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Clinical Pathology in Action > Liver Pathology > Flashcards

Liver Pathology Flashcards

1
Q

What is Hepatocellular Carcinoma (HCC)

A
  • Most common primary liver malignancy
  • There is hepatocellular differentiation
  • 80% of HCC cases arise in cirrhosis
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2
Q

What are the risk factors of HCC

A
  • Chronic Liver disease leading to cirrhosis
  • Infectious; viral hepatitis (HBV or HCV)
  • Metabolic: non-alcoholic fatty liver disease (obesity, diabetes), hemochromatosis
  • Environmental exposure: aflatoxin, alcohol, steroids, oral contraceptives, tobacco
  • Developmental/congenital: abernethy malformation, alagille syndrome

Chronic viral hepatitis is the leading cause of hepatocellular carcinoma worldwide

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3
Q

What is the stepwise process of HCC

A

1) Low grade dysplastic nodule

2) High grade dysplastic nodule

3) Early hepatocellular carcinoma

4) Progressed hepatocellular carcinoma

This is accompanied by the accumulation of molecular alterations

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4
Q

What are the molecular alterations in HCC

A
  • Telomere shortening
  • TERT activation
  • Cell cycle checkpoint inhibitor inactivation

TERT promoter mutation is a salient event to hepatocellular carcinoma

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5
Q

How is Telomere Shortening important for the progression of HCC

A

Telomeres are protective caps at the ends of chromosomes that shorten with each cell division

In HCC, chronic liver damage leads to repeated cell turnover, causing telomeres to shorten faster

Critically short telomeres trigger genomic instability, increasing the risk of mutations and transformation into cancer cells

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6
Q

How is TERT activation important for the progression of HCC

A

Most adult cells don’t express telomerase, which maintains telomere length

Cancer cells reactivate TERT, allowing unlimited divisions by keeping their telomere long

TERT activation bypasses the natural limit on cell division, helping tumour cells survive and proliferate indefinitely

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7
Q

How is Cell cycle checkpoint inhibitor inactivation important for the progression of HCC

A

Proteins like p53, Rb and other cell cycle regulators halt the cell cycle if theres DNA damage

In HCC, these checkpoints are often mutated or inactivated, allowing damaged cells to continue dividing

Without these safeguards, mutations accumulate unchecked, speeding up cancer progression

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8
Q

How do these molecular alterations work together to cause HCC progression

A

1) Chronic liver injury would cause excessive regeneration which leads to telomere shortening

2) To survive cells would activate TERT

3) Meanwhile, loss of cell cycle control allows mutated cells to escape death

4) This leads to progressive transformation into malignant hepatocytes (HCC)

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9
Q

What are the 3 major mutation clusters in HCC

A

1) CTNNB1-cluster

2) AXIN1-cluster

3) TP53-cluster

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10
Q

What is the CTNNB1-cluster in HCC and what are its key associated genes

A
  • Involves the mutation of CTNNB1 (Beta-catenin), part of the Wnt/Beta-catenin pathway

Associated genes include:
- TERT (telomere maintenance)
- ARID2 (Chromatin remodelers)
- APOB
- NFE2L2 (Oxidative stress regulator)

  • Excludes TP53 and AXIN1 mutations
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11
Q

What is the AXIN1-cluster in HCC and which genes are involved

A

Involves AXIN1, a negative regulator of the Wnt/β-catenin pathway.

Associated genes include:
- ARID1A (chromatin remodeling)
- RPS6KA3 (MAPK pathway)

Excludes CTNNB1 mutations

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12
Q

What defines the TP53-cluster in HCC and its associated genes?

A

Involves mutation of TP53, a tumor suppressor gene related to cell cycle control.

