HHS Public Access Author manuscript Author Manuscript
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01. Published in final edited form as: Curr Hepatol Rep. 2015 June ; 14(2): 128–138. doi:10.1007/s11901-015-0261-y.
Screening for hepatocellular carcinoma and cholangiocarcinoma: Can biomarkers replace imaging? Maria E. Lozada, BS, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905
Author Manuscript
Roongruedee Chaiteerakij, MD, and Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905 and Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand Lewis R. Roberts, MB ChB, PhD Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905 Maria E. Lozada: [email protected]; Roongruedee Chaiteerakij: [email protected]; Lewis R. Roberts: [email protected]
Author Manuscript
Keywords Early detection; Surveillance; Diagnosis; Liver Cancer; Bile Duct Cancer
Introduction
Author Manuscript
Based on the most recent data from 2007 to 2011, the United States (US) Surveillance, Epidemiology and End Results (SEER) Program reports an age-adjusted incidence rate of 7.9 per 100,000 people per year for liver and intrahepatic bile duct cancer, with a corresponding death rate of 5.8 per 100,000 people per year, resulting in a relatively high mortality ratio of 73%. Examination of trends in incidence from the SEER database shows that the age-adjusted incidence rate per year is rising and almost doubled between 1992 and 20111. Similar trends have been observed in Canada, Australia, New Zealand, and Western Europe 2. Further, despite the recent decrease in new cases in Japan, the Philippines and
Corresponding author: Lewis R. Roberts, MB ChB, PhD, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, Office: 507-538-4877 | Fax: 507-284-0762, [email protected]. Conflict of Interest Maria E. Lozada declares no conflict of interest. Roongruedee Chaiteerakij declares no conflict of interest. Dr. Roberts has received research grants from Wako Diagnostics and Inova Diagnostics, developers of serum biomarker tests. He has a current grant from Gilead Sciences, outside the submitted work. Compliance with Ethics Guidelines Human and Animal Rights and Informed Consent Some of the referenced articles by authors do include human participants. All have been approved by Institutional Review Board and were conducted with proper informed consent and following ethics guidelines.
Lozada et al.
Page 2
Author Manuscript
China, East Asia has the highest overall incidence rate in the world2. After East Asia, subSaharan Africa has the next highest incidence of hepatocellular carcinoma (HCC) in the world, but due to the limited medical and research infrastructure in this region, data on trends in incidence is very limited3.
Author Manuscript
Treatment of HCC and cholangiocarcinoma (CCA) is most effective for patients with early stage, localized disease while treatment of advanced liver cancer is merely palliative in nature. Unfortunately, in the US, only 20 to 30% of HCC and CCA cases are diagnosed with early stage disease4, 5. In Taiwan and Japan, where there are comprehensive nationwide programs for early diagnosis and surveillance of individuals at risk for HCC from chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, approximately 70% of HCCs are diagnosed at very early or early stages, resulting in 5 year survival estimates of 50– 70%6. In the US, CCA is often diagnosed in advanced stages when disease is incurable7. Thus national and international efforts to reduce the burden or morbidity and mortality from HCC and CCA need to focus on identification of the population at risk and aggressive surveillance using effective screening tools.
Author Manuscript
The emerging evidence suggests that biomarkers are optimally used as a complement, rather than a replacement for imaging studies. Biomarkers uniquely may be elevated before there is any evidence of imaging abnormalities and may also guide consideration of what the primary tumor type is, such as HCC versus CCA, or mixed HCC-CCA. Cancer biomarker development is described by Pepe and colleagues as a 5-phase process in which each stage is characterized by study design application (Figure 1)8, 9. In this review we provide an update on the current status of liver and biliary cancer surveillance and describe recent efforts that are taking advantage of novel technologies in next generation DNA sequencing, genome wide methylation and proteomic studies, and advances in metabolomics to usher in a new era of biomarker development. The novel biomarkers in development will hopefully result in substantial improvements in both surveillance and diagnosis of HCC and CCA. Biomarkers discussed in this review, their current stage in biomarker development and clinical applicability are summarized in Table 1 for HCC and in Table 2 for CCA.
