Introduction

Liver masses are very common and there are over twenty different causes. This article will concentrate on the most common forms: for a full review, including rare lesions, see Assy's review (World J Gastro, 2009). The differential diagnosis can be divided into two categories: those masses which are more likely to affect a cirrhotic liver and those that usually arise in an otherwise healthy liver. The remainder of these notes will be organised in this format.

 

In addition to tumours, cysts are a very common cause of liver masses seen on imaging. The most common malignant tumours found in the liver are metastases, which can affect normal and cirrhotic livers, and will be discussed at the end of these notes.

 

Generally, normal livers are affected by benign tumours (e.g. haemangioma, adenoma, FNH) whereas cirrhotic livers grow malignancies (e.g. HCC or cholangiocarcinoma). In a cirrhotic liver there is an increased turn-over of hepatocytes and usually some degree of inflammation, which increases the chance of mutations developing. It is possible for any lesions to be found in either disease state however the probability is much lower. For example, hepatic adenomas can occur in cirrhotic livers but only very rarely, contrary to non-cirrhotic livers where they are relatively common. Conversely, hepatocellular carcinomas may occur in previously normal livers but it is very rare. Liver masses in otherwise healthy people are often found incidentally; for example when having an ultrasound scan (USS) for a different reason. Patients with cirrhosis will be under regular follow-up with USS to screen for development of malignant masses.

 

These notes have been divided into three sections: benign tumours affecting non-cirrhotic livers; malignant tumours affecting cirrhotic livers; and metastases. There is overlap between the groups and this is discussed in the body of the text. 

Classification by state of liver

The differential diagnosis of a liver mass classified by whether it is more likely to be found in a

Haemangioma

A very common benign tumour of mesenchymal origin comprised of blood-filled sinusoids and connective tissue (see image “Histology of cavernous haemangioma” below) Reported to be found in up to 20% of the population and are more common in women. Typical age at diagnosis is 30-50 years.

 

The majority are found incidentally however they can present with pain or mass effects if large (>4cm). The best imaging modality is technetium-99m labelled red blood cell scintigraphy, however it is not always available. Haemangiomas can normally be diagnosed using a combination of ultrasound scan (USS) and contrast-enhanced computerised tomography (CT).

 

Complications are rare and the risk of rupture is small therefore resection is not justified. However if they are large and increasing in size rapidly, or there is uncertainty over the diagnosis they may be resected (misdiagnosis of malignancy as haemangiomas is reported).

 

Histology of cavernous haemangioma

Pathology of a haemangioma

Hepatic adenoma (HA)

A relatively common benign tumour of hepatocytes that almost always occurs in non-cirrhotic livers. They typically grow to 5-10cm. Histologically they appear as sheets of normal hepatocytes but without any portal tracts or central veins (see image “Histology of hepatic adenoma”).

 

Associations:

  • Oral contraceptive pill (OCP) – therefore HA is much morecommon in women
  • Anabolic steroid use (can induce multiple adenomas, known as “adenomatosis”)
  • Diabetes mellitus
  • Glycogen storage diseases type I and III

 

Unlike most other benign masses in the liver, incidental detection is uncommon. Patients tend to present with a mass or pain, which may be due to liver capsule stretch or rupture. The presence of symptoms, history of OCP use and imaging with USS and contrast-enhanced CT normally can give the diagnosis without need for a liver biopsy. HA are highly vascular tumours and 10-33% spontaneously rupture. 5% of HA are reported to transform in to hepatocellular carcinoma (HCC). For these reasons resection is recommended.

Histology of hepatic adenoma

Pathology of a hepatic adenoma

Focal nodular hyperplasia (FNH)

A common hyperplastic tumour-like malformation. It is most frequently found in women (4 times compared to in men) and at 20-50 years of age. Aetiology is unknown but is thought to be linked to a previous vascular malformation. On biopsy, there are proliferating hepatocytes in an area around a central scar, which contains a central artery.

 

The majority are asymptomatic and found incidentally; only 15% experience abdominal pain. Many can be diagnosed on contrast enhanced CT, the typical appearance of FNH is a mass <5cm in diameter with a central hypodense scar. If diagnosis is uncertain then a percutaneous biopsy can be performed. The complication rate is low and resection is not suggested unless there is doubt over the diagnosis.

 

Nodular regenerative hyperplasia (NRH)

A hyperplastic tumour-like malformation of hepatocytes that resembles cirrhosis except fibrosis is absent. It is associated with portal vein thrombosis; it is thought that reduction in blood supply causes hepatocyte atrophy and a reactive hyperplasia that is manifest as NRH. It is also associated with several systemic conditions, for example:

  • Rheumatoid arthritis
  • Polyarteritis nodosa
  • Behcet’s disease
  • Several drugs

 

There are nodules of replicating hepatocytes without fibrous septae that compress adjacent cells. Due to this, NRH can cause portal hypertension and in the West it is the most common cause of raised portal pressure in the absence of cirrhosis. It can normally be diagnosed using vascular studies and excluding portal vein thrombosis as the cause for portal hypertensison. Only rarely is a liver biopsy required. It is treated using standard guidelines for portal hypertension.

