Hepatocellular Carcinoma

Published on 09/08/2015 by admin

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Last modified 22/04/2025

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 Small tumors (< 3 cm without vascular invasion) are curable with resection, ablation, transplantation

image Achievable goal of surveillance program using US, CT, &/or MR (properly performed and interpreted)
image Use LI-RADS classification system for focal lesions in cirrhotic liver
• Key imaging features

image Heterogeneous hypervascularity on arterial phase (CT or MR) with washout on venous and delayed
image Presence of a capsule or fat content
image Evidence of portal or hepatic vein invasion
image Hypointense lesion on hepatobiliary phase of gadoxetate-enhanced MR
image Bright lesion on diffusion-weighted MR

TOP DIFFERENTIAL DIAGNOSES

• Regenerative and dysplastic nodules
• Cholangiocarcinoma (peripheral)
• Nodular regenerative hyperplasia
• Hypervascular metastases

CLINICAL ISSUES

• Which imaging modality should be used?

image Sonography

– Effective in expert hands in screening thin patients with relatively nonfibrotic livers
image Triphasic CT or MR (arterial, venous, and delayed phases) is mandatory in more advanced disease

– Any focal lesion; fibrotic, nodular liver; strong clinical concern for HCC
– MR with gadoxetate enhancement has greater sensitivity and specificity for analyzing nodules
image
The Liver Imaging Reporting and Data System (LI-RADS) is endorsed by the ACR for categorization of focal nodular lesions found on CT or MR in the cirrhotic liver. It is designed to standardize the interpreting and reporting of findings so that these are more uniform, accurate, and useful to referring physicians.

TERMINOLOGY

Abbreviations

• Hepatocellular carcinoma (HCC)

Synonyms

• Hepatoma
• Primary liver cancer

Definitions

• Most common primary malignant liver tumor, usually arising in a cirrhotic liver

IMAGING

General Features

• Best diagnostic clue

image Heterogeneous hypervascular mass with “washout” of contrast enhancement and portal vein invasion
• Size

image Small tumors < 2 cm
image Large tumors > 5 cm

– Diffuse: Subcentimeter to few cm lesions throughout liver
• Morphology

image Usually spherical
• Key concepts

image Most frequent primary visceral malignancy in world

– Accounts for 80-90% of all primary liver malignancies
image 2nd most common malignant liver tumor in children after hepatoblastoma
image Important to detect and stage accurately

– Small tumors are curable with resection, ablation, or transplantation
– Multiple, large, or those with venous invasion can be palliated with chemoembolization
image Signs of portal vein invasion by HCC

– Expansion of portal vein lumen
– Enhancement of tumor within vein
– Contiguity of tumor and portal vein

CT Findings

• NECT

image In noncirrhotic liver (usually a symptomatic patient, as with pain or rupture)

– Solitary HCC: Large hypodense mass; ± necrosis, fat, calcification
– Encapsulated HCC: Well-defined, rounded, hypodense mass

image Dominant hypodense mass with decreased attenuation “satellite” nodules
– Multifocal HCC: Multiple hypodense lesions rarely with central necrotic portion
image In cirrhotic liver (usually detected as part of a surveillance program)

– HCC may be hypodense to liver
– Regenerative nodules may be hyperdense to liver
• CECT

image Hepatic arterial phase (HAP) scan

– Heterogeneous hypervascular enhancement (for moderately and poorly differentiated HCC)

image Well-differentiated tumor may be hypodense to liver on all phases of enhancement
– Wedge-shaped areas of ↑ density on HAP: Perfusion abnormality due to portal vein occlusion by tumor thrombus and ↑ arterial flow
image Portal venous phase (PVP) scan

– HCC often nearly isodense to surrounding liver
image Delayed scan: HCC hypodense to surrounding liver

– Washout of contrast enhancement is key finding

image Helps to distinguish HCC from regenerative nodules and arterioportal shunts (both common in cirrhosis)
image Small hypervascular HCC