Hepatocellular carcinoma
Author Manuscript
HCC is the most common malignancy of the liver. Current practice guidelines from the American Association for the Study of Liver Diseases (AASLD) recommend surveillance for HCC in patients with an expected risk of HCC exceeding 1.5% per year or 0.2% per year in patients with chronic HBV. Based on these recommendations, surveillance for HCC should be offered to all patients with cirrhosis and to hepatitis B carriers who have a family history of HCC, are Asian-born males 40 years or older, are Asian females 50 years or older, or African-born individuals 20 years or older. Individuals with immune active chronic HBV and those with coinfection with HCV or HIV or who have other chronic liver diseases should also be enrolled in surveillance programs10, 11. Currently used biomarkers: AFP, AFP-L3 and DCP World-wide, the commonest modalities used for surveillance for HCC in at risk individuals are liver ultrasound and serum alpha fetoprotein (AFP) measurement. AFP is a glycoprotein
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
Lozada et al.
Page 3
Author Manuscript
produced by fetal liver and yolk sac; serum levels are high in utero but normalize to adult values rapidly after birth. High serum AFP values have been shown to occur in different cancers, including HCCs and germ cell tumors. The use of AFP as a screening modality has been controversial, particularly in low to medium incidence regions, but is widespread in high incidence countries, where it is incorporated into most national and regional guidelines. The main objection to the use of AFP is its low sensitivity of only 20–30% for the detection of HCC at an early stage, when it is most amenable to curative treatment. The sensitivity of AFP rises to 50–60% for the detection of intermediate to advanced stage disease12–14. Proponents of the use of AFP argue that while most studies evaluating the performance of AFP have evaluated it in the cross-sectional setting, experienced practitioners typically follow and act on trends and variations in AFP levels, rather than individual measurements alone15. Further, the combination of AFP with ultrasound improves the likelihood of detection of the more diffuse or infiltrating HCCs that do not develop as distinct nodules.
Author Manuscript
In addition to the AFP, other serum markers in clinical use for HCC surveillance include the lens culinaris binding subfraction of AFP (AFP-L3%) and the des gamma carboxyprothrombin (DCP). AFP-L3 is a glycosylated variant of AFP abnormally increased in HCC. DCP, also known as protein induced by vitamin K absence II (PIVKA-II), is a form of prothrombin generated when there is an acquired defect in post-translational carboxylation. These assays are routinely used in Japan and other Asian countries and are approved for use in risk stratification for HCC by the US Food and Drug Administration. AFP-L3 and DCP have been shown to increase sensitivity and specificity of AFP in diagnosing HCC12, 16, 17.
Author Manuscript Author Manuscript
A number of models have been developed which integrate the results of biomarker assays with different patient clinical and laboratory characteristics to enhance the diagnostic accuracy of biomarkers in specific patient settings. The GALAD model by Johnson et al. includes gender, age, AFP-L3, AFP and DCP as predictors of risk for HCC in the setting of chronic liver disease. This model has been has been validated and has shown consistency in stratifying patients based on risk of HCC18. A similar algorithm, known as BALAD-2, was developed by the same group for accurate prognostication of patients with HCC19. El-Serag et al. recently developed another model using platelet count, alanine aminotransferase (ALT), age and AFP to predict risk for HCC in patients with HCV-induced cirrhosis. In general, patients with high AFP who also had decreased platelet count, decreased ALT, or increased age showed higher risk of HCC. Their model-predicted probability levels showed a very close relationship with raw frequencies of HCC that only deviated in risks higher than 90% where there is no practical significance. This model is yet to be tested on other populations with liver disease due to causes other than HCV and in populations outside of the Veterans Affair (VA) Health system where males predominate20. The recently published ADRESS model can be used for predicting HCC probability in patients with cirrhosis using the variables of age, diabetes, race, cirrhosis etiology, sex and severity of liver dysfunction. Although no biomarkers are included in the model, it can possibly stratify patients with cirrhosis into groups based on their potential surveillance program benefit21. Finally, AFP and DCP biomarkers also have utility in combination with clinical factors for predicting recurrence of HCC after liver transplantation22–24.
