· Usually thought of as uncommon but although there is a low level of incidence in industrialised countries, worldwide it is one of the most common primary tumours.
WHO figures indicate 250,000 new cases of hepatocellular Ca annually
Highest incidence in Asian and Negro populations where it is believed to be linked to lifestyle rather than race.
North America & Australasia 0.1 – 0.6 % of Ca deaths West/South Africa 15 – 20% of Ca deaths
UK & USA 1.8 cases per 100,000 persons Japan 17.3 cases per 100,000 persons West Africa 58 cases per 100,000 persons
Highest known incidence in Mozambique 104 I 100,00
· Overall more common in men than women (figures vary between 4 and 11:1) Can occur in childhood
In populations with increased incidence linked to malnutrition, poor diet
Associated with carcinogens – hepatoxins eg. Aflatoxin produced by
Aspergillius flavus mould which grows on stored grain
· Hepatitis B – present in 40% of cases
Parasitic infections – schistosomiasis in the gut chinese liver fluke
Haemochromatosis – uncommon disease where there is excessive
absorption of iron giving rise to cirrhosis, splenomegaly, skin pigmentation &diabetes mellitus
In Western populations cirrhosis evident in 80% of hepatocellular Ca, therefore associated with high alcohol intake.
Suggested increase in incidence of benign liver adenoma in women using high Oestrogen contraceptive pill (Rooks cited in Fielding 1986)
A suggested link has been made between exposure to polyvinylchloride (PVC) and the development of Angiosarcoma of the liver (Souhami & Tobias 1986).
PRESENTING SIGNS & SYMPTOMS
Symptoms may vary depending on whether the disease is accompanied by cirrhosis.
· General malaise
· Localized pain – right hypchondriac /epigastric regions
· Signs of liver failure – progressive destructive jaundice
Prolonged drug activity
Increased clotting times
· Hepatomegaly – palpable mass
· Nutritional imbalance – hypoglycaemia
A differential diagnosis may be difficult – especially in the presence of cirrhosis, but also in cases of cysts, hepatic mets and cholangitis.
· History – predisposing factors
· Clinical examination
· Liver function tests – have no diagnostic pattern (ie. Always abnormal), however, blood tests may reveal abnormal levels in many of the metabolic indicators including:
– blood glucose & protein levels (hypoglycaemia etc)
– alkaline phosphatase & bilirubin levels
– alpha-feto protein
· Radionuclide imaging
· CT scan
· CXR (+lung tomos if +ve)
· Guided biopsy (if surgery not to be undertaken) – not recommended for vascular tumours due to life threatening risk of haemorrhage.
Primary liver tumours are classified as benign or malignant.
Classification of Tumours
Benign Epithelial Adenoma (liver or bile ducts)- most
common of benign tumours
Focal nodular hyperplasia
Primary Epithelial Hepatocellular (hepatoma)carcinoma
(most common) Multiple
Metastatic disease in the liver commonly originates from Ca Colon or Ca Breast.
The most common of benign liver tumours. Can range in size from small lesion to gigantic cavernous haemangioma. Tumours larger than 4cm are classified as ‘giant haemangioma’. These tend to develop more frequently in females with a ration of 6:1. Lesions smaller than 4cm seldom become symptomatic.
Surgery is the treatment option for symptomatic tumours. Procedure may range from minor wedge resection to an extended hepatectomy, depending on size and location of tumour. Contra-indication to surgery would be a result of size, multiplicity or operative risk. These cases are managed palliative with RT.
These tend to occur more frequently in young females with a history of long term use of oral contraceptive. Most of these tumours tend to be singular vascular , well circumscribed and sharply demarcated, although not necessarily encapsulated.
About 1/3 of patients have acute abdominal haemorrhage following rupture of the tumour.
Small tumours on the edge of liver is easily removed by surgery. Symptomatic patients who are not suitable for surgery should be advised against use of oral contraceptives and becoming pregnant. Association with oestrogens. These tumours do not show elevated levels of alpha-fetoproteins.
FOCAL NODULAR HYPERPLASIA
These tumours usually have a nodular surface and on gross examination may be confused with cirrhosis. Intratumoural haemorrhage may be present and lead to misdiagnosis of adenoma. The most characteristic feature is the proliferation of small bile ducts, usually accompanied by heavy infiltration of lymphocytes.
Emergency surgery is rarely needed since focal nodular hyperplasia seldom bleeds.. Operative management is usually reserved for those who present with pain or in whom there is diagnostic uncertainty.
Striking geographic variations can be seen. It is more common in males in high incidence and low incidence areas. In all populations, the incidence rises with age. However, high incidence areas show a shift towards the younger age group. This prevalence is maintained even when emigration to low incidence regions occurs, the increased risk is retained.
