Gastric cancer

Gastric cancer is the fifth most common type of cancer worldwide. Incidence is declining in the United States and Europe but continues to be high in Asia. Development of gastric cancer is associated with several risk factors, including consumption of cured or smoked foods rich in nitrates, increased nicotine intake, and Helicobacter pylori infection. Adenocarcinoma is the most common form, accounting for 95% of cases. Initially, gastric cancer is usually asymptomatic or manifests with nonspecific symptoms such as epigastric discomfort or nausea. Late-stage disease is characterized by symptoms of gastric outlet obstruction and/or signs of distant metastatic disease. Upper endoscopy with biopsy is used to confirm the diagnosis. The mainstay of treatment is endoscopic or surgical resection of the tumor. Depending on the stage of the disease, chemoradiation therapy can be used as neoadjuvant, adjuvant, or palliative therapy. The prognosis varies significantly with tumor stage, but 5-year survival rates are generally low (5% for late-stage disease) because diagnosis is often delayed due to lack of symptoms.

• 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

Confirmatory tests

• Upper endoscopy with biopsy (best initial and confirmatory test) ^[10][11]
• Upper GI series (barium studies): especially for linitis plastica

Laboratory tests

• Complete blood count: anemia
• Fecal occult blood test: positive
• Renal and liver function tests
• Serologic markers
  • Tumor markers: CA 72-4, CA 19-9, CEA
  • TNF-α ^[12]
• Immunohistochemistry: HER2 testing ^[13]

Workup of diagnosed gastric cancer

Imaging

• Endosonography
  • Depth of tumor invasion
  • Lymph node involvement
• Abdominal ultrasound
• CT scan (abdomen, pelvis, and thorax)
  • Lymph node involvement
  • Detection of distant metastases
• PET-CT/diagnostic laparoscopy: for occult metastases that could have been missed during endoscopy or on CT scan

About half of patients with gastric cancer present with advanced disease at the time of diagnosis.

Gastric adenocarcinoma

General features

• Accounts for ∼ 95% of cases ^[14]
• 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 ^[15]
• Intermediate type (the least common type): should be treated as the diffuse type, as the extent of tumor infiltration is difficult to assess

Gastric conditions

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

Other types of cancer

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

Gastrointestinal stromal tumor (GIST) ^[16]

• 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 → perpetuatal, 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%). ^[17]

The differential diagnoses listed here are not exhaustive.

Early-stage disease

• Endoscopic tumor resection
• Subtotal or total gastrectomy (if any lymph nodes are involved)
• H. pylori infection treatment

Late-stage disease

Perioperative chemotherapy or radiotherapy

• Used as both neoadjuvant and adjuvant therapy
• Trastuzumab is indicated for HER2-positive gastric adenocarcinomas.

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

Surgery

• Total gastrectomy and lymphadenectomy (operative standard)
  • Complete resection of the stomach with blind closure of the proximal duodenum
  • Resection of the lesser and greater omentum
  • Radical lymphadenectomy
• Subtotal gastrectomy (alternative approach)
  • Resection of the body and pylorus of the stomach with blind closure of the duodenal stump
  • Radical lymphadenectomy
• Roux-en-Y gastric bypass: a surgical technique used in the reconstruction of the gastric passage and to prevent GI obstruction after gastrectomy/bariatric surgery
  • The jejunum is divided transversely just distal to the duodenum and incised longitudinally further distally.
    • Esophagojejunostomy creation: end-to-end anastomosis between the distal esophagus (or remaining part of the stomach; gastrojejunostomy) and the distal limb of the transected jejunum
    • Jejunojejunostomy creation: end-to-side anastomosis between the proximal limb of the transected jejunum and the transversely incised distal jejunum

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.

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
• Pathophysiology: all resulting from bacterial overgrowth ^[18]
  • ↓ Absorption of vitamin B₁₂, fat-soluble vitamins, zinc, and iron
  • ↑ Production of folate
  • ↑ Deconjugation of the bile acids
• Clinical features
  • Diarrhea, steatorrhea
  • Weight loss, malabsorption
• Diagnostics ^[19]
  • 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 ^[20][21][22]

• 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. ^[11]
• If diagnosed at a very early stage, the 5-year survival rate is 95%. ^[23]
• Late-stage disease with distant metastases and/or peritoneal carcinomatosis has a poor prognosis (5-year survival rate of ∼ 5%). ^[24]