- Email: [email protected]
Surveillance and early diagnosis of hepatocellular carcinoma
Digestive and Liver Disease 42S (2010) S223–S227
Surveillance and early diagnosis of hepatocellular carcinoma Riccardo Lencioni * Division of Diagnostic Imaging and Intervention, Department of Liver Transplantation, Hepatology and Infectious Diseases, University of Pisa, Pisa, Italy
Abstract Patients at high risk for developing hepatocellular carcinoma (HCC) should be enrolled in surveillance programs based on ultrasound (US) examinations performed at 6-month intervals. Nodules found during US surveillance that are smaller than 1 cm should be followed-up with US at 3-month intervals. If the nodule found during US surveillance is larger than 1 cm, it should be investigated further with contrast-enhanced dynamic radiological studies, including US, multidetector computed tomography, or magnetic resonance imaging. If the appearance is typical for HCC (i.e., the lesion shows hypervascularization in the arterial phase with washout in the portal venous or the equilibrium phase), biopsy is considered unnecessary and the lesion can be treated as HCC. For nodules between 1 and 2 cm, it is currently recommended that such non-invasive diagnosis be based on the evidence of coincidental features typical for HCC from at least two dynamic imaging techniques. If the vascular profile on imaging is not characteristic or the nodule is detected in a non-cirrhotic liver, biopsy should be performed. If the biopsy is negative for HCC, patients should be followed-up by imaging studies performed at 3-month intervals until the nodule either disappears, enlarges, or displays diagnostic characteristics of HCC. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Hepatocellular carcinoma, diagnosis; Hepatocellular carcinoma, staging; Hepatocellular carcinoma, surveillance
1. Introduction Owing to surveillance of patients at high risk for the development of hepatocellular carcinoma (HCC), an increasing number of tumours are currently diagnosed at an early, asymptomatic stage [1]. Lesions detected by surveillance require proper diagnostic approach. In fact, diagnostic confirmation of small nodules detected by ultrasound (US) as true HCC may be challenging, as pathologic changes inherent in cirrhosis – such as dysplastic nodule (DN) – mimic a small tumor [2,3]. In this article, a rational approach to surveillance, diagnostic confirmation, and tumour staging – based on the conclusions of the 2000 and 2005 Monothematic Conferences
* Correspondence to: Professor Riccardo Lencioni, Director, Division of Diagnostic Imaging and Intervention, Department of Liver Transplantation, Hepatology, and Infectious Diseases, Pisa University School of Medicine, Cisanello Hospital, Building 30B, Suites 196-198, IT-56124 Pisa, Italy. Tel.: +39-050-997-321, fax +39-050-997-320. E-mail address: [email protected]
on HCC of the European Association for the Study of the Liver (EASL) [4] and the practice guideline document of the American Association for the Study of Liver Diseases (AASLD) [5] – is presented.
2. Surveillance The objective of surveillance must be to decrease mortality from the disease. Surveillance for HCC has become widely applied despite, until recently, the absence of evidence of benefit. There is a single randomized controlled trial (RCT) of surveillance versus no surveillance that has shown a survival benefit for a strategy of 6-monthly surveillance with alpha-fetoprotein (AFP) and US [6]. This study, which was performed in China, recruited 18,816 patients who had markers of current or prior hepatitis B infection. Adherence to surveillance was suboptimal (less than 60%), but in the subjects in the surveillance arm the HCC-related mortality was reduced by 37%. These results probably represent the
1590-8658/$ – see front matter © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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Table 1 Patients at risk for developing HCC who should be entered into surveillance programmes (modified from Bruix and Sherman [5]) • Hepatitis B carriers – – – – –
Asian males > 40 years Asian females > 50 years All cirrhotic hepatitis B carriers Family history of HCC Africans over age 20
For non-cirrhotic hepatitis B carriers not listed above the risk of HCC varies depending on the severity of the underlying liver disease, and current and past hepatic inflammatory activity. Patients with high HBV DNA concentrations and those with ongoing hepatic inflammatory activity remain at risk for HCC. • Non-hepatitis B cirrhosis – – – –
Hepatitis C Alcoholic cirrhosis Genetic hemochromatosis Primary biliary cirrhosis
Although the following groups have an increased risk of HCC no recommendations for or against surveillance can be made because a lack of data precludes an assessment of whether surveillance would be beneficial. – Alpha1-antitrypsin deficiency – Non-alcoholic steatohepatitis – Autoimmune hepatitis
