Hepatocellular Carcinoma

1. Definition

Hepatocellular carcinoma (HCC) is a primary malignant neoplasm arising from hepatocytes — the principal parenchymal cells of the liver. Let's break the name down:

• Hepato- (Greek hēpar) = liver
• -cellular = of cells
• Carcinoma (Greek karkinos = crab + -oma = tumour) = malignant epithelial neoplasm

So the name literally tells you: a malignant tumour of liver cells.

It is the most common primary liver cancer (~80%), with intrahepatic cholangiocarcinoma (ICC) accounting for ~15% and other rare subtypes making up the remainder ^[1][2][3].

HCC characteristically develops in a background of chronic liver disease and cirrhosis, making it almost unique among solid malignancies — the organ harbouring the cancer is itself already diseased and dysfunctional. This dual pathology (cancer + liver failure) is what makes HCC so challenging to manage and so lethal.

2. Epidemiology

2.1 Global Epidemiology

• HCC is the 6th most common cancer worldwide and the 3rd leading cause of cancer-related death globally (after lung and colorectal cancer) ^[1][2].
• Globally ~900,000 new cases/year and ~830,000 deaths/year (2020 GLOBOCAN data), reflecting the very high case-fatality ratio.
• There is a striking geographic variation linked to the prevalence of underlying aetiologies:

• The rising incidence in Western countries is driven by the NAFLD/NASH epidemic (obesity, metabolic syndrome) and ageing HCV cohorts ^[2].

2.2 Hong Kong Epidemiology

This is extremely high-yield for HKUMed exams.

• HCC is exceedingly common in Hong Kong ^[1][4].
• Second commonest cancer death in Hong Kong ^[4] (some older data cites 3rd — the ranking fluctuates between 2nd and 3rd with lung and colorectal cancer; as of recent data, it is the 3rd most common cause of cancer death in HK, but lecture slides from Prof Poon state second ^[4]).
• 5th most common cancer in HK overall by incidence ^[2].
• HCC is 6× more common than cholangiocarcinoma (HCC:CC = 6:1) ^[1].
• HCC constitutes 78.7% of primary malignant liver tumours in HK, CC = 9.7% ^[1].
• M:F = 4:1 ^[4] (some older data quotes 6:1 — the key point is a strong male predominance, partly explained by higher HBV carrier rates in males, androgen-related pathways, and higher rates of alcohol use).
• Most patients age > 50 years, but can occur in young patients ^[4].
• Peak age of mortality = 45–55 years in HK ^[1].
• 80% of HCC in Hong Kong are HBsAg-positive — i.e. Hepatitis B is the overwhelmingly dominant aetiology in HK ^[3][4].
• Frequent association with cirrhosis (80% in Hong Kong) ^[4].

2.3 Survival

• Insidious onset with rapidly progressing course which is fatal ^[1].
• Median survival of untreated HCC = 2–4 months (for symptomatic, advanced disease) ^[1].
• 5-year survival varies dramatically by stage:
  • Early stage (BCLC 0/A) with curative treatment: 50–70%
  • Intermediate stage (BCLC B): ~20%
  • Advanced/Terminal stage: < 5%

3. Anatomy and Function — Relevant Hepatic Anatomy

Understanding liver anatomy is critical for HCC because it determines resectability, blood supply for locoregional therapy, and patterns of spread.

3.1 Liver Segments (Couinaud Classification)

The liver is divided into 8 functionally independent segments (I–VIII), each with its own:

• Portal pedicle (portal vein branch, hepatic artery branch, bile duct)
• Hepatic venous drainage

This segmental anatomy is the basis for anatomical hepatic resection — you can remove segments independently because each is a self-contained unit.

3.2 Dual Blood Supply

The liver has a unique dual blood supply, which is essential for understanding HCC biology and treatment:

1. Portal vein (~75% of hepatic blood flow): carries nutrient-rich, relatively deoxygenated blood from the GI tract
2. Hepatic artery (~25% of hepatic blood flow): carries oxygenated blood from the coeliac trunk

Why does this matter for HCC?

• Normal hepatocytes derive most of their blood supply from the portal vein.
• HCC tumour nodules derive >90% of their blood supply from the hepatic artery (neoangiogenesis is predominantly arterial).
• This differential supply is the basis for:
  • Arterial enhancement on CT/MRI (tumour "lights up" in arterial phase → washes out in portal venous/delayed phase — the hallmark imaging feature of HCC)
  • Transarterial chemoembolisation (TACE) — you deliver chemotherapy and embolic material via the hepatic artery, selectively starving the tumour while relatively sparing normal liver parenchyma

3.3 Hepatic Venous Drainage

Three major hepatic veins (right, middle, left) drain into the inferior vena cava (IVC). This is relevant because:

• HCC has a high propensity for venous invasion (portal and hepatic veins) ^[4]
• Spread through portal vein branches → intrahepatic metastasis (the most common route of intrahepatic spread)
• Spread through hepatic vein branches → IVC → right heart → lungs ^[1]
• Portal vein tumour thrombus (PVTT) is one of the most significant adverse prognostic features

3.4 Glisson's Capsule

The liver is enveloped by Glisson's capsule (a thin layer of connective tissue derived from the peritoneum). The liver parenchyma itself has no pain fibres — pain only occurs when Glisson's capsule is stretched or invaded by tumour. This explains why:

• Small HCCs are painless (they don't stretch the capsule)
• Large HCCs cause RUQ pain ± referred right shoulder pain (diaphragmatic irritation via phrenic nerve, C3-C5) ^[2]
• Ruptured HCC causes sudden severe abdominal pain and peritonism

3.5 Relationship to Other Structures

• Hilum (porta hepatis): where the portal vein, hepatic artery, and common hepatic duct enter/exit. HCC spread to hilar lymph nodes occurs here ^[1].
• Diaphragm: the liver dome is in close proximity; large HCCs can invade or irritate the diaphragm.

4. Etiology (Focus on Hong Kong)

4.1 Hepatitis B Virus (HBV) — The Dominant Cause in HK (80%) [3][4]

Hepatitis B virus is responsible for ~80% of HCC cases in Hong Kong ^[3][4].

Why does HBV cause HCC? Two mechanisms:

1. Indirect (via cirrhosis): Chronic HBV infection → chronic hepatic inflammation → hepatocyte necrosis and regeneration → progressive fibrosis → cirrhosis → HCC

   • Risk of cirrhosis = 20–30% of chronically infected adults will develop cirrhosis over 10–15 years ^[1]

2. Direct oncogenic effect (unique to HBV, not HCV):

   • HBV DNA integrates into the host hepatocyte genome — this can activate proto-oncogenes or disrupt tumour suppressor genes ^[5]
   • HBV-encoded X antigen (HBxAg), Pre-S1, Pre-S2 proteins are responsible for carcinogenesis ^[1]:
     • HBx protein → transactivates cellular oncogenes, inhibits p53 tumour suppressor function, promotes cell proliferation, inhibits DNA repair, activates NF-κB and MAPK pathways
     • Pre-S mutants → cause ER stress, oxidative DNA damage, and genomic instability
   • Because of this direct oncogenic effect, HCC complicating HBV can present on a non-cirrhotic liver (20% of cases) ^[1]

Risk factors for HCC in HBV carriers:

• Male sex
• Older age (> 40 years)
• Family history of HCC
• High HBV DNA viral load (> 2000 IU/mL)
• HBeAg positivity
• Genotype C (common in HK)
• Co-infection with HCV, HDV, or HIV
• Active inflammation (elevated ALT)
• Presence of cirrhosis
• Aflatoxin exposure (synergistic with HBV)

4.2 Hepatitis C Virus (HCV)

• Common in Japan and Western countries ^[4] but accounts for only ~4% of HCC in HK ^[1].
• HCC complicating HCV ALWAYS presents on a cirrhotic liver (100%) ^[1] — HCV is an RNA virus that does not integrate into host DNA (unlike HBV). Therefore HCV causes HCC purely through the indirect pathway: chronic inflammation → cirrhosis → HCC.
• HCV causes HCC at a rate of ~1–4% per year in cirrhotic patients.
• With the advent of direct-acting antivirals (DAAs), HCV can now be cured in > 95% of cases, but the risk of HCC persists even after viral eradication (especially if cirrhosis is already established).

4.3 Cirrhosis (Any Cause) [3][4]

• Cirrhosis is present in 70–90% of HCC cases overall; 80% in HK ^[1][4].
• Any cause of cirrhosis can lead to HCC, because the final common pathway is: chronic hepatocyte injury → regenerative hyperplasia → dysplastic nodules → HCC.
• The annual risk of HCC development in a cirrhotic liver is 1–6%/year depending on the aetiology.

