Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide,
in particular fifth in men and seventh in women.
Cirrhosis is the most important clinical risk factor for HCC; 80% of cases of HCC develop in patient with a cirrhotic liver.
Imaging plays a critical role in HCC screening and diagnosis in high risk patients.
CT and MRI are performed to confirm the suspected lesions,
relegating histology to the most controversial cases (3).
The new EASL guidelines indicate that multiphasic contrast-enhanced CT or multiphasic contrast-enhanced MRI may be diagnostic when assessing lesions larger than 1 cm that show typical radiological presentation.
Biopsy must be performed only when neither CT nor MRI confirm the diagnostical suspect.
Development of HCC in cirrhotic liver is a multistep process with progressive dedifferentation of regenerative nodule: starting from a low grade dysplastic nodule (LGDN),
going through an high grade dysplastic nodule (HGDN) progressing to a focal HCC,
within a dysplastic nodule.
Eventually HCC may progress from an early stage to a mature form.
Along with carcinogenesis,
there are angiogenetic modifications,
which are necessary to support the rapid growth of HCC and that lead to a rich network of defective arteries.
As a result gradual predominance of arterial vascularization over portal venous is seen,
clearly visible in high grade dysplastic nodule and advanced forms of HCC.
In diagnostical imaging the development of unpaired non triadal arteries is responsible of the early enhancement in the arterial phase and washout in the portal phase.
Sinusoidal capillarization is an other relevant vascular change in cirrhosis,
but more evident in HCC nodule.
It consists of alteration in the sinusoidal endothelium: disappearance of the fenestrae,
development of a basal membrane with activation of hepatic stellate cells with fibrogenesis and intrahepatic vasocostriction.
endothelian CD 34 marker and the Actin Muscle Antigen (SMA) for muscolarized unpaired arteries,
allow evaluation of neovascularization,
which is a parameter of progression of carcinogenesis,
with the progressive rarefaction of the portal tract.
Fibrogenesis is linked to an over-expression of type I and III procollagen genes of stellate cells and does not depend on hepatocites.
Fibrogenesis involves development of the capsule and septum at the interface between two different tissues (e.g.,
capsule between cancer nodule and non-cancerous liver and septum between cancer nodule and another cancer nodule).
The capsule is typical of larger HCC nodules and is absent in rigenerative nodules and low grade dyspasic nodules.
The capsule is composed externally of looser fibrovascular tissue with portal venules,
newly formed bile ducts,
and prominent sinusoids,
and of internal layer of pure fibrous tissue with thin,
slit-like vascular channels.
Encapsulated HCC have a better prognosis because they tend to have a lower incidence of direct liver invasion compared to nonencapsulated HCC.
In imaging capsule is characterized by smooth peripheral rim enhancement during the portal venous and delayed phases.
only histological examination distinguishes between capsula and pseudocapsula.
Dysplasic nodules are similar to cirrhotic nodule since both peripherical fibrotic septi and diffuse peripherical integral ductal reaction (HE and CK 7/19) are present.
Distinguishing displastic nodules from cirrhotic nodules is a challenge because LGDN only differ from cirrhotic nodules for a milder increased cellular density and early cellular atypia.
HGDN have more cellular atypia and architectural alterations,
though these features are not yet sufficient to diagnose HCC.
Early HCC forms (< 2 cm) show a more infiltrative pattern and capsula is absent or incomplete.
In addition to increased cellula atypia,
small amount of unpaired arteries and intratumoral portal tract are present,
sometimes steatosis appears.
Stromal invasion in the portal trait or in the fibrous septa is a prognostically negative factor. Advanced HCC is the classical form of encapsulated HCC with a lot of unpaired arteries,
usually moderately differentiated but with marked cellular atypia and architectural distorsion (loss of reticulin).
Immunohistochemistry is helpful in differential diagnosis,
especially in difficult case as HCC and HGDN or when small specimens are available.
A combination of markers as heat shock protein 70 (HSP 70),
glutamine synthetase (GS) and glypican-3 (GPC-3) increase the diagnostic accuracy.
Positivity of two out of three markers determines detection of early and well differentiated HCC with 100% specificity,
rarely HCC are completely negative for these markers.
- CT requires the use of a multiphase study protocol,
including a phase prior to the intravascular administration of contrast agent (basal phase) and phases obtained after intravascular administration of contrast medium.
- Early arterial phase (15-20 seconds after the start of injection or right after the bolus tracking) to ensure only arteries appear enhanced
- Late arterial phase (30-40 seconds after the start of injection or 15 seconds right after the bolus tracking) to ensure every arterial-supplied tissues appear enhanced.
Contrast agent bolus tracking is recommended for hepatic arterial timing.
In this phase,
because of neoplastic neovascularization, HCC nodule are more enhanced than surrounding liver parenchyma.
After 60-90 seconds the hepatic veins appear more full of contrast and we therefore perform the portal phase,
while in the delayed phase (180-300 seconds) the portal veins,
hepatic veins and liver parenchyma are less enhanced.
During those phases wash out and capsule enhancement represent typical behavior of HCC.
Lesions appear hypoenhancing and/or show peripherical rim of smooth hyperenhancement compared with the background liver tissue for the reduced extracellular volume of HCC,
rapid venous drainage and reduced intranodular venous supply. CT permits diagnosis of HCC based mainly on the physiological changes in intranodular blood.
MRI post gadolinium also studies the vascularization of lesions,
but performing different sequences allows to perform a greater tissue characterization.
In addiction with the administration of hepatospecific contrast agent we can also evalute the hepatocellular function.
Prior to the intravascular administration of contrast agent sequences- T2w,
T1 in/out phase,
DWI- show more sensitivity and permit assessment of ancillary features as intralesional fat; DWI improves detection and characterization of HCC.
(Morever it allows a greater differential diagnosis with non malignant nodules).
MRI with extracellular agent is similar in acquisition times to CT though some scientific studies show that the former has higher sensitivity than the latter but similar specificity. Moreover,
MRI can give informations on the tissue function based on the ability of excretion of the contrast medium into the biliary system.
This phase is usually acquired about 20 minutes after the injection of gadoxetate disodium or 1-3 hours after injection of gadobenate dimeglumine.
During hepatocarcinogenesis 89 % of high-grade dysplastic nodules and HCC nodules lose OATP expression.
Specificity of CT and MRI ranges between 85% and 100%.
Sensitivity depends on the lesion size: sensitivity of 48% and 62% for CT and MRI for smaller tumors (< 2 cm); 92% and 95% in tumors equal or larger than 2 cm.
Our aim is to show the role of histology in false positive lesions.