Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is strongly associated with cirrhosis, from both alcohol and viral etiologies. HCC constitutes approximately 5% of all cancers partly due to the high endemic rates of hepatitis B infection 1.

Epidemiology

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:

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.

Clinical presentation

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:

Pathology

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. Microscopically they range from well differentiated to undifferentiated.

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.

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.

Fibrolamellar hepatocellular carcinoma is a distinct variant of HCC not associated with cirrhosis and has different demographics and risk factors.

Markers

Radiographic features

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 differentiated by the absence of delayed contrast enhancement of the scar (as seen in FNH). Also, rim enhancement on delayed post-contrast images represents a capsule which 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.

Ultrasound

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"
CT

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.

MRI

When seen in the setting of cirrhosis, small HCCs need to be distinguished from regenerative and dysplastic nodules (see cirrhosis article).

In general, MRI signal is:

  • T1
    • variable
    • 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 (referred to as a 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 required
DSA: angiography
  • 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.

Differential diagnosis

General imaging differential considerations include:

  • hypervascular hepatic metastases: metasteases to a cirrhootic liver are rare. often due to primary endocrine tummor. 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 enhancementpersists into delayed phases. Tc-99m sulphur colloid 80% positive.
  • hepatic adenoma
    • different demographics and risk factors
  • intrahepatic cholangiocarcinoma
    • peripheral location
    • biliary obstruction
    • delayed enhancement
  • THADs
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Article Information

rID: 1442
System: Hepatobiliary
Section: Pathology
Synonyms or Alternate Spellings:
  • HCC
  • Hepatoma
  • Hepatocellular cancer
  • Malignant hepatoma
  • HCCs
  • Hepatocellular carcinomas
  • Hepatocarcinoma
  • Hepatocellular carcinoma (HCC)
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    Figure 1: gross pathology: hepatocellular carcinoma
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    Case 1: arterial phase
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    Case 2: massive HCC
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    Case 3: diffuse HCC
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    HCC T1 Further Delay
    Case 4: showing scar and rim enhancement
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    t = 0
    Case 5
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    Note large HCC wi...
    Case 7: with multiple peritoneal implants
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    HCC
    Case 8
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    HCC -Arterial Pha...
    Case 8: arterial phase
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    HCC -Portovenous ...
    Case 8: portovenous phase
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    HCC - Arterial
    Case 9
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    arterial phase
    Case 10
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    Case 11: with atypical imaging features
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    Well defined low ...
    Case 12
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    Case 13: multifocal
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    Case 14
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    Case 15
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    Case 16
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    Case 17: with bony metastasis
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    Case 18: HCC with AV fistula
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    Case 19
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    Case 20
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    Case 21
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    Case 22
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    Case 23
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    Case 24
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    Case 25: HCC with right atrial invasion
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    CT performed 2 mo...
    Case 26: in segment II
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    Case 27
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    Case 28: diffuse HCC
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    Case 29
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    Case 30
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    Case 31: multifocal
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    Case 32: diffuse HCC
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    Heterogenous hype...
    Case 33: with IVC and left portal vein branch thrombosis
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