In the western world, hepatocellular carcinoma has a low incidence, occuring more frequently in males and generally on a background of cirrhosis. HCC occurs in two gross patterns; diffuse and focal form.
Intra-hepatic cholangiocarcinoma is an adenocarcinoma of the bile duct. It is distinguished from HCC by its mucin production. Surgery has been shown to be the most suitable treatment although many patients present with unresectable tumours, due to their multicentric nature. Short term surgical intubation provides good palliation. RT nor CT has been shown to be effective in controlling this lesion.
This multicentric tumour has variable differentiated endothelial cells which are associted with fibrosis. Factor VIII is usually present in the tumour, which helps to distinguish it. Tumours are usually large and clinically advanced on presentation. Survival is a matter of months following diagnosis. Little can be done in the way of treatment. Death usually results from liver failure, gastrointestinal bleeding or renal failure.
Approx 60% of cases have multiple lesions within the liver, most of these having a large mass accompanied by several smaller masses.
The remainder have diffuse disease -solitary masses are unusual. The presence of cirrhosis is very common.
T1 Single tumour up to 2cms no vascular invasion
T2 Single tumour less than 2cms with vascular invasion
or Multiple tumours all less than 2cms with no vascular
or Single tumour invasion greater than 2cms with no vascular
T3 Single tumour greater than 2cms with vascular invasion
or Multiple tumours limited to one lobe all less than 2cms with vascular
or Multiple tumours limited to one lobe all greater than 2cms without
T4 Multiple tumours in more than one lobe
orTumour(s) involve a major branch of portallhepatic veins
N1 Regional nodes positive
· Local invasion and spread within the liver is common as is venous
· Lymphatic spread to local nodes at porta hepatis then to cisterna chyli.
· Blood borne spread to lungs & bones.
1. First choice is SURGERY.
Resection of the tumour, particularly if it requires removal of only one lobe offers a chance of cure. The liver has the ability to regenerate (even after 75% removal) although this ability is reduced if cirrhosis is present – and surgery under these conditions may even lead to degeneration of liver function.
Surgery is more successful in children than in adults.
Resection usually follows laparotomy, undertaken to establish the full extent of the disease within the abdomen.
Resection may be:
good control of solitary mets from other primaries
However, resection carries a high mortality rate and only offers a chance of cure in 5% of cases!
Palliation may also be achieved by Hepatic Artery Ligation or Embolizafion. Embolization is particularly attractive as it is a non surgical procedure performed without anaesthetic, with a low mortality rate and possible pain relief achieved.
Liver Transplantation is still being developed as a management option for patients with liver tumours although it was these patients on which it was first pioneered. Patient selection is clearly critical with the physical condition of most patients eliminating this as a management option. Availability and cost vs benefit issues also arise. Local recurrence rates are high.
Chemotherapy for primary and secondary liver tumours takes a variety of forms.
Both single agent (5FU and Doxorubicin) and combination regimes have been tried in the management of liver tumours. A selection of studies show differing results, although most conclude that there is no significant benefit to be gained from combination systemic chemotherapy as opposed to single agent regimes.
Both approaches appear to offer reasonable (approx 50%) response rates in early primary disease treatment and show increased survival rates and measurable palliation in later stage and rnetastatic cases.
Howcver, it should be noted that many studies have low patient numbers due to the rarity of the tumours and the poor physical condition of the patients.
lntra-arterial infusion of chemotherapeutic agents via the hepatic and superior rnesenteric arteries is an alternative management option (Halnan 1990 p. 445). A combination of 5 FU and Adriamycin or FUDR (5-flurodeoxyuridine), agents with a very short half-life have been shown to offer increased survival rates and achieve a measurable palliative response in up to 61% of cases.
Due to the insensitivity of liver tumours to radiation and the low tolerance levels of normal liver tissue to radiation there is little role for radiotherapy in the management of these tumours. Radiation-induced hepatitis may occur after doses of 3OGy – eliminating the opportunity to apply radical tumouricidal doses.
Radiotherapy is occasionally used for symptom control in the case of painful metastases where large field sizes are used and small fractions of radiation are given. Careful monitoring of blood counts is required.
Liver tumours are commonly fast growing and consequently offer a very bad prognosis -mean survival is 3 months if left untreated!!
Prognosis is particularly bad with cirrhotic livers with at best 50% 3 months survival with treatment, falling to zero at 12 months.
Patients with non cirrhotic livers fair better although only 10% of these will be alive at 2 years. However, patients who have a complete surgical resection or show a complete response to chemotherapy fair better as do children where surgical resection is more often possible.
Death is commonly due to either: hepatic failure; widespread metastatic disease; secondary infections (lung/liver) or portal hypertension.
Overall 5 year survival approx 1%.