Lecture Notes 1

Lecture
Notes

Hepatocellular
carcinoma
( Surgical aspects )

Horus University Dr Mohamed El-Matary

2 Lecture Notes

Risk Factors

1) Chronic liver diseases :

- Hepatitis B or C : Chronic infection with hepatitis B or C viruses is a major risk factor for
HCC.
- Cirrhosis : Cirrhosis (scarring of the liver) is a major precursor to liver cancer, whether
caused by alcohol use, viral hepatitis, or non-alcoholic fatty liver disease (NAFLD).
- Fatty liver disease : Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis
and increase the risk of HCC.
2) Environmental factors :
- Aflatoxin exposure : Aflatoxins are toxins produced by molds that grow on improperly
stored grains and nuts, especially in developing countries.
- Alcohol abuse : Chronic alcohol consumption can cause liver cirrhosis, which increases the
risk of HCC.
3) Genetic factors :
- Hereditary conditions such as hemochromatosis (iron overload) or Wilson’s disease
(copper overload) can increase the risk.
4) Other factors :
- Obesity and type 2 diabetes are also emerging risk factors.

Pathogenesis and Development

- Liver injury : In conditions like hepatitis, cirrhosis, and fatty liver disease, the liver experiences
ongoing inflammation, which may lead to the formation of scar tissue.
- DNA mutations : Over time, the damaged liver cells may develop mutations in their DNA,
leading to uncontrolled growth and the formation of tumors.
- Angiogenesis : As the tumor grows, it forms new blood vessels (angiogenesis) to supply itself
with nutrients, which aids in tumor expansion.

Screening

- For people at high risk of developing HCC (such as those with cirrhosis or chronic hepatitis),
regular screening is recommended.
- This typically involves ultrasound imaging and blood tests for AFP every 6 months.

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 Lecture Notes 3

Staging of Primary Hepatocellular Carcinoma (HCC)

- Staging of HCC is critical for treatment planning and prognosis.

- There are several systems used for staging HCC, with the Barcelona Clinic Liver Cancer
(BCLC) system being the most widely used in clinical practice.
- Other systems, such as the TNM (Tumor, Node, Metastasis) and Okuda classification,
are also used, but BCLC is considered the most comprehensive.
1) Barcelona Clinic Liver Cancer (BCLC) Staging System :
- This system takes into account the tumor size, liver function, performance status, and
presence of vascular invasion or metastasis. It divides HCC into five stages :

Stage 0 (Very early stage)

- Solitary tumor ≤ 2 cm in size.
- No vascular invasion.
- Good liver function (Child-Pugh A).
- No symptoms (ECOG 0).
- Treatment : Liver transplantation or surgical resection may be considered.
Stage A (Early stage)
- Solitary tumor or up to 3 nodules ≤ 3 cm in size.
- No vascular invasion.
- Good liver function (Child-Pugh A).
- No symptoms (ECOG 0).
- Treatment : Surgical resection, liver transplantation, or ablation (e.g., radiofrequency
ablation or ethanol injection).
Stage B (Intermediate stage)
- Multiple tumors (typically > 3) or a single large tumor (> 3 cm).
- No vascular invasion.
- Good liver function (Child-Pugh A or B).
- Mild symptoms or no symptoms (ECOG 0-1).
- Treatment : Transarterial chemoembolization (TACE) or radiation therapy.
Stage C (Advanced stage)
- Tumors with vascular invasion (e.g., portal vein invasion)
- Extrahepatic spread (metastasis).
- Poor liver function (Child-Pugh B or C).
- More severe symptoms (ECOG 1-2).
- Treatment : Systemic therapy (e.g., sorafenib, lenvatinib, immunotherapy) and
palliative care.
Stage D (Terminal stage)
- Severe liver dysfunction (Child-Pugh C).
- End-stage disease with poor prognosis and symptoms that cannot be alleviated.
- Treatment : Palliative care.

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4 Lecture Notes

2) TNM Staging System (American Joint Committee on Cancer - AJCC) : ( Just to know )
- The TNM system is commonly used for other cancers but can also be applied to HCC. It
evaluates the extent of the primary tumor (T), the involvement of regional lymph
nodes (N),and the presence of distant metastasis (M).

T (Tumor)
- T1 : Single tumor, no vascular invasion
- T2 : Single tumor with vascular invasion, or multiple tumors without vascular
invasion
- T3 : Multiple tumors with vascular invasion
- T4 : Tumor invading major blood vessels or adjacent organs
N (Nodes)
- N0 : No regional lymph node involvement
- N1 : Regional lymph node involvement
M (Metastasis)

- M0 : No distant metastasis
- M1 : Distant metastasis present

- This system is often used in conjunction with other staging systems like BCLC, but it doesn’t
take liver function into account, which is a crucial factor in HCC prognosis.