4.4 Alcoholic Liver Disease [3][4]

• Accounts for ~4% of HCC cases in HK ^[1] but is a major cause in Western countries.
• HCC develops on top of alcoholic cirrhosis (100%) — alcohol does not have a direct oncogenic effect comparable to HBV ^[1].
• Mechanism: Chronic alcohol → acetaldehyde (toxic metabolite) → oxidative stress + lipid peroxidation → hepatocyte injury → inflammation → fibrosis → cirrhosis → HCC.
• High but NOT moderate level of alcohol consumption is the risk factor ^[1].
• Alcohol can also act synergistically with HBV or HCV to accelerate cirrhosis and HCC development.

4.5 Non-Alcoholic Fatty Liver Disease (NAFLD) / Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

• Now renamed MASLD (2023 nomenclature), encompassing:
  • Non-alcoholic fatty liver (NAFL) / metabolic dysfunction-associated steatotic liver (MASL)
  • Non-alcoholic steatohepatitis (NASH) / metabolic dysfunction-associated steatohepatitis (MASH)
• The fastest-growing cause of HCC worldwide, driven by the global obesity/metabolic syndrome epidemic.
• NASH-related HCC can occur without cirrhosis in up to 20–30% of cases — similar to HBV. This is thought to be due to the pro-inflammatory, pro-oxidative environment of steatohepatitis driving direct DNA damage.
• Key metabolic risk factors: obesity, type 2 diabetes mellitus, dyslipidaemia, metabolic syndrome ^[1][2].

4.6 Aflatoxin [3][4]

• Mycotoxins produced by Aspergillus flavus which contaminates corn, soybeans, and peanuts ^[1].
• Leads to mutation of the p53 tumour suppressor gene (specifically the R249S hotspot mutation — an arginine-to-serine substitution at codon 249) ^[1].
• Risk factor in Africa and rural areas of China but NOT Hong Kong ^[1][4].
• Aflatoxin has a synergistic effect with HBV: the combination of HBV + aflatoxin exposure increases HCC risk multiplicatively (up to 60× compared to neither alone).

4.7 Autoimmune Liver Diseases [1]

• Autoimmune hepatitis (AIH): chronic inflammation → cirrhosis → HCC
• Primary biliary cholangitis (PBC): progressive bile duct destruction → biliary cirrhosis → HCC
• Primary sclerosing cholangitis (PSC): biliary stricturing and inflammation → biliary cirrhosis → both cholangiocarcinoma (more common) and HCC

4.8 Genetic/Metabolic Diseases [1]

• Hereditary haemochromatosis: excess iron deposition → oxidative stress → hepatocyte injury → cirrhosis → HCC. Iron itself is also a direct mutagen via Fenton chemistry (Fe²⁺ + H₂O₂ → OH• free radicals).
• Wilson's disease: copper overload → oxidative liver damage → cirrhosis → HCC (though interestingly, the risk of HCC in Wilson's disease is lower than expected, possibly because excess copper has some anti-tumour properties).
• α1-antitrypsin deficiency: misfolded protein accumulates in hepatocyte ER → ER stress → chronic liver injury → cirrhosis → HCC.

4.9 Other Risk Factors

5. Pathophysiology

5.1 The Multistep Carcinogenesis Pathway

HCC develops through a well-characterised multistep process, beautifully illustrated on the lecture slide showing the progression from chronic liver disease to HCC ^[5]:

Chronic Liver Injury → Hepatocyte Proliferation → Fibrosis/Cirrhosis →
Hyperplastic Nodule → Dysplastic Nodule (Low → High Grade) →
Well-Differentiated HCC → Moderately Differentiated → Poorly Differentiated HCC

Let's walk through each step:

1. Chronic liver injury (HBV, HCV, alcohol, NASH, etc.) → ongoing hepatocyte death
2. Stellate cell activation → extensive scarring (collagen deposition) → fibrosis → cirrhosis ^[5]
3. Hepatocyte regeneration under proliferative pressure → telomere shortening with each cell division ^[5]
4. Hyperplastic nodules → still polyclonal, no dysplasia
5. Moderate genomic instability → Dysplastic nodules → monoclonal, contain cytological atypia ^[5]
6. Telomerase reactivation → cells escape senescence and gain replicative immortality ^[5]
7. Marked genomic instability → Loss of p53 and other tumour suppressors → HCC ^[5]
8. Progressive dedifferentiation: well-differentiated → moderately differentiated → poorly differentiated

5.2 Key Molecular Alterations in HCC

5.3 Vascular Biology of HCC

HCC is a vascular tumour with a high propensity for venous invasion (portal and hepatic veins) ^[4].

• Neoangiogenesis: HCC secretes high levels of VEGF, creating a rich network of abnormal arterial vessels → this is why HCC is a hypervascular tumour
• Arterial blood supply: as hepatocytes become dysplastic and then malignant, they progressively lose their portal venous supply and become increasingly dependent on hepatic artery branches via unpaired arteries (arteries not accompanied by portal tracts). This arterialisation is a hallmark of HCC.
• Sinusoidal capillarisation: normal liver sinusoids are fenestrated (with gaps); in HCC, sinusoids become capillarised (endothelium becomes continuous) → contributes to the imaging characteristics.

5.4 Pathology

Gross (Macroscopic) Appearance [1][4]

Three macroscopic types: massive, nodular, diffuse ^[4]:

Other gross features ^[1]:

• Soft in texture
• Light-brown or tan-coloured masses
• Yellow patches of necrosis — because the tumour outgrows its blood supply (central necrosis is common in large tumours)
• Extensive haemorrhagic areas — because the tumour is highly vascular and derives blood supply from sinusoids and hepatic artery ^[1]
• Green discolouration of tumour — production of bile by tumour cells → this is a diagnostic feature of HCC (because only hepatocytes make bile; if you see a green liver tumour, it's HCC until proven otherwise) ^[1]
• Formation of clear cells → secretion of insulin-like peptide (ILP) → induces attacks of hypoglycaemia → excess glycogen in the tumour (clear cells) ^[1]

Histological Appearance [1]

• Trabecular pattern of hepatocytes (80%) — the most common pattern; tumour cells arranged in plates/cords resembling normal hepatic architecture, separated by sinusoidal vascular spaces ^[1]
• Pseudoglandular pattern — tumour cells form gland-like structures (acini) ^[1]
• Vascular sinusoids — lined by endothelium; prominent vascularity ^[1]
• Compact/solid pattern — sheets of tumour cells with minimal sinusoidal framework
• Tumour cells resemble hepatocytes to varying degrees (well → moderately → poorly differentiated)
• Mallory-Denk bodies, fat, glycogen, and bile may be seen within tumour cells

Histological Variant: Fibrolamellar HCC (FLC) [2][4]

• Most common in younger women (and young patients generally) ^[4]
• Good prognosis compared to conventional HCC ^[4]
• Not associated with HBV or cirrhosis ^[2]
• Characterised by large eosinophilic tumour cells with abundant mitochondria, separated by dense lamellar fibrosis (parallel bands of collagen) — hence "fibro-lamellar"
• Often has a central scar (can mimic focal nodular hyperplasia on imaging)
• Pathognomonic molecular feature: DNAJB1-PRKACA fusion gene

6. Classification and Staging

6.1 TNM Staging (AJCC/UICC 8th Edition, 2017) [1]

6.2 Barcelona Clinic Liver Cancer (BCLC) Staging System

This is the most widely used staging system for HCC because, unlike TNM, it integrates tumour burden + liver function + performance status and links directly to treatment recommendations.

