L20 - Pathology of liver tumours and gall stones

Question 1

Site of origin of liver tumour

Answer 1

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.

Question 2

Types of primary liver tumour

Answer 2

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)

Question 3

Primary liver tumors relative incidence

Answer 3

1) Hepatocellular carcinoma (most common; 78.7%)
2) Cholangiocarcinoma (second common; 9.7%)

(malignant primary liver tumour more common than benign primary liver tumour)

Question 4

HCC epidemiology

Answer 4

• 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

Question 5

HCC Risk factors

Answer 5

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)

Question 6

HBV & HCC

Answer 6

• 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

Question 7

HCV & HCC

Answer 7

• 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.

Question 8

Cirrhosis & HCC

Answer 8

• 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.

Question 9

Aflatoxin & HCC

Answer 9

• 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

Question 10

Alcohol consumption & HCC

Answer 10

• 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.

Question 11

HCC clinical features

Answer 11

• 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

Question 12

Gross appearance of HCC

Answer 12

• 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]*

Question 13

Histology of HCC

Answer 13

• 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

Question 14

HCC & hypoglycemia

Answer 14

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)

Question 15

HCC & hemoperitoneum

Answer 15

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.

Question 16

Why is HCC usually discovered at late stages

Answer 16

Early HCCs cannot be detected due to lack of signs (no pain as there is no pain receptors in the liver)

Question 17

HCC metastasis

Answer 17

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]

Question 18

HCC serological test

Answer 18

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

Question 19

Cholangiocarcinoma definition

Answer 19

Carcinoma of the intrahepatic bile ducts (in contrast to tumors of extrahepatic bile ducts such as those of common bile duct)

Question 20

Cholangiocarcinoma Epidemiology

Answer 20

• 2nd commonest primary liver cancer; ~ 7.9% of all primary liver cancer
• In Hong Kong, CC is relatively common, with HCC being 6 times commoner than CC (HCC:CC = 6-7: 1). Together they account for the vast majority of “Primary malignant tumours of the liver” as classified in death certificate figures in Hong Kong.
• male predominance - male: female ratio in HK is about 2:1
• Peak age of mortality = 55 - 65

Question 21

Cholangiocarcinoma risk factors

Answer 21

1) Liver parasites
2) Hepatolithiasis
3) Primary sclerosing cholangitis
4) Chronic inflammatory bowel disease (ulcerative colitis)
5) Congenital liver disorders
6) Thorotrast

Question 22

Liver parasite and CC

Answer 22

Liver parasites are risk factors of CC:

- Clonorchis sinensis

• around 1cm
• found in snails & freshwater fish (carp)
• niche: bile duct (will die if entered gall bladder)

- Opisthorchis viverrini

In Hong Kong, (65% of?) CC is evidently associated with the occurrence of clonorchiasis (Clonorchis sinensis; found in freshwater carp, related to chinese habit of eating snails & raw carp in congee)

Question 23

Hepatolithiasis

Answer 23

Gall stones in the biliary duct of the liver, usually proximal to junction of Right and Left hepatic ducts

Question 24

Chronic inflammatory bowel disease & CC

Answer 24

• Only ulcerative colitis predisposes to CC
• The risk factor is x10.

Question 25

Congenital liver disorders that increase CC risk

Answer 25

• congenital dilatation and cysts of intrahepatic bile duct
• Caroli’s disease
• Congenital hepatic fibrosis.

Question 26

CC clinical features

Answer 26

• The onset is commonly insidious
• Peripheral CC presented without jaundice
• Central/ hilar CC presented with jaundice (however, jaundice might not be presented; if the tumour obstructs bile flow from an intrahepatic duct, the bilirubin can be subsequently reabsorbed into blood and is re-excreted through unaffected parts of the liver and ducts into the gut)
• Male : female = 2 : 1
• The peak age of mortality of HCC in Hong Kong is 55 - 65 yrs.
• May cause ascites due to the involvement of peritoneal lymphatics

Question 27

CC gross presentation

Answer 27

• grey to grey-white tumour
• firm and solid because of abundant fibrous stroma
• may be central necrosis

Question 28

CC histology

Answer 28

• an adenocarcinoma (structure is histologically indistinguishable from that of a metastasis from e.g. a pancreatic primary adenocarcinoma)
• mucin-secreting glandular formation often present
• lymph node involvement is common

Question 29

Spread of CC

Answer 29

• CC has a greater tendency to spread by lymphatics
• therefore lymph node involvement tends to be greater in CC
• Ascites may be resulted due to the involvement of peritoneal lymphatics.

