Management of Primary Liver Cancers

Primary liver cancers start in the liver rather than spreading to it from elsewhere. The two main types are hepatocellular carcinoma (HCC), which arises from hepatocytes and accounts for about 80 to 85% of cases, and cholangiocarcinoma, which arises from bile duct cells. Management of primary liver cancers turns on three questions: which cancer it is, how well the surrounding liver works, and whether the whole tumour can be removed.

Dr. Ashish George, Principal Consultant & Unit Head Liver Transplant, Fortis Hospital, Shalimar Bagh, New Delhi, India, built his masterclass around the doctor who first meets these patients: how to recognise the patient profile, how to assess the patient, and what to do next. His central message is that these are treatable tumours. Caught in time and treated appropriately, patients have a real chance of long-term survival.

This guide covers how the two cancers differ, who is at risk, screening, tumour markers, imaging and the limited place of biopsy, how treatment is decided, and follow-up. Two deeper articles cover HCC treatment, from resection and ablation to liver transplant, and cholangiocarcinoma surgery and the Bismuth-Corlette classification.

Primary liver cancer versus liver metastases

Most cancers found in the liver are not primary at all. They are secondaries: metastases from colorectal cancer, neuroendocrine tumours, breast cancer and other organs. These follow the biology and the treatment logic of the original cancer.

Primary liver cancers are a different problem. They originate in one of the liver's two major cell types:

• Hepatocytes, the main functional cells of the liver, which give rise to hepatocellular carcinoma.
• Cholangiocytes, the cells lining the bile ducts, which give rise to cholangiocarcinoma ("cholangio" refers to the bile duct).

The distinction matters from the first consultation, because the two cancers arise in different patients, present differently, carry different tumour markers, look different on a scan and follow different treatment pathways.

The scale of primary liver cancer

Dr. George put the toll at more than 800,000 deaths a year worldwide from primary liver cancers, the majority from hepatocellular carcinoma. The burden of HCC is concentrated in East Asia and Africa, the regions where chronic hepatitis B and C are most common.

Within primary liver cancers, HCC accounts for about 80 to 85% of cases. Intrahepatic cholangiocarcinoma accounts for about 10 to 15%.

Cholangiocarcinoma is subdivided by where along the biliary tree it arises:

• Intrahepatic cholangiocarcinoma arises from the smaller bile ducts inside the liver tissue.
• Perihilar (hilar) cholangiocarcinoma arises near the hilum, where the right and left hepatic ducts join. It was historically called a Klatskin tumour.
• Distal (extrahepatic) cholangiocarcinoma arises further down the bile duct, outside the liver. Dr. George left this group out of the session.

Who is at risk of primary liver cancer

The risk factors overlap, but the centre of gravity differs.

Hepatocellular carcinoma. Chronic viral hepatitis, cirrhosis, older age and a family history are the main risk factors. Most HCCs arise in patients who already have cirrhosis. In Dr. George's practice, of every 100 HCCs, perhaps 95 arise on a cirrhotic liver and only 5 on a non-cirrhotic one. The non-cirrhotic group includes some carriers of hepatitis B or C acquired by vertical (mother-to-child) transmission, whose background liver can be essentially normal.

Cholangiocarcinoma. Choledochal cysts (congenital dilatations of the bile duct) are an additional risk factor. For intrahepatic cholangiocarcinoma, the list also includes primary sclerosing cholangitis (PSC, a chronic inflammatory scarring of the bile ducts), hepatolithiasis (stones within the bile ducts inside the liver), liver fluke infection and cirrhosis itself.

How the two cancers present

Location dictates symptoms.

A perihilar cholangiocarcinoma narrows the bile duct at the confluence. Because these are the main channels through which bile leaves the liver, the result is biliary obstruction, and jaundice appears early and prominently.

An intrahepatic cholangiocarcinoma grows inside the liver tissue, away from the main ducts. Most present as a mass-forming lesion, and they tend to present late, unless the tumour is found incidentally while the patient is being investigated for something else. Symptoms, when they come, are non-specific: pain, weight loss and asthenia (generalised weakness).