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
Lozada et al.
Page 4
Ultrasound
Author Manuscript
Ultrasound is a widely used tool for both diagnosis and surveillance of various liver and cholestatic diseases and is currently established for surveillance of early stage HCC. AASLD Guidelines recommend HCC surveillance with liver ultrasound every 6 months11. Ultrasound offers clinicians a safe, noninvasive and low cost real-time imaging tool that is widely available. However, ultrasound efficacy is operator dependent and its performance in detecting lesions, especially smaller ones, is impaired. This becomes even more problematic given the increasing prevalence of obesity-related fatty liver disease and cirrhosis in North America, Europe and Asia. Regenerative nodules in cirrhotic livers can be confused with neoplastic masses, leading to additional diagnostic test that are more invasive, have increased costs and can unnecessarily increase patient anxiety. Together, these limitations raise a fundamental problem in relying solely on ultrasound for surveillance of HCC.
Author Manuscript Author Manuscript
A meta-analysis on surveillance performance for detecting HCC on cirrhotic patients via ultrasound reported a pooled sensitivity of 94%, specificity of 94% and a summary receiver operator curve (ROC) plot of 98%. However, these numbers were for detecting HCC at any stage of disease. When only looking at studies that reported detection of early HCC as defined by Milan criteria (one nodule 2 copies of at least 2 probes excluding cells with tetrasomy) Equivocal: ≥10 cells with trisomy (3 copies of a single probe) or ≥10 cells with tetrasomy (4 copies of each probe). Tetrasomy can represent replicating cells14–16.
PB FISH assay
Bile duct brushings
3
Diagnosis
Negative: 2 copies of each probe Positive: ≥5 cells with polysomy (>2 copies of at least 2 probes excluding cells with tetrasomy) Equivocal: ≥10 cells with trisomy (3 copies of a single probe) or ≥10 cells with tetrasomy (4 copies of each probe). Tetrasomy can represent replicating cells14–16.
Methylated BMP-3
Bile
1
Early detection
NA
Author Manuscript
1
Marrero JA, Feng Z, Wang Y, Nguyen MH, Befeler AS, Roberts LR, Reddy KR, Harnois D, Llovet JM, Normolle D, Dalhgren J, Chia D, Lok AS, Wagner PD, Srivastava S, Schwartz M. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110–8. 2
Gopal P, Yopp AC, Waljee AK, Chiang J, Nehra M, Kandunoori P, Singal AG. Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 2014;12:870–7.
3
Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, Lok AS. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients. Hepatology 2003;37:1114–21. 4
Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology 2012;55:483–90. 5
Cao FF, Yu S, Jiang ZY, Bao YX. Diagnostic accuracy of Golgi protein 73 in primary hepatic carcinoma using ELISA: a systematic review and meta-analysis. Clinical laboratory 2014;60:587–97.
Author Manuscript
6
Shen Q, Fan J, Yang XR, Tan Y, Zhao W, Xu Y, Wang N, Niu Y, Wu Z, Zhou J, Qiu SJ, Shi YH, Yu B, Tang N, Chu W, Wang M, Wu J, Zhang Z, Yang S, Gu J, Wang H, Qin W. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. The Lancet. Oncology 2012;13:817–26. 7
Reichl P, Fang M, Starlinger P, Staufer K, Nenutil R, Muller P, Greplova K, Valik D, Dooley S, Brostjan C, Gruenberger T, Shen J, Man K, Trauner M, Yu J, Gao CF, Mikulits W. Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma. International journal of cancer. Journal international du cancer 2014.
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
Lozada et al.
Page 20
8
Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008;48:1106–17.
Author Manuscript
9 Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19–9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Digestive diseases and sciences 2005;50:1734–40. 10
Siqueira E, Schoen RE, Silverman W, Martin J, Rabinovitz M, Weissfeld JL, Abu-Elmaagd K, Madariaga JR, Slivka A. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointestinal endoscopy 2002;56:40–7.
