Diagnosis and Management of Hepatocellular Carcinoma

Transcription

1 Diagnosis and Management of Hepatocellular Carcinoma Ayman A Abdo Huda Al Abdul Karim Turki Al Fuhaid Faisal M Sanai Munthir Kabbani AbdulRahman Al Jumah Kelly Burak

2 Diagnosis and Management of Hepatocellular Carcinoma Guidelines Editors Ayman A Abdo, Huda Al Abdul Karim, Turki Al Fuhaid, Faisal M Sanai, Munthir Kabbani, AbdulRahman Al Jumah, Kelly Burak Guidelines Contributors King Khalid University Hospital, Riyadh: Ayman Abdo* (coordinator), Huda Al Abdulkareem, Nizar Al Nakshabandi, Turki Al Fuhaid, Wael Al Kattan, Ahmed Al Sagheir, and Saleh Al Sumayer King Faisal Specialist Hospital and Research Center, Riyadh: Monthir Kabbani (coordinator), Shawki Bazarbashi, Hamad Al Ashgar, Mohammad Al Sagheir, Mohammad Al Sofayan, Hamad Al Suhaibani, and Mohammad Al Shammari Riyadh Armed Forces Hospital: Faisal Sanai (coordinator), Khalid Bzeizi, and Malfi Al Otaibi King Fahd Medical City Ali Al Shanqeety King Abdul Aziz Medical City, Riyadh: Abdulrahman Al Jumah (coordinator), AbdulJaleel Al Alwan King Abdul Aziz University Hospital, Jeddah: Hisham Akbar King Fahd Hospital, Jeddah: Mohamed Babatin, Abdallah Al-Ghamdi King Faisal University Hospital, Al Khobar: Mona Ismael King Khalid University, Abha: Sulaiman Al Humaid International expert: Kelly Burak, University of Calgary, Canada * Dr. Ayman A. Abdo College of Medicine, King Saud University Tel: Fax: Corresponding author P.O. Box 2925(59) Riyadh Saudi Arabia abdoayman@hotmail.com

3 1. To provide a concise evidence-based review of the diagnosis and management of hepatocellular carcinoma (HCC) 2. To help initiate plans to prevent HCC Goals of the Guidelines 3. To enhance early and accurate diagnosis of patients with HCC. 4. To suggest an evidence-based approach for the management of HCC patients 5. To facilitate a more effective referral system between primary/ secondary care physicians and tertiary care centers where advanced treatments are available. 6. To help adopt a more effective triaging system of patients within tertiary care centers. 7. To create a complementary system between the major tertiary care centers whereby specific centers may specialize in certain aspects of management or care. 8. To identify research questions that are applicable to our local circumstances and resources, and to facilitate recruiting patients in these studies. Methods After due recognition of the high prevalence of HCC in Saudi Arabia, the difficulties often encountered in accurate diagnosis, the need for evidence-based management and appropriate referral of HCC patients; a committee was formed from the editors at King Khalid University Hospital (KKUH) in Riyadh (first three editors, AAA, HAK, TF) who subsequently compiled the first draft of these guidelines. These editors first performed a comprehensive literature search on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC. All literature was examined critically and the available evidence was then classified according to its strength. After approval and implementation of the initial guidelines at KKUH, it was decided to utilize these guidelines as a backbone for a national project for Saudi Arabia. Three other editors (FMS, MK, AJ) from three of the major hospitals in Saudi Arabia joined at this stage and put in a considerable effort in updating the document. After that, representative expert contributors were invited to review the document. All contributors (who are experts in different specialties related to HCC management from different institutions in Saudi Arabia) then further refined and updated the sections related to their expertise. Multiple meetings were then called to approve the final document. After that, The Saudi Gastroenterology Association formed a committee, which reviewed these guidelines and approved them as the Saudi Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma. The recommendations were based on the best available evidence but were tailored to the needs of the patients in Saudi Arabia. We have benefited from the two published European guidelines. The first is the conclusion of the Barcelona European Association for the Study of the Liver conference(1), and the second is the guidelines published by the British Society of Gastroenterology(2). In addition, we have benefited from a special dedicated supplement issue of Gastroenterology (November 2004) containing extensive reviews of the topic, and from the American Association for the Study of the Liver (AASLD) guidelines that were recently published(3). We hope that these guidelines will improve the care of patients suffering from HCC and facilitate the performance of research in this important medical problem. Grading of Recommendations Grade A: Recommendation based on at least one high quality randomized controlled trial or at least one high quality meta-analysis of well-done randomized controlled trials. Grade B: Recommendation based on high quality casecontrol or cohort studies or a high quality systematic review. Grade C: Recommendation based on non-analytic studies (case reports or case series). Grade D: Recommendation based on expert s opinion only.

