Keith G. Chisholm
Scott D. Lind
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David Lee is a 68-year-old man who has been having progressive anorexia, postprandial fullness, and vague abdominal discomfort for the past 3 months. He has lost 20 pounds over this period. He denies dysphagia, vomiting, or bright red blood per rectum. His medical history is unremarkable with the exception of hypertension that is well controlled with an angiotensin-converting enzyme (ACE) inhibitor.
Mr. Lee’s physical examination is also unremarkable, other than mild midepigastric tenderness to deep palpation. Rectal examination reveals no masses, but his stool is guaiac positive. Laboratory values reveal a hemoglobin count of 9.2 g/dL, which indicates a mild anemia. Levels of serum electrolytes, transaminases, and alkaline phosphatase are within normal limits, and serum albumin is normal.
What is the differential diagnosis for this patient?
Considering the patient’s symptoms, both benign and neoplastic disease processes are part of the differential diagnosis. Given Mr. Lee’s age, however, malignancy is a prime concern. A cancer of the gastrointestinal (GI) tract must be high on the list, given the patient’s symptoms: anorexia, weight loss, anemia, and guaiac-positive rectal examination.
In the United States, colorectal cancer is the most common GI cancer, with an estimated 147,500 new cases diagnosed in 2003. Gastric cancer (estimated 22,400 new cases in 2003) and esophageal cancer (estimated 13,900 new cases in 2003) are the third and fifth most common GI malignancies in the United States (1). However, worldwide, gastric cancer is the second largest cause of cancer-related deaths (2). Peptic ulcer disease may present with similar symptoms of anorexia, anemia, and hemoccult-positive stools. Weight loss may also be present. In this situation, it is paramount for the clinician to eliminate the diagnosis of malignancy.
What are some of the early symptoms of gastric cancer?
Some of the initial symptoms of gastric cancer include weight loss, abdominal pain, nausea, and anorexia. These symptoms are nonspecific and are often overlooked by both the patient and the physician; as a result, the disease is often advanced when it is diagnosed. Currently, as with colorectal cancer, there are no screening recommendations for gastric cancer. Therefore, investigation is usually prompted by symptoms; however, symptoms are usually harbingers of advanced cancers. Proximal gastric cancer (i.e., cancer of the esophagogastric junction) causes dysphagia, and distal gastric cancer (i.e., prepyloric cancer) results in gastric outlet obstruction. GI hemorrhage resulting from gastric cancer is usually occult. Rarely is bleeding severe enough to result in gross hematochezia.
What is an acceptable initial diagnostic or therapeutic step for this patient?
Empiric therapy with H2 blockers or proton pump inhibitors (PPIs) for presumed peptic ulcer disease is probably inappropriate considering Mr. Lee’s age along with his symptoms. An acceptable initial diagnostic test is an upper GI (UGI) radiographic study. A UGI study is an appropriate screening test for suspected peptic ulcer disease or gastric malignancy. The accuracy of this study is increased with double contrasted technique to approximately 90% for diagnosing gastric cancer (3). However, do not allow normal results to preclude further evaluation of the patient’s symptoms.
Computed tomography (CT) scans are popular because they are relatively benign procedures and are fairly comprehensive imaging studies. For these reasons, a patient with similar symptoms may get referred to you having already undergone a CT scan, which is an inappropriate initial diagnostic test in this case. CT scans have nearly 100% sensitivity for detecting malignant or potentially malignant gastric lesions when the gastric wall thickness is 1 cm or greater. However, specificity is unacceptably low, at less than 50% (4).
An alternative initial study is an esophagogastroduodenoscopy (EGD) with a flexible fiberoptic endoscope. EGD is often combined with colonoscopy, using a separate, larger flexible fiberoptic endoscope. This double approach is sometimes useful when the symptoms are not specifically related to the upper or lower parts of the GI tract but when guaiac positive stools and anemia are thought to be caused by blood loss within the GI tract.
Endoscopy and contrast studies of the UGI tract are complementary in their diagnostic capabilities. In other words, endoscopy may provide information that was missed by UGI radiography and vice versa. If the surgeon does not perform endoscopy as part of his or her practice, UGI radiography provides a road map for any surgery that is contemplated. The advantage of endoscopy as a diagnostic test is that it permits biopsy of lesions that are visualized.
A UGI radiographic study reveals a 4-cm ulcer on the greater curve of the distal stomach.
What is the next step in the continuing evaluation of this patient?
Endoscopy is the next step for diagnostic workup for suspected gastric cancer. Unlike ulcers associated with peptic disease, ulcers located in the stomach deserve interrogation by biopsy because there is a higher incidence of malignancy with gastric ulcers. Endoscopy allows the physician to obtain a tissue sample for histologic diagnosis (i.e., to distinguish between benign and malignant ulcers) and to define the extent of the lesion. Because a single endoscopic biopsy sample does not have much diagnostic value, take multiple samples from various parts of the ulcer (e.g., the base, slope, and rim). Combine histologic analyses of these biopsy specimens with brush cytology to increase diagnostic accuracy. Occasionally, endoscopy fails to detect a gastric malignancy. In addition, false-negative results are obtained with endoscopic biopsies from patients with gastric lymphoma because this malignancy is submucosal.
