Stomach cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Parminder Dhingra, M.D. [3], Mohammed Abdelwahed M.D[4]

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. Additionally, early-onset stomach cancer is defined as onset of gastric cancer at age younger than 50 years. 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.

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

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.

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 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.

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.

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 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.

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%.

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.

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

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

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 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

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 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

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 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

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.

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.

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.

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 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

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.

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.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2] Mohammed Abdelwahed M.D[3]

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

• Around 1800, Dr. John Jones was the first to perform a gastric resection in animals ^[1]
• In 1881, Billroth’s performed the first human gastric surgery ^[2]
• In 1885, Billroth developed a second resection method. He used anterior gastro-enterostomy that was called Billroth II operation^[3]
• In 1897, Schlatter has done the first esophago-enterostomy after gastrectomy^[4]
• In 1898, a successful gastrectomy was performed on a patient without any complications by Mcdonald.^[5]
• Gastric cancer was the most common cancer in 1990 In 1990^[6]
• Between 1884 to 1929, Finney’s and Rienhoff were the first to perform partial gastrectomy showing fewer side effects and fewer mortality rates^[7]
• In 1940s, Coller, Kay, and McIntyre published a study of all regional lymph nodes^[8]
• Between November 1950 and January 1953, Sunderland et al. studied lymph node metastasis associated with gastric cancer^[9]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Parminder Dhingra, M.D. [3], Mohammed Abdelwahed M.D[4]

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.

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. The following tables briefly outline the major classification systems:^[1][2]

1. Negative for dysplasia
1.0	Normal
1.1	Reactive foveolar hyperplasia
1.2	Intestinal metaplasia (IM)
1.2.1	IM Complete type
1.2.2	IM Incomplete type
2. Indefinite for dysplasia
2.1	Foveolar hyperproliferation
2.2	Hyperproliferative IM
3. Non-invasive neoplasia (flat or elevated [synonym adenoma])
3.1	Low-grade
3.2	High-grade
3.2.1	Including suspicious for carcinoma without invasion (interglandular)
3.2.2	Including carcinoma without invasion (intraglandular)
4. Suspicious for invasive carcinoma
5. Invasive adenocarcinoma

Category	Definition
Group I	Normal mucosa and benign lesions with no atypia
Group II	Lesions showing atypia but diagnosed as benign (non-neoplastic)
Group III	Borderline lesions between benign and malignant
Group V	Lesions strongly suspected of carcinoma
Group V	Carcinoma

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Parminder Dhingra, M.D. [3], Mohammed Abdelwahed M.D[4]

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 precancerous lesion. 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.

• The stomach consists of two functional areas; oxyntic and pyloric glands. The oxyntic area contains parietal cells that produce gastric acid.
• Parietal cells are filled with secretory vesicles that coalesce with stimulation to form channels that drain to the apical lumen.^[1]
• The secretory membrane contains hydrogen-potassium-ATPase acid-secreting pump. While stimulated hydrogen-potassium exchange occur. The collected hydrogen unifies with chloride forming hydrochloric acid.^[2]
• The antrum contains pyloric glands that secrete gastrin and somatostatin.
• Gastrin enhances gastric acid secretions from parietal cells by increasing synthesis of histamine.^[3]
• Somatostatin: The secretion of somatostatin is increased by gastric acid and gastrin level.^[4]

The pathophysiology of gastric cancer is based on various factors leading to decreased apoptosis, increased proliferation and abnormal differentiation of gastric epithelial cells. The following etiological factors contribute to the development of gastric cancer:^[5]

• Helicobacter pylori infection leading to activation and dysregulation of three signaling pathways, involving three major components:^[6]
  • Nuclear factor-κB
  • Wnt/β-catenin
  • Proliferation/stem cell
• Dietary habits involving high consumption of starch, decreased consumption of high quality protein, fresh fruits and vegetables. These diets favor acid-catalyzed nitrosation in the stomach and leads to mechanical damage to the gastric mucosa.
• Family history of hereditary conditions which may lead to an increased risk of gastric cancer for example, Li-Fraumeni syndrome and hereditary non-polyposis colon cancer.^[7]

Molecular effect of H.pylori:

• There is a strong correlation between Helicobacter pylori and gastric cancer incidence.^[8]
• The main cause of this correlation is related to nitric oxides accumulation produced by inflammatory cells responding to H. pylori infection.^[9]
• Nitric oxides may induce abnormalities in the DNA of epithelial cells.
• Incidences of gastric cancer has been known to decrease with eradication of H. pylori infection.^[10]
• The exact pathway for oncogenesis is not known but many trials support the adenoma–carcinoma sequence.
• The intestinal type of gastric adenocarcinoma is the most common type of gastric cancer. The development of intestinal type gastric carcinoma progresses from chronic superficial (non atrophic) gastritis, to chronic atrophic gastritis to intestinal metaplasia, followed by dysplasia and finally, gastric adenocarcinoma.^[11]
• H. pylori hosts a virulence factor called cytotoxin-associated gene A (cag A) which leads to induction of growth factor receptors, increased proliferation, inhibition of apoptosis, and promotion of invasion and angiogenesis.^[12]
• H. pylori also leads to production of reactive oxygen and nitrogen species and leads to suppression of the host antioxidant defense mechanisms, causing oxidative DNA damage.^[13]

Beta-catenin/Wnt signaling

• Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer.^[14]
• Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation.
• Beta-catenin is normally bound to protein complexes in the cell membrane that are involved in normal intercellular adhesions.
• APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells.^[15]

{{#ev:youtube|oweNT288BXo}}

• Diffuse gastric carcinomas do not have a precancerous lesion.
• 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 plastic.^[16]
• Intracellular mucin pushes the nucleus giving the histological figure of signet ring carcinoma.
• The E-cadherin gene (CDH1) encodes a transmembrane cellular adhesion protein. Its cytoplasmic tail interacts with catenins making the adhesion.
• 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.^[17]
• Prostate stem cell antigen gene is also involved in regulating gastric epithelial cell proliferation.^[18]

• H. pylori infection results in the migration of neutrophils to the site of infection and adhesion to the surface epithelium.
• The neutrophils produce nitric oxide synthase which damage DNA.
• CD11a/CD18– and CD11b/CD18-neutrophils interact with intercellular adhesion molecule-1 (ICAM-1).^[19]
• Epithelial cells respond by signaling pathways leading to apoptosis, proliferation, differentiation, and autophagy.

• Apoptosis occurs as a protective mechanism to prevent replication of mutated DNA which leads to atrophy of epithelium so called atrophic gastritis which returns to normal following eradication therapy.^[20]
• H. pylori enhances expression of the Fas receptor on gastric epithelial cells and may mediate apoptosis through signaling mechanisms related to the Fas death receptor.
• Another trial supported that the source of tumorigenesis is from bone marrow-derived cells that differentiate into gastric epithelial cells in the presence of H. pylori.^[21]

{{#ev:youtube|SyvOPXeg4ig}}

Helicobacter pylori infection

Inflammatory response secretes IL-8 ,IL-1b

Production of alkaline ammonia

Production of urease bacterial phospholipase A

Infux of neutophils and macrophages release of lysosomal enzymes leukotrienes (LT)and reactive oxygen

inhibition of D-cells leads to inappropriate release of somatostatin and hypergastrinemia

Production of urease ,phospholipase A and C release toxic metabolities

Mucosal injury

Mutations of the following genes may lead to the development of gastric cancer:

• K-ras mutations are found in invasive cancers and intestinal metaplasia.^[22]
• C-met receptor has a high affinity for hepatocyte growth factor (HGF). Mutations leading to increased expression of c-met are known to be associated with some types of gastric cancer ( for example intestinal-type gastric cancer). Effector protein CagA made by H.pylori modulates c-met receptor signal transduction pathways.^[23][24]

• Almost 50% of gastric cancers have alterations in genes TP53, TP73, APC, TFF, DCC, LOH, and FHIT.^[25]
• Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis.^[26]

• Abnormalities are found in intestinal-type, intestinal metaplasia and dysplasia, and H. pylori-associated chronic gastritis.^[27]
• Mutations in the APC gene are found in intestinal-type gastric cancers. APC mutations alternate the Wnt/catenin signaling pathway.^[28]
• The trefoil factor family (TFF) is normally expressed in the gastroduodenal mucosa. Loss of TFF1 expression has been observed in gastric carcinomas.^[29]

• Cyclin E overexpression is found in gastric carcinomas.^[30]
• Cyclin E and Cyclin-dependent kinase inhibitor 1-B are cell cycle regulators.^[31]

• DNA methylation of gene promoters can silence the expression of CDH1.^[32]
• Hypermethylation of the Reprimo gene has been found in the plasma of patients with gastric cancer.

