Citation, DOI, disclosures and article data
At the time the article was created Frank Gaillard had no recorded disclosures.View Frank Gaillard's current disclosures
At the time the article was last revised Ashesh Ishwarlal Ranchod had no financial relationships to ineligible companies to disclose.View Ashesh Ishwarlal Ranchod's current disclosures
Hepatocellular carcinoma (HCC), also called hepatoma, is the most common primary malignancy of the liver. It is strongly associated with cirrhosis, from both alcohol and viral etiologies. Hepatocellular carcinomas constitute approximately 5% of all cancers partly due to the high endemic rates of hepatitis B infection 1.
On this page:
Hepatocellular carcinoma is the fifth most common cancer in the world and is the third most common cause of cancer-related death (after lung and stomach cancer). The incidence of hepatocellular carcinoma is rising, largely attributable to a rise in hepatitis C infection 2.
The highest prevalence occurs in Asia, in regions where chronic hepatitis B infection is endemic, and this accounts for >80% of hepatocellular carcinoma cases worldwide. In Western countries, the rate of hepatitis B infection is lower and alcohol accounts for the majority of cases.
Hepatocellular carcinoma is typically diagnosed in late middle-aged or elderly adults (average 65 years) and is more common in males (75% of cases) 7. In regions where chronic hepatitis B infection is endemic, young adults aged 20 to 40 (who had contracted the virus via maternal-fetal transmission) have the highest risk of developing hepatocellular carcinoma 30.
Hepatocellular carcinoma also occurs in the pediatric population, and is the second most common pediatric primary liver tumor after hepatoblastoma.
Fibrolamellar hepatocellular carcinoma is a distinct variant of hepatocellular carcinoma not associated with cirrhosis and has different demographics and risk factors.
Risk factors include 1:
hepatitis B (HBV) infection: 10% 5-year cumulative risk 3
hepatitis C (HCV) infection: 30% 5-year cumulative risk
alcoholism: 8% 5-year cumulative risk
biliary cholangitis: 5% 5-year cumulative risk
food toxins, e.g. aflatoxins
congenital biliary atresia
inborn errors of metabolism
hemochromatosis: ~20% 5-year cumulative risk
tyrosinemia type I 4
obesity and diabetes mellitus 6
The presentation is variable and, in affluent nations, is often found in the setting of screening programs for patients with known risk factors 8. Otherwise, presentation may include:
portal hypertension from the invasion of the portal vein
hemorrhage from tumor
The origin of hepatocellular carcinomas is believed to be related to repeated cycles of necrosis and regeneration, irrespective of the cause. Additionally, the genomes of HBV and HCV contain genetic material that may predispose cells to accumulate mutations or disrupts growth control, thus allowing for a second mechanism by which infection with these agents predisposes to hepatocellular carcinoma 1.
On gross pathology, hepatocellular carcinomas typically appear as pale masses within the liver and may be unifocal, multifocal or diffusely infiltrative at the time of presentation.
The macroscopic growth of hepatocellular carcinoma is usually categorized into three subtypes: nodular, massive and infiltrative. Each has different radiological features, which are detailed below 9. The infiltrative subtype is characterized by a growth of multiple tiny nodules throughout the entire liver or an entire liver segment.
Microscopically they range from well-differentiated to undifferentiated.
alpha-fetoprotein (AFP) levels are elevated in 50-75% of cases 2
Hepatocellular carcinomas can have a variety of appearances:
may have necrosis, fat and /or calcification
multiple masses of variable attenuation
may also have central necrosis
infiltrative (diffuse) 10
may be difficult to distinguish from associated cirrhosis: also called cirrhotomimetic-type hepatocellular carcinoma or cirrhosis-like hepatocellular carcinoma
Hepatocellular carcinoma receives most of its blood supply from branches of the hepatic artery, accounting for its characteristic enhancement pattern: early arterial enhancement with early "washout." Hence, small foci of hepatocellular carcinoma may be seen within a regenerative liver nodule as foci of arterial enhancement (nodule-in-nodule appearance) 11.
