Role of Surveillance in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver tumour with rising incidence and has significant mortality of over 600,000 deaths annually. HCC is ranked as the third-leading cause of cancer-related deaths worldwide. An important feature is its unique geographic distribution due to the associated risk factors related to the tumour. Surveillance programmes are recommended in the specified targeted population and help in early diagnosis of HCC with timely therapeutic intervention. Success of surveillance depends on multitude of factors including identification of the target population, proper use of surveillance tests through a structured programme and this in turn leading to proper management of HCC. The most important risk factor associated with HCC is hepatic cirrhosis. Important factors in the aetiology of cirrhosis include chronic infection from hepatitis B (HBV) and C (HCV) viruses and alcohol abuse. Another risk factor increasingly being recognised is non-alcoholic fatty liver disease. Radiological and serological investigations are employed in the screening and surveillance of HCC. Debatable issues in this regard include surveillance interval, efficacy of tests, outcomes of detected tumours and proper recall guidelines which are considered as important factors for success of surveillance programmes. Ultrasonography is considered as the most reliable test modality in surveillance programmes. *Corresponding author: Asghar Qasim, Consultant Gastroenterologist, UPMC Beacon Hospital, Gastroenterology & Internal Medicine, Sandyford, Dublin 18, Ireland, Tel: 00353857270282; E-mail: asgharqasim@yahoo.co.uk Received September 28, 2013; Accepted November 26, 2013; Published December 04, 2013 Citation: Qasim A (2013) Role of Surveillance in Hepatocellular Carcinoma. J Gastroint Dig Syst 3: 159. doi: 10.4172/2161-069X.1000159 Copyright: © 2013 Qasim A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
Surveillance being an important tool in the management of medical conditions consists of the periodic application of a diagnostic test to a set of defined population at risk for developing a given disease. Factors which influence the outcomes of surveillance programmes include the incidence of the surveyed disease in the target population, the availability of efficient diagnostic tests at acceptable cost and their feasibility for the target population. Post detection follow up with availability of therapeutic modalities enhances effectiveness of such programmes [1].
Reduction in disease related mortality is the main aim of surveillance which is achieved through an early diagnosis (stage migration) that, in turn, enhances the applicability and cost-effectiveness of curative therapies. Stage migration, however, cannot serve as a surrogate marker for the main end-point, which is patient survival. Identification of viral hepatitis and other liver conditions leading to cirrhosis helps in defining target population for surveillance. In the Western world, HCC arises in a cirrhotic liver in up to 90% of cases and cirrhosis being a progressive disease also affects patient survival [2]. Presence of cirrhosis influences the chance of success for anti-tumour treatment modalities and affects their outcome; it renders early diagnosis of HCC even more crucial in the management plan. Moreover, many available treatments can have a detrimental impact on cirrhosis. This means that the cause of mortality cannot be clearly defined as to the underlying disease or HCC and in this context a reduction in overall mortality will represent a more appropriate end-point to assess the efficacy of surveillance. This review focuses on various aspects of HCC surveillance including identification of target population and proper use of available tests.

Target Population for HCC Surveillance
Hepatocellular carcinoma (HCC) is a highly prevalent tumour. The most relevant risk factors for HCC which are well described include chronic hepatitis C (HCV) infection, hepatitis B (HBV) infection, alcoholic cirrhosis, and non-alcoholic steatohepatitis. Additionally, the increasing incidence of obesity and diabetes, which have also been identified as independent risk factors for chronic liver disease and HCC, is likely to further augment the number of Americans afflicted with HCC [3][4][5]. Table 1 includes patient groups suitable for surveillance.
The rising incidence of tumour in the Western countries and United States is mainly attributed to the current HCV epidemic and the burden of HCV related HCC is thus expected to continue to increase over the next two decades [6]. This dramatic increase in HCC is driven by the epidemic of HCV that peaked in the 1980s and the 20-30 year lag time in its natural history between the onset of infection and the development of cirrhosis. However, the overriding risk factor in 80-90% of HCC regardless of aetiology is the presence of cirrhosis [7,8]. There is a clear association of HCC with underlying cirrhosis and its annual incidence in cirrhotic patients is in the range of 3-5% with around one-third of individuals developing HCC during their lifetime [9]. Therapeutic modalities including surgical resection and liver transplantation offer  the best potential for cure in HCC. Success however depends on an early detection of tumour which currently is only achieved in 10-20% of cases [10]. This means that majority of patients are not suitable for curative therapies due to their advanced tumour stage at the time of diagnosis. Based on these facts, screening and surveillance strategies for HCC have been developed with the goal of detection at an earlier stage so that intervention strategy yields good results [11]. At the same time however, evidence in support of screening is not robust as it would be unethical to randomize at-risk patients into screened and nonscreened groups to compare outcomes. In an interesting randomised study, Zhang et al. compared surveillance and no surveillance in hepatitis B (HBV) patients using serum alpha-fetoprotein (AFP) and abdominal ultrasound at 6-month intervals [12]. Results of this study demonstrated the benefit of surveillance in terms of reduced mortality. Many other cohort studies have also strengthened this conclusion by showing a survival advantage for patients included in a surveillance programme while retrospective studies have demonstrated its cost-effectiveness [13][14][15][16].

