Malignant tumours of the liver

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1 Malignant tumours of the liver Irfan Ahmed Dileep N Lobo Abstract Malignant tumours of the liver are classified as primary or secondary (metastatic). Some of the tumours present with deranged liver function tests and symptoms, but most remain asymptomatic with normal liver function tests. Common primary tumours of the liver are hepatocellular carcinomas and cholangiocarcinomas. The former are confined to the liver and usually originate in cirrhotic livers. Cholangiocarcinomas arise from the intra- or extrahepatic biliary tree. Secondary tumours of the liver account for 95% of hepatic malignancies, are manifestations of systemic spread of the primary, and usually indicate end-stage disease. Metastases from colorectal cancer and neuroendocrine tumours are two types of cancer in which liver resection is potentially curative. More liver tumours are being discovered incidentally due to improved imaging techniques; CT, MRI and PET offer earlier diagnosis and staging. Tumour markers and liver biopsy help in diagnosing selected cases. Treatment of liver tumours requires a multidisciplinary approach. This should be offered in tertiary referral centres equipped with a full range of diagnostic and therapeutic facilities. Surgery offers potential cure for liver tumours. New chemotherapeutic agents and ablation techniques are promising and are being evaluated in the clinical setting. Recent medical advances have made treatment of malignant liver tumour safer and potentially curative. Keywords liver; tumours; hepatocellular carcinoma; cholangiocarcinoma; metastases; colorectal cancer Malignant tumours of the liver can be primary or secondary (Table 1). Most of them are asymptomatic, with normal liver function. These tumours are being discovered incidentally with increasing frequency by ultrasonography, CT and MRI; these imaging methods offer earlier diagnosis and potential cure. Technical advances in liver surgery over the past two decades have enabled safe and potentially curative resection for malignant tumours. The management of hepatic malignancy requires a multidisciplinary approach (medical oncologist, hepatobiliary surgeon, Classification of malignant tumours of the liver Primary Secondary epithelial tumours Gastrointestinal tumours Hepatocellular Colorectal Hepatoblastoma (7%)* Pancreas Hepatocellular carcinoma (75%)* Cholangiocellular (6%)* Cholangiocarcinoma Cystadenocarcinoma Mesenchymal tumours Tumours of blood vessels Angiosarcoma Haemangioendothelioma Other tumours Embryonal sarcoma Fibrosarcoma tumours of muscle tissue Leiomyosarcoma Rhabdomyosarcoma Miscellaneous Carcinosarcoma Teratoma Yolk sac tumour Carcinoid Squamous carcinoma Primary lymphoma *Percentage of primary tumours (excluding metastases). Table 1 Stomach Oesophagus Carcinoid non-gastrointestinal tumours Bronchus Breast Ovary Melanoma Lymphoma Renal radiotherapist, interventional radiologist) with access to liver transplant services. Development of novel approaches (e.g. neoadjuvant chemotherapy, ablative techniques) has increased the number of therapeutic options. The two commonest malignant primary tumours of the liver are hepatocellular carcinoma and cholangiocarcinoma. The former is ten times commoner than cholangiocarcinoma, and is one of the commonest malignant primary neoplasms worldwide. Secondary tumours of the liver account for 95% of hepatic malignancies and are manifestations of systemic spread; they are often a sign of end-stage disease. Metastases from colorectal adenocarcinoma and neuroendocrine tumours are two types of cancer in which liver resection is potentially curative. Hepatocellular carcinoma, intrahepatic cholangiocarcinoma and colorectal liver metastases are the focus of this review. Irfan Ahmed FRCS is a Specialist Registrar in General Surgery at Nottingham University Hospitals, Queen s Medical Centre, Nottingham, UK. Conflicts of interest: none declared. Dileep N Lobo FRCS is an Associate Professor in Gastrointestinal Surgery and a Consultant Hepatopancreatobiliary Surgeon at Nottingham University Hospitals, Queen s Medical Centre, Nottingham, UK. Conflicts of interest: none declared. Hepatocellular carcinoma 1,2 Incidence Hepatocellular carcinoma is the fifth commonest neoplasm in the world, and the third commonest cause of cancer-related death. More than 500,000 new cases are diagnosed annually worldwide. The incidence ranges from fewer than 10 cases per 100,000 population in North America and western Europe to cases per 100,000 population in parts of Africa and Asia. The incidence SURGERY 25: Elsevier Ltd. All rights reserved.

