Stomach cancer overview

# Overview
Stomach cancer (also called gastric cancer or gastric carcinoma) can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus and the small intestine. Stomach cancer causes nearly one million deaths worldwide per year. Risk factors vary according to the type of gastric cancer. Common risk factors for intestinal-type of stomach cancer are chronic superficial gastritis caused by; Helicobacter pylori infection, pernicious anemia, a high salt diet, chronic inflammation results in epithelial cell damage. Risk factors for diffuse-type gastric cancer are salt and salt-preserved foods, nitroso compounds, fruits and fibers, obesity, smoking, Helicobacter pylori, nonsteroidal antinflammatory, Ebstien-Barr virus, gastric surgery, irradiation, and familial predisposition. Stomach cancer may be classified into adenocarcinoma, lymphoma, gastrointestinal stromal tumor, and carcinoid tumor. Gastric cancer classifications are Padova classification that classified gastric cancer into five types according tot degree of dysplasia. Japanese classification subdivided gastric cancer according to the atypia degree to five types also. Symptoms of stomach cancer include abdominal pain, bloating, weight loss, hematemesis, melena, and dysphagia. Twenty-five percent of patients have a history of gastric ulcer. Endoscopic ultrasonography (EUS) is the most reliable diagnostic technique for evaluating the depth of invasion of primary gastric cancers. Endoscopic ultrasonography is not the procedure of choice for detecting lymph nodes. Abdominal CT scan may be helpful in the diagnosis of stomach cancer. It is used to evaluate metastatic disease, especially hepatic or adnexal metastases, ascites, or distant nodal spread. Integrated PET/CT imaging can be useful to confirm malignant involvement of CT-detected lymphadenopathy. Surgery is the mainstay of treatment for stomach cancer. endoscopic resection is suggested for early gastric cancer. There are criteria for endoscopic resection of early gastric cancer. Methods for endoscopic resection include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection. The optimal therapy for stomach cancer depends on the stage at diagnosis. It is indicated for; patients with unresectable or recurrent disease, after non-curative R2 resection, patients with unresectable T4b disease, extensive nodal disease, hepatic metastases, peritoneal dissemination or other M1 disease. Response to the treatment should be evaluated by examinations that may include CT, endoscopy and contrast radiography. Adjuvant therapy includes one cycle of fluorouracil (425 mg/m2) + leucovorin calcium (20 mg/m2) for five days followed by radiation therapy for one month given with the same chemotherapy regimen on days 1 through 4 and the last three days of the month. For patients with potentially resectable dsease not yet resected, neoadjuvant therapy is preferred over initial surgery.

# Historical perspective
John Jones was the first to perform a gastric resection in animals. In 1881, Billroths first human surgery. In 1897, Schlatter has done the first esophago-enterostomy after gastrectomy. Between 1884 to 1929, Finneys and Rienhoff were the first to perform partial gastrectomy showing less side effects and less mortality rates.

# Classification
Gastric cancer can be classified according to the Padova classification system based upon the grade of metaplasia, dysplasia and invasiveness of the disease. It may also be classified according to the Japanese classification system based on the type of lesions (benign or malignant) and atypia.

# Pathophysiology
Gastric cancer may occur secondary to a variety of causes including H. pylori and gastric cancer have strong correlation. This is related to nitric oxide accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends upon the histologic subtype. K-ras mutations is found in invasive cancers and intestinal metaplasia. Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis. DNA methylation of gene promoters can silence the expression of CDH1. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Diffuse gastric carcinomas do not have a precancerouslesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. There are many diseases associated with gastric cancer such as, hereditary diffuse gastric cancer, gastric adenocarcinoma, proximal polyposis of the stomach, Lynch syndrome, familial adenomatous polyposis, Li-Fraumeni syndrome, Peutz Jeghers syndrome, juvenile polyposis, hereditary breast and ovarian cancer syndrome and Cowden's syndrome. There are five gross pathological types of gastric cancer; superficical, ulcerative, infiltrative ulcerative, diffuse infiltrative, and unclassified. There are two major histological classifications for gastric cancer including Japanese classification and WHO classification. The main two types are intestinal type adenocarcinoma and diffuse type adenocarcinoma.

