An elevated risk above the threshold has been reported in cirrhosis due to genetic hemochromatosis irrespective of iron depletion.30 In patients with primary biliary cholangitis (PBC) at an advanced fibrotic stage (cirrhosis) the risk of HCC is similar to that seen in cirrhotic hepatitis C;31 hence, these patients also warrant surveillance.
For other types of liver diseases such as autoimmune, Wilson’s disease or α-1 antitrypsin deficiency, the risk of HCC is thought to be below the above mentioned threshold, and the guidelines do not recommend surveillance. In these instances, HCC incidence is thought to be increased only if cirrhosis is present. Concerns have been raised about the opportunity to offer regular surveillance to alcoholic cirrhotic patients who stopped drinking. A recent French study,32 however, showed that the incidence of HCC in alcohol-related cirrhosis is sufficient (being the lowest risk estimation in the best scenario of 1.4%) to justify performing HCC screening with regular imaging techniques, mainly US. The main problem is the high rate of noncompliant patients in this at-risk subgroup, given the large proportion of dropouts registered in the study.33
Surveillance of non alcoholic fatty liver disease (NAFLD) is still a matter of debate. The most recent epidemiological data34 provided two kinds of evidence: 1) although the risk of HCC is higher in NAFLD patients than that observed in the general clinical population without major liver disease risk factors, the absolute risk of HCC is too low to recommend universal HCC surveillance in the total NAFLD population; 2) cirrhosis is the major risk factor for HCC development in NAFLD patients, given that the risk of HCC in this subset of patients reached or exceeded the cut offs (0.8–2.3% per year) beyond which HCC surveillance becomes cost-effective.
In the NAFLD context, however, solid prospective information on the real cancer risk is still missing, and the precise indication to begin surveillance still remains unsettled.35 This conclusion also takes into account the notion that the accepted tool for screening (ie, US) is expected to under diagnose HCC at an early stage owing to the difficult assessment of severe fatty liver and/or obese patients. Moreover, first-line curative treatments (especially surgery) may be hampered in such a population where most of these patients are obese and carry concurrent cardiovascular diseases. However, it is conceivable that in the near future the population at risk for HCC will be broader due to the large number of NAFLD patients.
In non cirrhotic chronic viral hepatitis, the estimated risk of HCC is variable. In the absence of cost-efficacy modeling, expert opinion indicates that surveillance would be warranted if the annual incidence of HCC is at least 0.2%.36–38
In the HBV setting, the guidelines recommend surveillance in male patients aged >60 years, with a family history of HCC and higher levels of HBV replication.39,40 These patients carry a risk greater than the threshold as compared to the general population. Accordingly, international guidelines suggest that in non cirrhotic HBV patients, regular 6-month surveillance may not begin at baseline, but may be initiated whenever the abovementioned risk factors develop. This implies that these patients should undergo regular re assessment for entry into a surveillance program.
In the HCV setting, the incidence of HCC in F3 patients is too low to warrant regular surveillance.41However, the exact staging of fibrosis is a challenge even at histological examination since fibrosis is a dynamic process which can either progress or regress over time. These patients should be regularly monitored with Fibroscan even if a cut off threshold to begin surveillance remains to be defined.
In summary, surveillance should be offered to patients in whom cirrhosis has etiology due to viral infection, hemochromatosis, PBC, or alcohol (with ongoing alcohol consumption). In viral cirrhosis, the risk of HCC is not totally eliminated in patients at risk after achieving sustained viral response (SVR) with both PegIFN-based and DAA-based therapies; therefore, surveillance should invariably be carried out. In HBV non cirrhotic patients, surveillance should be carried out only in the presence of additional risk factors, while in non cirrhotic HCV patients standard surveillance is not recommended unless bridging fibrosis is histologically documented. In non cirrhotic viral (HBV and HCV) chronic liver disease, transient elastography has been proposed as a useful tool to stratify the variable risk of HCC.42,43
Third, available test procedures are acceptable, safe, relatively inexpensive and offer a good balance between sensitivity (for early HCC detection) and specificity (to reduce false positive-related harm). The above-mentioned professional societies9–11 agree that US is the cornerstone of HCC screening, due to its widespread availability, low costs, lack of ionizing radiation, repeatability and acceptability by patients. However, limits of US should be considered: operator and US equipment dependency and technical limitations (coarse liver echo-texture, severe steatosis and obesity) explain why early HCC may be detected only in approximately one-third of patients with cirrhosis by using US alone.44,45 In order to increase the diagnostic performance of screening, other imaging techniques, such as CT or magnetic resonance imaging (MRI) have been proposed. However, their use in clinical practice is hampered by several limitations including the dangerously high rate of false-positive results, low availability, radiation risk, long duration of scan and, primarily, elevated costs (see the Failure to detect HCC section). Indeed, the AASL and EASL guidelines9,10 do not recommend the routine use of CT or MRI as they are not considered cost-effective for screening programs.
