Gastric cancer

Gastric cancer refers to neoplasms in the stomach, including cancers of the esophagogastric junction. The incidence is declining in the United States and Europe, while it is rising in Japan and South Korea. Gastric cancer is associated with several risk factors (e.g., consumption of foods high in nitrates, increased alcohol and nicotine intake, Helicobacter pylori infection). In its early stages, the disease is often asymptomatic or accompanied by nonspecific symptoms (e.g., epigastric discomfort, postprandial fullness, or nausea). Late-stage disease may present with gastric outlet obstruction (mechanical obstruction of the pyloric canal), leading to weight loss and vomiting. Biopsy during endoscopy confirms the diagnosis. Adenocarcinomas are the most common form of gastric cancer. Treatment includes endoscopic or surgical resection. Depending on staging, chemotherapy may be indicated before or after surgery (neoadjuvant or adjuvant chemotherapy), or as a palliative therapy.

• Sex: ♂ > ♀
• Peak incidence: 70 years
• Geographical distribution: strong regional differences
  • High incidence in South Korea and Japan
  • Declining incidence in the United States and Europe

References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• Exogenous risk factors
  • Diet rich in nitrates and/or salts (e.g., dried, preserved food)
  • Alcohol and nicotine use
  • Low socioeconomic status
  • Obesity (for cancers of the gastroesophageal junction)
• Endogenous risk factors
  • Diseases associated with a higher risk of gastric cancer
    • Atrophic gastritis
    • H. pylori infection; : associated with a higher risk of intestinal gastric cancer but not with diffuse gastric cancer
    • Gastric ulcers
    • Partial gastrectomy
    • Gastroesophageal reflux disease (GERD; for cancers of the gastroesophageal junction)
    • Adenomatous gastric polyps
  • Hereditary factors (positive family history, hereditary non‑polyposis colorectal cancer)
  • Higher incidence in individuals with blood type A.

References:^{[1][3][4][5][6]}

Gastric cancer is often asymptomatic. Early signs are nonspecific and often go unnoticed. At later stages the following symptoms may occur:

• General signs
  • Weight loss
  • Chronic iron deficiency anemia; (paleness, fatigue, headaches)
• Gastrointestinal signs
  • Abdominal pain
  • Early satiety
  • Nausea or vomiting
  • Dysphagia
  • Acute gastric bleeding (hematemesis or melena)
• Late stage gastric cancer
  • Palpable tumor in epigastric region
  • Gastric outlet obstruction
  • Hepatomegaly, ascites
  • Virchow's node: left supraclavicular adenopathy, located where the thoracic duct joins the subclavian vein at the venous angle.
  • Sister Mary Joseph's node: umbilical node indicating metastasis from a gastrointestinal or abdominopelvic malignancy
  • Acanthosis nigricans (in particular associated with gastric adenocarcinoma)

Metastatic Disease

• Lymphangitic spread
  • All local lymph nodes (lesser and greater curvature)
  • Celiac, paraaortic, and mesenteric lymph nodes
  • Carcinoma of the cardia may spread to mediastinal lymph nodes.
• Hematogenous spread: liver, lung, skeleton, brain
• Local invasion of adjacent structures
  • Peritoneal carcinomatosis
  • Esophagus, transverse colon, pancreas, etc.
• Direct seeding
  • To the ovaries (Krukenberg tumor); : an ovarian malignancy comprised of signet ring cells that has metastasized from a primary site, most commonly the stomach
  • To the pouch of Douglas

Diagnostic procedures

• Upper endoscopy with biopsy (best initial test) : Biopsy confirms the diagnosis
• Barium upper GI series may be considered and would show loss of intestinal folds and stenosis

Laboratory test

• Iron deficiency anemia
• Serologic markers : TNF-α as possible future tumor marker

Staging

• Abdominal ultrasound
• Endosonography
  • Assessment of tumor depth and local lymph nodes (T-stage)
  • Does not exclude lymphatic metastases
• Abdominal and pelvic CT-scan using intravenous and oral contrast; sufficient oral contrast is required to fill the stomach
• Thoracic CT-scan
• Diagnostic laparoscopy

Staging of gastric cancer is essential to determine the correct treatment options. When first diagnosed with gastric cancer, ∼ 70% of patients already show metastatic spread to the lymph nodes!

