L20 - Pathology of liver tumours and gall stones Flashcards
Site of origin of liver tumour
In normal patients with no antecedent diseases, Metastatic (secondary) tumour from other sites are much more common in the liver than primary tumour of the liver (2.1%)
Common site of origin includes organs such as the large intestine, stomach and pancreas which have a portal venous drainage. Other common primary sites include lungs and breast.
In patients with cirrhosis, primary cancer of the liver (77.2%) is much more common than metastatic tumour of the liver.
Types of primary liver tumour
EPITHELIAL
Benign (rare)
- Liver cell adenoma (hepatocyte)
- intraepithelial bile duct adenoma (bile duct)
- intraepithelial bile duct cystadenoma (bile duct)
Malignant
- Hepatocellular Carcinoma (HCC; hepatocyte)
- Cholangiocarcinoma (bile duct)
- Bile duct cystadenocarcinoma (bile duct)
- Hepatoblastoma (hepatocyte)
- Undifferentiated embryonal sarcoma of the liver (UESL; hepatocyte)
NON-EPITHELIAL
Benign
- Hemangioma (endothelial cells)
Malignant
- Hemangiosarcoma (endothelial cells)
Primary liver tumors relative incidence
1) Hepatocellular carcinoma (most common; 78.7%)
2) Cholangiocarcinoma (second common; 9.7%)
(malignant primary liver tumour more common than benign primary liver tumour)
HCC epidemiology
- Global incidence = 500k to 1M annually
- Wide geographical variation in the incidence of HCC throughout the world:
- S.E. Asia, Southern China and Africa (south of Sahara) are high-incidence areas.
- U.K., America, North and South, and Australia are low-incidence areas.
- 55% of liver cancers occur in China including HK
- In every area, males are affected more frequently than females (male predominance - male: female ratio in HK is about 4- 6:1)
- In Hong Kong, HCC is exceedingly common, with HCC being 6 times commoner than CC. Together they account for the vast majority of “Primary malignant tumours of the liver” as classified in death certificate figures in Hong Kong.
- The crude mortality rate (number of deaths/total population) of HCC is 21.5 per 100,000 of population annually, according to department of health
- 3rd commonest fatal cancer in S.E. Asia and Hong Kong
- Peak age of mortality = 45 - 55
HCC Risk factors
1) HBV (associated with 80% HCC in HK)
2) HCV (associated with 3% HCC in HK)
3) Cirrhosis (associated with 60-80% HCC in HK)
4) Aflatoxin
5) Alcohol consumption
6) Others:
- sex hormones
- metabolic disorder
- drug
- thorotrast
- parasites (schistosoma)
- genetic factors (e.g. hemochromatosis)
HBV & HCC
- The risk of HCC is about x100 higher in carrier of HBsAg (chronic HBV carrier) than non-carriers
- 80% of HCC are related to HBV infection
Pathogenesis:
- The virus DNA is integrated into the host DNA (site of viral DNA integration for all tumor cells a given patient is the same i.e. monoclonal), leading to insertional mutagenesis
- Cirrhosis leads to recurring damage, cell death and regeneration of hepatocytes. This increased turnover rate will increase chance of oncogenesis.
- HBV might be an oncogene
HCV & HCC
- 3% of HCC are associated with HCV infection
Pathogenesis:
- Its role in hepatocarcinogenesis may predominantly act in the context of chronic liver injury & regeneration leading to cirrhosis
- Cirrhosis leads to recurring damage, cell death and regeneration of hepatocytes. This increased turnover rate will increase chance of oncogenesis.
Cirrhosis & HCC
- About 60 - 80% of HCC cases associated with cirrhosis
- many other risk factors of HCC are associated with cirrhosis as the carcinogenic mediator (e.g. alcohol, drug, metabolic disease, parasite, etc)
Pathogenesis:
- Cirrhosis leads to recurring damage, cell death and regeneration of hepatocytes. This increased turnover rate will increase chance of oncogenesis.