2 of hepatocellular carcinoma has increased in the last decade, reflecting the higher rates of infection by hepatitis- C virus and improvements in the management of cirrhosis. It is uncommon in the UK and accounts for only 2% of cancers. There are 1500 deaths per year due to hepatocellular carcinoma in the UK and the incidence is increasing annually. Risk factors More than 80% of hepatocellular carcinomas occur in patients with cirrhosis, and a number of conditions and risk factors have been implicated as the cause of the disease (Table 2). Presentation The commonest presentation is a cirrhotic patient with a mass discovered incidentally on ultrasound. α-fetoprotein is an important tumour marker and may be raised. Liver function tests may or may not be deranged. Other presenting complaints can be pain or a palpable mass. A diagnosis must be made and the disease must be staged when a patient presents with a liver mass. If the patient is known to have pre-existing cirrhosis and the mass is 2 cm in diameter, there is a >95% chance that the lesion is a hepatocellular carcinoma. A concentration of α-fetoprotein in serum of 400 μg/l confirms the diagnosis and further investigations are needed only to establish the most appropriate treatment. In patients without cirrhosis, hepatocellular carcinoma usually presents with an abdominal mass and abnormal liver function. Presentation is usually late in these cases, with vascular or diaphragmatic involvement. High-risk groups for developing hepatocellular carcinoma Sex Males and females Males and females Males and females Males Males Table 3 Primary disease Established cirrhosis due to hepatitis-b virus, particularly those with ongoing viral replication Established cirrhosis due to hepatitis-c virus Established cirrhosis due to genetic haemochromatosis Primary biliary cirrhosis Alcohol-related cirrhosis of sensitivity and specificity, aiding accurate diagnosis and staging. CT (Figures 2 and 3) has a greater sensitivity and specificity than ultrasonography, particularly for tumours <1 cm. The concentration of α-fetoprotein in serum is raised in 80% of patients with hepatocellular carcinoma, but may also be raised in patients with testicular or germ cell tumours (see Clarke, CROSS REFERENCES). Surveillance Surveillance should be offered to patients with cirrhosis who are in a high-risk group (Table 3). A surveillance and recall strategy has been proposed by the Barcelona Clinic Liver Cancer Group and is outlined in Figure 1. Diagnosis Modern imaging, combined with measurement of tumour markers, can exclude benign lesions of the liver with a high degree Major causes of hepatocellular carcinoma Cirrhosis Chronic viral hepatitis-b, -C and -D Toxins Alcohol Aflatoxins Hereditary metabolic liver diseases Hereditary haemochromatosis Deficiency of α1-antitrypsin Autoimmune hepatitis Obesity (particularly in males and in diabetes mellitus) Non-alcoholic steatohepatitis Non-alcoholic fatty liver disease Surveillance strategy for hepatocellular carcinoma for patients with cirrhosis (devised by the Barcelona Clinic Liver Cancer Group)* 1 2 cm FNAB Cirrhotic patients (ultrasonography and α-fetoprotein every 6 months) Liver nodule 2 cm α-fetoprotein 400 µg/l CT/MRI/ angiography HCC 1 cm Ultrasonography every 3 months No HCC Increased α-fetoprotein No liver nodule Spiral CT Surveillance (ultrasonography and α-fetoprotein every 6 months) *From reference 2; reproduced with permission from Elsevier. Normal α-fetoprotein FNAB: Fine-needle aspiration biopsy; HCC: Hepatocellular carcinoma. Table 2 Figure 1 SURGERY 25: Elsevier Ltd. All rights reserved.