– Early and late arterial phases: Hyperattenuating, more on 2nd or later arterial phase
– Later (portal venous and delayed): HCC washes out to become hypodense to liver

MR Findings

• Variable intensity depending on degree of fatty change, fibrosis, necrosis
• T1WI

image HCC may be hypo-, iso-, or hyperintense to liver
image Tumors with fat or hemorrhage are hyperintense
• T2WI

image Usually hyperintense to liver

– Regenerative nodules are hypointense on T2WI
image HCC arising within dysplastic nodule

– “Nodule within nodule” pattern
– HCC appears as small focus of increased signal intensity within decreased signal intensity nodule
• T1 C+ (gadolinium)

image Heterogeneously hyperintense, with washout on portal venous and delayed phase
image Rapid central washout with residual capsular enhancement = HCC, not arterioportal shunt
• Hepatobiliary contrast agent (gadoxetate)

image Trade names: Eovist or Primovist
image On 20 minute delayed phase

– Normal liver (and some portions of cirrhotic liver) enhance brightly
– Most HCCs are seen as hypointense focal masses
– Rare for well-differentiated HCC to show delayed persistent enhancement with gadoxetate
image Increases sensitivity of MR in diagnosing small HCC
• Diffusion-weighted MR

image Restricted diffusion within HCC often detected as bright signal in focal lesion
image Adds sensitivity and specificity to MR detection of HCC

Ultrasonographic Findings

• Grayscale ultrasound

image Lower sensitivity and specificity than CT or MR in diagnosing HCC

– Especially within nodular, fibrotic, cirrhotic liver
image Mixed echogenicity due to tumor necrosis and hypervascularity
image Hypoechoic: Due to solid tumor
image Hyperechoic: Due to fatty metamorphosis

– Small hyperechoic HCC can simulate hemangioma
image Capsule: In encapsulated HCC

– Thin hypoechoic band
• Color Doppler

image Shows hypervascularity and tumor shunting
image Small HCC: Indistinguishable from regenerative and dysplastic nodules

Angiographic Findings

• Conventional

image Hypervascular tumor

– Marked neovascularity and AV shunting
– Large hepatic artery and vascular invasion
image Threads and streaks sign

– Sign of tumor thrombus in portal vein

Nuclear Medicine Findings

• Hepatobiliary scan

image Uptake in 50% of lesions
• Technetium sulfur colloid

image HCC in cirrhotic liver: Seen as defect
image HCC in noncirrhotic liver: Heterogeneous uptake
• Gallium scan

image HCC is gallium avid in 90% of cases

Imaging Recommendations

• Best imaging tool

image In cirrhotic patient, multiphasic CT or MR
image Triphasic CT or MR (arterial, venous, and delayed phases)

– MR with gadoxetate enhancement has greater sensitivity and specificity

DIFFERENTIAL DIAGNOSIS

Regenerative and Dysplastic Nodules

• Regenerative: Small, multiple, very hypointense on T2WI and GRE
• Dysplastic: Hyperintense on T1WI; hypointense on T2WI; usually do not show vascularity, restricted diffusion, or appear as defects on delayed gadoxetate-enhanced MR

Cholangiocarcinoma (Peripheral)

• Peripheral tumor often obstructs bile ducts
• Capsular retraction, volume loss
• Delayed enhancement on C+ CT or MR

Nodular Regenerative Hyperplasia

• Focal form, a.k.a. large regenerative nodules
• Usually seen in Budd-Chiari syndrome
• Multiple masses (1-4 cm) with persistent hyperenhancement on arterial and portal venous phase
• Retain gadoxetate on hepatobiliary phase of MR imaging
• May have “halo” of nonenhancement around mass or in central scar

Hypervascular Metastases

• Mimic small nodular or multifocal HCC
• Metastases to a cirrhotic liver are rare
• Less likely to invade portal vein
• Usually due to endocrine primary tumor