Hepatocellular carcinoma usually arises in a cirrhotic liver, which is why patients with cirrhosis are placed under surveillance rather than waiting for symptoms.

Liver cancer screening for patients with cirrhosis

The surveillance protocol Dr. George described is simple: a patient known to have cirrhosis stays under follow-up and has an ultrasound and an alpha-fetoprotein (AFP) blood test every six months. It is a fair screening strategy, and it has been shown to improve survival.

Ultrasound is the screening tool. It is not the diagnostic test. A lesion found on ultrasound, or a rising AFP, leads to multiphase CT or MRI.

Tumour markers: AFP, PIVKA-II and CA19-9

Three blood markers are used, and none of them is sufficient on its own.

• Alpha-fetoprotein (AFP) is the primary tumour marker for hepatocellular carcinoma.
• PIVKA-II (protein induced by vitamin K absence or antagonist-II, also called des-gamma-carboxy prothrombin) is a second marker that can be elevated in HCC.
• CA19-9 comes primarily from the biliary system and is the main marker for cholangiocarcinoma and for biliary obstruction.

The limitation is sensitivity. Dr. George's figure is that of 100 HCC patients, only about 40 have an elevated AFP; 60 do not. Adding PIVKA-II raises the sensitivity a little. Even so, many patients have an entirely normal AFP and PIVKA-II, and the diagnosis is still made with confidence on imaging.

CA19-9 has the opposite weakness: it is sensitive but not very specific. It can be raised in patients with HCC who have advanced underlying liver disease, and in cirrhosis more generally, although in those settings the level is usually not very high.

The practical rule is that markers support the diagnosis and are used to track response and recurrence. Radiology makes the diagnosis.

Imaging: why a triphasic (multiphase) CT is the key test for HCC

CT is the primary radiological investigation Dr. George orders for suspected HCC. Surgeons are practised at reading CT, and CT gives a clear anatomical picture, including vascular invasion, which shapes every surgical decision.

The scan must be the right kind. A simple contrast-enhanced CT is not enough. What is needed is a phasic CT, often called a triple-phase or triphasic CT, with images taken in sequence:

1. An arterial phase.
2. A portal venous phase.
3. A hepatic venous phase.
4. A delayed phase. The washout of contrast from an HCC sometimes appears only at 5, 7 or 10 minutes.

The arterial enhancement and washout pattern

HCC has a characteristic signature, and its physiology explains why. Progressed HCCs are supplied mainly by branches of the hepatic artery. In the arterial phase they therefore enhance more brightly than the background liver. In the later phases (portal venous, hepatic venous and delayed), the arterial contrast has washed out of the tumour, and because the tumour has little portal venous supply, it appears darker than the surrounding liver. That darkening is called washout.

An arterially enhancing lesion with venous washout on a properly phased CT is, in Dr. George's words, almost diagnostic of HCC. Intrahepatic cholangiocarcinoma behaves differently: it shows progressive delayed enhancement, and peripheral tumours can pull in the liver capsule (capsular retraction).

CT or MRI?

Head to head, MRI picks up more lesions and detects them earlier. Its drawback is practical. Acquisition takes longer, and sick patients may not be able to hold their breath long enough, so image quality can suffer. When the CT does not settle the diagnosis, a contrast-enhanced MRI is the next step, looking for diffusion restriction as well as the same arterial enhancement and venous washout.

When is a liver biopsy needed for HCC?

Rarely. Dr. George estimated that about 95% of the HCC patients he sees are diagnosed on radiology alone, using a phasic or triple-phase scan of the liver. Biopsies are not done often.

Biopsy is reserved for two situations:

• A genuine diagnostic dilemma on imaging.
• Patients being considered for palliation only, because the disease is already metastatic or the patient is too unwell for curative treatment.