# Causes
Causes of stomach cancer depend on the type of cancer. Adenocarcinomas are caused by genetic modulations due to chronic inflammation mainly by H. pylori infection. Diffuse gastric carcinomas do not have a precancerous lesion. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers. The E-cadherin gene (CDH1) encodes a transmembrane cellular adhesion protein.

# Differential diagnosis
Stomach cancer must be differentiated from other diseases presenting with episodic abdominal pain, weight loss and loss of appetite such as gastric lymphoma, gastric metastasis, gastritis, benign gastric ulcer, Menetrier's disease.

# Epidemiology and Demographics
Stomach cancer is the fifth most common cancer worldwide. In the United States, stomach cancer represents roughly 1.3% of all new cancer cases yearly. In 2011, the age-adjusted prevalence of stomach cancer was estimated to be 23.5 cases per 100,000 individuals in the United States. Stomach cancer is two times more common in men than in women, and the incidence increases with age. Incidence of gastric cancer under 65 years is 2.9 per 100,000.

# Risk Factors
Risk factors vary according to the type of gastric cancer. Common risk factors for intestinal-type of stomach cancer are chronic superficial gastritis caused by Helicobacter pylori infection, pernicious anemia, a high salt diet, chronic inflammation results in epithelial cell damage. Risk factors for diffuse-type gastric cancer are salt and salt-preserved foods, nitroso compounds, lack of fruits and fibers in diet, obesity, smoking, Helicobacter pylori, nonsteroidal antinflammatory, Epstien-Barr virus, gastric surgery, irradiation, and familial predisposition.

# Screening
The two main modalities for gastric cancer screening are upper endoscopy and contrast radiography. Universal screening is recommended in countries with a high incidence of gastric cancer such as East Asian countries. In areas of low gastric cancer incidence, screening for gastric cancer with upper endoscopy should be reserved specifically for high-risk subgroups. Upper endoscopy has a sensitivity of 69 % and upper GI series has a sensitivity of 37%. Both studies have a specificity of 96%.

# Natural history, Complications and Prognosis
If left untreated, the five-year survival rates of gastric cancer range from almost no survival for patients with disseminated disease to almost 50% survival for patients with localized distal gastric cancers confined to resectable regions. Higher recurrence rates are seen in those who have piecemeal or incomplete resections. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor. Complications of gastric cancer are ascites, gastrointestinal bleeding, distant metastasis to other organs, weight loss, recurrence of cancer, and treatment complications. The prognosis of patients with gastric cancer is related to tumor extent that includes direct tumor extension and lymph nodes involvement. The five-year survival rate for treated early gastric cancer is over 90 percent; nearly 100 percent for mucosal tumors, and 80 to 90 percent for submucosal tumors.

# Staging
According to the American Joint Committee on Cancer, there are 4 stages of stomach cancer based on the tumor spread

# History and Symptoms
Symptoms of stomach cancer include abdominal pain, bloating, weight loss, hematemesis, melena, and dysphagia. Twenty-five percent of patients have a history of gastric ulcer

# Physical Examination
Patients with stomach cancer generally appear weak. Common physical examination findings include abdominal distention, palpation of an abdominal mass, and pallor. Leser-Trelat sign and presence of Virchow's node (left supraclavicular lymphadenopathy), Sister Mary Joseph nodule (visible periumbilical nodule), Blumer's shelf (rectal mass/shelf on rectal exam) and/or Trousseau's syndrome (migratory phlebitis) on physical examination are highly suggestive of stomach cancer

# Laboratory findings
Laboratory findings in gastric cancer include anemia of chronic disease on complete blood count, liver function tests may reveal abnormalities in liver function tests, antigens such as carcinoembryonic antigen, glycoprotein CA 125, carbohydrate antigen 19-9, cancer antigen 72-4, alpha-fetoprotein

# Endoscopy and Biopsy
Biopsy may be helpful in the diagnosis of stomach cancer. It has a sensitivity of 98% to diagnose gastric cancer but may be negative in linitis plastica. It is commonly used nowadays as first line of treatment for superficial lesions.