11
Chapman MH, Sandanayake NS, Andreola F, Dhar DK, Webster GJ, Dooley JS, Pereira SP. Circulating CYFRA 21-1 is a Specific Diagnostic and Prognostic Biomarker in Biliary Tract Cancer. Journal of clinical and experimental hepatology 2011;1:6–12. 12
Ruzzenente A, Iacono C, Conci S, Bertuzzo F, Salvagno G, Ruzzenente O, Campagnaro T, Valdegamberi A, Pachera S, Bagante F, Guglielmi A. A novel serum marker for biliary tract cancer: diagnostic and prognostic values of quantitative evaluation of serum mucin 5AC (MUC5AC). Surgery 2014;155:633–9. 13
Danese E, Ruzzenente O, Ruzzenente A, Iacono C, Bertuzzo F, Gelati M, Conci S, Bendinelli S, Bonizzato G, Guglielmi A, Salvagno GL, Lippi G, Guidi GC. Assessment of bile and serum mucin5AC in cholangiocarcinoma: diagnostic performance and biologic significance. Surgery 2014;156:1218–24. 14
Author Manuscript
Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, Sebo TJ, Therneau TM, Gores GJ, de Groen PC, Baron TH, Levy MJ, Halling KC, Roberts LR. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. The American journal of gastroenterology 2004;99:1675–81. 15 Barr Fritcher EG, Kipp BR, Halling KC, Clayton AC. FISHing for pancreatobiliary tract malignancy in endoscopic brushings enhances the sensitivity of routine cytology. Cytopathology: official journal of the British Society for Clinical Cytology 2014;25:288–301. 16
Barr Fritcher EG KB, Voss JS, Brankley SM, Keeney ME, Campion MB, Pestova EV, Sokolova IA, Roberts LR, Gores GJ, ClaBarr Fritcher, E. Guyton AC, Halling KC. The Development of a Tailored Pancreatobiliary Fluorescence in situ Hybridization (FISH) Assay to Improve Detection of Malignancy in Pancreatobiliary Brushings. The Journal of Molecular Diagnostics 2013;15:909.
Author Manuscript Author Manuscript Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01. Published in final edited form as: Curr Hepatol Rep. 2015 June ; 14(2): 128–138. doi:10.1007/s11901-015-0261-y.
Screening for hepatocellular carcinoma and cholangiocarcinoma: Can biomarkers replace imaging? Maria E. Lozada, BS, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905
Author Manuscript
Roongruedee Chaiteerakij, MD, and Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905 and Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand Lewis R. Roberts, MB ChB, PhD Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905 Maria E. Lozada: [email protected]; Roongruedee Chaiteerakij: [email protected]; Lewis R. Roberts: [email protected]
Author Manuscript
Keywords Early detection; Surveillance; Diagnosis; Liver Cancer; Bile Duct Cancer
Introduction
Author Manuscript
Based on the most recent data from 2007 to 2011, the United States (US) Surveillance, Epidemiology and End Results (SEER) Program reports an age-adjusted incidence rate of 7.9 per 100,000 people per year for liver and intrahepatic bile duct cancer, with a corresponding death rate of 5.8 per 100,000 people per year, resulting in a relatively high mortality ratio of 73%. Examination of trends in incidence from the SEER database shows that the age-adjusted incidence rate per year is rising and almost doubled between 1992 and 20111. Similar trends have been observed in Canada, Australia, New Zealand, and Western Europe 2. Further, despite the recent decrease in new cases in Japan, the Philippines and
Corresponding author: Lewis R. Roberts, MB ChB, PhD, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, Office: 507-538-4877 | Fax: 507-284-0762, [email protected]. Conflict of Interest Maria E. Lozada declares no conflict of interest. Roongruedee Chaiteerakij declares no conflict of interest. Dr. Roberts has received research grants from Wako Diagnostics and Inova Diagnostics, developers of serum biomarker tests. He has a current grant from Gilead Sciences, outside the submitted work. Compliance with Ethics Guidelines Human and Animal Rights and Informed Consent Some of the referenced articles by authors do include human participants. All have been approved by Institutional Review Board and were conducted with proper informed consent and following ethics guidelines.
Lozada et al.
