NEOPLASMS OF THE STOMACH
Gastric neoplasms are predominantly malignant, and nearly 90 to 95% of these tumours are adenocarcinomas. Less frequently observed malignant diseases include lymphomas, especially non-Hodgkin’s lymphoma, and sarcomas such as leiomyosarcoma. Benign gastric neoplasms include leiomyomas, carcinoid tumours, and lipomas.
The great geographic variation in the incidence of gastric cancer worldwide indicates that environmental factors influence the pathogenesis of gastric carcinogenesis. Further support for this notion comes from observations that groups emigrating from high-risk to low-risk areas, such as Japanese individuals moving to Hawaii and Brazil, acquire the low risk of the area into which they emigrate, presumably because of adoption of the endogenous lifestyle and exposure to different environmental factors.
Gastric adenocarcinoma was the most frequently observed malignant disease in the world until the mid-1980s, and it remains extremely common among men in certain regions such as tropical South America, some parts of the Caribbean, and Eastern Europe. Regardless of gender, it remains one of the most common malignancies in Japan and China.
Whereas gastric cancer was the most common cancer in the United States in the 1930s, its annual incidence has steadily decreased. The annual incidence is now fewer than 10,000 new cases per year. However, although the incidence of gastric adenocarcinoma localized to the distal stomach has declined, the incidence of proximal gastric and GE junctional adenocarcinomas has been steadily increasing in the United States, a finding that perhaps reflects differences in pathogenic factors. Typically, gastric cancer occurs between the ages of 50 and 70 years and is uncommon before age 30. The rates are higher in men than in women by 2 : 1. Five-year survival is less than 20%.
Risk factors for the development of gastric adenocarcinoma can be divided into environmental and genetic factors as well as precursor conditions. For example, Helicobacter pylori infection is significantly more common in patients with gastric cancer than in matched control groups. Epidemiologic studies of high-risk populations have also suggested that genotoxic agents such as N -nitroso compounds may play a role in gastric tumorigenesis. N -nitroso compounds can be formed in the human stomach by nitrosation of ingested nitrates, which are common constituents of the diet. High nitrate concentrations in soil and drinking water have been observed in areas with high death rates from gastric cancer. Atrophic gastritis, with or without intestinal metaplasia, is observed in association with gastric cancer, especially in endemic areas. Pernicious anaemia is associated with a several-fold increase in gastric cancer. Atrophic gastritis and gastric cancer have certain environmental risk factors in common. It is likely that atrophic gastritis and intestinal metaplasia represent intermediary steps to gastric cancer. The achlorhydria associated with gastritis related to H. pylori infection, pernicious anaemia, or other causes favours the growth of bacteria capable of converting nitrates to nitrites. The nitrosamine N-methyl-N′-nitro-N-nitrosoguanidine causes a high rate of induction of adenocarcinoma in the glandular stomach of rats. At the same time, most patients with atrophic gastritis do not develop gastric cancer, a finding suggesting that neither atrophic gastritis nor achlorhydria alone is responsible.
Conditions predisposing to or associated with gastric cancer
- Helicobacter pylori infection
- Dietary: excess of salt (salted pickled foods), nitrates/nitrites, carbohydrates; deficiency of fresh fruit, vegetables, vitamins A and C, refrigeration
- Low socioeconomic status
- Cigarette smoking
- Familial gastric cancer (rare)
- Associated with hereditary nonpolyposis colorectal cancer
- Blood group A
- Predisposing conditions
- Chronic gastritis, especially atrophic gastritis with or without intestinal metaplasia
- Pernicious anaemia
- Intestinal metaplasia
- Gastric adenomatous polyps (>2 cm)
- Postgastrectomy stumps
- Gastric epithelial dysplasia
- Ménétrier’s disease (hypertrophic gastropathy)
- Chronic peptic ulcer
Benign gastric ulcers do not appear to predispose patients to gastric cancer. However, patients who have a gastric remnant after subtotal gastrectomy for benign disorders have an increased relative risk for gastric cancer of 1.5 to 3.0 by 15 to 20 years after surgery.
Gastric adenocarcinomas can be divided into two types based on the Lauren classification: intestinal and diffuse. The intestinal type is typically in the distal stomach with ulcerations, is often preceded by premalignant lesions, and is declining in incidence in the United States. By contrast, the diffuse type involves widespread thickening of the stomach, especially in the cardia, and it often affects younger patients; this form may present as linitis plastica, a nondistensible stomach with the absence of folds and a narrowed lumen caused by infiltration of the stomach wall with tumour. Diffuse-type gastric cancers harbour mucin-producing cells. Other conditions may result in linitis plastica, such as lymphoma, tuberculosis, syphilis, and amyloidosis. The prognosis is generally worse in the diffuse type.
