Liver Tumours Primary and Secondary



A number of benign and malignant tumours may arise in the liver, the most important of which are:

Hepatocellular carcinoma (HCC)

HCC is the fifth most common cancer worldwide, but with great geographical variation in incidence, ranging from around 2 per 100 000 population in western Europe to 100 per 100 000 population in some parts of Africa. Most tumours arise on the background of cirrhosis, commonly due to hepatitis B, hepatitis C, or alcohol.

Symptoms may not be apparent until the cancer is already advanced, patients typically presenting with a triad of pain in the right upper quadrant, hepatomegaly, and weight loss. Decompensation in patients with cirrhosis may be precipitated by tumour and is signified by worsening ascites, variceal bleeding, jaundice, and/or encephalopathy.

The diagnosis of HCC is made primarily on contrast imaging (CT or MRI) where arterial enhancement and portal venous washout are characteristically seen. The tumour marker α-fetoprotein (AFP) is elevated in 80% of cases and is diagnostic when greater than 200 ng/ml in the presence of cirrhosis and a suspicious mass. Biopsy is reserved for indeterminate cases and immunohistochemical staining may help distinguish from adenocarcinoma.

Symptomatic presentation carries a poor prognosis, with less than 10% of patients surviving 3 years. However, ultrasound surveillance programmes of patients at risk (for example, those with cirrhosis or active hepatitis B infection) enable one-third of patients to be diagnosed at an early stage, when curative treatments are possible including (1) surgical resection, (2) ethanol/radiofrequency ablation, or (3) liver transplantation. Transarterial chemoembolization is an established palliative treatment. Cytotoxic drugs are generally not effective though new multikinase inhibitors appear promising.


Cholangiocarcinoma is an epithelial malignancy of the biliary tree that accounts for 7 to 10% of primary liver malignancies. Bile duct cancer is thought to be induced by chronic inflammation within the biliary tree, with risk factors including biliary infection by particular endemic trematodes and flukes, and primary sclerosing cholangitis.

Patients with peripheral intrahepatic masses typically present with upper abdominal pain, anorexia, malaise, and weight loss: jaundice is an early feature of those with hilar or extrahepatic tumours.

It can be difficult to establish the diagnosis of cholangiocarcinoma. Blood concentrations of CA19-9, a glycoprotein secreted by bile duct cells, are often elevated. Depending on tumour location, cross-sectional imaging or magnetic resonance cholangiopancreatography (MRCP) may be suggestive but not diagnostic. Options for obtaining tissue include (1) percutaneous biopsy if peripheral; (2) biliary brushings and/or intraductal biopsy at ERCP; (3) endoscopic ultrasound fine needle aspiration of hilar lesions where the differential includes inflammatory pseudotumour and metastasis.

Surgical resection can offer cure for a few patients, but results are generally disappointing. Useful palliation may be offered by photodynamic therapy, conventional radiotherapy and high-dose local irradiation, and biliary stenting.

Benign liver tumours

Haemangiomas are usually discovered incidentally during abdominal imaging and have a prevalence of 2 to 5% in the general population. Large symptomatic haemangiomas can be managed by surgical enucleation or embolization, but most do not require treatment and patients can be reassured.

Focal nodular hyperplasia (FNH) has a prevalence of 0.4 to 0.8% in the general population. FNH is usually found in women (female:male 9:1) and is typically discovered as an incidental solitary lesion during abdominal imaging. Appearances on MRI may be diagnostic, but biopsy is required if there is uncertainty particularly to differentiate from adenoma. The importance of diagnosing FNH is that it is a truly benign lesion.

Hepatic adenomas are associated with long-term use of the oral contraceptive pill, often incidental, but can present with abdominal pain. Lesions more than 5 cm in size should be considered for resection because of the risk of bleeding and malignant transformation. A conservative approach involves discontinuation of the oral contraceptive pill and surveillance imaging. Adenomas are currently being subclassified according to histopathological features and presence of somatic mutations (HNF1alpha, gp130, beta-catenin) with associated distinct prognosis.

Secondary liver tumours

Secondaries are commonly discovered as part of the staging process for primary malignancy (synchronous) or during follow-up (metachronous), or indeed may be the initial presentation. Symptoms and signs include abdominal pain and hepatomegaly; jaundice and ascites may occur with extensive infiltration. If the primary is not apparent, a targeted liver biopsy under ultrasound guidance usually confirms malignancy, with immunohistochemical assessment helpful in determining type.

For most primary cancers with liver involvement the prognosis is poor and treatment palliative. Surgical resection and other treatments have been shown to improve survival in the setting of colorectal liver metastases, neuroendocrine malignancies, and gastrointestinal stromal tumours (GISTs).


Liver Tumours Primary and Secondary in detail


A number of benign and malignant tumours may arise in the liver, given the proliferative nature of its component tissues which include hepatocytes, biliary epithelium, and vascular endothelium. Benign tumours are relatively common and often incidental; distinction is occasionally challenging and some may harbour malignant potential. Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, almost always arising on a background of liver damage. Early diagnosis and careful patient selection can lead to cure with treatment such as liver transplantation. Furthermore, advances in our understanding of molecular mechanisms involved in hepatocarcinogenesis are yielding novel therapeutic agents for this disease. The prognosis of cholangiocarcinoma remains poor although prospects for earlier diagnosis and curative treatment are improving; intrahepatic cholangiocarcinoma and intermediate hepatocellular-cholangiocarcinoma are increasingly recognized subtypes. Other primary liver malignancies are rare and thus optimal management, including the role of transplantation, is evolving. Secondary liver tumours are common and treatment is palliative save for colorectal metastases, for which surgical resection can achieve cure, and neuroendocrine tumour where liver-directed therapies and transplantation can be of benefit.

