Gastric Cancer

Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Hereditary syndromes, pernicious anemia, and prior partial gastrectomy are among the endogenous risk factors. When symptoms such as epigastric fullness, vomiting, and weight loss occur, it is likely that the cancer is in the advanced stage. Diagnosis is confirmed with esophagogastroduodenoscopy and biopsy. Imaging studies and laparoscopy aid in determining the cancer stage. Consequently, staging dictates the management approach. Management consists of gastrectomy and chemoradiotherapy. Most cases are diagnosed in late stages, indicating a generally poor prognosis.

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Overview

Epidemiology

  • 3rd-most common cause of cancer-related death worldwide
  • High incidence in Eastern Asia, Eastern Europe, and South America
  • Regional differences noted: ↓ incidence in the United States, but ↑ in Japan and South Korea
  • Men > women
  • Median age at the time of diagnosis: 70 years

Etiology

Endogenous risk factors:

  • Chronic atrophic gastritis 
  • Pernicious anemia
  • Previous partial gastrectomy (antrectomy)
  • Blood type A
  • Menetrier’s disease (extreme hypertrophy of gastric rugal folds)
  • Bile reflux
  • Genetic factors and hereditary syndromes:
    • Hereditary diffuse gastric cancer (associated with E-cadherin gene or CDH1 mutation)
    • Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)
    • Familial intestinal gastric cancer (FIGC)
    • Hereditary nonpolyposis colorectal cancer (HNPCC)
    • Peutz-Jeghers syndrome
    • Familial adenomatous polyposis (FAP)
    • Li-Fraumeni syndrome

Exogenous risk factors:

  • Chronic Helicobacter pylori infection (associated with distal intestinal-type adenocarcinoma)
  • Long-term diet rich in nitrates (found in dried, smoked, salted, and partially decayed foods) 
  • Low vegetable consumption
  • Smoking
  • Epstein-Barr virus (EBV) infection
  • Abdominal irradiation in cancer survivors

Types of Gastric Cancer

Adenocarcinoma

  • 85% of gastric cancers
  • Main histologic types:
    • Intestinal type (70%): 
      • Tumor cells exhibit adhesion and have glandular formations.
      • More common in men and older age groups
      • Associated with ↑ incidence in lower socioeconomic classes 
      • Better prognosis
    • Diffuse type (30%): 
      • Poorly cohesive histology, lacking intercellular adhesions (includes signet-ring cell carcinoma)
      • Tumor cells with likelihood of infiltration and manifestation as stomach wall thickening instead of a mass
      • Stomach loses distensibility.
      • Equal sex distribution
      • More common in younger age groups
      • Overall, worse prognosis

Primary gastric lymphoma

  • 13% of gastric cancers
  • Stomach: most common extranodal site of lymphoma
  • Ranges from superficial mucosa-associated lymphoid tissue (MALT) to large cell lymphoma
  • MALT development is associated with H. pylori infection.

Gastrointestinal stromal tumors (GIST)

  • Stromal or mesenchymal tumors, constituting approximately 1% of primary gastric cancers
  • Found in other areas of the digestive tract, but most are in the stomach

Carcinoid tumors

  • Rare
  • Slow-growing neuroendocrine tumors
  • Originate from the hormone-producing (enterochromaffin) cells

Pathophysiology

Intestinal type

  • Chronic infection with H. pylori: a primary risk factor for (intestinal-type) non-cardia gastric cancer
  • Prolonged exposure to risk factor → atrophic gastritis → achlorhydria or hypochlorhydria → ↑ stomach pH → microbial colonization and loss of cells (which produce epidermal and transforming growth factors) needed to regenerate damaged tissue 
  • Follows a pattern of stepwise progression (Correa’s cascade): chronic gastritis → chronic atrophic gastritis → intestinal metaplasia → dysplasia (direct precursor of cancer) → adenocarcinoma

Diffuse type

  • Associated with loss-of-function mutations of CDH1 (tumor suppressor gene that encodes E-cadherin, a cell-adhesion protein) 
  • Neoplastic cells without intercellular adhesion (due to loss of expression of E-cadherin) → infiltration of neoplastic cells within the gastric wall → diffuse thickening of the gastric wall → loss of distensibility (known as linitis plastica, or “leather-bottle” appearance)