Aflatoxin & HCC
- Aflatoxin is a mycotoxins produced by common fungus Aspergillus flavus in foodstuff
- Highly carcinogenic (can cause cancer in animals in exceptionally small doses after a long period)
- A risk factor in areas like Africa and rural areas near Shanghai
- Low aflatoxin levels in foodstuffs in HK, therefore unlikely to be the major risk factor responsible for the high incidence of HCC in Hong Kong
Alcohol consumption & HCC
- High level of consumption (but not moderate level) has increased risk of developing HCC
Pathogenesis:
- Increased risk of HCC is more related to cirrhosis developed due to chronic alcoholism
- Cirrhosis leads to recurring damage, cell death and regeneration of hepatocytes. This increased turnover rate will increase chance of oncogenesis.
HCC clinical features
- Male : female = 4-6 : 1
- Insidious clinical onset with rapidly fatal course
- Median survival with clinically apparent HCC is 2 - 4 months.
- The peak age of mortality of HCC in Hong Kong is 45 - 55 yrs.
- Hepatomegaly; but the enlargement is often less than that with secondary neoplasm of liver
- RUQ pain in advanced stage
Gross appearance of HCC
- usually light brown or tan-colored masses
- soft with very minimal supportive stroma
- Yellow patches of necrosis are common
- Hemorrhagic areas are usually present and often extensive, because the tumour is highly vascular wil minimal supportive stroma, deriving most of its support from very thin-walled sinusoids. The rich blood supply comes chiefly from branches of the hepatic artery which grow with the tumour
- Some areas of the tumour may be better differentiated to produce bile which gives the tumour a green discoloration (diagnostic feature of HCC)
- A range of gross appearance:
1) Unifocal, massive tumour
2) Multifocal, made of neoplastic nodules of various sizes (nodular tumours)
3) Diffusely infiltrative, permeating widely or even affecting entire liver (advanced, inoperable) - [4) Small HCC -> tumor less than 2 cm; distinct fibrous capsule; indicates early detection, easily resectable with good prognosis]*
Histology of HCC
- Range from well-differentiated to poorly differentiated cells
- Well differentiated variants produces cells that retain hepatocyte features; arranged in trabeculae (80%), cords, or pseudoglandular patterns
- Little stroma
- In better-differentiated variants, globules of bile may be found in cell cytoplasm, and pseudocanaliculi between cells
- In some variants, tumour cells will excessively store glycogen (and some fat), forming Clear cells
- Prone to venous invasion – very different from other carcinomas
HCC & hypoglycemia
Hypoglycemia is a common complication of HCC.
- lead to fatigue and easy fainting
Pathogenesis:
1) Some tumours may secrete insulin-like peptide and induce attacks of hypoglycemia
2) Replacement of liver by tumour – diminished glycogen storage in the remaining part of the liver without tumor
3) In clear cell type HCC, excessive glycogen storage occurs (within normal storage capacity, but stored glycogen cannot be readily released)
HCC & hemoperitoneum
HCC tumours easily rupture and bleed due to the nature of high vascularity & low supportive stroma. Haemorrhage of ruptured HCC tumour will lead to blood in the peritoneal cavity - hemoperitoneum.
Why is HCC usually discovered at late stages
Early HCCs cannot be detected due to lack of signs (no pain as there is no pain receptors in the liver)
HCC metastasis
HCC has a marked tendency for venous invasion (very unique to HCC):
- Intrahepatic metastasis: when HCC spread into portal vein branches in the liver and even into the main portal vein stem
- Distant metastasis: HCC invades into the hepatic venous system to affect the main hepatic vein branches, leading to:
- IVC,
- right heart
- lungs
- Others sites of metastases e.g. bones and lymph nodes at the liver hilum
[note: in many cases death occurs before metastases are extensive]
HCC serological test
Serum alpha-fetoprotein (AFP) most commonly used
- AFP only rises with advanced HCC & only in 50% of patients
- False positives in yolk-sac tumour & non-neoplastic conditions e.g. cirrhosis, chronic hepatitis, massive liver necrosis, normal pregnancy
- Neither specific or sensitive