minimum benefit that can be expected from surveillance, because of poor compliance. Ideally, these results should be validated in other geographical areas and therefore, additional RCTs assessing the benefits of surveillance are still considered necessary. Several uncontrolled studies have suggested that survival is improved after surveillance [7–9]. However, there are several sources of bias to be considered in assessing reports of surveillance studies, such as lead-time bias and length bias. Only a RCT can eliminate these biases completely. However, such trials would be difficult to undertake. Surveillance for HCC is widely practiced and international guidelines have been devised to provide a list of at-risk groups of patients who should be entered in a surveillance programme (Table 1) [4,5]. Tests that can be used in HCC surveillance fall into two categories, serological and radiological. Receiver operating curve analysis of AFP used as a diagnostic test suggests that a value of about 20 ng/mL provides the optimal balance between sensitivity and specificity [10]. However, at this level the sensitivity is only 60%, i.e., AFP surveillance would miss 40% of HCC if a value of 20 ng/mL is used as the trigger for further investigation. This is inadequately sensitive for general use. If a higher cut-off is used, a progressively smaller proportion of HCCs will be detected: if the AFP cut-off is raised to, e.g., 200 ng/mL, the sensitivity drops to 22%. Conversely, reducing the cut-off means that more HCCs would be identified, but at the cost of a progressive increase in the false-positive rate. Therefore, AFP is an inadequate screening test [11]. AFP still has a role in the diagnosis of HCC, since in cirrhotic patients with a mass in the liver an AFP greater than 200ng/mL has a very high positive
predictive value for HCC [12]. Furthermore, a persistently elevated AFP has been clearly shown to be a risk factor for HCC [13]. Thus, the AFP can be used to help define patients at risk, but appears to have limited utility as a screening test [5]. Another serological test used to diagnose HCC is the des-gamma-carboxy prothrombin (DGCP), also known as Prothrombin Induced by Vitamin K Absence II (PIVKA II) [14]. Most reports on the use of DGCP have evaluated the use of this test in a diagnostic mode, rather than for surveillance. Although there are reports of its use in a surveillance mode, these do not yet provide sufficient justification for routine use of this marker. Other tests that have been reported as screening tests included the ratio of glycosylated AFP (L3 fraction) to total AFP, alpha fucosidase, and glypican 3. None of these has been adequately investigated and cannot be currently recommended as a screening test. The radiological test most widely used for surveillance is US. US has been reported to have a sensitivity of 65–80% and a specificity greater than 90% when used as a screening test [9]. US detection of HCC, especially on a cirrhotic background, is a challenging issue. Liver cirrhosis is characterized by fibrous septa and regenerative nodules. These features produce a coarse pattern on US, that may impair identification of small tumors. Moreover, a comprehensive assessment of the liver parenchyma may sometimes be impossible because of patient’s body habitus, colonic interposition, or morphologic changes induced by cirrhosis – such as retraction of the right liver lobe – that reduce the ability to explore the liver via intercostals scans. Unfortunately, the use of contrast-enhanced US did not prove useful in increasing the ability of US to detect small HCC tumors [15]. As a general rule, contrastenhanced US techniques are subject to the same limitations as any other US mode: if the baseline scan is disappointing, the contrast-enhanced US study will be disappointing as well [15]. In addition, the highest contrast between tumor and liver parenchyma is seen during the short time of the arterial phase. While multidetector CT and dynamic MR sequences can automatically image the entire liver parenchyma in few seconds, a comprehensive manual scanning of the whole liver with US during the arterial phase is not possible, even when performing repeated contrast injections. Thus, there is currently no indication to use microbubble contrast agents to increase the detection rate of HCC in patients undergoing US surveillance [15]. Despite these limitations, the performance characteristics of US, when performed by experienced operators and with use of state-of-the-art equipment, are superior to any of the serological tests. In contrast, the value of US surveillance performed in a primary care setting by operators who do not have specific skills is questionable. If the expertise is not available, the efficacy of surveillance will be lost. Strategies such as alternating AFP and US at intervals have no basis. The guiding principle should be that the best available screening test should be chosen, and that it should be applied regularly. Combined use of AFP and US increases detection rates, but also increases costs and false-positive rates. There are no data to support the use of multidetector
R. Lencioni / Digestive and Liver Disease 42S (2010) S223–S227
computed tomography (CT) or dynamic magnetic resonance (MR) imaging for surveillance. Practical experience suggests that the false-positive rate will be very high [3,5]. The ideal surveillance interval is not known. A surveillance interval of 6–12 months has been proposed based on tumour doubling times. Most centres use a 6-month interval. The positive RCT described earlier used a 6 month interval [6]. The surveillance interval is determined by the tumour growth rates and not by the degree of risk. Recall policies are the policies instituted to deal with an abnormal screening test result. The first step is to define an abnormal result. In a cirrhotic liver, early HCC can be difficult to distinguish from background nodularity. The majority of nodules smaller than 1 cm are not HCC [16]. Therefore, any nodule larger than about 1 cm should be considered an abnormal screening result warranting further investigation. In addition, any mass which enlarges is abnormal, even if previously considered to be benign. Upon detection of a suspicious nodule, the recommended policy is to evaluate the patient in referral centres with optimal human and technical resources [5].