4 Prevalence Epidemiology HCC is the most common primary malignancy of the liver. It represents the fifth most common cancer and the third most common cause of cancer death worldwide(4). It has a variable geographical distribution around the world. The incidence in developing countries is two to three times higher than in Western countries. For example, in Eastern Asia and Middle Africa the age-adjusted incidence rate (AAIR) ranges from cases per 10 5 in men while it is about 1-3 per 10 5 in Northern Europe, Australia and North America(4). In the United States the incidence of HCC has increased from 1.4 per 10 5 population at the period from to 2.4 per 10 5 population for the period from (5). In Saudi Arabia, liver cancer accounts for 6.1% of all newly diagnosed cancers according to the most recent cancer registry covering the years (6). HCC was the second most common cancer affecting Saudi males and the eighth most common cancer affecting females with an overall age standardized rate of 4.5/100,000 population. Male to female ratio is 279:100. In Saudi Arabia, HCC accounts for 87.6% of all liver cancers. The median age at diagnosis is 65 years for males and 60 years for females. This incidence of HCC in Saudi Arabia is not surprising given the high prevalence of the two major risk factors, namely hepatitis B and hepatitis C infections. In a large epidemiologic study by Al Faleh et al, 7% of Saudi children were found to be positive for HBsAg(7). Not until universal vaccination was applied in Saudi Arabia did this prevalence rate decrease to less than 0.3%(8). Since the initial epidemiologic studies showing high prevalence of hepatitis B were done in children who are now adults, it is estimated that about 20% of these patients will probably develop cirrhosis along with an annual risk of 1-4% for HCC. Based on these figures the incidence of HCC is expected to increase dramatically in the Kingdome in the next 30 years. Hepatitis C is also common in Saudi Arabia with a prevalence rate of 1-3% of the population(9), which further increases the risk of HCC. More recently, the incidence of hepatitis C seems to have decreased to about 1.1%(10). The incidence of HCC increases with age. The mean age of acquisition is clearly lower in areas of high endemicity such as in China and Africa, where in Mozambique for example, more than 50% of affected men are younger than 30 years of age(11). In general, HCC is more common in men than in women especially in areas with high prevalence(4). Three relatively small studies done in the 1980 s described some aspects of the epidemiology of HCC in Saudi Arabia. In the first study by Kingston et al, all cases of liver tumors were studied over a period of 2 years in King Faisal Specialist Hospital in Riyadh(12). A total of 104 cases of HCC were found. These patients were predominantly male (6:1 ratio). In the second study by Ashraf et al, 75 patients with HCC were described from the Gizan area in Southern Saudi Arabia(13). Eighty percent of these patients were males. In the third study by Atiyah and Ali, the clinico-pathological features of 54 patients with HCC were described(14). The male to female ratio was found to be 10:1 with a peak incidence age between years. Risk factors The most significant risk factor for the development of HCC is the presence of cirrhosis, regardless of its etiology. Some of the important risk factors will be discussed briefly. 1) Cirrhosis The development of cirrhosis is the major risk factor for the development of HCC regardless of the cause. The annual incidence of HCC in patients with compensated cirrhosis is about 3% (15). European cohort studies have reported that, among persons who died of a liver related cause, HCC was responsible in 54% to 70% of patients with compensated cirrhosis of different etiologies and in 50% of patients with HCV related cirrhosis(16;17). This is thought to be secondary to a potent tumor promoter effect(18). Male sex, age, and duration of cirrhosis are associated with an increased risk of HCC in patients with cirrhosis (19). 2) Hepatitis B virus (HBV) This is considered the strongest epidemiologic factor associated with HCC in the majority of countries but more importantly in Asia and Africa. The carrier state of hepatitis B early in life carries a lifetime relative risk of developing HCC of over 100(20), while the annual incidence of HCC in hepatitis B patients with cirrhosis exceeds 2% (21-23). Many factors are important in

5 determining the risk of HCC in hepatitis B virus (HBV) infected patients. The most important factor is the stage of the liver disease. In a summary of all the follow-up studies of patients with hepatitis B, it was found that in HBV carriers with persistently normal ALT the annual incidence of HCC was 0%. This incidence increased to 1.2 % in patients with histological active hepatitis, and between 2-6 % in patients with established cirrhosis(24). On the other hand, studies from Asia suggest that the annual incidence of HCC in HBV carriers is around 0.5%(23;25). Another two related important factors are the race and the age of infection. In Caucasian HBV carriers, HCC occurs most often in the setting of cirrhosis(21) but in Africa and South East Asia, HCC may develop more frequently in non-cirrhotic livers(22). This is thought to be related to the duration of infection or to dietary aflatoxin. Hepatitis B virus is thought to be carcinogenic both directly and indirectly(18) because HBV DNA is integrated into cellular DNA of the host and can be demonstrated in HCC cells in 95% of the cases(26). 3) Hepatitis C virus (HCV) This is considered the most important risk factor for HCC in Western countries and Japan. In a meta-analyses of 32 case control studies, the estimated risk for the development of HCC was 17.5-fold greater in HCV carriers than in non carriers(27). Almost all HCC in hepatitis C patients occurs in those who have developed cirrhosis, where the yearly incidence varies between 3 to 8 %(15;28;29). In Japan, the summary of HCC incidence rate was 1.8 per 100 person years in subjects with chronic hepatitis C without cirrhosis and 7.1 in those with compensated cirrhosis(30). This suggests that hepatic parenchymal disease plays a major role in the development of cancer in this disease(19). To further clarify the importance of the stage of liver disease in the risk of HCC in HCV infected patients, Colombo summarized the follow-up studies of patients with hepatitis C. It was found that the annual risk for development of HCC was 0.4% for unselected HCV carriers with persistently high values of ALT, but it rose to 1.7% in patients with the histological diagnosis of chronic active hepatitis and to 2.5% in those with compensated cirrhosis(24). Although HCV does not integrate into the host genome, there is some evidence that the virus is directly oncogenic(31). 