Hepatocellular carcinoma (HCC)

HCC is the fifth most common cancer worldwide as well as the third most common cause of cancer-related death. Most tumours arise on the background of cirrhosis and typically grow slowly with late spread to extrahepatic sites. Symptoms may not be apparent until the cancer is already advanced and most deaths occur within one year of diagnosis. Selected at-risk patients benefit from enrolment into surveillance programmes with the prospect of early detection and potentially curative therapy, principally surgical.


The geographical distribution of HCC worldwide is uneven, with more than 80% of cases occurring in sub-Saharan Africa and eastern Asia. Indeed, half of global cases occur in China alone (incidence 35 per 100 000 males). The incidence is much lower in western Europe and North and South America—around 2 per 100 000 population vs up to 100 per 100 000 population in some parts of Africa. Certain Asian populations are now experiencing a decline in incidence, following the introduction of hepatitis B vaccination programmes. In the West, however, the incidence of HCC is rising partly due to a rise in cirrhosis due to hepatitis C and also because the usage and sensitivity of liver radiology has increased. In the United States of America HCC is the fastest-growing cause of cancer-related death in men, with marked ethnic variation and highest rates particularly in Asian Americans.

Men have higher primary liver cancer rates than women, approximately three-fold. As well as greater exposure to hepatitis viruses, alcohol, and cigarettes, the higher levels of androgenic hormones in males may be an important aetiological factor. In most populations the highest rates of HCC occur in those aged 75 and over. In Africa, where hepatitis B is often acquired very young, male rates peak between 60 and 65 years. In all regions female rates peak 5 years later than those for men. For tumours arising in noncirrhotic liver the sex incidence is equal and patients usually present younger. In Asia approximately 40% of HCC arises in noncirrhotic livers, mainly hepatitis B-related; in the West the proportion is closer to 5% but incidence may be increasing.

Aetiology and prevention

HCC usually occurs in the context of chronic liver disease: worldwide, 80% of patients with HCC are cirrhotic and 80% can be attributed to hepatitis B, C, or alcohol. Prevention of HCC on a global scale is therefore linked to ameliorating these factors in particular. HCC is long established as the commonest cause of death in haemochromatosis, and HCC complicating cirrhosis due to nonalcoholic steatohepatitis is increasingly recognized. HCC is seen less commonly in cirrhosis due to α1-antitrypsin deficiency and autoimmune hepatitis. Often several factors may contribute to cirrhosis and subsequent tumour development. In addition, acute intermittent porphyria is a rare hepatic condition prone to complication by HCC.

Hepatitis B virus (HBV) is the most common cause for HCC worldwide, with an estimated 380 million infected individuals harbouring a 100-fold relative risk of developing HCC compared with noncarriers. HCC can arise in chronic HBV infection without cirrhosis—integration of viral DNA into the hepatocyte genome appears to be a prerequisite for oncogenic transformation of these cells. In HBV endemic areas vertical transmission results in high rates of chronic infection, whereas in low-risk areas the virus is acquired horizontally and 90% will clear the acute infection. Risk factors for HCC among HBV carriers include male sex, cirrhosis, older age, family history of HCC, Asian or African ethnicity, and coinfection with hepatitis C or D. Aflatoxin B1, a hepatocarcinogen produced by the Aspergillus fungus and present on stored foods in HBV-endemic areas, has been implicated in susceptibility to HCC via a direct disruption of the TP53 tumour-suppressor gene. Higher circulating viral DNA levels are associated with greater risk of HCC and treatment which suppresses viral load appears to partly protect against HCC development. In Taiwan, following the introduction of routine infant hepatitis B immunization, the incidence of HCC is expected to fall by 80% over the next three decades and with other countries following suit global mortality from HBV-related HCC should reduce.

Hepatitis C virus (HCV) is a leading cause for cirrhosis and HCC development in Western countries and in Japan where HBV is not endemic. HCV-infected individuals have a 17-fold relative risk of developing HCC compared with the general population. Approximately 25% of HCV-infected individuals will develop cirrhosis over a period of 25 years with an annual incidence of HCC thereafter of 1 to 4%. Although most tumours will arise following the lag period to cirrhosis, HCC can occur in noncirrhotic hepatitis C. In the West the peak incidence of HCC in hepatitis C may not have been reached, particularly as many individuals remain undetected. Although no vaccine is currently available, successful antiviral therapy has been shown to reduce cancer risk and continuing advances in treatment together with improvements in prevention and screening are the mainstay for lessening the future burden of HCV-related HCC.

Alcohol is a well-established risk factor for HCC and acts synergistically with hepatitis B and C in causing cirrhosis. Attempts to reduce per capita alcohol consumption may impact favourably on HCC prevalence. Patients with haemochromatosis and cirrhosis have up to a 200-fold relative risk of HCC, which persists despite iron removal. Iron has a direct mitogenic effect through stimulation of hepatocyte proliferation. Early recognition and venesection treatment before the onset of significant fibrosis should reduce deaths from HCC in this condition. Importantly, obesity is associated with a two- to threefold increased risk of HCC, most likely via its association with cirrhosis due to nonalcoholic steatohepatitis. Obesity rates are increasing in the West and this may adversely influence future incidences of HCC. Diabetes mellitus, associated with nonalcoholic fatty liver disease, has been similarly identified as an independent risk factor for HCC. For both obesity and type 2 diabetes a direct effect of hyperinsulinaemia on hepatocyte mitogenesis has been proposed.

Pathogenetic mechanisms

Important strides have been made in understanding the molecular biology of HCC development and progression. Alterations of proteins involved in cell cycle regulation, such as p53 and cyclin/CDK complex, and several intracellular signalling pathways undergoing oncogenic activation (specifically Ras/Raf/Mek/Erk, Wnt/β-catenin and PI3k/Akt/mTOR) appear key. Moreover. the role of several growth factors and angiogenic factors in the tissue microenvironment such as epidermal growth factor (EGF) and vascular EGF has been confirmed. Increasing evidence supports the notion that HCCs are monoclonal tumours with different oncogenic pathways and distinct biological phenotypes.

