CARCINOMA OF THE GALLBLADDER

INTRO

• Most common malignancy of the extrahepatic biliary tract• Slightly more common in women • Occurs most frequently in the seventh

decade of life• Mean 5-year survival rate has remained for

many years at about 5% to 12% despite surgical intervention

• The most common sites of involvement are the fundus and the neck; about 20% involve the lateral walls.

ETIOLOGY

• The most important risk factor associated with gallbladder carcinoma is gallstones (cholelithiasis), which are present in 95% of cases• However, it should be noted that only 0.5%

of patients with gallstones develop gallbladder cancer after twenty or more years

• Carcinogenic derivatives of bile acids are believed to play a role.• Genetic factors • Previous surgery on the biliary tract • IBD

MORPHOLOGY

• Carcinomas of the gallbladder show two patterns of growth: infiltrating and exophytic

• The infiltrating pattern is more common and usually appears as a poorly defined area of diffuse thickening and induration of the gallbladder wall that may cover several square centimeters or may involve the entire gallbladder.

• Deep ulceration can cause direct penetration of the gallbladder wall or fistula formation to adjacent viscera into which the neoplasm has grown.

• These tumors are scirrhous and have a very firm consistency

• The exophytic pattern grows into the lumen as an irregular, cauliflower mass but at the same time invades the underlying wall.

• The luminal portion may be necrotic, hemorrhagic, and ulcerated

The opened gallbladder contains a large, exophytic tumor that virtually fills the lumen

HISTOLOGY

• Most carcinomas of the gallbladder are adenocarcinomas.

• Some of the carcinomas are papillary in architecture and are well to moderately differentiated; others are infiltrative and poorly differentiated to undifferentiated

• About 5% are squamous cell carcinomas or have adenosquamous differentiation

NORMAL ADENOCARCINOMA

Malignant glandular structures are present within a densely fibrotic gallbladder wall.

Papillary pattern

• By the time these neoplasms are discovered, most have invaded the liver centrifugally, and many have extended to the cystic duct and adjacent bile ducts and portal-hepatic lymph nodes.

• The peritoneum, gastrointestinal tract, and lungs are common sites of seeding.

GASTRIC ADENOCARCINOMA

INTRO

• Adenocarcinoma is the most common malignancy of the stomach, comprising over 90% of all gastric cancers

• Early symptoms resemble those of chronic gastritis. As a result, these tumors are often discovered at advanced stages,

EPIDEMIOLOGY

• Gastric cancer incidence varies markedly with geography

• The cause of the overall reduction in gastric cancer is unknown.

• One possible explanation is the decreased consumption of dietary carcinogens, such as N-nitroso compounds and benzopyrene, because of reduced use of salt and smoking for food preservation and the widespread availability of food refrigeration.

• Conversely, intake of green, leafy vegetables and citrus fruits, which contain antioxidants such as vitamin C, vitamin E, and beta-carotene, and is correlated with reduced risk of gastric cancers, may have increased as a result of improved food transportation networks.

• Gastric cancer is more common in lower socioeconomic groups and in individuals with multifocal mucosal atrophy and intestinal metaplasia.

• PUD does not impart an increased risk of gastric cancer, but patients who have had partial gastrectomies for PUD have a slightly higher risk of developing cancer in the residual gastric stump as a result of hypochlorhydria, bile reflux, and chronic gastritis.

• Although overall incidence of gastric adenocarcinoma is falling, cancer of the gastric cardia is on the rise.

• This is probably related to Barrett esophagus and may reflect the increasing incidence of chronic GERD and obesity.

ETIOPATHOGENESIS

• Helicobacter Pylori Infection: • Chronic H. pylori infection is the most important cause of

distal gastric adenocarcinoma • It commonly generates chronic gastritis, and over

several decades may induce mucosal atrophy, which in some patients precedes the development of cancer .