Page 2
Author Manuscript
China, East Asia has the highest overall incidence rate in the world2. After East Asia, subSaharan Africa has the next highest incidence of hepatocellular carcinoma (HCC) in the world, but due to the limited medical and research infrastructure in this region, data on trends in incidence is very limited3.
Author Manuscript
Treatment of HCC and cholangiocarcinoma (CCA) is most effective for patients with early stage, localized disease while treatment of advanced liver cancer is merely palliative in nature. Unfortunately, in the US, only 20 to 30% of HCC and CCA cases are diagnosed with early stage disease4, 5. In Taiwan and Japan, where there are comprehensive nationwide programs for early diagnosis and surveillance of individuals at risk for HCC from chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, approximately 70% of HCCs are diagnosed at very early or early stages, resulting in 5 year survival estimates of 50– 70%6. In the US, CCA is often diagnosed in advanced stages when disease is incurable7. Thus national and international efforts to reduce the burden or morbidity and mortality from HCC and CCA need to focus on identification of the population at risk and aggressive surveillance using effective screening tools.
Author Manuscript
The emerging evidence suggests that biomarkers are optimally used as a complement, rather than a replacement for imaging studies. Biomarkers uniquely may be elevated before there is any evidence of imaging abnormalities and may also guide consideration of what the primary tumor type is, such as HCC versus CCA, or mixed HCC-CCA. Cancer biomarker development is described by Pepe and colleagues as a 5-phase process in which each stage is characterized by study design application (Figure 1)8, 9. In this review we provide an update on the current status of liver and biliary cancer surveillance and describe recent efforts that are taking advantage of novel technologies in next generation DNA sequencing, genome wide methylation and proteomic studies, and advances in metabolomics to usher in a new era of biomarker development. The novel biomarkers in development will hopefully result in substantial improvements in both surveillance and diagnosis of HCC and CCA. Biomarkers discussed in this review, their current stage in biomarker development and clinical applicability are summarized in Table 1 for HCC and in Table 2 for CCA.
Hepatocellular carcinoma
Author Manuscript
HCC is the most common malignancy of the liver. Current practice guidelines from the American Association for the Study of Liver Diseases (AASLD) recommend surveillance for HCC in patients with an expected risk of HCC exceeding 1.5% per year or 0.2% per year in patients with chronic HBV. Based on these recommendations, surveillance for HCC should be offered to all patients with cirrhosis and to hepatitis B carriers who have a family history of HCC, are Asian-born males 40 years or older, are Asian females 50 years or older, or African-born individuals 20 years or older. Individuals with immune active chronic HBV and those with coinfection with HCV or HIV or who have other chronic liver diseases should also be enrolled in surveillance programs10, 11. Currently used biomarkers: AFP, AFP-L3 and DCP World-wide, the commonest modalities used for surveillance for HCC in at risk individuals are liver ultrasound and serum alpha fetoprotein (AFP) measurement. AFP is a glycoprotein
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
Lozada et al.
Page 3
Author Manuscript
produced by fetal liver and yolk sac; serum levels are high in utero but normalize to adult values rapidly after birth. High serum AFP values have been shown to occur in different cancers, including HCCs and germ cell tumors. The use of AFP as a screening modality has been controversial, particularly in low to medium incidence regions, but is widespread in high incidence countries, where it is incorporated into most national and regional guidelines. The main objection to the use of AFP is its low sensitivity of only 20–30% for the detection of HCC at an early stage, when it is most amenable to curative treatment. The sensitivity of AFP rises to 50–60% for the detection of intermediate to advanced stage disease12–14. Proponents of the use of AFP argue that while most studies evaluating the performance of AFP have evaluated it in the cross-sectional setting, experienced practitioners typically follow and act on trends and variations in AFP levels, rather than individual measurements alone15. Further, the combination of AFP with ultrasound improves the likelihood of detection of the more diffuse or infiltrating HCCs that do not develop as distinct nodules.