Cirrhosis is characterized by decreasing hepatocyte proliferation as regenerative capacity becomes exhausted. A hypothesis for HCC development in the context of hepatocyte senescence involves critical telomere shortening which then triggers DNA repair mechanisms and chromosomal instability as the first step. Some tumours may originate from a particular subpopulation of stem cells which persist in the adult liver and are found in portal triads. These ‘oval’ cells retain the potential to proliferate and differentiate into either hepatocytes or biliary epithelial cells; they have been implicated in the development of HCC as well as intermediate hepatocellular-cholangiocarcinoma.

Clinical presentation

HCC may present with a triad of pain in the right upper quadrant, hepatomegaly, and weight loss. In high-incidence areas the presentation is usually shorter, over a period of weeks, whereas in low-incidence areas patients tend to present more insidiously over several months. Diarrhoea is also a common feature. Patients presenting with these symptoms usually have significant-sized tumours which may be palpable; a bruit may be auscultated. Decompensation in cirrhotic individuals may be a sign of tumour and is signified by worsening ascites, variceal bleeding (particularly if the portal vein is directly invaded by tumour), jaundice, encephalopathy, or a combination of these. Occasionally patients present with sudden abdominal pain and swelling associated with haemoperitoneum due to tumour rupture. The latter diagnosis is usually confirmed by imaging and ascitic fluid sampling. Other presentations include secondary Budd–Chiari syndrome, obstructive jaundice, haemobilia, and pyrexia of unknown origin. Paraneoplastic manifestations include polycythaemia, hyperthyroidism, hypercalcaemia, and hypoglycaemia. Asymptomatic tumours are increasingly being detected through surveillance imaging, typically 1 to 2 cm in size.


The diagnosis of HCC may be confirmed following a combination of blood tests, various imaging techniques and histology if necessary.

Serum markers

α-Fetoprotein (AFP) is the only commonly used laboratory test for the diagnosis of HCC. AFP is a glycoprotein synthesized by the fetal liver and its plasma concentrations reach their maximum at the end of the first trimester, declining rapidly after birth to adult levels (0–10 ng/ml). Elevated levels are found in about 80% of patients with HCC and tend to be higher in African and east Asian populations (median 10 000 ng/ml) than in those from low-incidence areas (median 1000 ng/ml). Concentrations of AFP above 500 ng/ml in patients with a liver mass suggest HCC, the differential diagnosis including nonseminomatous germ cell tumours, hepatoblastoma (in infants), and hepatic metastases usually from pancreas or stomach. In patients with cirrhosis and a suspicious liver mass on imaging, an AFP level above 200 ng/ml can be considered diagnostic. Serum AFP increases with tumour growth, and serial measurements showing a steady rise are strongly indicative of HCC. Note that 50% of noncirrhotic patients with HCC have a normal AFP level. A modestly raised and fluctuating AFP level is common in patients with chronic HCV infection.

Liver imaging

Ultrasound is relatively inexpensive, safe, and can detect an HCC as small as 1 cm in size. Such tumours typically appear hypoechoic. Further imaging is usually required for confirmation of diagnosis, although ultrasound remains a useful screening modality. Sensitivity depends on operator experience, however, and tumours within an irregular and heterogeneous liver may be easily missed. Use of microbubble contrast enhancement improves sensitivity. Visibility on ultrasound may inform subsequent attempts at biopsy or ablation, and use of Doppler can confirm forward portal vein flow prior to hepatic arterial embolization.

Multislice CT is an established imaging modality for diagnosis and staging of HCC, as well as for planning surgical resection. Use of intravenous contrast allows more detailed characterization: a combination of arterial enhancement and portal venous ‘washout’ is virtually diagnostic for HCC in lesions over 2 cm with known cirrhosis. Smaller lesions and those with a less typical vascular profile require additional dynamic imaging which may improve diagnostic certainty. Sensitivity of CT remains imperfect with 30% of tumours under 2 cm undetected when compared with subsequent explant histology. CT may be helpful in demonstrating hepatic features consistent with cirrhosis and the presence of portal hypertension. Portal venous invasion and extrahepatic disease, both signifying poor prognosis, can be evaluated using this technique.

The sensitivity and specificity of MRI for detection of HCC is similar to that of CT, but without the radiation exposure. For 1 to 2 cm tumours MRI is slightly more sensitive than CT and can be used for follow-up of indeterminate lesions particularly where the background liver is difficult to assess by ultrasound. For such lesions a low signal on T2-weighted imaging and lack of arterial enhancement are example features which would suggest a regenerative nodule rather than HCC. Excellent visualization of the hepatic arterial supply can be obtained by selective catheterization at angiography; as the vascular supply for HCC is predominantly arterial, a diagnostic ‘tumour blush’ is seen in a high proportion of cases. An absent blush or indeterminate appearance may point towards an alternative explanation such as dysplastic or regenerative nodule or a region of fibrosis.

If uncertainty remains, the clinician must weigh up the pros and cons of obtaining liver tissue to establish a firm diagnosis. Where biopsy is not possible or is nondiagnostic, close surveillance with dynamic imaging to look for temporal changes in characteristics, number and size of lesions is the preferred option.

Liver biopsy

Histology is the gold standard for diagnosis, although interpretation of core biopsies may be challenging, e.g. distinguishing well-differentiated HCC from severe dysplasia. On microscopic examination, HCC is typically composed of large eosinophilic or clear cells, arranged in trabeculae; intercellular bile is diagnostic when present. Immunohistochemical markers for hepatocytes, such as HepPar-1 and AFP, may help where morphology is not characteristic. Biopsy of the background liver to confirm cirrhosis greatly increases the probability of a focal lesion being HCC where this is uncertain.