3 the lesion, percutaneous fine-needle aspiration, or biopsy may be indicated if diagnosis is still not made. The risk of seeding of hepatocellular carcinoma does not appear to be related to tumour size and biopsy should be avoided if surgery is possible. The initial investigation should be α-fetoprotein in a noncirrhotic patient where the first presentation is a liver mass. The diagnosis of hepatocellular carcinoma is confirmed if α-fetoprotein is raised in the absence of a primary tumour of the testis. If the lesion is potentially operable, biopsy of the normal tissue surrounding liver parenchyma (to look for steatosis, fibrosis or cirrhosis) may be required to determine the best treatment. A search for other causes (non-liver primary tumour) and further imaging of the mass is required if α-fetoprotein is normal. Biopsy of a nonliver tumour determines the surgical approach if investigations suggest hepatocellular carcinoma. Figure 2 Contrast-enhanced CT (arterial phase) showing a well-defined enhancing mass (arrowheads) in the right lobe of the liver. Biopsy is unnecessary and should be avoided to reduce the risk of tumour seeding. If α-fetoprotein is normal, further imaging (CT, MRI, lipiodol angiography with follow-up CT) usually permits a confident diagnosis. The patient can than be assessed for treatment without the need for a biopsy. Biopsy may be indicated in the few cases where diagnostic doubt persists. In the uncommon situation of discovery of a small mass (<2 cm diameter) on ultrasound, the level of diagnostic certainty remains low, but about 75% of such new nodules are found to be hepatocellular carcinoma in a patient with cirrhosis. Other imaging or a raised α-fetoprotein may establish a definitive diagnosis. An increase in serial α-fetoprotein (even if <400 μg/l) is virtually diagnostic. Repeat imaging to show enlargement of Treatment The treatment of hepatocellular carcinoma depends on the: extent of the disease inside and outside the liver overall condition of the liver overall health of the patient. Cirrhotic patients can be classified according to the Child Pugh criteria (Table 4; see Portal hypertension and ascites, page 28). Treatment for hepatocellular carcinoma can be divided into four categories (Table 5). An algorithm based on the staging system proposed by the Barcelona Clinic Liver Cancer Group is shown in Figure 4. Surgery: liver resection and transplantation are the only potentially curative treatments for hepatocellular carcinoma, but only a minority of the patients will be suitable for these treatments. Child Pugh criteria for classification of severity of liver disease Clinical and biochemical measurements Points scored for increasing abnormality Hepatic encephalopathy None (grade)* Total bilirubin (mg/dl) < >3.0 Ascites Absent Mild Moderate severe Concentration of albumin (g/dl) in serum > <2.8 Prothrombin time (second prolonged) or Prothrombin time International Normalized Ratio <4 or or >6 or >2.3 Figure 3 CT (portal venous phase) of the patient in Figure 2. The liver has enhanced and there is relatively less enhancement of the lesion (arrowheads), consistent with a hepatocellular carcinoma. *Based on Trey, Burns and Saunders (1996) Grade A = 5 6 points Grade B = 7 9 points Grade C = points Table 4 SURGERY 25: Elsevier Ltd. All rights reserved.

4 Therapeutic interventions for the treatment of malignant tumours of the liver Surgical intervention Liver resection Liver transplantation Percutaneous or minimally-invasive interventions (may be combined with open surgery) Ethanol injection Radiofrequency thermal ablation Microwave thermal ablation Cryoablation Transarterial interventions Embolization Chemoperfusion Chemoembolization Drugs Gene therapy Immune therapy Table 5 Owing to local spread of tumour and severity of pre-existing cirrhosis, such treatment is feasible in <20% of patients. Surgical mortality is >10% in cirrhotic patients and five-year survival is about 15%. Transplantation patients with cirrhosis and small (<5 cm single or up to three lesions of <3 cm) tumours are potential candidates for orthotopic liver transplantation (see page 42). Liver resection non-cirrhotic patients, and selected patients with cirrhosis (Child Pugh class A) who are not suitable for transplantation are candidates for liver resection. A cirrhotic liver is a threat for development of further malignant liver lesions. Liver dysfunction after liver resection is a major issue, particularly in the compromised cirrhotic liver. Tumour ablation techniques are used if surgical therapy is not an option due to tumour characteristics or the overall medical condition. Injection of alcohol or radiofrequency microwave ablation (see Rai, CROSS REFERENCES) can induce tumour necrosis, improving survival in patients with small tumours who are unsuitable for transplantation. Chemoembolization: for larger tumours, transarterial embolization (Figures 5 and 6) with lipiodol and cytotoxic drugs (cisplatin or doxorubicin) may induce tumour necrosis in some patients. This treatment is also useful in palliating pain or bleeding from large symptomatic hepatocellular carcinomas. Chemotherapy has not been shown to be beneficial in hepatocellular carcinoma and should not be used outside the setting of a clinical trial. Gene therapy and immune therapy are currently being investigated and may hold promise for the future. Staging classification and treatment schedule for patients with hepatocellular carcinoma (devised by the Barcelona Clinic Liver Cancer Group)* HCC Stage 0 PST 0, Child Pugh A, Okuda 1 Stage A C PST 0 2, Child Pugh A B, Okuda 1 2 Stage D PST 2, Child Pugh C, Okuda 3 Very early stage (0) 1 HCC 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules 3 cm, PST 0 Intermediate stage (B) Multinodular PST 0 Advanced stage (C) Portal invasion N1, M1, PST 1 2 Terminal stage (D) 1 HCC 3 nodules 3 cm Portal pressure/bilirubin Increased Associated diseases Portal invasion N1, M1 Normal No Yes No Yes Resection Liver transplantation PEI/radiofrequency Chemoembolization New agents Curative treatments Randomized controlled clinical trials Symptomatic treatment *From reference 2: reproduced with permission from Elsevier. HCC: Hepatocellular carcinoma; PST: Performance status test; PEI: Percutaneous ethanol injection. Figure 4 SURGERY 25: Elsevier Ltd. All rights reserved.

