Gastric Adenocarcinoma

Essentials of Diagnosis

• Dyspeptic symptoms with weight loss in patients age > 40

• Iron deficiency anemia; occult blood in stools

• Abnormality on upper gastrointestinal series or endoscopy

General Considerations

• There are two main histologic variants of gastric cancer

  • Intestinal-type

  • Diffuse

• Intestinal-type gastric cancer resembles intestinal cancers in forming glandular structures

  • Accounts for 70–80% of cases

  • Occurs twice as often in men as women

  • Primarily affects older people (mean age 68 years)

  • More strongly associated with environmental factors

• Diffuse gastric cancer is poorly differentiated, has signet-ring cells, and lacks formation of glandular structures

  • Accounts for 20–30% of cases

  • Affects men and women equally

  • Occurs more commonly in young people

  • Not as strongly related to Helicobacter pylori infection

  • Has a worse prognosis than the intestinal type with early metastasis

  • Most diffuse gastric cancers are attributable to acquired or hereditary mutations in the genes regulating the E-cadherin cell adhesion protein

• In addition to the hereditary diffuse gastric cancer, there are other hereditary cancer predisposition syndromes that account for 3–5% of gastric cancers

  • Lynch syndrome

  • Juvenile polyposis syndrome

  • Peutz-Jeghers syndrome

  • Familial adenomatous polyposis

• Most gastric cancers arise in the body and antrum

• Chronic H pylori gastritis is the major risk factor

• Other risk factors for intestinal-type gastric cancer

  • Pernicious anemia

  • Partial gastric resection > 15 years previously

  • Smoking

  • Diets that are high in nitrates or salt and low in vitamin C

Demographics

• Gastric adenocarcinoma is the third most common cancer worldwide

• Incidence in the United States has declined rapidly over last 70 years

• In 2019 in the United States, there were an estimated 27,510 new cases and 11,140 deaths

• Incidence is higher in Asian Americans, Hispanics, African Americans and American Indian/Alaska Natives

Symptoms and Signs

• Generally asymptomatic or nonspecific symptoms until advanced disease

• Dyspepsia, vague epigastric pain, anorexia, early satiety, and weight loss

• Acute upper gastrointestinal bleeding with hematemesis or melena

• Postprandial vomiting suggests pyloric obstruction

• Progressive dysphagia suggests lower esophageal obstruction

• Physical examination rarely helpful

• Gastric mass is palpated in < 20%

• Signs of metastatic spread include

  • Left supraclavicular lymph node (Virchow node)

  • Umbilical nodule (Sister Mary Joseph nodule)

  • Rigid rectal shelf (Blumer shelf)

  • Ovarian metastases (Krukenberg tumors)

Differential Diagnosis

• Benign gastric ulcers

• Lymphoma

• Ménétrier disease

Laboratory Tests

• Iron deficiency anemia or anemia of chronic disease

• Liver biochemical test abnormalities, particularly elevation of alkaline phosphatase, if there is metastasis to liver

• Tumor markers

  • Do not have established clinical validity in screening, diagnosis, or management of gastric cancer

  • However, can assist in monitoring treatment response when checked serially

Imaging Studies

• Upper gastrointestinal series may not detect small or superficial lesions and cannot reliably distinguish benign from malignant ulcerations

• Preoperative evaluation with contrast CT of chest, abdomen, and pelvis and endoscopic ultrasonography

• Endoscopic ultrasonography

  • Superior to CT in determining the depth of tumor penetration

  • Useful for evaluating early gastric cancers that may be removed by endoscopic mucosal resection

• Positron emission tomography (PET) or combined PET-CT imaging is recommended for detection of distant metastasis

Diagnostic Procedures

• Staging by TNM system

  • T1 tumors invade the lamina propria (T1a) or submucosa (T1b)

  • T2 invade the muscularis propria

  • T3 penetrate the serosa

  • T4 invade adjacent structures

  • Lymph nodes are graded as N0 if there is no involvement, and N1, N2, or N3 if there are is involvement of 1–2, 3–6, or more than 7 regional nodes

