Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis

From Clinical Gastroenterology and Hepatology,

Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis


Authors and Disclosures

Ju Dong Yang and W. Ray Kim
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota

Posted: 01/19/2012; Clin Gastroenterol Hepatol. 2012;10:16-21. © 2012 AGA Institute

Clinical Scenario
A59-year-old man was referred to liver transplantation clinic for the evaluation of enlarging abdominal girth and swelling of feet during the preceding 2 months. The patient was a Cambodian native who immigrated to the United States 5 years ago. The patient was first diagnosed with chronic hepatitis B virus (HBV) infection shortly after his entry into the United States. However, he was not further evaluated, treated, or followed. He had no personal or family history of liver disease or liver cancer. Physical examination of the abdomen showed mild hepatosplenomegaly with positive shifting dullness from a moderate amount of ascites. There was no abdominal tenderness. Laboratory results included platelet count, 95,000/μL; aspartate aminotransferase, 100 U/L; alanine aminotransferase, 45 U/L; and Model for End-Stage Liver Disease score, 13. Viral serology showed hepatitis B surface antigen–positive and eantigen– positive and HBV DNA of 5 million IU/mL. Serum alpha-fetoprotein (AFP) was normal at 4 ng/mL. An abdominal ultrasound (US) showed cirrhotic liver contour and evidence of portal hypertension. An esophagogastroduodenoscopy showed large esophageal varices. The patient was started on the following medications: spironolactone and furosemide for the ascites, propranolol for the varices, and entecavir for HBV. Patient was further assessed and then listed for liver transplantation.

During the ensuing 12 months, the patient had substantial clinical improvement including resolution of ascites as well as hepatitis B e seroconversion. He also underwent abdominal US and serum AFP measurement on a 6-month interval. An abdominal US performed 18 months after his presentation showed a new 2.1-cm hyperechoic nodule in the right lobe of the liver along with mild elevation of serum AFP at 22 ng/mL. A subsequent triphasic abdominal computed tomography (CT) scan showed a 2.2-cm well-circumscribed vascular mass that had arterial enhancement and venous washout, thus meeting the radiographic diagnosis criteria for hepatocellular carcinoma (HCC) of the American Association for the Study of Liver Disease (AASLD). The patient underwent transarterial chemoembolization and subsequently received a liver transplant. Four years later, the patient is doing well with satisfactory liver function with no evidence of recurrent HBV or HCC.

The Problem
Our patient represents a case in which implementation of HCC surveillance likely improved his ultimate outcome. HCC is a major global health problem because it is the third leading cause of cancer-related death in the world. GloboCan reported that the incidence and mortality of HCC continued to increase as of 2008. In general, HCCs tend to be asymptomatic until the tumor is in an advanced stage. Although there has been substantial progress in the treatment of HCC, long-term survival is only achievable in a small proportion of patients— those presenting in an early stage where potentially curative modalities such as liver transplantation and surgical resection are feasible. Therefore, it is widely held and recommended that early detection of HCC is imperative in improving the prognosis.

Screening is defined as application of diagnostic tests in patients at risk for a condition (eg, HCC) without a high index of suspicion that the condition is already present. Surveillance is conducted by repeated application of screening tests. In the case of HCC, the stated goal of surveillance is to decrease HCC mortality or at least to increase the meaningful duration of life through the early detection of HCC in asymptomatic patients. Existing evidence indicates that HCCs detected by surveillance are more likely to be amenable to curative treatment. Because long-term survival can be achieved in a majority of patients eligible for liver transplantation or resection, surveillance might decrease HCC mortality. This is a main rationale for which HCC surveillance is recommended in high-risk individuals.

There have been 2 randomized controlled trials that investigated the efficacy of surveillance. Both studies were conducted in China in patients with HBV infection. The first study, involving 19,000 patients, showed that surveillance is efficacious in reducing HCC mortality. Patients assigned to semiannual surveillance with serum AFP and abdominal US had a 37% decrease in HCC mortality compared with patients not under surveillance. Although the study was limited by a high dropout rate of study participants and suboptimal randomization and concealment schemes, it provides the best evidence to date that has shown the benefit of surveillance on "hard end points" in HCC. The other study was performed with 5581 HBV patients. In contrast to the first study, it used serum AFP as the primary tool for surveillance. This study showed that surveillance increased the detection of early-stage tumors but did not affect overall survival and liver cancer mortality. Besides these trials, a number of observational studies have suggested that surveillance improves survival in HCC patients (Table 1).

