• Information
  1. Cancers of the Stomach
  2. Incidence
  3. Risk Factors for Gastric Cancer
  4. Symptoms
  5. Diagnosis
  6. Gross and Microscopic Pathology
  7. Staging
  8. Metastases
  9. Treatment of Gastric Adenocarcinoma

A. Cancers of the Stomach

1. Adenocarcinoma - ~90%
2. Non-Hodgkin's Lymphoma (NHL)
3. Leiomyosarcoma
4. Hepatoid Adenocarcinoma - very rare
5. Gastrointestinal Stromal Tumors (GIST) - relatively rare; low metastatic potential
6. Hereditary Diffuse Gastric Cancer [4,5]
7. This discussion focuses on gastric adenocarcinoma

B. Incidence

1. Rates have dropped over past 50 years, especially in developed countries
2. 10 cases per 100,000 persons per year in men, rate half as high in women
3. In 2002, incidence 934,000 cases and 700,000 deaths worldwide
4. Risk is ~2X higher for disease in non-white persons in USA
5. Highest incidence worldwide is in Japan > Costa Rica > China > Brazil
   1. Japanese classify non-invasive neoplastic cells as true adenocarcinoma
   2. Western pathologists usually classify these lesions as adenomas or dysplasi
   3. This may partially explain high incidence and better prognosis of gastric tumors in Japan
6. Death Rate
   1. USA 5 per 100,000 / year
   2. Japan 90 per 100,000 / year

C. Risk Factors for Gastric Cancer

1. ~5% of gastric ulcers are neoplastic (adenocarcinoma)
2. Atrophic gastritis is found in >80% of patients with gastric adenocarcinoma
   1. Chronic inflammation is very common in patients with gastric cancer
   2. Over production of gastric acid may contribute significantly to transformation
3. Chronic Atrophic Gastritis (CAG) Type B
   1. Environmental Factors - mainly smoking, alcoholism (independent gastric cancer risks)
   2. Increased risk with chronic ingestion of smoked foods
   3. Associated with H. pylori and adenocarcinoma of the stomach [6]
4. Helicobacter pylori Infection [6]
   1. Definite association with adenocarcinoma [7,8]
   2. Causes both intestinal type and diffuse type gastric cancers
   3. Severe gastric atrophy, corpus predominant gastritis, intestinal metaplasia are risk factors for adenocarcinoma [8]
   4. CagA toxin produced by some H. pylori may be key in development of adenocarcinoma
   5. H pylori eradication in China with 7.5 year followup showed no reduction in gastric cancer [2]
5. Mucosa Associated Lymphoid Tissue Lymphoma
   1. Causative agent in mucosa-associated lymphoid tissue (MALT) lymphomas (NHL)
   2. Eradication of H. pylori in gastric MALT NHL can lead to remission or cure in ~75% [9]
   3. Resistance of MALT NHL to H. pylori eradication associated with t(11;18) in neoplasm [10]
6. Chronic Atrophic Gastritis (CAG) Type A [11]
   1. Pernicious Anemia is strongly associated with gastric adenocarcinoma
   2. Anti-parietal cell and intrinsic factor autoantibodies
   3. May be associated with autoimmune polyendocrine failure syndromes
   4. Gastric achlorhydria stimulates gastrin production
   5. Gastrin producing cells may progress to carcinoids
7. Gastric Adenomatous Polyps
   1. However, polyps are not a common precursor to gastric cancer
   2. This contrasts with colon cancer, where polyps are a very common precursor
8. Barrett's Esophagus (esophageal metaplasia)
9. Menetrier's Disease
10. Partial Gastrectomy for Benign Disease (usually ulcer)
11. Blood Type A
12. Hereditary Diffuse Gastric Cancer (HDGC) [4,5,7]
    1. Signet ring invasive carcinoma, average onset age 38 years
    2. Due to germ-line truncating mutations in epithelial (E)-cadherin (CDH1) gene
    3. E-cadherin is transmembrane glycoprotein involved in epithelial architecture
    4. Independent mutational and hereditary events occur in affected families
    5. Increased risk (~45% lifetime) for breast cancer, mainly lobular, as well
    6. Prophylactic gastrectomy recommended
    7. Routine screening with endoscopic biopsy is not sensitive for detecting cancer
13. Hereditary Nonpolyposis Colon Cancer Syndrome

D. Symptoms

1. Weight Loss ~60%
2. Abdominal Pain ~50%
3. Nausea ~35%
4. Anorexia ~30%
5. Dysphagia ~25%
6. Melena ~20%
7. Early Satiety ~20%
8. Dyspepsia ~15%

E. Diagnosis

1. Flexible Upper Endoscopy with Biopsy
   1. Method of choice for diagnosis
   2. Usually of gastric ulceration or erosion
   3. Multiple biopsies are recommended
   4. Overall accuracy ~95%
2. CT Scanning of the Abdomen - for staging but often underestimates disease
3. Laparoscopy with sonography is main staging for abdominal involvement
4. Sentinal lymph node (LN) evaluation is under study, has ~90% sensitivity
5. Upper Gastrointestinal Series
   1. Reasonable screening method
   2. False negative rate up to 25% for small lesions (5-10mm diameter)
6. Tumor Markers - none specific; CEA, CA 19-9, AFP may be elevated in some cases