4) Alcohol The risk of HCC is increased up to 40% with heavy alcohol consumption(32). In a study from Italy, the risk of HCC was found to be 13 times greater in drinkers than in non-drinkers(33). In a recent met-analyses of 3 cohort and 17 case-control studies there was a clear trend toward increased risk of HCC in heavy drinkers(34). Infection with HCV or HBV in alcoholic drinkers clearly increases this risk suggesting a synergistic effect(35;36). 5) Aflatoxin B1 Aflatoxin B1 derived from Aspergillus flavus and Aspergillous parasiticus is an important risk factor for HCC in parts of Africa and Asia(19). Most authorities believe that the effect of Aflatoxin is only important in patients who have pre-existing chronic hepatitis B (1). 6) Other risk factors In patients with hereditary hemochromatosis, the estimated risk of development of HCC is increased 200 times more than the general population once cirrhosis is established (37) with an annual risk of 5% (38), mostly with advanced cirrhosis but also rarely in patients without cirrhosis (39). HCC develops occasionally in Wilson s disease but usually in association with cirrhosis (40). Other inherited metabolic diseases of the liver such as type 1 glycogen storage diseases and alfa 1 antitrypsin deficiency may all be associated with HCC. The studies on the effect of smoking on the risk of HCC are conflicting but this is probably a minor risk factor(19). Early small studies on chronic oral contraceptive pills showed an increased risk of HCC with a relative risk of 3.8 to 13.5, but larger more recent studies showed no increased risk at all (41). HCC may also develop in 40% of patients with membranous obstruction of the inferior vena cava (42). Natural history The natural history of HCC depends on the stage of the disease but generally carries a poor prognosis in the majority of cases. Tumor size at presentation is an important factor in the natural history but its use as a sole predicting factor is hindered by the fact that tumordoubling time may in fact be very variable. In some patients the tumor growth is slow, doubling in size in twenty months or more, while in others the tumor grows

6 much faster and doubles in less that 1 month (43; 44). In symptomatic patients in China and Africa, death usually ensures within four months (45), while other reports have suggested a longer survival and a more indolent course in Western countries (46). Other important factors in the natural history include the stage of the underlying liver disease and the patient s performance status as discussed in the staging systems below. Conclusions: HCC is a common tumor in Saudi Arabia and the incidence is likely to increase dramatically in the next 30 years. There are no large epidemiologic studies to define this disease in Saudi Arabia. Hepatitis B and hepatitis C appear to be the two most important risk factors for HCC in Saudi Arabia but other risk factors need to be studied further. Recommendations» Much more resources should be allocated to this important medical problem in Saudi Arabia.» Large epidemiologic studies are needed to further define the epidemiologic features of HCC in Saudi Arabia.» Patients with cirrhosis of any etiology, but especially cirrhosis caused by hepatitis B or C, are at an increased risk for the development of HCC and these patients should be targeted for a screening program (grade A)» The incidence of HCC in those with hepatitis B infection without underlying cirrhosis, in Saudi Arabia needs to be studied further before firm screening recommendations can be given. Clinical Features The classical features of HCC include right upper quadrant abdominal pain and weight loss. Weakness, abdominal swelling, non-specific gastrointestinal symptoms, and jaundice are other presenting features. Special clinical scenarios should raise the suspicion of HCC. These include acute deterioration of liver function in a patient with stable cirrhosis, new onset ascites, and acute intraabdominal bleeding. Physical findings vary according to the stage of the disease. If the tumor is small, no signs may be found except those related to underlying cirrhosis where present. In more advanced cases, hepatomegaly is common, with the possibility of palpating a mass or a hard irregular liver surface which in turn may be tender. A bruit may be heard over the liver. Ascites is often found, most commonly as a result of the underlying cirrhosis leading to portal hypertension but rarely due to tumor invasion of the peritoneum. Muscle wasting is common and is usually progressive. HCC is known to cause many paraneoplastic syndromes. These are generally rare, but important to identify. Type B hypoglycemia is seen in 5% of patients and may be seen early in the disease (47). Polycythemia may be seen in less than 10% of patients (48). Hypercalcemia may also be seen in the absence of bone invasion. Skin manifestations like pityriasis rotunda have been described. Other less likely paraneoplastic features include sexual dysfunction, watery diarrhea, thyrotoxicosis, neuropathy, and carcinoid syndrome (19). In the three epidemiological studies done on patients with HCC in Saudi Arabia, patient s presentations were not different from those described above. In the study by Ashraf et al, 91% of the patients presented with hepatic enlargement, 76% with abdominal pain, 33% with splenic enlargement, and 33% with ascites(13). Abnormal liver function tests were found in 97% of the patients. The study by Kingston et al was very similar in its findings(12). Conclusions: HCC usually presents with weight loss and right upper quadrant pain in addition to the symptoms and signs of underlying liver cirrhosis. Recommendations» In patients with stable cirrhosis, rapid deterioration of liver function, new onset ascites, weight loss, or increased jaundice should initiate investigations for HCC (Grade C).

