Gastric Cancer

Epidemiology
Gastric cancer is the third leading cause of cancer-related mortality worldwide, with
significant geographic variation.
The highest incidence rates are observed in East Asia, particularly Japan and South
Korea, where mass screening programs help in early detection. In contrast, the inci-
dence has declined in North America and Western Europe, largely due to improved
dietary habits, refrigeration, and better management of Helicobacter pylori infections.
The disease predominantly affects older adults, with a median age of diagnosis around
70 years in Western countries. Men are nearly twice as likely to develop gastric cancer
as women. Socioeconomic status and ethnicity also play a role, with higher rates
observed in specific racial and ethnic groups, such as Native Americans and Hispanic
populations. While non-junctional gastric cancers have been decreasing in incidence,
adenocarcinomas at the esophagogastric junction (EGJ) have been on the rise.

Etiology and Pathogenesis

Definite Risk Factors
These factors have strong evidence linking them to gastric adenocarcinoma develop-
ment:
• Helicobacter pylori (H. pylori) Infection: The primary and strongest risk
factor. Chronic H. pylori infection leads to chronic-active inflammation of the
gastric mucosa, atrophic gastritis, and eventually gastric cancer.
• Chronic Atrophic Gastritis: Persistent inflammation causes glandular atrophy
and promotes metaplastic changes in the stomach lining, increasing cancer risk.
• Intestinal Metaplasia: A precancerous condition in which gastric mucosa is
replaced by intestinal-type epithelium. It marks a significant step in gastric
carcinogenesis.
• Dysplasia: Represents early neoplastic changes in the gastric epithelium, often
preceding malignant transformation.
• Epstein-Barr Virus (EBV) Infection: EBV-associated gastric cancer comprises
a distinct molecular subtype characterized by high immune infiltration and
PD-L1 overexpression.
• Cigarette Smoking: Increases the risk of both cardia and non-cardia gastric
cancer by promoting chronic inflammation and DNA damage.
• History of Gastric Surgery (Billroth II): Alters gastric physiology and in-
creases bile reflux into the stomach, which is linked to carcinogenesis.
• Adenomatous Gastric Polyps: Have significant malignant potential, particu-
larly if they are larger than 2 cm or display dysplastic changes.

Genetic Factors
Inherited syndromes and family history contribute significantly to gastric cancer risk:
• Family History of Gastric Cancer: Having a first-degree relative with gastric
cancer nearly doubles the risk.
• Hereditary Syndromes:

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 – Hereditary Diffuse Gastric Cancer (HDGC): Associated with CDH1
mutations, leading to diffuse-type gastric cancer at a young age.
– Familial Adenomatous Polyposis (FAP): Increases the risk due to fundic
gland polyps and adenomatous changes.
– Hereditary Nonpolyposis Colorectal Cancer (HNPCC/Lynch Syn-
drome): Increases susceptibility to intestinal-type gastric cancer.
– Peutz-Jeghers Syndrome: Characterized by gastrointestinal polyps with
a predisposition for malignancy.
– Juvenile Polyposis Syndrome: Leads to multiple gastrointestinal polyps,
some of which may undergo malignant transformation.

Probable Risk Factors

These factors are associated with gastric cancer but have varying levels of supporting
evidence:
• Dietary Factors:
– High Salt Intake: Salt-preserved and smoked foods damage the gastric
mucosa and increase the carcinogenic effects of H. pylori infection.
– Diet High in Nitrates: Found in processed meats and certain preserved
foods, nitrates are converted into carcinogenic N-nitroso compounds in
the stomach.
• Obesity: Particularly associated with adenocarcinoma of the gastric cardia.
Obesity-induced chronic inflammation contributes to cancer progression.
• History of Gastric Ulcer: Chronic irritation and inflammation may promote
carcinogenesis.
• Pernicious Anemia: Leads to chronic atrophic gastritis and achlorhydria,
increasing cancer risk.
• Snuff Tobacco Use: A form of smokeless tobacco that may contribute to gastric
cancer, particularly in non-cardia regions.
• Regular Aspirin or NSAID Use (Protective): Some studies suggest these
drugs may lower gastric cancer risk by reducing chronic inflammation.

Possible Risk Factors

These factors have weaker evidence but may play a role in gastric cancer development:
• Heavy Alcohol Use: May act synergistically with other carcinogens but has
an inconsistent association with gastric cancer.
• Low Socioeconomic Status: Associated with poorer nutrition, increased H.
pylori prevalence, and limited access to healthcare.
• Ménétrier Disease: A rare hypertrophic gastropathy that may predispose
patients to gastric cancer.
• Protective Factors:
– High Ascorbate Intake (Vitamin C): May neutralize nitrosamines and
protect against gastric carcinogenesis.
– High Fresh Fruit and Vegetable Intake: Provides antioxidants and
reduces oxidative stress, potentially lowering cancer risk.
– Statin Use: Some studies suggest statins may have a protective effect, but
evidence is inconclusive.