6.3 Child-Pugh Score (Liver Function Classification)

This is indispensable for HCC management. It uses 5 parameters ("ABCDE" mnemonic: Albumin, Bilirubin, Clotting/PT-INR, Distension/ascites, Encephalopathy):

6.4 Hong Kong Liver Cancer (HKLC) Staging System

Developed at Queen Mary Hospital, HKU — tailored for the Hong Kong/Asian HBV-dominant population. It differs from BCLC by being more aggressive with surgical/locoregional treatments in intermediate-advanced stages, reflecting the better outcomes observed in Asian centres with high surgical expertise. It classifies patients based on:

• ECOG performance status
• Child-Pugh classification
• Tumour extent (intra/extrahepatic, vascular invasion)

7. Patterns of Spread

HCC has a characteristic pattern of spread that you must know ^[1][4]:

7.1 Intrahepatic Metastasis [4]

• The most common route of spread
• Via portal venous circulation — tumour invades a portal vein branch, and tumour cells seed downstream portal territories
• This is why you often see satellite nodules around the main tumour and in other segments

7.2 Portal Vein Tumour Thrombus (PVTT)

• High propensity for portal vein invasion ^[4]
• Can extend from segmental branches → main portal vein → even into the superior mesenteric vein
• Consequences:
  • Worsens portal hypertension (→ variceal bleeding, ascites)
  • Makes the non-tumorous liver completely dependent on hepatic arterial supply
  • Contraindication to TACE (because embolising the artery when the portal vein is already blocked = ischaemic necrosis of the entire liver)

7.3 Hepatic Vein Invasion → IVC → Right Heart → Lungs [1][4]

• Spread through hepatic vein branches → IVC → right atrium
• Can form a tumour "tongue" extending into the IVC (similar to renal cell carcinoma)
• Lung metastasis via hepatic vein dissemination ^[4]

7.4 Extrahepatic Metastasis [1][4]

• Lung (most common extrahepatic site) — via hepatic veins/systemic circulation
• Bone — often osteolytic, can present with pathological fractures or cord compression
• Lymph nodes (porta hepatis) ^[1] — regional spread
• Peritoneal metastasis ^[4] — especially after rupture
• Adrenal glands ^[1]
• Brain — rare but possible
• Usually death precedes extensive metastasis ^[1] — most patients die of liver failure or variceal bleeding before metastases become clinically dominant

8. Clinical Features

8.1 Clinical Presentations — Overview [4]

The lecture slide from Prof Poon lists 4 major clinical presentations ^[4]:

1. Subclinical (detected on screening with AFP and USG in HBsAg carriers or cirrhotic patients)
2. RUQ pain, hepatomegaly
3. Decompensation of cirrhosis (ascites, variceal bleeding, hepatic encephalopathy)
4. Intraperitoneal haemorrhage (rupture of HCC)
5. Paraneoplastic features: fever, hypercalcaemia, hypoglycaemia, erythrocytosis

8.2 Symptoms

Local Symptoms

Symptoms Related to Decompensation of Cirrhosis [4]

When HCC develops in a cirrhotic liver, the additional metabolic demand and mass effect can push a previously compensated cirrhosis into decompensation:

Systemic/Constitutional Symptoms

8.3 Signs

Hepatic Signs

Signs of Cirrhosis and Portal Hypertension

Since 80% of HCC in HK occurs on a cirrhotic background, look for:

Signs of Ruptured HCC [4]

• Sudden haemodynamic collapse: tachycardia, hypotension, pallor, diaphoresis
• Acute abdomen: diffuse peritonism (guarding, rigidity, rebound tenderness)
• This is a life-threatening emergency (mortality 30–70%)
• Occurs in ~10% of HCC patients, more common with large, subcapsular tumours
• Mechanism: the tumour erodes through Glisson's capsule and bleeds into the peritoneal cavity

Paraneoplastic Signs [2][4]

These are non-metastatic systemic manifestations caused by bioactive substances secreted by tumour cells. They occur in ~5–10% of HCC patients and can sometimes be the presenting feature.

Signs of Metastatic Disease

9. Screening for HCC

Screening with AFP and USG in HBsAg carriers or cirrhotic patients ^[4].

Who to Screen [2]

Screening Tools

• Ultrasound (USG): sensitivity ~60–80% for early HCC. Limited by operator dependence, body habitus, and cirrhotic liver background.
• Alpha-fetoprotein (AFP): see below.
• CUHK-HCC score: a validated risk prediction model incorporating age, albumin, bilirubin, cirrhosis, HBV DNA level ^[2] — helps stratify which HBV carriers need more intensive screening.

10. Why is the Prognosis So Poor? [1]

This was explicitly addressed in the senior notes and is a favourite exam question:

1. Patients present with symptoms at late stage — symptoms usually don't appear until the tumour is > 8 cm ^[1]
2. Majority have underlying cirrhosis which limits scope for resection or other interventions — you can't resect half the liver if the remaining half is cirrhotic and can barely function ^[1]
3. Early or pre-malignant lesions are present in other parts of the liver — "field cancerisation" — the entire liver is exposed to the oncogenic influence of HBV/HCV/cirrhosis, so even after curative treatment, there's a high risk of a 2nd primary HCC developing ^[1]
4. Early IV spread leads to early metastasis or portal vein thrombosis ^[1]

References

^[1] Senior notes: felixlai.md (Hepatocellular carcinoma sections, pp. 473–497) ^[2] Senior notes: maxim.md (Hepatocellular carcinoma section, p. 260, 271) ^[3] Lecture slides: HCC and Gallstone acute cholangitis_Prof TT Cheung.pdf (p. 3) ^[4] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p. 3) ^[5] Lecture slides: GC 202. Surgery may cure your cancer Surgical oncology.pdf (p. 3 — multistep carcinogenesis diagram)

Differential Diagnosis of a Liver Mass / Suspected HCC

When you encounter a patient with a liver mass — whether detected incidentally on imaging, found during screening of a chronic HBV carrier, or presenting with RUQ pain and hepatomegaly — you need a systematic framework to work through the differential diagnosis. The critical first question is always: Is this mass malignant or benign? If malignant, is it primary or secondary (metastatic)?

Let's build this framework from first principles, then work through each entity, explaining why it can mimic HCC and how to distinguish it.

Overarching Framework

The lecture slide from Prof Poon provides a clean framework for the differential diagnosis of hepatomegaly ^[4]:

Malignancy:

• Primary liver malignancies
• Metastasis
• Haematological malignancies (lymphoma, leukaemia, myeloproliferative disease)

Benign disease:

• Benign neoplasms (haemangioma, adenoma, focal nodular hyperplasia)
• Cyst (simple cyst, polycystic disease)
• Alcoholic cirrhosis
• Others (e.g. liver abscess)

The senior notes ^[1] present a slightly more granular version:

Benign primary liver tumours:

• Hepatic haemangioma
• Hepatic adenoma
• Focal nodular hyperplasia

Malignant primary liver tumours:

• Hepatocellular carcinoma
• Cholangiocarcinoma
• Fibrolamellar carcinoma
• Haemangioendothelioma

Metastatic or disseminated tumours:

• Leukaemia
• Lymphoma
• Myeloma
• Metastatic solid tumour

Let me now walk through each of these in clinical detail, explaining what they are, why they enter the differential, and the key distinguishing features from HCC.

Mermaid Diagram — Approach to a Liver Mass

1. Benign Primary Liver Tumours

1.1 Hepatic Haemangioma

• What it is: A congenital vascular malformation composed of dilated blood-filled vascular spaces lined by endothelium. It is the most common benign liver tumour ^[2][6].
• Why it enters the differential: Both haemangioma and HCC are hypervascular on imaging. Both can present as incidental liver masses. A large haemangioma can cause RUQ pain and hepatomegaly.
• Key distinguishing features:

1.2 Focal Nodular Hyperplasia (FNH)

• What it is: A hyperplastic regenerative nodule that forms in response to a pre-existing arterial malformation (an aberrant "feeding" artery). It is not a true neoplasm — it's a hyperplastic response to abnormal blood flow ^[6].
• Why it enters the differential: Arterially enhancing liver mass in a young/middle-aged patient. Can be mistaken for HCC especially if a background liver disease is present.
• Key distinguishing features:

1.3 Hepatic Adenoma

• What it is: A benign proliferation of hepatocytes (a true neoplasm, unlike FNH). The name "hepat-oma" literally means liver tumour — confusingly, some older texts use "hepatoma" for HCC, but strictly it should refer to this benign lesion ^[6].
• Why it enters the differential: Arterially enhancing solid liver mass, can be large, and importantly can rupture (like HCC) causing haemoperitoneum. Also has malignant potential → can transform into HCC.
• Key distinguishing features:

2. Malignant Primary Liver Tumours

2.1 Cholangiocarcinoma (CC) [4][7][8]

• What it is: Adenocarcinoma of the bile duct epithelium (cholangio- = bile duct, carcinoma = malignant epithelial tumour). > 90% are adenocarcinoma ^[7][8].
• Intrahepatic cholangiocarcinoma (ICC) accounts for 5–20% of primary liver malignancy ^[7] and is the second most common primary liver cancer after HCC ^[2].
• Why it enters the differential: Intrahepatic cholangiocarcinoma presents as a liver mass, often in a patient with chronic liver disease (HCV, PSC), and can be difficult to distinguish from HCC on imaging.