3. Diagnostic confirmation In the setting of a patient with known hepatitis B or cirrhosis of other etiology, a solid nodular lesion found during US surveillance has a high likelihood of being HCC. However, it has been shown by pathologic studies that many small nodules detected by US in cirrhotic livers do not correspond to HCC [16]. The differential diagnosis between small HCC and non-malignant hepatocellular lesions may be very challenging. Percutaneous US-guided biopsy could appear as the most straightforward approach. Unfortunately, biopsy of small nodular lesions in cirrhosis is not entirely reliable. In fact, needle placement may be difficult and a sampling error may occur. Moreover, it is very difficult to distinguish well-differentiated HCC from DN on small biopsy specimens, as there is no clear-cut dividing line between dysplasia and well-differentiated tumor. Therefore, a positive biopsy – as assessed by an expert pathologist – is helpful, but a negative biopsy can never be taken as a criterion to rule out malignancy [4,5]. In addition, biopsy is associated with a low, but not negligible rate of complications, including tumour seeding along the needle track [17]. Both the 2005 EASL conference on HCC and the AASLD practice guideline have recommended further investigation of nodules detected during US surveillance with dynamic imaging techniques – including contrast-enhanced US, multidetector CT, or dynamic MR imaging – to highlight the different vascular supply of HCC versus non-malignant entities. In fact, through the progression from regenerative nodule, to low-grade DN, to high-grade DN, to frank HCC, one can note a loss of visualization of portal tracts and development of new arterial vessels, termed nontriadal arteries, which become the dominant blood supply in overt HCC lesions [2,3]. It is this neovascularity that permits diagnosis of HCC and is the key for imaging cirrhotic patients.
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A rational diagnostic protocol should be structured according to the actual risk of malignancy and the possibility of achieving a reliable diagnosis. Since the prevalence of HCC among US-detected nodules is strongly related to the size of the lesion, the diagnostic work-up depends on the size of the lesion [5]. Lesions smaller than 1 cm in diameter have a low likelihood of being HCC. However, such minute nodules may become malignant over time. Therefore, these lesions need to be followed-up in order to detect growth suggestive of malignant transformation. A reasonable protocol is to repeat US every 3 months, until the lesion grows to more than 1 cm, at which point additional diagnostic techniques are applied [5]. It has to be emphasized, however, that the absence of growth during the follow-up period does not rule out the malignant nature of the nodule because an early HCC may occasionally take more than one year to increase in size [4]. When the nodule exceeds 1 cm in size, the lesion is more likely to be HCC and diagnostic confirmation should be pursued. It is accepted that the diagnosis of HCC can be made without biopsy in a lesion larger than 1 cm that shows characteristic vascular features of HCC – i.e., arterial hypervascularization with washout in the portal venous or the late phase – even in patients with normal AFP value [5]. While for lesions above 2 cm a single imaging technique showing the characteristic vascular profile of HCC mentioned above may confidently establish the diagnosis, in lesions ranging from 1 to 2 cm, AASLD guidelines recommend that typical imaging findings are confirmed by two coincident dynamic imaging modalities to allow a non-invasive diagnosis [5] (Table 2). Such lesions ranging from 1 to 2 cm are the true target of screening programs, as they identify the population of patients with very-early HCC tumors, who have the highest likelihood of being cured with surgical resection or percutaneous ablation [1]. Specificity of imaging diagnosis is crucial to prevent therapeutic mistakes due to false positive diagnoses of malignancy. In a prospective validation of AASLD criteria conducted in a series of consecutive patients with a solitary focal lesion smaller than 2 cm detected during US surveillance, the specificity for the diagnosis of HCC was 100% [18]. If the lesion does not show typical features of HCC, or the vascular profile is not coincidental between the imaging techniques, biopsy is recommended [5]. It is important to point out that the absence of arterial hypervascularization Table 2 Diagnostic criteria for HCC (modified from Bruix and Sherman [5]) • Cyto-histological criteria • Non-invasive criteria (restricted to cirrhotic patients) 1. One imaging technique * Focal lesion > 2 cm with arterial hypervascularization and venous wash-out 2. Two coincident imaging techniques * Focal lesion 1–2 cm with arterial hypervascularization and venous wash-out * Three techniques considered: contrast US, multidetector CT, and dynamic MR imaging.
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on imaging does not rule out HCC. It is well established that HCC tumors at a very early stage may not exhibit the characteristic vascular features of overt HCC [19]. Delaying the diagnosis of HCC until imaging detection of arterial hypervascularization could reduce the chances of radical cure, since the incidence of microscopic vascular invasion and satellite nodules significantly increases when tumour exceeds 2 cm and develops imaging-detectable neoangiogenesis [16]. As a matter of fact, in the setting of cirrhotic patients in whom a solitary nodule smaller than 2 cm is detected during US surveillance, biopsy is still needed in about two thirds of the cases, and repeated biopsies are needed in as many as 30% of the cases [18]. A significant reduction in the number of cases that require biopsy confirmation would be achieved if identification of the typical vascular pattern of HCC in a single technique were accepted for HCC diagnosis even in nodules ranging between 1 and 2 cm [19]. In a recent investigation on consecutive patients undergoing surveillance in a large referral centre in Italy, the typical vascular pattern of HCC was identified in 65% of the cases by a single imaging technique and in 35% of the cases by at least two coincidental imaging techniques. The specificity was 100% with either approach [20]. Recent advances in imaging techniques based on the use of liver-specific contrast agents and research on new diagnostic tools - including immunostaining, gene expression assessment, or protein profiling – are expected to further improve the ability to characterize such small lesions [21].