Author Manuscript
In addition to the AFP, other serum markers in clinical use for HCC surveillance include the lens culinaris binding subfraction of AFP (AFP-L3%) and the des gamma carboxyprothrombin (DCP). AFP-L3 is a glycosylated variant of AFP abnormally increased in HCC. DCP, also known as protein induced by vitamin K absence II (PIVKA-II), is a form of prothrombin generated when there is an acquired defect in post-translational carboxylation. These assays are routinely used in Japan and other Asian countries and are approved for use in risk stratification for HCC by the US Food and Drug Administration. AFP-L3 and DCP have been shown to increase sensitivity and specificity of AFP in diagnosing HCC12, 16, 17.
Author Manuscript Author Manuscript
A number of models have been developed which integrate the results of biomarker assays with different patient clinical and laboratory characteristics to enhance the diagnostic accuracy of biomarkers in specific patient settings. The GALAD model by Johnson et al. includes gender, age, AFP-L3, AFP and DCP as predictors of risk for HCC in the setting of chronic liver disease. This model has been has been validated and has shown consistency in stratifying patients based on risk of HCC18. A similar algorithm, known as BALAD-2, was developed by the same group for accurate prognostication of patients with HCC19. El-Serag et al. recently developed another model using platelet count, alanine aminotransferase (ALT), age and AFP to predict risk for HCC in patients with HCV-induced cirrhosis. In general, patients with high AFP who also had decreased platelet count, decreased ALT, or increased age showed higher risk of HCC. Their model-predicted probability levels showed a very close relationship with raw frequencies of HCC that only deviated in risks higher than 90% where there is no practical significance. This model is yet to be tested on other populations with liver disease due to causes other than HCV and in populations outside of the Veterans Affair (VA) Health system where males predominate20. The recently published ADRESS model can be used for predicting HCC probability in patients with cirrhosis using the variables of age, diabetes, race, cirrhosis etiology, sex and severity of liver dysfunction. Although no biomarkers are included in the model, it can possibly stratify patients with cirrhosis into groups based on their potential surveillance program benefit21. Finally, AFP and DCP biomarkers also have utility in combination with clinical factors for predicting recurrence of HCC after liver transplantation22–24.
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
Lozada et al.
Page 4
Ultrasound
Author Manuscript
Ultrasound is a widely used tool for both diagnosis and surveillance of various liver and cholestatic diseases and is currently established for surveillance of early stage HCC. AASLD Guidelines recommend HCC surveillance with liver ultrasound every 6 months11. Ultrasound offers clinicians a safe, noninvasive and low cost real-time imaging tool that is widely available. However, ultrasound efficacy is operator dependent and its performance in detecting lesions, especially smaller ones, is impaired. This becomes even more problematic given the increasing prevalence of obesity-related fatty liver disease and cirrhosis in North America, Europe and Asia. Regenerative nodules in cirrhotic livers can be confused with neoplastic masses, leading to additional diagnostic test that are more invasive, have increased costs and can unnecessarily increase patient anxiety. Together, these limitations raise a fundamental problem in relying solely on ultrasound for surveillance of HCC.
Author Manuscript Author Manuscript
A meta-analysis on surveillance performance for detecting HCC on cirrhotic patients via ultrasound reported a pooled sensitivity of 94%, specificity of 94% and a summary receiver operator curve (ROC) plot of 98%. However, these numbers were for detecting HCC at any stage of disease. When only looking at studies that reported detection of early HCC as defined by Milan criteria (one nodule 2 copies of at least 2 probes excluding cells with tetrasomy) Equivocal: ≥10 cells with trisomy (3 copies of a single probe) or ≥10 cells with tetrasomy (4 copies of each probe). Tetrasomy can represent replicating cells14–16.
PB FISH assay
Bile duct brushings
3
Diagnosis
Negative: 2 copies of each probe Positive: ≥5 cells with polysomy (>2 copies of at least 2 probes excluding cells with tetrasomy) Equivocal: ≥10 cells with trisomy (3 copies of a single probe) or ≥10 cells with tetrasomy (4 copies of each probe). Tetrasomy can represent replicating cells14–16.