2.2 Fibrolamellar Carcinoma (FLC)

• Already discussed in the pathology section but worth reiterating as a differential:
• Histologic variant of HCC; most common in younger women, good prognosis ^[4]
• Not associated with HBV or cirrhosis ^[2]
• AFP is typically normal (because the well-differentiated tumour cells don't secrete AFP efficiently)
• Imaging: large mass with central calcified scar (unlike FNH, the scar does NOT enhance on delayed phase)
• If you see a large liver mass in a young patient without cirrhosis and normal AFP → think fibrolamellar HCC

2.3 Haemangioendothelioma

• Epithelioid haemangioendothelioma (EHE): a rare low-to-intermediate grade vascular malignancy
• Presents as multiple liver lesions, often at the periphery with capsular retraction (a fairly characteristic finding)
• Can mimic metastatic disease on imaging
• Distinguished from HCC by: no association with HBV/cirrhosis, normal AFP, IHC positive for vascular markers (CD31, CD34, Factor VIII)
• In children, infantile haemangioendothelioma is a distinct entity (benign vascular tumour of infancy)

2.4 Hepatic Angiosarcoma

• Extremely rare, highly aggressive malignant vascular tumour
• Associated with Thorotrast (thorium dioxide — an old radiological contrast agent), vinyl chloride, arsenic, and anabolic steroids
• Presents with rapidly enlarging liver mass, haemoperitoneum (rupture), consumptive coagulopathy
• Prognosis is dismal

2.5 Primary Hepatic Lymphoma

• Rare; liver is more commonly involved secondarily in systemic lymphoma
• Can present as a solitary mass or diffuse infiltration
• Distinguished from HCC by: LDH elevation, normal AFP, imaging may show a "low density" mass, and diagnosis requires biopsy with IHC (CD20+ for B-cell lymphoma)

3. Metastatic / Secondary Liver Tumours [4][9]

Metastatic carcinoma to the liver is commoner than primary liver cancer ^[9]. In fact, liver metastases are 20× more common than primary liver tumours ^[2].

Why? Because the liver receives the entire portal venous drainage from the GI tract — any cancer shedding cells into the portal circulation has direct access to the liver sinusoids. The liver also has a dual blood supply and a rich sinusoidal network that acts as a "filter" trapping circulating tumour cells.

Common Primary Sources [2][9]

The mnemonic from the senior notes is helpful: "Some GU Cancers Produce Bumpy Lumps" ^[2]:

• Stomach
• GU: kidney, ovary, uterus
• Colon (most common — accounts for ~1/3 of liver metastases) ^[2]
• Pancreas
• Breast
• Lung

Commonest site is from GI tract (portal venous circulation): colorectal, stomach, pancreas ^[9].

Key Distinguishing Features from HCC

4. Cystic Lesions [4]

Cysts (simple cyst, polycystic disease) ^[4] should be mentioned:

5. Other Non-Neoplastic Causes of Hepatomegaly [4]

While not true "liver masses," these conditions cause hepatomegaly and may enter the differential on physical examination:

• Alcoholic cirrhosis ^[4] — early cirrhosis can cause hepatomegaly (fatty, enlarged liver); later it becomes shrunken
• Congestive hepatopathy (right heart failure) — smooth, tender hepatomegaly; pulsatile if tricuspid regurgitation
• Budd-Chiari syndrome — hepatic vein thrombosis → congestive hepatomegaly, ascites, abdominal pain
• Amyloidosis — diffuse infiltration → massive firm hepatomegaly
• Glycogen storage diseases — paediatric; massive hepatomegaly

6. Clinical Approach to Hepatomegaly [4]

The lecture slides give a structured approach that you should follow on the wards:

History ^[4]:

• Pain, change of bowel habit, other GI symptoms, tea-colour urine
• Systemic symptoms of malignancy (anorexia, nausea, weight loss), fever
• Systemic review of other systems
• Past history of chronic liver disease
• Social history: alcohol
• Family history: any malignancy

Physical Examination ^[4]:

• General examination: cachexia, pallor, jaundice, lymphadenopathy, chronic stigmata of liver disease
• Abdominal examination: hepatomegaly — size, tenderness, consistency, surface, edge, bruit
• Other organomegaly (spleen), mass, ascites
• PR examination

Investigations ^[4]:

• Blood tests: complete blood count, liver function test, coagulation, hepatitis serology (B and C), tumour markers (AFP, CEA, CA 19.9)
• Imaging: chest X-ray, ultrasound, CT scan, MRI
• Endoscopy (for suspected GI primary): upper endoscopy, colonoscopy
• Biopsy: fine needle aspiration cytology (FNAC), Trucut biopsy

Summary Table — Differential Diagnosis of a Liver Mass

References

^[1] Senior notes: felixlai.md (Hepatocellular carcinoma — Etiology and Differential Diagnosis sections) ^[2] Senior notes: maxim.md (Hepatocellular carcinoma section; Liver metastasis section; Benign liver neoplasm table) ^[4] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p. 2–3, 5–6) ^[6] Senior notes: maxim.md (Benign liver neoplasm comparative table) ^[7] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p. 5 — Cholangiocarcinoma) ^[8] Senior notes: felixlai.md (Cholangiocarcinoma sections) ^[9] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p. 6 — Metastatic Carcinoma to Liver)

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for HCC

1. Diagnostic Principles — Why HCC is Unique

HCC holds a remarkable position in oncology: it is one of the very few solid malignancies that can be diagnosed definitively by imaging alone, without biopsy. Why?

1. Characteristic vascular signature: HCC derives > 90% of its blood supply from the hepatic artery (normal liver parenchyma is ~75% portal vein-supplied). This creates a pathognomonic imaging pattern — arterial hyperenhancement followed by portal venous/delayed washout — that is essentially diagnostic.
2. Clinical context narrows the differential: HCC almost always occurs in a known high-risk population (HBV carriers, cirrhotic patients). A new arterially enhancing nodule in a cirrhotic liver is HCC until proven otherwise.
3. Biopsy carries real risks: the tumour is hypervascular (bleeding risk) and there is a risk of needle tract tumour seeding that could upstage the disease and make liver transplantation unsuitable ^[1][2].

2. Diagnostic Criteria

2.1 Non-Invasive Diagnostic Criteria (AASLD / EASL / APASL — Unified Approach)

The diagnosis of HCC can be established non-invasively when ALL of the following are met:

1. At-risk population: chronic liver disease (HBV carrier, HCV, cirrhosis of any aetiology)
2. Nodule ≥ 1 cm on surveillance imaging
3. Characteristic enhancement pattern on one dynamic contrast-enhanced imaging study (triphasic CT or dynamic MRI):
   • Arterial phase hyperenhancement (APHE): the nodule "lights up" brighter than the surrounding liver in the arterial phase
   • Non-peripheral "washout": the nodule becomes hypo-attenuating/intense relative to the surrounding liver in the portal venous and/or delayed phase
   • Additional supporting features (for MRI): enhancing "capsule" appearance on delayed phase, restricted diffusion, T2 mild hyperintensity

If both APHE + washout are present → HCC is diagnosed. No biopsy required.

2.2 LI-RADS Classification (Liver Imaging Reporting and Data System)

LI-RADS was developed by the ACR (American College of Radiology) to standardise the reporting of liver observations in at-risk patients. It assigns a category from LR-1 to LR-5:

LR-5 criteria (simplified): ≥ 1 cm + APHE + non-peripheral washout AND/OR enhancing "capsule" AND/OR threshold growth (≥ 50% in ≤ 6 months).

2.3 AFP-Based Diagnostic Criteria

• AFP > 400 ng/mL is almost diagnostic of HCC ^[4] in the right clinical context (HBV carrier, cirrhosis)
• However, normal AFP level in 30% of patients (i.e. < 20 ng/mL) ^[4] — so a normal AFP does not exclude HCC
• AFP alone is insufficient for diagnosis — it must be combined with imaging

3. Diagnostic Algorithm

3.1 Screening Pathway

Surveillance should be performed at intervals of 6 months (doubling time of HCC ≈ 3–4 months) ^[1][2][10].

Screening targets ^[2][10]:

• HBV carriers > 40 years old
• HBV carriers with cirrhosis (any age)
• HBV/HCV co-infected with HIV
• Cirrhosis of any aetiology

Screening method: USG + AFP every 6 months ^[2][4][10]

Rationale for 6-month interval ^[1]:

• Based on expected HCC growth rates (doubling time ≈ 3–4 months ^[2])
• No difference in outcomes compared with 3-month interval surveillance ^[1]
• Better survival compared with 12-month interval surveillance ^[1]
• USG has higher sensitivity than AFP alone ^[1]

The data from the HKU screening study (Chan AC et al., Ann Surg 2008) ^[10] demonstrates the clear advantage of screening vs symptomatic presentation:

This is the power of screening — patients are caught with smaller tumours, better liver function, and less advanced disease, translating into more curative treatment options.