7 Radiological Features Diagnosis Various imaging modalities particularly cross-sectional imaging are essential keys in the management of patients with HCC. These powerful techniques allow the detection, characterization and staging of HCC, as well as planning the appropriate therapy and follow-up of these patients post-treatment. 1) Ultrasonography (US) At the present time, the main role of US towards the diagnosis of HCC lies in screening. While US has the advantage of being safe, easily available, and being cost effective, it is hindered by its low specificity and its operator dependent nature. Newly discovered focal liver masses in patients with liver cirrhosis have a high likelihood of being HCC(2). Abdominal US is associated with a sensitivity and specificity of 20-51% and 92-96% respectively for detecting lesions consistent with HCC in patients with cirrhosis (49;50). The majority of small masses are homogeneously hypoechoic rendering them indistinguishable from regenerating nodules (51). Detection rates for lesions between 2 to 3 cm and 1 to 2 cm with US are estimated to be as low as 20% and 13%, respectively (52). Larger HCC tend to follow a mosaic pattern due to fatty degeneration or coagulation necrosis. Occasionally HCC appears hyperechoic, which is probably due to fatty changes or dilated sinusoids. HCC may present variously as a solitary mass or a dominant mass with surrounding satellite nodules, or multifocal masses, or less commonly as a diffusely infiltrating mass. In more advanced cases of HCC, vascular invasion, particularly of the portal vein, and biliary obstruction may occur. In spite of the limitations of US in diagnosing HCC, due to its low cost, safety and availability, it is still considered the best initial test to be performed when HCC is suspected. 2) Computerized Tomography (CT) Using multi-detector scanners, triphasic CT scan of the liver has proven to be very useful in the diagnosis of HCC. This technique encompasses non-contrast, hepatic arterial (HA) and portal venous (PV) phases. Arterial and portal venous phases are acquired around 20 and 60 seconds from the start of injection respectively, by a power injector intravenously at a rate of 4 cc/sec. This technique utilizes the fact that the blood supply to HCC is predominantly from the hepatic artery resulting in a hypervascular nature. Consequently, HCC appears hyperdense during the HA and relatively hypodense during the PV phases due to contrast washout. Large HCC is typically inhomogeneous. Imaging during the arterial phase of the contrast pass is of paramount importance if a small HCC is to be detected and the relatively specific diagnosis of HCC to be made. This phase has also replaced conventional angiogram in delineating the hepatic arterial anatomy prior to liver transplantation. In recent studies, contrast-enhanced CT scan has been reported to have sensitivity and specificity rates of 71-80% and 80-96% respectively, compared with explants histology (55-55). CT has the advantage of detecting extrahepatic spread and accurately staging HCC. Its local extension and complications including vascular invasion, biliary obstruction and peritoneal hemorrhage due to tumoral rupture are exquisitely demonstrated with CT. Presence of small abdominal lymphadenopathy does not upstage the tumor as it is common in patients with cirrhotic patients without underlying HCC, especially in patients with hepatitis C (56). 3) Magnetic Resonance Imaging This test has become the diagnostic procedure of choice for HCC in many institutions (57). While HCC has variable signals on T1 weighted imaging, it is usually hyperintense on T2. Because of the abundant neovascularity, HCC enhances vividly during the arterial phase of gadoliniumenhanced imaging. In the portal venous phase, HCC is usually isointense. In the delayed phase, HCC will be hypointense because of contrast medium wash out. If the tumor is well-differentiated, it exhibits a high signal on T1 weighted imaging that is likely attributed to fat deposition, copper or glycoproteins, and is therefore isointense on T2 weighted imaging (58). 4) Hepatic Angiography Hepatic angiography in the present era has no significant role in the diagnosis of HCC. It is however, sometimes used to delineate the hepatic artery anatomy when

8 planning OLT. It is also an essential component during chemoembolization of HCC. Laboratory Investigations 1) Serum Alfa Fetoprotein (AFP) AFP is an alfa 1 globulin that is normally present in high concentrations in fetal serum but in only minute concentrations in adults. The seven major studies reporting on the sensitivity and specificity of AFP in screening for HCC are nicely summarized by Daniele and colleagues and show sensitivities of 39-65%, specificities of 76-94%, but a poor positive predictive value of 9-50% (59). In a recent systematic review it was confirmed that AFP has a poor diagnostic ability to detect HCC at any level of pretest risk (60). However, as a confirmatory test in patients with a mass on imaging studies, AFP determination remains clinically useful (61). AFP presence and level of elevation is related to many factors, most importantly the prevalence of the disease. In high endemic areas the vast majority of patients have an elevated level (above 20 ng/ml) and more than 75% of patients have levels that are higher than 500ng/L. These figures are lower in patients from low prevalence areas for HCC. In addition, the mean serum level in high incidence areas is around 60,000 ng/ml compared to about 3000 ng/ml in regions with low incidence. AFP elevation of less than 500 ng/ml may be seen in patients with active necroinflammatory changes in the liver secondary to active hepatitis. In fact, in one study, of 44 HBV carriers with elevated AFP levels detected during surveillance for HCC, only 6 were found to have HCC on further investigations and in 18 patients the elevated AFP was associated with an exacerbation of underlying liver disease (62). A progressively rising AFP level even at low concentrations is highly suggestive of HCC (63-64). Elevations above 1000 ng/ml have a high specificity rate. AFP level may also be affected by the patient s age. The younger the patient, the more likely is the level to be raised and a higher level attained. Provided that the patients are age-matched, no gender differences are seen in the level of AFP. No obvious correlation exists between the serum concentration of AFP and any of the clinical or biochemical features of the tumor or the survival time after diagnosis. However, some studies have shown that symptomatic patients have a higher level of AFP than asymptomatic patients. Studies are now under way to try and refine the assay of AFP in order to try to improve its specificity including the detection of fucosylated AFP which is more specific for malignant hepatocytes(19). Other tumor markers are under investigation but are not primed for clinical use yet. These include Des-y-carboxy prothrombin and alfa-l-fucosidase. 