Gastric cancer
Classification and external resources
A suspicious stomach ulcer that was diagnosed as cancer on biopsy and resected. Surgical specimen kept for educational purposes.
ICD-10	C16
ICD-9	151.9
OMIM	137215
DiseasesDB	12445
eMedicine	med/845
MeSH	D013274

Stomach cancer, or gastric cancer, refers to cancer arising from any part of the stomach. Stomach cancer causes about 800,000 deaths worldwide per year.^[1]

Signs and symptoms[link]

Endoscopic image of linitis plastica, a type of stomach cancer where the entire stomach is invaded, leading to a leather bottle-like appearance with blood coming out of it.

Endoscopic image of early stage of the stomach cancer. Its histology was poorly differentiated adno carcinoma with signet ring cells.Left above=Normal, right above=FICE, left low=acetate stained, right low= AIM stained

Stomach cancer is often asymptomatic or causes only nonspecific symptoms in its early stages. By the time symptoms occur, the cancer has often reached an advanced stage (see below), one of the main reasons for its poor prognosis.^{[citation needed]} Stomach cancer can cause the following signs and symptoms:

Stage 1 (Early)

• Indigestion or a burning sensation (heartburn)
• Loss of appetite, especially for meat
• Abdominal discomfort or irritation

Stage 2 (Middle)

• Weakness and fatigue
• Bloating of the stomach, usually after meals

Stage 3 (Late)

• Abdominal pain in the upper abdomen
• Nausea and occasional vomiting
• Diarrhea or constipation
• Weight loss
• Bleeding (vomiting blood or having blood in the stool) which will appear as black. This can lead to anemia.
• Dysphagia; this feature suggests a tumor in the cardia or extension of the gastric tumor in to the esophagus.

Note that these can be symptoms of other problems such as a stomach virus, gastric ulcer or tropical sprue.

Causes[link]

Infection by Helicobacter pylori is believed to be the cause of most stomach cancer while autoimmune atrophic gastritis, intestinal metaplasia and various genetic factors are associated with increased risk levels. The Merck Manual states that diet plays no role in the genesis of stomach cancer.^[2] However, the American Cancer Society lists the following dietary risks, and protective factors, for stomach cancer: "smoked foods, salted fish and meat, and pickled vegetables (appear to increase the risk of stomach cancer.) Nitrates and nitrites are substances commonly found in cured meats. They can be converted by certain bacteria, such as H. pylori, into compounds that have been found to cause stomach cancer in animals. On the other hand, eating fresh fruits and vegetables that contain antioxidant vitamins (such as A and C) appears to lower the risk of stomach cancer."^[3] A December 2009 article in American Journal of Clinical Nutrition found a statistically significant inverse correlation between higher adherence to a Mediterranean Dietary Pattern and stomach cancer.^[4]

In more detail, H. pylori is the main risk factor in 65–80% of gastric cancers, but in only 2% of such infections.^[5] The mechanism by which H. pylori induces stomach cancer potentially involves chronic inflammation, or the action of H. pylori virulence factors such as CagA.^[6] Approximately ten percent of cases show a genetic component.^[7] Some studies indicate that bracken consumption and spores are correlated with incidence of stomach cancer, though causality has yet to be established.^[8]

A very important but preventable cause of gastric cancer is tobacco smoking. Smoking increases the risk of developing gastric cancer considerably; from 40% increased risk for current smokers to 82% increase for heavy smokers which is nearly twice the risk for non-smoking population. Gastric cancers due to smoking mostly occur in upper part of stomach near esophagus^[9][3][10] Another lifestyle cause of gastric cancer besides smoking is consumption of alcohol.^[11][12][13] Alcohol along with tobacco smoking increase the risk of developing other cancers as well.

Gastric cancer shows a male predominance in its incidence as up to three males are affected for every female. Estrogen may protect women against the development of this cancer form.^[14] A very small percentage of diffuse-type gastric cancers (see Histopathology below) are thought to be genetic. Hereditary Diffuse Gastric Cancer (HDGC) has recently been identified and research is ongoing. However, genetic testing and treatment options are already available for families at risk.^[15]

Some researchers^{[16][17][18][19][20][21]} showed a correlation between Iodine deficiency or excess, iodine-deficient goitre and gastric cancer; a decrease of the incidence of death rate from stomach cancer after implementation of the effective I-prophylaxis was reported too.^[22] The proposed mechanism of action is that iodide ion can function in gastric mucosa as an antioxidant reducing species that can detoxify poisonous reactive oxygen species, such as hydrogen peroxide.

