Gastric Adenocarcinoma: Epidemiology, Causes, Pathogenesis, Symptoms, Diagnosis, Treatment and Prevention

Gastric Adenocarcinoma: Pathogenesis, Clinical Features, Diagnosis, and Modern Therapeutic Approaches

Gastric adenocarcinoma—commonly referred to as stomach cancer—is the most prevalent form of gastric malignancy, accounting for more than 90% of all primary gastric cancers. Despite advances in diagnostic and therapeutic modalities, gastric adenocarcinoma remains a leading cause of cancer-related morbidity and mortality worldwide. Its complex pathogenesis, diverse subtypes, late clinical presentation, and significant geographic variability make it a unique oncological challenge. This article provides an in-depth overview of its epidemiology, risk factors, molecular pathways, clinical manifestations, diagnostic strategies, staging, treatment, prognosis, and preventive measures.

~Introduction and Epidemiology

Gastric adenocarcinoma develops from the epithelial cells lining the stomach. Globally, it ranks among the top five most common cancers and is a leading cause of cancer death—particularly in East Asia, Eastern Europe, and parts of South America. Although incidence has declined in many Western countries due to improved sanitation, widespread antibiotic use, and refrigeration reducing preserved food consumption, gastric cancer remains a significant global health concern.

There are two major anatomical and epidemiological subtypes:

1. Distal (non-cardia) gastric cancer, historically more common and strongly linked to Helicobacter pylori infection.

2. Proximal (gastric cardia) cancer, increasingly prevalent in high-income countries and associated with obesity and gastroesophageal reflux disease (GERD).

Age is a prominent factor; gastric cancer rarely occurs before age 40, with most cases occurring between the ages of 60 and 80. Men are affected more frequently than women, possibly due to higher exposure to environmental risks such as smoking and dietary carcinogens.

~Risk Factors and Etiology

Gastric adenocarcinoma is a multifactorial disease resulting from environmental exposures, infections, genetic predispositions, and progressive mucosal changes. Key risk factors include:

1. Helicobacter pylori Infection

The strongest recognized risk factor for non-cardia gastric cancer is chronic infection with H. pylori, a gram-negative bacterium that colonizes the stomach lining. Long-standing infection induces chronic gastritis, leading to mucosal atrophy, intestinal metaplasia, dysplasia, and finally adenocarcinoma—a sequence known as the Correa cascade. Certain strains expressing cytotoxin-associated gene A (CagA) proteins dramatically increase malignancy risk.

2. Dietary Factors

Historically, high consumption of salt-preserved foods, nitrates, smoked meats, and pickled items contributed to gastric cancer burden. These foods contain nitrosamines and other carcinogens that damage gastric epithelial DNA. Conversely, diets rich in fresh fruits, vegetables, and antioxidants exhibit a protective effect.

3. Smoking and Alcohol

Smoking increases gastric cancer risk by up to 50%, particularly for cancers involving the upper stomach. Alcohol, especially heavy consumption, also contributes to gastric mucosal injury and promotes carcinogenesis.

4. Genetic Predispositions

Approximately 10% of gastric adenocarcinoma cases have familial clustering, and 1–3% are due to hereditary syndromes, such as:

• Hereditary Diffuse Gastric Cancer (HDGC) linked to germline CDH1 mutations (E-cadherin).

• Lynch syndrome (DNA mismatch repair defects).

• Familial adenomatous polyposis (FAP) involving APC mutations.

• Peutz-Jeghers syndrome and Li-Fraumeni syndrome.

5. Pre-existing Gastric Conditions

Several chronic gastric disorders predispose individuals to cancer:

• Chronic atrophic gastritis

• Pernicious anemia

• Gastric adenomas

• Gastric intestinal metaplasia

• Previous partial gastrectomy

6. Obesity and GERD

Obesity and chronic acid reflux increase the risk of proximal (cardia) gastric cancer, analogous to esophageal adenocarcinoma.

7. Environmental and Occupational Exposures

Exposures to asbestos, coal dust, and metal processing fumes are linked to elevated gastric cancer risk.

~Pathogenesis and Molecular Classification

The World Health Organization (WHO) and the Lauren classification system describe gastric adenocarcinoma subtypes based on pathological and molecular features.

1. Lauren Classification

A classic framework dividing gastric adenocarcinoma into:

• Intestinal type: Forms glandular structures; strongly tied to environmental factors such as H. pylori. Represents the Correa cascade.

• Diffuse type: Poorly cohesive, infiltrative cells (including signet ring cells). Often linked to genetic defects like CDH1 mutation.

• Mixed type: Overlapping features of both.

2. Molecular Classification

Advancements in genomic profiling (TCGA) categorize gastric adenocarcinoma into four molecular subgroups:

1. EBV-positive tumors (Epstein–Barr virus linked)

2. Microsatellite instability (MSI) tumors

3. Genomically stable tumors (often diffuse type)

4. Chromosomal instability tumors (intestinal type predominant)

These classifications have significant therapeutic implications, especially for immunotherapy responsiveness.

~Clinical Features

Gastric adenocarcinoma is often asymptomatic in early stages, contributing to late diagnoses and poor outcomes. Common signs and symptoms include:

1. Early Symptoms

• Indigestion or persistent dyspepsia

• Epigastric discomfort

• Early satiety

• Mild nausea or bloating

• Loss of appetite

These non-specific ulcer-like symptoms often mimic benign gastrointestinal disorders, delaying diagnosis.