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Although HCC surveillance is generally accepted, its implementation is suboptimal in real-life practices. In the United States, a study that used the Surveillance Epidemiology and End Results-Medicare database showed that only 17% of cirrhotic patients were under regular surveillance 3 years before the diagnosis of HCC. In a more recent study involving 13,000 cirrhotic hepatitis C virus patients at Veterans Administration health care facilities throughout the United States, only 12% received routine HCC surveillance.

Who Are the Candidates for Hepatocellular Carcinoma Surveillance?
Hepatocellular carcinoma surveillance should be performed in a group of patients whose risk for HCC development is sufficiently high to make it cost-effective Table 2-below- Surveillance is considered effective if it increases life expectancy by more than 3 months and considered cost-effective if less than $50,000 is needed to increase 1 quality-adjusted life-year. Under this concept, the incidence of HCC is the primary determinant of the cost-effectiveness of surveillance.

The first category of candidates for surveillance is patients with cirrhosis. Cirrhosis is the single most important risk factor for HCC, and most patients with HCC have underlying liver cirrhosis. According to a guideline from AASLD, surveillance is recommended when the HCC incidence is higher than 1.5% in a patient with cirrhosis. This category of patients includes those with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis, and thus these patients should be under a surveillance program. In addition, experts recommend patients with other types of cirrhosis to receive surveillance, although firm data about the incidence of HCC in this group of patients are lacking.

In implementing surveillance, one of the common challenges is to identify patients with cirrhosis. Because viral hepatitis is easily recognizable, patients at risk for chronic viral hepatitis infection need to be screened for HBV and/or hepatitis C virus according to the established guidelines. It is also important to have a high index of suspicion of chronic liver disease in patients with abnormal liver function test, significant alcohol history, or metabolic syndrome.

The diagnosis of cirrhosis is straightforward in patients with hepatic decompensation, on the basis of the characteristic symptoms of portal hypertension and liver failure. Hepatocellular carcinoma surveillance in this group of patients would be most meaningful if liver transplantation is available. Under the current allocation system, an early-stage HCC within the socalled Milan criteria increases the priority of receiving a liver transplant from a deceased donor. In contrast, if liver transplantation is not available, surveillance in patients with hepatic decompensation severe enough to disallow meaningful therapy is unlikely to be beneficial.

Diagnosing patients with compensated liver cirrhosis might present a challenge because patients are usually asymptomatic without an overt sign of portal hypertension. Although histology is considered the gold standard for the diagnosis of cirrhosis, a liver biopsy is invasive and subject to sampling variability. Various laboratory data and mathematical models have been proposed to noninvasively identify patients with cirrhosis. Transient elastographic techniques with magnetic resonance imaging (MRI) or US measure the stiffness of the liver, which correlates with hepatic fibrosis. As data accumulate in support of accuracy of these techniques in identifying asymptomatic cirrhotic patients, they are gaining wider acceptance in clinical practice.

The other category of candidates for surveillance is HBV carriers who might develop HCC without cirrhosis. In those subjects, surveillance is warranted when the HCC incidence is higher than 0.2%/year. These high-risk hepatitis B carriers include Asian men older than 40 years and Asian women older than 50 years. Although the annual incidence of HCC in individuals of African race or those with family history of HCC cannot be firmly established, they are also recommended to undergo surveillance starting at an earlier age(Table 2 ).

Table 2. Target Subjects for HCC Surveillance

Cirrhosis, threshold incidence (>1.5%	Incidence	Noncirrhotic HBV carrier, threshold incidence (>0.2%)	Incidence
HBV cirrhosis	3%–8%/y	Asian men >40 y	0.4%–0.6%/y
HCV cirrhosis	3%–5%/y	Asian women > 50 y	0.3%–0.6%/y
Primary biliary cirrhosis	3%–5%/y	Family history of HCC	Unknown
Nonalcoholic steatohepatitis	2.6%/y	African race	Unknown
Other cause of cirrhosis	Unknown

What Modality is to be Used for Surveillance?
Most guidelines advocate abdominal US as the standard surveillance test for HCC. It has sensitivity greater than 60% and specificity greater than 90% as a screening test for HCC. It is widely available and less expensive than CT or MRI. It does not expose patients with repeated radiation. However, there are several weaknesses of US as a surveillance test for HCC. Abdominal US is highly dependent on the operator. Because small HCC often presents with a nonspecific appearance, detecting an early HCC nodule can be challenging, particularly in a patient with a nodular cirrhotic liver. Sensitivity of US is further decreased in obese subjects. Because of the high prevalence of obesity in the United States, the utility of US as an HCC surveillance test in those patients has been questioned.
These limitations of US have prompted some clinicians to use abdominal CT or MRI in select patient groups, eg, those waiting for liver transplantation. However, the risk of repeated radiation and contrast exposure and high cost are obvious limitations that prevent its routine use in the broader population at risk. Finally, serum AFP is commonly used as an adjunct to abdominal US, although its use as a surveillance test for HCC remains controversial.