Percutaneous biopsy carries a small risk (<2%) of tumour seeding along the tract and historically has been avoided prior to potentially curative surgical treatment. Coagulopathy and ascites are additional hazards. For inaccessible lesions of sufficient concern, and where imaging is not diagnostic, laparoscopic biopsy or wedge resection is an alternative. Furthermore histological examination and staging of surgical specimens are important for prognosis in HCC—poor differentiation and vascular invasion are strongly associated with tumour recurrence following resection or transplantation. Determining prognosis based on needle-derived specimens is more challenging due to variation of differentiation and vessel involvement across the tumour. However, identification of prognostically accurate biological markers may change practice in favour of always obtaining tissue prior to radical therapies.


Ultrasound surveillance has been shown to be cost-effective in cirrhosis where the annual risk of HCC exceeds 1.5%. Fulfilling this criterion includes cirrhosis due to HBV, HCV, alcohol, and haemochromatosis as well as stage 4 primary biliary cirrhosis. Incidence data for HCC in cirrhosis due to nonalcoholic steatohepatitis, autoimmune hepatitis, and α1-antitrypsin deficiency are less robust. At-risk HBV carriers who should be surveyed include Asians (men >40 years, women >50 years), Africans from adulthood, and older white men with active disease. With HCV infection the risk rises following the onset of severe fibrosis and noninvasive fibrosis markers appear promising for determining this time-point. Ultrasound has 65 to 80% sensitivity and greater than 90% specificity for HCC when used as a surveillance tool and the standard 6-month interval is based on average tumour doubling times. AFP alone is inadequate as a screening test, as it lacks sensitivity, though is typically used in addition to ultrasound. Proteomic profiling may in future yield useful serum biomarkers for detection of HCC.


Several treatment options may be available but selecting the one with the highest benefit/risk ratio is key. Importantly, survival may be limited by liver disease as well as by tumour. Transplantation, resection, and ablation are potentially curative and surgery in particular should be considered if at all eligible. Chemoembolization is an established palliative treatment with associated survival benefit. Cytotoxic drugs are generally nonefficacious but novel agents against specific molecular targets are showing promise.

Surgical resection

Nowadays operative mortality is low, following careful patient selection, and laparoscopic approaches may be feasible. The best candidates are noncirrhotic with a single tumour or cirrhotic but with well-preserved liver function, i.e. Child–Pugh A. Survival in those with normal bilirubin and absence of portal hypertension (hepatic venous pressure gradient <10 mmHg) reaches 70% at 5 years. However, this falls to 50% in the presence of portal hypertension and 30% if the bilirubin is also raised. In cirrhosis, therefore, transplantation would usually be the preferred option if feasible. Apart from liver decompensation, the principal problem with resection is tumour recurrence, which reaches 70% at 5 years. Early recurrence is usually due to previous dissemination whereas later recurrence is a result of de novo tumour development. Recurrence is associated with microvascular invasion and presence of satellite nodules, rather than size of lesion per se, although larger lesions are more likely to have adverse features. Surgery for recurrence can only be justified if thought to be a de novo tumour. Surgical resection for spontaneously ruptured tumours appears to offer satisfactory outcomes despite the expectation of intraperitoneal seeding at time of rupture.

Liver transplantation

This confers significant long-term survival benefit for patients with cirrhosis curing both the tumour and the liver disease, but not without risk. Donor shortages have restricted selection to those with predicted survival comparable to non-HCC indications. When adhering to the Milan criteria (single tumour ≤5 cm or up to 3 tumours ≤3 cm) a 70% 5-year survival and 10% recurrence rate are anticipated. Long waiting times result in dropout due to tumour growth, approximately 25% after 12 months. Patients awaiting transplantation therefore commonly receive embolization or ablative therapy with a view to staying within criteria—the benefit of this on an intention-to-treat basis is unproven, however. Compared with non-HCC patients, those with HCC have a typically lower severity of liver disease so should be afforded greater priority on the list and may tolerate a marginal donor liver with less chance of early graft dysfunction.

Expansion of the Milan criteria is currently being debated, the risk being that of listing a greater number of patients who would be subject to dropout or recurrence post-transplant. Better methods to predict tumour behaviour, independently of size, are required. With recurrent HCC, 50% is extrahepatic; treatment options have to be individualized, and surgery or indeed radiotherapy may be useful for isolated secondary deposits. Recent observations suggest that post-transplant immunosuppression using the mTOR inhibitor sirolimus reduces risk of tumour recurrence—a strategy perhaps for those with adverse prognostic features on explant histology.

Ablative therapies

Local ablation involves destruction of tumour cells by chemical substances (alcohol or acetic acid) or temperature (radiofrequency, microwave, laser, high-intensity focused ultrasound, or cryoablation) with the aim of creating a 1 cm ‘ablation ring’ around the tumour. Ablation is potentially curative but usually reserved for those where surgery is contraindicated. The procedure is most commonly performed using ultrasound guidance and carries a small risk (c.1%) of needle-track seeding. Follow-up arterial-phase imaging is required to ensure the tumour has been adequately treated and to identify local recurrence due to incomplete therapy.

Percutaneous ethanol injection is well tolerated, inexpensive, and highly efficacious for solitary tumours under 3 cm. Survival figures are similar to those for surgical resection in this group. For larger tumours mortality and recurrence rates increase exponentially with size. Radiofrequency ablation (RFA) has comparable efficacy to ethanol for small tumours, with 75% survival at 3 years. Furthermore, fewer treatments are required and RFA can be used intraoperatively. RFA is superior to ethanol for larger tumours although beyond 5 cm local recurrence is common. This technique works less well if the tumour is adjacent to a major blood vessel, as the latter removes heat. Subcapsular tumours are more likely to result in pain and risk of neoplastic seeding. Morbidity is generally higher than with ethanol but RFA has become the established method in most centres. Data on the remaining thermal techniques is limited although these are showing promise as adjuncts to embolization therapy for prolonging survival in a palliative setting.