Cirrhotic Patients
Not all cirrhotic individuals have the same risk of developing HCC. In general terms a decision analysis and cost-effectiveness model will suggest that an intervention is considered cost-effective if it provides gains of life expectancy of at least 3 months with a cost lower than approximately US$ 50,000 per year of life saved [17]. Cost-effectiveness studies indicate that an incidence of 1.5%/year or greater would warrant surveillance of HCC in cirrhotic patients irrespective of its aetiology [18][19][20][21]. On one had it may be possible to identify cirrhotic patients at low risk of developing HCC and hence exclude them from surveillance, thereby saving costs although this approach is not proven yet [9,22,23]. On the other hand, the presence of advanced cirrhosis (Child-Pugh class C) prevents potentially curative therapies from being employed, and thus surveillance is not cost-effective in those individuals [24,25]. One significant exception is patients on the waiting list for liver transplantation, regardless of the hepatic functional status and they should be screened for HCC in order to detect tumours exceeding conventional criteria to help define priority policies for transplantation. Although it seems that surveillance might not be cost effective above a certain age cut-off, however, the lack of data prevents the adoption of any specific recommendation.

Non-Cirrhotic Subjects
Individuals who have chronic HBV infection are at a risk of HCC development even in the absence of cirrhosis. In these cases, the recommended cut-off of annual incidence above which surveillance should be recommended cannot be applied. The cut-off of annual incidence in these patients is ill-defined, albeit expert opinion indicates that it would be warranted if HCC incidence is at least 0.2%/year [26,27]. Thus, cost-benefit modelling needs to be considered in this scenario. Current available data suggests that the incidence of HCC in adult Asian or African active HBV carriers or with a family history of HCC exceeds this value, whereas HCC incidence ranges from 0.1% to 0.4%/year in Western populations with chronic HBV infection [28,29].
In individuals with HBV infection another important risk factor is viral load which appears to increase the risk of developing HCC. For Asian patients, serum HBV-DNA above 10,000 copies/ml was associated with an annual risk above 0.2%/year [29]. There is scanty and sometimes contradictory information on the incidence of HCC in patients with chronic hepatitis C without cirrhosis. Data from Japan would suggest that patients with mild fibrosis have a yearly HCC incidence of 0.4% [30]. Similar results were reported from United States and HCC risk was higher in patients with chronic hepatitis C and bridging fibrosis in the absence of cirrhosis (Metavir F3) [31]. The fact that the transition from advanced fibrosis and cirrhosis cannot be accurately defined led the EASL guidelines to recommend surveillance also for patients with bridging fibrosis [26]. This panel also recommends such surveillance policy. In this regard, transient elastography appears to be a promising tool with ability to stratify patients at different HCC risks [32].
With the current available data the incidence of HCC in patients with nonviral chronic liver disease without cirrhosis, such as nonalcoholic and alcoholic steatohepatitis, autoimmune liver disease, genetic hemachromatosis, a1-antitripsin deficiency, and Wilson disease remains largely unknown [33]. However, available evidence suggests that HCC usually arises in these contexts once cirrhosis is established [1]. It is advisable that patients with metabolic syndrome or non-alcoholic steatohepatitis leading to cirrhosis should also undergo surveillance; however the risk of HCC development is not fully established in noncirrhotic individuals [34].