Hepatocellular carcinoma uncommonly demonstrates a central scar similar to focal nodular hyperplasia but may be differentiated by the absence of delayed contrast enhancement of the scar (as seen in focal nodular hyperplasia).
Rim enhancement on delayed post-contrast images causing a capsule-appearance is considered relatively specific for hepatocellular carcinoma (see case 4).
Additionally, these tumors have the propensity to invade vascular structures, most commonly the portal vein, but also the hepatic veins, IVC, and right atrium. One should remember that a large number of patients will have concomitant cirrhosis, and thus also be at risk for bland portal vein thrombosis from synthetic dysfunction of clotting factors.
Variable appearance depending on the individual lesion, size, and echogenicity of background liver. Typically:
small focal hepatocellular carcinoma appears hypoechoic compared with normal liver
larger lesions are heterogeneous due to fibrosis, fatty change, necrosis and calcification 12
a peripheral halo of hypoechogenicity may be seen with focal fatty sparing (see the discussion below on the CT session)
diffuse hepatocellular carcinoma may be difficult to identify or distinguish from background cirrhosis
contrast-enhanced ultrasound 13
arterial enhancement from neovascularity
portal venous phase
decreased echogenicity relative to background liver ("washout")
tumor thrombus may be visible
variants have been described with arterial phase hypovascularity with no enhancement or arterial enhancement with no "washout"
Several patterns can be seen, depending on the subtype of hepatocellular carcinoma. Enhancement pattern is the key to the correct assessment of hepatocellular carcinomas.
Usually, the mass enhances vividly during late arterial (~35 seconds) and then washes out rapidly, becoming indistinct or hypoattenuating in the portal venous phase, compared to the rest of the liver.
Additionally, they may be associated with a wedge-shaped perfusion abnormality due to arterioportal shunts (APS), and this, in turn, can result in a focal fatty change in the normal liver or focal fatty sparing in the diffusely fatty liver 14. A halo of focal fatty sparing may also be seen around a hepatocellular carcinoma in an otherwise fatty liver 15.
Portal vein tumor thrombus can be distinguished from bland thrombus by demonstrating enhancement.
When seen in the setting of cirrhosis, small hepatocellular carcinomas need to be distinguished from regenerative and dysplastic nodules 16.
In general, MRI signal is:
iso- or hypointense cf. surrounding liver 17
hyperintensity may be due to
intratumoral fat 3
decreased intensity in the surrounding liver
T1 C+ (Gd)
enhancement is usually arterial ("hypervascularity")
rapid "washout", becoming hypointense to the remainder of the liver (96% specific) 3
this is because the supply to hepatocellular carcinoma is predominantly from the hepatic artery rather than the portal vein
rim enhancement may persist ("capsule")
an imaging classification system (LI-RADS) has been developed to stratify lesions
T1 C+ (Eovist/Primovist)
similar to assessment with extracellular gadolinium, but evaluation of the hepatobiliary phase requires care
arterial hyperenhancement with washout assessed on the portal venous phase
washout on transitional phase (3 minutes delayed) is less reliable (see: Eovist and LI-RADS)
T2: variable, typically moderately hyperintense
C+ post-SPIO (iron oxide): increases sensitivity in diagnosing small hepatocellular carcinomas
DWI: intratumoral high signal; increases sensitivity and specificity
threads and streaks pattern: sign of tumor thrombus in the portal vein
Treatment and prognosis
The typical TNM staging system seen in most other epithelial cancers is not as prognostically useful for stratification of patients with hepatic cancers.
There are several substitute staging systems used in guiding therapy for hepatocellular carcinoma (see hepatocellular carcinoma staging)18. The LI-RADS imaging classification system is also used to stratify lesions in an at-risk liver.
If the lesion is small then resection is possible (partial hepatectomy) and may result in remission. The remarkable ability of the liver to regenerate means that up to two-thirds of the liver can be resected 19.
Liver transplantation is also a curative option. To be suitable for liver transplantation it is agreed that certain criteria should be met (see Milan criteria).
