ESOPHAGUS: SQUAMOUS CELL CARCINOMA

1.    Describe the lesion shown.
 
The organ shown is the middle and lower thirds of the esophagus.
There is an intraluminal mass in the middle portion. The mass is exophytic, cauliflower-like and is white, firm and fleshy, occluding nearly the entire lumen.  

2.    What are the risk factors associated with this condition?
 
a.    Dietary: vitamin deficiency (A, C, thiamine), high content of nitrites / nitrosamines, betel chewing, deficiency of trace metals (zinc, molybdenum).
b.    Lifestyle: alcohol consumption, tobacco use.
c.    Esophageal disorders: long-standing esophagitis, achalasia, Plummer-Vinson syndrome.

3.    What is the distribution of this lesion?
 
a.    Upper esophagus: 20%.
b.    Middle esophagus: 50%.
c.    Lower esophagus: 30%.

4.    What are the clinical manifestations of this condition?
 
a.    Dysphagia and recent weight loss are the two most common symptoms.
b.    Development of symptoms is insidious and most tumors are far advanced at the time of diagnosis.
c.    The trachea is the adjacent tissue most commonly involved and tracheo-esophageal fistula is found in up to 30% of cases.
d.    These will have symptoms of aspiration such as pneumonia or coughing due to aspiration of mucus.

5.    What is the prognosis?
 
Prognosis is poor. The 5-year-survival is only 5%.

ESOPHAGEAL VARICES

The patient, a 55-year-old man with a 10-year-history of chronic liver disease due to alcoholism, die after a massive hematemesis from a bleeding esophageal varice.    
 
1.    Describe the lesion shown.
 
The organ shown is the gastro-esophageal junction. There are violaceous / red protrusions into the distal esophagus with surrounding erythema.

2.    What is the likely pathogenesis in this case?
 
Cirrhosis secondary to chronic alcoholism leads to an increase in portal venous pressure due to compression of central veins and sinusoids by fibrosis and regenerative parenchymal nodules, in addition to arterial-portal venous anastomoses within the scarred liver. 

3.    How does chronic alcohol abuse leads to liver damage?
 
Alcoholic cirrhosis is the final irreversible outcome of alcoholic liver disease. The liver is transformed from a fatty, enlarged organ to a brown, shrunken, nonfatty organ.
 
Alcohol damages the liver through the following mechanisms:
 
a.    Steatosis results from shunting of substrates toward lipid biosynthesis, impaired lipoprotein assembly and secretion, and increased peripheral catabolism of fat.
b.    Cellular injury due to induction of cytochromes P-450 augmenting biotransformation of other drugs to toxic metabolites, generation of free radicals by microsomal ethanol oxidizing system and acetaldehyde generated from alcohol induces lipid peroxidation and acetaldehyde-protein adduct formation. 
c.    Fibrosis is the result of collagen deposition by perisinusoidal stellate cells stimulated by Kupffer cell activation and influx of neutrophils into the parenchyma with release of their noxious substances.
d.    Deranged hepatic blood flow is the result of progressive fibrosis and alcohol-induced release of vasoconstrictive endothelins from sinusoidal endothelial cells. 

4.    Where else can you find this lesion?
 
a.    Rectum: hemorrhoids.
b.    Falciform ligament and umbilicus: caput medusa.
c.    Retroperitoneum. 

5.    What other clinical signs can you find in this patient?
 
a.    Ascites.
b.    Congestive splenomegaly.
c.    Hepatic encephalopathy.

6.    How would you manage this patient at first presentation.?
 
a.    Resuscitate then proceed to urgent endoscopy.
b.    Give octreotide.
c.    After identifying bleeding varices check for bleeding elsewhere before proceeding to sclerotherapy or banding.
d.    If bleeding continues, pass a Sengstaken-Blakemore tube.
e.    Give sucralfate to protect against stress ulceration.
f.     Long-term: transjugular intrahepatic porto-systemic anastomosis.

