Gastric Tumors: Adenocarcinoma Epidemiology

Gastric Tumors

• Broadly categorized as benign or malignant.
• Malignant types include epithelial tumors like adenocarcinomas, lymphomas, neuroendocrine tumors, and stromal tumors like malignant GIST.

Adenocarcinoma: Epidemiology

• Frequency varies geographically and temporally, with more than a 10-fold difference between countries with high and low-risk rates.
• Incidence rates increase substantially after age 50 in all populations.
• The male to female ratio is 2:1 in populations over 50, but 1 or less in younger demographics.
• Incidence has declined in both high and low-risk countries since 1973.
• Decline in Western countries resulted from modern refrigeration, year-round fresh produce, and H. pylori treatment.
• In the mid-20th century, gastric carcinoma was the leading cause of cancer-related deaths in the US, with a death rate of 30/100,000.
• Today, gastric carcinoma is the second leading cause of cancer deaths in the US.
• There has been a decrease in the intestinal type of gastric carcinoma, while the incidence of the diffuse type has remained constant.
• In the US, gastric cancer is observed more often among African-Americans and Native-Americans than Caucasians.
• The highest incidence is in Japan, followed by Central and South America, China, and Eastern Europe.
• Individuals at the highest risk are often those in lower economic strata of developing countries, frequently associated with H. pylori infection.
• Familial stomach cancer clusters can be attributed to shared exposures to environmental hazards and inherited factors.
• Napoleon's family had numerous cases of gastric cancer.
• First-degree relatives of sporadic gastric carcinoma patients have a 2-3 fold increased risk.
• Individuals with blood group A face a higher risk.

Predisposing Factors and Conditions

• Genetic alterations in gastric carcinogenesis involve several factors.
• These include mutations, chromosomal losses, amplification or overexpression, microsatellite instability, genetic polymorphisms and telomerase activation.
• Inherited gastric cancer predisposition syndromes, resulting from germ-line mutations, account for approximately 10% of gastric cancers
• Hereditary nonpolyposis colon cancer syndrome (HNPCC) involves autosomal dominant inheritance and germline mutations in mismatch repair genes, including hMLH1, hMLH2, hMSH2, hMSH3, and hMSH6.
• Familial adenomatous polyposis (FAP) may affect the stomach and large intestine, resulting from an APC mutation.
• Germline mutations in E-cadherin/CDH1 genes characterize hereditary diffuse gastric cancer (HDGC), seen in diffuse gastric and lobular breast cancer.
• BRCA1/2 mutations elevate the risk of breast and ovarian cancer, as well as cancer in other sites including the stomach.
• Germline p53 mutations (Li-Fraumeni syndrome) are associated with cancers in various sites.

Genetic Alterations in Sporadic Gastric Cancers

• Tumor suppressor genes: p53, p16, APC, Rb, DCC, etc.
• Mismatch repair genes.
• Oncogenes: Cyclin D1.
• Growth factors and their receptors: EGFR, TGF-α, etc.
• Cell Adhesion molecules: E-cadherin, a-catenin, β-catenin.

Environmental Factors

• Helicobacter pylori infection typically acquired in childhood.
• 75% of the infected high-risk population develops H pylori gastritis, while no more than 5% develops gastric cancer.
• Diet: Nitrate/nitrite in food preservatives and high salt intake, especially dried salted fish in Japan.
• Smoking magnitude of smoking-related gastric cancer risk is low.
• Radiation: ionizing radiation, like that among atomic bomb survivors, and radiotherapy in young patients.
• Previous gastric surgery.