3) Okuda Staging System : ( Just to know )

- The Okuda system is less commonly used now but still has some relevance. It evaluates :
- Tumor size and extent.
- Ascites (fluid in the abdomen).
- Serum albumin levels and bilirubin levels.
- It categorizes the disease into early, intermediate, and advanced stages based on these
factors.

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 Lecture Notes 5

Prognostic Factors

- In addition to the staging systems, liver function is a key prognostic factor in HCC.
- The Child Pugh score is commonly used to assess liver function based on bilirubin, albumin
levels, prothrombin time, and ascites.
- ECOG performance status (Eastern Cooperative Oncology Group) also plays a role in
determining prognosis.

Child-Pugh A (Good liver function).

Child-Pugh B (Moderate liver dysfunction).

Child-Pugh C (Severe liver dysfunction).

- Other Staging Considerations : ( just to know )

- Vascular invasion : The presence of vascular invasion (especially in the portal vein)
significantly impacts prognosis and treatment decisions.
- Metastasis : Spread beyond the liver to distant organs (like the lungs or bones) indicates
advanced disease and significantly worsens the prognosis.

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6 Lecture Notes

Microscopic Features ( Not important )

- Hepatocellular origin : HCC is characterized by the proliferation of abnormal

hepatocytes that often form a well-differentiated or poorly differentiated architecture.
Well-differentiated tumors resemble normal hepatocytes, while poorly differentiated
tumors appear more abnormal and may lack the typical structure of normal liver tissue.
- Nuclear atypia : Hepatocytes in HCC often have enlarged, irregular nuclei with
prominent nucleoli.
The cell cytoplasm may appear eosinophilic (pink staining), and the tumor cells may form
trabecular or pseudoglandular patterns.
- Vascular invasion : HCC often invades small blood vessels within the liver, which can be
seen as tumor cells inside blood vessels (vascular invasion), leading to metastasis or
spread within the liver.
- Bile production : In some cases, the tumor cells may produce bile, which is sometimes
visible on histology. This is not seen in all cases but can be a feature of well differentiated
tumors.

Gross Features ( Not important )

- Solitary vs. multifocal tumors : HCC can present as a single large mass or as multiple
smaller tumors scattered throughout the liver.
- Color and consistency : The tumor is often tan or yellowish due to its high fat content,
with some areas being necrotic or hemorrhagic (especially in large or poorly differentiated
tumors), The surrounding liver tissue may show signs of cirrhosis.
- Capsule : A fibrous capsule may surround the tumor in some cases, although it is not always
present,The tumor often extends beyond the capsule in more aggressive cases.

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 Lecture Notes 7

Clinical Picture

- Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer.
- Its clinical presentation can vary depending on the size, location, and stage of the tumor, as
well as the underlying liver function and cirrhosis.
- Below are the key features of the clinical presentation :
1) Asymptomatic in Early Stages :
- In the early stages, many patients are asymptomatic, and the tumor is often found
incidentally during imaging for other conditions.
- History of risk factor ; hcv, hbv, alcohol, aflatoxin exposure
2) Symptoms Related to Liver Dysfunction :
- Fatigue : General feeling of tiredness or weakness.
- Weight loss : Unexplained weight loss may occur due to metabolic changes.
- Loss of appetite (anorexia) : Often accompanies weight loss.
- Jaundice :Yellowing of the skin and/or eyes, caused by impaired liver function.
- Abdominal pain : Often in the upper right side or epigastric region due to liver
enlargement, stretching of the liver capsule, or invasion into surrounding structures.
- Ascites : Abdominal swelling due to fluid buildup, commonly seen in advanced stages
or when cirrhosis is present.
- Pruritus : Itching due to bile salt accumulation in the skin, especially if jaundice is
present.
3) Signs of Portal Hypertension (due to Cirrhosis or HCC Invasion) :
- Variceal bleeding : From esophageal or gastric varices due to increased pressure in
the portal venous system.
- Splenomegaly : Enlarged spleen, which can occur in the context of portal
hypertension.
4) Mass Effect Symptoms :
- Palpable mass : If the tumor is large, it may be palpable in the upper abdomen during
physical examination.
- Hepatomegaly : Enlargement of the liver due to the tumor itself or associated liver
disease (cirrhosis).
5) Symptoms of Advanced Disease :
- Cachexia : Severe weight loss and muscle wasting.
- Encephalopathy : Due to liver failure and inability to detoxify ammonia, leading to
mental confusion, disorientation, or even coma.