If neither of these options are possible, then a variety of options exist including chemotherapy, transarterial chemoembolisation (TACE), transarterial radioembolization (TARE) / selective internal radiation therapy (SIRT), thermal ablation (RFA, cryoablation, or microwave ablation), and chemical ablation 20-22.
If a tumor is resectable, then 5-year survival is ~45% (range 37-56%) 23.
Metastasis occurs in the final stages of disease (IVa) and carries a poor prognosis 24,25. The most frequently involved sites are the lung, adrenal glands, lymph nodes, and bone.
General imaging differential considerations include:
hypervascular hepatic metastases
metastases to a cirrhotic liver are rare, often due to primary endocrine tumor
less venous invasion
focal nodular hyperplasia (FNH)
no vascular invasion or neovascularization
may have non-enhancement "halo" around mass or in central scar
early arterial Eovist enhancement persists into delayed phases
Tc-99m sulphur colloid 80% positive
different demographics and risk factors
hepatic tuberculoma 27
- 1. Kumar V, Abbas AK, Fausto N et-al. Robbins and Cotran pathologic basis of disease. W B Saunders Co. (2005) ISBN:0721601871. Read it at Google Books - Find it at Amazon
- 2. Parkin DM, Bray F, Ferlay J et-al. Estimating the world cancer burden: Globocan 2000. Int. J. Cancer. 2001;94 (2): 153-6. Int. J. Cancer (link) - Pubmed citation
- 3. Willatt JM, Hussain HK, Adusumilli S et-al. MR Imaging of hepatocellular carcinoma in the cirrhotic liver: challenges and controversies. Radiology. 2008;247 (2): 311-30. doi:10.1148/radiol.2472061331 - Pubmed citation
- 4. Sniderman King L, Trahms C, Scott CR. Tyrosinemia Type I. 2006 Jul 24 [Updated 2014 Jul 17]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1515/
- 5. Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. (2017) British journal of haematology. 176 (4): 527-538. doi:10.1111/bjh.14459 - Pubmed
- 6. Janevska D, Chaloska-Ivanova V, Janevski V. Hepatocellular Carcinoma: Risk Factors, Diagnosis and Treatment. (2015) Open Access Macedonian Journal of Medical Sciences. 3 (4): 732. doi:10.3889/oamjms.2015.111 - Pubmed
- 7. Davis GL, Dempster J, Meler JD et-al. Hepatocellular carcinoma: management of an increasingly common problem. Proc (Bayl Univ Med Cent). 2011;21 (3): 266-80. Free text at pubmed - Pubmed citation
- 8. Bialecki ES, Di Bisceglie AM. Diagnosis of hepatocellular carcinoma. HPB (Oxford). 2005;7 (1): 26-34. doi:10.1080/13651820410024049 - Free text at pubmed - Pubmed citation
- 9. Kojiro M. Histopathology of liver cancers. Best Pract Res Clin Gastroenterol. 2005;19 (1): 39-62. doi:10.1016/j.bpg.2004.10.007 - Pubmed citation
- 10. Reynolds AR, Furlan A, Fetzer DT et-al. Infiltrative hepatocellular carcinoma: what radiologists need to know. Radiographics. 2015;35 (2): 371-86. doi:10.1148/rg.352140114 - Pubmed citation
- 11. Parente DB, Perez RM, Eiras-Araujo A et-al. MR imaging of hypervascular lesions in the cirrhotic liver: a diagnostic dilemma. Radiographics. 2012;32 (3): 767-87. doi:10.1148/rg.323115131 - Pubmed citation
- 12. Lau WY. Hepatocellular Carcinoma. World Scientific Pub Co Inc. (2008) ISBN:9812707999. Read it at Google Books - Find it at Amazon
- 13. Malhi H, Grant EG, Duddalwar V. Contrast-Enhanced Ultrasound of the Liver and Kidney. Radiol. Clin. North Am. 2014;52 (6): 1177-1190. doi:10.1016/j.rcl.2014.07.005 - Pubmed citation