Whether adding α-fetoprotein (AFP) to US improves screening performance is a matter of debate. Conflicting results are reported in the literature, and the variable suggestions from liver disease societies across the world reflect such uncertainty: EASL guidelines9 do not recommend AFP in addition to US given its insufficient sensitivity and specificity; in contrast, AASLD10 states that is not possible to establish whether US should be coupled with AFP for HCC surveillance. A recent meta-analysis showed that, in studies comparing sensitivity for HCC with or without AFP, the pooled sensitivity of US alone was poor (63%) for early HCC and even worse in the subgroup of prospective studies (42%).46 By adding AFP measurement, a significant gain in pooled sensitivity (63%) was achieved in the subgroup of early HCCs, and this advantage of AFP was maintained in the subgroups of prospective studies (pooled sensitivity of 60%).
On the other hand, adopting AFP as a single tool for screening cannot be recommended since it is both a tumor marker and a regeneration marker. In chronic liver disease, elevated AFP serum levels may indeed simply reflect inflammation and subsequent regeneration.
Fourth, curative treatments are available to patients in whom HCC is discovered at an early stage owing to regular surveillance. Potentially curative treatments include orthotopic liver transplantation (OLT), resection and ablation and offer survival rates at 5 years ranging from 50% to 70%.9–11 In population-based series and in large prospective cohorts worldwide, the rate of patients receiving curative treatments is steadily increasing, thanks to the expansion of surveillance programs.16,47–49Conversely, to avoid futility, this pre requisite would also imply that patients with either decompensated cirrhosis or severe co morbidities would not benefit from surveillance, and therefore they should not be offered any.50
HCC SCREENING: LIMITS
Although the efficacy of screening for HCC detection at an early stage has been affirmed by several studies and constitutes the basis of guidelines on HCC surveillance delivered by specialist societies, its translation into clinical practice is less than ideal.
This poor effectiveness might represent one of the reasons why HCC mortality has increased over the last two decades.51
A recent study by Moon et al52 failed to demonstrate a relationship between HCC screening and the decline in cancer-specific mortality, ie, one of the main goals of a screening program. These authors applied a matched case–control study design by selecting patients from the largest integrated health care system in the United States (Veterans Affairs): cirrhotic patients with fatal cancer (cases) were compared to those who did not die from it (controls), on the assumption that a lower adherence to screening programs in the cases should be expected. This analysis did not provide any evidence for a protective effect of specific mortality. The authors ascribed these findings to the low diagnostic performance of diagnostic tests which allow the identification only of slow-growing tumors (length bias) and/or the inadequacy of current treatments.
These results seem to reinforce those concerns raised regarding HCC surveillance which has been adopted in the United States in the absence of sufficient data to demonstrate its efficacy.53,54
In addition, potential screening-related undesired effects have recently been highlighted: in a retrospective cohort study 27.5% of patients under surveillance experienced physical harm, defined as CT or MRI scans or biopsies performed for false-positive or indeterminate surveillance findings.55Similarly, Konerman et al56 found that 17% of 999 patients under a well-structured surveillance program had suspicious nodules without a final HCC diagnosis and experienced severe harm (eg, CT/MRI tests ≥4 or a liver biopsy). Although these two studies highlighted the potential harm mainly as multiple imaging evaluation, it should be pointed out that a detection rate of early HCC as high as 70–75%, allowing curative treatments, was reported in both papers. To date, albeit data on harm (including the not yet explored psychological and financial aspects) related to HCC screening are scanty, it seems that advantages of surveillance programs outweigh potential harm.
Indeed, benefits of well-structured surveillance programs have recently been confirmed by a prospective study57: in a large cohort of patients, the adherence to a HCC surveillance program after correction for lead-time bias played a pivotal role in the outcome of screened patients. Indeed, a timeframe <7 months was associated with a median survival twice as long as the survival observed in non compliant patients.
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