Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is strongly associated with cirrhosis, from both alcohol and viral aetiologies. HCC constitutes approximately 5% of all cancers partly due to the high endemic rates of hepatitis B infection 1.
HCC 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 HCC is rising, largely attributed to a rise in hepatitis C infection 11.
The demographics are strongly influenced by the regions in which chronic hepatitis B infection is common, which account for over 80% of cases worldwide. The highest prevalence is in Asia.
In Western countries, the rate is lower and alcohol accounts for a greater proportion of cases.
Risk factors include 1:
- hepatitis B (HBV) infection: 10% 5-year cumulative risk 5
- hepatitis C (HCV) infection: 30% 5-year cumulative risk
- alcoholism: 8% 5-year cumulative risk
- biliary cirrhosis: 5% 5-year cumulative risk
- food toxins, e.g. aflatoxins
- congenital biliary atresia
- inborn errors of metabolism
- obesity and diabetes mellitus 24
- chronic cholestatic syndromes 24
HCC is typically diagnosed in late middle age or elderly adults (average 65 years) and is more common in males (75% cases) 21. The tumour can also occur in the paediatric population; however, it is the second most common paediatric primary liver tumour after hepatoblastoma.
Fibrolamellar hepatocellular carcinoma is a distinct variant of HCC not associated with cirrhosis and has different demographics and risk factors.
The presentation is variable and, in affluent nations, is often found in the setting of screening programs for patients with known risk factors. Otherwise, presentation may include:
- constitutional symptoms
- portal hypertension from the invasion of the portal vein
- haemorrhage from tumour
The origin of HCCs is believed to be related to repeated cycles of necrosis and regeneration, irrespective of cause. Also the HBV and HCV genome contains 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 HCC 1.
On gross pathology, HCCs 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 HCCs is usually categorised into three subtypes: nodular, massive and infiltrative. Each has different radiological features, which are detailed below 18. The infiltrative subtype is characterised 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 11
Hepatocellular carcinomas can have a variety of appearances:
- massive (focal)
- large mass
- may have necrosis, fat and /or calcification
- nodular (multifocal)
- multiple masses of variable attenuation
- may also have central necrosis
infiltrative (diffuse) 19
- may be difficult to distinguish from associated cirrhosis – they also have been called cirrhotomimetic-type HCC or cirrhosis-like HCC
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 HCC may be seen within a regenerative liver nodule as foci of arterial enhancement (nodule-in-nodule appearance) 15.
HCC uncommonly demonstrates a central scar similar to the FNH, but may be differentiated by the absence of delayed contrast enhancement of the scar (as seen in FNH).
Rim enhancement on delayed post-contrast images causing a capsule-appearance is considered relatively specific for HCC (case 4).
Additionally, these tumours 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 HCC appears hypoechoic compared with normal liver
- larger lesions are heterogeneous due to fibrosis, fatty change, necrosis and calcification 8
- a peripheral halo of hypoechogenicity may be seen with focal fatty sparing (see the discussion below on the CT session)
- diffuse HCC may be difficult to identify or distinguish from background cirrhosis
- contrast-enhanced ultrasound 17
- arterial phase
- arterial enhancement from neovascularity
- portal venous phase
- decreased echogenicity relative to background liver ("wash out")
- tumour thrombus may be visible
- variants have been described with arterial phase hypovascularity with no enhancement or arterial enhancement with no "washout"
- arterial phase
Several patterns can be seen, depending on the subtype of HCC. Enhancement pattern is the key to the correct assessment of HCCs.
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 7. A halo of focal fatty sparing may also be seen around an HCC in an otherwise fatty liver 6.
Portal vein tumour thrombus can be distinguished from bland thrombus by demonstrating enhancement.
In general, MRI signal is:
- iso- or hyperintense c.f. surrounding liver
- hyperintensity may be due to
- intratumoral fat 5
- decreased intensity in surrounding liver
T1 C+ (Gd)
- enhancement is usually arterial ("hypervascularity")
- rapid "washout," becoming hypointense to the remainder of the liver (96% specific) 5
- this is because the supply to HCCs 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 Gd, but evaluation of the hepatobiliary phase requires care (see: Eovist and LI-RADS)
- T2: variable, typically moderately hyperintense
- C+ post-SPIO (iron oxide): increases sensitivity in diagnosing small HCCs
- DWI: intratumoural high signal; increases sensitivity and specificity ref
- hypervascular tumour
- threads and streaks pattern: sign of tumour thrombus in portal vein
Staging and classification
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 16. An imaging classification system (LI-RADS) has been developed to stratify lesions in an at-risk liver.
Treatment and prognosis
If the lesion is small then resection is possible (partial hepatectomy) and may result in the cure. The remarkable ability of the liver to regenerate means that up to 2/3rds of the liver can be resected 10.
Liver transplantation is also a curative option. To be suitable for a liver transplantation it is agreed that certain criteria should be met (see Milan criteria).
If neither of these options is possible, then a variety of options exist including chemotherapy, transarterial chemoembolisation (TACE), thermal ablation (RFA, cryoablation, or microwave ablation) and selective internal radiation therapy (SIRT) 12.
If a tumour is resectable, then 5-year survival is ~45% (range 37-56%) 3.
Metastasis occurs in the final stages of disease (IVA) and carries a poor prognosis 13,14. 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 tumour. less venous invasion,
- focal nodular hyperplasia (FNH): no vascular invasion or neovascularisation. may have nonenhancement "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
- intrahepatic cholangiocarcinoma
- peripheral location
- biliary obstruction
- delayed enhancement
- primary hepatic lymphoma 23
- 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. Dähnert W. Radiology review manual. Lippincott Williams & Wilkins. (2003) ISBN:0781738954. Read it at Google Books - Find it at Amazon
- 3. 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
- 4. 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
- 5. 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
- 6. 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
- 7. 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
- 8. Lau WY. Hepatocellular Carcinoma. World Scientific Pub Co Inc. (2008) ISBN:9812707999. Read it at Google Books - Find it at Amazon
- 9. 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
- 10. 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
- 11. 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
- 12. 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
- 13. Kummar S, Shafi NQ. Metastatic hepatocellular carcinoma. Clin Oncol (R Coll Radiol). 2003;15 (5): 288-94. Pubmed citation
- 14. Katyal S, Oliver JH, Peterson MS et-al. Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000;216 (3): 698-703. Radiology (full text) - Pubmed citation
- 15. 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
- 16. 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
- 17. 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
- 18. 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
- 19. 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
- 20. 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
- 21. 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
- 22. 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/
- 23. 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
- 24. 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