 

Localised steatosis

The accumulation of fat within the liver (‘fatty liver’) is very common and in 10% of patients there is a focal accumulation, which can appear as a mass. Fat accumulates as macrovesicular steatosis within hepatocytes (see image "Hepatic steatosis"). It is thought to arise due to aberrant venous drainage from the pancreas that causes an area of hyperinsulinaemia, which drives the steatosis. Most common aetiological factors associated are:

  • Diabetes mellitus
  • Hyperlipidaemia (and the metabolic syndrome)
  • Alcohol consumption
  • Steroid use

 

It can be diagnosed with a combination of imaging modalities: hyperechoic on USS, hypodense on CT and increased signal on T1-weighted MRI (the gold-standard). Given that more serious lesions are excluded, there is no management.

Hepatic steatosis

Pathology of hepatic steatosis

Hepatocellular carcinoma (HCC)

Epidemiology & aetiology

Despite being the 18th most frequent cancer in the UK, HCC is the 6th most common cancer world-wide due to a high prevalence in Asia. Risk factors include:

  • Cirrhosis. 90% of all HCC arise in cirrhotic livers with 4% of people with cirrhosis developing HCC per year.
  • Chronic hepatitis B virus infection (HBV). Increases risk 100x and has an additive effect when combined with other risk factors.
  • Hepatitis C virus, but to a lesser extent than hepatitis B.
  • Alcohol. Cirrhosis due to alcoholic liver disease is the most common cause of HCC in the West.
  • Metabolic liver disease, especially haemochromatosis. The multiple oxidation states of iron is thought to cause a carcinogenic effect.
  • Aflatoxin. This molecule is produced by fungi that live on nuts which are stored in damp conditions. It is a pro-carcinogen that forms DNA-adducts. The combination of aflatoxin and HBV is the most common aetiology in North Africa and parts of China.

 

Pathology

Usually a solitary tumour, though it may be multi-centric or with satellite lesions around a central mass. In cirrhosis it is common to have multiple dysplastic nodules synchronously of which some will progress to HCC, so there may be more than one primary HCC present.

HCC tend to metastasize late with haematogenous spread to the lungs.

Histologically, there are largedysplastichepatocytes with round nuclei and clear cytoplasm. There are no bile ducts visible.

Subtypes of HCC are (in order of descending frequency):

Trabecular (over half of all), mixed, compact, pseudo-glandular, fibrolamellar and scirrhous.

A variant of HCC is the fibrolamellar HCC, which constitutes only 1.5% of all HCC. This subtype does not have the same risk factors and most commonly presents as a single painful mass in an otherwise normal liver. Peak age of onset is at 20-30 years. It has a better prognosis, with 50% resectable at presentation and 60% 5-year survival.

 

Presentation

Abdominal pain (due to liver capsule stretch), anorexia, malaise, persistent fever and weight loss are the most common symptoms. In a patient with known cirrhosis, development of HCC may trigger decompensation and hepatic encephalopathy and ascities (in 30-60%). Some patients (10%) may present with variceal bleeding, which may be associated with thrombosis of the portal vein from vascular invasion.

It is rare to present with jaundice, unless the tumour compresses a large bile duct.

Finally, HCC are associated with several paraneoplastic effects that may be the method of presentation:

  • Hypoglycaemia
  • Leukocytosis
  • Erythrocytosis
  • Hypercholesterolaemia
  • Hypercalcaemia

 

The possible examination findings of a patient with HCC are:

  • Cachexia
  • Pyrexia
  • Signs of chronic liver disease (suggesting underlying cirrhosis)
  • Hepatic asterixis
  • Irregular hepatomegaly
  • Ascities
  • Hepatic bruit may be heard over the tumour

 

Investigations

Patients with cirrhosis should be screened with USS (plus or minus alpha-feto protein (AFP) measurement) every 6 months. Non-cirrhotic patients with chronic HBV and haemochromatosis patients should also be screened. A mass may be seen on USS and for 1.5-3cm tumours USS has 95% sensitivity.

AFP is raised in 70% of HCC and very high levels of AFP may correlate with tumour size. In the context of a mass >2cm and AFP >400ng/ml in a cirrhotic liver, diagnosis can be made non-invasively using CT or MRI. Angiography and lipiodol-enhanced CT scans can be used.