3.2 AASLD Diagnostic Algorithm [1]

Key logic explained:

• Lesion < 1 cm: Followed with USG at intervals of 6 months ^[1]. Why not immediately do CT/MRI? Because tiny nodules < 1 cm cannot be reliably characterised by any imaging modality (spatial resolution is insufficient), and the pre-test probability of malignancy is lower. The doubling time of HCC ≈ 3 months ^[1], so a 6-month follow-up provides enough time for a true HCC to grow and become characterisable while remaining within a potentially curable window.
• Lesion ≥ 1 cm: Evaluate with helical multidetector CT with contrast or dynamic MRI ^[1]. If typical features → diagnosis made. If atypical → second modality or biopsy.
• Resume routine surveillance if the lesion shows no growth over 2 years ^[1] — a true HCC would be expected to at least double in that time frame.

4. Investigation Modalities — Detailed Breakdown

I'll organise this systematically: Blood tests → Tumour markers → Liver function assessment → Imaging → Biopsy → Staging investigations.

4.1 Blood Tests

Blood tests: CBP, LFT, alpha fetoprotein (> 400 ng/mL almost diagnostic of HCC, normal AFP level in 30% of patients i.e. < 20 ng/mL), hepatitis B and C serology ^[4].

4.2 Tumour Markers

Alpha-Fetoprotein (AFP) [1][2][4]

AFP is a glycoprotein (molecular weight ~72 kDa) normally produced by the fetal liver and yolk sac. In adults, it should be < 10 ng/mL (some labs use < 6 or < 20 as the upper limit of normal).

Other Tumour Markers

4.3 Liver Function Reserve Assessment

This is critical because in HCC, you're treating two diseases — the cancer and the cirrhosis. Before planning any intervention (especially resection), you must know whether the liver remnant can sustain life.

Indocyanine Green (ICG) Clearance Test [4]

ICG clearance test: a special dye excreted solely by the liver, best test for liver function reserve if planning for surgical excision ^[4].

How it works:

• ICG (indocyanine green) is an inert fluorescent dye injected intravenously
• It is taken up exclusively by hepatocytes (via organic anion transporter OATP1B3) and excreted unchanged into bile — it is NOT metabolised, conjugated, or excreted by kidneys
• After injection, serum ICG levels are measured over time (typically at 15 minutes)
• The ICG retention rate at 15 minutes (ICG-R15) reflects how well the liver can clear the dye

Why is ICG superior to Child-Pugh score for surgical planning? Because Child-Pugh uses subjective parameters (ascites severity, encephalopathy grade) and coarse categories (A/B/C), whereas ICG-R15 provides a continuous, objective, quantitative measurement of liver function along the entire excretory pathway. It's particularly useful for distinguishing patients within Child-Pugh A who may still have marginal reserve.

Child-Pugh Score

Already covered in detail in the prior section. Quick recap — ABCDE: Albumin, Bilirubin, Clotting (INR), Distension (ascites), Encephalopathy ^[2].

ALBI Score (Alternative to Child-Pugh)

ALBI (Albumin-Bilirubin) score ^[2]: uses only albumin and bilirubin — purely objective, no subjective assessment of ascites or encephalopathy. Increasingly used as it removes inter-observer variability.

Formula: ALBI = (log₁₀ bilirubin × 0.66) + (albumin × −0.085)

4.4 Imaging Modalities

4.4a Ultrasound (USG) [1][2][4]

4.4b Triphasic CT Scan with Contrast [1][2][4] — The Workhorse

This is the most commonly used diagnostic imaging ^[4] and is essentially the gold standard for HCC diagnosis.

What is "triphasic"? It refers to scanning the liver at three specific time points after IV contrast injection, each capturing a different phase of hepatic perfusion:

Key explanation from first principles ^[1]:

• Normal liver has 1/3 blood supply from hepatic artery and 2/3 from portal vein
• HCC has its majority of blood supply from hepatic artery
• Therefore: HCC appears hypervascular during arterial phase and usually not in the portal venous phase
• HCC appears hypodense during delayed phases due to early washout of contrast medium by the arterial blood

Comparison with other lesions ^[1][2]:

4.4c MRI Scan [1][2][4]

MRI is an alternative to CT scan and may also be useful in uncertain diagnosis after CT scan ^[4].

Why is Primovist (gadoxetate disodium) special?

• It is a gadolinium-based contrast agent that is taken up by functioning hepatocytes via OATP1B1/B3 transporters and excreted into bile
• In the hepatobiliary phase (20 minutes post-injection), normal liver parenchyma retains the contrast and appears bright, while:
  • HCC: lacks normal OATP transporters → does NOT take up Primovist → appears dark (hypointense) against the bright background liver
  • FNH: contains functioning hepatocytes → takes up Primovist → appears bright (isointense or hyperintense)
  • Dysplastic nodule vs early HCC: Primovist can distinguish these because early HCC starts losing hepatocyte transporter function
• This is superior to CT in detecting small HCC vs regenerative nodules ^[6]

4.4d Contrast-Enhanced Ultrasound (CEUS) [2]

• Uses microbubble contrast agents (e.g. SonoVue/Lumason) injected IV
• Allows real-time assessment of arterial, portal venous, and late phases — similar principle to triphasic CT
• HCC shows: arterial hyperenhancement + late/mild washout
• Advantages: no radiation, no nephrotoxic contrast, can be done at bedside
• Limitations: operator-dependent, limited by body habitus
• Accepted by APASL guidelines as a diagnostic modality for HCC (not yet endorsed by AASLD as first-line)

4.4e Hepatic Arteriography and Post-Lipiodol CT Scan [1][4]

Rarely performed nowadays ^[1] but important to know for exams as it appears on Prof Poon's slides.

Hepatic arteriography (typical neovascularization, for uncertain cases after CT scan) ^[4]:

• Contrast injected intra-arterially (usually via SMA, hepatic, or splenic artery) ^[1] immediately prior to CT scan
• Identification of: neovascularization, portal vein thrombosis, tumour staining, AV shunting ^[1]

Post-Lipiodol CT scan ^[4]:

• Lipiodol injected via arteriogram, repeat CT scan in 2 weeks for uptake by tumour ^[4]
• Lipiodol is retained in HCC because HCC does not contain Kupffer cells to ingest lipiodol ^[1][2]
• Why? Lipiodol is an iodinated poppy seed oil. Normal liver has abundant Kupffer cells (resident macrophages) that phagocytose lipiodol within days. HCC lacks functioning Kupffer cells, so lipiodol persists in the tumour for weeks — appearing as a bright spot on follow-up CT (HCC shows up on Day 10 ^[2])
• May pick up areas of tumour not demonstrated by pre-lipiodol CT scan ^[1]
• Used for uncertain cases after CT scan and hepatic arteriography ^[4]

4.4f Dual Tracer PET Scan [1][2]

PET-CT has limited sensitivity as HCC does not take up FDG well and the liver has high background metabolic activity ^[2].

Why doesn't standard FDG-PET work well for HCC?

• FDG (¹⁸F-fluorodeoxyglucose) is a glucose analogue. It is taken up by metabolically active cells. However, well-differentiated HCC cells retain glucose-6-phosphatase activity (like normal hepatocytes), so they can dephosphorylate FDG and excrete it — hence low FDG uptake.
• The normal liver also has high background FDG metabolism, making it hard to distinguish tumour from background.

Solution: Dual-tracer PET ^[1][2]:

• ¹¹C-acetate: picks up well-differentiated HCC ^[1] — these tumours preferentially use fatty acid metabolism (acetate is incorporated into lipid synthesis), which standard FDG misses
  • Half-life of ¹¹C = 30 minutes ^[1] (very short — must be produced on-site by cyclotron)
• ¹⁸F-FDG: picks up poorly differentiated HCC ^[1] — these have high glycolytic activity (Warburg effect)
  • Half-life of FDG = 2 hours ^[1]
• By combining both tracers, sensitivity is dramatically improved because well-differentiated and poorly differentiated components are captured by complementary metabolic pathways ^[2]

4.5 Biopsy [1][2][4]

FNAC or Trucut biopsy ^[4] — but with important caveats:

Percutaneous liver biopsy is NOT recommended in general ^[1] for the following reasons:

• Risk of tumour cell seeding along the needle tract — making liver transplantation unsuitable ^[1]
• Risk of bleeding — since HCC is a hypervascular tumour ^[1][2]
• Risk of organ puncture ^[2]

Indications ^[1][2]:

• Only done in inconclusive diagnosis and unresectable cases ^[2] — when diagnostic imaging is uncertain and histological diagnosis is required to guide treatment (e.g. differentiate primary from secondary tumour, or HCC from cholangiocarcinoma)
• When considering systemic therapy where pathological confirmation is required

Contraindications to liver biopsy ^[2]:

• Bleeding tendency (INR > 1.2 despite vitamin K)
• Thrombocytopenia (platelets < 50,000)
• High-grade biliary obstruction (risk of bile peritonitis)

Histological findings ^[1]:

• Pathological hallmark for HCC = Stromal invasion ^[1]
• Trabecular, pseudoglandular, or solid pattern of malignant hepatocytes
• IHC for HCC: HepPar-1 (+), Glypican-3 (+), AFP (+), CK7 (−/variable)

IHC to determine liver metastasis of unknown origin ^[1][2]:

• CK-7: Lung cancer
• CK-19: Breast cancer
• CK-20: Colorectal cancer
• TTF-1: Lung adenocarcinoma / Thyroid cancer

4.6 Staging Investigations (After Diagnosis is Established)

Once HCC is confirmed, staging determines treatment allocation.