Where the diagnosis is certain, even patients heading into downstaging before transplant usually proceed without a biopsy: HCC on a cirrhotic background with portal venous involvement is treated on the imaging diagnosis.

For a small, indeterminate liver lesion that is resectable, Dr. George's advice to referring surgeons is pragmatic. For a tumour of about 3 to 3.5 cm, there is no need to establish the diagnosis first: resect it with a margin and send it for histopathology. With a lesion that small, loss of liver tissue or derangement of liver function should not be an issue, and the specimen provides the answer.

HCC vs cholangiocarcinoma at a glance

• Cell of origin: hepatocytes in HCC; bile duct cells in cholangiocarcinoma.
• Usual background: cirrhosis in most HCC; choledochal cysts, PSC, hepatolithiasis and liver flukes add to the risk of cholangiocarcinoma.
• Tumour marker: AFP and PIVKA-II for HCC; CA19-9 for cholangiocarcinoma.
• CT appearance: arterial enhancement with delayed venous washout in HCC; progressive delayed enhancement in intrahepatic cholangiocarcinoma.
• Presentation: HCC usually arises in a cirrhotic liver under surveillance; perihilar cholangiocarcinoma presents with early jaundice; intrahepatic cholangiocarcinoma presents late, as a mass.
• Treatment pathway: different for each, as below.

How treatment of primary liver cancer is decided

Every patient should be discussed at a multidisciplinary team (MDT) meeting. Dr. George's point is that the team is not planning the treatment of one lesion. It is planning the patient's long-term course, which in HCC means anticipating what the rest of the liver will do over the following years.

For hepatocellular carcinoma, the decision rests on tumour stage and on liver function, using the Barcelona Clinic Liver Cancer (BCLC) framework. Options run from resection and ablation through transarterial chemoembolisation (TACE), radiotherapy and systemic therapy to liver transplant. As a transplant surgeon, Dr. George makes a strong case for upfront transplant in HCC on a cirrhotic liver, set out in full in the article on HCC treatment: resection, ablation or liver transplant.

For cholangiocarcinoma, surgery is the only curative option. The aim is complete removal with negative margins and removal of the draining lymph nodes, and for perihilar tumours the extent of the operation follows the Bismuth-Corlette classification. The detail is in the article on cholangiocarcinoma surgery.

In both cancers, as Dr. George put it, surgery is the only chance of cure in hepatobiliary cancers. For small, early HCC, ablation is also a treatment given with curative intent. Locoregional and systemic treatments, many of them delivered by interventional radiologists, extend who can reach surgery or transplant and control disease that cannot be removed. Dr. Shobhit Singh's separate masterclass covers interventional radiology for liver cancer from the radiologist's side.

Follow-up after treatment for primary liver cancer

Follow-up is about catching the next tumour while it can still be treated with curative intent.

After treatment for HCC. Patients treated by resection, or by an interventional procedure such as microwave ablation, radiofrequency ablation or TACE, keep their own liver, and that background liver still carries a risk of new cancers. They need strict follow-up with more detailed imaging than ultrasound alone. CT can be used, but repeated scans carry radiation exposure and a risk of contrast nephropathy (kidney injury from iodinated contrast), so MRI is used more often. The aim is to find small lesions early, while they can still be resected or treated with a salvage transplant.

After treatment for cholangiocarcinoma. CT or MRI is again preferred to ultrasound, which may not detect a recurrence early enough.

Tumour markers are tracked alongside imaging: AFP and PIVKA-II for HCC, CA19-9 for cholangiocarcinoma.

Further reading from Dr. George's masterclasses

The questions doctors raised during the session, on biopsy, bilirubin thresholds for surgery, follow-up and setting up a transplant centre, are answered in the Live Discussion for this masterclass. Dr. George's separate 2024 masterclass covers indications, donor evaluation and outcomes in his complete guide to liver transplant. Indicative costs are set out for hepatectomy for liver cancer and liver transplant, and related specialists are listed under hepatobiliary and liver transplant surgery.