  • M1 signifies the presence of metastatic disease

• Testing for microsatellite instability (MSI), deficiency in mismatch repair proteins (dMMR) and programmed death ligand-1 (PD-L1) is recommended in advanced disease to identify tumors that may respond to immunotherapy

Medications

• Systemic therapy may be considered in patients with metastatic disease who still have good functional status and expected survival of at least several months

• Two-drug combination regimens are preferred for first-line therapy, with most common regimens including a fluoropyrimidine (eg, 5-fluorouracil or capecitabine) or a taxane agent (eg, docetaxel or paclitaxel) plus a platinum agent (eg, cisplatin or oxaliplatin)

• A three-drug combination of epirubicin or docetaxel plus cisplatin and 5-fluorouracil may be appropriate for first-line treatment in medically fit patients

• Trastuzumab

  • Prolongs survival in ~15% of patients with advanced gastric adenocarcinomas harboring amplification of EGFR-2 (HER2) when added to standard chemotherapy

  • Not recommended for combination with anthracyclines, such as epirubicin, due to risk of cardiotoxicity

• After progression on first-line chemotherapy, further chemotherapy treatments are associated with better overall survival than supportive care alone

• Second-line treatments include

  • Ramucirumab, a monoclonal antibody

    • Targets the VEGF receptor-2

    • Can be used both as monotherapy and in combination with paclitaxel

  • Irinotecan

  • Taxol

• Of note, adding lapatinib to chemotherapy does not result in improvement in overall survival

• Pembrolizumab, a drug that targets lymphocyte PD-L1, is approved by the FDA for second-line or subsequent therapy for MSI-H or dMMR cancers and for third-line or beyond therapy for PD-L1-positive adenocarcinomas

• In Japan, nivolumab is approved for advanced gastric cancers after progression on standard therapies

Surgery

• For patients with clinically localized disease (stages I–III), surgical exploration

  • Patients with confirmed localized disease should undergo radical surgical resection

  • Approximately 25% will be found to have locally unresectable tumors or peritoneal, hepatic, or distant lymph node metastases, and "curative" surgical resection is not warranted

• For patients with unresectable disease, gastrojejunostomy can prevent obstruction

Therapeutic Procedures

• For adenocarcinoma localized to the distal two-thirds of the stomach, a subtotal gastrectomy should be performed

• D2 lymphadenectomy

  • Has been shown to improve disease-specific survival

  • However, it is associated with increased postoperative mortality

• For proximal gastric cancer or diffusely infiltrating disease, total gastrectomy is necessary

Follow-Up

• After surgical therapy, further follow-up is determined by clinical course

• Routine follow-up not recommended

• Vitamin B₁₂ supplementation is required after gastrectomy

Complications

• Acute or chronic gastrointestinal blood loss

• Pyloric obstruction

Prognosis

• Survival related to tumor stage, location, and histologic features

• 5-year survival is about 30%

• Stage I and stage II tumors resected for cure have a > 60% long-term survival

• Patients with stage III tumors have a < 20% long-term survival

• Tumors of the diffuse and signet ring type have a worse prognosis than those of the intestinal type

• Tumors of the proximal stomach (fundus and cardia) have 5-year survival of < 15%, a far worse prognosis than distal lesions

Prevention

• Prophylactic gastrectomy should be considered in patients known to carry specific mutations in the genes regulating the E-cadherin cell adhesion protein

When to Refer

• Patients with dysphagia, weight loss, protracted vomiting, iron-deficiency anemia, or new-onset of dyspepsia (especially if age 55 years or older or associated with other alarm symptoms) in whom gastric cancer is suspected should be referred for endoscopy

• Patients should be referred to a surgeon for attempt at curative resection in stage I, II, or III cancer, including staging laparoscopy if indicated

• Prior to surgery, patients should be referred to an oncologist to determine the role for neoadjuvant chemotherapy or adjuvant chemoradiation or chemotherapy

• Patients who have undergone gastrectomy require consultation with a nutritionist due to propensity for malnutrition and postoperative complications such as dumping syndrome and vitamin B₁₂ deficiency

• Patients with unresectable or metastatic disease should be referred to an oncologist for consideration of palliative chemotherapy or chemoradiation

When to Admit

• Patients with protracted vomiting, inability to maintain hydration or nutrition, or acute bleeding