**3. Surveillance for hepatocellular carcinoma**

Surveillance is defined as periodic application of diagnostic test to individuals who have specific risk factors for disease. Surveillance depends on the incidence of the surveyed disease in the target population, the availability of efficient diagnostic test(s) at bearable costs and acceptability for the target population, and the availability of treatments and their effectiveness if disease is diagnosed early in course of disease. Primary objective of surveillance program is early diagnosis of disease so that curative treatments can be offered to the patients [64].

#### **3.1 Target population for surveillance**

While deciding the appropriate population it is necessary to consider incidence of HCC in the population, probability that curative therapies can be offered to the patients who are diagnosed as having the disease and cost effectiveness of surveillance. In case of HCC, application of curative therapies not only depend on extent of tumor but also on underlying liver function. Hence appropriate patients should be enrolled in the surveillance program [3, 24].

#### *3.1.1 Cirrhotic patients*

Nearly 90% HCC develop on the background of cirrhosis of liver. The annual incidence of HCC is 2.0–6.6% in patients with cirrhosis [24]. Cost-effectiveness studies in western patients have shown that surveillance for HCC would be beneficial if the incidence is 1.5%/year or greater, irrespective of etiology of cirrhosis [65]. However, advanced cirrhosis with Child score C or Child score B with gross ascites, hepatorenal syndrome, clinical jaundice do not qualify for curative therapies for HCC and do not warrant surveillance unless they are considered for liver transplantation. Child A cirrhotic patients or those decompensated cirrhotic patients who are listed for liver transplant warrant surveillance as diagnosis of HCC modifies the priority and decision to transplant [66–68].

#### *3.1.2 Noncirrhotic patients*

HCC can develop in noncirrhotic liver in patients infected with hepatitis B virus. The risk varies with geographical distribution and is higher in Asia and Africa than Western countries. Higher levels of HBV replication, age and gender (males higher than females) are the risk factors for development of HCC which is lower than cirrhotic but definitely higher than general population [69, 70]. In a cohort study of males belonging to multiple race and age-groups, risk of HCC was highest among Asian Pacific Islanders, followed by whites and African Americans. Also, regardless of race, annual incidence of HCC was more than 0.2% for all patients older than 40 years with high levels of alanine aminotransferase [71]. A similar HCC incidence rate of 0.2 per 100 personyears has been observed in inactive carriers with chronic HBV infection from East Asian countries. Asian females >50 years of age and patients with family history of HCC are also at increased risk of HCC. Hence, surveillance should be offered in the above subset of patients as these patients are noncirrhotic with preserved liver function and fit for curative resection for HCC [66, 67]. Patients with chronic hepatitis B on therapy with advanced fibrosis or cirrhosis at baseline should also be enrolled under surveillance program [72, 73]. Various scoring systems are available which can help in stratifying the patients based on risk of HCC and those with significant risk should be offered surveillance [74]. Examples of such scoring systems include GAG-HCC score, LSM-HCC score, PAGE-B score, REACH-B score. REVEAL risk model [74].

Patients with chronic hepatitis C infection with bridging fibrosis are at increased risk of development of HCC. Transition from advanced fibrosis to cirrhosis cannot be accurately determined [75]. Several studies show that liver stiffness assessment performed by transient elastography correlates with risk of development of HCC [76, 77]. Hence these patients warrant surveillance for HCC. Patients with chronic HCV infection previously treated, who have achieved sustained virological response but had advanced fibrosis or cirrhosis need HCC surveillance [74].

Prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in all part of the world. Nonalcoholic steatohepatitis (NASH) is associated with morbidity and mortality due to cirrhosis and its complications and development of HCC [3]. Similar to cirrhotic patients with other etiologies, patients with NASH cirrhosis should be included in surveillance program. A systematic review and metanalysis of studies on HCC in noncirrhotic NASH subjects showed that these subjects were at greater odds of developing HCC than non-cirrhotic subjects of other etiologies (OR 2.61, 95% CI 1.27–5.35, P = 0.009) [78]. The incidence of HCC in patients with non-advanced fibrosis is expected to be insufficiently high to deserve universal surveillance, given the large prevalence of NAFLD in the general population [79]. American society of gastroenterology clinical practice update on screening and surveillance of HCC in NAFLD suggest to use two noninvasive tests to assess level of fibrosis [79]. Those patients with significant fibrosis on both tests to be enrolled in the screening program. Genetic studies have shown the presence of the PNPLA3 risk allele is increased in those NAFLD with HCC. However limited availability of the test restricts its use in clinical practice [79].