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8 Lecture Notes

6) Other Complications :
- Intra-abdominal hemorrhage : Tumor rupture can cause acute hemorrhage into the,
symptoms related to those organs may occur..abdominal cavity, which may
present as sudden, severe abdominal pain and shock.
- Extrahepatic spread : If the cancer spreads to other organs such as the lungs or
bones.
- Because HCC is often diagnosed at a later stage when symptoms become apparent, regular
screening is essential for patients with risk factors, particularly those with cirrhosis or
chronic viral hepatitis.

Laboratory Findings

1) Routine : Cbc, kidney function, blood glucose, virology

2) Specific tests :
- Elevated alpha-fetoprotein (AFP) : AFP is often elevated in HCC but not always; it’s
used as a marker for diagnosis, particularly in patients with chronic liver disease.
- Liver function tests : May show elevated transaminases (AST, ALT), bilirubin, and
alkaline phosphatase if liver damage is significant.
- Prothrombin time (PT) : Often prolonged in cases with cirrhosis or liver dysfunction.

Investigations
A) Investigations to prove the diagnosis as hcc :
1) Ultrasound (US) :
- Initial screening tool : Ultrasound is commonly used for the surveillance of HCC,
especially in high-risk patients (e.g., those with cirrhosis or chronic hepatitis B or C).

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 Lecture Notes 9

- Findings :
a) A mass may be seen as a hypoechoic (dark) lesion in the liver, although this
can vary.
b) Can detect ascites, hepatomegaly, and changes in liver texture.
c) Doppler ultrasound can assess blood flow and detect vascular involvement
or portal hypertension.
- Limitations : Ultrasound sensitivity can be lower in obese patients or those with
poor acoustic windows.

Small HCC on US Large HCC on US

2) Contrast-Enhanced Ultrasound (CEUS) :

- Higher sensitivity : This technique uses a contrast agent to improve the delineation
of lesions in the liver.
- Findings : HCC typically shows hypervascularity (increased blood flow) during the
arterial phase and can show washout in the venous phase.
- Indications : Can be used as a diagnostic tool in patients with cirrhosis who have
liver nodules.
3) Computed Tomography (CT) Scan :
- Triple-phase CT scan : A contrast-enhanced CT scan is the gold standard for imaging
the liver and assessing HCC.
a) Arterial phase : HCC typically enhances early (hypervascular) during the
arterial phase.
b) Portal venous phase : Washout (hypodensity) of the tumor is seen, as HCCs
often lose their enhancement compared to the surrounding liver tissue.
c) Delayed phase : The tumor may show further washout and remain
hypodense.
- Findings :
a) Hypervascular lesion in the arterial phase with washout in the venous/
delayed phases.
b) Size, location, and vascular involvement (e.g., invasion into the portal vein or
hepatic veins).
c) Intrahepatic metastasis : Can detect spread to other parts of the liver or to
nearby structures.
- Indications : Used for staging, assessment of extrahepatic spread, and treatment
planning.

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10 Lecture Notes

Precontrast Arterial phase Portal phase Venous phase

4) Magnetic Resonance Imaging (MRI) :

- Preferred for characterization : MRI with contrast (gadolinium-based agents) is
highly effective for characterizing liver lesions and differentiating HCC from other
liver tumors, such as metastases or benign lesions.
- Findings :
a) Arterial phase : Similar to CT, HCC shows hypervascularity.
b) Venous phase : Washout occurs due to reduced blood supply.
c) Delayed phase : HCC may show progressive washout.
d) MRI is particularly useful for vascular invasion, tumor staging, and when a
non-invasive approach is preferred.
- Liver-specific contrast agents (e.g., gadolinium-based agents) can help better
define HCC borders and vascular features.
- Indications : Used in complex cases or when CT is inconclusive. Also, preferred for
patients with contrast allergies or those requiring liver-specific imaging.
5) Biopsy (when radiology is inconclusive) :
- In cases where imaging findings are unclear, a liver biopsy can be performed to
confirm the diagnosis, but it is generally not needed if classic radiological features of
HCC are present.
- Radiological Features Suggestive of HCC :
- Hypervascularity in the arterial phase.
- Washout in the venous phase.
- Delayed enhancement or persistent hypoattenuation in delayed phases.
- Tumor size and presence of vascular invasion (portal vein or hepatic vein).
- Capsule formation (a thin rim around the tumor, sometimes seen in larger
HCCs).
- In summary :
a) Ultrasound is commonly used for screening.
b) while CT and MRI with contrast are the primary tools for diagnosing and staging
HCC.
c) MRI is particularly valuable in characterizing liver lesions and evaluating the extent
of disease.
B) Additional investigations for staging :
1) CT Angiography (Hepatic Arteriography) : FOR ASSESMENT of portal vein ,hepatic veins
and artery invasion
2) CT volumetry to assess the remaining liver for resection.