The International Cancer Genome Consortium is leading efforts to map stomach cancer's complete genome.^{[citation needed]}

Diagnosis[link]

To find the cause of symptoms, the doctor asks about the patient's medical history, does a physical exam, and may order laboratory studies. The patient may also have one or all of the following exams:

• Gastroscopic exam is the diagnostic method of choice. This involves insertion of a fiber optic camera into the stomach to visualize it.
• Upper GI series (may be called barium roentgenogram)
• Computed tomography or CT scanning of the abdomen may reveal gastric cancer, but is more useful to determine invasion into adjacent tissues, or the presence of spread to local lymph nodes.

Abnormal tissue seen in a gastroscope examination will be biopsied by the surgeon or gastroenterologist. This tissue is then sent to a pathologist for histological examination under a microscope to check for the presence of cancerous cells. A biopsy, with subsequent histological analysis, is the only sure way to confirm the presence of cancer cells.

Various gastroscopic modalities have been developed to increased yield of detect mucosa with a dye that accentuates the cell structure and can identify areas of dysplasia. Endocytoscopy involves ultra-high magnification to visualize cellular structure to better determine areas of dysplasia. Other gastroscopic modalities such as optical coherence tomography are also being tested investigationally for similar applications.^[23]

A number of cutaneous conditions are associated with gastric cancer. A condition of darkened hyperplasia of the skin, frequently of the axilla and groin, known as acanthosis nigricans, is associated with intra-abdominal cancers such as gastric cancer. Other cutaneous manifestations of gastric cancer include tripe palms (a similar darkening hyperplasia of the skin of the palms) and the sign of Leser-Trelat, which is the rapid development of skin lesions known as seborrheic keratoses.^[24]

Various blood tests may be done; including: Complete Blood Count (CBC) to check for anemia. Also, a stool test may be performed to check for blood in the stool.

Histopathology[link]

Poor to moderately differentiated adenocarcinoma of the stomach. H&E stain.

Gastric signet ring cell carcinoma. H&E stain.

Adenocarcinoma of the stomach and intestinal metaplasia. H&E stain.

• Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. Stomach cancers are overwhelmingly adenocarcinomas (90%).^[25] Histologically, there are two major types of gastric adenocarcinoma (Lauren classification): intestinal type or diffuse type. Adenocarcinomas tend to aggressively invade the gastric wall, infiltrating the muscularis mucosae, the submucosa, and thence the muscularis propria. Intestinal type adenocarcinoma tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Often, it associates 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 (mucinous, colloid, linitis plastica, leather-bottle stomach) Tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid (optically "empty" spaces). It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus to the periphery- "signet-ring cell".
• Around 5% of gastric malignancies are lymphomas (MALTomas, or MALT lymphoma).^[26]
• Carcinoid and stromal tumors may also occur.

Staging[link]

If cancer cells are found in the tissue sample, the next step is to stage, or find out the extent of the disease. Various tests determine whether the cancer has spread and, if so, what parts of the body are affected. Because stomach cancer can spread to the liver, the pancreas, and other organs near the stomach as well as to the lungs, the doctor may order a CT scan, a PET scan, an endoscopic ultrasound exam, or other tests to check these areas. Blood tests for tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) may be ordered, as their levels correlate to extent of metastasis, especially to the liver, and the cure rate.

Staging may not be complete until after surgery. The surgeon removes nearby lymph nodes and possibly samples of tissue from other areas in the abdomen for examination by a pathologist.