{{#ev:youtube|_aAhcNjmvhc}}

• Although most gastric cancers are sporadic, 10 percent of cases are familial.

• CDH1 gene encodes the cell adhesion protein E-cadherin, mutations in this gene have been identified in hereditary diffuse gastric cancer.
• It is inherited as an autosomal dominant trait with high penetrance.^[34]
• Promoter hypermethylation, mutation, and loss of heterozygosity result is loss of expression of the cell adhesion molecule E-cadherin.
• The asymptomatic carriers of a pathogenic CDH1 gene mutation may require prophylactic gastrectomy.
• Risk for gastric cancer for CDH1 gene mutation carriers is 70 percent in men and 56 percent in women.^[35]
• Women in these affected families are also at high risk of developing breast cancer. The cumulative risk of breast cancer at 80 years of age for CDH1 mutation carriers is 42 percent.

• GAPPS is an autosomal dominant fundic gland polyposis that is restricted to the proximal stomach, with no evidence of duodenal or colorectal polyposis or other hereditary gastrointestinal cancer syndrome.^[36]

• FIGC should be considered a potential diagnosis when histopathological reports denote intestinal-type gastric cancers that segregate within families without gastric polyposis.^[37]

• Lynch syndrome (hereditary nonpolyposis colorectal cancer)
• Familial adenomatous polyposis (FAP)
• Li-Fraumeni syndrome
• Peutz Jeghers syndrome
• juvenile polyposis
• Hereditary breast and ovarian cancer syndrome
• Cowden’s syndrome

The gross pathological findings in gastric cancer may be classified into the following types based on appearance of the tumor:

Type	Description
Type 0	(superficial) typical of T1 tumors
Type 1	(mass) polypoid tumors sharply demarcated from the surrounding mucosa
Type 2	(Ulcerative) ulcerated tumors with raised margins surrounded by a thickened gastric wall with clear margins
Type 3	(Infiltrative ulcerative) ulcerated tumors with raised margins, surrounded by a thickened gastric wall without clear margins
Type 4	(Diffuse infiltrative) Tumors without marked ulceration or raised margins, the gastric wall is thickened and indurated and the margin is unclear
Type 5	(Unclassifiable) Tumors that cannot be classified into any of the above types

{{#ev:youtube|ih-npVIJA6U}}

• Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. It invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and hence the muscularis propria. Histologically, there are two major types of gastric cancer (Lauren classification): intestinal type and diffuse type.
  • Intestinal type adenocarcinoma:
    • Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, and reduced stroma. It induces intestinal metaplasia in neighboring mucosa.
    • Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiated.
  • Diffuse type adenocarcinoma:
    • Tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid. It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery giving a signet ring cell appearance.

Types	Histological features
Epithelial tumors	Adenoma Carcinoma Adenocarcinoma Intestinal type Diffuse type Papillary adenocarcinoma Tubular adenocarcinoma Mucinous adenocarcinoma Signet-ring cell carcinoma Adenosquamous carcinoma Squamous cell carcinoma Small cell carcinoma Undifferentiated carcinoma Carcinoid (well differentiated endocrine neoplasm)
Non-epithelial tumors	Leiomyoma Schwannoma Granular cell tumor Glomus tumor Leiomyosarcoma GI stromal tumor Benign Uncertain malignant potential Malignant Kaposi sarcoma
Malignant lymphomas	Marginal zone B-cell lymphoma or MALT-type lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma

Types	Histological features
Epithelial tumors	Benign epithelial tumor Adenoma Malignant epithelial tumor (Common types) Papillary adenocarcinoma Tubular adenocarcinoma Well-differentiated Moderately differentiated Poorly differentiated adenocarcinoma Solid type Non-solid type Signet-ring cell carcinoma Mucinous adenocarcinoma
Special types	Carcinoid tumor Endocrine carcinoma Carcinoma with lymphoid stroma Hepatoid adenocarcinoma Adenosquamous carcinoma Squamous cell carcinoma Undifferentiated carcinoma
Miscellaneous carcinoma	Non-epithelial tumor Gastrointestinal stromal tumor (GIST) Smooth muscle tumor Neurogenic tumor Miscellaneous non-epithelial tumors Lymphoma B-cell lymphoma MALT (mucosa-associated lymphoid tissue) lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Other B-cell lymphomas T-cell lymphoma Other lymphomas Metastatic tumor Tumor-like lesion Hyperplastic polyp Fundic gland polyp Heterotopic submucosal gland Heterotopic pancreas Inflammatory fibroid polyp Gastrointestinal polyposis Familial polyposis coli Peutz–Jeghers syndrome

Video shows microscopic pathology of gastric cancer {{#ev:youtube|lRvq1fEW8sY}} {{#ev:youtube|lWeECaiEfSs}}

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Mohammed Abdelwahed M.D[3]

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.

