Hepatocellular Carcinoma: Causes, Symptoms, Treatment

Describe In Detail The Htiopathogenesis, Premalignant Conditions, Clinical Features, Investigations, Staging And Treatment Options Available For Treatment Of Hepatocellular Carcinoma. Also Types Of Hepatic Resections.

Aetiology of HCC

1. Hepatitis B virus (HBV): High titres of hepatitis B surface antigen (HBsAg) was found in 50 to 60% of patients with HCC. Its incidence is higher in chronic carriers and it is increased, if patients consume alcohol, aflatoxin and tobacco.
2. Hepatitis C virus (HCV): HCV infection induces cirrhosis and increases the incidence of development of HCC.
3. Hepatitis D: It is another viral infection also called delta hepatitis. This virus requires hepatitis B virus (HBV) for replication. It can cause dangerous hepatitis—HCC.
4. Cirrhosis: It is a definite premalignant condition. A palpable hard liver in a cirrhotic patient suggests development of HCC. It is the single most common risk factor for HCC.
5. Aflatoxin consumption (a fungus found in infected butter yellow, bread) is responsible for increased incidence of HCC as in Mozambique.
6. Oral contraceptive pills are known to cause adenoma and there is a rare chance of adenoma turning into HCC.
7. Other risk factors: Heavy alcohol consumption, cigarette smoking, diabetes mellitus, and haemochromatosis are the other factors responsible for HCC. Wilson’s disease is rarely associated with an increased risk of HCC.
8. Hereditary tyrosinaemia is a metabolic disorder characterised by a deficiency of enzyme fumaryl acetoacetate resulting
9. Other causes: Type 1 glycogen storage disease and familial polyposis coli alpha-1 antitrypsin deficiency, Budd-Chiari syndrome. It is 4 times more common in Asians and two times in Hispanics. Less common in Caucasians.

Hepatocellular Carcinoma Clinical Features

• Age group: Highest incidence is found after 50 years of age. It is rarely seen in children also.
• Sex: Male alcoholics are commonly affected.
• It can be a rapidly growing neoplasm, highly vascular and clinically palpable as a soft to firm pulsatile mass with or without a bruit.
• Rapid development of anorexia, asthaenia, anaemia and loss of weight.
• Jaundice is not common unless the tumour arises in a cirrhotic liver in hepatocellular failure.
• Worsening of portal hypertension.
• Low grade pyrexia is common. It is due to tumour necrosis.
• Liver being an important organ of metabolism, hypo-glycaemia is found in 10% of patients.
• Ascites
• Triad of abdominal pain, weight loss and abdominal mass is the most common clinical presentation.

Spread of Hepatoma

1. Direct infiltration of the neighbouring structures such as diaphragm results in hiccoughs due to irritation of phrenic nerve.
2. Lymphatic spread: Lymph nodes at the hilum (porta hepatis) are involved first. Later, mediastinal nodes and left supraclavicular nodes (Virchow’s node) are involved.
3. Blood spread causes massive malignant pleural effusion by dislodgement of tumour emboli into the inferior vena cava because of spread through the hepatic veins. Vertebral involvement follows soon.
4. Haemoperitoneum due to spread involving peritoneal surface or due to rupture of an enlarging hepatoma may occur.

Hepatocellular Carcinoma Investigations

1. CBP: Hb% is usually low.
2. Liver function tests may show hepatocellular failure in the form of high bilirubin, low albumin and high globulin levels.
3. Chest X-ray: CT chest pulmonary metastasis
4. Abdominal USG: Findings
   • Diffuse distortion of hepatic parenchyma and a well-circumscribed hyperechogenic mass suggests HCC.
   • Mosaic pattern of the tumour with thin halo and lateral shadows, nodule in nodule pattern with separating fibrous septa and posterior echo enhancement.
   • Tumour thrombi in portal vein, hepatic vein or IVC.
5. Contrast-enhanced CT of the abdomen: It appears as a hypodense mass with internal mosaic architecture in the early phase and hypodense lesion with an enhanced fibrous capsule in late phase. Guided FNAC can be done to confirm the diagnosis. A small fear of tumour embolisation via portal venous radicles exists and is a complication. Enhancement in arterial phase and washout in delayed port venous phase is diagnostic of HCC.
6. Alpha-fetoprotein
   • It is a foetal antigen which disappears after birth. Hence, it is not measurable in normal persons.
   • Values above 20 ng/ml are suggestive of hepatoma.
   • Levels above 400 ng/ml in cirrhotic patients with a hypervascular mass larger than 2 cm in diameter is diagnostic.
     a-fetoprotein levels indicate size of the tumour, invasion and even recurrence.
   • In patients who are not operated, levels reflect response to treatment.
   • Values around 200 ng/ml is also seen with regenerating nodules.
   • 20 to 40% HCCs do not secrete LFP.
7. Selective angiography: It is done only if hepatic resec¬tion is planned. It can demonstrate a highly vascular tumour (tumour blush due to neovascularisation) or involvement of portal vein thrombus in the IVC. Hence, venous phase must be recorded. It can define arterial supply also.
8. MRI: It appears as a high-intensity lesion (adenomatous hyperplasia as a low-intensity lesion). MRI is much more sensitive for diagnosis of 1-2 cm HCC.
9. Liver biopsy for HCC:
   • It is done only in unresectable cases or metastatic disease before starting other treatment such as chemotherapy, etc.
   • The images from contrast CT scan and MRI and raised levels of a-fetoprotein—almost always suggest HCC. Hence, biopsy is not done.
   • Also rises of haemoperitoneum and peritoneal implantation of tumour cells present.
   • Corebiopsy has increased risks of all the complications mentioned above.
   • With normal INR, fine needle aspiration can be done in selected cases (clinical trials) with minimal risk.