The clinical stages of stomach cancer are:^[27][28]

• Stage 0. Limited to the inner lining of the stomach. Treatable by endoscopic mucosal resection when found very early (in routine screenings); otherwise by gastrectomy and lymphadenectomy without need for chemotherapy or radiation.
• Stage I. Penetration to the second or third layers of the stomach (Stage 1A) or to the second layer and nearby lymph nodes (Stage 1B). Stage 1A is treated by surgery, including removal of the omentum. Stage 1B may be treated with chemotherapy (5-fluorouracil) and radiation therapy.
• Stage II. Penetration to the second layer and more distant lymph nodes, or the third layer and only nearby lymph nodes, or all four layers but not the lymph nodes. Treated as for Stage I, sometimes with additional neoadjuvant chemotherapy.
• Stage III. Penetration to the third layer and more distant lymph nodes, or penetration to the fourth layer and either nearby tissues or nearby or more distant lymph nodes. Treated as for Stage II; a cure is still possible in some cases.
• Stage IV. Cancer has spread to nearby tissues and more distant lymph nodes, or has metastatized to other organs. A cure is very rarely possible at this stage. Some other techniques to prolong life or improve symptoms are used, including laser treatment, surgery, and/or stents to keep the digestive tract open, and chemotherapy by drugs such as 5-fluorouracil, cisplatin, epirubicin, etoposide, docetaxel, oxaliplatin, capecitabine, or irinotecan.

The TNM staging system is also used.^[29]

In a study of open-access endoscopy in Scotland, patients were diagnosed 7% in Stage I 17% in Stage II, and 28% in Stage III.^[30] A Minnesota population was diagnosed 10% in Stage I, 13% in Stage II, and 18% in Stage III.^[31] However in a high-risk population in the Valdivia Province of southern Chile, only 5% of patients were diagnosed in the first two stages and 10% in stage III.^[32]

Management[link]

As with any cancer, treatment is adapted to fit each person's individual needs and depends on the size, location, and extent of the tumor, the stage of the disease, and general health. Cancer of the stomach is difficult to cure unless it is found in an early stage (before it has begun to spread). Unfortunately, because early stomach cancer causes few symptoms, the disease is usually advanced when the diagnosis is made. Treatment for stomach cancer may include surgery, chemotherapy, and/or radiation therapy. New treatment approaches such as biological therapy and improved ways of using current methods are being studied in clinical trials.^{[citation needed]} An antibody-drug conjugate IMGN242 is in phase II clinical trials.^[33][34]

Surgery[link]

Surgery is the most common treatment. The surgeon removes part or all of the stomach, as well as the surrounding lymph nodes, with the basic goal of removing all cancer and a margin of normal tissue. Depending on the extent of invasion and the location of the tumor, surgery may also include removal of part of the intestine or pancreas. Tumors in the lower part of the stomach may call for a Billroth I or Billroth II procedure.

Endoscopic mucosal resection (EMR)^[35] is a treatment for early gastric cancer (tumor only involves the mucosa) that has been pioneered in Japan, but is also available in the United States at some centers. In this procedure, the tumor, together with the inner lining of stomach (mucosa), is removed from the wall of the stomach using an electrical wire loop through the endoscope. The advantage is that it is a much smaller operation than removing the stomach. Endoscopic submucosal dissection (ESD) is a similar technique pioneered in Japan, used to resect a large area of mucosa in one piece. If the pathologic examination of the resected specimen shows incomplete resection or deep invasion by tumor, the patient would need a formal stomach resection.

Surgical interventions are currently curative in less than 40% of cases, and, in cases of metastasis, may only be palliative.

Chemotherapy[link]

The use of chemotherapy to treat stomach cancer has no firmly established standard of care. Unfortunately, stomach cancer has not been particularly sensitive to these drugs, and chemotherapy, if used, has usually served to palliatively reduce the size of the tumor, relieve symptoms of the disease and increase survival time. Some drugs used in stomach cancer treatment have included: 5-FU (fluorouracil) or its analog capecitabine, BCNU (carmustine), methyl-CCNU (Semustine), and doxorubicin (Adriamycin), as well as Mitomycin C, and more recently cisplatin and taxotere, often using drugs in various combinations. The relative benefits of these different drugs, alone and in combination, are unclear.^[36] Clinical researchers have explored the benefits of giving chemotherapy before surgery to shrink the tumor, or as adjuvant therapy after surgery to destroy remaining cancer cells. Combination treatment with chemotherapy and radiation therapy has some activity in selected post surgical settings. For patients who have HER2 overexpressing metastatic gastric or gastroesophageal (GE) junction adenocarcinoma, who have not received prior treatment for their metastatic disease, the US Food and Drug Administration granted approval (2010 October) for trastuzumab (Herceptin, Genentech, Inc.) in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil). This was based on an improvement of the median overall survival (OS) of 2.5 months^[37] with trastuzumab plus chemotherapy treatment compared to chemotherapy alone (BO18255 ToGA trial). The combination of Herceptin with chemotherapy for treating metastatic gastric cancer was also sanctioned by the European regulatory authorities (2010 January). Doctors have also tested putting the anticancer drugs directly into the abdomen, often with warmed solutions of the medication (intraperitoneal hyperthermic chemoperfusion).^[38]