Causes of stomach cancer depend upon the type of cancer:^[1][2][3][4]

• Adenocarcinomas are caused by genetic modulations due to chronic inflammation mainly by H. pylori bacteria.^[3][5]
• K-ras mutations oncogenes are found in invasive cancers and intestinal metaplasia.
• Hepatocyte growth factor receptor c-met oncogene is found in intestinal-type gastric cancers.
• Almost 50% of gastric cancers have alterations in genes TP53, TP73, APC, TFF, DCC, LOH, and FHIT.
• Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis.

• 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.^[6][4]
• Prostate stem cell antigen gene is also involved in regulating gastric epithelial cell proliferation. Its cytoplasmic tail interacts with catenins making the adhesion.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

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.

Stomach cancer must be differentiated from other diseases presenting with episodic abdominal pain, weight loss and loss of appetite. The differentials include the following:^{[1][2][3][4][5][6][7][8][9]}

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Rim Halaby, M.D. [3], Mohammed Abdelwahed M.D[4]

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.

• Stomach cancer represents roughly 1300 cases of 100,000 all new cancer cases yearly in the United States.^[1]
• In the United States, the age-adjusted prevalence of stomach cancer is 23.5 per 100,000 in 2011.^[2]

• The worldwide incidence of gastric cancer has declined rapidly over the recent few decades.^[3]

• The delay-adjusted incidence of stomach cancer in 2011 was estimated to be 7.27 per 100,000 persons in the United States.^[2]

• In 2011, the age-adjusted incidence of stomach cancer was 7.17 per 100,000 persons in the United States.^[2]
• Part of the decline may be due to the recognition of certain risk factors such as H. pylori and other dietary and environmental risks.
• The decline first took place in countries with low gastric cancer incidence such as the United States while the decline in countries with high incidence like Japan was slower.^[4]
• The absolute number of new cases per year is increasing, mainly due to aging in the world population.^[5]

• While the overall age-adjusted incidence of stomach cancer in the United States between 2007 and 2011 was 7.5 per 100,000, the age-adjusted incidence of stomach cancer by age category was:^[2][6]
  • Under 65 years: 2.9 per 100,000
  • 65 and over: 38.8 per 100,000
• In the United States, the age-adjusted prevalence of stomach cancer by gender in 2011 was:^[2]
  • In males: 30.3 per 100,000
  • In females: 18.2 per 100,000

• Gastric cancer is more common in men than in women, in both developed and developing countries.
• Intestinal gastric cancer is more common in males and older age groups.
• The diffuse or infiltrative type, is equally frequent in both sexes, is more common in younger age groups, and has a worse prognosis than the intestinal type.

• In the United States, the delay-adjusted incidence of stomach cancer by gender in 2011 was:^[2]
  • In males: 9.95 per 100,000 persons
  • In females: 5.14 per 100,000 persons

• In the United States, the age-adjusted incidence of stomach cancer by gender on 2011 was:^[2]
  • In males: 9.82 per 100,000 persons
  • In females: 5.06 per 100,000 persons.^[2]

• Shown below is a table depicting the age-adjusted prevalence of stomach cancer by race in 2011 in the United States.^[2]

	All Races	White	Black	Asian/Pacific Islander	Hispanic
Age-adjusted prevalence	23.5 per 100,000	18.9 per 100,000	28.8 per 100,000	47.5 per 100,000

• The incidence of gastric cancer is particularly high in Korea, Japan, Mongolia, central Asia, Eastern Europe, and parts of Central and South America.^[7][8]
• Stomach cancer is the most common type of cancer in Korea. It is suspected that several risk factors are involved including diet, gastritis, intestinal metaplasia and Helicobacter pylori infection.
• A Korean diet, high in salted, stewed and broiled foods, is thought to be a contributing factor.
• Ten percent of cases show a genetic component.^[9]
• In Japan and other countries bracken consumption and spores are correlated to stomach cancer incidence.^[10][11]