2) Histological Sampling Obtaining a tissue diagnosis for HCC is not considered a mandatory step in the majority of cases of HCC. In liver nodules less than 2 cm in size, confirmatory histology or fine needle aspiration FNA is important to diagnose HCC as current radiological methods are not accurate enough to establish a definitive diagnosis. However, it should be borne in mind that the false negative rate of biopsy in these small lesions is about 40% (65). On the other hand, in the case of nodules above 2 cm in diameter the diagnosis of HCC may be established confidently without requiring histological evidence (66; 67). In these patients the likelihood of this lesion being HCC is more than 95% (68; 69). Combining this high likelihood of HCC to the advantage of new imaging studies detecting arterial perfusion, the diagnosis of HCC can be made positively in the majority of cases without biopsy. These tests offer the advantage that they can differentiate HCC from benign liver lesions and secondary tumors with a high degree of accuracy (70-72). Among 160 patients with 225 focal liver lesions evaluated by means of sequential radiological imaging studies, in preparation for planned surgical therapy, the preoperative diagnostic accuracy rate without histological confirmation was reported to be 98.2%, with a sensitivity of 100%, and a specificity of 98.9% (66). In addition, it has been reported that the overall false negative rate for FNA or even trucut biopsy in detecting HCC is as high as 20% (71; 73; 74). An important, although seemingly rare, complication of tumor biopsy is needle tract tumor seeding. This complication has been estimated to occur in about 1-5% of biopsies and is especially important if the patient is awaiting liver transplantation or resection (65; 70; 74). In liver lesions without cirrhosis or in situations when imaging is unclear, tissue diagnosis is important (75). If histology is required, the highest rate of diagnostic accuracy (97%) is achieved by combined use of FNA

9 cytology plus intranodular and extranodular fine needle microhistology (76). Liver biopsy may be useful not just in the diagnosis of HCC but also to evaluate the rest of the liver to guide further therapy. If the clinical presentation is doubtful and the stage of cirrhosis needs further clarification then a biopsy of the non-tumorous liver may be helpful. The European Association for the Study of the Liver recommended non-invasive HCC diagnostic criteria that can be used in cirrhotic patients. These include two coincident imaging techniques showing focal lesion(s) more than 2 cm in size with arterial hypervasularization or one imaging technique showing the above in addition to an AFP >400ng/mL (1). If a diagnosis cannot be reached by these non-invasive criteria then a histological confirmation is warranted. The British Society of Gastroenterology has also recommended a similar approach (2). The recent guidelines by the American Association for the Study of the Liver went a step further in this non-invasive approach to the diagnosis of HCC and recommended that only one imaging modality showing the typical early arterial enhancement and venous washout would be enough to diagnose HCC if the lesion is larger than 2 cm and the liver is cirrhotic (3). In an interesting, recent study examining the non-invasive criteria recommended by these guidelines, Bolondi et al prospectively compared the presence of arterial hypervasularity on contrast perfusional US and CT to results of biopsy in 72 liver nodules (77). They found that in nodules larger than 2 cm all lesions demonstrating arterial hypervascularity turned out to be HCC. In lesions less than or equal to 2 cm only 71% of these lesions were diagnosed as HCC. On the other hand, 8.3% of proven HCC on biopsy did not show typical hypervascular enhancement on radiological examinations (all less than 3 cm). This study strongly supports the non-invasive criteria of relying on radiological tests only, without biopsy in lesions larger than 2 cm, and performing biopsy in lesions less than or equal to 2 cm. Staging After establishing the diagnosis of HCC, the next step in the management of such patients should entail staging of the disease. This should only be done if treatment is to be offered. An ideal staging system should be able to Diagnosis Recommendations» US should be the initial radiological investigation performed when HCC is suspected (Grade C).» Further imaging should be performed if an abnormality is found or if the suspicion of HCC is high even if the US is normal (Grade C).» Triphasic CT scan and MRI are the radiological procedures of choice to confirm the diagnosis of HCC (Grade B).» It is extremely important that the CT scan is done in a standard triphasic technique and is read by a trained abdominal radiologist (Grade A).» The diagnosis of HCC may be positively made if the following conditions are achieved (Grade B): 1. The liver is cirrhotic 2. The lesion is larger than 2 cm in diameter 3. One of the two following criteria is met: a. AFP is higher than 400 ng/l and one imaging modality confirms early arterial enhancement and venous washout. OR b. AFP is normal and two imaging modalities confirm early arterial enhancement and venous washout.» A histological diagnosis is recommended in the following circumstances (Grade B): 1. If a lesion is found in a non-cirrhotic liver and radiological investigations are not conclusive for hemangioma, focal nodular hyperplasia, or adenoma. 2. If the suspicion of HCC is high but the noninvasive criteria mentioned above are not satisfied.» Although AFP is a poor screening tool for HCC, it should be measured in all suspected cases. Levels below 400 ng/l are suggestive of HCC, but may be seen in patients with active hepatitis without HCC. Levels above 1000 ng/l are more specific for HCC. A persistently increasing AFP is highly suggestive of HCC (grade B). separate patients into distinct clinical groups based on survival so that appropriate treatment modalities can be applied. This system should be able to incorporate the tumor characteristics as well as the liver function. There are now more than 10 staging systems for

