The rise of infection with hepatitis C virus worldwide and the lack of effective treatment for this infection has led to a rise in the incidence of hepatocellular carcinoma (HCC). Moreover, it is now accepted that the cirrhotic liver, regardless of etiology, is a nidus for tumor formation. A landmark study of 60 patients by Mazzaferro et al, published in 1996, forever changed the way in which surgeons approach this disease. The Milan criteria (one lesion < 5 cm or three lesions < 3 cm each) were adopted by the United Network for Organ Sharing in 2002 as the criteria by which patients would be given exception points for liver transplantation for HCC. Resection for HCC in the cirrhotic patient has poor outcomes, and many patients' livers cannot be resected due to underlying portal hypertension and thrombocytopenia. Results of transplantation are excellent, with an 80% 5-year survival. Finally, it has been demonstrated that the use of sirolimus for immunosuppression management in these patients may improve long-term disease-free survival; however, no consensus has been reached across the transplant community.
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. In the majority of cases, HCC develops in the setting of cirrhosis. Treatment with curative intent is possible in only 20% to 25% of cases and consists of resection or liver transplantation.
Epidemiology of HCC
The incidence of HCC continues to rise worldwide, due in large part to the rising number of persons who are positive for infection with hepatitis C virus (HCV). HCV is an RNA virus that infects around 300 million persons worldwide, with approximately 4 million new cases per year. At this time, there is no effective therapy that can reliably cure the infection, nor is there a preventive vaccine. Current therapy with interferon and ribavirin is often difficult to tolerate because of the side effect profiles of both agents. Moreover, the majority of patients are infected with HCV genotype 1, which exhibits the lowest response to therapy—namely, a 50% sustained viral response (SVR) after 48 weeks of therapy, compared with the 80% SVR after 24 weeks of therapy that is seen with genotypes 2 and 3. In the setting of HCV infection, the odds ratio of HCC developing in a patient with cirrhosis is 6.1 compared with a non-cirrhotic, with a yearly incidence of 2% to 8%. These data come from a clinic-based study, which also showed that the patients who were HCV-positive were at a 20-fold increased risk of developing HCC compared with the HCV-negative cohort.[3-5] In the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) study, the 5-year risk of non-cirrhotic HCV-positive patients developing HCC was 4.8%.
Infection with hepatitis B virus (HBV) also portends a risk of HCC, but not to the same degree as HCV infection. In one study by Beasley et al, the annual incidence in HBV-positive patients was 0.5%; in the setting of known cirrhosis, the incidence was 2.5%, with a relative risk (RR) of 100 compared with non-infected matched controls.[7,8] Interestingly, Asian carriers of the virus continue to have a risk of HCC even in the setting of normal liver morphology. This trend is not seen in Caucasians who have cleared the virus and have normal morphology. Therefore, surveillance for HCC is not warranted in non-cirrhotic HBV-positive Caucasian patients. In contrast, surveillance should be continued from age 40 onward in Asian men of similar status, in whom there is an annual incidence of HCC of 0.2%. Of course, in patients co-infected with either HCV or HIV, the incidence of HCC is exponentially greater, necessitating surveillance in these patients.[6-8]
The most rapidly rising cause of cirrhosis, especially in the developed world, is non-alcoholic fatty liver disease.[8,9] The incidence of HCC in the non-viral cirrhotic is not accurately known. In older studies, the presence of alcoholic liver disease and cirrhosis accounted for 32% of HCC cases.[10,11] Whether or not these cohorts were infected with HCV as well is not known. What can be said, based on a review of all relevant studies, is that any form of cirrhosis increases the risk of HCC developing in the native liver. Genetic hemochromatosis is also known to pose a high risk of HCC, with a RR of 20 and a yearly incidence of 3% to 4%.[12-14] Lastly, autoimmune hepatitis is associated with a 1.1% incidence of HCC per year, and end-stage primary biliary cirrhosis poses the same risk as HCV infection. In these latter groups, yearly surveillance is recommended.
Diagnosis of HCC
The tests used to diagnose HCC include radiologic imaging and alpha-fetoprotein (AFP) serology. We will limit our discussion to those patients with cirrhosis because the incidence of HCC in the non-cirrhotic is quite low. Given the current sensitivity/specificity of MRI, a biopsy is rarely, if ever, needed.
There are no blood tests that are currently validated for use in the diagnosis of HCC. AFP levels have long been known to lack the sensitivity and/or specificity needed to diagnose HCC. AFP levels can be elevated in a number of conditions, including intra-hepatic cholangiocarcinoma and HCV infection. Because of this, AFP serology is no longer recommended as a diagnostic test for HCC; thus, the diagnosis is dependent on the radiologic appearance.[16,17]
Currently, most screening for HCC is done by ultrasound. Conventional ultrasound lacks the sensitivity and specificity needed to accurately diagnose small HCCs, and in fact, the American Association for the Study of Liver Diseases (AASLD) recommends that two imaging modalities be used if ultrasound is one of the tests.[18,19] Only contrast-enhanced ultrasound (CE-US) has the diagnostic sensitivity and specificity to be used as a screening tool. Unfortunately, ultrasound is so user-dependent that it has not been adopted globally as the preferred screening test. In a consensus conference hosted by the American Hepato-Pancreato-Biliary Association (AHPBA) in 2009, CE-US was left off as a possible surveillance modality because of this limitation. To prove the unreliability of US as a screening modality, a 1997 European study looked at 43 cirrhotic patients with multiple liver lesions (50 regenerative nodules, 6 benign lesions, 13 HCCs). All 43 patients received US, CT, and MRI imaging within 2 weeks; the lesions detected in the US group were as follows: 1/50 regenerative nodules, 2/6 benign lesions, and 2/16 HCCs. As is apparent from these numbers, US does a poor job of screening for HCC in the cirrhotic liver. This is especially true in the case of small lesions, where the sensitivity of US in one reported study was as low as 14%.