Question 30

Types of CC

Answer 30

2 types based on location:

1) Hilar/ central CC

• When the tumour originates from the hilum of the liver i.e. right and left hepatic ducts and the areas of their junction, it is called hilar type of CC or Klatskin tumour.
• Tumour of this kind may block both right and left hepatic ducts and cause jaundice and so may present early

2) Peripheral CC

• when tumour originates from periphery of liver
• Often asymptomatic (no jaundice as biliary ducts not blocked) and presents late

Question 31

Jaundice and different tumours of biliary systems

Answer 31

Intrahepatic biliary duct carcinoma is least associated with jaundice because:

• intrahepatic stones are usually not present
• If the tumour obstructs bile flow from an intrahepatic duct, the bilirubin is subsequently reabsorbed into blood and is re-excreted through unaffected parts of the liver and ducts into the gut.
• Central/ hilar CC is more associated to jaundice than peripheral CC

Extrahepatic bile duct carcinoma, on the other hand, may cause jaundice early

Carcinoma of the gall bladder (GB), as it is commonly associated with gall stones, is more likely to be associated with jaundice.

• In the west, Carcinoma of the GB is commoner than CC
• In Hong Kong, CC > carcinoma of GB

Question 32

HCC vs CC comparisons

Answer 32

(HCC vs CC)

1) M:F ratio: 4-6:1 vs 2:1
2) Peak age: 45-55 vs 55-65
3) Gross appearance: Tan / variegated in colour; soft with necrosis & hemorrhage vs white/ greyish white in color and firm
4) Architecture: Trabecular with sinusoids & little stroma vs Glandular with fibrous stroma
5) Bile production: common vs none
6) Common mode of spread: venous vs lymphatics
7) Associated cirrhosis: 60-80% vs no increased frequency
8) Associated HBsAg: 80% vs no increased frequency
9) Clonorchiasis: no increased frequency vs common (65%)
10) Serum AFP : increased vs not increased

Question 33

hepatoblastoma and embryonal sarcoma

Answer 33

usually appear in the first decade of life

Question 34

Cholelithiasis

Answer 34

Gallstones are usually formed in the gallbladder and only occasionally in the biliary ducts

Question 35

Gall stone constituents

Answer 35

Stones are composed of different combinations of the three constituents of the bile:

1) cholesterol
2) calcium bilirubinate
3) calcium carbonate.

Question 36

Basic types of gall stones

Answer 36

There are 3 types of gallstones based on different combination of constituents - [cholesterol, calcium bilirubinate, calcium carbonate]:

1) Pure stones (1%) - composed almost entirely of one substance

2) Mixed stones (80%) - composed of a mixture of the the 3 constituents in varying proportions

3) Combination/ combined stones (10%) - composed of a combination in which one kind of substance forms the nucleus and another the shell

Question 37

Pure stones

Answer 37

• composed almost entirely of one substance
• 10% of all gallstones
• 3 types (from common to rare):

1) Cholesterol stone

• commonest pure stone
• composed of cholesterol
• egg-shaped
• yellow
• radiolucent (as it does not contain calcium; cannot be detected by plain X ray)

2) Pure Pigment stone

• second common pure stone
• composed of calcium bilirubinate
• multiple
• black/brown
• radio-opaque

3) Calcium carbonate stone

• rarest pure stone
• composed of calcium carbonate
• multiple
• grayish white
• radio-opaque

Question 38

Mixed stones

Answer 38

• composed of a mixture of the the cholesterol, calcium bilirubinate, calcium carbonate in varying proportions
• 80% of all gallstones
• Multiple
• Multifaceted
• Colours vary
• radio-opaque

Question 39

Combination stones

Answer 39

• composed of a combination of cholesterol, calcium bilirubinate & calcium carbonate, in which one kind of substance forms the nucleus and another the shell
• 10% of all gallstones
• Colors vary acccording to composition
• Often solitary
• radio-opaque

Question 40

Size of gallstones

Answer 40

Smaller stones are more dangerous as they are more likely to enter the cystic/common bile duct to produce obstruction.