10 HCC. They each have their specific advantages and disadvantages. We will briefly review here the most clinically relevant systems. 1) TNM Classification System: This system is similar to other cancers classification systems (78). It has the advantage of accurately describing the tumor characteristics and stage, but it does not take into consideration the underlying liver function. Liver function is extremely important in the long-term prognosis of the patient as well as in deciding on some therapeutic modalities like resection or transplantation. In addition, the TNM classification system does not seem to be able to predict the rates of tumor recurrence after OLT, a feature that has a very important prognostic value and is not related to the liver function. In an analysis of 58 patients who underwent OLT for HCC there was no difference in the rates of tumor recurrence comparing TNM stages 1 and 4 (79). 2) Okuda Classification System: This system takes into account both the tumor characteristics and the liver function (80). It is basically based on gross tumor factors and is not very useful clinically. It has enjoyed wide acceptance at a time when there were limited options for patients with HCC and the main goal of a classification system was to separate patients with advanced disease who should only be offered palliative care, from patients who should be included in clinical trials. This system serves this purpose well as it is excellent in identifying the very advanced patient who will likely not tolerate any mode of therapy (Okuda 3). On the other hand this system performs less well when it tries to separate other less advanced patients (81). This is mainly related to the simple fact that before stage 3 there are only two other stages, one and two. These will include a heterogeneous group of patients some of whom may have good prognosis while others do not. 3) Cancer of the Liver Italian Program (CLIP) Classification System This system has been developed based on a large retrospective analysis of 435 Italian patients with HCC using a Cox proportion hazard model (82). This system has the advantage over the Okuda score in that it is evidence-based and in that it gives more leeway to assess patients who are not so terminal (81). It has been further prospectively validated in two Italian studies of 196 and 154 patients (83) with HCC, and retrospectively in 662 Japanese patients (84). In the Japanese and an Italian study, this scoring system was found to be superior to the Okuda system. Some groups have criticized the CLIP score for not being adequately assessed in patients undergoing radical resection (81). 4) Barcelona Clinic Liver Cancer Classification System (BCLC): This scoring system is very clinically oriented. It takes into account the three major factors that are important in deciding the treatment options i.e. the tumor stage, the liver function, and the patient s performance status (85). It clearly separates patients with early disease who should undergo aggressive therapy, from end-stage patients. This system is difficult to interpret when factors are not aligned with the designed table. For instance, a patient who has Child-Pugh category C cirrhosis, a small lesion, and excellent performance status, would be inaccurately classified by this system. In addition, this system has not been externally validated. Liver transplantation Management Orthotopic liver transplantation (OLT) is theoretically the best treatment for HCC because it results in the widest possible resection margins from the cancer, removes the remaining liver tissue that is at risk for the development of de novo cancer, and restores hepatic function (81). The major practical obstacle is the extreme shortage of organs which makes this an impractical option in the present circumstances. In 1996, Mazzaferro and colleagues reported their experience in transplanting patients with HCC (86). They reported a 75% 4 year survival rate when using the criteria of only transplanting single HCC s that are less than 5 cm, or multiple HCC s that are less than 3 in number and less than 3 cm each. The excellent survival rates seen in the Mazzaferro series was confirmed by many other series using the same inclusion criteria (87). These criteria (named the Milan criteria) have been accepted as standard of care and are applicable to date. The survival 10

11 Staging Recommendations» Liver tumor weekly rounds should be started at every tertiary care center dealing with HCC patients. In this meeting, all cases of liver tumors should be discussed. The group should be composed of a hepatologist, an oncologist, a hepatobiliary surgeon, and an intervention radiologist. The goal of this meeting is to discuss new cases of liver tumors and to reach a joint decision on the most appropriate management route for these patients. It will also improve recruitment in clinical trials and will facilitate the teaching of residents and fellows (Grade D).» Patients with a liver mass should be evaluated in the weekly liver tumor rounds. This evaluation will help determine the next step in obtaining a final diagnosis, determine the extent of hepatic involvement, rule out extrahepatic disease, evaluate the general medical status and performance of the patient, and evaluate functional hepatic reserve (Grade D). Initial evaluation of patients with HCC should include the following (Grade D): 1. A complete history 2. A full physical examination 3. Initial laboratory tests including: A complete blood count, random serum glucose, serum electrolytes, renal function, alfa-feto protein, serum calcium, prothrombin time, and liver function tests. 