Multi-detector computed tomography (MDCT) and MRI are now the modalities of choice when screening for HCC in the cirrhotic liver (Figure 1). MDCT uses radiation and iodinated contrast to opacify the liver during the arterial phase, the portal venous phase, and the hepatic vein phase. The downside of MDCT is the nephrotoxicity caused by the contrast agent and the radiation exposure to the patient. The radiation exposure from just two CT scans is about 40 mSV, which is equivalent to the radiation exposure 2.4 km from Hiroshima's ground zero. Most large series demonstrate a sensitivity of about 70% (65% to 78%) for CT scanning in the detection of HCC in the cirrhotic liver. The benefit of CT is its more universal acceptance; also, image acquisition is not as onerous as with MRI.
Unlike MDCT, MRI is limited only by the code and acquisition sequences that the radiologist can envision. MRI is a non-invasive and non-radioactive imaging modality that views the human body at the tissue level. In multiple large series, the sensitivity of MRI in detecting small HCCs approaches 90%, and in lesions > 2 cm, it has a sensitivity of 100% and a specificity of 99%, with an overall accuracy of 99.1%. These data were prospectively collected and pathologically correlated. The benefit of MRI is truly realized when we compare its ability to detect small HCCs to that of CT. The sensitivity of CT in patients with small HCCs is around 50%, and in some series no better than 36%. Moreover, recent work by Martin et al shows that liver lesions > 2 cm on MRI can be diagnosed with greater than 99% accuracy without a liver biopsy.[25-37] Given these levels of sensitivity, specificity, and diagnostic accuracy, the usefulness of any additional imaging modality is questionable, and the pursuit of biopsy for pathologic correlation should be discouraged.
Partial Hepatectomy for HCC
The initial treatment decision in patients with HCC and cirrhosis is still based on the basic principles of hepatic surgery: inflow, outflow, and parenchymal reserve. The most important issue in the cirrhotic patient is the functional liver remnant (FLR). Most experts agree that in the cirrhotic liver, an FLR of 40% of the total liver volume is the minimum required for safe resection. The presence of portal hypertension and thrombocytopenia can complicate the picture: both of these negatively affect the outcomes of resection. For these reasons, and based on review of multiple center-specific series, the AHPBA said in their 2010 consensus statement that liver transplantation is the preferred approach for patients with HCC and cirrhosis, or in patients with Child A cirrhosis in the absence of portal hypertension.
1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94:153-6.
2. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127(Suppl 1):S5-S16.
3. Razmkhah M, Jaberipour M, Erfani N, et al. Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-beta1 and upregulate expression of regulatory molecules on T cells: do they protect breast cancer cells from the immune response? Cell Immunol. 2011;266:116-22.
4. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463-72.
5. Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology. 1998;28:1687-95.
6. Lok AS, Seeff LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009;136:138-48.
7. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 1981;2:1129-33.
8. Beasley RP, Shiao IS, Wu TC, Hwang LY. Hepatoma in an HBsAg carrier—seven years after perinatal infection. J Pediatr. 1982;101:83-4.
9. Shimada M, Hashimoto E, Taniai M, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol. 2002;37:154-60.
10. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134-40.
11. Coelho-Little ME, Jeffers LJ, Bernstein DE, et al. Hepatitis C virus in alcoholic patients with and without clinically apparent liver disease. Alcohol Clin Exp Res. 1995;19:1173-6.
12. Befrits R, Hedman M, Blomquist L, et al. Chronic hepatitis C in alcoholic patients: prevalence, genotypes, and correlation to liver disease. Scand J Gastroenterol. 1995;30:1113-8.
13. Hsing AW, McLaughlin JK, Olsen JH, et al. Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark. Int J Cancer. 1995;60:160-2.
14. Emberg M HR, Ekbom A, Brandt L, et al. Cancer risk in patients with hereditary hemochromatosis and their first degree relatives. Gastroenterology. 2003;125:1733-41.
15. Fracanzani AL, Conte D, Fraquelli M, et al. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology. 2001;33:647-51.
16. Yeoman AD, Al-Chalabi T, Karani JB, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening. Hepatology. 2008;48:863-70.
17. Sato Y, Sekine T, Ohwada S. Alpha-fetoprotein-producing rectal cancer: calculated tumor marker doubling time. J Surg Oncol. 1994;55:265-8.