PATHOLOGY

General Features

• Etiology

image Cirrhosis (60-90%): Due to chronic viral hepatitis (HBV, HCV) or alcoholism

– Even patients without cirrhosis usually have chronic liver injury (e.g., by hepatitis B)
image Nonalcoholic steatohepatitis (NASH)

– Increasingly common cause for cirrhosis and HCC
image Carcinogens

– Aflatoxins, siderosis, Thorotrast, androgens
image α-1-antitrypsin deficiency, hereditary hemochromatosis, Wilson disease, tyrosinosis
• Genetics

image HBV DNA integrated into host’s genomic DNA in tumor cells

Gross Pathologic & Surgical Features

• Solitary, nodular or multifocal, diffuse, encapsulated
• Soft tumor ± necrosis, hemorrhage, calcification, fat, vascular invasion

Microscopic Features

• Histologic appearances: Solid (cellular) or acinar
• Increased fat and glycogen in cytoplasm

CLINICAL ISSUES

Presentation

• Most common signs/symptoms

image Usually detected in screening/surveillance program in patients with cirrhosis or chronic hepatitis
image May present with acute pain due to rupture through hepatic capsule
• Other signs/symptoms

image Other symptoms are nonspecific and difficult to distinguish from those due to cirrhosis and portal hypertension
• Clinical profile

image Elderly patient with history of cirrhosis, ascites, weight loss, RUQ pain, and ↑ α-fetoprotein (AFP)
• Lab data: Increased AFP and liver function tests
• Diagnosis

image CT and MR findings are often specific enough to guide therapy without tissue confirmation

Demographics

• Age

image Low incidence areas (e.g., USA and Europe)

– HCC diagnosed at age 50-60
image Endemic areas: 30-45 years old
• Gender

image M:F = 2.5:1 for low-incidence areas
image M:F = 8:1 for high-incidence areas
• Epidemiology

image 250,000-1,000,000 deaths per year globally

– 2nd leading cause of cancer death in men worldwide
– In USA, HCC is 7th leading cause of cancer death
image High incidence: Africa and Asia

– Due to endemic HBV and aflatoxins
image Lower incidence in North and South America, Western Europe, Australia

– But increasing due to chronic hepatitis C (drug use and blood transfusions in 1980s)

image Also due to immigrants from areas with endemic viral hepatitis
image Likely also due to prevalence of obesity with nonalcoholic steatohepatitis (NASH)
image NASH may become the leading cause of HCC in USA and Europe
image Risk factors

– Hepatitis B

image Especially in men with high viral loads
image Onset of HCC may precede development of cirrhosis
– Hepatitis C

image Accounts for ∼ 1/3 of cases in USA
image Alone or in combination with alcohol abuse
image Onset of HCC usually decades after HCV infection; after onset of cirrhosis
– Alcoholic cirrhosis

image HCC develops after cirrhosis
– “Cryptogenic cirrhosis”

image Probably the end result of NASH
image Increasing cause for HCC
– Other causes of cirrhosis

image Primary biliary cirrhosis, hemochromatosis, autoimmune hepatitis, etc.

Natural History & Prognosis

• Complications

image Spontaneous rupture and massive hemoperitoneum
image IVC invasion, possible tumor embolism to lungs
image Metastases (adrenals and lungs most common)
• Prognosis

image > 90% mortality rate; 17% resectability rate

– Appropriate candidates for transplantation have good disease-free survival

image ∼ 85% 5-year survival
image Average survival time 6 months after diagnosis of symptomatic HCC