Key histopathologic features of gastric cancer include its degree of differentiation, invasion through the gastric wall, lymph node involvement, and the presence or absence of signet ring cells within the tumour itself. Other pathologic manifestations include a polypoid mass, which may be difficult to distinguish from a benign polyp. Early gastric cancer, a condition that is common in Japan and has a relatively favourable prognosis, consists of superficial lesions with or without lymph node involvement. Here, the Borrmann classification scheme is helpful: I, polypoid; II, fungating ulcer with sharp raised margins; III, ulcer with poorly defined infiltrative margins; and IV, infiltrative, mostly intramural lesion, not well demarcated.
The leading hypothesis explaining the way in which H. pylori predisposes to gastric cancer risk is the induction of an inflammatory response, in which IL-1β may be pivotal. Chronic H. pylori infection also leads to chronic atrophic gastritis with resulting achlorhydria, which in turn favours bacterial growth that can convert nitrates (dietary components) to nitrites. These nitrites, in combination with genetic factors, promote abnormal cellular proliferation, genetic mutations, and eventually cancer. In a mouse model of gastric cancer, H. pylori infection may play a role in the recruitment of bone marrow–derived stem cells that facilitate gastric carcinogenesis. Animal models can now recapitulate the cardinal features of gastric adenocarcinoma, either through the use of carcinogens or through genetic approaches.
It is clear that genetic factors play a role in gastric cancer. For example, blood group A is associated with a higher incidence rate of gastric cancer, even in nonendemic areas. A three-fold increase in gastric cancer has been reported among first-degree relatives of patients with the disease. Furthermore, germline or inherited mutations in the genes for E-cadherin and α-catenin, albeit rare, have been described in diffuse hereditary gastric cancer, which is seen in young patients. In addition, in Lynch syndrome, patients have associated extracolonic cancers, including gastric cancer. Patients with familial adenomatous polyposis (FAP) have an increased risk of distal (antral) gastric adenocarcinoma.
It now appears that several genetic mechanisms are important in gastric cancer: oncogene activation, tumour suppressor gene inactivation, and DNA microsatellite instability. For example, loss of heterozygosity of the APC (adenomatous polyposis coli) gene has been observed in gastric cancers. The p53 tumour suppressor gene product regulates the cell cycle at the G 1 -S phase transition and probably also functions in DNA repair and apoptosis (programmed cell death). The p53 gene is mutated not only in gastric cancer but also in gastric precancerous lesions, a finding suggesting that mutation of the p53 gene is an early event in gastric carcinogenesis. Microsatellite DNA alterations or instability in dinucleotide repeats occur frequently in sporadic gastric carcinoma. Mutations in genes may accumulate as a result of DNA microsatellite instability.
In its early stages, gastric cancer may often be asymptomatic or may produce only nonspecific symptoms that make early diagnosis difficult. Later symptoms include bloating, dysphagia, epigastric pain, or early satiety. Early satiety or vomiting may suggest partial gastric outlet obstruction, although gastric dysmotility may contribute to the vomiting in patients with nonobstructive cases. Epigastric pain reminiscent of that associated with peptic ulcer occurs in about one fourth of patients, but in most patients with gastric cancer, the pain is not relieved by food or antacids. Pain that radiates to the back may indicate that the tumour has penetrated the pancreas. When dysphagia is associated with gastric cancer, this symptom suggests a more proximal gastric tumour at the GE junction or in the fundus.
Signs of gastric cancer include bleeding, which can result in iron deficiency anaemia that produces the symptoms of weakness, fatigue, and malaise, as well as (rarely) more serious cardiovascular and cerebrovascular consequences. Perforation related to gastric cancer is unusual. Gastric cancer metastatic to the liver can lead to right upper quadrant pain, jaundice, and fever. Lung metastases can cause cough, hiccups, and haemoptysis. Peritoneal carcinomatosis can lead to malignant ascites unresponsive to diuretics. Gastric cancer can also metastasize to bone.
In the earliest stages of gastric cancer, the physical examination may be unremarkable. At later stages, patients become cachectic, and an epigastric mass may be palpated. If the tumour has metastasized to the liver, hepatomegaly with jaundice and ascites may be present. Portal or splenic vein invasion and thrombosis can cause splenomegaly. Lymph node involvement in the left supraclavicular area is termed Virchow’s node, and periumbilical nodal involvement is called Sister Mary Joseph’s node . The faecal occult blood test may be positive. Metastasis to the ovary is termed Krukenberg’s tumour.