4. Chest x- ray (or a CT chest if there are suspicious lesions for metastases on the chest X-ray) 5. Bone scan (only on initial visit and every 9 months thereafter)» Follow up visits should also include all the above tests at least every 3 to 6 months as long as the patient is in an active treatment arm of the management plan (Grade D).» It is clear that no single classification system is superior to the others with there being advantages and disadvantages for each one.» Although each staging system has its own advantages and disadvantages, the CLIP score enjoys epidemiologic support and prospective validation while the BCLC is probably preferred in planning future treatment (Grade B). data presented in the Mazzaferro series demonstrated comparable survival of patients receiving OLT with and without HCC. In addition, the recurrence rates posttransplantation, when these criteria are used, is extremely low. Practically speaking, these criteria were developed at a time when the waiting list for OLT was around 6 months, while the present era waiting lists are much longer, allowing patients to drop out of the transplant list because of contraindications. These contraindications include: extrahepatic spread, increase in size of the tumor beyond transplantation criteria, or vascular invasion. This clinical observation has been shown elegantly by the Llovet et al group who compared, in an intent-to-treat analysis, the 2 year survival of patients transplanted in two periods, and found a drop in survival from 84% to 54% as the mean waiting time increased from 62 days to 162 days (88). Many strategies have been suggested to overcome these major limitations in transplantation for HCC. One is living-related transplantation. There are limited data on this modality in HCC but preliminary data of livingrelated transplantation in non- HCC patients shows that it is probably as effective as cadaveric transplantation (89). Multiple statistical and mathematical models have also shown that living-related transplantation for HCC may be cost-effective and life saving, compared to cadaveric transplantation (90; 91). The other method used to increase the accessibility to transplantation is to expand the tumor size criteria described by Mazzaferro. Yao et al, reported on the survival of 70 consecutive patients undergoing OLT for HCC including 25% with either solitary tumors cm in diameter, or less than or equal to 3 nodules each being less than or equal to 4.5 cm with total tumor diameter less than 8 cm (54). These patients survival was not different from patients transplanted according to the Milan criteria. This series (and many recent abstracts from other centers) suggest that the Milan criteria can indeed be expanded which may give patients the opportunity to stay on current waiting lists. A different approach to the expansion of the Milan criteria was presented by investigators from the University of Pittsburgh (92). These investigators suggest that size should not be a selection criterion for transplantation but rather other histologic and radiologic factors including: vascular invasion, lymph node spread, and obvious metastatic spread. Results using this approach are encouraging, with only 9% recurrence rates being reported, but is disadvantaged by not being studied prospectively or requiring a pre-transplantation histology. 11

12 In patients with small HCC s and advanced liver disease, liver transplantation is clearly a better option compared to resection but, owing to the organ shortage, another strategy has been suggested. This strategy starts with radical resection and is followed with salvage transplantation if the patient develops liver failure. Markov modeling by Majno et al showed that this may not be a cost-effective strategy given the high recurrence rate and that primary OLT may be better (93). In many centers, adjuvant therapy is given to delay the progression of HCC while patients are awaiting OLT or shrink the size of the tumor in order to fit OLT criteria (down staging). For instance, RFA has been tried in a number of small case series. In a recent study, 50 patients meeting the Milan criteria were treated with RFA and with a mean waiting time of 9.5 months before transplantation there were no dropouts from the waiting list. This study showed a 3-year survival of 83% and a 4% post-transplantation recurrence (94). Similarly, chemoembolization has been used in this setting. In a study by Graziadei et al, 48 patients satisfying the Milan criteria were treated with chemoembolization while waiting for transplantation. They reported no waiting list drop-outs and 5-year survival rates of 94% despite a mean waiting time of 178 days (95). In another study, 45 patients were treated in a similar protocol with a 6 month 15% drop-out rate due to tumor progression and 25% at 12 months (96). One study compared patients who received chemoembolization with those who did not and found that responders to treatment fared better than non-responders with a trend towards improved survival compared with the untreated group (97). Most importantly, complications arising from chemoembolization in these pre-transplantation patients were rare and did not frequently cause drop-outs from the list in the majority of the studies (87). It is important to note here that the survival of patients discovered to have incidental tumors in explanted livers is similar to patients transplanted without evidence of tumor. In Saudi Arabia, although liver transplantation is available and successful and while a long and rich experience has accumulated over the last 10 years, all programs are crippled by the lack of organ donation. With current long waiting lists, OLT does not seem to be a practical option for the majority of HCC patients in Saudi Arabia. Living-related transplantation is being increasingly performed in the Kingdom and its role in HCC is yet to be defined. With the encouraging post-olt survival rates for HCC obtained with the Mazzaferro criteria and the extreme lack of donors in Saudi Arabia, we recommend using these criteria as the current transplantation criteria and only expanding them in limited circumstances. We also recommend that living-related transplantation be expanded and studied further in the management of HCC. Hepatic resection Rapid advances in the field of hepatobiliary surgery have occurred in the past 20 years making major hepatic resection a less morbid procedure. In most large centers in the world, operative mortality in cirrhotic patients is less than 5% (98). In fact, some leading centers report no mortality after over 100 consecutive cases (99; 100). Although tumor resection removes the visible portion of the