4. Tumour staging Accurate tumour staging is essential for the proper clinical management of patients with HCC, particularly given the propensity of HCC, even at early stages, to produce satellite lesions via the invasion of peripheral portal vein branches. It is well established that US has limited sensitivity in the detection of tiny satellite lesions. When careful imagingpathologic correlation on explanted livers was performed, the sensitivity of US was as low as 14% in the detection of lesions smaller than 2 cm, and as low as 0% for cancerous foci smaller than 1 cm [22,23]. Although these data have been mostly collected in patients with advanced cirrhosis who underwent liver transplantation – and therefore may not be applicable to the general population of cirrhotic patients with HCC – the rate of underestimation of the extent of the disease with US is clearly unacceptable. Unfortunately, as discussed earlier, the use of contrast agents did not result in any significant improvement in the ability of US to detect small tumors [15]. The duration of the arterial phase – during which HCC tumors stand out against the faintly enhanced liver parenchyma – is far too short to allow a comprehensive manual scanning of the entire organ. In the portal venous and the late phase – contrary to hepatic metastases – the contrast between tumor and liver is usually low, preventing identification of small tumors not detected on baseline scans. Thus, the use of either multidetector CT or dynamic MR
imaging for intrahepatic staging of HCC is a mandatory step before therapeutic planning. In a recent meta-analysis evaluating the accuracy of different imaging modalities in the assessment of the extent of the disease in pre-transplant settings, spiral CT had a sensitivity of 67.5% (95% CI, 55–80%) and a specificity of 92.5% (95% CI, 89–96%), compared to a sensitivity of 80.6% (95% CI, 70–91%) and a specificity of 84.8% (95% CI, 77– 93%) for dynamic MR imaging [24]. In one comparative study with explant correlation, the sensitivity for the identification of HCC lesions ranging from 1 to 2 cm was significantly higher for MR imaging than for spiral CT [25]. However, even optimized CT or MR imaging techniques remain relatively insensitive to the detection of tiny satellite nodules associated with the main tumor [2]. In five series that reported careful lesion-by-lesion imaging-pathologic correlation in explanted livers, only 10–47% of HCC lesions smaller than 1 cm were detected with CT compared to 4–71% with MR imaging [3]. In most solid malignancies, tumor stage at presentation determines prognosis and treatment management. Most patients with HCC, however, have two diseases – liver cirrhosis and HCC – and complex interactions between the two have major implications for prognosis and treatment choice. Therefore, the TNM system has limited usefulness in the clinical decision making process, because it does not take into account hepatic functional status. Several scoring systems have been developed in the past few years in attempts to stratify patients according to expected survival. However, the only system that links staging with treatment modalities is the Barcelona Clinic Liver Cancer (BCLC) staging system [1,26]. The BCLC includes variables related to tumor stage, liver functional status, physical status, and cancer related symptoms and provides an estimation of life expectancy that is based on published response rates to the various treatments [26]. Any patient with HCC should be evaluated in referral centres by multidisciplinary teams involving hepatologists, oncologists, interventional radiologists, surgeons, and pathologists to guarantee careful selection of candidates for each treatment option and ensure the expert application of these treatments [5].
Conflict of interest: The author has received a fee from Bayer HealthCare for his contribution to this supplement. Bayer HealthCare played no role in the preparation, review, or approval of the manuscript.
References [1] Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17. [2] Lencioni R, Cioni D, Della Pina C, et al. Imaging diagnosis. Semin Liver Dis 2005;25:162–70. [3] Lencioni R, Crocetti L, Della Pina MC, et al. Guidelines for imaging focal lesions in liver cirrhosis. Expert Rev Gastroenterol Hepatol 2008;2:697–703.