Paraneoplastic syndromes may precede or occur concurrently with gastric cancer. Examples include the following: Trousseau syndrome, which is recurrent migratory superficial thrombophlebitis indicating a possible hypercoagulable state; acanthosis nigricans, which arises as raised and hyperpigmented skin lesions of flexor areas, neck, axilla, groin, and mucosal membranes; neuromyopathy with involvement of the sensory and motor pathways; and central nervous system syndromes with altered mental status and ataxia.
Laboratory studies may reveal iron deficiency anaemia. Microangiopathic haemolytic anaemia has been reported. Abnormalities in liver tests generally indicate metastatic disease. Hypoalbuminemia is a marker of malnutrition. Protein-losing enteropathy is rare but can be seen in Ménétrier’s disease, another predisposing condition. Serologic test results, such as those for CEA and CA72.4, may be abnormal. Although these tests are not recommended for initial diagnosis, they may be useful for monitoring disease after surgical resection.
The diagnostic accuracy of upper endoscopy with biopsy and cytologic examination approaches 95 to 99% for both types of gastric cancer. Cancer may arise as a small mucosal ulceration, a polyp, or a mass. In some patients, gastric ulceration may first be noted in an upper gastrointestinal barium contrast study. A benign gastric ulcer is associated with a smooth, regular base, whereas a malignant ulcer is associated with a surrounding mass, irregular folds, and an irregular base. Although these and other radiographic characteristics historically helped to predict benign versus malignant disease, upper gastrointestinal endoscopy with biopsy and cytologic examination is mandatory whenever a gastric ulcer is found in the radiologic study, even if the ulcer has benign characteristics.
Endoscopic ultrasonography (EUS) is very helpful in both diagnosis and staging of gastric cancer. The extent of tumour, including gastric wall invasion and local lymph node involvement, can be assessed by EUS, which provides information complementary to that obtained from CT scans. EUS can help guide aspiration biopsies of lymph nodes to determine their malignant features if any. CT of the chest, abdomen, and pelvis should be performed to document lymphadenopathy and extragastric organ (especially lung and liver) involvement. In some centres, staging of gastric cancer entails bone scans because of the proclivity of gastric cancer to metastasize to bone.
The only chance for cure of gastric cancer remains surgical resection, which is possible in 25 to 30% of cases. If the tumour is confined to the distal stomach, subtotal gastrectomy is performed, with resection of lymph nodes in the porta hepatis and the pancreatic head. By contrast, tumours of the proximal stomach merit total gastrectomy to obtain an adequate margin and to remove lymph nodes; distal pancreatectomy and splenectomy are usually also performed as part of this procedure, which carries with it higher mortality and morbidity rates. The addition of para-aorta nodal dissection does not improve survival. Even if a curative procedure is not possible because of metastasis, limited gastric resection may be necessary for patients with excessive bleeding or obstruction. If cancer recurs in the gastric remnant, limited resection may again be necessary for palliation. Most recurrences in both types of gastric cancer are in the local or regional area of the original tumour.
Gastric cancer is one of the few gastrointestinal cancers that is somewhat responsive to chemotherapy. In patients with gastric cancer who undergo gastrectomy and extended lymph node dissection with curative intent, S-1 (an oral fluoropyrimidine, 80 mg daily for 4 weeks followed by 2 weeks off, repeated in 6-week cycles for 1 year starting within 6 weeks after surgery) significantly improves 3-year survival from 70 to 80%. Chemotherapy with the combination of epirubicin, cisplatin, and fluorouracil, given both preoperatively and postoperatively, significantly improves 5-year survival from 23 to 36% in patients with resectable GE cancer. Similarly, the combination of chemotherapy (fluorouracil and leucovorin) with radiation therapy has been shown to improve median survival from 27 to 36 months compared with surgery alone in patients with adenocarcinoma of the stomach or GE junction. With a more than 10-year median follow-up, overall survival and relapse-free survival demonstrate continued strong benefit from postoperative radiochemotherapy.