18. Adachi Y, Tsuchihashi J, Shiraishi N, et al. AFP-producing gastric carcinoma: multivariate analysis of prognostic factors in 270 patients. Oncology. 2003;65:95-101.
19. 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;35:421-30.
20. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-36.
21. Vauthey JN, Dixon E, Abdalla EK, et al. Pretreatment assessment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford). 2010;12:289-99.
22. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52-60.
23. Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med. 2009;361:849-57.
24. Lauentstein TC, Salman K, Morreira R, et al. Gadolinium-enhanced MRI for tumor surveillance before liver transplantation. Center-based experience. Am J Radiol. 2007;189:563-570.
25. Barth MM, Smith MP, Pedrosa I, et al. Body MR imaging at 3.0 T: understanding the opportunities and challenges. Radiographics. 2007;27:1445-62; discussion 62-4.
26. Burrel M, Llovet JM, Ayuso C, et al. MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology. 2003;38:1034-42.
27. Kim HJ, Kim KW, Byun JH, et al. Comparison of mangafodipir trisodium- and ferucarbotran-enhanced MRI for detection and characterization of hepatic metastases in colorectal cancer patients. AJR Am J Roentgenol. 2006;186:1059-66.
28. Kim YK, Kim CS, Chung GH, et al. Comparison of gadobenate dimeglumine-enhanced dynamic MRI and 16-MDCT for the detection of hepatocellular carcinoma. AJR Am J Roentgenol. 2006;186:149-57.
29. Frericks BB, Loddenkemper C, Huppertz A, et al. Qualitative and quantitative evaluation of hepatocellular carcinoma and cirrhotic liver enhancement using Gd-EOB-DTPA. AJR Am J Roentgenol.. 2009;193:1053-60.
30. Brismar TB, Dahlstrom N, Edsborg N, et al. Liver vessel enhancement by Gd-BOPTA and Gd-EOB-DTPA: a comparison in healthy volunteers. Acta Radiol. 2009;50:709-15.
31. Kim SH, Lee J, Kim MJ, et al. Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the preoperative detection of hepatocellular carcinoma. AJR Am J Roentgenol. 2009;192:1675-81.
32. Tamada T, Ito K, Sone T, et al. Dynamic contrast-enhanced magnetic resonance imaging of abdominal solid organ and major vessel: comparison of enhancement effect between Gd-EOB-DTPA and Gd-DTPA. J Magn Reson Imaging. 2009;29:636-40.
33. Zech CJ, Grazioli L, Breuer J, et al. Diagnostic performance and description of morphological features of focal nodular hyperplasia in Gd-EOB-DTPA-enhanced liver magnetic resonance imaging: results of a multicenter trial. Invest Radiol. 2008;43:504-11.
34. Hammerstingl R, Huppertz A, Breuer J, et al. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions. Eur Radiol. 2008;18:457-67.
35. Dohr O, Hofmeister R, Treher M, Schweinfurth H. Preclinical safety evaluation of Gd-EOB-DTPA (Primovist). Invest Radiol. 2007;42:830-41.
36. Zech CJ, Herrmann KA, Reiser MF, Schoenberg SO. MR imaging in patients with suspected liver metastases: value of liver-specific contrast agent Gd-EOB-DTPA. Magn Reson Med Sci. 2007;6:43-52.
37. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693-9.
38. Jarnagin W, Chapman W, Curley S, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB. 2010;12:302-10.
39. Maithel SK, Kneuertz PJ, Kooby DA, et al. Importance of low preoperative platelet count in selecting patients for resection of hepatocellular carcinoma: a multi-institutional analysis. J Am Coll Surg. 2011;212:638-48.
40. DuBay D, Sandroussi C, Sandhu L, et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg. 2011;253:166-72.
41. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394-403.
42. Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10:35-43.
43. DuBay DA, Sandroussi C, Kachura JR, et al. Radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. HPB (Oxford). 2011;13:24-32.
44. Schwarz RE, Abou-Alfa GK, Geschwind JF, et al. Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement. HPB (Oxford). 2010;12:313-20.
45. Belghiti J, Durand F. Criteria for liver transplantation for hepatocellular carcinoma: what is an acceptable outcome? Liver Int. 2011;31 (Suppl 1):161-3.
46. Zhou J, Wang Z, Qiu SJ, et al. Surgical treatment for early hepatocellular carcinoma: comparison of resection and liver transplantation. J Cancer Res Clin Oncol. 2010;136:1453-60.
47. Vivarelli M, Bellusci R, Cucchetti A, et al. Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation. 2002;74:1746-51.
48. Kneteman NM, Oberholzer J, Al Saghier M, et al. Sirolimus immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl. 2004;10:1301-11.
49. Zimmerman MA, Trotter JF, Wachs M, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 2008;14:633-8.
50. Zhou J, Wang Z, Wu Q, et al. Sirolimus-based immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria. Transpl Proc. 2008;41:3548-53.
51. Castroagudin JF, Molina-Perez E, Ferreiro-Iglesias R, Varo-Perez E. Strategies of immunosuppression for liver transplant recipients with hepatocellular carcinoma. Transplant Proc. 2011;43:711-3.