Gastric cancer

Gastric cancer is the fifth most common cancer worldwide. Although the incidence is declining in the United States, it remains high in some Asian countries, most notably Japan, South Korea, and Mongolia. The main risk factor for developing gastric cancer is infection with Helicobacter pylori. Other risk factors include GERD, a diet high in salts and nitrates, and tobacco use. Adenocarcinoma accounts for 95% of gastric cancer and is further classified as intestinal or diffuse type. Less frequent gastric cancers include gastric lymphomas, gastrointestinal stromal tumors, and neuroendocrine tumors. Early on, patients are commonly asymptomatic or have nonspecific symptoms (e.g., dyspepsia, epigastric pain). Later on patients may develop signs of metastatic disease or complications (e.g., gastric outlet obstruction, GI bleeding, ascites). Diagnosis is confirmed with upper endoscopy and biopsy. Staging via imaging or diagnostic laparoscopy helps inform the treatment. Early nonmetastatic disease is typically treated with surgery and perioperative chemotherapy. Unresectable or metastatic disease is treated with systemic chemotherapy or chemoradiation. Targeted therapy can be added based on tumor molecular characteristics. Palliative care is the mainstay of therapy for patients with frailty and an advanced cancer stage. The prognosis varies according to tumor stage, but the overall 5-year survival rate is low as the diagnosis is often made late once symptoms progress.

• Incidence
  • An estimated 27,600 new cases were diagnosed in the US in 2020. ^[1][2]
  • Highest incidence in South Korea, Mongolia, and Japan ^[3]
• Sex: ♂ > ♀ ^[2]

Epidemiological data refers to the US, unless otherwise specified.

Exogenous risk factors ^[2]

• Diet rich in nitrates and/or salts (e.g., dried foods, foods preserved by curing or smoking); and low in fresh vegetables containing antioxidants ^[4]
• H. pylori infection ^[5]
• Nicotine use
• Epstein-Barr virus
• Low socioeconomic status ^[6]
• Obesity ^[7]

Endogenous risk factors ^[2]

• Gastric conditions
  • Chronic atrophic gastritis and associated pernicious anemia ^[8]
  • Achlorhydria (e.g., due to Ménétrier disease)
  • Gastric ulcers ^[9]
  • Partial gastrectomy
  • Adenomatous gastric polyps
  • Gastroesophageal reflux disease
• Hereditary factors
  • Positive family history
  • Blood type A
  • Hereditary nonpolyposis colorectal cancer

Early stages of gastric cancer

• Often asymptomatic
• Loss of appetite, nausea

Late stages of gastric cancer

• General signs
  • Weight loss (may be aggravated by reduced calorie intake due to abdominal pain after meals)
  • Signs of chronic iron deficiency anemia
  • Palpable tumor in epigastric region
• Signs of gastric outlet obstruction
  • Dysphagia
  • Abdominal pain
  • Early satiety
  • Vomiting
• Signs of upper gastrointestinal bleeding
  • Hematemesis
  • Melena
• Signs of metastatic disease
  • Hepatomegaly
  • Ascites
  • Left supraclavicular adenopathy (Virchow node)
  • Palpable umbilical nodule (Sister Mary Joseph node)
  • Palpable mass on digital rectal examination (Blumer shelf)
  • Ovarian mass (Krukenberg tumor)
  • See “Complications” below.
• Paraneoplastic syndromes
  • Leser-Trélat sign
  • Malignant acanthosis nigricans

Gastric cancer is frequently diagnosed during the endoscopic evaluation of nonspecific symptoms or findings (e.g., heartburn, dyspepsia, anemia, weight loss). Patients typically need repeat endoscopic tissue sampling for histopathologic studies and imaging studies for cancer staging.