Treated Viral Chronic Hepatitis
An interesting development relates to the recent advances in antiviral therapies which have led to relatively high rates of viral clearance or suppression among patients being treated for chronic hepatitis B or C. Successful treatment, leading to sustained virological response in chronic hepatitis C, and HBeAg seroconversion or sustained HBV-DNA suppression in chronic hepatitis B, decreases, but does not eliminate the risk of HCC [35][36][37][38]. A safe approach will be to offer surveillance to treated patients with chronic hepatitis B if they remain at risk of HCC development due to baseline factors, and to those with HCV-induced advanced fibrosis or cirrhosis, even after achieving sustained virological response.

Surveillance Tests
HCC surveillance is mainly based on two types of tests including serological and imaging examinations. While using any surveillance test it is important that test is validated for accuracy and has reasonable predictive value. An important additional consideration is that the natural history of sub-clinical HCC is not the same as for clinical cancer. In particular growth rates of sub-clinical HCC may be very different than tumour growth rates in clinically observed cancers. Second, sub-clinical cancer may not progress to clinically detectable cancer in all cases. Thus it cannot be assumed that all sub-clinical lesions found on surveillance will ultimately develop into cancer. Similarly, the performance characteristics of a test used to diagnose subclinical disease (i.e., as a screening test) are not the same as when the test is used for diagnosis. Therefore one cannot take the performance characteristics of a test used in diagnosis (e.g., CT scan) and extrapolate the sensitivity and specificity to the surveillance situation.

Radiological Tests in HCC Surveillance
The imaging test most widely used for surveillance is ultrasonography (US). The widespread popularity of US also relies on the absence of risks, non-invasiveness, good acceptance by patients and relatively moderate cost. Nonetheless, US detection of HCC on a cirrhotic background is a challenging issue. US has an acceptable diagnostic accuracy when used as a surveillance test (sensitivity ranging from 58% to 89%; specificity greater than 90%) [39,40]

Serological Tests in HCC Surveillance
Among the serological tests the performance characteristics of AFP have been studied extensively. 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 [50]. 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 HCC's 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 HCC's would be identified, but at the cost of a progressive increase in the falsepositive rate. This analysis was performed in a case control study where the prevalence of HCC was artificially set at 50%. At this prevalence the positive predictive value of an AFP of 20 ng/mL was 84.6%. However, if the HCC prevalence rates were more like those seen in most liver clinics, i.e., about 5%, the positive predictive value (PPV) of an AFP of 20 ng/mL is only 41.5%, and even at a cut-off of 400 ng/mL the PPV is only 60% [50]. In cohorts undergoing surveillance the incidence of HCC may be even lower than 5%, depending on the criteria for entry into surveillance. For example, in non-cirrhotic hepatitis B carriers infected in infancy the incidence of HCC is usually less than 1%. The lack of efficacy of AFP as a surveillance test has been confirmed recently as part of the HALT-C study [51]. In a prospective study Lok et al. [51] evaluated the efficacy of maintenance interferon and ribavirin for the treatment of patients with hepatitis C unresponsive to an initial standard course of therapy. These were all patients with cirrhosis, and over the period of the study HCC developed in 39 subjects. AFP and des-carboxy-prothrombin (DCP) were measured at intervals, so that measurements were available at the time of diagnosis and 12 months prior to diagnosis. These results clearly showed that both serological markers were inadequate for surveillance purposes, even when combined. Despite these facts the performance characteristics of AFP as a screening test remain inadequate.
It is important to remember that serum AFP has very poor sensitivity and specificity and should not be used as a screening tool in isolation unless ultrasonography (or other imaging modality) is unavailable [52]. Diagnostic and surveillance potential for other serum biomarkers for early detection of HCC on the horizon such as desgamma-carboxy prothrombin, the lectinbound AFP fraction (AFP-L3) and glypican 3 remain to be fully investigated [53]. Marrero et al. in a recent multicentre, phase 2 biomarker studies showed that AFP was more sensitive than DCP and AFP-L3 for the diagnosis of early-stage HCC at a cut-off of 10.9 ng⁄mL, this finding however needs further evaluation [54].
Other serological test investigated in HCC surveillance include DCP, also known as Prothrombin Induced by Vitamin K Absence II (PIVKA II) [55][56][57][58]. Most reports on the use of DCP have evaluated its use in a diagnostic mode, rather than for surveillance. There are reports of its use in a surveillance mode. However, as discussed above DCP is insufficiently accurate for routine use in surveillance. Another factor which fails to support its use as screening test is its use as a marker for portal vein invasion by tumour [59]. Results would also suggest that DCP is not a good screening test as tumour is only detected late in its course. In other words screening test should be able to identify early disease, not late disease. The HALT-C study also confirmed that DCP was not a good surveillance tool [60]. Other tests that have been reported as screening tests included the ratio of glycosylated AFP (L3 fraction) to total AFP, alpha fucosidase, glypican 3, and HSP-70 [61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Use of these biochemical markers has not been adequately investigated and at this stage cannot be recommended as a screening or surveillance test. It is suggested that proteomic profiling may aid the development of more accurate markers [75].