Associated genes include:
- CCND1 (Cyclin D1, promotes cell cycle progression)
- KEAP1 (oxidative stress regulation)
- TSC2 (mTOR pathway regulator)

Excludes CTNNB1 mutations

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13
Q

What are the genetic abnormalities that are associated with Steatohepatitis subtype

A

Frequent IL6/JAK/STAT activation

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14
Q

What are the genetic abnormalities that are associated with Macrotrabecular massive subtype

A

TP53 mutation and FGF19 amplification

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15
Q

What are the genetic abnormalities that are associated with Fibrolamellar subtype

A

DNAJB1-PRKACA fusion gene

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16
Q

What is Fibrolamellar Hepatocellular Carcinoma

A

A rare liver cancer, primarily affects young adults without underlying liver disease, characterized by distinctive fibrous bands under a microscope and a unique DNAJB1-PRKACA fusion protein

It is has a better prognosis

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17
Q

What are the subtypes associated with worse prognosis compared with conventional HCC

A
  • Cirrhotomimetic
  • Sarcomatoid carcinoma
  • Carcinosarcoma
  • Macrotrabecular
  • Neutrophil rich
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18
Q

What are the subtypes associated with similar to better prognosis compared with conventional HCC

A
  • Steatohepatitic
  • Clear cell
  • Chromophobe
  • Fibrolamellar
  • Lymphocyte rich
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19
Q

What are the subtypes associated with variable to unknown prognosis compared with conventional HCC

A
  • Scirrhous
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20
Q

What is Cholangiocarcinoma

A

A malignant tumor that arises from the epithelial cells lining the bile ducts. Since bile ducts span inside and outside the liver, cholangiocarcinoma can develop in multiple anatomical locations and is considered an adenocarcinoma

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21
Q

What is intrahepatic Cholangiocarcinoma (iCCA)

A
  • Arises from bile ducts within the liver
  • Often presents as a liver mass and can resemble hepatocellular carcinoma radiologically
22
Q

What is Extrahepatic Cholangiocarcinoma (eCCA)

A
  • Occurs outside the liver, in the bile ducts draining the liver into the duodenum

Further divided into:
- Perihilar
- Distal: closer to the pancreas and duodenum

  • More common than intrahepatic
23
Q

How is Cholangiocarcinoma diagnosed

A

Diagnosis of exclusion is used because Cholangiocarcinoma can mimic metastases from other adenocarcinomas (e.g., from colon, breast, pancreas)

It is confirmed by exclusion of other primary sites, through imagine, immunohistochemistry and clinical history

Biliary cytology and biopsies as well as markers like:
- CK7
- CK19
- CA19-9
are useful for confirming diagnosis

24
Q

What is Cirrhosis

A

A serious, advanced stage of liver disease characterized by permanent scarring and damage to the liver where healthy tissue is replaced by scar tissue, hindering its ability to function properly