• Rates are highest in Eastern Asia, Eastern Europe, and South America, while the lowest rates are in North America and parts of Africa.^[12]
• Over 70 percent of gastric cancers occur in developing countries.
• Studies of Japanese migrants to the Unites States have confirmed that early exposure to environmental rather than genetic factors have a greater influence on mortality and incidence rates.^[13]

• In the past decades, gastric cancer survival rates have increased in most areas of the world.^[14]
• Screening for early detection in high-risk areas has led to a decrease in mortality. In Japan, mortality rates for gastric cancer in men have dereased to half due to mass screening programs.
• Gastric cardia tumors have a much poorer prognosis compared to the pyloric antrum tumors.^[15]
• The five-year relative survival rates in USA is less than 20% due to late discovery and vary from 10% to 20% in European countries.

• Epidermoid carcinoma: 0.9%
  • Squamous cell carcinoma: 0.8%
• Adenocarcinoma: 83.7%
  • Adenocarcinoma not otherwise specified: 48.3%
  • Adenocarcinoma, intestinal type: 8.4%
  • Adenocarcinoma, diffuse type: 3.5%
  • Linitis plastica: 0.6%
  • Mucinous adenocarcinoma: 1.4%
  • Mucin producing adenocarcinoma: 0.5%
  • Signet ring adenocarcinoma: 16.8%
  • Other adenocarcinoma: 4.1%
• Other specific carcinoma: 6.3%
• Unspecified carcinoma: 2.5%
• Sarcoma and other soft tissue tumors: 0.3%
• Other specific type: 6%
• Unspecified: 0.5%

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Parminder Dhingra, M.D. [3], Mohammed Abdelwahed M.D[4]

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.

• Chronic superficial gastritis caused by:
• Helicobacter pylori infection
• Pernicious anemia
• A high salt diet
• Chronic inflammation results in epithelial cell damage. It is accompanied by a loss of parietal cell mass and therefore a reduction in acid production and increase in gastric PH.
• The increase in gastric pH permits colonization of bacteria capable of converting dietary nitrates to potent nitroso compounds.

• Atrophic gastritis is an autoimmune disorder that is characterized by atrophy of the glandular epithelium with loss of parietal and chief cells.
• This causes a decrease in hydrochloric acid and a resultant increase in gastric pH.
• There is also loss of endocrine cells that secrete transforming growth factors that help the stomach in regenerating damaged tissue.

Intestinal metaplasia and dysplasia

• Metaplasia is the transformation of one differentiated cell type to another differentiated cell type.
• Dysplasia is an abnormality of development or an epithelial anomaly of growth and differentiation.
• It occurs as a result of Helicobacter pylori infection, bile reflux, or can be induced experimentally by irradiation.^[1]
• It was estimated that approximately 1 in 39 patients with intestinal metaplasia and 1 in 19 with dysplasia would develop gastric cancer within 20 years.^[2]

Salt and salt-preserved foods

• A high intake of salt and salt-preserved foods such as salted fish and salted vegetables increases the risk of gastric cancer.^[3]
• Salt damages stomach mucosa and increases the susceptibility to carcinogenesis.^[4]

Nitroso compounds

• Nitroso compounds are generated after consumption of nitrates.^[5]
• Diets that are high in fried food and processed meat have been associated with an increased risk of gastric carcinoma.^[6]
• A high pH environment increases bacterial growth in stomach that transform nitrate in nitrose compunds.^[7]

Fruits and fibers

• Consumption of fruits and dietary fibres is protective against gastric cancer due to high vitamin C content that reduce the formation of carcinogenic N-nitroso compounds inside the stomach.^[8]

Obesity

• Excess body weight is associated with an increased risk of gastric cancer.^[9]

Smoking

• Eighteen percent of gastric cancer cases were linked to smoking.^[10]

Helicobacter pylori

• H. pylori infection has been associated with an increase in the risk with adenocarcinoma, including both the intestinal and diffuse types.

Nonsteroidal antinflammatory (NSAID):

• Regular use of NSAIDs has been inversely associated with the risk of distal gastric adenocarcinoma.^[11]

Epstein Barr virus (EBV)

• Ten percent of gastric cancers worldwide are associated with EBV.^[12]
• It is related to DNA methylation of genetic alleles that protect against multiple cancers. Methylation of these alleles inhibit the expression of these alleles.^[13]

Gastric surgery

•  There is an increased risk of gastric cancer after gastric surgery.^[14]
• Gastrojejunostomy (Billroth II procedure) carries a higher risk than the Billroth I due to regurgitation of alkaline bile and pancreatic juice.