What is the Next Step if a Suspicious Lesion is Found by a Surveillance Test? (Recall Policy)
Once a suspicious lesion is found on US, a systematic algorithm, also known as the recall policy, can be followed to appropriately and expeditiously diagnose an HCC (Figure 1). If the nodule is smaller than 1 cm, a close follow-up with a repeat US at 3 months is recommended. If the lesion is found to enlarge to a size larger than 1 cm, a dynamic imaging study (CT or MRI) should be performed. If the size of the lesion remains the same for more than 2 years, the original 6-month follow-up might be resumed.

Figure 1. Lesions on surveillance US: recall policy.

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For lesions that appear larger than 1 cm on US, a contrastenhanced dynamic CT or MRI must be performed. If characteristic vascular features (arterial enhancement and venous washout) are seen, a diagnosis of HCC is established. If the imaging characteristics are not typical, a second dynamic scan should be performed (if the first modality was CT, then MRI, and vice versa). If it shows the characteristic vascular features, a diagnosis of HCC might be made. If not, a percutaneous biopsy of the lesion should be considered, although the biopsy might not always be diagnostic. Finally, if there is considerable increase in serum AFP in the absence of a demonstrable lesion on US, a contrast-enhanced dynamic CT or MRI should be performed.

Areas of Uncertainty

Is Serum Alpha-Fetoprotein Beneficial?
There is broad agreement that serum AFP alone is inadequate as an independent tool for HCC surveillance and must not be used. For example, investigators of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial serially measured the serum AFP every 3 months before the diagnosis of HCC and reported that serum AFP has inadequate efficacy as a surveillance test. Many other studies investigating the performance of AFP were in the setting of diagnosis rather than surveillance, where pretest probabilities are higher and the performance of the test is overestimated. The biggest limitation of serum AFP, when used alone, is its low sensitivity. Whereas the test might be made sufficiently specific if a high cutoff value is used, modest elevations might be seen in patients with viral hepatitis especially hepatitis C, pregnant women, and in those with tumors other than HCC, most notably gonadal tumors. Thus, depending on the cutoff value, serum AFP has suboptimal sensitivity and/or specificity. More recent serum markers such as des-carboxy prothrombin and the ratio of lecithinbound AFP to total AFP are even less sensitive than AFP for the detection of early-stage HCCs and have not been shown to be useful for surveillance.

Compared with US alone, the combination of US and serum AFP might slightly enhance the sensitivity to detect an HCC lesion. A study from China showed that the combination of US and serum AFP increases the liver cancer detection rate by 9%. However, the combination was associated with a 2.4-fold increase in false positivity and a 2.2-fold decrease in the positive predictive value. A cost-effectiveness analysis performed in the United States showed abdominal US is most cost-effective, and addition of AFP to US in HCC surveillance provides a small gain at a significant increase in cost. This increase in cost stems not only from adding the cost of AFP testing but also from the expenses needed to investigate false-positive results. For this reason, the AASLD guideline recommends the use of US alone for the surveillance of HCC.

Despite these limitations of serum AFP, a recent study that used the Surveillance Epidemiology and End Results-Medicare database reported that the combination of serum AFP and US, followed by serum AFP alone, is most commonly used for HCC surveillance in the United States. The reality in practice is that AFP is widely available and inexpensive. Proponents point out that given the poor adherence to US-based surveillance, even a suboptimal test might still be better than complete lack of any surveillance. This might be more relevant in settings with limited health care access and resources, such as in Alaskan natives with chronic HBV infection in whom serum AFP was found to be beneficial.

How Often Should Tests be Repeated?
Most guidelines recommend surveillance to be conducted every 6 months. The principle for determining the interval for surveillance is that it should not be based on the anticipated incidence of HCC, but on the rate of tumor growth. Even if the incidence is high, if all of the tumors grow slowly, infrequent surveillance would be sufficient. On the other hand, if many tumors grow fast, frequent surveillance is needed for any hope of early diagnosis to exist. Thus, the absolute risk (incidence) of HCC determines whether surveillance should be performed, whereas the rate of tumor growth dictates the interval for surveillance.

It is currently uncertain whether surveillance every 6 months is superior to every 12 months in decreasing HCC mortality and improving patient survival ( Table 3 ).

