L20 - Pathology of liver tumours and gall stones Flashcards

1
Q

Site of origin of liver tumour

A

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.

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2
Q

Types of primary liver tumour

A

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)
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3
Q

Primary liver tumors relative incidence

A

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

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

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4
Q

HCC epidemiology

A
  • 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
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5
Q

HCC Risk factors

A

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)

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6
Q

HBV & HCC

A
  • 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
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7
Q

HCV & HCC

A
  • 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.
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8
Q

Cirrhosis & HCC

A
  • 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.
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9
Q

Aflatoxin & HCC

A
  • 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
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10
Q

Alcohol consumption & HCC

A
  • 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.
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11
Q

HCC clinical features

A
  • 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
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12
Q

Gross appearance of HCC

A
  • 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]*
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13
Q

Histology of HCC

A
  • 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
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14
Q

HCC & hypoglycemia

A

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)

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15
Q

HCC & hemoperitoneum

A

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.

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16
Q

Why is HCC usually discovered at late stages

A

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

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17
Q

HCC metastasis

A

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]

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18
Q

HCC serological test

A

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
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19
Q

Cholangiocarcinoma definition

A

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

20
Q

Cholangiocarcinoma Epidemiology

A
  • 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
21
Q

Cholangiocarcinoma risk factors

A

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

22
Q

Liver parasite and CC

A

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)

23
Q

Hepatolithiasis

A

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

24
Q

Chronic inflammatory bowel disease & CC

A
  • Only ulcerative colitis predisposes to CC
  • The risk factor is x10.
25
Q

Congenital liver disorders that increase CC risk

A
  • congenital dilatation and cysts of intrahepatic bile duct
  • Caroli’s disease
  • Congenital hepatic fibrosis.
26
Q

CC clinical features

A
  • 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
27
Q

CC gross presentation

A
  • grey to grey-white tumour
  • firm and solid because of abundant fibrous stroma
  • may be central necrosis
28
Q

CC histology

A
  • 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
29
Q

Spread of CC

A
  • 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.
30
Q

Types of CC

A

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
31
Q

Jaundice and different tumours of biliary systems

A

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
32
Q

HCC vs CC comparisons

A

(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

33
Q

hepatoblastoma and embryonal sarcoma

A

usually appear in the first decade of life

34
Q

Cholelithiasis

A

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

35
Q

Gall stone constituents

A

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

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

36
Q

Basic types of gall stones

A

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

37
Q

Pure stones

A
  • 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
38
Q

Mixed stones

A
  • 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
39
Q

Combination stones

A
  • 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
40
Q

Size of gallstones

A

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

41
Q

Pathogenesis of gallstones

A

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
42
Q

Risk factors for gallstones

A

- 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)

43
Q

Effects of gallstones

A

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

44
Q

Acute pancreatitis definition, etiology, pathogenesis

A

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
45
Q

From cholelithiasis to pancreatitis

A

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