Question 41

Pathogenesis of gallstones

Answer 41

1) Abnormalities in bile composition (aka lithogenic bile)

• increased cholesterol secretion (e.g. obesity, hyperlipidemia), producing cholesterol stones
• decrease in bile __acid pool (e.g. due to ileal resection & consequent decrease in ileal bile salt reabsorption) will lead to decrease in cholesterol solubility & supersaturation of cholesterol, producing cholesterol stones
• increase in the unconjugated bilirubin (e.g. hemolytic anemias), producing black pure pigment stones

2) Infection

• Bacterial infection of intrahepatic bile ducts will lead to **recurrent pyogenic cholangitis **(RPC), producing gallstones in intrahepatic bile ducts (mixed pigment stone, usually brown)

3) Stasis

• smooth muscle relaxation
• increased resorption of water & accumulation of mucoproteins
• e.g. in pregnancy

Question 42

Risk factors for gallstones

Answer 42

- Age

- The 4 Fs

• Female
• Forty
• Fat
• Fertile

[contributes to cholesterol stone)

- Regional difference:

• cholesterol stone: uncommon in developing countries but there is a high incidence in the West, particularly in Northern & South America, Europe
• intrahepatic stone (mixed pigment stone): common in S.E. Asia, infrequently seen in the West

**- Racial: **American indians, white >> black

- Obesity, hyperlipidemia (increases cholesterol secretion in bile -> lithogenic bile that promotes cholesterol stone)

- ileal bypass (decreased reabsorption of bile salts from the small bowel and this leads to a decrease in bile acid pool size, decreasing solubility of cholesterol leading to supersaturation -> lithogenic bile that promotes cholesterol stone)

- Hemolytic anemia (increase unconjugated bilirubin in bile -> lithogenic bile that promotes black pigment stone)

- Infection: Intrahepatic stones often associated with recurrent pyogenic cholangitis (a form of infection of intrahepatic bile ducts with stones in the bile ducts)

Question 43

Effects of gallstones

Answer 43

A) asymptomatic

B) symptomatic

1) Stone in gallbladder will cause:
- acute or chronic cholecystitis
- empyema, if the cholescystitis inflammation is suppurative with pus formation
2) Stone may obstruct cystic duct or common bile duct, leading to:
- acute biliary colic (pain)
- obstructive jaundice
- acute or chronic cholangitis
- acute or chronic biliary pancreatitis
3) Gallstones are very often found in association with a carcinoma of the gall bladder; Hepatolithiasis is a known risk factor of cholangiocarcinoma

Question 44

Acute pancreatitis definition, etiology, pathogenesis

Answer 44

Definition: A sudden, more or less diffuse destruction of pancreatic substance

Etiology:

• Biliary tract disease (acute biliary pancreatitis) - most common cause of pancreatitis
• Alcoholism
• Hypercalcaemia
• Hyperlipidaemia
• Familial
• Idiopathic

Pathogenesis:

• Caused by autolysis of pancreas by interstitially leaked activated pancreatic enzymes in the parenchyma
• Interstitial pancreatic enzymes will cause lipolysis, proteolysis & haemorrhage

Question 45

From cholelithiasis to pancreatitis

Answer 45

1) Cholelithiasis will lead to obstruction of bile duct and pancreatic duct
2) Activation of pancreatic enzymes; Interstitial leak of activated enzymes
3) Interstitial enzymes will cause lipolysis, proteolysis & haemorrhage of the pancreas, leading to cell necrosis & pancreatitis