Miscellaneous Approaches in HCC Surveillance
Strategies such as alternating different surveillance modalities at intervals have no basis. The guiding principle should be that the best available screening test should be chosen, and it should be applied regularly. Combined use of AFP and ultrasonography increases detection rates, but also increases costs and false-positive rates [76]. AFP-only surveillance had a 5.0% false positive rate, ultrasound alone had a 2.9% false positive rate, but in combination the false positive rate was 7.5%. Ultrasound alone cost about $2000 per tumour found, whereas the combination cost about $3000 per tumour found. Cirrhosis is characterized by fibrous septa and regenerative nodules and these features produce a coarse pattern on US, which may impair identification of small tumours. Because of these limitations, the performance of US in early detection of HCC is highly dependent on the expertise of the operator and the quality of the equipment. The recent introduction of US contrast agents has not proven to increase the ability of US to detect small HCC tumours [77].
There are no data to support the use of multidetector CT or dynamic MR imaging for surveillance. Practical experience suggests that the rate of false-positive results that will trigger further investigation is very high and not cost-effective. In the setting of the waiting list for liver transplantation CT scan or MRI are alternatives to US. These techniques should be also considered when obesity, intestinal gas, and chest wall deformity prevent an adequate US assessment. Even in these circumstances, radiation risk due to repeated exposure to CT scan and high cost of MR make their use debatable in long-term surveillance.

Surveillance Interval
The ideal interval of surveillance for HCC should be dictated by two main features including the rate of tumour growth up to the limit of its detection, and tumour incidence in the target population. Based on available knowledge on mean HCC volume doubling time, a 6-month interval represents a reasonable choice [78]. Considering cases where inter-patient variability is huge, a shorter 3-month interval has been proposed by Japanese guidelines [79,80]. However, Nouso et al. in a randomized study comparing 3-versus 6-month based programmes failed to detect any differences [80]. On the other hand, cohort comparisons of 6 versus 12-month schemes provide similar results [81].
A surveillance interval of 6-12 months has been proposed based on tumour doubling times. The positive randomized control trial by Zhang et al. used a 6 month interval [82]. Based on retrospective study by Trevisani et al. one may question the benefit of screening as survival was no different in patients screened at 6 or 12 monthly intervals [83]. Another study by Santagostino et al. in HCV infected hemophiliacs suggested that the likelihood of finding HCC at the single nodule stage (as opposed to multinodular HCC) was the same with 6 and 12month surveillance intervals [84]. These and other studies looking at surveillance intervals have used surrogate outcome markers, such a number of lesions, lesion size, or ability to provide potentially curative treatment. Most of these studies were in patients with hepatitis C. One (non-randomized) prospective cohort study by Kim et al. has evaluated survival (in patients with hepatitis B) and demonstrated that survival is improved with 6 months surveillance intervals compared to 12 months [85].
The decision to provide surveillance or not depends upon the magnitude of risk for HCC, but the surveillance interval is determined by the tumour growth rates and not by the degree of risk. In other words the surveillance interval need not be shortened for patients who are thought to be at higher risk. At the same time it is important to make the distinction between patients undergoing surveillance, i.e., those in whom although high risk is recognized, do not have any reason to suspect HCC, and those in whom surveillance tests have been abnormal and there is a concern that HCC is already present. Such patients are strictly speaking no longer candidates for surveillance, but should be receiving enhanced follow-up. Conversely, lengthening the surveillance interval for patients perceived to be a lower risk of HCC means that when an HCC develops it might be diagnosed at a later stage, thus possibly negating the benefits of surveillance. Meta-analysis of prospective studies by Singal et al. has shown that the pooled sensitivity of USbased surveillance decreases from 70% with the 6-month program to 50% with the annual programme [41]. Finally, cost-effectiveness studies have shown that 6 monthly US-based surveillance improves qualityadjusted life expectancy at a reasonable cost [86]. In light of available knowledge a 6-month scheduled surveillance appears the preferable choice. Further trials in this setting would be difficult to implement due to ethical issues.