- 14. Choi BI, Lee KH, Han JK et-al. Hepatic arterioportal shunts: dynamic CT and MR features. Korean J Radiol. 3 (1): 1-15. Korean J Radiol (link) - Free text at pubmed - Pubmed citation
- 15. Kim KW, Kim MJ, Lee SS et-al. Sparing of fatty infiltration around focal hepatic lesions in patients with hepatic steatosis: sonographic appearance with CT and MRI correlation. AJR Am J Roentgenol. 2008;190 (4): 1018-27. doi:10.2214/AJR.07.2863 - Pubmed citation
- 16. Antila KM, Mäkisalo H, Arola J et-al. Best cases from the AFIP: biliary papillomatosis. Radiographics. 28 (7): 2059-63. doi:10.1148/rg.287085010 - Pubmed citation
- 17. Cho ES, Choi JY. MRI features of hepatocellular carcinoma related to biologic behavior. (2015) Korean journal of radiology. 16 (3): 449-64. doi:10.3348/kjr.2015.16.3.449 - Pubmed
- 18. Pons F, Varela M, Llovet JM. Staging systems in hepatocellular carcinoma. HPB (Oxford). 2005;7 (1): 35-41. doi:10.1080/13651820410024058 - Free text at pubmed - Pubmed citation
- 19. Kelsen D, Daly JM, Kern SE et-al. Principles and practice of gastrointestinal oncology. Lippincott Williams & Wilkins. (2008) ISBN:0781776171. Read it at Google Books - Find it at Amazon
- 20. Stubbs RS, Wickremesekera SK. Selective internal radiation therapy (SIRT): a new modality for treating patients with colorectal liver metastases. HPB (Oxford). 2004;6 (3): 133-9. doi:10.1080/13651820410025084 - Free text at pubmed - Pubmed citation
- 21. Mahnken AH. Current status of transarterial radioembolization. (2016) World journal of radiology. 8 (5): 449-59. doi:10.4329/wjr.v8.i5.449 - Pubmed
- 22. Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, Atassi B, Baker T, Gates V, Miller FH, Sato KT, Wang E, Gupta R, Benson AB, Newman SB, Omary RA, Abecassis M, Kulik L. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. (2010) Gastroenterology. 138 (1): 52-64. doi:10.1053/j.gastro.2009.09.006 - Pubmed
- 23. Smith MT, Blatt ER, Jedlicka P et-al. Best cases from the AFIP: fibrolamellar hepatocellular carcinoma. Radiographics. 28 (2): 609-13. doi:10.1148/rg.282075153 - Pubmed citation
- 24. Kummar S, Shafi NQ. Metastatic hepatocellular carcinoma. Clin Oncol (R Coll Radiol). 2003;15 (5): 288-94. Pubmed citation
- 25. Katyal S, Oliver JH, Peterson MS et-al. Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000;216 (3): 698-703. Radiology (full text) - Pubmed citation
- 26. Bohlok A, De Grez T, Bouazza F, De Wind R, El-Khoury M, Repullo D, Donckier V. Primary Hepatic Lymphoma Mimicking a Hepatocellular Carcinoma in a Cirrhotic Patient: Case Report and Systematic Review of the Literature. (2018) Case Reports in Surgery. doi:10.1155/2018/9183717
- 27. Zorbas K, Koutoulidis V, Foukas P, Arkadopoulos N. Hepatic tuberculoma mimicking hepatocellular carcinoma in an immunocompetent host. (2013) BMJ case reports. doi:10.1136/bcr-2013-008775 - Pubmed
- 28. Dähnert W. Radiology review manual. Lippincott Williams & Wilkins. (2003) ISBN:0781738954. Read it at Google Books - Find it at Amazon
- 29. Grendell JH, Friedman SL, McQuaid KR. Current diagnosis & treatment in gastroenterology. McGraw-Hill Medical. (2003) ISBN:0838515517. Read it at Google Books - Find it at Amazon
- 30. Vinay Kumar, Abul K. Abbas, Jon C. Aster. Robbins & Cotran Pathologic Basis of Disease. (2020) ISBN: 9780323531139 - Google Books