Methylated BMP-3
Bile
1
Early detection
NA
Author Manuscript
1
Marrero JA, Feng Z, Wang Y, Nguyen MH, Befeler AS, Roberts LR, Reddy KR, Harnois D, Llovet JM, Normolle D, Dalhgren J, Chia D, Lok AS, Wagner PD, Srivastava S, Schwartz M. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110–8. 2
Gopal P, Yopp AC, Waljee AK, Chiang J, Nehra M, Kandunoori P, Singal AG. Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 2014;12:870–7.
3
Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, Lok AS. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients. Hepatology 2003;37:1114–21. 4
Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology 2012;55:483–90. 5
Cao FF, Yu S, Jiang ZY, Bao YX. Diagnostic accuracy of Golgi protein 73 in primary hepatic carcinoma using ELISA: a systematic review and meta-analysis. Clinical laboratory 2014;60:587–97.
Author Manuscript
6
Shen Q, Fan J, Yang XR, Tan Y, Zhao W, Xu Y, Wang N, Niu Y, Wu Z, Zhou J, Qiu SJ, Shi YH, Yu B, Tang N, Chu W, Wang M, Wu J, Zhang Z, Yang S, Gu J, Wang H, Qin W. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. The Lancet. Oncology 2012;13:817–26. 7
Reichl P, Fang M, Starlinger P, Staufer K, Nenutil R, Muller P, Greplova K, Valik D, Dooley S, Brostjan C, Gruenberger T, Shen J, Man K, Trauner M, Yu J, Gao CF, Mikulits W. Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma. International journal of cancer. Journal international du cancer 2014.
Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
Lozada et al.
Page 20
8
Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008;48:1106–17.
Author Manuscript
9 Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19–9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Digestive diseases and sciences 2005;50:1734–40. 10
Siqueira E, Schoen RE, Silverman W, Martin J, Rabinovitz M, Weissfeld JL, Abu-Elmaagd K, Madariaga JR, Slivka A. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointestinal endoscopy 2002;56:40–7.
11
Chapman MH, Sandanayake NS, Andreola F, Dhar DK, Webster GJ, Dooley JS, Pereira SP. Circulating CYFRA 21-1 is a Specific Diagnostic and Prognostic Biomarker in Biliary Tract Cancer. Journal of clinical and experimental hepatology 2011;1:6–12. 12
Ruzzenente A, Iacono C, Conci S, Bertuzzo F, Salvagno G, Ruzzenente O, Campagnaro T, Valdegamberi A, Pachera S, Bagante F, Guglielmi A. A novel serum marker for biliary tract cancer: diagnostic and prognostic values of quantitative evaluation of serum mucin 5AC (MUC5AC). Surgery 2014;155:633–9. 13
Danese E, Ruzzenente O, Ruzzenente A, Iacono C, Bertuzzo F, Gelati M, Conci S, Bendinelli S, Bonizzato G, Guglielmi A, Salvagno GL, Lippi G, Guidi GC. Assessment of bile and serum mucin5AC in cholangiocarcinoma: diagnostic performance and biologic significance. Surgery 2014;156:1218–24. 14
Author Manuscript
Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, Sebo TJ, Therneau TM, Gores GJ, de Groen PC, Baron TH, Levy MJ, Halling KC, Roberts LR. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. The American journal of gastroenterology 2004;99:1675–81. 15 Barr Fritcher EG, Kipp BR, Halling KC, Clayton AC. FISHing for pancreatobiliary tract malignancy in endoscopic brushings enhances the sensitivity of routine cytology. Cytopathology: official journal of the British Society for Clinical Cytology 2014;25:288–301. 16
Barr Fritcher EG KB, Voss JS, Brankley SM, Keeney ME, Campion MB, Pestova EV, Sokolova IA, Roberts LR, Gores GJ, ClaBarr Fritcher, E. Guyton AC, Halling KC. The Development of a Tailored Pancreatobiliary Fluorescence in situ Hybridization (FISH) Assay to Improve Detection of Malignancy in Pancreatobiliary Brushings. The Journal of Molecular Diagnostics 2013;15:909.
Author Manuscript Author Manuscript Curr Hepatol Rep. Author manuscript; available in PMC 2016 June 01.