Diagnostic approach ^[10][11][12]

• Diagnostic confirmation: EGD with biopsy (test of choice)
• Staging: evaluate for lymph node involvement and metastatic disease.
  • All patients: Obtain CT abdomen, pelvis, and thorax. ^[11]
  • Potentially resectable disease (M0): Consider endoscopic ultrasound (EUS) and diagnostic laparoscopy. ^[10][13]
  • Additional modalities include upper GI series and PET-CT.
• Additional diagnostics (case by case)
  • Laboratory studies; : e.g., to identify anemia
  • Tissue analysis for biomarkers: e.g., HER2; , TNF-α

Over half of patients with gastric cancer in the US present with advanced disease (stage III or higher) at the time of diagnosis. ^[14]

EGD with biopsy ^[15][16]

• Indications include:
  • Clinical features suspicious for gastric cancer
  • Incidental finding of gastric cancer on previous EGD
• Procedure
  • Visual identification and biopsy of suspicious lesions
  • Frequently combined with EUS
• Findings
  • Location, size, and depth of the tumor
  • Macroscopic appearance: exophytic mass, ulcer, or diffuse infiltration (linitis plastica) ^[17]
  • Histopathology findings include the presence of biomarkers (see “Additional diagnostics”)

Staging investigations ^[10][11][13]

Imaging

• Routine modalities
  • CT abdomen, pelvis, and thorax with oral and IV contrast: evaluation for distant metastasis and locoregional staging for all patients
  • EUS with or without fine-needle aspiration biopsy (FNAB): locoregional staging for potentially resectable cancers
• Additional modalities
  • PET-CT: may be considered for the detection of metastatic disease
  • Upper GI series (UGI): may identify linitis plastica ^[15][18]
  • Abdominal ultrasound: may be used to scan for liver metastasis and ascites ^[19]
  • MRI abdomen and pelvis: if CT and EUS are inconclusive or patients have contraindications for iodinated IV contrast
• Findings
  • Local tumor extension and lymph node involvement
  • Metastatic disease, e.g., of the liver or peritoneum
  • Signs of unresectable disease, e.g., encasement of major blood vessels

Diagnostic laparoscopy ^[10][13][20]

• Procedure: direct visualization and biopsy of peritoneal lesions, collection and cytology of peritoneal fluid
• Indication: Consider in patients with potentially resectable carcinoma.
• Findings: peritoneal carcinomatosis (frequently not visible on imaging) ^[13]

The peritoneum is the most common site of metastasis in gastric cancer. Curative gastrectomy is typically not attempted if diagnostic laparoscopy or peritoneal cytology indicate peritoneal metastasis. ^[13][21]

Additional diagnostics ^[10][12][13]

• Laboratory studies
  • CBC: may show anemia ^[22][23]
  • CMP: baseline renal and hepatic function
  • H. pylori diagnostics: indicated after endoscopic resection ^[12][24][25]
• Biomarkers
  • Serologic biomarkers: not routinely used in the US ^[12][26]
    • CEA, CA-19-9, CA 72-4
    • TNF-α ^[27][28]
  • Tissue analysis
    • HER2: used to select patients with unresectable disease for targeted therapy ^[29]
    • Additional biomarkers: microsatellite instability (MSI) , programmed death-ligand 1 (PD-L1) ^[13][30][31]
• Fecal occult blood testing: may be positive ^[32]

Gastric adenocarcinoma

General features

• Accounts for ∼ 95% of cases ^[34]
• Most commonly located on the lesser curvature
• Arises from glandular cells in the stomach

Lauren classification of gastric adenocarcinoma

• Intestinal type gastric carcinoma
  • Typically localized
  • Polypoid, glandular formation
  • Similar to an ulcerative lesion with clear raised margins
  • Commonly located on the lesser curvature
• Diffuse type gastric carcinoma
  • No clear border
  • Spreads earlier in the course of disease
  • Infiltrative growth
  • Diffuse spread in the gastric wall
  • Linitis plastica: gastric wall thickening and leather bottle appearance
  • Composed of signet ring cells: round cells filled with mucin, with a flat nucleus in the cell periphery
  • Associated with E-cadherin mutation ^[35]
• Intermediate type (the least common type): should be treated as the diffuse type, as the extent of tumor infiltration is difficult to assess

See also “Approach to dyspepsia” and “Acute abdominal pain.”