Biopsy is generally avoided due to the risk (<2%) of seeding along the needle track, however in smaller lesions with moderately raised AFP and equivocalimagingfine-needle aspiration may be needed (given that clotting is normal).

Other investigations:

  • Chest X-ray and CTchest to look for metastases.
  • Liver function tests may show a raised AST:ALT ratio and increased alkaline phosphatase (ALP).
  • The paraneoplastic effects (above) may also be found on biochemistry and blood count.

 

Management

The majority of HCC are not resectable at diagnosis (only in 9-37% of patients). The main contraindications to surgery are:

  • Disease in both lobes or multi-centric tumours.
  • Decompensatedcirrhosis (where resection would further worsen hepatic function).
  • Extra-hepatic metastases.

If surgery is possible then outcome for small (T1) tumours is good with 70% 5-year survival.

Liver transplantation may be the primary treatment for HCC. The Milan criteria define appropriate patients as those with decompensated cirrhosis with one tumour <5cmor less than 3 tumours all <3cm.

For non-resectable tumours TACE (transcatheter chemoembolization) can be used to induce ischaemia and deliver high dose chemotherapy, which is then repeated 2-3 times. This is useful to debulklarge tumours however it is contraindicated in multi-centric tumours and decompensated cirrhosis due to the risk of acuteliver failure.

Other local therapies include percutaneous ethanol injection and radiofrequency ablation, which can be as effective as surgery for small tumours.

Systemic chemotherapy has been used but little efficacy has been seen. Sorafenib, a multi-target tyrosine kinase inhibitor, gives modest survival benefit in advanced disease.

 

Prognosis

Overall survival is poor with <10% alive at 3 years within the UK. However those patients suitable for liver transplantation have a much better prognosis because the underlying cirrhosis is also cured. However in some diseases the underlying pathology may not be cured despite transplant due to relapse (e.g. hepatitis C and haemochromatosis).

 

Pathology of hepatocellular carcinoma

Gross and microscopic pathology of hepatocellular carcinoma

Cholangiocarcinoma (CC)

A primary malignant tumour of biliary epithelial cells, which is 10 times less common than HCC. It accounts for 1.5% of all cancers in the UK but the incidence is rising.

 

Associations:

  • Primary sclerosing cholangitis (PSC). 20% of all patients with long-standing PSC will develop CC however only 5% of all CC are attributed to PSC
  • Cirrhosis
  • Biliary disease e.g. bile duct adenoma, liver fluke (Clonorchis sinesis)

 

Pathology

CC can be intra-hepatic or extra-hepatic. Intra-hepatic CC (20-25%) of all enter into the differential of a liver mass. Extra-hepatic CC are an important cause of biliary strictures. 50-60% are perihilar (also known as Klatskin tumours) and 20-25% involve the distal bile duct.

Tumours can either be mass forming (more common), which will occlude ducts; or infiltrating, which grow along duct and slowly cause a stricture to form.

Histologically they are adenocarcinomas with glands lined with cuboidal epithelium.

Spread is initially to lymph nodes, and then later there is direct invasion of surrounding structures and peritoneal carcinomatosis.

 

Clinical features

The most common presentation is with painless jaundice, weight loss and abdominal discomfort; therefore an important differential diagnosis is pancreatic cancer. There may also be itching and episodes of cholangitis due to strictures causing cholestasis. On examination, the gall bladder may be palpable and in association with jaundice this suggests that gallstones are not the cause of the jaundice, according to Courvoisier’s law.

 

Investigations

Work-up as for any recent onset jaundice. Liver function tests will show signs of obstructive jaundice:

  • Markedly raised ALP
  • ALT and ASTmildly raised, however they may be up to 5x above upper limit of normal if cholangitis is present.
  • Impaired coagulation due to vitamin K deficiency. This occurs because no bile salts can enter the gut, impairing absorption of fat-soluble vitamins.

CA19-9 is a tumour marker raised in 85% of cases of CC, however it is non-specific.

USS will demonstrate dilated bile ducts. CT and magnetic resonance cholangio-pancreatography (MRCP) will demonstrate the anatomy of the lesion. In the setting of PSC, differentiating malignant from benign strictures is difficult.

Positron emission tomography (PET) scanning has a role in increasing the sensitivity of diagnosis.

Endoscopic retrograde cholangiopancreatography (ERCP) also shows the presence of strictures and allows intervention with stenting and allows brushings or biopsies to be taken.

 

Management and prognosis

Surgery forms the mainstay of CC treatment however resection is only possible in 10-15% of cases. If there are no distant metastases and invasion of the porta hepatis vessels then major surgery can be attempted e.g. hepatectomy with extrahepatic bile duct resection and removal of the caudate lobe. 5-year survival following resection is 10-30% (better for more distal tumours) due to 75% recurrence. Liver transplant is very rarely performed for intrahepatic CC.