Single-agent chemotherapy treatment, which provides partial response rates of 20 to 30%, is reserved for patients with a poor performance status. Combination regimens that can yield partial response rates of 35 to 50% include the following: ECF, which is most popular in Europe (epirubicin, 50 mg/m 2 on day 1; cisplatin, 60 mg/m 2 on day 1; 5-fluorouracil, 200 mg/m 2 /day as a continuous infusion through a central venous access device [CVAD] given throughout treatment, repeated every 21 days for a maximum of 8 cycles); CF (5-fluorouracil infusion, 1000 mg/m 2 /day for 4 days; cisplatin, 75 to 100 mg/m 2 on day 1, every 4 weeks); or TCF (docetaxel [Taxotere], 75 mg/m 2 on day 1; cisplatin, 75 mg/m 2on day 1; and 5-fluorouracil, 750 mg/m 2 /day for 5 days, every 3 weeks), or capecitabine plus cisplatin. A randomized trial of triple chemotherapy for advanced esophagogastric cancer showed that oral capecitabine is at least as effective as infused fluorouracil, and that oxaliplatin (which does not require hydration) is at least as effective as cisplatin (which does require hydration) with respect to overall survival. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), administered at a dose of 7.5 mg/kg by intravenous infusion every 3 weeks, was found to increase progression-free survival and overall response rate when it was given along with capecitabine-cisplatin chemotherapy as first-line treatment of advanced gastric cancer. Ramucirumab (a VEGF receptor antagonist) given as 8 mg/kg intravenously every two weeks can improve median survival from 3.8 to 5.2 months in advanced gastric cancer. Trastuzumab (8 mg/kg intravenously once, then 6 mg/kg every 3 weeks) can increase survival of HER2-positive advanced gastric or GE junction cancer from 11.1 months to 13.8 months. Radiation therapy alone is ineffective and is generally employed only for palliative purposes in the setting of bleeding, obstruction, or pain. Gene therapy and immune-based therapy are currently only investigational in animal models.
Implicit in the management of the patient with gastric cancer is meticulous attention to nutrition (jejunal enteral feedings or total parenteral nutrition), correction of metabolic abnormalities that arise from vomiting or diarrhoea, and treatment of infection from aspiration or spontaneous bacterial peritonitis. H. pylori eradication treatment reduces the risk for metachronous gastric carcinoma by about two thirds. To maintain lumen patency, endoscopic laser treatment or prosthesis placement can be used in a palliative fashion.
- Primary tumour (T)
- Primary tumour cannot be assessed
- No evidence of primary tumour
- Carcinoma in situ: intraepithelial tumour without invasion of the lamina propria
- Tumour invades lamina propria, muscularis mucosa, or submucosa
- Tumour invades lamina propria or muscularis mucosa
- Tumour invades submucosa
- Tumour invades muscularis propria*
- Tumour penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures†‡
- Tumour invades serosa (visceral peritoneum) or adjacent structures†‡
- Tumour invades serosa (visceral peritoneum)
- Tumour invades adjacent structures
- Regional lymph nodes (N)
- Regional lymph nodes(s) cannot be assessed
- No regional lymph nodes metastasis
- Metastasis in 1-2 regional lymph nodes
- Metastasis in 3-6 regional lymph nodes
- Metastasis in 7 or more regional lymph nodes
- Metastasis in 7-15 regional lymph nodes
- Metastasis in 16 or more regional lymph nodes
- Distant metastasis (M)
- No distant metastasis
- Distant metastasis
* Note: A tumour may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumour is classified T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumour should be classified T4.
† The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
‡ Intramural extension to the duodenum or oesophagus is classified by the depth of the greatest invasion in any of these sites, including the stomach.
- Note: A designation of pN0 should be used if all examined lymph nodes are negative, regardless of the total number removed and examined.
Approximately one third of patients who undergo a curative resection are alive after 5 years. In aggregate, the overall 5-year survival rate in patients with gastric cancer is less than 10%. Prognostic factors include anatomic location and nodal status. Distal gastric cancers without lymph node involvement have a better prognosis than proximal gastric cancers with or without lymph node involvement. Other prognostic factors include depth of penetration and tumour cell DNA aneuploidy. Linitis plastica and infiltrating lesions have a much worse prognosis than polypoid disease or exophytic masses. In the subset of mostly Japanese patients with early gastric cancer that is confined to the mucosa and submucosa, surgical resection may be curative and definitely improves the 5-year survival rate to more than 50%. In fact, when early gastric cancer is confined to the mucosa, endoscopic mucosal resection may be an alternative.
Gastric lymphoma represents about 5% of all malignant gastric tumours and is increasing in incidence. Most gastric lymphomas are non-Hodgkin’s lymphomas, and the stomach is the most common extranodal site for non-Hodgkin’s lymphomas. Patients with gastric lymphoma are generally younger than those with gastric adenocarcinoma, but the male predominance remains.