# Chest X-Ray
Chest x-ray may show spread to the lungs as a cannon-ball appearance on radiography. Advanced gastric carcinoma may be visible on an abdominal x-ray as an uneven stomach contours or small masses indenting the stomach contours

# CT
Abdominal CT scan may be helpful in the diagnosis of stomach cancer. It is used to evaluate metastatic disease, especially hepatic or adnexal metastases, ascites, or distant nodal spread. Integrated PET/CT imaging can be useful to confirm malignant involvement of CT-detected lymphadenopathy. A negative PET CT is not helpful, since even large tumors with a diameter of several centimeters may not be visible on PET scan if the tumor cells have a fairly low metabolic activity.

# MRI
MRI has better soft tissue sensitivity than CT.Individual layers may be better differentiated on MRI compared with CT. Hence, better T staging of stomach cancer. Water or effervescent granules are used to distend stomach to perform MRI

# Echocardiography/Ultrasound
Endoscopic ultrasonography (EUS) is the most reliable diagnostic technique for evaluation of the depth of invasion of primary gastric cancers. Endoscopic ultrasonography is not the procedure of choice for detecting nodal spread.

# Other imaging findings
Barium studies may be diagnostic of stomach cancer. The sensitivity of barium meals may be 14%. False-negative barium studies can occur in 50 percent of cases. There are three types of early gastric cancer which include polypoid, ulcerated, and superficial.

# Other diagnostic studies
Laparoscopy has the advantage of directly visualizing the liver surface, the peritoneum, and local lymph nodes. Diagnostic laparoscopy is especially important for patients who are being considered for a trial of neoadjuvant therapy.

# Medical therapy
The optimal therapy for stomach cancer depends on the stage at diagnosis. Medical therapy is indicated for patients with unresectable or recurrent disease, after non-curative R2 resection (macroscopic tumor removal), patients with unresectable T4b disease, extensive nodal disease, hepatic metastases, peritoneal dissemination or other M1 disease. Response to the treatment should be evaluated by examinations such as CT scan, endoscopy and contrast radiography. Adjuvant therapy includes one cycle of fluorouracil (425 mg/m2 of body surface area) plus leucovorin calcium (20 mg/m2 of body surface area) for five days followed by radiation therapy for one month given with the same chemotherapy regimen on days 1 through 4 and the last three days of the month. For patients with potientially resectable disease not yet resected, neoadjuvant chemotherapy is preferred over initial surgery. Another benefit of neoadjuvant chemotherapy is that patients who are at high risk of developing distant metastases may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after chemotherapy. Preoperative combined chemotherapy and radiation therapy is more commonly used for esophageal, esophagogastric junction cancers, and cancer affecting the gastric cardia rather than for potentially resectable adenocarcinomas. For locally advanced unresectable and metastatic tumors, goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival. Patients with the presence of human epidermal growth factor receptor 2 (HER2) overexpression are potential candidates for trastuzumab

# Surgery
Surgery is the mainstay of treatment for stomach cancer. Endoscopic resection is suggested for early gastric cancer. There are criteria for endoscopic resection of ealry gastric cancer. Methods for endoscopic resection include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Side effects of endoscopy includes bleeding and perforation. For T1 tumors, a 2cm macroscopic resection of tumor margin should be performed. Proximal margin of at least 3 cm is recommended for T2 or deeper tumors with an expansive growth pattern and 5 cm for those with an infiltrative growth pattern. For tumors invading the esophagus, a 5-cm margin is not necessarily required, but frozen section examination of the resection line is desirable to ensure a R0 resection. There is a debate about optimal lymph node removal. D1 lymphadenectomy refers to a dissection of only the perigastric lymph nodes. D2 lymphadenectomy is an extended lymph node dissection, includes removal of nodes along the hepatic, left gastric, celiac, and splenic arteries, as well as those in the splenic hilum. D3 dissection is a super-extended lymphadenectomy. The surgery includes D2 lymphadenectomy plus the removal of nodes within the porta hepatis and periaortic regions

# Primary prevention
Effective measures for the primary prevention of stomach cancer include smoking cessation, eradication of Helicobacter pylori infection, and having a balanced diet rich in fruits and vegetables. In areas of low gastric cancer, incidence and screening for gastric cancer with upper endoscopy should be reserved for specific high-risk subgroups. Individuals at increased risk for gastric cancer include gastric adenomas, pernicious anemia, gastric intestinal metaplasia, familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome.

# Secondary prevention
Gastric cancer secondary prevention is indicated for all patients after gastric surgeries. Physical examination, complete blood count, imaging or endoscopy are indicated to decrease chances of recurrence.