Radiation[link]

Radiation therapy (also called radiotherapy) is the use of high-energy rays to damage cancer cells and stop them from growing. When used, it is generally in combination with surgery and chemotherapy, or used only with chemotherapy in cases where the individual is unable to undergo surgery. Radiation therapy may be used to relieve pain or blockage by shrinking the tumor for palliation of incurable disease.

Multimodality therapy[link]

While previous studies of multimodality therapy (combinations of surgery, chemotherapy and radiation therapy) gave mixed results, the Intergroup 0116 (SWOG 9008) study^[39] showed a survival benefit to the combination of chemotherapy and radiation therapy in patients with nonmetastatic, completely resected gastric cancer. Patients were randomized after surgery to the standard group of observation alone, or the study arm of combination chemotherapy and radiation therapy. Those in the study arm receiving chemotherapy and radiation therapy survived on average 36 months; compared to 27 months with observation.

Epidemiology[link]

Age-standardized death from stomach cancer per 100,000 inhabitants in 2004.^[40]

no data   <3.5   3.5-8   8-12.5   12.5-17   17-21.5   21.5-26

26-30.5   30.5-35   35-40   40-45   45-50   >50

Stomach cancer is the fourth most common cancer worldwide with 930,000 cases diagnosed in 2002.^[41] It is a disease with a high death rate (~800,000 per year) making it the second most common cause of cancer death worldwide after lung cancer.^[1] It is more common in men and in developing countries.^[41][42]

It represents roughly 2% (25,500 cases) of all new cancer cases yearly in the United States, but it is more common in other countries. It is the leading cancer type in Korea, with 20.8% of malignant neoplasms.

Metastasis occurs in 80-90% of individuals with stomach cancer, with a six month survival rate of 65% in those diagnosed in early stages and less than 15% of those diagnosed in late stages.

One in 50 patients of all ages who seek medical attention for burping and indigestion are diagnosed with stomach cancer.^[43] Out of 10 million people in the Czech Republic, only 3 new cases of stomach cancer in people under 30 years of age in 1999 were diagnosed.^[44] Other studies show that less than 5% of stomach cancers occur in people under 40 years of age with 81.1% of that 5% in the age-group of 30 to 39 and 18.9% in the age-group of 20 to 29.^[45]

For Taiwan (statistic not shown on the above map), the mortality was 11.75 per 100,000 (1996).

In other animals[link]

The stomach is a muscular organ of the gastrointestinal tract that holds food and begins the digestive process by secreting gastric juice. The most common cancers of the stomach are adenocarcinomas but other histological types have been reported. Signs vary but may include vomiting (especially if blood is present), weight loss, anemia, and lack of appetite. Bowel movements may be dark and tarry in nature. In order to determine whether cancer is present in the stomach, special X-rays and/or abdominal ultrasound may be performed. Gastroscopy, a test using an instrument called endoscope to examine the stomach, is a useful diagnostic tool that can also take samples of the suspected mass for histopathological analysis to confirm or rule out cancer. The most definitive method of cancer diagnosis is through open surgical biopsy.^[46] Most stomach tumors are malignant with evidence of spread to lymph nodes or liver, making treatment difficult. Except for lymphoma, surgery is the most frequent treatment option for stomach cancers but it is associated with significant risks.

References[link]

External links[link]

Wikimedia Commons has media related to: Stomach cancer

• National Cancer Institute Gastric cancer treatment guidelines
• GeneReview/NIH/UW entry on Hereditary Diffuse Gastric Cancer
• Gastric Cancer Surgery