5 Risk factors for cholangiocarcinoma Figure 5 Selective hepatic arteriogram of the patient in Figures 2 and 3 showing a dense arterial blush (arrowheads) in the hepatocellular carcinoma. Fibrolamellar carcinoma Fibrolamellar carcinoma is an important, but uncommon, variant of hepatocellular carcinoma. It occurs in patients without cirrhosis or previous hepatitis; it accounts for 1 9% of cases of hepatocellular carcinoma in western countries. α-fetoprotein is usually normal. The prognosis is better than for other hepatocellular carcinomas (five-year survival of 40 50% after hepatic resection). Cholangiocarcinoma 3 Cholangiocarcinoma is an uncommon tumour arising from the epithelial cells of the biliary tract. The term cholangiocarcinoma previously referred only to primary tumours of the intrahepatic bile ducts, but the term now encompasses intrahepatic, perihilar, and distal extrahepatic tumours of the bile ducts; 20 25% of diagnosed cholangiocarcinomas are intrahepatic. Risk factors for cholangiocarcinoma are listed in Table 6. Intrahepatic cholangiocarcinomas are discussed in this section. Patients with cholangiocarcinoma typically present at an advanced stage, and cure rates are low, even with aggressive Figure 6 Post-chemoembolization selective hepatic arteriogram. Tumour blush is absent: the procedure was successful. Age (65% of patients are aged >65 years) primary sclerosing cholangitis, with or without ulcerative colitis, is the commonest known predisposing factor for cholangiocarcinoma in the UK (lifetime risk is 5 15%) Chronic intraductal gallstones Bile duct adenoma and biliary papillomatosis Caroli s disease (cystic dilation of ducts, lifetime risk is 7%) choledochal cysts (about 5% transform, risk increases with age) thorotrast (a radiological agent no longer licensed for use, although the risk of cholangiocarcinoma lasts several decades) Smoking (increased risk in association with primary sclerosing cholangitis) in Southeast Asia (where the tumour is quite common), the associated risk factors are liver flukes (Opisthorchis viverrini, Clonorchis sinensis) and chronic typhoid carriers (sixfold increase in risk of hepatobiliary malignancy) Table 6 therapy. Most patients present with unresectable disease and have a survival of <12 months. Progress has been made by the appropriate selection of patients for treatment options, including liver resection and ablation techniques; neoadjuvant and adjuvant therapies have not improved survival. Mortality rates from intrahepatic cholangiocarcinoma have risen steeply and steadily over the past 30 years. Since the mid- 1990s, more deaths have been coded annually in England and Wales as being due to this tumour rather than to hepatocellular carcinoma. In 1997 and 1998, cholangiocarcinoma caused almost 1000 deaths/year in England and Wales (approximately equal numbers of men and women). Presentation Most patients present with the symptoms of obstructive jaundice. Pain in the right upper quadrant, or fever with rigors (cholangitis) are not uncommon. Most patients present quite late, so the features of advanced malignancy (fatigue, malaise, weight loss) may be the presenting symptoms in the absence of jaundice. Some cases are detected incidentally via imaging. Diagnosis Liver function tests might show an obstructive picture (high bilirubin and alkaline phosphatase). Tumour markers might be useful. Cancer antigen 19-9 is raised in about 85% of the patients with cholangiocarcinoma, with high carcinoembryonic antigen and cancer antigen-125 in about one-third. Diagnosis and staging is by: ultrasound triple-phase CT MRI/magnetic resonance cholangiopancreatography PET (see Chambers, CROSS REFERENCES). Percutaneous transhepatic cholangiography and endoscopic retrograde cholangiopancreatography can be diagnostic and therapeutic, helping specimen accrual for cytology or histology, SURGERY 25: Elsevier Ltd. All rights reserved.