Gastric conditions

• Gastric ulcer
• Gastroesophageal reflux disease (GERD)
• Ménétrier disease
• Functional dyspepsia

Other types of cancer

• Gastric lymphoma (e.g., MALT lymphoma)
• Sarcoma
• Neuroendocrine tumor (e.g., carcinoid tumor)

Gastrointestinal stromal tumor (GIST) ^[36]

• Definition: malignant mesenchymal neoplasm of the gastrointestinal tract that arises from interstitial cells of Cajal or precursor cells
• Epidemiology
  • Incidence: ∼ 3,300–4,350 annually in the US
  • Age of onset: ∼ 60 years of age
• Etiology: associated with c-KIT gene mutations and PDGFRA gene mutations
• Pathophysiology: mutations in c-KIT or PDGFRA → phosphorylation of receptor tyrosine kinases → perpetual, ligand-independent activation of downstream effectors → ↓ apoptosis and ↑ cellular proliferation → neoplasia
• Localization
  • Stomach (60%)
  • Small intestine (35%, more frequent in familial forms and syndromes)
  • Colon, rectum, esophagus, or omentum (5%)
• Clinical features
  • Small tumors (< 2 cm): often asymptomatic
  • Large tumors (> 2 cm)
    • Ulceration, bleeding → anemia, melena, and hematemesis
    • Obstruction → ileus
• Diagnostics
  • Imaging: CT, MRI, ultrasound
  • Endoscopy with biopsy
  • Immunohistochemistry
  • Molecular genetic testing: c-KIT or PDGFRA mutations
• Treatment: Treatment involves surgical removal and treatment with tyrosine kinase inhibitors such as imatinib or dasatinib.
  • Small GIST (< 2 cm)
    • Stomach: to be observed; endoscopic removal possible
    • Other localization: resection
  • Large GIST (> 2 cm)
    • Surgical excision is required.
    • Neoadjuvant and/or adjuvant treatment with imatinib may be considered.
  • Nonresectable/metastatic GIST
    • Palliative treatment using imatinib
    • In the case of imatinib resistance, the second-line treatment is sunitinib.
• Prognosis
  • Depends predominantly on tumor size, mitotic rate, and tumor location
  • Small tumors (> 2 cm but ≤ 5 cm) and gastric location are associated with a low risk of disease progression, metastases, and recurrence (2%).
  • However, large tumors (> 10 cm), tumors > 5 cm with a mitotic count higher than 5/50 HPF, and jejunal/ileal location carry a significantly increased risk of progression (90%). ^[37]

The differential diagnoses listed here are not exhaustive.

Approach ^[10][13]

Provide multidisciplinary care where available (e.g., tumor board) and base treatment plan on patient fitness, disease characteristics, and goals of care (see “Principles of cancer care” for more information).

• Localized, resectable disease
  • Stages 0 and IA (≤ T1 and ≤ N0): surgical or endoscopic resection
  • Stage IB or higher (≥ T2 and/or N > 0): surgical resection plus perioperative chemotherapy or adjuvant chemoradiotherapy
• Specific molecular markers present: Consider adding targeted therapy and/or immunotherapy.
• Metastatic or unresectable cancer: Provide palliative care.

The mainstay of treatment for nonmetastatic gastric cancer is surgical resection with perioperative chemotherapy.