Palliative biliary stenting is needed to maintain liver function and prevent progressive cholangitis. This can be performed percutaneously or endoscopically. In the future photodynamic therapy may be used as a further palliative method.

Chemotherapy has limited effect and CC are not generally radiosensitive.

 

Metastases

Distant metastases are 40 times more common as a malignant cause of hepatic mass than a primary livertumour. The liver is the most common site for distant metastases and is involved in 40% of all metastatic disease. 80% of all metastases are multiple but colorectal cancer and renal cell carcinoma often cause solitary metastatic deposits.

Most common primary lesions causing liver metastases in women:

  • Colon
  • Breast
  • Uterus
  • Stomach

Most common primary lesions causing liver metastases in men:

  • Colon
  • Lung
  • Stomach
  • Pancreas

Leukaemia, lymphoma and carcinoid tumours are also associated with disseminated disease in the liver.

For certain primaries (e.g. colorectal) resection of the metastasis may be appropriate however for most the presence of liver metastases is a contraindication for radical therapy. Prognosis is poor with <6 months survival for most patients.

 

Imaging of liver metastases

A cross-sectional CT scan showing multiple liver metastases

Conclusion

  • Hepatic tumours are common and the majority are diagnosed incidentally.
  • The most common masses in a well patient without previous liver disease are haemangioma, adenoma or a simple cyst.
  • Haemangiomas rarely have complications therefore are usually observed. Adenomas are associated with the OCP and anabolic steroid use. They have a high risk of rupture so surgical resection is performed.
  • Malignant metastases are much more common that primary hepatic malignancies, often arising from the GIT, or other sites via haematogenous spread.
  • Hepatocellular carcinoma is the most common primary hepatic malignancy. It is most often associated with cirrhosis and hepatitis B infection. Local treatment includes surgery and radiofrequency ablation. Metastases are rare.
  • Cholangiocarcinoma is a primary malignancy of biliary epithelial cells. It is associated with primary sclerosing cholangitis. It has a very poor prognosis with early metastases and local invasion.

References

Image “Histology of cavernous haemangioma” from: from: User: KGH (Own work). Cavernous hemangioma histopathology. 9th January 2009. English Wikimedia Commons. Available at: http://upload.wikimedia.org/wikipedia/commons/4/4b/Cavernous_hemangioma_histopathology_(2).jpg

Image “Histology of hepatic adenoma” from: User: Nephron (Own work) [CC-BY-SA-3.0 (www.creativecommons.org/licenses/by-sa/3.0) or GFDL (<a href="http://www.gnu.org/copyleft/fdl.html" class="external free" rel="nofollow">http://www.gnu.org/copyleft/fdl.html</a>)], via Wikimedia Commons

Image “Steatosis” from: Laboratory of Experimental Pathology, Division of Intramural Research, NIEHS (NIH) [Public domain], via Wikimedia Commons. Available at http://upload.wikimedia.org/wikipedia/commons/1/19/Liver_steatosis_fatty_change.jpg

Image: “Gross pathology of a large HCC from an autopsy specimen” from: Ed Uthman (Own work), via Wikimedia Commons. Available at: http://upload.wikimedia.org/wikipedia/commons/2/24/Hepatocellular_carcinoma_1.jpg

Image “Histopathology of HCC” from: from: User: KGH (Own work). Hepatocellular carcinoma histopathology 9th January 2009. English Wikimedia Commons. Available at: http://upload.wikimedia.org/wikipedia/commons/a/ab/Hepatocellular_carcinoma_histopathology_(1).jpg

Image “Imaging of liver metastases” from: James Heilman, MD (Own work) [CC-BY-SA-3.0 (www.creativecommons.org/licenses/by-sa/3.0) or GFDL (<a href="http://www.gnu.org/copyleft/fdl.html" class="external free" rel="nofollow">http://www.gnu.org/copyleft/fdl.html</a>)], via Wikimedia Commons. Available at: http://upload.wikimedia.org/wikipedia/commons/8/81/MultipleLiverMets2008.jpg

Assy N., Nasser G., et al. Characteristics of common solid liver lesions and recommendations for diagnostic workup. World J Gastro (2009) 15(26):3127-3227

Clouston, A. An approach to the surgical pathology of tumour and tumour-like conditions of the liver. Pathology (2004) 36(1):5-18

Cassidy J., Bissett D., Spence R. A. J., Payne M. Oxford handbook of oncology 2nd Edition (2006). Oxford University Press

Longmore M., Wilkinson I., et al. Oxford handbook of clinical medicine 8th Edition (2010). Oxford University Press

Bloom S., Webster G. Oxford handbook of gastroenterology and hepatology (2006). Oxford University Press

 

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