6 as well as offering temporary or permanent stenting for symptomatic relief. Treatment Surgery is the only intervention offering potential cure. The principal goal is complete excision of the tumour with tumour-free resection margins. Patients should be discussed in multidisciplinary meetings before intervention is offered. Patients evaluated for resectability must be suitable for a potentially major hepatic resection. The traditional determinants of resectability are: extent of tumour vascular invasion hepatic lobar atrophy metastatic disease. Palliative treatments (see Wilcock, CROSS REFERENCES) are aimed at increasing quality of life by relieving symptoms. These patients are offered permanent metallic stents for relief of obstructive jaundice. Liver transplantation for cholangiocarcinoma is controversial and most Liver Transplant Centres have abandoned this as an indication for liver transplantation because of the high recurrence rate. Secondary hepatic tumours Liver metastases are common and are found in about one-half of patients dying from cancer. They are usually associated with carcinomas of the gastrointestinal tract (colorectal, pancreas, stomach) but are nearly as common in carcinomas of the bronchus, breast, ovary and lymphoma. With the exception of liver metastases of colorectal cancer and neuroendocrine tumours, deposits are usually multiple and seldom amenable to resection. Colorectal liver metastases 4 Liver metastases occur in 40 70% of patients with colorectal cancer; 15 30% of patients present with synchronous metastases (metastases detected within six months of the primary tumour). Metachronous metastases develop in a similar proportion within three years. In the UK, 28,000 new cases of colorectal cancer (see Dorundi, CROSS REFERENCES) are diagnosed each year and 18,000 of these patients develop liver metastases. Only 10 20% ( ) of these patients have operable disease, and 24 44% of patients undergoing liver resection will be alive at five years. Resection is considered the sole potentially curative treatment for hepatic metastases from colorectal cancer. After diagnosis, the median survival for untreated patients with colorectal liver metastases is <9 months, and only months for patients treated with chemotherapy alone. The prognosis for patients with untreated disease is related to tumour burden. The main causes of unresectability are oncological (inadequate clearance of tumour) and functional (inadequate functional residual liver); the latter leads to postoperative liver failure. Cancer cells metastasize to the liver via the portal circulation. They develop an autonomous blood supply in the liver and grow at variable rates. The disease is limited to the left or right hemiliver in one-third of patients. Staging Tumours are assessed for suitability for resection; these patients should be discussed in multidisciplinary meetings. CT and MRI Figure 7 Contrast-enhanced CT (portal venous phase) showing three hypodense lesions (arrowheads) in the liver of a patient who had a colonic resection for a colorectal carcinoma: colorectal liver metastases are present. are the mainstays for staging. Hepatic metastases appear as lowattenuating lesions with peripheral enhancement in the portal venous phase of contrast-enhanced CT (Figures 7 and 8). New hepatic lesions developing in patients who have had previous bowel resections for colorectal cancer are most likely to represent metastatic disease. Local recurrence of the primary tumour should be excluded and lung metastases should be looked for, particularly in patients who have had rectal primaries. Three-dimensional reconstructions (Figure 9) can help in surgical planning and in calculating residual liver volume. PET and PET CT identify residual or new extrahepatic disease and increase the accuracy of assessment, but are available in only a few UK centres. Treatment Liver resection: the five-year survival for patients with liver metastases without surgical resection is zero; the overall five-year Figure 8 Post-chemotherapy (oxaliplatin + 5-fluorouracil + folinic acid) CT of the patient in Figure 7. Only one lesion (arrowhead) is visible, indicating downstaging of the disease. SURGERY 25: Elsevier Ltd. All rights reserved.