CHRONIC PEPTIC ULCER

1.    Describe the lesion shown.
 
The organ shown is the stomach. The prominent feature is a oval sharply punched-out ulcer with straight walls. The base of the ulcer is smooth and clean. There is puckering of the surrounding mucosa with mucosal folds radiating from the ulcer in a spoke-like pattern. 

2.    What is the likely pathogenesis?
 
Peptic ulcers are produced by an imbalance between the gastroduodenal mucosal defense mechanisms and damaging forces of gastric acid and pepsin, combined with superimposed injury from environment or immunologic agents . 
 
H.pylori infection is present in almost all patients with duodenal ulcers and 70% with gastric ulcers. It causes damage by the following:
 
a.    Secretion of urease, protease, or phospholipases.
b.    Bacterial lipopolysaccharide attracts inflammatory cells to the mucosa.
c.    A bacterial platelet-activating factor promotes thrombotic occlusion of surface capillaries.
d.    Mucosal damage permits leakage of tissue nutrients into the surface microenivronment, sustaining the bacillus.

3.    What are the likely microscopic findings?
 
a.    Thin superficial layer of necrotic debris.
b.    Zone of inflammation with non-specific inflammatory infiltrate.
c.    Granulation tissue.
d.    Collagenous scar.

4.    What are the complications?
 
a.    Hemorrhage. 
b.    Penetration: the ulcer penetrates the full thickness of the stomach, progressing into adherent underlying tissue, particularly the pancreas or liver.
c.    Perforation leading to peritonitis.
d.    Fibrous stricture: fibrous thickening caused by healing leads to scarring and obstruction leading to pyloric stenosis.
e.    Malignant change is extremely rare. 

5.    How would you manage this condition?
 
a.    Eradicate H.pylori: triple therapy of omeprazole, amoxicillin and clarithromycin for one week.
b.    Acid suppression with H2-receptor antagonist such as cimetidine.
c.    Elective surgery in persistent cases.

CHRONIC GASTRITIS

A 45-year-old man complains of a month history of nausea, vomiting and upper abdominal discomfort. An endoscopy was performed.
 
1.    Describe the lesion shown.
 
The organ shown is the stomach. The prominent feature is a reddened, boggy-appearing mucosa with thickened rugal folds. 

2.    What are the possible causes?
 
The above morphological features are suggestive of chronic gastritis of the stomach mucosa. Chronic gastritis is defined as the presence of chronic mucosal inflammatory changes leading eventually to mucosal atrophy and epithelial metaplasia, usually in the absence of erosion.
 
The three main patterns of chronic gastritis are:
 
a.    Helicobacter-associated gastritis is the most common form, arising at any age. H.pylori colonize the surface of the epithelium beneath the thin layer of mucus. The presence of the organisms is associated with epithelial damage and a mixed acute and chronic inflammatory cell reaction in the lamina propria and superficial epithelium.
 
b.    Autoimmune gastritis is associated with pernicious anemia and is generally seen in elderly patients in whom severe atrophy of the mucosa develops. Those affected have antibodies against gastric parietal cells (90%) and intrinsic factor (60%). This pattern of gastritis particularly affects the body of the stomach.
 
c.    Reactive gastritis occurs when alkaline duodenal fluid refluxes into the lower part of the stomach. It is common in people who have had previous gastric surgery to the pyloric area.
 
Other causes are:
 
a.    Toxic: alcohol ingestions and cigarette smoking.
b.    Motor and mechanical: obstruction, gastric atony.
c.    Radiation.
d.    Granulomatous conditions.

3.    What are the likely microscopic findings?
 
a.    Presence of lymphocytes and plasma cells within the lamina propria.
b.    Presence of neutrophils within glandular and surface epithelial layer.
c.    Lymphoid aggregates with germinal centers. 

4.    A urea breath test detects the presence of Helicobacter infection. How is the test conducted and what are methods can be used to diagnose presence of H.pylori?
 
Urea breath test: Helicobacter produces the enzyme urease. If radiolabeled urea is administered and Helicobacter urea is present, radioactive carbon dioxide can be detected in the breath.
 
Other methods are:
 
a.    Serology: antibodies to H.pylori can be detected in serum.
b.    Histology: organisms can be seen in biopsy material, particularly if specially stained.
c.    Culture: H.pylori, a curved microaerophilic organism, can be cultured from biopsy material.