• Increased α-Fetoprotein Levels
  • Hepatoma—hepatoblastoma
  • Carcinoma stomach
  • Carcinoma pancreas
  • Embryonal cell carcinoma of testis
  • Not increase in fibrolamellar carcinoma

Hepatocellular Carcinoma Differential Diagnosis

• Secondaries in the livernodular surface and usually both lobes are enlarged.
• Polycystic disease of the liver.
• Hydatid cyst of the liver—smooth surface, round borders.
• Fibrolamellar carcinoma
• Secondaries in the liver
• Haemangioma
• Focal nodular hyperplasia
• Polycystic liver

AJCC 8th edition-hepatocellular carcinoma

• Primary tumour (T)
  • T1a Solitary tumour ≤ 2 cm with/without vascular invasion
  • T1b Solitary tumour >2 cm without vascular invasion
  • T2 Solitary tumour >2 cm with vascular invasion or multifocal tumours, note >5 cm
  • T3 Multiple tumours at least one of which is >5 cm
  • T4 Single tumour or multifocal tumours of any size involving a major branch of the portal vein or hepatic vein or tumour(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum.
• Regional lymph nodes (N)
  • Nx Regional lymph nodes cannot be assessed
  • N0 No regional lymph node metastasis
  • N1 Regional lymph node metastasis
• Distant metastasis (M)
  • M0 No distant metastasis
  • M1 Distant metastasis
• Stage
  • Stage 1A T1a N0 M0
  • Stage 1B T1b N0 M0
  • Stage 2 T2 N0 M0
  • Stage 3A T3 N0 M0
  • Stage 3B T4 N0 M0
  • Stage 4A Any T N1 M0
  • Stage 4B Any T Any N M1

Hepatocellular Carcinoma Prognosis: The Prognosis of HCC depends upon not only any about stage of the disease but also about whether patient can withstand/tolerate surgery or not. As most of the patients have active hepatitis/cirrhosis, resection may carry very high mortality. Hence, the Eastern Cooperative Oncology Group (ECOG) have adopted a performance status which is called ECOG performances status as given below.

Hepatocellular Carcinoma ECOG

1. Fully active, able to carry on all pre-disease performance without restriction.
2. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, and office work.
3. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
4. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
5. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
6. Dead

Child-Turcotte-Pugh (CTP) Score

Child-Turcotte-Pugh (CTP) Score: Classification of hepatocellular function in cirrhosis

Treatment of Hepatocellular Carcinoma: It can be classified under following headings.

1. Resection is the best possible treatment for hepatocellular carcinoma. Up to 3 segments of the liver can be resected. Rest of the liver will be enough to maintain life provided the remaining liver is healthy/ noncirrhotic.

• Functional liver remnant (FLR) should be >20% of standardised total liver volume after resection.
• The remnant liver should have vascular inflow, venous outflow, and biliary drainage.
• Two contiguous liver segments must be left behind.

Liver:

Liver Treatment Of HCC:

2. Systemic chemotherapy using intravenous doxorubicin has been tried with some success in the postoperative period. Intra-arterial 5-FU has also been tried.

3. Transcatheter arterial embolisation (TAE): By introducing gel foam into the branches of the hepatic artery some amount of tumour necrosis occurs. This arterial embolisation is combined with chemotherapeutic agents such as doxorubicin, results are better because the tumour has prolonged exposure to the drug. This is called transarterial chemoembolisation (TACE). This method is followed only as a palliative procedure.

• Basically, they are used for unresectable HCC not suitable for other treatments.
• The most commonly used agents are doxorubicin, cisplatin and mitomycin.
• Contraindications are portal vein occlusion and poor liver function.
  • Embolising agents:
  • Gel foam
  • Chemotherapeutic agent (like doxorubicin) with or without lipiodol
  • Side effects are abdominal pain, liver abscess, acute pancreatitis, etc.
  • As a definitive curative intent, TAE is not recommended, as there is no strong evidence.

4. Transarterial radioembolisation (TARE)

• It is another option for unresectable HCC.
• It is called internal radiation.
• Most commonly used radioactive material is Yttrium-90 (90Y).
• It emits β-radiation.
• It is delivered through feeding vessels of the tumour.
• Thus, any tumour, any size, any nodule can be irradiated.
• Survival is prolonged with this treatment.
• Can be used in cirrhotic patients of poor liver function.
• It is indicated in advanced disease, portal vein thrombosis.
• Thus, later resection or transplant can be an option.

