Dear Drs,

What is the Epidemiology of Biliary Cancer:?

The "Excretory Apparatus" of the liver means the Bile Collection System. From a network of microscopic bile ducts within the liver. Convergence is achieved at the porta hepatis (along the transverse fissue) and the bile exits via two similarly sized "Hepatic Ducts," one from each major lobe. The two Hepatic Ducts join to form the "Cystic Duct" which empties into the Gallbladder. Bile collects in the gallbladder until it is stimulated to be released by cholescystokinin ("CCK") which acts to contract the gallbladder's muscular wall. The bile is then propelled through the "Common Bile Duct" (which also has a direct connection to the cystic duct) toward the "Sphincter of Odi," where it enters the duodenum to emulsify fats. Afterward, some of the bile salts tend to get re-absorbed by the small intestine and reprocessed by the liver, accounting for the "enterohepatic circulation" of bile salts.

The "Microscopic" appearance of the liver, as seen with the light microscope, show that the basic unit of the liver is the "hepatic lobule" . Each lobule is a mass of hepatic cells, surrounded by a capillary plexus. Vessels penetrate from the plexus into the lobule, and commutate in a a single "straight vein" in the center of each lobule, which is about the size of a millet seed. Between the hepatic cells ("hepatocytes") the minutest portion of the aforementioned bile ducts originate. The actual hepatocytes tend to be hexagonal and adjoin each other in a honeycomb network, each contains one or two nuclei. They also contain yellow particles which are the incipient bile. The hepatocytes are nourished by intrahepatic branches from the hepatis artery, and recieve blood from the terminal microscopic branches of the portal vein draining the intestines. Processed blood is drained by intralobular veins which ultimately form the sublobular veins which coalesce hepatic veins which empty into the Inferior Vena Cava.

Epidemiology of Liver Cancer:
Liver cancer is fairly uncommon in the U.S.A. with 20,000 new cases and 15,000 deaths each year in the United States. It thus represents about 2% of all new cancers. About 3000 of the cases are in the liver itself, the remainder are in the Gall Bladder and bile drainage ducts. However, in Asia and Africa liver cancers are one of the most common cancers. Worldwide there are 1 million new cases of lever cancer per year. Males are effected four times more commonly than females, and the average patient is 50 years old. The death rate from liver cancer in the U.S.A. is 2 per 100,000 per year, compared to 20 person per 100,000 per year in South Aftrica and 150 per 100,000 per year in Korea. In these high-risk countries, the Hepatocellular Carcinoma is considered endemic. By contrast, benign liver tumors are more common in females and tend to occur at a younger age. The Overall the death rate from liver cancer has dropped in the U.S.A. over the past 50 years. This is both from a decline in the number of cases, and better treatment for the disease.

Risk Factors for Liver Cancer:
1. Chronic Hepatitis can lead to hepatic steatosis and dysplasia, and to most common type of liver cancer, hepatocellular carcinoma (HCC). a) Hepatitis B -- evidence of prior infection is found in 75% of liver cancer patients worldwide. It can lead to cirrhosis, below. The more common Hepatitis A (spread by feces) isn't associated with liver cancer, but Hepatitis "C" (non A non B) is. Auto-immune chronic active hepatitis is a risk factor for later cirrhosis and HCC.
b)Carcinogens such as aflatoxin B (which is the most potent natural carcinogen and is found in stored grains. It was used as a war agent (by Iraq on the Kurds). Other agents include androgenic steroids, Industrial dyes and colorants, rice toxins, and nitrosamines.

2. Cirrhosis of the liver, Causes of cirrhosis include:
a) Alcoholism-- alcoholic cirrhosis leads to 5% of liver cancer.
b) Hemochromatosis is an overload of iron in the liver. 20% of patients who get cirrhosis from the overload may develop HCC.
c) Alpha 1- antitrypsin deficiency is a rare condition where a necessary enzyme is lacking to break down metabolites in the liver and lung. HCC can develop in 40% of patients who get this type of cirrhosis.

d) Primary Biliary Cirrhosis (seen in young women, tested for by AMA).

3. Genetic Diseases either via cirrhosis or impairment of normal liver function:
a) Lipid Storage Diseases (glycogen storage disease types I and III).
b) Enzyme Deficiency Diseases leading to overloads of metabolites, (Orotic Aciduria, Tyrosinemia, Citrullinemia, Galactosemia)
c) Other Disorders of Metabolism (Wilson's Disease, Porphyria Tarda, Genetic Hemachromatosis, Chronic Hepatic Steatosis)
d) Interference with Normal Drainage (Ataxia Telangiectasia, Alagille's Syndrome -- [a congenital cholestatic syndrome], Hepatic Atresia.

4. Miscellaneous irritants to the liver including:
a) Polyvinyl Chloride (PVC) is linked to angiosarcoma.
b) Liver flukes are linked with bile duct cancer in China.
c) Thorotrast is a contrast dye for radiology studies no longer used after being linked to angiosarcoma.
d) Radiation Exposure can lead to liver sarcomas, sometimes as long as five decades after the exposure.

The common thread to liver cancer risk factors is chronic irritation, which causes hepatocytes to mitose more frequently than normal to repair perceived damage. This increases the chance for mutations including oncogene activation and suppressor gene inactivation, presaging frank neoplasia.

Testing of the Biopsy Material:
Besides for conventional light-microscopy indications of carcinoma (dysmorphism of nuclei, frequent mitosis, invasion of surrounding structures) study of the surrounding "normal tissue" is mandatory to establish the degree of cirrhosis. Staining is done for AFP; however this is only positive in 50% of HCC. In-Situ testing for RNA hybridization is over 90% accurate at diagnosing HCC. Aneuploidy is seen in 78% of HCCs and the remaining 22% are diploid. Elevated AFP is more likely in an aneuploid tumor.

The biopsy material is studied for viral inclusion particles from hepatitis. Growth factors stimulating the cancer include EGF, TGF-alpha, and HGF (hepatocyte growth factor). Retinoic acid receptor-alpha is ubiquitious on HCC cells. Retinoic acid inhibits division of differentiated cells; in contrast it stimulates more poorly differentiated HCC.

Investigational studies may be made for oncogene activation and suppressor gene inactivation. The amplification of an errant gene often corresponds to the clinical aggresiveness of the tumor. Oncogenes include v-ERB and Suppressor genes p-53.

TESTIMONIALS FROM PHYSICIANS

Thank you preparing this series of subject reviews in Radiation Oncology. Like many others in my field, I've experienced the frustration in trying to "weed" through the major texts to glean information essential for board review.
Dr. J.H., Ashland, Ky

I'm very glad that you have followed through with your idea to publish your reviews. With a little bitterness, I will never understand why leaders in our field have not done this years earlier. Just about any other medical specialty has ample board review materials available to their residents at resonable cost.
Dr. T.N., Clarksville, TN

Your notes are very good!
Dr. M.S., Chicago, IL

Thank you for your help, and effort. As a first year Rad/Onc resident, I know your information will guide me in my studies.
Dr. D.R., Beverly Hills, CA

My Department Head recommended your service to me, I passed my boards. Thank you so much.
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