Clinical Presentation

Symptoms

  • Asymptomatic in early stages when the cancer is more curable
  • By the time symptoms start, the cancer is already advanced.
  • Initial symptoms occur with insidious onset:
    • Epigastric discomfort (postprandial fullness, steady pain)
    • Anorexia
    • Nausea 
  • Later symptoms as disease progresses:
    • Weight loss
    • Increased nausea and early satiety (noted in linitis plastica as the stomach is unable to distend)
    • Vomiting or gastric outlet obstruction (especially with pyloric tumors)
    • Dysphagia (especially with diffuse-type, esophagogastric and cardiac tumors)
    • Melena or hematemesis

Signs

  • Normal physical exam early in the disease 
  • Epigastric mass indicates long-standing growth.
  • Signs of metastatic gastric carcinoma:
    • Hepatomegaly or palpable liver mass
    • Virchow’s node: palpable node in the left supraclavicular region
    • Irish node: palpable nodes in the left axillary
    • Blumer’s shelf (mass in the pouch of Douglas): palpable on digital rectal or vaginal examination
    • Sister Mary Joseph’s nodule: periumbilical nodule 
    • Krukenberg tumor: malignancy in the ovaries representing metastasis from another site (gastrointestinal source most often)
    • Ascites: can indicate peritoneal carcinomatosis

Paraneoplastic findings

  • Malignant acanthosis nigricans: rapid appearance/growth of dark and velvety patches (usually on skin folds) 
  • Diffuse seborrheic keratoses (Leser-Trélat syndrome)
  • Dermatomyositis
  • Hypercoagulable state
  • Membranous nephropathy

Diagnosis

Surveillance

  • No recommendations for the general population
  • High-risk patients for whom upper endoscopy may be of benefit:
    • Familial adenomatous polyposis
    • Gastric adenomas
    • Elderly with atrophic gastritis or pernicious anemia
    • Hereditary nonpolyposis colorectal cancer 
    • History of partial gastrectomy
    • High risk immigrant ethnic population

Diagnosis

  • Esophagogastroduodenoscopy (EGD):
    • Diagnostic imaging procedure of choice
    • Evaluates gastric mucosa and lymph node involvement
    • Allows deep mucosal/ulcer biopsy (to distinguish benign from malignant ulcers)
    • Possible findings suggesting gastric cancer:
      • Friable ulcerated mass
      • Gastric ulcer with irregular or thickened margins 
      • In linitis plastica, normal mucosa is noted but with poor stomach distensibility.
  • Double-contrast barium swallow study:
    • Low sensitivity 
    • Useful in evaluating linitis plastica, which has a leather-bottle appearance

Endoscopic image of linitis plastica, where the entire stomach is invaded with cancer, leading to a leather-bottle appearance

Image: “Linitis plastica” by Samir. License: Public Domain

Staging procedures

  • Computed tomography (CT) of the chest, abdomen, and pelvis:
    • Provides information on the primary tumor and the local extent of the disease
    • Evaluates areas for distant metastasis 
  • Endoscopic ultrasonography (EUS): 
    • Most reliable in evaluating depth of tumor invasion 
    • Detects regional nodal involvement and allows fine-needle aspiration of lymph node
  • 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan:
    • Detection of occult metastatic lesions (especially in ≥ T2N0 disease)
    • More sensitive than CT in detecting distant metastases
  • Staging laparoscopy:
    • As peritoneal metastases can be missed by CT, laparoscopy helps determine occult peritoneal dissemination. 
    • Allows peritoneal washings and cytology

(a) Upper gastric endoscopy revealing a giant polypoid-type tumor extending from the duodenum bulb to the pyloric ring
(b) An endoscopic ultrasound test suggesting tumor invasion of the muscular tunic (white arrows)

Image: “Giant polypoid tumor expressing on the pyloric ring” by Sonoda H, Kobayashi T, Endo Y, Irie S, Hirata T, Minamimura K, Mafune K, Mori M. License: CC BY 3.0