5. Percutaneous ethanol ablation (PEA): It is cheaper and is a palliative treatment. Tumours less than 3 cm and nodules not more than 3 are candidates. It reduces the tumour size and decreases pain.

• Tumour necrosis occurs as a result of cellular dehydration denaturation of proteins and occlusion of small tumour vessels.
• It requires 4–6 sessions under ultrasound guidance with 2–10 ml alcohol injection.
• Injections are given on an outpatient basis. Easy to give because of the soft consistency of the tumour.

6. Radiofrequency ablation (RFA)

• It is now being tried for inoperable tumours or patients who are not ideal candidates for surgery, as per Milan’s criteria
• Indications: Tumour deep in parenchyma, away from hilum and less than 3 cm.
• Electrical energy (500 kHz) is delivered through an 18 G needle inserted under US or CT guidance through the skin into the tumour. In the following few months, the tumour is destroyed and the cells are killed.
• The route of insertion of this needle can be per-cutaneous, laparoscopic or by open route.
• There should not be any evidence of extrahepatic disease preoperatively or intraoperatively.
• Mode of actions: Cytodestruction of the tumour. In one sitting 6-7 cm of necrosis zone can be achieved for a 5 cm tumour.
• In most cases a tumour can be adequately treated in one session. The procedure can also be repeated. It is done under general anaesthesia.
• It is better to avoid RFA when the tumour is in the hilar plate wherein portal vein and the hepatic arterial branches enter the liver. Damage to these structures and bile duct can occur.
• Thus, RFA is considered for small HCCs, CP grade A cirrhotic patients who are not candidates for resection and it is to be considered as a bridging procedure before transplantation.

7. Injection octreotide, an analogue of somatostatin, has been used in advanced cases. It has shown promising results in decreasing the size of the tumour. It also reduces the pain and discomfort. This is combined with chemotherapy such as gemcitabine and carboplatin. However, the treatment is costly and the results are temporary.

8. Sorafenib is the drug of choice in advanced HCC and with good liver function.

• It is a multi-tyrosine kinase inhibitor.
• It promotes apoptosis and inhibits angiogenesis.
• These agents because of their mode of action, inhibit cell proliferation and thus control growth and improve survival.
• It also inhibits vascular endothelial growth factors (VEGF).
• Thus, it is indicated in the management of advanced HCC with good systemic function.
• Side effects: Fatigue, skin rashes, hand-foot syndrome, hypertension, hair loss, itching.

Liver Resections

It should be the first choice in HCC, provided there is no extrahepatic disease or vascular invasion. After getting a negative margin, adequate functioning liver tissue should be present.

Incision

• Aim of the incision is to get adequate exposure.
• A transverse abdominal incision in the right upper quadrant with a vertical extension to the xiphoid process gives excellent exposure to the liver.

Mobilisation 

• The key point is division of ligaments which are attached to it or which support the liver and suspend the liver.
• The falciform ligament is divided and followed along the anterior surface of the liver.
• The left triangular ligament is divided by gentle pull on the left lobe of liver towards the right side.
• The right triangular ligament is divided between the diaphragm and right lobe of the liver by traction and counter traction.
• Lesser omentum is divided. Thus, separating the liver from the stomach.
• Small multiple veins from the inferior surface of the liver join the inferior vena cava. These should be divided.
• Last hepatic veins to be dissected and divided above renal veins.

Hilar Dissection

• Cholecystectomy is done by ligating the cystic artery and cystic duct. The CBD is then exposed at the free edge of lesser omentum. A sling is applied around CBD to isolate it and gently traction is applied.
• This visualises the common hepatic artery.
• By dissection of common hepatic artery, its right and left branches are dissected out.
• Slings are applied to these arteries, portal vein is exposed. This facilitates the freeing of portal vein by dividing lymphatic tissues joining portal vein.
• The congenital anomalies such as aberrant right hepatic artery and accessory left hepatic artery also should be looked for.
• CBD, CHD, left and right hepatic ducts are exposed at the hilum.

Division of the Parenchyma

• This requires ligation of artery or branch by 4/0 proline, transfixion of the bile duct by 4/0 PDS and transfixion of portal vein with 4/0 prolene.
• Once the demarcation appears on the liver, parenchyma is divided by using diathermy.
• Cavitron ultrasonic surgical aspirator (CUSA) is the commonly used dissector for dividing liver parenchyma.
• Vessels and bile duct branches which are exposed are clipped or diathermised.
• Continue dissection till you reach hepatic veins/ branches. They are ligated or divided.

Segmental and Local Resection

• Since each segment (see segmental anatomy) carries its own arterial supply, venous drainage and bile drainage, resection can be done with 1 cm margin.
• In a few cases, hilar dissection may not be necessary.

Liver Resections Complications

• Intraoperative bleeding
• Biliary leakage
• Hepatic decompensation
• Ascites due to portal HTN, severing of lymphatics
• Infection