Resection ^[13][14]

Margin-free resection (R0 resection) is the only potentially curative therapy. However, it is only possible in 30% of patients and is associated with a high recurrence rate. ^[32][38]

Surgical

The following procedures are typically combined with radical lymphadenectomy and reconstructive procedures (e.g., Roux-en-Y anastomosis). ^[10]

• Total gastrectomy
  • Indication: resectable cancer in the proximal or middle third of the stomach
  • Technique: complete resection of the stomach
• Subtotal gastrectomy
  • Indication: can be considered for resectable cancer in the distal stomach
  • Technique: resection of the body and pylorus of the stomach
• Esophagectomy (with mediastinal lymphadenectomy): may be required for adenocarcinoma of the esophagogastric junction (see “Esophageal cancer”) ^[39]

Endoscopic

• Options
  • Endoscopic mucosal resection
  • Endoscopic submucosal dissection
• Indication: well-differentiated, nonulcerated tumor ≤ 2 cm limited to the mucosa ^[10][13]
• Technique: tumor resection or dissection completely through an endoscope
• Additional consideration: H. pylori testing, and if positive, H. pylori eradication therapy ^[24]

Reconstructive procedures ^[40][41][42]

• Roux-en-Y anastomosis
  • Applications: reestablishing continuity of the GI tract following gastrectomy (total or subtotal); bariatric surgery
  • Technique
    • The jejunum is divided transversely distal to the duodenum.
    • Esophagojejunostomy or gastrojejunostomy: end-to-end anastomosis between the distal esophagus or remaining part of the stomach and the distal limb of the transected jejunum
    • Jejunojejunostomy: end-to-side anastomosis between the proximal limb of the transected jejunum and the transversely incised distal jejunum
• Billroth I or Billroth II procedures: alternative reconstruction techniques for subtotal gastrectomy

Chemotherapy and radiotherapy ^[10][13]

• Indications for chemotherapy
  • Perioperative treatment (neoadjuvant and adjuvant therapy) of resectable disease
  • Primary treatment of metastatic or unresectable disease
• Typical chemotherapy regimens
  • Fit patients: double- or triple-agent therapy consisting of a platinum-based agent PLUS fluoropyrimidine, ± taxane
  • Frail patients: single-agent therapy with a fluoropyrimidine, irinotecan, or taxane
• Radiotherapy (not routinely used)
  • Chemoradiation can be used as adjuvant therapy or as primary treatment for unresectable disease. ^[32][43]
  • Consider radiotherapy for palliative symptom control. ^[44]

A combination of preoperative and postoperative chemotherapy significantly improves survival in resectable disease. ^[45]

Personalized treatment ^[10][12][13]

Gastric cancers are genetically diverse and have multiple possible genetic mutations amenable to therapeutic manipulation. Systemic therapy may be modified based on the presence of specific molecular markers.

• Targeted therapy
  • Trastuzumab is added to the chemotherapy regimen for HER2-positive metastatic disease. ^[29]
  • Ramucirumab, a monoclonal antibody against VEGF, is used as part of second-line regimens.
• Cancer immunotherapy: may be added in cases of MSI and/or PD-L1 overexpression ^[30][31]

For the forms of cancer associated with HER2 gene overexpression and the medication used for treatment, think: TRUST HER, GaBriel (TRUSTuzumab; HER2; Gastric cancer; Breast cancer).

Supportive and palliative care ^[46]

• Nutritional support ^[47][48]
  • Enteral nutrition (preferred): enteral feeding tube, e.g., jejunostomy tube
  • Parenteral nutrition: in patients unable to tolerate enteral nutrition or to briefly complement enteral nutrition
• Management and prevention of complications
  • Management of GI bleeding
    • Endoscopic intervention (first-line) ^[46]
    • Transcatheter arterial embolization ^[49]
    • External beam radiotherapy
  • Ascites control ^[50]
    • Diuretics and sodium restriction
    • Therapeutic paracentesis
    • Peritoneovenous shunt
  • See also “Gastric outlet obstruction” and “Postgastrectomy complications.”