Transarterial chemoembolization (TACE)

This has been the most widely used primary treatment for unresectable HCC. TACE involves injection of chemotherapeutic agent (typically doxorubicin or cisplatin) into hepatic arterial branches supplying the tumour, followed by embolic occlusion. Infarction and necrosis ensue, since tumours derive 95% of their blood supply from the hepatic artery. To avoid infarction of neighbouring liver tissue, adequate portal vein flow is required. Up to 60% of patients respond and tumour progression is delayed with a 20 to 60% improvement in 2-year survival. A postembolization syndrome of abdominal pain and fever is common, indicating tumour necrosis. Complications include liver failure and abscess formation, hence prophylactic antibiotics are advised. The best candidates have preserved liver function and no vessel involvement or extrahepatic spread. Although transarterial embolization (TAE) achieves similar objective responses, only TACE has shown survival benefit on recent meta-analysis. New embolic agents incorporating a radio-isotope or gene vector are under study.


HCC is a highly chemoresistant cancer with little benefit from systemic therapy. Responses to cytotoxic drugs, typically doxorubicin, are limited and hampered by side effects. Tamoxifen, octreotide, pravastatin, and gemcitabine have not shown any impact on survival. Agents targeting molecular abnormalities have shown promise and are being studied in patients with advanced HCC. Sorafenib is a multikinase inhibitor against Ras kinase, involved in proliferative signalling, and VEGF receptors which stimulate angiogenesis. In a recent randomized placebo-controlled trial in patients with advanced HCC and Child–Pugh A cirrhosis this agent demonstrated a significant survival advantage (median 10.7 vs 7.9 months). Targeted drug therapies may become useful in preventing progression while awaiting liver transplantation and as adjuvant treatment after resection or transplantation, particularly where there is histological evidence of aggressive tumour biology.


Symptomatic presentation carries a poor prognosis with less than 10% of patients surviving 3 years. Surveillance programmes, however, enable one-third of patients to be diagnosed at the early stages when curative treatments are possible. Accurate prognostic modelling requires not only tumour stage but other tightly-related aspects such as liver reserve and general condition. Several staging systems have been proposed though none is universally accepted. The Barcelona Clinic Liver Cancer system usefully links tumour stage and Child–Pugh status with treatment strategy to optimize prognosis. Molecular profiling of tumours will be incorporated undoubtedly into staging systems of the future.

Fibrolamellar HCC

This rare variant presents in younger individuals with median age of presentation around 20 years. Risk factors are not apparent, cirrhosis is typically absent and AFP levels normal. The tumour is generally slow growing, although regional lymph node metastases are common. Histology reveals dense fibrotic bands surrounding eosinophilic tumour cells. The prognosis is better than for HCC although recurrence is common following surgical resection.


This primary hepatic malignancy occurs in children, mostly under 3 years of age. The optimal treatment approach of resection combined with chemotherapy may achieve a 5-year survival of 80%. Transplantation has proved to be an effective rescue therapy.


This is an epithelial malignancy of the biliary tree which on anatomical grounds can be separated into intrahepatic or extrahepatic, the latter divided into hilar and lower duct tumours. Cholangiocarcinoma is less common than HCC and comprises around 7 to 10% of primary liver malignancies. Prognosis is generally poor unless detected very early or a more favourable subtype.

Epidemiology and aetiology

Cholangiocarcinoma occurs most commonly in the sixth and seventh decades, is 50% more common in men and twice as common in Asians. Furthermore the incidence of intrahepatic cholangiocarcinoma worldwide appears to be increasing. The highest incidence is in northern Thailand, due to endemic biliary infection by the trematode Opisthorchis viverrini. High incidence is also seen in Korea where similar infection by the fluke Clonorchis sinensis is prevalent. Other risk factors for the intrahepatic variant include oriental fibrocholestatic hepatitis, primary sclerosing cholangitis (PSC), EBV, HCV infection, and exposure to thorotrast. The developmental abnormalities Caroli’s disease, congenital hepatic fibrosis, and von Meyenburg complexes are also associated with intrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinoma is associated with PSC, abnormal choledochopancreatic junction, choledochal cysts, and infection by Clonorchis sinensis and Opisthorchis viverrini.


Most of the aetiological factors associated with cholangiocarcinoma induce chronic inflammation within the biliary tree. Chronic inflammation stimulates inducible nitric oxide and free radical production in bile duct epithelial cells. These processes in turn induce oxidative DNA damage and telomere shortening with resultant loss or gain of critical genes involved in cellular control. Methylation of tumour suppressor promoters and cholangiocyte resistance to apoptosis are thought to be relevant mechanisms in oncogenesis.


Cholangiocarcinoma is an adenocarcinoma with a prominent stromal reaction. Histological variants include adenosquamous, signet cell, sarcomatous, clear cell, and lymphoepithelial. Three contrasting growth patterns have been applied to both intrahepatic and extrahepatic cholangiocarcinoma: mass-forming, periductal-infiltrating, and intraductal-growing.