References:^{[9][10][11][12]}

• Adenocarcinoma (90% of cases)
  • Typically localized, exophytic lesion +/- ulceration
  • Arise from glandular cells in the stomach; usually located on the lesser curvature of the stomach
• Signet ring cell carcinoma
  • Diffuse growth
  • Multiple signet ring cells = round cells filled with mucin, with a flat nucleus in the cell periphery
• Less common
  • Adenosquamous carcinoma
  • Squamous cell carcinoma
  • Undifferentiated carcinoma

Lauren classification of gastric adenocarcinoma

• Intestinal type (∼ 50% of cases): polypoid, glandular formation; expanding (not infiltrative) growth pattern; clear border
• Diffuse type (∼ 40% of cases): infiltrative growth and diffuse spread in the gastric wall, no clear border
• Mixed type (∼ 10% of cases)

References:^[9]

• Gastric ulcer
• Gastroesophageal reflux disease (GERD)
• Ménétrier's disease
• Non-ulcer dyspepsia
• Other types of cancer
  • MALT lymphoma
  • Sarcoma
  • Gastrointestinal stromal tumor (GIST)
    • Description: GIST is a malignant mesenchymal neoplasm of the gastrointestinal tract, resembling the intestinal cells of Cajal
    • Localization
      • 50–60% stomach
      • 20–30% small intestine (more frequently in familial and syndromal forms)
      • Rare: colon, rectum, esophagus, omentum
    • Clinical features
      • Often small (< 2 cm) and asymptomatic → mainly benign
      • Large tumors may cause ulceration and bleeding, or an obstruction leading to ileus → mostly malignant
      • Clinical sign for progression and malignancy: size of the tumor > 2 cm and localization outside of the stomach
    • Treatment
      • Small GIST (< 2 cm)
        • Stomach: to be observed, endoscopic removal possible
        • Other localization: resection
      • Large GIST (> 2 cm): surgical excision ± neoadjuvant and/or adjuvant treatment with imatinib
      • Palliative treatment using imatinib, if the tumor is not resectable and has developed metastases.

The differential diagnoses listed here are not exhaustive.

Principles of treatment

• Exact therapy, which may be either curative or palliative , depends on staging and the type of tumor.
  • Endoscopic resection
  • Surgery
  • Perioperative chemotherapy, sometimes radiotherapy
    • Neoadjuvant chemotherapy to reduce the size of the tumor and ensure curative resectability
    • Adjuvant chemotherapy to ensure treatment success and reduce rate of recurrence
  • Trastuzumab is indicated for HER2+ gastric adenocarcinomas

Endoscopic resection of superficial gastric cancer

• Curative treatment: up to T1a (N0M0) → endoscopic resection
  • En bloc resection using endoscopic mucosal resection (= EMR) or endoscopic submucosal dissection (= ESD)
  • Local recurrence (up to T1a) may be resected endoscopically.

Surgery (stage-adapted)

• T1b and more (NxM0): surgical resection with curative intent (if operable and resectable)
• Radical gastrectomy and D2 lymphadenectomy (operative standard)
  • Resection of the lesser and greater omentum and radical lymphadenectomy of compartments I (perigastric lymph nodes along the greater and lesser curvature of the stomach) and II (lymph nodes along the left gastric artery, common hepatic artery, splenic artery, celiac trunk, and along the vessels in hepatoduodenal ligament)
  • Splenectomy only in the case of pathological lymph nodes in the splenic hilus and/or a carcinoma of the greater curvature infiltrating the spleen
  • Diffuse type (Lauren classification) requires 8 cm proximal safety margin; intestinal type requires 5 cm
  • Roux-en-Y gastric bypass
    • The surgeon separates the proximal jejunum from the duodenum and creates an end-to-end anastomosis of the jejunum with the remaining part of the stomach (gastrojejunostomy), or in the case of a total gastrectomy, with the esophagus (esophagojejunostomy).
    • Duodenal stump is connected distally with the jejunum using an end-to-side anastomosis.
    • Advantage: The stomach is more protected against bile reflux and consequent complications, such as ventricular ulcer and anastomotic recurrent gastric cancer.
  • Extended in the case of cardia carcinoma EGJ Siewert type II and III: abdominothoracic resection of the distal esophagus and cardia, intrathoracic anastomosis by gastric pull-up
• Alternative: subtotal gastrectomy
  • Carcinoma of the lower third of the stomach or intestinal carcinoma of the middle third of the stomach
  • Subtotal gastrectomy (4/5 resection) with lymphadenectomy
• No R0 resection: curative reresection aiming at R0, neoadjuvant chemotherapy may complement the treatment

Perioperative management

• Brief explanation: combination of neoadjuvant and adjuvant radiochemotherapy in curative intent
  • In particular, preoperative chemotherapy is essential to downsize the tumor and make it resectable.