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 Lecture Notes 11

3) Positron Emission Tomography (PET) Scan :

- Limited role in HCC diagnosis but useful for
staging and detecting extrahepatic
metastasis.
- Findings : Tumors with high glucose metabolism
(like HCC) often appear as areas of high uptake
of the radiotracer (fluorodeoxyglucose or FDG).
- Indications : Primarily used in advanced stages to
detect distant metastasis, especially if there are
uncertain findings on other imaging modalities. Angiography
4) Bone survey, Bone scan ,Ct chest and brain.

(PET) Scan show Colorectal Metastasis

CT lung showing multiple lung metastases

C) Investigations to assess fitness for surgery :

1) Labouratory :
- Blood picture, Liver function, kidney Function, blood glucose.
2) Ecg, Echocardiography, Cardiac and Chest Assement
3) Anaesthetic assement.

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12 Lecture Notes

Treatment options

- Primary hepatocellular carcinoma (HCC) is the most common type of liver cancer.
- Treatment options depend on various factors, including the tumor's size, location, and stage, as
well as the underlying liver function and the presence of cirrhosis.
- Here are the main treatment options for HCC :
1) Surgical Treatment :
- Liver Resection : Surgical removal of the tumor is gold standard option if the cancer
is confined to a part of the liver and the liver function is relatively well-preserved.
- Various hepatic resection techniques can be done ranging from localized resection
with safety margin to extensive hepatic resection and vascular reconstructions.
- Liver Transplantation : In cases where the tumor is confined to the liver but the
patient has underlying cirrhosis or other liver dysfunction, liver transplantation may
be considered. It's particularly effective for patients with small, early-stage tumors
(e.g., Barcelona Clinic Liver Cancer stage 0 or A).
2) Ablation Therapy :
- Radiofrequency Ablation (RFA) : Uses heat generated by radiofrequency energy to
destroy tumor cells. It’s effective for small tumors and is often used in patients who
are not candidates for surgery.
- Microwave Ablation (MWA) : Similar to RFA, but uses microwave energy to heat and
destroy tumor tissue.
- Percutaneous Alcohol Injection (PAI) : Involves injecting alcohol directly into the
tumor, which causes necrosis of the tumor tissue. It is typically used for small
tumors.
3) Transarterial Therapies :
- Transarterial Embolization (TAE) : A procedure where the blood vessels supplying
the tumor are blocked to limit the tumor's blood supply, leading to tumor necrosis.
This is often used for tumors that can't be surgically removed.
- Transarterial Chemoembolization (TACE) : A combination of embolization and
chemotherapy, where chemotherapy drugs are delivered directly to the tumor along
with embolizing agents to block the blood supply.
This is a common treatment for intermediate-stage HCC.

Radiofrequency Microwave Ablation Transarterial

Ablation (RFA) (MWA) Embolization (TAE)

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 Lecture Notes 13

4) Systemic Therapies :
- Tyrosine Kinase Inhibitors (TKIs) : Drugs like sorafenib and lenvatinib target specific
pathways involved in tumor growth and angiogenesis.
These are typically used in advanced stages or for patients who are not candidates
for surgery or local therapies.
- Immunotherapy : Immune checkpoint inhibitors like nivolumab and pembrolizumab
have shown promise in advanced HCC. These drugs help to boost the body’s
immune system to fight the cancer.
- Chemotherapy : While HCC is generally resistant to traditional chemotherapy, it
may still be used in some cases, especially in combination with other treatments.
5) Radiation Therapy :
- Stereotactic Body Radiation Therapy (SBRT) : This is a form of radiation therapy
used for patients with small to medium tumors who cannot undergo surgery or
other local therapies.
6) Supportive Care :
- In cases where the cancer is not amenable to curative treatment, palliative care
(such as pain management, liver support, and improving quality of life) becomes an
important focus.
7) Clinical Trials :
- There are ongoing clinical trials exploring new treatment options for HCC, including
novel drug therapies, targeted therapies, and combination treatments.

Liver resections (Hepatectomy procedures)

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 14 Lecture Notes

Right hepatectomy
Segment V,VI,VII and VIII (± segment I).
Extended Right or right trisectionectomy
Segment IV,V,VI,VII and VIII (± segment I).
Left hepatectomy
Segment II, III and IV (± segment I).
Extended Left or left trisectionectomy
Segment II, III, IV,V and VIII (± segment I).
Right posterior sectionectomy
Segment VI and VII.
Right anterior sectionectomy
Segment V and VIII.
Left medial sectionectomy
Segment IV.
Left lateral sectionectomy
Segment II and III.

- Indications of liver resection :

1) Benign tumors.
2) Malignant tumors.
3) Trauma.
4) Others.
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