 Table 3. Comparison Between 6-Month and 12-Month Surveillance

Study	Study design	Patient population	Definition of surveillance	Main outcome	Result
Santi et al, 2010	Cohort	Italian cirrhotic patients with HCC, n = 595	Abdominal US ± AFP	Overall survival	5-y survival: 57% vs 21% in semiannual surveillance and annual surveillance, respectively (P <.0001)
Santagostino et al, 2003	Cohort	Italian hemophiliac with HCV, n = 559	Abdominal US ± AFP	HCC-related death	At 6-follow-up: 1/210 (0.5%vs 2/349 (0.6%died of HCC in semiannual surveillance and annual surveillance, respectively (P >.05)
Trevisani et al, 2002	Cohort	Italian cirrhotic patients with HCC, n = 821	Abdominal US ± AFP	Overall survival	Median survival: 36 vs 34 mo in semiannual surveillance and annual surveillance, respectively (P <.05)

Several retrospective studies showed that there is no difference in survival between 6-month and 12-month surveillance intervals. However, the most recent study showed that surveillance every 6 months improved patient survival compared with that every 12 months. In short, to date, there is no robust evidence from a randomized controlled trial to determine the optimal surveillance interval. Most hepatologists tend to err on being more conservative with frequent (ie, semiannual) surveillance.

Published Guidelines and Summary

Most practice guidelines suggest that patients at risk of HCC undergo surveillance. Published guidelines for HCC surveillance are summarized in - Table 4

Table 4. HCC Surveillance in Published Guidelines

	AASLD	EASL	APASL	NCI
Target subjects	All patients with cirrhosis, certain individuals with HBV infection	All patients with cirrhosis	High-risk population: cirrhotic patients with HBV and HCV	No recommendation on HCC surveillance
Modality	US	US	US and AFP
Interval	6 mo	6 mo	6 mo

APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; NCI, National Cancer Institute.

Although not ideal, US is the preferred modality for surveillance. The AASLD guideline recommends patients with cirrhosis from any cause to undergo HCC surveillance by using abdominal US at 6-month intervals. AFP is inadequate as a surveillance test. The European Association for the Study of the Liver recommends that the ideal target population is Child–Pugh class A cirrhotic patients without severe comorbid conditions. Patients not suitable for curative therapy might be excluded from surveillance. The Asian Pacific Association for the Study of the Liver specifies cirrhotic patients with HBV and HCV as candidates for surveillance in whom the combination of US and AFP is to be used every 6 months. In contrast to these liver societies, the National Cancer Institute calls for additional data before HCC surveillance is routinely recommended, even in high-risk patients. They note that data to date suffer from several methodological flaws and limited generalizability and thus have not proved that surveillance decreases HCC mortality.

Against the backdrop of these recommendations, in the particular case of our patient, we have little doubt that he benefited from the surveillance because it led to detection of an early HCC lesion, followed by successful liver transplantation. He was "fortunate" to have experienced hepatic decompensation that drew close medical attention to his liver disease, which resulted in institution of surveillance for HCC. Because he had not been followed for his HBV, he could very well have presented with advanced HCC, if his liver disease had remained compensated. Although our patient would have been a candidate for surveillance according to most guidelines, he belonged in the majority of patients in whom surveillance is not practiced as a result of patient preference, lack of socioeconomic or health insurance support, or poor awareness of or adherence to guideline recommendations by the physician.

Among human malignancies, HCC is unique in that cirrhosis or advanced fibrosis is essentially a prerequisite condition, which makes it relatively straightforward to identify subjects who should be subjected to surveillance. However, it is obvious that not all patients with cirrhosis develop HCC, and the best informed surveillance strategy should include accurate risk stratification. As of today, we lack detailed knowledge for individualized risk stratification, which prevents formulation of an optimal surveillance program. Clearly, more high-quality data are needed to improve the outcome of patients with HCC, whose incidence is rising in the United States and globally. In the meantime, the clinician is encouraged by cases like ours that careful adherence to surveillance in at-risk individuals provides opportunities to make a meaningful difference in the patient's outcome.

References

1. Bruix J, Aasld SM. AASLD practice guideline, management of hepatocellular carcinoma: an update. Available at: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf. Accessed August 02, 2010.
2. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.
3. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL Conference—European Association for the Study of the Liver. J Hepatol 2001;35:421–430.
4. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–422.
5. Davila JA, Morgan RO, Richardson PA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 2010;52:132–141.
6. Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110–118.
7. Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology 2010;138:493–502.
8. Santi V, Trevisani F, Gramenzi A, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol 2010;53:291–297.
9. Chen JG, Parkin DM, Chen QG, et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 2003;10:204–209.
10. Davila JA, Henderson L, Kramer JR, et al. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med 2011;154:85–93.