Surveillance Efficacy
Surveillance efficacy has been well documented in randomised trials. In a population-based study by Zhang et al. where cluster randomization was performed comparing surveillance (US and AFP measurements every 6 months) versus no surveillance in a population of Chinese patients with chronic hepatitis B infection, regardless of the presence of cirrhosis [12]. Although there was suboptimal adherence to the surveillance program (55%), HCC-related mortality was reduced by 37% in the surveillance arm as a result of increased applicability of resection in detected cases. The other AFP-based surveillance study carried out in Qidong (China) in high-risk individuals (males, HBsAg+) did not identify differences in overall survival [87]. Other types of evidence include population and non-population-based cohorts and cost-effectiveness analysis, which mostly reinforce the benefits of regular US schemes [79,84,88,89]. These studies can be criticised due to their heterogeneous nature on account of variable disease stage, different aetiology of liver disease and used surveillance protocols. Additionally, almost all studies suffer from methodological biases such as lead-time bias (apparent improvement of survival due to an anticipated diagnosis) and length time bias (over-representation of slower-growing tumours). While the latter is unavoidable in this type of study, lead-time bias can be minimized using correction formulas. Application of corrections did demonstrate the advantage of surveillance [90].

Recall Policies
Recall policies are the policies instituted to deal with an abnormal screening test result. This is different than surveillance. Recall policy is crucial for the success of surveillance programmes. It consists of a defined algorithm which needs to be followed when surveillance tests show an abnormal result. The tests are different, and the interval of follow-up is different. Recall policies cover the investigations and follow-up that determines whether an abnormality identified on surveillance is or is not HCC. Recall is intimately intertwined with the process of making a diagnosis. The first step is to define an abnormal result. Any nodule not seen on a prior study should be considered abnormal. A mass that enlarges is abnormal, even if previously considered to be benign. An obvious issue is with nodular cirrhotic liver which poses problems in ultrasound interpretation and early HCC can be difficult to distinguish from background nodularity. Some benign cirrhotic nodules can be as large as 2 cm; however, the majority of nodules smaller than 1 cm are not HCC [91].

Clinical Practice Summary
The current American Association for the Study of Liver Diseases (AASLD) guidelines recommend HCC surveillance for high-risk groups such as all patients with cirrhosis and certain HBV-infected patients regardless of the presence of cirrhosis using an abdominal ultrasound at 6-12 month intervals [92]. Similar recommendations have been made by the European Association for the Study of the Liver (EASL) [93].
The ideal target of surveillance should be the identification of HCC at a very early stage (2 cm or less), as this gives the chance of commencing radical treatments and highest probability of long-term cure. In case of HCC, abnormal US results are either a newly detected focal lesion or a known hepatic lesion that enlarges and/or changes its echo pattern. In summary, recommendations in relation with surveillance and re-call policy should be followed to improve HCC outcomes in the following fashion.

A-Surveillance
1-Patients at high risk for developing HCC should be entered into surveillance programs.
2-Surveillance should be performed by experienced personnel in all at-risk populations using abdominal ultrasound every 6 months.
3-A shorter follow-up interval (every 3-4 months) is recommended in the following cases: a-Where a nodule of less than 1 cm has been detected (see recall policy) b-In the follow-up strategy after resection or loco-regional therapies.
4-Patients on the waiting list for liver transplantation should be screened for HCC in order to detect and manage tumor progression and to help define priority policies for transplantation.
1. In cirrhotic patients, nodules less than 1 cm in diameter detected by ultrasound should be followed every 4 months for the first year and with regular follow up every 6 months thereafter.
2. In cirrhotic patients, diagnosis of HCC for nodules of 1-2 cm in diameter should be based on non-invasive criteria or biopsyproven pathological confirmation. It is recommended that biopsies are assessed by an expert hepatopathologist. A second biopsy is recommended in case of inconclusive findings, or growth or change in enhancement pattern identified during follow-up.
3. In cirrhotic patients, nodules more than 2 cm in diameter can be diagnosed for HCC based on typical features on one imaging technique. In case of uncertainty or atypical radiological findings, diagnosis should be confirmed by biopsy.