Premalignant Lesions

• Helicobacter pylori gastritis: Chronic atrophic gastritis caused by H. pylori is a common cause of gastric cancer.
• H. pylori infection is associated with intestinal and diffuse histologic types of carcinoma.
• Infections also affect carcinomas involving the pyloric antrum and body.
• The WHO classifies H. pylori as a major carcinogen.
• H. pylori stimulates mucosal cell proliferation due to urease production.
• Urease generates intraluminal ammonia which stimulates cell proliferation, increasing the risk of mutations from carcinogenic agents.
• Vitamin C’s antioxidant properties may reduce the conversion of nitrites to carcinogenic nitroso compounds in the stomach.
• Antioxidants also prevent oxidative damage to DNA.
• H. pylori infection is the most common cause of prolonged carcinogenesis.
• The sequence is severe active gastritis to multifocal atrophic gastritis, then intestinal metaplasia, increased dysplasia and invasive carcinoma.
• Chronic Autoimmune Atrophic Gastritis allows the overgrowth of anaerobic bacteria in the lumen, which metabolizes nitrites in the food to produce carcinogenic nitroso compounds.
• Intestinal Metaplasia, which is especially type III-sulfomucin positive, has has a low predictive value for future malignancy.

Gastric Adenoma and Hyperplastic Polyps

• Gastric adenomas commonly present with a tubular architecture; tubulovillous and villous adenomas are rare and pose a high risk of malignancy.
• Forty percent of malignant adenomas are larger than 2cm.
• Hyperplastic polyps rarely transform, with a malignancy prevalence of 0.3-1%, especially when exceeding 2cm.
• Gastric Ulcers: Ulcer cancer defines a gastric carcinoma that arises in a pre-existing peptic ulcer, accounting for fewer than 1% of all gastric carcinomas
• Gastric Dysplasia, particularly of the high grade type.

Classification of Gastric Carcinoma

• Classification based on tumor location, invasiveness, histological features, and growth patterns.

Location

• Proximal: Occurs in the cardia mucosa and gastroesophageal junction, described as true.

Invasiveness

• Early: Invasion limited to the submucosa, including intramucosal and submucosal types.
• Late: Invasion of the muscularis externa.

Degree of differentiation

• Well: Well-developed tubular glands
• Moderate: Complex glands

Histological Features

• WHO: Adenocarcinoma (papillary, tubular, mucinous, signet ring cell).
• Adenosquamous carcinoma, and Squamous cell carcinoma.
• Undifferentiated and unclassified carcinoma.
• Lauren Classification: Intestinal type shows a male:female ratio of 2:1.

Intestinal

• Intraluminal mass with an expansile growth pattern that infiltrates the wall.
• There is almost 100% association with intestinal metaplasia and H. pylori infection.
• Dietary and environmental factors are contributing factors, with a 5-year survival rate of 20%.

Diffuse

• Infiltrates the wall, with lower association with intestinal metaplasia and H. pylori.
• Genetic factors tend to play a greater role; 5-year survival rate is less than 10%.
• Growth Pattern: Ming classification includes expanding and infiltrative types.

Pathological Features

• Divided into gross and microscopic features.
• Also based on the advancement of early and advanced types.
• Gross appearance of advanced gastric carcinoma:

Type II

• A malignant ulcer or a fungating tumor with an ulceration at the dome.

Type III

• Ulcerated tumor with an infiltrative base.

Type IV

• Diffuse thickening of the gastric wall without a mucosal mass or ulcer, known as the classical linitis plastica type.
• About 60-70% of advanced gastric carcinoma are large polypoid.

Gross appearance of early gastric carcinomas

Type I

• Protruding or polypoid type.

Type II

• Superficial type with unevenness of the mucosa surface, divided into elevated (type IIA), flat (type IIB), and depressed (type IIC).

Type III

• Excavated type.
• Microscopic Features
• Over 95% of gastric carcinomas are adenocarcinomas, with varying degrees of differentiation.
• Mucinous carcinomas have well-differentiated glands in extracellular mucin lakes.
• Mucin may be intracellular in signet ring types.
• Around 1% of gastric carcinomas are histologically unusual.
• Examples include pure squamous cell carcinoma, clear cell adenocarcinoma, adenocarcinoma with yolk sac carcinoma, primary gastric choriocarcinoma, hepatoid carcinoma, and small-cell undifferentiated carcinoma.