5. Summary — Putting It All Together

The diagnostic journey for HCC follows a clear, stepwise algorithm:

References

^[1] Senior notes: felixlai.md (HCC — Diagnosis, Prevention, and Case Study sections) ^[2] Senior notes: maxim.md (HCC — Investigations for diagnosis and staging sections; HCC Screening; Benign liver neoplasm) ^[4] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p. 2–3) ^[6] Senior notes: maxim.md (HBP investigations section; MRI liver with Primovist) ^[10] Lecture slides: Advanced liver surgery for HBP malignancy_ACY Chan.pdf (p. 3 — Screening table, Chan AC et al. Ann Surg 2008)

Management of Hepatocellular Carcinoma

1. Management Principles — The "Triple Assessment"

HCC management is uniquely complex because you are always treating two diseases simultaneously: the cancer itself AND the underlying chronic liver disease. Before selecting any treatment, you must perform a triple assessment ^[3][11]:

1. General status — patient fitness (ECOG performance status), comorbidities
2. Tumour status — number, size, location, vascular invasion, extrahepatic spread
3. Liver function status — Child-Pugh class, ICG clearance, portal hypertension

This triple assessment determines whether a patient gets curative vs palliative treatment, and which specific modality is appropriate. No other solid tumour requires this level of integration between oncological staging and organ function assessment.

2. Treatment Overview

The treatment options for HCC ^[3][11]:

Curative options ^[1][2]:

• Partial hepatectomy (liver resection)
• Liver transplantation
• Local ablation (radiofrequency ablation, etc.)

Palliative options ^[1][2]:

• Transarterial oily chemoembolisation (TOCE/TACE)
• Systemic therapy (sorafenib, lenvatinib, atezolizumab-bevacizumab, etc.)
• Best supportive care

Other treatments listed by Prof Cheung ^[11]:

• Percutaneous intralesional alcohol injection
• Local ablative therapy

3. Management Algorithm — HKLC Staging System

The Hong Kong Liver Cancer (HKLC) Staging System is the locally preferred staging and treatment allocation system ^[1][3][11]. It is more aggressive than BCLC — particularly in intermediate and locally advanced disease — reflecting the high surgical expertise at centres like Queen Mary Hospital and the HBV-dominant patient population.

3.1 HKLC Staging Flowchart

The HKLC classification of liver tumour status ^[1]:

Key difference from BCLC: The HKLC system offers resection as an option even for intermediate and locally advanced tumours (Stage IIa and IIb), whereas BCLC would recommend only TACE for intermediate (BCLC-B) and systemic therapy for advanced (BCLC-C) disease. This reflects the fact that multiple tumours and intrahepatic vascular invasion (e.g. main hepatic vein, left/right portal vein) are NOT considered absolute contraindications for liver resection ^[2] in Hong Kong practice.

3.2 BCLC Treatment Algorithm (For Reference)

BCLC algorithm — for reference, different from local management approach ^[2]:

4. Curative Treatment Modalities

4.1 Partial Hepatectomy (Liver Resection) [1][2][4][11]

Surgical resection is the first-choice treatment ^[4] for HCC. It offers the best chance of long-term cure for patients with preserved liver function and favourable tumour characteristics. However, only 20% of patients are resectable ^[4][11].

Indications [4][11]

Indication for partial hepatectomy ^[11]:

1. Unilobular involvement
2. No invasion into IVC or main portal vein
3. Acceptable liver function for major hepatectomy
   • Child's A
   • ICG retention at 15 minutes < 14%
4. No severe chronic medical illness

Factors Affecting Resectability — The "Three Factors" [1][2]

Liver Augmentation Strategies — When FLR is Insufficient [1][2]

If the planned FLR is too small, several techniques can grow the remnant before definitive resection:

Surgical Techniques During Hepatectomy [2]

Outcomes [1][4][11]

Postresection recurrence occurs in about 50% (mainly in the liver remnant due to intrahepatic metastasis via portal vein or multicentric tumours) ^[4]. Recurrence is classified as:

• Intrahepatic metastasis (< 2 years after resection) — tumour cells that had already invaded portal vein branches before surgery ^[2]
• De novo HCC (> 2 years after resection) — new primary arising from the "field cancerisation" effect of the underlying chronic liver disease ^[2]

Post-Resection Surveillance [2][4]

Need regular 3-monthly surveillance with serum AFP and CT scan for recurrence ^[4]:

• Imaging (USG alternating with CT) + AFP — follow-up every 3 months for 2 years, then every 6 months until 5 years ^[2]
• Early detection of recurrence allows treatment with re-resection, TACE, or ablation ^[4]

Post-Operative Complications [2]

4.2 Liver Transplantation [1][2][4][11]

Liver transplantation is the only treatment that addresses both the tumour AND the underlying liver disease (removes the diseased liver entirely and replaces it with a healthy one). This eliminates the problem of "field cancerisation" and treats the portal hypertension/cirrhosis simultaneously.

Indications [4][11]

Liver transplantation is indicated for ^[4][11]:

• HCC < 5 cm solitary tumour (or < 3 cm if 2–3 tumours) ^[4][11] — i.e. Milan criteria
• With no macroscopic venous invasion in imaging studies ^[4]
• Especially for those in association with cirrhosis ^[4] — patients with poor liver function (Child B/C) who are NOT candidates for resection
• ≤ 65 years with Child C cirrhosis / unresectable HCC who meet transplant criteria ^[2]

Transplant Criteria [1][2]

Contraindications [1][2][4]

NOT for tumours > 5 cm, presence of macroscopic venous invasion, or presence of distant metastasis ^[4]:

• Tumours > 5 cm in diameter ^[1]
• Presence of distant metastasis ^[1]
• Presence of macroscopic venous invasion (portal vein thrombosis) — high recurrence rate due to circulating tumour cells ^[1]
• Active uncontrolled infection ^[2]
• Active alcohol/substance abuse ^[2]

Bridging Therapy [2]

Bridging therapy (e.g. RFA, TACE) is possible to shrink the disease to fulfil transplant criteria, and to prevent tumour progression whilst waiting for transplant ^[2]. The waiting time for a deceased donor liver in HK can be prolonged (median ~12 months), during which the tumour may grow beyond transplant criteria. Bridging therapy keeps the tumour in check.

HBV carriers: antivirals × 2 months before transplant + long-term HBIG after transplant ^[2] — to prevent HBV reinfection of the graft.

Types of Transplant

• Deceased Donor Liver Transplant (DDLT): whole liver from a brain-dead donor
• Living Donor Liver Transplant (LDLT): right lobe graft from a living donor (exploits the liver's regenerative capacity — both the donor remnant and recipient graft regenerate to near-normal volume within weeks). Particularly important in HK given the chronic shortage of deceased donor organs.

Complications of Transplant [2]

Outcomes [11]

5-year survival rate for transplantation: 75% ^[11] — the best long-term survival of any HCC treatment, because the entire diseased liver is removed.

4.3 Local Ablation [1][2][4]

Ablation destroys tumour tissue in situ using various energy sources, without removing it surgically. It is potentially curative for small tumours and is also used as bridge therapy to transplant or palliative treatment ^[2].