7 Techniques to improve resectability Portal vein embolization Staged resection Neoadjuvant chemotherapy Ablative techniques Alcohol injection Radiofrequency ablation Electrolysis Cryotherapy Microwave ablation Table 8 Figure 9 Three-dimensional reconstruction (surface-rendering) of MRI images showing four colorectal metastases (blue) in the liver. survival after resection is >30%. Patients most suited for resection are those with fewer than three or four metastases in one lobe of the liver, but tumours need not be confined to one lobe. Extrahepatic disease is not an absolute contraindication, and selected patients can be offered potentially curative surgery (Table 7). The principle of complete removal of tumour is a prerequisite, and one limitation is the need to leave sufficient liver to prevent post-resection hepatic failure; this depends on: the extent and distribution of the tumour burden the fitness of the patient preoperative liver function. The liver has an enormous capacity for regeneration. A fit patient with a healthy liver will regenerate a 75% resection within three months. Methods to improve resectability are listed in Table 8. The perioperative mortality for patients undergoing liver resections should be <3 5%, and mortality rates of <1% have been reported in high-volume, specialized centres. Perioperative morbidity is about 30%; factors affecting surgical outcome are listed in Table 9. Patients with non-resectable tumours are likely to be offered chemotherapy, which can downstage the tumours in 30 40% of patients and make them resectable. These patients are restaged after chemotherapy and, if the tumour becomes operable, they are likely to be offered liver resection, depending on their fitness for surgery. Increased resectability rates can also be achieved by: portal vein embolization two-stage hepatectomy a combination of surgery and ablation techniques. Patients with colorectal liver metastases and extrahepatic disease who should be considered for liver resection Resectable pulmonary metastases resectable/ablatable isolated extrahepatic sites (e.g. spleen, adrenal or resectable local recurrence) local direct extension of liver metastases (e.g. diaphragm/adrenal) that can be resected Liver transplantation is contraindicated for patients with colorectal metastases because immunosuppressive treatment posttransplant can initiate rapid recurrence. Chemotherapy: neoadjuvant chemotherapy is a novel approach to colorectal liver metastases. These agents can convert nonresectable disease to resectable. Guidelines issued by the UK National Institute for Health and Clinical Excellence recommend oxaliplatin-based chemotherapy regimens (oxaliplatin+ 5-fluorouracil + folinic acid). Other effective drugs include irinotecan, capecitabine, bevacizumab and cetuximab (see Potter, CROSS REFERENCES). Tumours should be considered for surgery or ablation after downstaging. The postoperative complication rate (including hepatic insufficiency) may be higher after chemotherapy. Other tumour ablation techniques offering palliative or potentially curative options to small metastatic nodules include radiofrequency ablation, cryotherapy, laser and microwave ablation. Factors adversely affecting morbidity and mortality after liver surgery Malignant disease Multifocal involvement Age >70 years Diabetes mellitus Cirrhosis Portal hypertension Concentration of bilirubin in serum of >200 μmol/l Concentration of alanine aminotransferase in serum of >100 U/l Concentration of albumin in serum of <30g/l Haematocrit of <30% Deranged clotting Fatty liver (alcoholic/non-alcoholic/chemotherapy-associated fatty liver disease) Renal impairment Leukocytosis Temperature >38 C Table 7 Table 9 SURGERY 25: Elsevier Ltd. All rights reserved.

8 Contraindications to liver resection in patients with colorectal liver metastases Unresectable primary tumour Unresectable pulmonary disease Locoregional recurrence Peritoneal disease Extensive nodal disease Metastases in bone or CNS Table 10 Radiotherapy has failed to show an effect on survival and should not be used outside the setting of clinical trials. Synchronous metastases Colorectal cancer resection and liver resection is not usually done synchronously, but management of accessible small metastases detected preoperatively should be discussed with the local Liver Centre for consideration of combined resection. Suspicious lesions discovered at the time of surgery should not be biopsied, and postoperative cross-sectional imaging should be done. Follow-up Follow-up involves regular monitoring of the concentration of carcinoembryonic antigen in serum and cross-sectional imaging. Rising concentration of carcinoembryonic antigen indicates local recurrence or recurrent hepatic metastasis; re-imaging and re- resection should be considered. If resection or ablative therapy is contraindicated Patients with advanced disease unsuitable for liver resection or ablative therapy (Table 10) should be referred to the clinical or medical oncologist with a special interest in colorectal cancer for further management and supportive/palliative care. References 1 ryder SD. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut 2003; 52(suppl III): iii1 iii8. 2 llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma. Gut 2002; 51(suppl VI): vi1 vi9. 4 Garden OJ, Rees M, Poston GJ, et al. Guidelines for resection of colorectal liver metastases. Gut 2006; 55(suppl III): iii1 iii8. Cross references Chambers RJ, Wong WL, Cook GJR. Positron emission tomography imaging in oncology. Surgery 2004; 22(4): i 96d. Clarke NW. Management of testicular tumours. Surgery 2006; 24(5): Dorundi S, Banerjea A. Colorectal cancer: early diagnosis and predisposing causes. Surgery 2006; 24(4): Potter V, Conn A. Chemotherapy and radiotherapy in the treatment of colorectal cancer. Surgery 2006; 24(4): Rai R, Manas D. Radiofrequency ablation of liver tumours. Surgery 2003; 21(8): iii vi. Wilcock A, Twycross R. Medical and psychological aspects of palliative care. Surgery 2006; 24(2): SURGERY 25: Elsevier Ltd. All rights reserved.