Pathology results of the endoscopic biopsy and brushing specimens from Mr. Lee’s EGD reveal poorly differentiated adenocarcinoma.
What are the histologic types of gastric malignancies, and what is the relative incidence of each type?
Approximately 95% of malignant neoplasms of the stomach are adenocarcinomas. Several methods of classifying gastric cancer have been developed. In 1926, Borrmann classified gastric cancer into four types: I, polypoid; II, ulcerated; III, ulcerated and infiltrating; and IV, infiltrating. In 1965, Lauren reclassified gastric cancer into intestinal and diffuse types. The intestinal type includes polypoid and superficial spreading cancers and the diffuse type includes linitis plastica (5). This classification is not part of the formal staging of gastric cancer. Prognosis remains more dependent on depth of invasion and nodal status rather than the histologic classification.
The intestinal type is more common in populations in which gastric cancer is highly prevalent. It develops mostly in the distal one third of the stomach. Patients with intestinal type gastric cancer have a better prognosis. The diffuse type, on the other hand, is more common in populations at low risk. It arises more commonly on the proximal stomach and gastroesophageal junction. A separate, distinct entity called early gastric cancer (EGC) is defined as gastric cancer confined to the mucosa or submucosa, regardless of size, histologic type, or lymph node status.
There are other types of gastric malignancy. GI stromal tumors (GISTs); primary gastric lymphoma (the most common extranodal lymphoma); and adenosquamous, squamous, and carcinoid neoplasms occur in the stomach relatively rarely.
What is linitis plastica?
Linitis plastica literally means leather bottle. It is a morphologic variant of gastric adenocarcinoma characterized by a diffusely infiltrating tumor that incites a desmoplastic response, which results in a rigid, nondistensible stomach with no discernable intraluminal mass. Patients with linitis plastica have a dismal prognosis.
What additional tests can help determine the extent of disease and why is this important?
In addition to a chest radiograph to detect pulmonary metastasis, radiographic studies should include CT of the abdomen and pelvis. CT yields information about possible liver metastases, invasion of adjacent organs, and lymph node involvement. CT is not, however, sensitive for peritoneal carcinomatosis and it cannot reliably establish unresectability of a tumor.
Endoscopic ultrasonography (EUS) is used to assess the depth of penetration of the lesion into the gastric wall as well as localized lymph node involvement. These findings usually correlate well with the operative findings. EUS and CT findings allow more accurate preoperative staging and thus help identify patients who may benefit from neoadjuvant (preoperative) therapy.
What is the anatomic distribution of adenocarcinoma of the stomach and its pattern of spread?
Approximately half of all gastric cancers arise in the gastric antrum, and about one-fourth arise in the body of the stomach. Recently, there has been an increase in cancer of the proximal stomach and gastroesophageal junction, particularly in young white men. The incidence of distal cancers has decreased (2). A thorough understanding of the patterns of spread of the disease is necessary to plan rational therapy. The patterns of extension of gastric carcinoma are as follows:
Direct spread within the wall of the stomach, either proximally to involve the esophagus or, less commonly, distally to involve the pylorus and duodenum
Direct extension to involve contiguous organs, such as the spleen, pancreas, colon, and left lobe of the liver
Peritoneal dissemination as a result of serosal penetration by the tumor
Lymphatic spread to involve local or distant lymph nodes
Bloodborne metastases, particularly to the liver
Virchow’s node, Irish’s node, Sister Mary Joseph’s node, Krukenberg’s tumor, and Blumer’s shelf are all eponyms that may be associated with gastric cancer. How is each defined?
Virchow’s node is a palpable left supraclavicular lymph node that is often associated with an advanced GI malignancy.
Irish’s node denotes a palpable left axillary lymph node.
Sister Mary Joseph’s node is a palpable periumbilical lymph node.
Krukenberg’s tumor is a malignant tumor of the ovary that arises from a GI malignancy because of either peritoneal or hematogenous metastases.
Blumer’s shelf is an extraluminal mass that is palpable during a rectal or pelvic examination; it is the result of peritoneal metastases from a GI malignancy to the pelvic cul-de-sac.
Is the incidence of gastric cancer increasing or decreasing worldwide?
Over the past 70 years, the incidence of gastric cancer has declined dramatically in the United States. In 1930, gastric cancer was the most frequent cancer in adults, with an incidence of 38 per 100,000 individuals. The incidence decreased to 8 per 100,000 in 1980 and leveled off in the mid-1980s (6). With approximately 25,000 new cases being reported per year and with about 15,000 deaths per year, gastric cancer remains a significant national health problem.