R. Lencioni / Digestive and Liver Disease 42S (2010) S223–S227 [4] Bruix J, Sherman M, Llovet JM, et al. EASL Panel of Experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421–30. [5] Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. [6] Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–22. [7] McMahon BJ, Bulkow L, Harpster A, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 2000;32:842–6. [8] Wong LL, Limm WM, Severino R, et al. Improved survival with screening for hepatocellular carcinoma. Liver Transpl 2000;6:320–5. [9] Bolondi L, Sofia S, Siringo S, et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost-effectiveness analysis. Gut 2001;48:251–9. [10] Pateron D, Ganne N, Trinchet JC, et al. Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 1994;20:65–71. [11] Sherman M. Alphafetoprotein: An obituary. J Hepatol 2001;34:603–5. [12] Trevisani F, D’Intino PE, Morselli-Labate AM, et al. Serum alphafetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 2001;34:570–5. [13] Oka H, Tamori A, Kuroki T, et al. Prospective study of alphafetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 1994;19:61–6. [14] Marrero JA, Su GL, Wei W, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients. Hepatology 2003;37:1114–21. [15] Lencioni R, Piscaglia F, Bolondi L. Contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma. J Hepatol 2008;48:848–57. [16] Kojiro M, Roskams T. Early hepatocellular carcinoma and dysplastic nodules. Semin Liver Dis 2005;25:133–42. [17] Stigliano R, Marelli L, Yu D, et al. Seeding following percutaneous
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diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev 2007;33:437–47. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2007;47:97–104. Bolondi L, Gaiani S, Celli N, et al. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology 2005;42:27. Sangiovanni A, Manini MA, Iavarone M, et al. The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59(5):638–44. Llovet JM, Chen Y, Wurmbach E, et al. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 2006;131:1758–67. Bennett GL, Krinsky GA, Abitbol RJ, et al. Sonographic detection of hepatocellular carcinoma and dysplastic nodules in cirrhosis: correlation of pretransplantation sonography and liver explant pathology in 200 patients. AJR Am J Roentgenol 2002;179:75–80. Liu WC, Lim JH, Park CK, et al. Poor sensitivity of sonography in detection of hepatocellular carcinoma in advanced liver cirrhosis: accuracy of pretransplantation sonography in 118 patients. Eur Radiol 2003;13:1693–8. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 2006;101:513–23. Burrel M, Llovet JM, Ayuso C, et al. Barcelona Clinic Liver Cancer Group. MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology 2003;38:1034–42. Llovet JM, Di Bisceglie AM, Bruix J, et al. Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698–711.
Surveillance and early diagnosis of hepatocellular carcinoma Riccardo Lencioni * Division of Diagnostic Imaging and Intervention, Department of Liver Transplantation, Hepatology and Infectious Diseases, University of Pisa, Pisa, Italy
Abstract Patients at high risk for developing hepatocellular carcinoma (HCC) should be enrolled in surveillance programs based on ultrasound (US) examinations performed at 6-month intervals. Nodules found during US surveillance that are smaller than 1 cm should be followed-up with US at 3-month intervals. If the nodule found during US surveillance is larger than 1 cm, it should be investigated further with contrast-enhanced dynamic radiological studies, including US, multidetector computed tomography, or magnetic resonance imaging. If the appearance is typical for HCC (i.e., the lesion shows hypervascularization in the arterial phase with washout in the portal venous or the equilibrium phase), biopsy is considered unnecessary and the lesion can be treated as HCC. For nodules between 1 and 2 cm, it is currently recommended that such non-invasive diagnosis be based on the evidence of coincidental features typical for HCC from at least two dynamic imaging techniques. If the vascular profile on imaging is not characteristic or the nodule is detected in a non-cirrhotic liver, biopsy should be performed. If the biopsy is negative for HCC, patients should be followed-up by imaging studies performed at 3-month intervals until the nodule either disappears, enlarges, or displays diagnostic characteristics of HCC. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Hepatocellular carcinoma, diagnosis; Hepatocellular carcinoma, staging; Hepatocellular carcinoma, surveillance
1. Introduction Owing to surveillance of patients at high risk for the development of hepatocellular carcinoma (HCC), an increasing number of tumours are currently diagnosed at an early, asymptomatic stage [1]. Lesions detected by surveillance require proper diagnostic approach. In fact, diagnostic confirmation of small nodules detected by ultrasound (US) as true HCC may be challenging, as pathologic changes inherent in cirrhosis – such as dysplastic nodule (DN) – mimic a small tumor [2,3]. In this article, a rational approach to surveillance, diagnostic confirmation, and tumour staging – based on the conclusions of the 2000 and 2005 Monothematic Conferences
* Correspondence to: Professor Riccardo Lencioni, Director, Division of Diagnostic Imaging and Intervention, Department of Liver Transplantation, Hepatology, and Infectious Diseases, Pisa University School of Medicine, Cisanello Hospital, Building 30B, Suites 196-198, IT-56124 Pisa, Italy. Tel.: +39-050-997-321, fax +39-050-997-320. E-mail address: [email protected]
on HCC of the European Association for the Study of the Liver (EASL) [4] and the practice guideline document of the American Association for the Study of Liver Diseases (AASLD) [5] – is presented.