Patients with Wilson's disease, autoimmune liver disease and alpha 1- antitrypsin deficiency have lower risk of developing HCC unless cirrhosis is developed. Hence routine surveillance is not recommended [24].

#### **3.2 Surveillance tests**

Surveillance tests should be sensitive, easily available to large population, less costly, safe, acceptable to the people and permits early diagnosis of disease. Surveillance tests used for HCC surveillance can be classified as radiological, serological or combination of both. Section 2.2 and 2.4 describe imaging and tumor markers, their sensitivity, specificity and accuracy.

#### *3.2.1 Radiologic surveillance tests*

Ultrasonography (USG) of liver is the most commonly used method for surveillance. It is non-invasive, relatively inexpensive, easily available and without any associated risk of radiation. It has the sensitivity of 84% for any stage HCC and 63% for early-stage HCC [80]. In patients with cirrhosis, USG may have a suboptimal performance due to the presence of fibrous septa and regenerative nodules, which appear as a coarse pattern on ultrasound and may mask the presence of a small tumor. In a meta-analysis, the sensitivity and specificity of USG for detection of HCC at any stage were 84% (95% CI, 76–92%) and 91% (95% CI, 86–94%), respectively, but, the pooled sensitivity of ultrasound was only 47% (95% CI, 33–61%) for detection of early-stage HCC [81]. Hence, it is recommended that USG of liver for HCC surveillance should be done by an expert radiologist. Compared to ultrasonography, computed tomography and MRI had better sensitivity and specificity for diagnosis of early HCC (Refer to Section 2.2 for details). However use of radiation, complex imaging techniques, availability, cost of imaging are the important limiting factors. While comparing 6-monthly USG and yearly triphasic CT for HCC surveillance, it was found that biannual ultrasound was more sensitive (71.4%) when compared to CT (66.7%) with lower overall cost [82].

#### *3.2.2 Serological tests*

Serological test for early diagnosis of HCC include AFP, PIVKA II, AFP-L3, alpha fucosidase and glypican. (Refer to Section 2.4). Out of all AFP is most widely studied. In a study evaluating the biomarkers AFP had the best area under the receiver operating characteristic curve (0.80, 95% confidence interval [CI]: 0.77–0.84), followed by des-gamma carboxy-prothrombin (DCP) (0.72, 95% CI: 0.68–0.77) and lectin-bound AFP (AFP-L3%) (0.66, 95% CI: 0.62–0.70) for early-stage HCC and the sensitivity of AFP was 66% [83]. As a serological test alone for surveillance AFP has suboptimal performance however, it may used if ultrasound is not easily available [84, 85]. One problem with use of AFP as surveillance test is that only in 10–20% of early HCC have elevated AFP and on the other hand AFP can be falsely elevated in chronic hepatitis B and C infections [24]. Instead of single biomarker for surveillance combination of multiple biomarkers are being increasingly studied. GALAD, which includes gender, age, lectin-bound AFP % (AFPL3%), AFP, and des-gamma carboxy prothrombin (DCP) studied in a multinational phase II study involving 6,834 patients (2,430 HCC and 4,404 chronic liver disease), achieved sensitivities ranging from 60–80% for early HCC detection. Another panel including AFP, fucosylated kininogen, age, gender, alkaline phosphatase, and alanine aminotransferase demonstrated a c-statistic of 0.97 (95% CI 0.95–0.99) for early HCC detection. A methylated DNA marker panel had a c-statistic of 0.96 (95% CI 0.93–0.99), with a sensitivity exceeding 90%, for early HCC detection in a phase II study. Although these studies appear promising further research is needed in this field [3].

#### *3.2.3 Combination of both*

Meta-analysis had shown that combination of AFP and USG to be superior to only USG or AFP alone. Ultrasound with vs. without AFP detected early-stage HCC with 63% sensitivity (95% CI, 48–75%) and 45% sensitivity (95% CI, 30–62%), respectively (P = .002) [86]. The benefit of AFP in addition to ultrasound was consistent across subgroups, including prospective studies, studies conducted in the United States, and studies conducted after the year 2000 [86]. Counter argument to this approach is that, although addition of AFP to USG helps in detection of 6–8% additional tumors does not balance the increase in false positive results resulting due to active inflammation causing raise in AFP levels in absence of HCC, adding to cost of screening without significant benefit [24].