  • Mass-forming is the commonest mode of presentation of intrahepatic cholangiocarcinoma and these tumours are often large, up to 15 cm in diameter. The margin is typically well circumscribed and lobulated and central necrosis may be present. Multicentricity is common, probably because of the propensity of the tumour to invade the adjacent peripheral branches of the portal vein. Mass-forming tumours arising from the extrahepatic ducts tend to be smaller, typically less than 2 cm.
  • Periductal-infiltrating cholangiocarcinoma is most common at the hilum, growing along the bile ducts and therefore elongated, spiculated, or branchlike. These tumours tend to be difficult to detect radiologically.
  • Most intraductal-growing cholangiocarcinomas are papillary adenocarcinomas comprising innumerable frond like infoldings of proliferated columnar epithelial cells with slender fibrovascular cores. The tumours are usually small, sessile, or polypoid, often spreading superficially along the mucosal surface and resulting in multiple tumours (papillomatosis) along various regions of the biliary tree. Occasionally a large mass occludes the bile duct and some tumours produce profuse amounts of mucin akin to pancreatic intraductal papillary mucinous tumours.

Signs and symptoms

With peripheral intrahepatic masses, patients present with upper abdominal pain, anorexia, malaise, and weight loss. Jaundice is an early feature of hilar tumours. Hepatomegaly is usual and splenomegaly may occur in the context of a secondary biliary cirrhosis due to prolonged obstruction.


Liver function tests are typically cholestatic with elevation of plasma bilirubin and alkaline phosphatase concentrations. AFP concentrations are usually normal or only slightly raised. CA19-9, a glycoprotein secreted by bile duct cells, is a commonly used tumour marker. In patients with PSC a CA19-9 level over 100 U/mL is 80% specific for the presence of complicating cholangiocarcinoma.

Mass-forming intrahepatic cholangiocarcinomas may show persistent peripheral enhancement on contrast-enhanced CT imaging. For extrahepatic hilar tumours MR cholangiopancreatography (MRCP) demonstrates first- and second-order duct involvement and a mass may be evident which is hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging. Differential diagnosis of hilar lesions includes inflammatory pseudotumour and metastasis. A periductal-infiltrating tumour appears on MRCP as a concentric irregular thickening of the bile duct with an abrupt transition. An intraductal-growing neoplasm may be visualized as an enhancing mass confined to the lumen of the bile duct. In all three types, the ducts peripheral to the tumour may appear dilated with associated atrophy of the liver.

Percutaneous transhepatic cholangiography (PTC) may be used if the proximal involvement of the biliary tree cannot be determined adequately by MRCP and to drain segments prior to surgery. Endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology and biopsy or with newer choledochoscopy may assist in the diagnosis of a malignant biliary stricture. Analysis on cytological specimens of aneuploidy by digital image analysis or of chromosomal alterations using fluorescence in situ hybridization improves diagnostic accuracy but is not routinely available. Endoscopic ultrasound-guided fine-needle aspiration of hilar masses can achieve a sensitivity and specificity for malignancy of 89% and 100%, respectively, in expert hands. This technique can also be used to identify neighbouring malignant lymph nodes. Positron emission tomography (PET) imaging may be a useful adjunct for diagnosis and laparoscopy can detect occult peritoneal spread.

Treatment and prognosis

For peripheral tumours the main treatment approach is resection with prospect of cure, although results are generally disappointing. Poor prognostic factors include a preoperative CA19-9 more than 1000 U/mL, multifocal disease, liver capsule invasion, R1 resection, regional lymph node metastases, and mass-forming or periductal infiltrating type.

Extrahepatic tumors of the distal duct may be treated by pancreaticoduodenectomy (Whipple’s operation). Hilar tumours may be suitable for curative resection with extended hemihepatectomy and anastomosis of a Roux loop of jejunum to a hilar bile duct. Contraindications to surgery include bilateral involvement of the second-order radicles and portal vein or hepatic artery encasement contralateral to the side being resected. Despite surgical advances, the median 5-year survival for hilar tumours following resection is around 20% and controlled trials of adjuvant chemotherapy are needed. More commonly curative excision is not possible, and the aim is to establish biliary drainage. A stent can be placed through the growth endoscopically or via a percutaneous transhepatic route. Unilateral self-expanding metal stent placement has been shown to be as efficacious as bilateral and cost-effective compared with plastic if survival more than 6 months is expected. MRCP may assist in optimum stent positioning and method. A recent palliative advance is photodynamic therapy which has been shown to prolong survival. Conventional radiotherapy and high-dose local irradiation within the biliary tree, by means of iridium-192 wire, may produce useful symptomatic relief. If biliary drainage can be achieved by these procedures, survival for 1 to 2 years is not unusual.

Within the UK, liver transplantation is not an accepted treatment option for cholangiocarcinoma as historical data indicates an unacceptably high level of recurrence and mortality. However, long-term survival has been achieved in highly selected cases with unresectable hilar cholangiocarcinoma. A regimen involving high-dose neoadjuvant radiotherapy (external and internal) with chemosensitization and operative staging, to exclude patients with regional lymph node metastases, has recently been associated with a 5-year post-transplant survival of greater than 80%. In one-quarter of explants no tumour was identified and—of note—pretransplant histological confirmation of the diagnosis was not a prerequisite. Furthermore, a high rate of arterial and venous complications in the post-operative period has been reported. These results are nonetheless impressive and await validation in other centres before transplantation can be universally accepted as a treatment for cholangiocarcinoma.

Malignant vascular tumours


Angiosarcoma of the liver is a rare and aggressive primary tumour, often multifocal, which may arise in a cirrhotic liver. Worldwide, 200 new cases are reported annually. Peak incidence is in the sixth and seventh decades of life and men are three times more commonly affected than women. In 75% of cases there is no recognized cause. Previous research has outlined the associations with specific carcinogens such as arsenic, vinyl chloride, and thorotrast. Thorotrast (thorium dioxide) was used as a radiological contrast dye during angiographic procedures between the 1930s and 1950s. More recently the tumour has been found in workers in the vinyl chloride industry and, though strict safety regulations have been introduced, new cases continue to present due to the long latent period. Long-term androgen use, haemochromatosis, and von Recklinghausen’s disease are known associations. The genetics associated with angiosarcoma vary according to the aetiological agent. For vinyl chloride-associated tumours, TP53 mutations with A:T→T:A transversions have been identified, generally uncommon in other carcinomas. K-ras-2 mutations have been associated with thorotrast-related and sporadic angiosarcoma.