cancer, it is clearly inferior to transplantation in that it cannot guarantee the removal of invisible tumor seeding. Resection also entails leaving the non-tumorous portions of the liver, which by itself is at high risk of developing malignancy. Furthermore, this surgery does not address the underlying disease and fails to improve hepatic function. Unfortunately, there are no randomized studies that prove the effectiveness of resection in managing patients with HCC. Large series of liver resection for HCC report a 38-65% 3-year survival and 33-44% 5-year survival(84). The population in these studies was heterogeneous with different stages of cirrhosis. In patients with small HCCs and relatively preserved liver function, Bismuth et al have shown excellent long term survival results of 40% and 26% at 5 and 10 years respectively (101). When more stringent criteria are applied, survival rates have been reported to be as high as 50% in 5 years (102). These criteria include solitary tumors less than 5 cm in diameter, with no evidence of vascular invasion or extrahepatic spread, and with either no evidence of cirrhosis or well-compensated Child-Pugh class A cirrhosis. When all the patients in Japan treated with hepatic resection were considered, the most powerful predictor of survival was the combination of three factors: AFP, tumor size, and the number of tumors (103). One of the major factors determining the candidacy of 12

13 patients for radical resection is the stage of the underlying liver disease. Although many surgeons still use the Child-Pugh classification to assess the liver function and would perform a liver resection on non-cirrhotic Child-Pugh class A, or good Child-Pugh class B patients (98), we feel that the best evidence suggests that other parameters may be more accurate in determining surgical hepatectomy risk in terms of hepatic decompensation. Two such parameters have been shown to be most predictive of decompensation post liver resection. These are: signs of clinically relevant portal hypertension (defined as presence of varices, splenomegaly, platelet count <100,000 or a hepatic veinous pressure gradient > 10 mm Hg) and elevated bilirubin (more than 1 mg/dl) (104). When these criteria are used to select patients, the 5 year survival after resection may be as high as 70% (88). Two issues make this modality difficult. First, the majority of patients with HCC will either have too advanced a liver disease that makes liver resection impossible, or have extensive disease at the time of presentation. For this reason, most series show that less than 10% of patients with HCC will be candidates for resection (104). This problem is expected to be even worse in Saudi Arabia since effective HCC screening programs are not widely implemented. The other problem is that even in patients who undergo resection, the intra-hepatic recurrence rate is high (around 50-60% in 5 years) (105; 106). This recurrence rate is directly proportional to the tumor size. In addition, patients are at an increased risk for new tumors since the cirrhotic liver has not been removed. We feel that in patients without cirrhosis or with early cirrhosis (indicated by a normal bilirubin and no signs of clinically significant portal hypertension), liver resection should be considered if there is no evidence of extrahepatic or vascular spread. As a general guideline, noncirrhotic patients can recover well from resections that preserve at least 2 segments of functioning liver, while patients with well-compensated cirrhosis will tolerate a maximum of 2 resected functional segments of the liver. In some centers pre-operative portal vein thrombosis is performed when a resection of more than 2 functional segments of the liver is performed, with the intention of inducing hypertrophy of the remaining liver (107). Many experts do not consider tumor size as an important factor in deciding on resection since size may not represent a technical problem for the skilled hepato-biliary surgeons. However, we feel that the data is clear in that the larger the tumor the more likely the recurrence after resection thereby compromising the patient s survival. In addition, most studies have shown that local ablative therapies may produce similar survival compared to resection. Similarly, the most recent evidence (described shortly) shows that chemoembolization probably has a significant survival benefit, a feature not shown clearly in the case of resection. For these reasons we feel that the best treatment option in a Child-Pugh category A or B cirrhotic patient with a large tumor is probably chemoembolization rather than surgical resection, even if it is technically feasible. Surgical resection should be reserved for patients who are not cirrhotic or patients with well-compensated cirrhosis with small tumors. In some centers, palliative surgical resection with near total tumor mass resection is practiced after which local ablative therapy is performed to deal with the remaining tumor (98). This approach is awaiting support by prospective studies. Ablative therapy Most patients with HCC are unsuitable for surgical therapies due to extension of the disease, poor hepatic reserve, or coexistent morbidity. Therefore, non-surgical therapies play a central role in the management of this disease (108). Ablation of HCC has been carried out for many years now. This could be done by either chemical means (absolute alcohol or trichloracetic acid) or physical means (cryoablation, radiofrequency ablation, microwave coagulation, or injection of hot saline). We will only discus the percutaneous ethanol injection (PEI) and radio-frequency ablation (RFA) in this review. 1) Percutaneous ethanol injection (PEI): PEI is a widely accepted, minimally invasive method of treating HCC. Its acceptance is based on the ease of treatment, minimal and inexpensive therapeutic equipment required, and good clinical results. It is achieved by injection of 95% absolute ethanol into the tumor under US and/ or CT guidance. Ethanol causes cellular dehydration and subsequent necrosis of the tumor. The goal of this therapy is to achieve complete necrosis of the tumor with extension into the perineoplastic tissue. The amount needed to ablate a given HCC varies with its size. The typical amount given per session is 1-8cc, which can be done two times per week and is usually performed 13