– But greater for HCC discovered in surveillance program
– Goal is to diagnose tumors < 3 cm in diameter that are limited to liver

image Properly performed and interpreted CT or MR can accomplish this goal

Treatment

• Surgical resection

image Optimal treatment, but limited by inadequate hepatic reserve in most patients
image Ideal candidate: Small peripheral tumor without vascular invasion
• Radiofrequency ablation

image Small (generally < 3-4 cm) isolated tumors
image In patients who are not candidates for surgical resection
• Transarterial chemoembolization (TACE)

image For patients with multifocal unresectable tumor

– Often limited due to insufficient hepatic reserve
image May be used as bridging therapy before transplantation
• Radioembolization

image With yttrium-90Y-tagged microspheres
image Alternative to TACE
• Transplantation

image For those with small tumor, no vascular invasion or metastases
image Milan criteria  for transplantation

– Solitary HCC ≤ 5 cm diameter, or up to 3 HCC nodules, each ≤ 3 cm diameter
– No vascular invasion or extrahepatic tumor
• Systemic therapy

image Modest survival benefit with sorafenib (tyrosine kinase inhibitor)

Surveillance for HCC

• Goal is to detect early, small HCC at curable stage
• Who should be screened?

image All patients with proven cirrhosis (any etiology)
image Hepatitis B carriers who also have cirrhosis, or

– Are Asian or African American
– Have family history of HCC
– Have high viral loads
• Which imaging modality should be used?

image Sonography

– Usually repeated at ∼ 6-month intervals
– Effective in expert hands in examining thin patients with relatively nonfibrotic livers
image Computed tomography or MR

– To evaluate any focal lesion > 1 cm detected by US
– To evaluate liver that is distorted by fat, fibrosis, nodularity
– To evaluate patient considered at high risk for HCC even with normal US
– Usually repeated at ∼ 12-month intervals as problem-solving test

DIAGNOSTIC CHECKLIST

Image Interpretation Pearls

• Within cirrhotic liver

image Encapsulated or fat-containing mass is likely HCC
image Mass with restricted diffusion or no uptake of gadoxetate is likely HCC

Reporting Tips

• Use LI-RADS classification system

image Provides standardized criteria for interpreting findings of CT & MR examinations in patients with chronic liver injury
• Accurately report vascular invasion and number and size of lesions
image
(Left) Graphic shows a heterogeneous hypervascular mass invading the portal vein image. The surrounding liver is cirrhotic with a nodular contour, and there is ascites. Satellite nodules of HCC image surround the dominant mass.

image
(Right) Axial CECT in venous phase shows a hypodense mass image in a cirrhotic liver invading and occluding the posterior branch of the right portal vein image. Nonocclusive thrombus image is present within the main portal vein. This HCC was hypervascular on arterial phase CECT.
image
(Left) Axial venous phase T1WI MR in a 54-year-old man with alcoholic cirrhosis shows a multifocal hypointense mass image that directly invades the portal vein and obstructs intrahepatic bile ducts image. Note ascites image and typical signs of cirrhosis.

image
(Right) Axial T1W MR in the same patient shows a mass in the right adrenal image, a metastasis that has a similar appearance to the tumor within the portal vein image. While extrahepatic metastases from HCC are uncommon, the adrenals are among the more common sites of these.
image
(Left) Axial NECT shows a mass image with portions that are unusually hypodense due to the presence of fat within the tumor. The fatty elements within the HCC were still evident on portal venous phase CECT (not shown).

image
(Right) Longitudinal ultrasound in the same patient shows an unusually echogenic mass image corresponding to the fatty foci within the HCC seen on CT. Macroscopic fat within a mass in a cirrhotic liver is very suggestive of HCC though it is present in only a minority of cases.
image
(Left) Multifocal HCC may simulate metastases, as in this case. Axial arterial phase CECT shows multiple hypervascular foci image and expansion of the left portal vein image by enhancing tumor thrombus.