Patients may present with an hepatic venous outflow syndrome of abdominal pain and ascites, mimicking primary Budd–Chiari syndrome; 15% present with an acute intrabdominal crisis due to tumour rupture and 15% present with splenomegaly and pancytopenia. A small number present with distant metastases, especially to lung, spleen, and bone marrow. An hepatic bruit and signs of high-output cardiac failure may be present, and ascites may be bloodstained due to spontaneous haemoperitoneum. Disseminated intravascular coagulation may be associated (Kasabach–Merritt syndrome). On CT and MRI these tumours demonstrate a variety of appearances although the majority have focal hypodense areas, often haemorrhagic, which demonstrate arterial enhancement with intravenous contrast. A typical reticular pattern due to thorotrast accumulation may be evident on CT and vascular lakes may be observed on angiography. Diffuse infiltration may give rise to a nonspecific heterogeneous appearance of the liver.

Liver biopsy is diagnostic in 25% of percutaneous and 65% of open procedures, the latter preferred because of bleeding risk. Histology shows typical spindle or pleomorphic tumour cells with eosinophilic cytoplasm growing along the lumina of previous vascular structures. The growth and blockage of sinusoids is associated with sinusoidal congestion and liver cell atrophy. As these cells are derived from vascular structures they stain positive with antibody markers to CD34. If thorotrast or vinyl chlorides are the cause there may be considerable periportal and subcapsular fibrosis. Four growth patterns are typically recognized: nodular, large dominant nodule, mixed features, and a rarer diffusely infiltrating type. Curative resection is rarely possible and chemotherapy may increase survival for what is an otherwise poor prognosis.

Hepatic epithelioid haemangioendothelioma

This rare malignant tumour of vascular endothelial origin runs a clinical course akin to a low-grade angiosarcoma. It is usually multifocal and slow growing, with a slight female preponderance. Patients present typically around 40 to 45 years with right upper quadrant pain. Histological appearances are fairly characteristic, with a spindle lesion infiltrating hepatocyte plates and hepatic veins. Immunohistochemistry for vascular markers, such as CD34, can aid diagnosis. Resection is associated with a 5-year survival of 75% but this approach is usually not feasible and aggressive recurrence has been reported. Transplantation is an acceptable therapy even with limited extrahepatic disease—again unpredictable and rapid recurrence can occur. The role of chemotherapy is unclear.

Benign liver tumours


This is the most common benign tumour of the liver with a prevalence of 2 to 5% in the general population and a reported female preponderance. Although thought to be congenital, growth can occur, and in 50% of cases more than one lesion is present. Histology reveals multiple large blood-filled spaces, lined by endothelial cells, with varying degrees of hyalinization and fibrosis. The term ‘cavernous’ haemangioma is used for larger lesions over 4 cm. These are fed by hepatic artery branches and have a slow internal circulation.

Haemangiomas are usually discovered incidentally during abdominal imaging. Larger tumours can cause abdominal symptoms from mass affect and have been reported to cause portal hypertension, haemobilia, caval thrombosis, and a consumptive coagulopathy (Kasabach–Merritt syndrome). Spontaneous and traumatic rupture have also been reported. The typical appearance on ultrasound is a well-circumscribed and uniform hyperechoic mass. MRI is a more sensitive and specific modality demonstrating a lesion which is hypointense on T1-weighted imaging and hyperintense on T2-weighted views. Dynamic imaging characteristically shows nodular peripheral enhancement with progressive centripetal ‘fill-in’ and retention of contrast in the portal phase. Occasionally biopsy is required to confirm diagnosis in larger lesions where typical features are not present. Usually no treatment is required and patients can be given reassurance. Large symptomatic haemangiomas can be managed by surgical enucleation or embolization. Liver transplantation has rarely been performed when unresectable and causing intractable symptoms.

Focal nodular hyperplasia (FNH)

FNH is the second most common benign tumour of the liver, with a prevalence of 0.4 to 0.8% in the general population. It is nine times more prevalent in women than men and usually presents in the third or fourth decade. Typically a solitary lesion is present which may be over 5 cm in size. The oral contraceptive pill is not thought to induce FNH formation, but studies have suggested that oestrogens can promote FNH growth and vascularity.

Histology typically shows a central large fibrous septum containing a branch of hepatic artery which divides in a star-shaped manner and is not accompanied by either portal vein or bile duct. Within this central ‘stellate scar’ there is bile ductular proliferation and surrounding it is polyclonal nodular hyperplasia of the hepatic parenchyma giving a pseudobiliary cirrhotic pattern. The hyperplastic response of the hepatic parenchyma may be driven by angiopoietins released from the hepatic artery branch, or in response to a hyperperfusion injury. The less common, recently recognized ‘telangiectatic’ variant is thought to be better classified as an adenoma (see below).

FNH is usually detected on ultrasonography but requires further characterization. On MRI the lesion demonstrates homogenous signal intensity with the central scar appearing hypointense on T1-weighted imaging and usually hyperintense on T2-weighted imaging. With administration of contrast, dense enhancement occurs and the lesion then becomes isointense in the portal phase. With delayed imaging the central scar may become hyperintense. It is noteworthy that in 80% of lesions under 3 cm in size, a central scar may not be visible. If the imaging techniques are nondiagnostic, targeted biopsy usually confirms the diagnosis. The prognosis is excellent and malignant change has not been recorded. For women on the oral contraceptive pill where FNH appears likely, but biopsy is not straightforward, a surveillance approach with cessation of oestrogen use may provide reassurance.