25
What is Hep B Virus infection lead to
Usually subclinical disease but may lead to * fulminant hepatic failure, * chronic liver disease * Cirrhosis * Spread by acutely infected patients or chronic viral carriers through sexual contact, intravenous drug abuse, contaminated blood or infected instruments, maternal to infant via delivery
26
What is Hep C virus
Usually subclinical Acute liver failure is rare If left untreated, it can cause serious liver damage, potentially leading to cirrhosis, liver failure, or liver cancer. However, with modern treatments, Hep C can be cured in most cases, and many people with the virus can live a normal life expectancy.
27
What is the histology of Hep C infection
1) Sinusoidal lymphocytic infiltrate 2) Lymphoid follicles near bile ducts 3) Mallory hyaline (mild/focal) 4) Macrovesicular steatosis 5) Minimal necrosis 6) Lymphoid aggregates are somewhat specific
28
What is sinusoidal lymphocytic infiltrate
White blood cells (mostly lymphocytes) are seen inside the liver's small blood channels (sinusoids), showing an immune reaction to the virus.
29
What is Lymphoid follicles near bile ducts
Small clusters of immune cells form "follicles" and often gather around damaged bile ducts. This usually happens in the portal tracts (areas where blood vessels and bile ducts enter the liver).
30
What is Mallory hyaline (mild/focal):
A type of damaged protein inside liver cells. It's not very common or severe in Hep C—just seen in small, scattered areas.
31
What is Macrovesicular steatosis (mild)
A few liver cells contain large fat droplets—a mild form of fatty liver often seen in Hep C.
32
What does it mean when there is only Minimal necrosis
Only a small amount of liver cell death (necrosis) is observed—so damage isn’t widespread.
33
What does it mean by lymphoid aggregates are somewhat specific
Those immune cell clusters (lymphoid follicles) are a clue pointing to Hepatitis C infection—but they're only present in about 50% of cases, so not always reliable on their own
34
What is Non Alcoholic Fatty Liver Disease
- Hepatic steatosis generated in association with overweight/obesity, type 2 diabetes mellitus or other metabolic dysregulations - Macroscopically it is soft, yellow and greasy
35
What is the histology of Non alcoholic fatty liver disease
- It is assessed using a scoring system including steatosis, lobular inflammation and ballooning degeneration - Predominantly macrovesicular steatosis in more than 5% of hepatocytes Macrovesicular steatosis sole histologic requirement for diagnosis
36
What is primary biliary cholangitis
Chronic, progressive cholestatic liver disease with granulomatous destruction of interlobular bile ducts, leading to fibrosis and ultimately cirrhosis Typically occurs in middle aged women
37
What is the criteria for diagnosing Primary biliary cholangitis
- elevated alkaline phosphatase - elevated IgM - Classic antimitochondrial antibody (AMA)
38
What is the pathogenesis of Primary Biliary Cholangitis
- It is possibly autoimune - It is associated with Sjogren syndrome, thyroiditis, Raynaud's and SLE - AMA positive
39
What are the histologic changes found in primary biliary cholangitis
pathognomonic florid duct lesions - They are characterized by granulomatous destruction of the interlobular bile ducts, a specific inflammatory infiltrate, and associated changes in the bile duct epithelium
40
What is primary sclerosing cholangitis
A chronic liver disease characterized by progressive inflammation and scarring of the bile ducts, which can lead to bile duct narrowing and obstruction, ultimately causing liver damage and potentially cirrhosis
41
What is Wilson's disease
- An autosomal recessive disorder - Senescent ceruloplasmin is endocytosed by the liver, degraded within lysosomes and excreted into bile. - In Wilson disease copper accumulates within the liver, exceeding the capacity for ceruloplasmin binding and causing liver injury
42
What is ceruloplasmin
A protein in the blood that carries copper and senescent ceruloplasmin means that it is old or worn out and no longer function.
43
Where else do toxin levels of copper accumulate
- Kidneys - Bones - Joints - Parathyroid gland
44
What is Haemochromatosis
Iron overload, increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress. - Usually deposited in the liver, pancreas and heart
45
What is Primary Haemochromatosis
- Causes: a genetic mutation, most commonly in the HFE gene - Inheritance: Autosomal recessive (Need two copies of the fault gene) - Effect: Increased intestinal absorption of iron - In females, iron accumulation is delayed due to menstruation which naturally remove iron from the body
46
What is Secondary Haemochromatosis
Causes: - Repeated blood transfusions - Excessive iron therapy - Certain chronic liver diseases
47
What are the clinical features of Haemochromatosis
- Fatigue - Joint pain - Diabetes - Liver dysfunction
48
Treatment for Haemochromatosis
- Phlebotomy: regularly removing blood reduces iron levels - Avoiding iron supplements If left untreated, iron overload damages organs irreversibly and the cirrhosis caused by haemochromatosis significantly increases the risk of HCC
49
What is Alpha 1 anti-trypsin deficiency
Genetic metabolic disorder causing deficiency of alpha-1 antitrypsin deficiency (AAT) and leading to disease in the lungs and liver - Autosomal recessive disease - Abnormal protein accumulates in the liver - Fibrosis ranges from minimal periportal fibrosis to cirrhosis
50
What are the symptoms of Alpha 1 anti-trypsin deficiency
- Fibrosis: ranges from minimal periportal fibrosis to cirrhosis * Increase risk of HCC - Mild portal inflammation: predominantly lymphocytic - Mild steatosis: often in periportal hepatocytes - Eosinophilic intracytoplasmic globules in hepatocytes * Most suggestive feature of AAT deficiency
51
What is Cirrhosis
The end stage of chronic liver disease There is diffuse nodulation of liver due to fibrous bands subdividing the liver into regenerative nodules

Clinical Pathology in Action (18 decks)

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