## **3.3 Surveillance interval**

It depends on rate of tumor growth and incidence of cancer in the population [24]. Median doubling time of an HCC lesion is 6.5 months +/− 5.7 months [87]. Analysis of prospectively maintained multi-center Italian database showed a better overall median survival of 40.3 months in the 6-monthly surveillance group, compared to 30 months in the 12-monthly surveillance group (P = 0.03) [88]. Subsequently a French study evaluated impact of shortening of surveillance to 3 months. It showed that 3-months surveillance group had higher incidence of non-malignant lesions, similar number of patients in both 3-months and 6-months group were detected with HCC at an early stage (79% vs. 71%; P = 0.40) and similar proportions received curative therapies (62% vs. 58%; P = 0.88) [89]. Hence it appears that 6 months interval is optimal.

#### **3.4 Benefits of surveillance**

Cancer surveillance programs are aimed to detect tumors early so that curative treatments can be provided to patients. Evidence in favor of surveillance programs


*Recommendations, screening tests, screening interval by various societies across the world. (SVR-sustained virological response).*

*Hepatocellular Carcinoma - Challenges and Opportunities of a Multidisciplinary Approach*

*Hepatocellular Carcinoma: Diagnosis and Surveillance DOI: http://dx.doi.org/10.5772/intechopen.99839*

in HCC has remained controversial. One randomized controlled trial supporting HCC surveillance with 6-monthly abdominal ultrasound was performed in more than 18,000 Chinese patients and showed a 37% reduction in mortality risk in screened patients [90]. Other studies are retrospective, observational and has suffered some biases. Lead time which means the given proportion of survival benefit is due to early diagnosis due to surveillance and length time bias arises due to detection of slow growing tumors during surveillance programs where as fast growing tumors become symptomatic early in their course [3]. Surveillance programs can create a state of anxiety in mind of patients. Additional tests and financial burden if screening tests are indeterminate. There is also possibility of overtreatment of tumor which might never become symptomatic [3]. Considering dismal prognosis of HCC, all societies recommend screening of at risk patients for HCC [24, 33, 91–93].

#### **3.5 Summary of recommendations by various societies**

**Table 6** summarizes recommendations, screening tests, screening interval by various societies across the world [24, 33, 91–93].

### **4. Role of multidisciplinary team in surveillance and diagnosis of HCC**

Optimal care of patients with HCC involves specialists from multiple disciplines like gastroenterology/hepatology, surgical oncologist, liver transplant team, medical oncologist, radiologist, interventional radiologist, primary care physician, radiation oncologist, pathologists, palliative care specialist, nursing staff and dieticians. Multidisciplinary teams (MDTs) have evolved to facilitate care coordination, reassessments of clinical course, and fine changes in treatment plans required for these complex group of patients. MDTs provide platform to facilitate prompt diagnosis of HCC by reviewing patients imaging, tumor markers and also assessing the need for biopsy which is associated with complications like bleeding and needle track seeding. As mentioned in previous sections, diagnosis of HCC is primarily based on imaging and there are restricted indications for biopsy of lesion. Experts in MDTs can also play a role in suggesting next investigation if one of the diagnostic investigation is inconclusive [94].

#### **5. Conclusion**

To conclude, small HCC rarely become symptomatic. HCC can be a cause for new onset decompensation. Diagnosis of HCC requires multiphase computed tomography or MRI scan. In cirrhotic liver, diagnosis of HCC is based on typical imaging features and rarely needs biopsy. In noncirrhotic liver and vascular liver diseases biopsy may be required to confirm diagnosis. Contrast enhanced ultrasound and MRI with hepatobiliary contrast agents are promising modalities for evaluation of small and indeterminate nodules. Tumor markers play adjunct role in diagnosis but has prognostic significance. Pathologically HCC is heterogenous tumor with multiple subtypes with distinct molecular signatures. HCC surveillance in high risk groups with biannual ultrasound with or without alfa-fetoprotein helps in early detection of lesions which are amenable to curative treatment. Multidisciplinary teams provide platform for care coordination, reassessments of clinical course, and fine changes in treatment plans required for this complex group of patients.

*Hepatocellular Carcinoma - Challenges and Opportunities of a Multidisciplinary Approach*