Mode of Spread

• Gastric carcinoma spreads by 4 different means.
• Local invasion through the wall in both vertical and horizontal directions, rarely directly spreading to.
• Lymphovascular extension represents a major cause of treatment failures.
• Lymphatic invasion results in regional or distant lymph node involvement.
• Involvement of the left supraclavicular lymph node at the point of entry of the thoracic duct into the jugular vein (Virchow's node) is a classical presenting manifestation.
• Tran’s celomic spread: Peritoneal involvement leads to ascites with positive cytology, multiple peritoneal nodules, bilateral ovarian involvement, and deposits in the rectovesical/rectovaginal area i.e. Blumer's shelf.
• Hematogenous spread: occurs in the liver, lungs, and other organs.

Immunohistochemical markers

• Cytokeratin 20 (CK20) more is expressed by antral adenocarcinomas, while CK7 is expressed by adenocarcinomas of the cardia, and MUC1 and MUC5AC.
• EGF and EGFR overexpression are associated with frequent metastases and poor prognosis, VEGF, and overexpression of cyclooxygenase -2 (COX-2).

Clinical Presentation

• Early gastric cancer cases can be asymptomatic.
• Patients typically experience dyspepsia or epigastric pain.
• Weight loss, melena, and anemia may be present in a minority of patients.
• Metastasis is the time of diagnosis.
• Other symptoms are outlet obstruction, massive bleeding, chronic bleeding causing occult blood in stool and anemia.

Prognosis

• The prognosis of gastric carcinoma correlates with the pathologic stage.
• Early gastric cancer has a 5-year survival rate of 90%.
• Histologic type influences prognosis; well-differentiated adenocarcinomas of the intestinal type have the best prognosis, while poorly differentiated diffuse carcinomas with signet ring cells have the worst prognosis.
• Prognosis is better in Japan than the US.

Gastric Lymphoma

• Primary lymphoma accounts for about 5% of all malignant stomach tumors and 20% of all extranodal lymphomas.
• Diagnosed between usually 40-60 years, with no sex predominance.
• Most gastric lymphomas are low-grade B-cell neoplasm.
• Tumors are typically cannot be differentiated from carcinoma because they may be polypoid, ulcerating, or diffuse.
• Symptoms: Weight loss, dyspepsia, and abdominal pain.

Malignant Gastrointestinal Stromal Tumor (GIST)

• GISTs account for approximately 1% of gastric cancers.
• Macroscopically, malignant GISTs are larger than benign GISTs.
• Cellular pleomorphism and hyperchromasia may be present in both benign and malignant tumors, but the number and size of mitoses are greater in malignant GISTs.
• Metastasis usually goes to the liver and the peritoneal surfaces.
• Treatment is surgical excision.

Carcinoid Tumor

• Carcinoid tumors are neoplasms of various endocrine cells in the gastric mucosa.
• Tumors have the potential for local recurrence and metastasis.
• The possibilities of metastasis depend more on the size than histological characteristics.

Benign Gastric Tumors

• Most present as gastric polyps that are found during upper gastrointestinal endoscopy.
• Polyps may be small and solitary, or more rarely, multiple.

Classification of Benign Gastric Tumor

• Adenomatous polyps
• Mesenchymal polyps: leiomyoma, granular cell tumor, glomus

Gastric Polyps

Hyperplastic polyps

• These are the most common, may be pedunculated or sessile.
• They are common in the body and fundus of patients with autoimmune atrophic gastritis.
• May also occur in the antrum of patients with H. pylori.
• There is no malignant potential.

Adenomatous polyps

• Tubular adenoma, most commonly in the atrum, sessile and usually solitary.
• They manifest malignant potential.
• The risk increases with the size of the polyp.

Fundic gland polyp

• Characterized by dilated oxyntic glands lined by parietal and chief cells.
• There is no malignant potential.
• Mostly seen in patients treated with.