image
(Right) Axial portal venous phase CECT in the same patient shows washout of contrast from the HCC foci image, as well as the portal vein tumor thrombus image. The presence of the tumor thrombus is useful in distinguishing HCC from metastases, which rarely invade the portal vein.
image
(Left) Arterial phase CECT in an 80-year-old man with no known liver disease shows a large mass with a “mosaic” pattern of enhancement and a thin rim or capsule image. These are typical features of HCC that arise in a noncirrhotic liver, such as someone with chronic hepatitis B infection.

image
(Right) A catheter angiogram in the same patient shows that the “capsule” is composed of large feeding arteries image along the periphery of the mass.
image
(Left) (A) T2WI shows a focal mass image that is slightly hyperintense to background liver. (B) The same lesion is hypervascular on arterial phase C+ T1WI.

image
(Right) In the same patient, on delayed phase T1WI (A) the mass image demonstrates contrast washout and a capsule, very typical signs of HCC. Diffusion-weighted image (B) shows bright signal representing restricted diffusion, another typical feature of HCC.
image
(Left) Axial T2WI MR in a 66-year-old man with chronic hepatitis B shows a moderately hyperintense spherical mass image in the hepatic dome, along with 2 smaller cysts.

image
(Right) Fat-suppressed T1WI MR in the same patient shows the mass image as hypointense to surrounding liver.
image
(Left) T1WI GRE in-phase MR in the same patient shows the mass image as slightly hypointense to liver.

image
(Right) T1WI GRE opposed-phase MR in the same patient shows signal dropout from the mass image, indicating lipid content. The presence of microscopic fat (as in this case) or macroscopic fat is a very suggestive sign of HCC in a mass within a cirrhotic liver.
image
(Left) Arterial phase contrast-enhanced T1WI MR in the same patient shows heterogeneous hypervascularity within the mass image, which is essentially diagnostic of HCC in this setting.

image
(Right) Delayed phase contrast-enhanced T1WI MR in the same patient shows washout of contrast from the mass image and a suggestion of a capsule image, another characteristic sign of HCC.
image
(Left) Transverse (A) and longitudinal (B) US images show a spherical mass image that is solid, encapsulated, and nearly isoechoic to the background cirrhotic liver. This was interpreted as a solitary HCC.

image
(Right) A delayed phase CECT image on the same patient shows an encapsulated mass image in the hepatic dome, in addition to the mass identified at US, which was also seen on CT (not shown).
image
(Left) Axial CECT (same patient) shows the same mass image seen on the sonogram as hypervascular to liver on this arterial phase image. In addition, a similar hypervascular HCC is identified in the posterior right lobe image, along with tumor thrombus in the portal vein image.

image
(Right) CT in the venous phase (same patient) shows washout from the left lobe HCC image and tumor thrombus in the portal vein image. These additional findings identified this patient as stage 4 HCC, limiting his therapeutic options.
image
(Left) CT (A & B) in a man with alcoholism, acute pain and hypotension shows perihepatic bleeding image. The source of the bleeding was an ruptured large HCC image. The liver is diffusely steatotic.

image
(Right) In this case of known HCC following TACE, axial T1WI MR (A) shows a larger mass image that has typical features of a nonviable tumor, being hyperintense on T1WI, while a viable smaller tumor image is hypointense on T1WI. On the C+ T1WI (B) the viable lesion enhances image, while the nonviable mass image does not.
image
Axial CECT in arterial phase shows a hypervascular mass in the right lobe of a cirrhotic liver.

image
Axial CECT in portal venous phase shows a mass isodense to the liver. A hyperdense capsule delineates the tumor.
image
Axial T1 C+ MR in arterial phase shows a heterogeneous, hypervascular mass.
image
Axial T2WI MR barely detects this mass as a subtle hyperintense lesion.
image
Axial CECT in arterial phase shows a heterogeneous mass in the right lobe with an enhancing tumor thrombus in the IVC image and right hepatic vein. The liver mass had foci of fat most evident on NECT (not shown).
image
Axial CECT in arterial phase shows a large heterogeneous hypervascular mass that occupies the right lobe and causes intrahepatic biliary obstruction image.