Tumor, Nodes, Metastases (TNM) Classification and Stages

Table: TNM classification for the staging of gastric carcinoma
T (primary tumor)N (lymph nodes affected)M (distant metastases)
TXCannot be assessedN0No regional lymph nodesM0No distant metastases
T0No evidence of tumorN11–2 regional nodesM1Confirmed metastases
TisCarcinoma in situN23–6 regional nodes
T1Invasion up to submucosaN37 or more regional nodes
T2Invasion of muscularis propria
T3Invasion of serosa
T4aPerforates serosa
T4bAdjacent structures affected
Table: Clinical Staging System for Gastric Carcinoma
StageTNMFeatures
0TisN0M0Node negative; limited to mucosa
1T1-2N0M0Node negative; invasion of submucosa up to muscularis propria
2aT1N1-3M0
T2N1-3M
Node positive; invasion of muscularis propria
2bT3N0M0
T4aN0M0
Node negative; invasion up to serosa
3T3,N1-3,M0
T4a,N1-3, M0
Node positive; invasion up to serosa
4aT4b, any N, M0Node positive; beyond serosa, up to adjacent structures
4bAny T, N, M1Distant metastases

Clinical staging of gastric cancer:
Stage 0: node negative; limited to mucosa
Stage 1: node negative; invasion of submucosa and part of muscularis propria
Stage 2: node negative with invasion up to serosa or node positive with invasion up to muscularis propria
Stage 3: node positive; invasion of serosa
Stage 4: node positive; invasion up to adjacent structures with or without distant metastasis

Image by Lecturio.

Management and Prognosis

Management

  • H. pylori eradication therapy for those with positive infection
  • Clinical staging dictates initial therapy. 
  • Locoregional disease (stage I–III):
    • Preoperative (neoadjuvant) chemotherapy for downstaging
    • Surgery for proximal tumors: total gastrectomy and resection of adjacent lymph nodes 
    • Surgery for distal (lower ⅔) tumors: subtotal gastrectomy and resection of adjacent lymph nodes
    • Postoperative (adjuvant) combination chemotherapy ± chemoradiotherapy (depending on the stage)
  • Locally advanced unresectable or metastatic (stage IV):
    • Limited palliative gastric resection 
    • Palliative chemotherapy
    • Radiation therapy 
    • Trastuzumab if human epidermal growth factor receptor 2 (HER2)–positive tumor
    • Endoscopic stenting
  • Other: prophylactic gastrectomy considered in those with E-cadherin gene or CDH1 mutation

Prognosis

  • 5-year survival of gastric adenocarcinoma is 30%.
  • 5-year survival for those who undergo curative surgical resection is > 45%.
  • Main factors determining prognosis after resection: 
    • Staging 
    • Histologic type
    • Resection margins

Postgastrectomy Complications

Small intestinal bacterial overgrowth (SIBO)

  • The normally low amount of bacteria in the small intestine increases or other pathogens have significant growth.
  • Bacterial overgrowth facilitated by decreased gastric acid secretion and blind loops
  • Clinical features: 
    • Diarrhea, bloating
    • Malabsorption that leads to weight loss
    • Steatorrhea and osmotic diarrhea
  • Diagnosis: 
    • Jejunal aspirate cultures
    • Carbohydrate (lactulose) breath test 
  • Management: antibiotics and nutrient supplementation

Dumping syndrome

  • Related to motility (rapid gastric emptying)
  • Due to bypass of pyloric sphincter
  • Early dumping type:
    • Impaired pyloric sphincter leads to rapid emptying of hyperosmolar chyme.
    • Vomiting, diarrhea, abdominal cramps
    • Vasomotor symptoms (sweating, flushing, and palpitations) occur after ingestion of a meal.
  • Late dumping type: 
    • Rapid glucose absorption causes hyperinsulinemic response.
    • Postprandial hypoglycemia 
    • Tremor and faintness occurring 1 hour after the meal
  • Management: 
    • Dietary modifications (more fiber); frequent small meals that are rich in protein and fat
    • Consider octreotide; reoperation in certain cases

Gastric stasis

  • Related to motility (slow transit)
  • Due to vagal denervation, small stomach remnant, or postsurgical atony
  • Clinical features: early satiety, vomiting, abdominal pain
  • Management: 
    • Use of prokinetic agents
    • If severe, total gastrectomy considered

Other long-term effects

  • Reduced iron absorption: anemia 
  • Reduced B12 absorption (no intrinsic factor): B12 deficiency 
  • Reduced calcium absorption: osteoporosis 
  • Gallstones
  • Peptic ulcer
  • Partial gastrectomy is a risk for remnant cancer.

References

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