Palliative treatment

• Indication: distant metastases; advanced tumor stage with unresectable cancer ; functionally inoperable patients
• Potential treatment options: Usual palliative measures (e.g., analgesic treatment); in addition chemotherapy, medical management of cancer and/or surgical management may be depending on the patient's general condition
  • Chemotherapy and medical management of cancer
    • Patients with a good ECOG performance status (ECOG 0-2) may particularly benefit from chemotherapy and medical management, as these measures may prolong life and improve the quality of life.
  • Surgical management
    • Surgical or endoscopic management of gastrointestinal obstruction
    • Partial gastrectomies may be used in exceptional cases

References:^[13]

Malignant acanthosis nigricans

• A paraneoplastic syndrome seen in adenocarcinomas of GI origin, especially in gastric adenocarcinoma
• Pathophysiology: caused by exogenous transforming growth factor TGF-α and epidermal growth factor (GF)
• Clinical findings
  • Brown to black, intertriginous and/or nuchal hyperpigmentation that can turn into itching, papillomatous, poorly-defined efflorescence
  • Rapid growth and verrucous or papulous surface helps to differentiate it from benign acanthosis nigricans
  • Localization: axilla, groin, neck

Malignant acanthosis nigricans always requires further diagnostic measures to look for malignancy!

Postgastrectomy syndromes

Related to resorption

• Maldigestion
  • Consequences and management
    • Lack of protein and carbohydrates
      • → Supplement pancreatic enzymes during meals
      • → Small meals rich in proteins and low in simple carbohydrates
    • Malabsorption of fats leads to fatty stools → Supplement pancreatic enzymes in case of weight loss and inefficient medium-chain triglyceride (MCT) diet.
    • Iron deficiency → supplement iron
    • Pernicious anemia due to lack of intrinsic factor, usually produced by gastric parietal cells → supplement vitamin B₁₂

Related to anastomosis

• Small intestinal bacterial overgrowth (SIBO)
  • Definition: bacterial overgrowth within the small intestine
  • Causes
    • Anatomic abnormalities: (e.g., surgery causing blind intestinal loops – blind loop syndrome ), strictures)
    • Motility disorders
  • Pathophysiology: bacterial overgrowth → bacteria deconjugate bile acids, increase vitamin B₁₂ turnover, and produce increased amounts of vitamin K and folic acid
  • Clinical features: diarrhea, steatorrhea, weight loss, malabsorption (e.g., deficiency of vitamin B₁₂, A, E, D, zinc, and iron)
  • Diagnostics
    • Jejunal aspirate cultures collected during endoscopy
    • Positive lactulose breath test
  • Treatment: antibiotics and parenteral supplementation of vitamins and proteins, possibly surgical treatment
• Efferent loop syndrome
  • Only an acute abdomen would be an immediate surgical indication, otherwise, watch and wait
  • Kinking or anastomotic narrowing of the efferent loop → emesis, feeling of fullness
• Afferent loop syndrome
  • 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 → loss of appetite, feeling of fullness, bilious vomiting with subsequent relief of nausea
  • Surgical treatment

Related to motility

• Dumping syndrome: rapid gastric emptying due to either defective gastric reservoir function or pyloric emptying mechanism, or anomalous postsurgery gastric motor function.
  • Early dumping
    • Cause: rapid emptying of undiluted chyme into the small intestine caused by a dysfunctional or bypassed pyloric sphincter
    • Clinical features
      • Appears within 15–30 minutes after ingestion of a meal
      • Symptoms may include nausea, vomiting, diarrhea, and cramps, as well as 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 to cover protein and energy requirements are preferable.
      • 30–60 min of rest in the supine position after meals
      • Beta-blockers may be helpful.
      • Often spontaneous improvement after a couple of months
  • Late dumping
    • Cause: postprandial hypoglycemia; dysfunctional pyloric sphincter → chyme containing glucose immediately reaches the small intestine → glucose is quickly resorbed → hyperglycemia → excessive release of insulin → hypoglycemia and release of catecholamines
    • Treatment
      1. Dietary modifications
      2. Octreotide and surgery are second and third-line therapies
  • Prevention: Constructing an esophagojejunostomy with a pouch may prevent dumping syndromes as it creates a useful reservoir. Therefore, this procedure is becoming more common.

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

Remnant carcinoma is a complication associated with the remnant stomach. Follow-up is important!References:^[14][15][16]

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