2. Surveillance The objective of surveillance must be to decrease mortality from the disease. Surveillance for HCC has become widely applied despite, until recently, the absence of evidence of benefit. There is a single randomized controlled trial (RCT) of surveillance versus no surveillance that has shown a survival benefit for a strategy of 6-monthly surveillance with alpha-fetoprotein (AFP) and US [6]. This study, which was performed in China, recruited 18,816 patients who had markers of current or prior hepatitis B infection. Adherence to surveillance was suboptimal (less than 60%), but in the subjects in the surveillance arm the HCC-related mortality was reduced by 37%. These results probably represent the
1590-8658/$ – see front matter © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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Table 1 Patients at risk for developing HCC who should be entered into surveillance programmes (modified from Bruix and Sherman [5]) • Hepatitis B carriers – – – – –
Asian males > 40 years Asian females > 50 years All cirrhotic hepatitis B carriers Family history of HCC Africans over age 20
For non-cirrhotic hepatitis B carriers not listed above the risk of HCC varies depending on the severity of the underlying liver disease, and current and past hepatic inflammatory activity. Patients with high HBV DNA concentrations and those with ongoing hepatic inflammatory activity remain at risk for HCC. • Non-hepatitis B cirrhosis – – – –
Hepatitis C Alcoholic cirrhosis Genetic hemochromatosis Primary biliary cirrhosis
Although the following groups have an increased risk of HCC no recommendations for or against surveillance can be made because a lack of data precludes an assessment of whether surveillance would be beneficial. – Alpha1-antitrypsin deficiency – Non-alcoholic steatohepatitis – Autoimmune hepatitis
minimum benefit that can be expected from surveillance, because of poor compliance. Ideally, these results should be validated in other geographical areas and therefore, additional RCTs assessing the benefits of surveillance are still considered necessary. Several uncontrolled studies have suggested that survival is improved after surveillance [7–9]. However, there are several sources of bias to be considered in assessing reports of surveillance studies, such as lead-time bias and length bias. Only a RCT can eliminate these biases completely. However, such trials would be difficult to undertake. Surveillance for HCC is widely practiced and international guidelines have been devised to provide a list of at-risk groups of patients who should be entered in a surveillance programme (Table 1) [4,5]. Tests that can be used in HCC surveillance fall into two categories, serological and radiological. Receiver operating curve analysis of AFP used as a diagnostic test suggests that a value of about 20 ng/mL provides the optimal balance between sensitivity and specificity [10]. However, at this level the sensitivity is only 60%, i.e., AFP surveillance would miss 40% of HCC if a value of 20 ng/mL is used as the trigger for further investigation. This is inadequately sensitive for general use. If a higher cut-off is used, a progressively smaller proportion of HCCs will be detected: if the AFP cut-off is raised to, e.g., 200 ng/mL, the sensitivity drops to 22%. Conversely, reducing the cut-off means that more HCCs would be identified, but at the cost of a progressive increase in the false-positive rate. Therefore, AFP is an inadequate screening test [11]. AFP still has a role in the diagnosis of HCC, since in cirrhotic patients with a mass in the liver an AFP greater than 200ng/mL has a very high positive
predictive value for HCC [12]. Furthermore, a persistently elevated AFP has been clearly shown to be a risk factor for HCC [13]. Thus, the AFP can be used to help define patients at risk, but appears to have limited utility as a screening test [5]. Another serological test used to diagnose HCC is the des-gamma-carboxy prothrombin (DGCP), also known as Prothrombin Induced by Vitamin K Absence II (PIVKA II) [14]. Most reports on the use of DGCP have evaluated the use of this test in a diagnostic mode, rather than for surveillance. Although there are reports of its use in a surveillance mode, these do not yet provide sufficient justification for routine use of this marker. Other tests that have been reported as screening tests included the ratio of glycosylated AFP (L3 fraction) to total AFP, alpha fucosidase, and glypican 3. None of these has been adequately investigated and cannot be currently recommended as a screening test. The radiological test most widely used for surveillance is US. US has been reported to have a sensitivity of 65–80% and a specificity greater than 90% when used as a screening test [9]. US detection of HCC, especially on a cirrhotic background, is a challenging issue. Liver cirrhosis is characterized by fibrous septa and regenerative nodules. These features produce a coarse pattern on US, that may impair identification of small tumors. Moreover, a comprehensive assessment of the liver parenchyma may sometimes be impossible because of patient’s body habitus, colonic interposition, or morphologic changes induced by cirrhosis – such as retraction of the right liver lobe – that reduce the ability to explore the liver via intercostals scans. Unfortunately, the use of contrast-enhanced US did not prove useful in increasing the ability of US to detect small HCC tumors [15]. As a general rule, contrastenhanced US techniques are subject to the same limitations as any other US mode: if the baseline scan is disappointing, the contrast-enhanced US study will be disappointing as well [15]. In addition, the highest contrast between tumor and liver parenchyma is seen during the short time of the arterial phase. While multidetector CT and dynamic MR sequences can automatically image the entire liver parenchyma in few seconds, a comprehensive manual scanning of the whole liver with US during the arterial phase is not possible, even when performing repeated contrast injections. Thus, there is currently no indication to use microbubble contrast agents to increase the detection rate of HCC in patients undergoing US surveillance [15]. Despite these limitations, the performance characteristics of US, when performed by experienced operators and with use of state-of-the-art equipment, are superior to any of the serological tests. In contrast, the value of US surveillance performed in a primary care setting by operators who do not have specific skills is questionable. If the expertise is not available, the efficacy of surveillance will be lost. Strategies such as alternating AFP and US at intervals have no basis. The guiding principle should be that the best available screening test should be chosen, and that it should be applied regularly. Combined use of AFP and US increases detection rates, but also increases costs and false-positive rates. There are no data to support the use of multidetector
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computed tomography (CT) or dynamic magnetic resonance (MR) imaging for surveillance. Practical experience suggests that the false-positive rate will be very high [3,5]. The ideal surveillance interval is not known. A surveillance interval of 6–12 months has been proposed based on tumour doubling times. Most centres use a 6-month interval. The positive RCT described earlier used a 6 month interval [6]. The surveillance interval is determined by the tumour growth rates and not by the degree of risk. Recall policies are the policies instituted to deal with an abnormal screening test result. The first step is to define an abnormal result. In a cirrhotic liver, early HCC can be difficult to distinguish from background nodularity. The majority of nodules smaller than 1 cm are not HCC [16]. Therefore, any nodule larger than about 1 cm should be considered an abnormal screening result warranting further investigation. In addition, any mass which enlarges is abnormal, even if previously considered to be benign. Upon detection of a suspicious nodule, the recommended policy is to evaluate the patient in referral centres with optimal human and technical resources [5].
