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Definition, Etiology, PathogenesisTop
A precancerous stage of gastric cancer is intraepithelial neoplasia (formerly called cancer in situ, preinvasive cancer, or high-grade dysplasia). It is diagnosed microscopically. Early cancer is an invasive cancer involving mucosa or submucosa, regardless of involvement of regional lymph nodes.
Although it is one of the most common types of cancer in the world, the overall incidence of gastric cancer has decreased over the last few decades. The frequency is highest in countries like Japan and South Korea but much lower in North America, except for the first generation of immigrants from high-prevalence countries.
For intestinal-type gastric cancer, precancerous lesions include gastric atrophy (most commonly due to chronic Helicobacter pylori infection; 3-fold to 18-fold risk increase), intestinal metaplasia (6-fold risk increase), dysplasia (10-fold risk increase), and adenomatous gastric polyp. For diffuse-type gastric cancer, no precancerous pathology has been identified and it could be difficult to diagnose with ordinary investigations.
Factors increasing the risk of gastric cancer include male sex, atrophic gastritis, partial gastrectomy, Ménétrier disease, dietary factors (salt or salt-preserved food; food with high nitrite levels; diet low in fruits, vegetables, or folate), lifestyle factors (smoking and obesity), infection with H pylori, and genetic factors.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data and indirectness for specific countries. Fock KM, Talley N, Moayyedi P, et al; Asia-Pacific Gastric Cancer Consensus Conference. Asia-Pacific consensus guidelines on gastric cancer prevention. J Gastroenterol Hepatol. 2008 Mar;23(3):351-65. doi: 10.1111/j.1440-1746.2008.05314.x. PubMed PMID: 18318820. Two hereditary types of gastric cancer are known:
1) Hereditary diffuse gastric cancer (HDGC), which is due to an autosomal dominant mutation in CDH1 gene regulating E-cadherin. Most affected patients require early preventive total gastrectomy.
2) Familial intestinal gastric cancer, which is also an autosomal dominant disease.
Gastric cancer has been associated with group A blood type. It can also be linked to other hereditary cancer syndromes (Lynch syndrome, juvenile polyposis syndrome, Peutz-Jeghers syndrome, familial adenomatous polyposis [FAP]).
Clinical Features and Natural HistoryTop
1. Symptoms of early cancer: Epigastric discomfort or vague pain, early satiety, nausea, belching. The disease is rarely asymptomatic.
2. Typical and late clinical manifestations of gastric cancer: Loss of appetite, weight loss and malnutrition, vomiting, early satiety (especially in diffuse-type cancer), dysphagia/odynophagia, constant epigastric pain, sometimes a palpable epigastric tumor; these features develop very late and indicate advanced cancer. Specific symptoms of gastric cancer spread include metastases to the liver (palpable liver mass, jaundice), peritoneum (ascites), left supraclavicular lymph nodes (Virchow node), enlarged ovary (Krukenberg tumor), metastatic umbilical nodule (Sister Mary Joseph nodule), a shelf-like tumor of the anterior rectal wall palpable on rectal examination (Blumer shelf). Overt or occult bleeding may occur. Paraneoplastic manifestation is rare in gastric cancer.
1. Endoscopy: The accuracy of endoscopy in detecting early gastric cancer has been reported to be >95%; however, the lesions may be difficult to detect, flat, or erosion-like (narrow-band imaging [NBI] and indigo carmine stain or magnifying endoscopy may be helpful). Advanced cancer presents as a tumor (frequently irregularly ulcerated), a fairly uniform infiltrate with impaired gastric distention on insufflation of air (in the case of diffuse-type gastric cancer or linitis plastica), or both. Mapping biopsy defined as taking ≥2 biopsy specimens from each of the antrum, incisura, and body of the stomach is often recommended to check for precancerous lesions while performing gastroscopy in people at higher risk of gastric cancer. All patients with gastric ulcers should undergo follow-up endoscopy to verify healing. Multiple (6-8) biopsy specimens should be obtained from suspicious lesions for histologic examination and particularly from the edge of any unhealed ulceration, even in patients with known peptic ulcer disease (in 10% of chronic peptic ulcers gastric cancer tissue is found).
2. Endoscopic resection: Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of early gastric cancer will provide an accurate T stage of the tumor.