F. Gross and Microscopic Pathology

1. Location
   1. Pylorus and Antrum 50-60%
   2. Cardia 25%
   3. Other areas 15-25%
   4. Lesser curvature ~40%
   5. Greater curvature ~10%
   6. Anterior and posterior walls ~50%
2. Cellular Composition
   1. Nearly all gastric adenocarcinomas have two cell types
   2. Metaplastic intestinal cells
   3. Gastric mucous ("glandular") cells
   4. These gastric mucous cells may secrete large amounts of mucin
   5. They contain many vacuoles which causes their "signet-ring" appearance
3. Classification of Adenocarcinomas [12]
   1. Intestinal type - glandlike tubular structures (glandular type, often ulcerative)
   2. Intestinal type usually arises in distal stomach, mainly found in elderly patients
   3. Diffuse type - individual cells infiltrate and thicken stomach wall; no discrete mass
   4. Diffuse type may be accompanied by abundatnt fibrous stroma
   5. This stroma leads to diffuse thickening of gastric wall
   6. Such thickening has been called "leather-bottle" stomach, or linitis plastica
   7. Diffuse type usually in younger patients; associated with blood group A

G. Staging [1]

1. Primary Tumor (T)
   1. Tis - carcinoma in situ, intraepithelial tumor
   2. T1 - invades lamina propria (T1a) or submucosa (T1b)
   3. T2 - invades muscular propria or subserosa
   4. T3 - penetrates serosa
   5. T4 - invades adjacent structures
2. Lymph-Node (LN) Metastases (N)
   1. N0 - no regional LN involved
   2. NX - <15 investigational LN for analysis
   3. N1 - 1-6 regional LN
   4. N2 - 7-15 regional LN involved
   5. N3 - >15 regional LN metastases
   6. M1 - metastases in retropancreatic, mesenteric or para-aortic nodes
3. Distant Metastases (M)
   1. M0 - none
   2. M1 - distant M present
4. Stages
   1. Stage Ia - T1N0M0
   2. Stage Ib - T2N0M0 or T1N1M0
   3. Stage II - T3N0M0 or T2N1M0 or T1N2M0
   4. Stage IIIa - T4N0M0 or T3N1M0 or N2N2M0
   5. Stage IIIb - T3N2M0
   6. Stage IV - M1 with any T or N; N3 with any T or M; T4N1M0 or T4N2M0

H. Metastases

1. Spread by direct extension through stomach wall to perigastric tissue
2. May cause outlet obstruction (gastroduodenal junction)
3. May invade adjacent structures (liver, colon, pancreas)
4. Lymphatic Spread
   1. Supraclavicular LN - Virchow's Node
   2. Periumbilical LN - Sister Mary Joseph's Node
   3. Intra-abdominal LN
   4. LN spread present in 44% of T2 and 64% of T3 cancers
5. Ovarian Spread - Krukenberg Tumor (gastric cancer on / in ovary)
6. Mass in the cul-de-sac (Blumer's Shelf)
7. Unusual frank peritoneal carinomatosis and malignant ascites
8. May be associated with acanthosis nigricans (velvety hyperpigmented plaques)

I. Treatment of Gastric Adenocarcinoma

1. Based on Staging / Symptoms
   1. Only localized tumors are curable by surgery (up to 90% survival at 5 years)
   2. Generally poor response of tumors to chemo- or radiotherapy
   3. Expandable metal stents for gastroduodenal obstruction [13]
   4. Gastroesophageal junction tumors should be considered as gastric adenocarcinoma
2. Surgery
   1. Surgical eradication of tumor with LN removal is only chance for cure
   2. Attempt at curative resection should be made, even if it is only palliative
   3. Extended LN removal (D2) is no better than more limited (D1) removal [14]
   4. S-1, an oral fluoropyrimidine, given to Stage 2or 3 gastric cancer patients following D2 "curative" resection improved overall 3-year survival from 70% to 80% []
3. Radiotherapy is not very effective
4. Combination Chemotherapy
   1. "FAM" Regimen: 5-Fluorouracil (5-FU), Adriamycin, Mitomycin C
   2. Addition of radiation therapy may improve survival in advanced gastric cancer
   3. ECF (epirubicin, cisplatin, 5-FU) improves survival in locally advanced and metastatic gastric adenocarcinoma when given after surgery
   4. ECF for 3 cycles preoperatively and 3 cycles postoperatively improves overall and progression free-survival compared with surgery alone after 4 years [18]
   5. Perioperative ECF had 36% five year survival compared with 23% for surgery alone [18]
   6. In metastatic esophageal or gastric adenocarcinoma, E+oxaliplatin+capecitabine (Xeloda®) (denoted EOX) gave longer survival than ECF: 11.2 versus 9.9 months [3]
   7. Capecitabine oral is not inferior to infused 5-FU when combined with either EC or EO [3]
   8. Oxaliplatin main side effects diarrhea and neuropathy; reduced neutropenia, alopecia, renal toxicity, thromboembolism versus cisplatin
   9. Adjuvant chemoradiotherapy (5-FU/leucovorin + radiation) improves survival [15]
   10. Consider postoperative chemoradiotherapy in all patients at high risk for recurrence
5. 5-FU + mitomycin with tegafur adjuvant therapy for T1/2 serosa negative gastric cancer did not improve survival (versus surgery alone) [16]
6. Endoscopic mucosal resection may be used for early gastric cancer [17]
7. Under investigation: irinotecan, "ACF" adriamycin, cisplatin and 5-FU
8. Helicobacter pylori eradication did not reduce gastric cancer in China over ~8 years [2]

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