3. Diagnostic confirmation In the setting of a patient with known hepatitis B or cirrhosis of other etiology, a solid nodular lesion found during US surveillance has a high likelihood of being HCC. However, it has been shown by pathologic studies that many small nodules detected by US in cirrhotic livers do not correspond to HCC [16]. The differential diagnosis between small HCC and non-malignant hepatocellular lesions may be very challenging. Percutaneous US-guided biopsy could appear as the most straightforward approach. Unfortunately, biopsy of small nodular lesions in cirrhosis is not entirely reliable. In fact, needle placement may be difficult and a sampling error may occur. Moreover, it is very difficult to distinguish well-differentiated HCC from DN on small biopsy specimens, as there is no clear-cut dividing line between dysplasia and well-differentiated tumor. Therefore, a positive biopsy – as assessed by an expert pathologist – is helpful, but a negative biopsy can never be taken as a criterion to rule out malignancy [4,5]. In addition, biopsy is associated with a low, but not negligible rate of complications, including tumour seeding along the needle track [17]. Both the 2005 EASL conference on HCC and the AASLD practice guideline have recommended further investigation of nodules detected during US surveillance with dynamic imaging techniques – including contrast-enhanced US, multidetector CT, or dynamic MR imaging – to highlight the different vascular supply of HCC versus non-malignant entities. In fact, through the progression from regenerative nodule, to low-grade DN, to high-grade DN, to frank HCC, one can note a loss of visualization of portal tracts and development of new arterial vessels, termed nontriadal arteries, which become the dominant blood supply in overt HCC lesions [2,3]. It is this neovascularity that permits diagnosis of HCC and is the key for imaging cirrhotic patients.
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A rational diagnostic protocol should be structured according to the actual risk of malignancy and the possibility of achieving a reliable diagnosis. Since the prevalence of HCC among US-detected nodules is strongly related to the size of the lesion, the diagnostic work-up depends on the size of the lesion [5]. Lesions smaller than 1 cm in diameter have a low likelihood of being HCC. However, such minute nodules may become malignant over time. Therefore, these lesions need to be followed-up in order to detect growth suggestive of malignant transformation. A reasonable protocol is to repeat US every 3 months, until the lesion grows to more than 1 cm, at which point additional diagnostic techniques are applied [5]. It has to be emphasized, however, that the absence of growth during the follow-up period does not rule out the malignant nature of the nodule because an early HCC may occasionally take more than one year to increase in size [4]. When the nodule exceeds 1 cm in size, the lesion is more likely to be HCC and diagnostic confirmation should be pursued. It is accepted that the diagnosis of HCC can be made without biopsy in a lesion larger than 1 cm that shows characteristic vascular features of HCC – i.e., arterial hypervascularization with washout in the portal venous or the late phase – even in patients with normal AFP value [5]. While for lesions above 2 cm a single imaging technique showing the characteristic vascular profile of HCC mentioned above may confidently establish the diagnosis, in lesions ranging from 1 to 2 cm, AASLD guidelines recommend that typical imaging findings are confirmed by two coincident dynamic imaging modalities to allow a non-invasive diagnosis [5] (Table 2). Such lesions ranging from 1 to 2 cm are the true target of screening programs, as they identify the population of patients with very-early HCC tumors, who have the highest likelihood of being cured with surgical resection or percutaneous ablation [1]. Specificity of imaging diagnosis is crucial to prevent therapeutic mistakes due to false positive diagnoses of malignancy. In a prospective validation of AASLD criteria conducted in a series of consecutive patients with a solitary focal lesion smaller than 2 cm detected during US surveillance, the specificity for the diagnosis of HCC was 100% [18]. If the lesion does not show typical features of HCC, or the vascular profile is not coincidental between the imaging techniques, biopsy is recommended [5]. It is important to point out that the absence of arterial hypervascularization Table 2 Diagnostic criteria for HCC (modified from Bruix and Sherman [5]) • Cyto-histological criteria • Non-invasive criteria (restricted to cirrhotic patients) 1. One imaging technique * Focal lesion > 2 cm with arterial hypervascularization and venous wash-out 2. Two coincident imaging techniques * Focal lesion 1–2 cm with arterial hypervascularization and venous wash-out * Three techniques considered: contrast US, multidetector CT, and dynamic MR imaging.