3. Imaging studies: Endoscopic ultrasonography (EUS), computed tomography (CT), and positron emission tomography (PET) are used to assess the extent and depth of local cancer infiltration before surgery and to detect metastases to regional lymph nodes (mainly endosonography) as well as distant metastases. CT is superior to EUS in detecting distant metastases, but EUS is significantly more sensitive and specific in detecting the depth of invasion and lymph node involvement with a possibility of fine-needle aspiration (FNA). EUS is also very accurate in detecting early gastric cancer and determining the criteria for endoscopic resectability. PET is more sensitive than CT in identifying distant metastases.
4. Histology: Adenocarcinoma in 95% of patients.
5. Serology: Currently available serologic markers do not provide reasonable sensitivity or specificity in detecting gastric cancer.
Diagnosis is based on histologic examination of gastric mucosa specimens obtained during endoscopy.
Gastric cancer is staged based on the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) recommendations. Initial staging should include physical examination, blood tests (blood count, liver and renal function tests), endoscopy, pathology, and imaging studies including CT (of the thorax, abdomen, and possibly pelvis) and EUS with or without FNA of suspected lymph nodes. Staging laparoscopy may be required for accurate results. The AJCC recommends evaluating a minimum of 16 and preferably 30 lymph nodes for the purpose of staging. Early stages are considered curable but more advanced stages are usually palliative.
The rationale for screening depends on the baseline risk, which differs between countries and depends on additional personal risk factors. At present, in North America screening of the general population is not recommended. Screening with endoscopy every 2 to 3 years is currently implemented in some high-risk areas (eg, Japan and South Korea). In Western countries screening is considered controversial and if done, it is reserved for individuals with conditions that are supposed to be precancerous, such as gastric atrophy, intestinal metaplasia, adenoma, pernicious anemia, FAP, Lynch syndrome, Peutz-Jeghers syndrome, or juvenile polyposis syndrome. Patients with low-grade or high-grade gastric dysplasia require more frequent endoscopic surveillance. It might be reasonable to screen patients with a strong family history of gastric cancer as the risk is increased 2-fold to 3-fold.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the retrospective and observational nature of data. Yaghoobi M, McNabb-Baltar J, Bijarchi R, Hunt RH. What is the quantitative risk of gastric cancer in the first-degree relatives of patients? A meta-analysis. World J Gastroenterol. 2017 Apr 7;23(13):2435-2442. doi: 10.3748/wjg.v23.i13.2435. PubMed PMID: 28428723; PubMed Central PMCID: PMC5385410.
Treatment and PrognosisTop
Formerly gastric cancers were thought to be insensitive to radiotherapy and to show poor response to chemotherapy. Recently there have been attempts to use preoperative (neoadjuvant) chemoradiotherapy, with some success. The criteria for unresectability in gastric cancer are distant metastases and involvement of major vessels.
1. Early cancer: In patients with suspicion of cancer based on endoscopic findings, endoscopic resection (EMR or ESD) may be performed. If histologic examination of the removed lesion reveals advanced cancer, gastrectomy should be done. The overall 5-year survival rates after resection of early gastric cancer are >90%. H pylori infection should be treated if present.
2. Advanced cancer: A multidisciplinary approach in a specialized center is required. Patients with resectable cancers at stage T2 or higher and any N stage may benefit from perioperative chemotherapy or chemoradiation, with trastuzumab for human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic carcinoma. Total or subtotal gastrectomy with regional lymphadenectomy should include as many lymph nodes as reasonably safely possible (D1 dissection: limited to perigastric nodes; D2 dissection: extended to include nodes along the main branches of the celiac axis). The overall postoperative 5-year survival rates differ between countries but are usually >20%. The prognosis in patients undergoing this radical surgery depends on dimensions of the resected tumor, depth of infiltration, and number of lymph nodes with metastases.
A reasonable approach may involve follow-up visits every 3 to 6 months for the first 1 to 2 years and then every 6 to 12 months for the next 3 to 5 years (clinical evaluation, complete blood count, and liver function tests). Imaging studies (chest CT, CT of the abdomen and pelvis) should be performed every 12 months.
In patients with early cancer, particularly after EMR, reasonable follow-up includes endoscopic evaluation with the collection of mucosal specimens 3 to 6 months after surgery, then every 6 to 12 months for 3 to 5 years, and annually thereafter.
After subtotal gastrectomy endoscopy should be performed every year for 4 to 5 years after the surgery and later based on clinical manifestations. The follow-up schedule in patients after total gastrectomy is less certain.