Irradiation

• An elevated risk of gastric cancer has been reported in adult survivors of testicular cancer and Hodgkin lymphoma, and in childhood cancer survivors who received abdominal radiotherapy.^[15]

Blood group

• Blood group A individuals have an incidence ratio of 1.2 compared to blood group O individuals, which means that people with type A blood group have a slightly increased risk for the development of gastric cancer.^[16]

Familial predisposition

• Although most gastric cancers are sporadic, 10 percent of cases are familial.
• Familial gastric cancer accounts for 1 to 3 percent of the global burden of gastric cancer and includes hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS), and familial intestinal gastric cancer (FIGC).

Hereditary diffuse gastric cancer (HDGC)

• Clinical criteria for the diagnosis of HDGC has been described by the International Gastric Cancer Linkage Consortium.
• Germline mutations in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been identified HDGC is inherited in an autosomal dominant fashion with high penetrance.
• The cumulative risk for gastric cancer by the age of 80 years for CDH1 mutation carriers is up to 70 percent in men and up to 56 percent in women.^[17]
• Promoter hypermethylation, mutation, and loss of heterozygosity play key roles in the development of HDGC.
• The end result is loss of expression/reduced expression of the cell adhesion molecule E-cadherin.
• The risk of gastric cancer in asymptomatic carriers of a pathogeneic CDH1 mutation who belong to families with high penetrance hereditary diffuse gastric cancer is sufficiently high to warrant prophylactic gastrectomy.^[18]
• Women in these affected families are also at high risk of developing breast cancer, predominantly lobular.
• The cumulative risk of breast cancer at the age of 80 years for CDH1 mutation carriers is approximately 42 percent, and like the gastric cancers, the increased relative risk starts early.^[19]

Gastric adenocarcinoma proximal polyposis of the stomach (GAPPS)

• GAPPS is characterized by an autosomal dominant transmission of fundic gland polyposis that is restricted to the proximal stomach, with no evidence of duodenal or colorectal polyposis or other hereditary gastrointestinal (GI) cancer syndrome.
• It exhibits incomplete penetrance.

Familial intestinal gastric cancer (FIGC)

• FIGC should be considered a potential diagnosis when histopathological reports denote intestinal-type gastric cancers that segregate within families without gastric polyposis.
• An autosomal dominant inheritance pattern has been noted in many such families.^[20]

Other hereditary cancer syndromes:

• Lynch syndrome (hereditary nonpolyposis colorectal cancer)
• Familial adenomatous polyposis (FAP)
• Li-Fraumeni syndrome
• Peutz Jeghers syndrome
• juvenile polyposis
• Hereditary breast and ovarian cancer syndrome
• Cowden’s syndrome

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2] Mohammed Abdelwahed M.D[3]

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%.

 The two main modalities for gastric cancer screening are upper endoscopy and contrast radiography.

• Upper endoscopy is more sensitive than other screening studies. It allows direct visualization of the gastric mucosa and allows for obtaining biopsies.^[1]

• Barium radiographs can identify malignant gastric ulcers, infiltrating lesions, and some early gastric cancers.^[2]
• Barium studies can be false negative in 50 percent of cases and the sensitivity of a barium study may be 14 percent.^[3]
• In patients with linitis plastica, a barium study may be superior to upper endoscopy.

• Upper endoscopy has a sensitivity of 69 % and upper GI series has a sensitivity of 37%.

• Both studies had a specificity of 96%.

• The upper endoscopy sensitivity in detecting a localized gastric cancer is higher than upper GI series.^[4]

• Universal screening is recommended in countries with a high incidence of gastric cancer such as East Asian countries.^[5]

• In Japan, population-based screening for gastric cancer is recommended for individuals older than 50 years with conventional double-contrast barium radiograph with photofluorography every year or upper endoscopy every two to three years^[6]

• Screening interval is recommended to be every two years but may be widened to a three-year interval without significant effect.^[7]

• In areas of low gastric cancer incidence, screening for gastric cancer with upper endoscopy should be reserved for specific high-risk subgroups.^[8]

• Individuals at increased risk for gastric cancer include those patients having the following:
  • Gastric adenomas
  • Pernicious anemia
  • Gastric intestinal metaplasia
  • Familial adenomatous polyposis
  • Lynch syndrome
  • Peutz-Jeghers syndrome
  • Juvenile polyposis syndrome

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Parminder Dhingra, M.D. [3], Mohammed Abdelwahed M.D[4]

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.