Radiofrequency Ablation (RFA) — Most commonly used modality [1]

• Insert a single needle electrode into the tumour via percutaneous, laparoscopic, or open route and induce tumour destruction by heating tissue to temperatures exceeding 60°C ^[1]
• At > 60°C, irreversible protein denaturation occurs → coagulative necrosis
• Heating to even higher temperatures will lead to char formation which is a heat insulator and decreases effectiveness in heat transmission ^[1] — this is why there's a "sweet spot" of temperature

Indications ^[2]:

• Small single tumour < 2 cm (as alternative to resection — resection is preferred if 2–5 cm ^[2])
• Inoperable solitary HCC < 5 cm
• Inoperable ≤ 3 nodules ≤ 3 cm where transplant not feasible ^[2]

Contraindications ^[2]:

• Too close to major vessels (heat-sink effect — flowing blood in adjacent large vessels dissipates heat, reducing ablation efficacy and increasing risk of incomplete treatment)
• Too close to major bile ducts (risk of bile duct injury → stricture)
• Too close to diaphragm (if percutaneous route — risk of diaphragmatic injury/pneumothorax)

Complications ^[2]:

• Bile duct injury
• Thermal injury to surrounding tissues

5-year survival rate: 40% ^[11]

Other Ablative Techniques [1]

5. Palliative Treatment Modalities

5.1 Transarterial Chemoembolisation (TACE) [1][2][4][11]

TACE is the cornerstone palliative treatment for unresectable HCC. Understanding TACE requires understanding the dual blood supply concept:

• Normal liver → 75% portal vein, 25% hepatic artery
• HCC → > 90% hepatic artery
• TACE exploits this difference: you deliver chemotherapy + embolisation via the hepatic artery → selectively kills tumour while relatively sparing normal parenchyma (which survives on portal venous flow)

Procedure [1][2]

1. Access via femoral artery through aorta into the coeliac trunk and hepatic artery ^[1]
2. Chemotherapeutic agents (e.g. cisplatin, doxorubicin) are directly infused into hepatic artery branches that feed the tumours ^[1][2] — this is regional chemotherapy that minimises systemic drug adverse effects as they are subject to first-pass effect ^[1]
3. Agents are mixed with lipiodol by emulsification ^[1] — lipiodol is an oily contrast agent that promotes intratumoural chemotherapy retention because lipiodol is retained in HCC as HCC does not contain Kupffer cells and lymphatics to ingest lipiodol ^[1]
4. Partial embolisation of the major tumour artery with gelfoam ^[1][2]:
   • Promotes tumour necrosis by decreasing blood supply
   • Delays flushing out of agents to prevent rapid clearance of chemotherapy ^[1]

Indications [1][4][11]

Indications for TOCE ^[11]:

1. Bilobar involvement without distant spread, without complete portal vein obstruction or IVC involvement
2. Unilobular involvement but liver function not acceptable for hepatectomy

More specifically ^[1]:

• Unresectable tumours (bilobar or unilobar with inadequate liver function)
• Reasonable liver function (bilirubin < 50 µmol/L ^[4]) — to prevent liver failure from ischaemic damage
• NO evidence of vascular invasion (IVC or portal vein) ^[1]
• NO distant metastasis ^[1]
• Subsequent cycles of TACE should be performed at 3–4 month intervals ^[1]

Contraindications [1][2]

Contraindications to TACE ^[1]:

• Distant metastasis ^[1]
• Moderate or severe liver function impairment — Child-Pugh Class C ^[1][2]
• Portal vein thrombosis — embolisation of hepatic artery will lead to liver ischaemia in the presence of complete obstruction of the portal vein ^[1] (because the non-tumorous liver is then entirely dependent on the hepatic artery; embolise that, and the entire liver dies)
• AV shunting around the tumour ^[1]:
  • Shunting to portal vein is acceptable
  • Shunting to hepatic vein is contraindicated since systemic lipiodol embolus can potentially cause pulmonary embolism ^[1]
• Diffuse HCC — response is very unlikely ^[1]

Complications [2]

Outcomes

5-year survival rate for TACE: 10–25% ^[4][11]

5.2 Transarterial Radioembolisation (TARE) [1][2]

TARE uses Yttrium-90 microspheres (TheraSphere) which induce extensive tumour necrosis with acceptable safety profile ^[1].

• Radioactive microspheres are directly injected into hepatic artery branches that supply the tumour and deliver doses of high-energy, low-penetration radiation selectively to the tumour ^[1]
• Y-90 is a pure β-emitter with a tissue penetration of only ~2.5 mm — so radiation is highly localised to the tumour bed

Key advantage over TACE:

• Preferred over TACE ONLY in the setting of HCC complicated by malignant branch or lobar portal vein thrombosis ^[1] — less arterial ischaemia induced by radioembolisation because of the smaller particle size, suggesting it should be safer in the setting of portal vein thrombosis ^[1]
• This is a critical distinction: TACE is contraindicated in portal vein thrombosis, but TARE can be used because the microspheres are smaller and cause less occlusion of the hepatic artery.

5.3 Systemic Therapy [1][2][11]

For patients with advanced or metastatic disease where curative treatments and TACE are not feasible.

Historical Context [11]

Previously used therapies ^[11]:

• Chemotherapy (doxorubicin) — minimal benefit
• Hormonal therapy (tamoxifen, octreotide) — no proven benefit
• Immunotherapy (interferon) — no proven benefit

These were essentially treatments of unproven benefit ^[4].

Current Systemic Therapy Landscape (2019–2026) [1][2][11]

6. Management of Ruptured HCC [2][4][11]

Ruptured HCC is a surgical emergency occurring in 5–10% of HCC patients ^[2], typically in large, peripherally located tumours ^[2].

Pathogenesis [2]

• Increased intra-tumoural pressure with occlusion of hepatic veins by tumour thrombi or invasion
• Rapid tumour growth and necrosis
• Vascular dysfunction → friable vessels

Clinical Features [2]

• Sudden onset of epigastric pain with abdominal distension
• Hypovolaemic shock
• Increased likelihood of peritoneal seeding
• Prognosis poor: mortality 25–100%

Management Algorithm [11]

First-choice treatment for ruptured HCC is transarterial embolisation (TAE) ^[4][2]:

• TAE if portal vein is patent and reasonable liver function ^[2]
• Complications of TAE: liver failure, embolism, arterial dissection ^[2]

If uncontrolled bleeding — laparotomy ^[4]:

• Perihepatic packing + suture plication (small bleeding site only)
• Absolute alcohol injection
• Selective hepatic artery ligation (HAL)
• Staged liver resection ^[2]

Acute management principles ^[2]:

• Admit ICU
• NPO, IV access, fluid resuscitation ± blood products transfusion, monitor vitals, I/O, CVP
• CBC, LRFT, clotting, cross-match, HBsAg (may need entecavir cover)
• CXR, USG
• CT scan when stabilised to rule out portal vein thrombosis ^[2]

7. Outcomes Summary

Long-term survival rates ^[11]:

8. Best Supportive Care

For BCLC Stage D (Child-Pugh C, ECOG 3–4) or HKLC Stage Vb.

• Symptom management: pain control (WHO analgesic ladder), management of ascites (diuretics, paracentesis), encephalopathy (lactulose, rifaximin), nutritional support
• Palliative care referral
• Median survival: 3 months ^[2]

References

^[1] Senior notes: felixlai.md (HCC — Treatment, Case Study, Prevention sections) ^[2] Senior notes: maxim.md (HCC — Management overview, Liver resection, Liver transplantation, Local ablation, TACE, Ruptured HCC sections) ^[3] Lecture slides: HCC and Gallstone acute cholangitis_Prof TT Cheung.pdf (p. 25, 73, 74 — Treatment protocol, HKLC staging) ^[4] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p. 4 — Treatment) ^[10] Lecture slides: Advanced liver surgery for HBP malignancy_ACY Chan.pdf (p. 7 — BCLC staging) ^[11] Lecture slides: HCC and Gallstone acute cholangitis_Prof TT Cheung.pdf (p. 24, 33, 42, 64, 65, 66, 67 — Treatment modalities, indications, outcomes, systemic therapy)

Complications of Hepatocellular Carcinoma

HCC is a disease that kills through multiple, often overlapping pathways. The complications arise from three interconnected sources: (A) the tumour itself (local effects, spread, rupture), (B) the underlying chronic liver disease/cirrhosis (which is present in 80% of HCC patients in HK), and (C) treatment-related complications. Let's work through each systematically, explaining the "why" from first principles.

1. Complications of the Tumour Itself

1.1 Ruptured HCC — The Surgical Emergency [1][2][4]

This is the single most dramatic and life-threatening complication of HCC. Rupture occurs in 5–10% of HCC patients ^[2] and carries a mortality of 25–100% ^[2].