SELECTED REFERENCES

1. Gaddikeri, S, et al. Hepatocellular carcinoma in the noncirrhotic liver. AJR Am J Roentgenol. 2014; 203(1):W34–W47.

2. Jha, RC, et al. LI-RADS categorization of benign and likely benign findings in patients at risk of hepatocellular carcinoma: a pictorial atlas. AJR Am J Roentgenol. 2014; 203(1):W48–W69.

3. Roth, CG, et al. Hepatocellular carcinoma and other hepatic malignancies: MR imaging. Radiol Clin North Am. 2014; 52(4):683–707.

4. Gonzalez, SA, et al. Risk assessment for hepatocellular carcinoma in chronic hepatitis B: scores and surveillance. Int J Clin Pract. 2012; 66(1):7–10.

5. Becker-Weidman, DJ, et al. Hepatocellular carcinoma lesion characterization: single-institution clinical performance review of multiphase gadolinium-enhanced MR imaging—comparison to prior same-center results after MR systems improvements. Radiology. 2011; 261(3):824–833.

6. Haradome, H, et al. Additional value of gadoxetic acid-DTPA-enhanced hepatobiliary phase MR imaging in the diagnosis of early-stage hepatocellular carcinoma: comparison with dynamic triple-phase multidetector CT imaging. J Magn Reson Imaging. 2011; 34(1):69–78.

7. Sano, K, et al. Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology. 2011; 261(3):834–844.

8. Starr, SP, et al. Cirrhosis: diagnosis, management, and prevention. Am Fam Physician. 2011; 84(12):1353–1359.

 

Suh, YJ, et al. Differentiation of hepatic hyperintense lesions seen on gadoxetic acid-enhanced hepatobiliary phase MRI. AJR Am J Roentgenol. 2011; 197(1):W44–W52.

Vivarelli, M, et al. Liver transplantation for hepatocellular carcinoma on cirrhosis: strategies to avoid tumor recurrence. World J Gastroenterol. 2011; 17(43):4741–4746.

Yu, JS, et al. Detection of small intrahepatic metastases of hepatocellular carcinomas using diffusion-weighted imaging: comparison with conventional dynamic MRI. Magn Reson Imaging. 2011; 29(7):985–992.

Hanna, RF, et al. Double-contrast MRI for accurate staging of hepatocellular carcinoma in patients with cirrhosis. AJR Am J Roentgenol. 2008; 190(1):47–57.

Willatt, JM, et al. MR Imaging of hepatocellular carcinoma in the cirrhotic liver: challenges and controversies. Radiology. 2008; 247(2):311–330.

Laghi, A, et al. Hepatocellular carcinoma: detection with triple-phase multi-detector row helical CT in patients with chronic hepatitis. Radiology. 2003; 226(2):543–549.

Brancatelli, G, et al. Hepatocellular carcinoma in noncirrhotic liver: CT, clinical, and pathologic findings in 39 U.S. residents. Radiology. 2002; 222(1):89–94.

Kim, T, et al. Discrimination of small hepatic hemangiomas from hypervascular malignant tumors smaller than 3 cm with three-phase helical CT. Radiology. 2001; 219(3):699–706.

Murakami, T, et al. Hypervascular hepatocellular carcinoma: detection with double arterial phase multi-detector row helical CT. Radiology. 2001; 218(3):763–767.

Peterson, MS, et al. Pretransplantation surveillance for possible hepatocellular carcinoma in patients with cirrhosis: epidemiology and CT-based tumor detection rate in 430 cases with surgical pathologic correlation. Radiology. 2000; 217(3):743–749.

Oliver, JH, 3rd., et al. Detecting hepatocellular carcinoma: value of unenhanced or arterial phase CT imaging or both used in conjunction with conventional portal venous phase contrast-enhanced CT imaging. AJR Am J Roentgenol. 1996; 167(1):71–77.

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