy alone after a complete resection does not prolong survival. In the setting of surgically unresectable disease limited to the epigastrium, patients treated with 3500–4000 cGy did not live longer than similar patients not receiving radiotherapy; however, survival was prolonged slightly when 5-fluorouracil (5-FU) plus leucovorin was given in combination with radiation therapy (3-year survival 50% vs 41% for radiation therapy alone). In this clinical setting, the 5-FU likely functions as a radiosensitizer.
The administration of combinations of cytotoxic drugs to patients with advanced gastric carcinoma has been associated with partial responses in 30–50% of cases; responders appear to benefit from treatment. Such drug combinations have generally included cisplatin combined with epirubicin or docetaxel and infusional 5-FU or capecitabine, or with irinotecan. Despite the encouraging response rates, complete remissions are uncommon, the partial responses are transient, and the overall impact of multidrug therapy on survival has been limited; the median survival time for patients treated in this manner remains less than 12 months. As with adenocarcinomas arising in the esophagus, the addition of bevacizumab (Avastin) to chemotherapy regimens in treating gastric cancer appears to provide limited benefit. However, preliminary results utilizing another antiangiogenic compound—ramucirumab (Cyranza)—in the treatment of gastric cancer are encouraging. The use of adjuvant chemotherapy alone following the complete resection of a gastric cancer has only minimally improved survival. However, combination chemotherapy administered before and after surgery (perioperative treatment) as well as postoperative chemotherapy combined with radiation therapy reduces the recurrence rate and prolongs survival.
Primary lymphoma of the stomach is relatively uncommon, accounting for <15% of gastric malignancies and ~2% of all lymphomas. The stomach is, however, the most frequent extranodal site for lymphoma, and gastric lymphoma has increased in frequency during the past 35 years. The disease is difficult to distinguish clinically from gastric adenocarcinoma; both tumors are most often detected during the sixth decade of life; present with epigastric pain, early satiety, and generalized fatigue; and are usually characterized by ulcerations with a ragged, thickened mucosal pattern demonstrated by contrast radiographs or endoscopic appearance. The diagnosis of lymphoma of the stomach may occasionally be made through cytologic brushings of the gastric mucosa but usually requires a biopsy at gastroscopy or laparotomy. Failure of gastroscopic biopsies to detect lymphoma in a given case should not be interpreted as being conclusive, because superficial biopsies may miss the deeper lymphoid infiltrate. The macroscopic pathology of gastric lymphoma may also mimic adenocarcinoma, consisting of either a bulky ulcerated lesion localized in the corpus or antrum or a diffuse process spreading throughout the entire gastric submucosa and even extending into the duodenum. Microscopically, the vast majority of gastric lymphoid tumors are lymphomas of B-cell origin. Histologically, these tumors may range from well-differentiated, superficial processes (mucosa-associated lymphoid tissue [MALT]) to high-grade, large-cell lymphomas. Like gastric adenocarcinoma, infection with H. pylori increases the risk for gastric lymphoma in general and MALT lymphomas in particular. Large-cell lymphomas of the stomach spread initially to regional lymph nodes (often to Waldeyer’s ring) and may then disseminate.
TREATMENT Primary Gastric Lymphoma
Primary gastric lymphoma is a far more treatable disease than adenocarcinoma of the stomach, a fact that underscores the need for making the correct diagnosis. Antibiotic treatment to eradicate H. pylori infection has led to regression of about 75% of gastric MALT lymphomas and should be considered before surgery, radiation therapy, or chemotherapy is undertaken in patients having such tumors. A lack of response to such antimicrobial treatment has been linked to a specific chromosomal abnormality, i.e., t(11;18). Responding patients should undergo periodic endoscopic surveillance because it remains unclear whether the neoplastic clone is eliminated or merely suppressed, although the response to antimicrobial treatment is quite durable. Subtotal gastrectomy, usually followed by combination chemotherapy, has led to 5-year survival rates of 40–60% in patients with localized high-grade lymphomas. The need for a major surgical procedure has been questioned, particularly in patients with preoperative radiographic evidence of nodal involvement, for whom chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) plus rituximab is highly effective therapy. A role for radiation therapy is not defined because most recurrences develop at distant sites.