5.    What special traits does H.pylori possess to flourish under the acidic conditions of the stomach?
 
a.    Motility (via flagella), allowing it to swim through viscous mucus.
b.    Elaboration of a urease, which produces ammonia from endogenous urea, thereby buffering gastric acid in the immediate vicinity of the organism.
c.    Binding of H.pylori to gastric epithelial cells via a bacteria adhesin. 

6.    H.pylori infection is more common in those with which blood group?
 
Blood group O. 

STOMACH ADENOCARCINOMA

A 50-year-old man complains of a 3-month history of weight loss, abdominal pain, altered bowel habits and dysphagia. A gastrectomy was done.

1.    Describe the lesion shown.
 
The organ shown is the stomach. The prominent feature is a exophytic mass protruding into the lumen and causing puckering of the surrounding mucosa, throwing them into thickened rugal folds. There appears to be superficial erosion of the mucosa over the mass with conspicuous vessels, some of which may have bled. The surrounding lymph nodes are not enlarged. There are no signs of perforation.  

2.    Where else can the lesion be found?
 
a.    Pylorus and antrum: 50 - 60%.
b.    Cardia: 25%.
c.    Remainder in the body and fundus.

3.    What are the risk factors for this condition?
 
a.    Diet: nitrites derived from nitrates, smoked and salted foods, pickled vegetables.
b.    Cigarette smoking.
c.    Chronic gastritis.
d.    Infection by H.pylori.
e.    Partial gastrectomy.
f.    Genetic: blood group A, family history of gastric cancer, hereditary nonpolyposis colon cancer syndrome.

4.    How is it spread?
 
a.    Direct invasion through the wall of the stomach leads to involvement of adjacent viscera.
b.    Lymphatic spread (the main route) is to nodes on the greater and lesser curves of the stomach, then to other nodal groups.
c.    Hematogenous spread to liver, lung and brain is common. Spread to the ovaries leads to development of Krukenberg tumors.
d.    Transcelomic spread through the peritoneum results in malignant ascites.    

5.    What is the prognosis?
 
Prognosis of gastric adenocarcinoma is poor in most cases. The 5-year survival rate in gastric carcinoma is low and depends on the stage of the tumor. Many tumors are locally advanced at diagnosis and have spread to nodes or metastasized. Prognosis after surgery is 20% 10-year survival for advanced gastric cancer, but 90% 10-year survival for lesions confined to the mucosa and submucosa, as with small polypoid tumors. 

APPENDIX: APPENDICITIS

A 23-year-old Malay man presented to the A&E Department of acute abdominal pain over the umbilicus later shifting to the right iliac fossa, fever, nausea and vomiting. An open abdominal surgery was performed.

1.    Describe the lesion shown.
 
The organ shown is the appendix:
 
a.    This appendix has been cross sectioned at one end.
b.    The cross sectioned end appears dilated and the wall appears thickened and edematous.
c.    The serosa is congested with yellow plaques of exudate.
d.    The serosal surface of the intact appendix shows congested vessels. 

2.    What is the pathogenesis?
 
a.    Obstruction of the lumen (fecalith, calculus, tumor, worms) predisposes to build-up of intraluminal pressure.
b.    Increased intraluminal pressure eventually exceeds intravenous pressure leading to stoppage in venous flow and ischaemia.
c.    Ischaemic damage leads to bacterial invasion of the mucosa with ischemic and septic necrosis. 
 
Peptic ulcers are produced by an imbalance between the gastroduodenal mucosal defense mechanisms and damaging forces of gastric acid and pepsin, combined with superimposed injury from environment or immunologic agents . 

3.    What are the likely microscopic findings?
 
a.    Early: neutrophil infiltrate of lumen, mucosa and muscularis.
b.    Late: mucosal necrosis, fibrinopurulent exudate on serosa.
c.    Later: extensive necrosis of mucosa and muscularis, with microabscesses within the appendiceal wall.