In addition, gastric cancer is an enormous health problem worldwide. The incidence of gastric cancer in Japan is 10 times higher than in the United States. In Japan, gastric cancer screening programs have greatly improved the detection of early lesions. In Western countries, screening is not economically justified except in high-risk patients.
What are some risk factors for gastric cancers?
Gastric polyps occur in two histologic types: hyperplastic and adenomatous. Hyperplastic polyps are not considered premalignant: however, patients with adenomatous polyps of the stomach are at increased risk for gastric cancer. The incidence of malignancy in patients with adenomatous gastric polyps correlates with the size and number of polyps (7).
Chronic atrophic gastritis and intestinal metaplasia are both associated with an increased risk of gastric cancer. In fact, some physicians have proposed a pathway of disease progression from chronic atrophic gastritis (with intestinal metaplasia as a maladaptive response) to dysplasia, then to carcinoma in situ, and finally to invasive carcinoma (8).
Pernicious anemia is not precisely defined as a risk factor for gastric cancer, but the risk is established. Patients may benefit from periodic endoscopic surveillance.
Ménétrier’s disease, or giant hyperplasia of the gastric mucosal folds, is a rare protein-losing enteropathy associated with a slightly increased incidence of gastric cancer.
Gastric remnant carcinoma arises in the part of the stomach that remains after a previous gastric resection, usually done for previous benign disease. It is more common after Billroth II reconstruction than Billroth I. Despite the decreasing incidence of primary gastric cancer, the incidence of gastric remnant cancer is rising, probably due to the high frequency of gastric resections performed in the 1950s and 1960s. One proposed theory is that the high pH in the gastric remnant permits the overgrowth of bacteria that convert dietary nitrates and nitrites into carcinogenic compounds. In addition, bile reflux may also promote gastric cancer. These cancers develop many years after gastric resection; therefore, some physicians advocate endoscopic screening of patients beginning 10 to 20 years after surgery. On one hand, existing data do not justify endoscopic screening of asymptomatic patients. On the other hand, asymptomatic patients who have undergone a gastric resection merit intensive investigation, including endoscopy. Gastric remnant cancer was first described by Balfour in 1922 (9).
Gastric ulcers are rarely associated with cancer. However, in any gastric ulcer, malignancy must be ruled out. Nonhealing gastric ulcers especially should raise suspicion of malignancy because such ulcers are probably malignant from the outset.
Helicobacter pylori infection has been strongly implicated in the pathogenesis of adenocarcinoma of the stomach. Because almost all patients with gastric cancer are infected with this gram-negative bacillus, it is postulated that the presence of longstanding, untreated H. pylori modifies the exposure of other risk factors, such as deficiency in dietary antioxidants, tobacco smoking, or alcohol consumption. This leads to chronic gastritis that slowly progresses to cancer. In addition, certain strains of H. pylori may be more carcinogenic than others (e.g., cagA+) (10). Whether adequate antibiotic treatment of H. pylori reduces the risk of gastric adenocarcinoma remains to be determined. There is also an association between H. pylori and low-grade B cell lymphoma of the stomach. These lesions usually regress with eradication of H. pylori, and patients have a good prognosis (11). Although the oncogenic potential of viruses has long been known, the association between H. pylori and gastric malignancy suggests that bacteria may also play a role in cancer.
What are some of the molecular mechanisms of gastric cancer?
Our understanding of the molecular biology of gastric cancer is still in its infancy, but some important advances have been made. Several abnormalities in oncogenes, tumor suppressor genes, and growth factor expression have been identified in gastric cancer. The tumor suppressor gene p53 on the short arm of chromosome 17 plays a key role in regulating the cell cycle. Advanced gastric cancers have a higher rate of p53 tumor suppressor gene mutation than do early cancers, suggesting that p53 suppression may have prognostic significance. Overexpression of the ras protein p21 has also been found in gastric cancer. In addition, the bcl-2 protooncogene, which plays a critical role in programmed cell death (apoptosis), is associated with gastric cancer.
Abnormalities of several growth factors and growth factor receptors have also been found in gastric cancer, including fibroblast growth factor, transforming growth factor, and epidermal growth factor receptor. Overexpression of epidermal growth factor receptor is associated with aneuploidy, proliferation, and lymph node involvement in gastric cancer. H. pylori may help facilitate carcinogenesis. In a single-family cluster of gastric cancer, eradication of H. pylori eliminated DNA aneuploidy, p53 expression, and c-myc expression (12). Understanding the molecular basis of gastric cancer will lead to more effective methods of primary prevention, secondary prevention (early diagnosis), and treatment.
If Mr. Lee is of Japanese descent, is he at any greater or lesser risk for having an aggressive gastric cancer?
Although population studies demonstrate a nearly 10-fold incidence of gastric cancer in Japan (75 to 150 per 100,000) compared to the United States (8 to 15 per 100,000), migration studies have failed to show a continued increased incidence when persons move from areas of high incidence to areas of low incidence. In fact, the incidence decreases as new generations assimilate into new environments. However, stage for stage, Japanese-American patients show a better survival than other American patients (13).
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