Metastatic disease

• Local invasion of adjacent structures
  • Peritoneal carcinomatosis
  • Infiltration of structures such as the esophagus, transverse colon, and pancreas
• Hematogenous spread
  • Skeleton
  • Liver
  • Lung
  • Brain
• Lymphangitic spread
  • Virchow node: left supraclavicular lymph node metastasis
  • Celiac, paraaortic, and mesenteric lymph nodes
  • Sister Mary Joseph node: periumbilical lymph node metastasis (subcutaneous)
  • Krukenberg tumor
  • Lymph nodes of the lesser and greater curvature
  • Mediastinal lymph nodes (in carcinoma of the cardia)
• Direct seeding: Blumer shelf (direct seeding to the pouch of Douglas)

The Skeleton (bones), Liver, Lung, and Brain are the structures most commonly affected by hematogenous spread of gastric cancer: Zombie SKELETONs don't LIVE LONG (lung) without eating BRAINs.

Paraneoplastic syndromes

Paraneoplastic syndromes may be signs of visceral malignancies, especially GI carcinomas. These syndromes include:

• Malignant acanthosis nigricans
• Leser-Trélat sign

Always rule out malignancy in patients with acanthosis nigricans.

Gastric outlet obstruction (GOO) ^[46][51]

• Definition: mechanical obstruction of the distal stomach, pyloric channel, or duodenum
• Etiology
  • Malignancy (most common)
    • Intrinsic lumen reduction: gastric or duodenal cancer
    • Extrinsic compression: pancreatic or biliary malignancy, lymphoma
  • Peptic ulcer disease (PUD)
  • Other: gastric volvulus, strictures , foreign bodies
• Clinical features
  • Postprandial, nonbilious vomiting
  • Early satiety
  • Weight loss
  • Progressive abdominal dilation
  • Succussion splash: a splashing sound created by the movement of gastric contents
    • Physiological if present immediately after a meal
    • Pathological if present after ≥ 3 hours of fasting
• Diagnostics
  • UGI series
  • CT or MRI abdomen
  • EGD (confirmatory)
  • Laboratory studies (supportive): hypokalemic hypochloremic metabolic alkalosis
  • Saline load test ^[52]
• Supportive care
  • Establish NPO status.
  • Consider NG tube placement.
  • Consider parenteral nutrition.
  • Administer IV fluid therapy and replete electrolytes.
  • IV PPI, e.g., pantoprazole
  • Analgesics and antiemetics as needed
• Definitive treatment
  • Treat the underlying cause (e.g., H. pylori eradication).
  • Relieve the obstruction.
    • Endoscopic options: stent placement, ultrasound-guided gastrojejunostomy ^[53][54]
    • Surgical options: gastrectomy, gastrojejunostomy
    • Consider radiation or chemotherapy for malignant obstruction.

Postgastrectomy complications

Malabsorption

• Pathophysiology
  • Lack of chyme stimulation → ↓ pancreatic enzyme levels → protein and carbohydrate maldigestion → fat-soluble vitamin deficiency and weight loss
  • Loss of parietal cells → ↓/absent intrinsic factor production → vitamin B₁₂ deficiency → pernicious anemia
  • Critical reduction of the absorptive surface → ↓ time for chyme absorption → ↓ iron absorption → iron deficiency anemia
• Management
  • Diet modifications
    • Increased protein intake
    • Supplementation of medium-chain triglycerides
    • Low carbohydrate diet
  • Supplementation of pancreatic enzymes and deficient nutrients (e.g., vitamin B₁₂, iron, fat-soluble vitamins)

Small intestinal bacterial overgrowth (SIBO)