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on imaging does not rule out HCC. It is well established that HCC tumors at a very early stage may not exhibit the characteristic vascular features of overt HCC [19]. Delaying the diagnosis of HCC until imaging detection of arterial hypervascularization could reduce the chances of radical cure, since the incidence of microscopic vascular invasion and satellite nodules significantly increases when tumour exceeds 2 cm and develops imaging-detectable neoangiogenesis [16]. As a matter of fact, in the setting of cirrhotic patients in whom a solitary nodule smaller than 2 cm is detected during US surveillance, biopsy is still needed in about two thirds of the cases, and repeated biopsies are needed in as many as 30% of the cases [18]. A significant reduction in the number of cases that require biopsy confirmation would be achieved if identification of the typical vascular pattern of HCC in a single technique were accepted for HCC diagnosis even in nodules ranging between 1 and 2 cm [19]. In a recent investigation on consecutive patients undergoing surveillance in a large referral centre in Italy, the typical vascular pattern of HCC was identified in 65% of the cases by a single imaging technique and in 35% of the cases by at least two coincidental imaging techniques. The specificity was 100% with either approach [20]. Recent advances in imaging techniques based on the use of liver-specific contrast agents and research on new diagnostic tools - including immunostaining, gene expression assessment, or protein profiling – are expected to further improve the ability to characterize such small lesions [21].
4. Tumour staging Accurate tumour staging is essential for the proper clinical management of patients with HCC, particularly given the propensity of HCC, even at early stages, to produce satellite lesions via the invasion of peripheral portal vein branches. It is well established that US has limited sensitivity in the detection of tiny satellite lesions. When careful imagingpathologic correlation on explanted livers was performed, the sensitivity of US was as low as 14% in the detection of lesions smaller than 2 cm, and as low as 0% for cancerous foci smaller than 1 cm [22,23]. Although these data have been mostly collected in patients with advanced cirrhosis who underwent liver transplantation – and therefore may not be applicable to the general population of cirrhotic patients with HCC – the rate of underestimation of the extent of the disease with US is clearly unacceptable. Unfortunately, as discussed earlier, the use of contrast agents did not result in any significant improvement in the ability of US to detect small tumors [15]. The duration of the arterial phase – during which HCC tumors stand out against the faintly enhanced liver parenchyma – is far too short to allow a comprehensive manual scanning of the entire organ. In the portal venous and the late phase – contrary to hepatic metastases – the contrast between tumor and liver is usually low, preventing identification of small tumors not detected on baseline scans. Thus, the use of either multidetector CT or dynamic MR
imaging for intrahepatic staging of HCC is a mandatory step before therapeutic planning. In a recent meta-analysis evaluating the accuracy of different imaging modalities in the assessment of the extent of the disease in pre-transplant settings, spiral CT had a sensitivity of 67.5% (95% CI, 55–80%) and a specificity of 92.5% (95% CI, 89–96%), compared to a sensitivity of 80.6% (95% CI, 70–91%) and a specificity of 84.8% (95% CI, 77– 93%) for dynamic MR imaging [24]. In one comparative study with explant correlation, the sensitivity for the identification of HCC lesions ranging from 1 to 2 cm was significantly higher for MR imaging than for spiral CT [25]. However, even optimized CT or MR imaging techniques remain relatively insensitive to the detection of tiny satellite nodules associated with the main tumor [2]. In five series that reported careful lesion-by-lesion imaging-pathologic correlation in explanted livers, only 10–47% of HCC lesions smaller than 1 cm were detected with CT compared to 4–71% with MR imaging [3]. In most solid malignancies, tumor stage at presentation determines prognosis and treatment management. Most patients with HCC, however, have two diseases – liver cirrhosis and HCC – and complex interactions between the two have major implications for prognosis and treatment choice. Therefore, the TNM system has limited usefulness in the clinical decision making process, because it does not take into account hepatic functional status. Several scoring systems have been developed in the past few years in attempts to stratify patients according to expected survival. However, the only system that links staging with treatment modalities is the Barcelona Clinic Liver Cancer (BCLC) staging system [1,26]. The BCLC includes variables related to tumor stage, liver functional status, physical status, and cancer related symptoms and provides an estimation of life expectancy that is based on published response rates to the various treatments [26]. Any patient with HCC should be evaluated in referral centres by multidisciplinary teams involving hepatologists, oncologists, interventional radiologists, surgeons, and pathologists to guarantee careful selection of candidates for each treatment option and ensure the expert application of these treatments [5].
Conflict of interest: The author has received a fee from Bayer HealthCare for his contribution to this supplement. Bayer HealthCare played no role in the preparation, review, or approval of the manuscript.
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