2. Advanced Symptoms

• Unexplained weight loss

• Vomiting (sometimes due to gastric outlet obstruction)

• Anemia-related fatigue

• Hematemesis (vomiting blood) or melena

• Persistent abdominal pain

• Difficulty swallowing (if proximal tumor)

3. Physical Signs

• Palpable epigastric mass (late)

• Virchow’s node: left supraclavicular lymphadenopathy

• Sister Mary Joseph nodule: periumbilical metastasis

• Krukenberg tumor: ovarian metastasis

• Blumer's shelf: rectal shelf metastasis

~Diagnosis

Early diagnosis significantly improves survival. The standard approach involves:

1. Upper Gastrointestinal Endoscopy

The gold standard for diagnosis. This allows:

• Direct visualization of lesions.

• Targeted biopsies.

• Assessment of mucosal changes.

Multiple biopsies from suspicious areas ensure histologic confirmation.

2. Endoscopic Ultrasound (EUS)

Critical for determining tumor depth (T staging) and regional lymph node involvement.

3. Imaging

• CT scan of chest, abdomen, pelvis for staging.

• PET-CT to detect distant metastasis.

• MRI for liver lesion characterization.

• Diagnostic laparoscopy to exclude peritoneal metastasis before curative surgery.

4. Laboratory Studies

• Complete blood count (CBC): Detects anemia.

• Tumor markers (CEA, CA 19-9): Not diagnostic, but useful for monitoring.

~Staging (TNM Classification)

The American Joint Committee on Cancer (AJCC) TNM system stages gastric cancer based on:

• T: Tumor invasion depth.

• N: Regional lymph node involvement.

• M: Distant metastasis.

Early gastric cancer (limited to mucosa/submucosa) has an excellent prognosis, while advanced stages with nodal or distant metastasis have drastically lower survival rates.

~Treatment Approaches

Optimal management requires a multidisciplinary team including surgeons, oncologists, gastroenterologists, radiologists, and nutritionists. Treatment depends on tumor stage, location, and patient fitness.

1. Early-stage Disease

Endoscopic Resection

For select early-stage lesions confined to the mucosa:

• Endoscopic Mucosal Resection (EMR)

• Endoscopic Submucosal Dissection (ESD)

These minimally invasive techniques preserve gastric function and offer excellent outcomes.

2. Surgery

Partial or Total Gastrectomy

Curative intent for operable tumors:

• Distal gastrectomy for lower stomach tumors.

• Proximal or total gastrectomy for upper or diffuse tumors.

Lymph node dissection (D1 or D2) accompanies surgery to improve staging accuracy and survival.

3. Chemotherapy

Neoadjuvant Chemotherapy

Given before surgery to shrink tumors and improve resectability. Regimens often include:

• FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)

Adjuvant Chemotherapy

Postoperative chemotherapy helps reduce recurrence.

4. Chemoradiation

Used in select cases, especially where surgical margins are close or tumor resection is incomplete.

5. Targeted Therapy

Molecular profiling guides precision therapy:

• HER2-positive tumors: Treated with trastuzumab.

• VEGF inhibitors: Ramucirumab for advanced cancer.

6. Immunotherapy

A major advancement in gastric cancer treatment:

• PD-1 inhibitors such as pembrolizumab and nivolumab.

• Particularly effective in MSI-high, EBV-positive, or PD-L1-expressing tumors.

7. Treatment of Metastatic Disease

Palliative therapies aim to improve quality of life:

• Systemic chemotherapy

• Palliative gastrectomy for bleeding/obstruction

• Endoscopic stenting for obstruction relief

~Prognosis

Survival varies widely based on stage, location, and tumor biology:

• Early gastric cancer: >90% 5-year survival.

• Locally advanced with nodal involvement: 30–50% 5-year survival.

• Metastatic disease: <10% 5-year survival.

Diffuse-type gastric cancer tends to have a poorer prognosis due to aggressive infiltration and late detection.

~Prevention and Screening

1. Eradication of H. pylori

One of the most effective preventive strategies, reducing cancer risk by decreasing chronic inflammation and mucosal damage.

2. Dietary Modifications

• Reduce intake of smoked, salted, and nitrate-rich foods.

• Increase consumption of fresh produce.

• Limit alcohol and smoking.

3. Screening Programs

Implemented in high-incidence countries (Japan, South Korea), using:

• Endoscopy

• Radiographic contrast imaging

These programs significantly improve early detection rates and survival.

4. Genetic Counseling and Prophylactic Surgery

Individuals with CDH1 mutations may undergo preventive total gastrectomy due to high risk of diffuse gastric cancer.

~Future Directions and Research

Advances in genomics, liquid biopsies, artificial intelligence–assisted endoscopy, and nanotechnology-based drug delivery systems are transforming the landscape of gastric cancer diagnosis and treatment.

Key ongoing research areas:

• Enhancing immunotherapy effectiveness.

• Identifying biomarkers for early detection.

• Developing personalized therapeutic vaccines.

• Studying tumor microenvironment and drug resistance mechanisms.

~Conclusion

Gastric adenocarcinoma remains a major global health concern due to its aggressive nature, late diagnosis, and complex pathogenesis. While progress in early detection, targeted therapy, and immunotherapy has improved outcomes, significant challenges persist, especially in advanced disease. Comprehensive understanding of its risk factors, clinical behavior, and modern treatment strategies is essential for improving patient survival and quality of life. Continued investment in research, screening programs, and public health initiatives offers hope for reducing the burden of this formidable cancer in the coming decades.