• Definition: a pathologically increased growth of bacteria in the small intestine
• Etiology
  • Anatomic causes
    • Short bowel syndrome
    • Blind loop syndrome: bacterial overgrowth in the bypassed intestinal segment (blind loop) that occurs as a result of gastrectomy
    • Small bowel diverticulosis
    • Inflammatory bowel disease
  • Motility disorders
    • Irritable bowel syndrome
    • Diabetes mellitus
    • Scleroderma
  • Gastrointestinal conditions
    • Atrophic gastritis
    • Chronic pancreatitis
  • Iatrogenic: as complication of gastric bypass procedures
• Pathophysiology: all resulting from bacterial overgrowth ^[55]
  • ↓ Absorption of vitamin B₁₂, fat-soluble vitamins, zinc, and iron
  • ↑ Production of folate
  • ↑ Deconjugation of the bile acids
• Clinical features
  • Diarrhea, steatorrhea
  • Abdominal discomfort, flatulence
  • Weight loss, malabsorption
• Diagnostics ^[56]
  • Jejunal aspirate cultures collected during endoscopy
  • Positive lactulose breath test
• Management
  • Antibiotic therapy
  • Parenteral supplementation of vitamins and proteins
  • In some cases, surgical treatment

Efferent loop syndrome

• Definition: kinking or anastomotic narrowing of the efferent loop that causes emesis and/or a feeling of fullness
• Management
  • Acute abdomen requires immediate surgical treatment.
  • In uncomplicated cases: watch and wait

Afferent loop syndrome

• Definition
  • Biliary and pancreatic obstruction due to stenosis, kinking, or incorrect anastomosis of the afferent loop
  • Chyme enters the afferent loop instead of the efferent loop and causes loss of appetite, a feeling of fullness, and bilious vomiting with subsequent relief of nausea.
• Management: surgical treatment

Dumping syndrome

• Definition: rapid gastric emptying as a result of defective gastric reservoir function, impaired pyloric emptying mechanisms, or anomalous postsurgery gastric motor function

Early dumping

• Pathophysiology: dysfunctional or bypassed pyloric sphincter → rapid emptying of undiluted hyperosmolar chyme into the small intestine → fluid shift to the intestinal lumen → small bowel distention → vagal stimulation → increased intestinal motility
• Clinical features
  • Occur within 15–30 minutes after meal ingestion
  • Include nausea, vomiting, diarrhea, and cramps
  • Vasomotor symptoms such as sweating, flushing, and palpitations
• Management
  • Dietary modifications: small meals that include a combination of complex carbohydrates and foods rich in protein and fat
  • 30–60 min of rest in the supine position after meals
  • Beta blockers may be helpful to ease tachycardia arising from hypovolemia.

Late dumping

• Pathophysiology: dysfunctional pyloric sphincter → rapid emptying of glucose-containing chyme into the small intestine → quick reabsorption of glucose → hyperglycemia → excessive release of insulin → hypoglycemia and release of catecholamines
• Clinical features
  • Occur hours after meal ingestion
  • Include signs of hypoglycemia (e.g., hunger, tremor, lightheadedness)
  • GI discomfort
• Management
  • Dietary modifications
  • Second-line treatment: octreotide
  • Third-line treatment: surgery

Suspect late dumping syndrome in a patient with previous gastric surgery and hypoglycemia.

Remnant gastric cancer ^[57][58][59]

• Definition: the development of carcinoma in the remnant stomach after gastrectomy, regardless of the initial gastric condition or its duration
• Pathophysiology: Studies suggest that duodenogastric reflux, chronic irritation due to biliary or pancreatic secretions, and the denervation of gastric mucosa after surgery result in chronic inflammation of the remnant mucosa.
• Management: total gastrectomy with Roux-en-Y anastomosis and radical lymph node dissection

We list the most important complications. The selection is not exhaustive.

• Because there are no early signs, gastric cancer is often diagnosed very late. Around 50% of cancers have already reached an advanced stage that does not allow for curative treatment due to tissue invasion and metastases. ^[33]
• If diagnosed at a very early stage, the 5-year survival rate is 95%. ^[60]
• Late-stage disease with distant metastases and/or peritoneal carcinomatosis has a poor prognosis (5-year survival rate of ∼ 5%). ^[61]