• Bacterial virulence factors, such as CagA and Vac A (vacuolating enzyme), play an important role in the severity of gastritis and intestinal metaplasia

• Dietary and Lifestyle Factors: • Smoking and dietary habits (high intake of salt-preserved

and/or smoked foods) also play a role in increasing cancer risk, either individually or by compounding the role of H. pylori infection

• Genetic Susceptibility • Some individuals are at increased risk of developing

gastric cancer, as well as other malignancies, because of dominantly inherited cancer predisposition syndromes, such as FAP, Lynch syndrome, and Li-Fraumeni syndrome . Patients with Peutz-Jeghers are also at risk for developing gastric cancers

• Hereditary Diffuse Gastric Cancer (HDGC):• Familial diffuse gastric cancer with autosomal dominant

inheritance, caused by germline mutation of E-cadherin(CDH1), is a recently reported syndrome

• Precursor Lesions• Whether in H. pylori-associated chronic gastritis or

autoimmune gastritis, atrophy followed by intestinal metaplasia develops over time, beginning a sequence of events that may culminate in neoplasia, particularly adenocarcinoma of tubular type.

• Gastric Polyps: Various polypoid lesions have the potential to develop into adenocarcinoma

• Adenomatous Polyps: The risk of malignant transformation is related to size (>2 cm) and the presence of high-grade intraepithelial neoplasia/dysplasia

• Non-neoplastic Polyps: Hyperplastic polyps and rare syndromic examples, as well as hamartomatous polyps that generally occur as part of hereditary polyposis syndromes (Peutz-Jeghers polyp, juvenile polyp, Cronkhite-Canada syndrome-associated polyp), also may undergo malignant transformation

MORPHOLOGY

• Most gastric adenocarcinomas involve the gastric antrum; the lesser curvature is involved more often than the greater curvature

• Gastric tumors with an intestinal morphology tend to form bulky tumors composed of glandular structures , while cancers with a diffuse infiltrative growth pattern are more often composed of signet-ring cells

Gastric adenocarcinoma. Intestinal-type adenocarcinoma consisting of an elevated mass with heaped-up borders and central ulceration.

NORMAL HISTOLOGY

Gastric adenocarcinoma. Intestinal-type adenocarcinoma composed of columnar, gland-forming cells infiltrating through desmoplastic stroma.

• When there are large areas of infitration, diffuse rugal flattening and a rigid, thickened wall may impart a leather bottle appearance termed linitis plastica

• Breast and lung cancers that metastasize to the stomach may also create a linitis plastica–like appearance.

Linitis plastica. The gastric wall is markedly thickened, and rugal folds are partially lost.

Signet-ring cells can be recognized by their large cytoplasmic mucin vacuoles and peripherally displaced, crescent-shaped nuclei.

CLINICAL FEATURES

• Intestinal-type gastric cancer predominates in high-risk areas and develops from precursor lesions including flat dysplasia and adenomas. The mean age of presentation is 55 years, and the male-to-female ratio is 2 : 1.

• In contrast, the incidence of diffuse gastric cancer is relatively uniform across countries, there are no identified precursor lesions, and the disease occurs at similar frequencies in males and females.

• The depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis remain the most powerful prognostic indicators for gastric cancer

• In advanced cases gastric carcinoma may first be detected as metastases to the supraclavicular sentinel lymph node, also called Virchow's node.

• Gastric tumors can also metastasize to the periumbilical region to form a subcutaneous nodule, termed a Sister Mary Joseph nodule, after the nurse who first noted this lesion as a marker of metastatic carcinoma.

• Local invasion into the duodenum, pancreas, and retroperitoneum is also characteristic. In such cases efforts are usually focused on chemotherapy or radiation therapy and palliative care

• Surgical resection remains the preferred treatment for gastric adenocarcinoma.

• After surgical resection, the 5-year survival rate of early gastric cancer can exceed 90%, even if lymph node metastases are present. In contrast, the 5-year survival rate for advanced gastric cancer remains below 20%

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