4.    What are the complications?
 
a.    Necrosis of appendix wall leading to perforation, with subsequent generalized peritonitis. 
b.    Involvement of adjacent bowel loops, causing perforation of small bowel.
c.    The omentum may become adherent, localizing the peritonitis to the right iliac fossa. Fibrosis and continued inflammation cause development of a mass in the right iliac fossa. This may resolve with scarring, may form an abscess that drains to the surface, or may rupture, with development of generalized peritonitis.
d.    Spread of infection by portal vein branches may propagate to the liver forming hepatic abscesses.

DIVERTICULOSIS

1.    Describe the lesion shown.
 
The organ shown is the colon:
 
a.    The prominent feature here are small flask-like outpouchings 0.5 - 1cm in diameter dissecting into appendices epiploicae.  
b.    The closely adjacent diverticula are held together by adhesions, indicating a possible inflammatory reaction has occurred. 
c.    There are no complications such as obstruction, perforation, hemorrhage or fistula formation seen. 

2.    What is the pathogenesis?
 
a.    Focal weakness in bowel wall at sites of penetrating blood vessels (vasa rectae). 
b.    Increased intraluminal pressure resulting from exaggerated peristaltic contractions.

3.    What are the likely clinical manifestations of this condition?
 
a.    Usually asymptomatic unless inflamed.
b.    Pain: a persistent ache with colicky exacerbations in the left iliac fossa.
c.    Indigestion: distension, flatulence and belching.
d.    Constipation.

4.    What are the complications?
 
The complications are usually due to acute inflammation of the diverticula:
 
a.    Abscess formation: ulceration and perforation of an inflamed diverticulum can lead to a well-localized pericolic abscess containing thick and foul-smelling pus.
b.    Diffuse peritonitis: an inflamed diverticulum will perforate freely into the peritoneal cavity, causing a generalized faecal peritonitis.
c.    Obstruction: a thickened, narrowed, distorted and rigid segment of the colon may precipitate large bowel obstruction.
d.    Fistula formation: internal fistula formation occurs when a pericolic abscess points and discharges into an adjacent and adherent viscus.
e.    Haemorrhage: blood loss per rectum. 

FAMILIAL ADENOMATOUS POLYPOSIS

This is a section of a colon resected from a 22-year-old man. A few hundreds of such lesions were found. 

1.    What is your diagnosis?
 
Familial adenomatous polyposis. 

2.    Why is there a need for a total colectomy in this patient?
 
Familial adenomatous polyposis is a rare autosomal dominant condition in which large numbers of adenomatous polyps develop in the colon and rectum. They may begin to develop in childhood, and by the age of 30 - 40 years there are hundreds, of varying sizes, throughout the entire length of the colon and rectum. Inevitably, one or more of these many polyps will convert into an invasive adenocarcinoma by the age of 45. Therefore, it is necessary for a total colectomy in this patient. 

This condition arises from a defect in a tumor-suppressor gene. 

3.    What are tumor suppressor genes and what is their role in the pathogenesis of cancer? Give an example to illustrate your answer.
 
Tumor suppressor genes:
 
a.    Are genetic elements whose loss or inactivation induces deregulated cell proliferation and tumorigenesis.
b.    Prevent inappropriate cell proliferation and the development of cancers.
c.    Prevent tumorigenesis by blocking inappropriate cell proliferation, promoting cell differentiation or apoptosis.
 
For mutations of tumor suppressors to contribute to cancer development:
 
a.    2 mutations are required as both alleles need to be deleted or mutated.
b.    The mutations need to be loss-of-function mutations. 
 
P53 is one of the most important tumor suppressor. P53 inactivation is the most frequent (50 - 60%) genetic alteration in human cancers. Upon activation P53 delays the cell cycle for repairs to DNA. P53 kills cell if DNA damage is too extensive. 

4.    Describe the molecular genetics behind the development of this lesion.
 
The genetic defect in familial adenomatous polyposis is in the APC gene on chromosome 5q21, site of the APC tumor-suppressor gene. APC proteins binds to B-catenin and directs it toward degradation. When it is not bound, B-catenin activates genes that stimulate cell proliferation and inhibiting apoptosis.