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Questionable Risk Factors
• High Green Tea Consumption: Some epidemiological studies suggest a pro-
tective effect due to polyphenols, but findings remain inconsistent.
• Hyperplastic and Fundic Gland Polyps: Generally considered benign, though
some studies suggest an increased risk of malignant transformation.

Pathogenesis
The progression of gastric cancer follows a well-recognized multistep sequence, par-
ticularly for intestinal-type adenocarcinoma.

Correa’s Cascade of Gastric Carcinogenesis

1. Chronic H. pylori Infection or Other Irritants: Persistent immune response
leads to increased production of pro-inflammatory cytokines.
2. Chronic Gastritis: Ongoing inflammation damages the gastric mucosa, pro-
moting oxidative stress and genetic mutations.
3. Mucosal Atrophy and Intestinal Metaplasia: Loss of normal gastric glands
and replacement by intestinal-type epithelium.
4. Dysplasia: Further genetic mutations cause cellular abnormalities, increasing
malignant potential.
5. Invasive Adenocarcinoma: Cancer cells invade deeper layers of the stomach,
leading to full malignancy.

Molecular Mechanisms in Gastric Cancer Development

• Genetic Mutations:
– TP53 mutations are commonly seen in gastric adenocarcinoma.
– CDH1 mutations lead to loss of E-cadherin function, promoting diffuse
gastric cancer.
• Inflammatory Pathways:
– Chronic inflammation triggers the release of reactive oxygen species (ROS),
causing DNA damage.
– Cytokines such as IL-1β and TNF-α contribute to tumor progression.
• Microbiome Alterations:
– H. pylori infection modifies gastric microbiota, favoring the growth of
carcinogenic bacteria.
• Epigenetic Changes:
– Hypermethylation of tumor suppressor genes silences protective pathways.
– Histone modifications and non-coding RNA dysregulation influence cancer
growth.

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Differences Between Intestinal and Diffuse-Type Gastric Cancer

Feature Intestinal-Type Gastric Cancer Diffuse-Type Gastric Cancer

Histology Well-differentiated glandular Poorly cohesive cells,
structures signet-ring cells
Pathogene- Correa’s cascade De novo carcinogenesis, CDH1
sis mutation
Risk H. pylori, diet, smoking, high salt Genetic predisposition, CDH1
Factors intake mutations
Prognosis Better Poorer

Histological Classification
• Intestinal Type: Characterized by glandular formations, it is strongly linked
to environmental factors and H. pylori infection. It is more common in older
individuals and has a relatively better prognosis.
• Diffuse Type: Comprised of poorly cohesive cells that infiltrate the stomach
wall, often leading to linitis plastica (thickened, rigid stomach). This type has
a worse prognosis and is more frequently associated with genetic mutations,
particularly CDH1.

Clinical Features
Early Symptoms
Early-stage gastric cancer is usually silent (asymptomatic) or presents with mild
symptoms, including:
• Dyspepsia: A common but vague symptom that includes bloating, discomfort,
and a burning sensation in the upper abdomen.
• Epigastric Pain: Mild, persistent discomfort or dull aching pain in the upper
abdomen, often mistaken for acid reflux or gastritis.
• Early Satiety: A sensation of fullness after consuming small amounts of food,
often due to tumor-induced gastric motility impairment.
• Nausea and Occasional Vomiting: Intermittent nausea, sometimes accompa-
nied by vomiting, particularly when the tumor affects gastric emptying.
• Unintentional Weight Loss: A gradual loss of weight due to reduced appetite,
increased metabolism from tumor growth, or malabsorption.

Advanced Symptoms
As the tumor grows and spreads, symptoms become more pronounced and include:
• Persistent and Worsening Abdominal Pain: Pain may become more intense
and constant, radiating to the back if the pancreas is involved.
• Severe Nausea and Vomiting: More frequent vomiting, especially in cases
where the tumor obstructs gastric emptying.
• Gastrointestinal Bleeding: Tumor ulceration can lead to:
– Melena and Hematemesis
– Hematochezia
– Iron-Deficiency Anemia: Resulting from chronic blood loss.