Patients commonly present with symptoms and signs similar to those of gastric adenocarcinoma. Lymphoma in the stomach can be a primary tumour, or it can be secondary to disseminated lymphoma.
B-cell lymphomas of the stomach are most commonly large cell with a high-grade type. Low-grade variants are noted in the setting of chronic gastritis and are termed mucosa-associated lymphoid tissue (MALT) lymphomas. MALT lesions are strongly associated with H. pylori infection.
Radiographically, gastric lymphomas usually arise as ulcers or exophytic masses; diffusely infiltrating lymphoma is more suggestive of secondary lymphoma. Thus, upper gastrointestinal barium studies usually show multiple nodules and ulcers for a primary gastric lymphoma and typically have the appearance of linitis plastica with secondary lymphoma. As with gastric adenocarcinoma, however, upper endoscopy with biopsy and cytologic examination are required for diagnosis and have an accuracy of nearly 90%. Apart from conventional histopathologic analysis, immunoperoxidase staining for lymphocyte markers is helpful in diagnosis. As with gastric adenocarcinoma, proper staging of gastric lymphoma involves EUS, chest and abdominal/pelvic CT scans, and bone marrow biopsy as needed.
Treatment of gastric diffuse large B-cell lymphoma is best pursued with combination chemotherapy with or without radiation therapy. For MALT lesions, eradication of H. pylori infection with antibiotics should be attempted, but patients with refractory lesions that are confined to the stomach can sometimes be cured with chemoradiotherapy.
Leiomyosarcoma, which constitutes approximately 1% of all gastric cancers, usually occurs as an intramural mass with central ulceration. Symptoms may include bleeding accompanied by a palpable mass. Leiomyosarcomas are often relatively indolent; surgical resection yields a 5-year survival rate of about 50%. Metastasis can occur to lymph nodes and the liver. Other gastric sarcomas include liposarcomas, fibrosarcomas, myosarcomas, and neurogenic sarcomas.
Most gastrointestinal stromal tumours (GISTs) have been associated with activating mutations in the C- kit gene; a subset of such tumours is associated with mutations in the platelet-derived growth factor receptor (PDGFR) gene. C- kit mutations are also found in chronic and acute myelogenous leukaemia, and approximately 50% of GISTs respond to imatinib mesylate, which should be continued for at least 3 years. If imatinib is not successful, sunitinib increases survival. If both fail, regorafenib, a multikinase inhibitor, can be tried. Carcinoid tumours may begin in the stomach and are curable by removal if they have not yet spread to the liver.
Primary tumours can also spread to the stomach. In addition to lymphomas, other tumours found in the stomach include primary lung and breast cancers as well as malignant melanoma.
Leiomyomas, which are smooth muscle tumours of benign origin, occur with equal frequency in men and women and are typically located in the middle and distal stomach. Leiomyomas can grow into the lumen, with secondary ulceration and consequent bleeding. Alternatively, they can expand to the serosa with extrinsic compression. Endoscopy may reveal a mass that has overlying mucosa or mucosa replaced by ulceration. On upper gastrointestinal series, leiomyomas are usually smooth with an intramural filling defect, with or without central ulceration. However, benign leiomyomas can be difficult to distinguish from their malignant counterparts radiographically or endoscopically; tissue diagnosis is imperative. Symptomatic leiomyomas should be removed, but those without associated symptoms do not require therapy.
Other benign gastric tumours include lipoma, neurofibroma, lymphangioma, ganglioneuroma, and hamartoma, the last associated with Peutz-Jeghers syndrome or juvenile polyposis (when restricted to the stomach).
Gastric adenomas and hyperplastic polyps are unusual but may be found in middle-aged and elderly patients. Polyps may be sessile or pedunculated. Although isolated gastric adenomatous polyps are generally asymptomatic, some patients may have dyspepsia, nausea, or bleeding. Gastric adenomas and hyperplastic polyps are smooth and regular on upper gastrointestinal series, but the diagnosis must be confirmed by upper endoscopy with biopsy. Pedunculated polyps that are larger than 2 cm or that have associated symptoms should be removed by endoscopic snare cautery polypectomy, whereas large sessile gastric adenomatous polyps may merit segmental surgical resection. If polyps progress to an intermediary stage of severe dysplasia or culminate in cancer, treatment is the same as for gastric adenocarcinoma.