Pathogenesis ^[2]:

• Tend to occur in large and peripherally located tumours — subcapsular tumours have less surrounding parenchyma to contain them
• Increased intra-tumoural pressure with occlusion of hepatic veins by tumour thrombi or invasion — venous outflow obstruction raises pressure within the tumour, like a balloon with a blocked outlet
• Rapid tumour growth and necrosis — the tumour outgrows its blood supply, leading to central necrosis with softening and structural weakness
• Vascular dysfunction → friable vessels — HCC neoangiogenesis produces structurally abnormal, thin-walled vessels that lack the smooth muscle and elastic layers of normal vessels; these are prone to spontaneous rupture

Clinical features ^[1][2]:

• Leads to intraperitoneal haemorrhage ^[1]
• Presents with severe abdominal pain with peritoneal signs and shock ^[1]
• Sudden onset of epigastric pain with abdominal distension ^[2]
• Hypovolaemic shock — tachycardia, hypotension, pallor, diaphoresis, altered consciousness
• Increased likelihood of peritoneal seeding ^[2] — rupture exposes tumour cells directly to the peritoneal cavity, dramatically increasing the risk of peritoneal carcinomatosis. Even patients who survive the acute event face a much worse long-term prognosis.

Management ^[1][2][4]:

• Treatment of choice is transarterial embolisation (TAE) ^[1][4] — if portal vein is patent and liver function is reasonable
• Uncontrolled bleeding should proceed directly to laparotomy ^[1][4]:
  • Perihepatic packing + suture plication
  • Absolute alcohol injection
  • Selective hepatic artery ligation (HAL)
  • Staged liver resection

1.2 Portal Vein Tumour Thrombus (PVTT)

HCC is a vascular tumour with a high propensity for venous invasion (portal and hepatic veins) ^[4]. Portal vein tumour thrombus is found in 30–60% of HCC patients at diagnosis or during disease course.

Why does HCC invade the portal vein?

• HCC grows into the path of least resistance. The portal vein branches run through the liver parenchyma immediately adjacent to hepatocytes. Malignant hepatocytes can directly invade through the thin sinusoidal walls into portal venule tributaries, then grow "upstream" along the portal vein like ivy growing along a pipe.

Consequences of PVTT (each explained from first principles):

1.3 Hepatic Vein / IVC Invasion

Spread through hepatic vein branches and spread to IVC, right heart and lungs ^[1][4].

• Tumour can grow as a "tongue" of tissue extending from hepatic veins into the IVC and even into the right atrium
• Budd-Chiari-like syndrome: hepatic venous outflow obstruction → hepatic congestion, worsened ascites, hepatomegaly
• Right atrial tumour extension: can cause acute right heart obstruction → cardiogenic shock, sudden death
• Pulmonary tumour embolism: tumour fragments can embolise to the lungs → acute dyspnoea, right heart failure

1.4 Metastatic Disease [1][3][4]

Spread of HCC ^[3]:

• Local invasion: portal vein, hepatic vein, bile duct
• Lymphatic spread: one quarter of patients
• Transperitoneal spread: rare
• Haematogenous spread: lung and bone

1.5 Biliary Invasion

Local invasion into bile duct ^[3]:

• HCC can invade the biliary tree causing obstructive jaundice (though this is NOT common ^[2])
• Haemobilia — tumour eroding into bile ducts causes bleeding into the biliary system → melaena, jaundice, RUQ pain (Quincke's triad)
• Biliary obstruction can precipitate ascending cholangitis (Charcot's triad: fever, jaundice, RUQ pain)

1.6 Paraneoplastic Syndromes

These were covered extensively in the Clinical Features section but represent a category of "complications" in their own right:

• Hypoglycaemia — can be severe and recurrent, causing seizures, LOC, and even death if not recognised. Occurs via IGF-2 secretion and high metabolic tumour demand ^[2][3]
• Hypercalcaemia — via PTHrP secretion; can cause cardiac arrhythmias, delirium, renal failure ^[2][3][4]
• Erythrocytosis — secondary polycythaemia from ectopic EPO; increases blood viscosity → risk of thrombosis ^[2][4]
• Diarrhoea — from VIP secretion; causes dehydration and electrolyte derangement ^[2][3]

2. Complications of the Underlying Liver Disease (Cirrhosis)

Since 80–100% of HCC patients have underlying cirrhosis ^[1], the complications of cirrhosis run in parallel with — and are worsened by — the tumour. HCC accelerates cirrhotic decompensation through several mechanisms:

• Mass effect replacing functioning hepatic parenchyma → ↓ functional reserve
• Portal vein invasion → worsened portal hypertension
• Increased metabolic demands of the tumour → metabolic stress on the failing liver

2.1 Portal Hypertension and Its Sequelae

2.2 Hepatic Encephalopathy [4]

Decompensation of cirrhosis: ascites, variceal bleeding, hepatic encephalopathy ^[4].

• The cirrhotic liver cannot adequately clear ammonia (from GI bacterial metabolism and deamination of amino acids)
• Ammonia crosses the blood-brain barrier → astrocytes convert it to glutamine (via glutamine synthetase) → ↑ intracellular osmolality → astrocyte swelling → cerebral oedema → altered consciousness
• HCC worsens this by: (a) further reducing functional hepatic mass, (b) portal vein thrombosis creating more portosystemic shunting of ammonia-rich blood
• Precipitants in HCC patients: GI bleeding (blood = protein load in gut → ↑ ammonia production), infection (SBP), constipation, sedatives

2.3 Coagulopathy

• The cirrhotic liver has ↓ synthesis of clotting factors (II, V, VII, IX, X, fibrinogen) AND ↓ synthesis of anticoagulant proteins (protein C, S, antithrombin)
• Thrombocytopenia from hypersplenism compounds this
• Result: "rebalanced" haemostasis that is fragile — patients can bleed OR clot unpredictably
• In the context of HCC: surgery, biopsy, or ruptured HCC can provoke life-threatening haemorrhage

2.4 Spontaneous Bacterial Peritonitis (SBP)

• Cirrhotic ascites provides a culture medium for bacteria; impaired hepatic reticuloendothelial function (↓ Kupffer cell activity) fails to clear portal bacteraemia
• Presents with fever, abdominal pain, worsening ascites, encephalopathy
• Diagnosis: ascitic fluid PMN ≥ 250/mm³
• Common in HCC patients because they often have refractory ascites requiring frequent paracentesis (entry point for infection)

3. Treatment-Related Complications

3.1 Post-Hepatectomy Complications [1][2]

Overall post-hepatectomy outcomes ^[1][4][11]:

• Operative mortality: 1–5%
• Morbidity: ~30%
• 5-year recurrence rate: ~50% — due to "field cancerisation" effect ^[1][4]

3.2 Post-Transplantation Complications [2]

3.3 Post-Ablation (RFA) Complications [2]

3.4 Post-TACE Complications [2]

3.5 Systemic Therapy Complications

4. Why the Prognosis is So Poor — The 4 Reasons [1]

This is a favourite exam question. The senior notes explicitly outline 4 reasons for poor prognosis ^[1]:

1. Present in the late stage ^[1]

   • Asymptomatic when the tumour is < 8 cm — no nerve fibres in the liver parenchyma itself; pain only occurs when Glisson's capsule is stretched, which requires a sizeable tumour
   • By the time symptoms develop, the tumour is usually too advanced for curative treatment

2. Presence of underlying liver diseases ^[1]

   • 80–100% of patients with HCC have underlying cirrhosis (80% HBV, 100% HCV/alcohol)
   • This limits the scope for resection — you can't remove half a cirrhotic liver
   • Predisposes patients to post-treatment liver failure ^[1]

3. Early venous permeation ^[1]

   • High recurrence rate due to circulating tumour cells
   • HCC's propensity for portal and hepatic vein invasion means microscopic vascular invasion is often already present at the time of "curative" resection

4. Field cancerisation effect ^[1]

   • Whole liver is exposed to oncogenic influence of HBV/HCV or cirrhosis
   • Presence of multiple small tumours in sites that are not identified on preoperative imaging
   • Even after complete resection, a second primary HCC can develop from the remaining at-risk liver parenchyma
   • This explains the 5-year recurrence rate of ~50% after hepatectomy ^[1][4]

5. Summary Table — Complications of HCC

References

^[1] Senior notes: felixlai.md (HCC — Complications, Prognosis, Post-hepatectomy complications, Case Study Q6) ^[2] Senior notes: maxim.md (HCC — Ruptured HCC, Post-operative care, Liver transplantation complications, TACE complications, RFA complications, Systemic therapy) ^[3] Lecture slides: HCC and Gallstone acute cholangitis_Prof TT Cheung.pdf (p. 13 — Spread; p. 23 — Presentation; p. 65 — Survival rates) ^[4] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p. 3–4 — Pathology, Clinical Presentation, Treatment, Prognosis) ^[11] Lecture slides: HCC and Gallstone acute cholangitis_Prof TT Cheung.pdf (p. 65 — Long-term survival rates)