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Physical Examination Findings
• Cachexia: Common in advanced disease due to tumor metabolism and malnu-
trition.
• Epigastric Tenderness: May be present, especially if the tumor is ulcerating.
• Palpable Abdominal Mass: In advanced cases, a tumor mass may be detected
in the epigastric region upon physical examination.
• Hepatomegaly: Liver enlargement in cases of metastatic disease.
• Peripheral Edema: Can result from protein loss (hypoalbuminemia) due to
cancer-induced malnutrition.
• Pallor: Suggestive of chronic anemia due to occult gastrointestinal bleeding.
• Jaundice: If liver metastases obstruct the biliary system.
• Ascites: Due to peritoneal carcinomatosis or portal vein obstruction.

Signs of Metastatic Disease

Once gastric cancer metastasizes, it presents with distinct clinical signs:
• Virchow’s Node: Enlarged left supraclavicular lymph node, a classic sign of
metastatic gastric cancer.
• Sister Mary Joseph’s Nodule: A periumbilical nodule indicating peritoneal
spread.
• Irish Node: Left axillary lymph node involvement, suggestive of widespread
dissemination.
• Blumer’s Shelf: A rectal mass palpable on digital rectal examination, signifying
peritoneal metastases.
• Krukenberg Tumor: Ovarian metastases in female patients, often leading to
abdominal pain and bloating.

Paraneoplastic Syndromes Associated with Gastric Cancer

• Acanthosis Nigricans: Hyperpigmented, velvety plaques in skin folds, associ-
ated with gastric malignancy.
• Trousseau Syndrome: Migratory thrombophlebitis, a hypercoagulable state
leading to spontaneous blood clot formation.
• Hypertrophic Osteoarthropathy: Joint pain, swelling, and clubbing of fingers.
• Membranous Nephropathy: Associated with protein loss in urine.

Diagnosis
1. Endoscopy with Biopsy
• Gold standard for diagnosis, allowing direct visualization and tissue sampling.
• Biopsies from suspicious lesions should be taken from multiple sites to
increase accuracy.

2. Endoscopic Ultrasound
• Used to assess tumor invasion depth (T stage), lymph node involvement (N
stage) and guide fine-needle aspiration/biopsy of suspicious lymph nodes.

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3. Imaging Studies
• CT Scan: Evaluates tumor spread and detects metastases.
• PET Scan: Helps identify distant metastases not detected by CT.

Staging and Prognosis

TNM Staging System

Category Description
T (Tumor Invasion)
T1 Confined to the mucosa (T1a) or submucosa (T1b).
T2 Infiltrates the muscularis propria.
T3 Extends beyond the muscularis but not into adjacent
organs.
T4 Invades adjacent structures.
N (Lymph Node)
N0 No lymph node involvement.
N1 1-2 lymph nodes affected.
N2 3-6 lymph nodes affected.
N3 More than 7 lymph nodes affected.
M (Metastasis)
M0 No distant metastases.
M1 Presence of distant metastases.

Clinical Staging of Gastric Cancer Based on the TNM Classification

T Stage N0 N1 N2 N3 M1 (Any N)
Tis 0 — — — —
T1 IA IB IIA IIB IV
T2 IB IIA IIB IIIA IV
T3 IIA IIB IIIA IIIB IV
T4a IIB IIIA IIIB IIIC IV
T4b IIIB IIIB IIIC IIIC IV

Prognosis
• Localized distal gastric cancer: Over 50% of patients can achieve a cure.
• Early-stage disease: Only 10%–20% of cases are diagnosed at this stage in the
United States.
• Metastatic disease: Most patients present with regional or distant metastases.
• 5-year survival rates:
– Localized distal gastric cancer: ~50%.
– Localized proximal gastric cancer: 10%–15%.
– Disseminated disease: Near 0%.
• Advanced disease treatment: Primarily palliative; long-term remissions are
rare.

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Treatment
1. Endoscopic/Surgical Management
• Endoscopic Resection (EMR, ESD): Used for early-stage tumors confined to
the mucosa or superficial submucosa.
• Gastrectomy: Partial or total gastrectomy with lymphadenectomy is the pri-
mary curative treatment.

2. Systemic Therapies
• Chemotherapy: Perioperative chemotherapy with regimens like FLOT (5-FU,
leucovorin, oxaliplatin, docetaxel) improves survival.
• Targeted Therapy:
– HER2-Positive Tumors: Trastuzumab improves outcomes in HER2-
overexpressing cancers.
– VEGF-Targeting Agents: Ramucirumab is used in advanced disease.
• Immunotherapy: Checkpoint inhibitors such as pembrolizumab are promising
for MSI-high and PD-L1-positive tumors.

3. Radiotherapy
• Often used in combination with chemotherapy for locally advanced or unre-
sectable cases.
• Palliative radiotherapy helps alleviate symptoms like pain and bleeding.

Figure 1: Gastric cancer treatment