Hepatic adenoma

Hepatic adenoma is 10 times less common than FNH and rare in men, with a female to male ratio of 4:1. The incidence of adenomas among long-term users of the oral contraceptive pill is approximately 4 per 100 000 and increases with length of contraceptive use. In women who do not use oral contraceptives, or have used them for less than 2 years, the incidence is 1 per million. In addition, the incidence of adenoma is increased in patients with type 1 glycogen storage disease, diabetes mellitus, haemochromatosis, acromegaly, and in men using anabolic steroids. The presence of more than 10 adenomas defines hepatic adenomatosis. Adenomas may increase in size in pregnancy and shrink with suspension of oestrogen use. Abdominal pain is relatively common and, rarely, spontaneous rupture and bleeding can occur.

On microscopic examination, adenomas consist of trabeculae of mature-appearing hepatocytes with absent portal tracts and Kupffer cells, though arterial branches are present. Recently genetic mutations have been identified which correlate with distinct biological phenotypes. Biallelic HNF1A mutations define adenomas with marked steatosis, a lack of both cytological abnormalities and inflammatory infiltrates, and a very low risk of malignant transformation. Mutations resulting in β-catenin (CTNNB1) activation are present in 15% of cases and are associated with a high risk of transformation into hepatocellular carcinoma. A third group of adenomas has been defined by the absence of known mutations but presence of inflammatory infiltrates and features such as sinusoidal dilatation, ductular reaction and cytological abnormalities. These ‘telangiectatic’ adenomas, originally called telangiectatic FNH, are thought to have a higher risk of bleeding and may harbour malignant potential. Mutations in the IL6ST gene encoding gp130, activating the interleukin-6 pathway, have been associated with the majority of these inflammatory lesions. A fourth group comprises adenomas without known mutations or inflammatory infiltrates.

CT imaging of adenomas may demonstrate an area of haemorrhage and occasionally internal fat or calcification. After intravenous contrast homogeneous enhancement in the hepatic arterial phase is characteristic with lesions becoming isoattenuating in the portal venous phase. With MRI adenomas are hyperintense or isointense lesion on T1-weighted imaging and often slightly hyperintense to liver tissue on T2-weighted imaging. It is suggested that lesions over 5 cm should be considered for resection because of risk of bleeding and malignant transformation. A conservative approach involves discontinuation of the oral contraceptive pill and surveillance imaging with AFP monitoring. Predicting subsequent behaviour is key and inhibitors of β-catenin are being sought for targeted therapy.


Lymphangiomas are made up of dilated lymphatic channels that compress the normal liver parenchyma. Often these occur as part of a multisystem disease affecting bone, brain, soft tissues, and lung. Typically with MRI multiple cystic areas in the liver are seen that do not enhance with contrast.


While common in the adrenals and kidneys, these lesions can be found in the liver and are associated in 6 to 10% of cases with tuberous sclerosis.

Mesenchymal hamartoma

This lesion is more common in males and usually manifests within the first 2 years of life. Patients usually present with progressive abdominal swelling. Structurally the tumour is composed of mixed endodermal and mesodermal components in a connective tissue stroma. Surgical resection is the treatment of choice.

Biliary cystadenoma

This cystic lesion usually occurs in middle-aged women. Papillary infoldings are a characteristic finding on ultrasound or CT. Malignant potential is recognized and distinguishing from cystadenocarcinoma on radiology alone is difficult. Cystic aspiration for diagnosis is unhelpful and complete excision is required to avoid recurrence.

Secondary liver tumours

The liver is a common site for metastases which thrive on a rich blood supply and favourable milieu for tumour growth. Secondaries are commonly discovered as part of the staging process for primary malignancy (synchronous) or during follow-up (metachronous) or indeed may be the initial presentation. Liver function tests may be normal but the alkaline phosphatase level usually rises as the tumour mass enlarges. Symptoms include abdominal pain and, with extensive infiltration, jaundice and ascites may occur. If a primary tumour is not apparent a targeted liver biopsy under ultrasound usually confirms malignancy and an immunohistochemical panel for antigens may point to the origin.

For most primary cancers with liver involvement the prognosis is poor and treatment palliative. However, there are notable exceptions such as colorectal and neuroendocrine. A quarter of patients with colorectal cancer have liver metastases at presentation with a median survival untreated of between 6 and 9 months. Hepatic resection in appropriate candidates, where the primary has been removed, can achieve a 30 to 40% 5-year survival with cure in some patients. The liver remnant must be adequate and disease should be preferably unilobar. The role of adjuvant chemotherapy is unclear, as is whether there is any benefit in synchronous resection of primary and secondary disease. Portal vein embolization of the tumour-affected lobe has become a standard method for increasing the size of the liver remnant to reduce the risk of decompensation. Innovative approaches include down-staging tumour using systemic chemotherapy to within criteria for resection, hepatic arterial infusion of chemotherapy, targeted therapies against EGF receptors, and combining RFA with surgery to preserve liver volume. None of these modalities has been subject to randomized study.

Neuroendocrine tumours typically grow slowly and are therefore amenable to therapy even when multifocal within the liver. Directed therapies such as surgical debulking, embolization, TACE, and ablation have been shown to improve symptoms and slow progression although survival benefit is unproven. Sirolimus, somatostatin analogues, and targeted agents against VEGF activity also appear efficacious. For carcinoid tumour, where the primary has been removed and there is no evidence of extrahepatic disease, survival after liver transplantation approaches 70% at 5 years with recurrence-free survival nearer 50%. Gastrointestinal stromal tumours (GISTs) are also slow-growing and metastasize to the liver—good control can be achieved using a combination of surgical resection and tyrosine kinase inhibitors.