The symptoms of gastric cancer usually develop in the fifth decade of life, and start with loss of appetite and loss of weight. The symptoms of gastric cancer typically progress to dysphagia, abdominal pain, and vomiting. Without treatment, 63 percent of patients with early gastric cancer will progress to advanced disease within five years. Metastasis occurs in 80-90% of individuals with stomach cancer.^[1]

Complications of gastric cancer include the following:

• Ascites
• Gastrointestinal bleeding
• Distant metastasis to other organs
• Weight loss

• Recurrence following curative resection was local or regional in 40 % and systemic in 60%.
• Regional recurrences may be more frequent in patients treated with surgery alone or surgery plus postoperative chemotherapy without radiotheapy, and among those who have a fewer number of negative resected lymph nodes.^[2]
• Sites of regional recurrence include the luminal margins, the resection bed, and the regional nodes.^[3]
• The predominant sites of systemic recurrence are the liver and peritoneum.^[4]
• Metastatic disease beyond the abdomen is uncommonly the first site of recurrence aside from the supraclavicular nodes.^[5]
• In a Japanese series, 9.2 % with early gastric cancers had a second cancer within the first year after therapy.^[6]
• The overall incidence of recurrence is 9.5 %t at five years, 13.1 % at seven years, and 22.7 % at 10 years.^[7]

• Anastomotic leakage^[8]
• Anastomotic strictures^[9]
• Obstruction
• Dumping syndrome: Dumping is a phenomenon caused by the destruction or bypass of the pyloric sphincter. Dumping symptoms include gastrointestinal discomfort, abdominal pain, flushing, nausea and diarrhea.^[10]
• Gastric stasis may develop as a result of post-surgical atony, vagal denervation, or from a small gastric remnant following surgical resection.
• Symptoms consist of epigastric fullness with meals, often followed by emesis of undigested food, abdominal pain, and weight loss^[11]

• Neutropenia 
• Anemia 
• Gastrointestinal side effects:
  • Nausea and vomiting 
• Mucositis 
• Weight gain
• Alopecia 
• Fatigue 
• Sexual and reproductive side effects

• The prognosis of patients with gastric cancer is related to tumor extent that includes direct tumor extension and lymph node 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.^[12]
• Survival rates are similar between patients who undergo endoscopic resection and those who undergo surgical resection.^[13]
• For advanced cases, the five-year survival rate ranges from almost no survival for patients with disseminated disease to almost 50% survival for patients with localized distal gastric cancers confined to resectable regions.
• The 5-year survival rate of patients with proximal gastric cancer is only 10% to 15%.
• The recurrence rate after surgery is approximately 1 to 5 percent in reports from Korea and Japan and 5 to 15 percent in studies from Western centers.^[14]
• These variable recurrence rates partially reflect differences in length of follow-up, but may also be due to differences in the pathologic diagnosis of malignancy.^[15]
• Among patients undergoing endoscopic resection, recurrence rates have been reported to be between 0 and 30%.^[16]
• Higher recurrence rates are seen with those who have piecemeal or incomplete resections.

Prognosis with lymph node involvement

• Long-term survival was 95 percent in patients with no lymph node involvement, 88 percent in those with one to three nodes involved, and 77 percent in those with more than three nodes involved.^[17][18]

• Between 2004 and 2010, the 5-year relative survival of patients with stomach cancer was 29%.^[19]

• The 5-year relative survival of patients with stomach cancer was 31.4% and 26% for patients <65 years.^[19]

• The survival of patients with stomach cancer varies with the stage of the disease. Shown below is a table depicting the 5-year relative survival by the stage of stomach cancer:^[19]

Stage	5-year relative survival (%), (2004-2010)
All stages	28.3%
Localized	64.1%
Regional	28.8%
Distant	4.2%
Unstaged	20.2%

• Shown below is an image depicting the 5-year conditional relative survival (probability of surviving in the next 5-years given the cohort has already survived 0, 1, 3 years) between 1998 and 2010 of stomach cancer by stage at diagnosis according to SEER. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[19]

Template:WH Template:WS