Pathology and clinical condition of HCC

This is a well-known medical truth that Hepatocellular carcinoma (HCC) now involving about the fifth of all malignant tumors in the world, and it’s one of the most common causes of deaths resulting from cancer in the world and USA (1).

It causes about 250.000 to 1000.000 deaths/year (2).

HCC develop mainly in the cirrhotic liver.

Liver damage which eventually leads to liver illness (cirrhosis or fibrosis ) can occur due to several causes.

We can numerate Viral infections, Alcoholism, Obesity, Toxic agents, metabolic function disease. In Asia and Africa (3), HCC has higher incidence more than other regions.

The main cause of HCC in there are endemic Hepatitis B, C, and Aflatoxins. In the USA and Europa HCC has a lower incidence (5), however, it still has a high incidence. Hepatitis C consider causing more than 30% of HCC in the state, either alone or with other cause like alcohol, others (4).

Another noncirrhotic cause is found to spread nowadays, especially in western countries. We can mention hemochromatosis,
Primary biliary cirrhosis, autoimmune hepatitis, and obesity with nonalcoholic steatohepatitis, or can also call (NASH) (4).

NASH now considered one of the most important causes of HCC in the states and Europe.the end result of NASH is called cryptogenic cirrhosis which increases HCC incidence. (4)

As the clinical presentation of HCC is variable and limited mainly to the underlying cause. so it’s mostly discovered late during the patient survey and that affects the disease prognosis. so the surveillance in cirrhotic and hepatitis patients is very important in reducing the incidence and deaths of HCC (2).

HCC has a male predominance(2). typical usual presentation of HCC is an old man with cirrhosis and Ascites with splenomegaly and weight loss, increase alpha-fetoprotein (2). However acute presentation of acute RUQ pain may occur due to rupture of liver capsule.(2)

In cirrhotic patients the pathology of HCC  evolute form necrosis and fibrosis of hepatocytes to the neoplasm. This evolution takes multiple steps from regeneration nodules to low-grade dysplastic nodules to high-grade dysplastic nodules to early HCC and finally advanced HCC (6).

This figure shows a high vascular heterogenous mass lesion which invades the adjacent portal vein in cirrhotic liver. (2)


MRI sequences of Localize and characterizations of HCC:

Hepatocellular Carcinoma is typically a hyper-vascular spherical heterogenous mass with contrast enhancement wash-out and portal vein invasion. The size of HCC may be small, less than 2 cm, or large, more than 5 cm.

The smaller ones are more liable to be cured by ablation or resection, or transplantation. While the larger ones especially if associated with venous invasion, those are more able to TACE (trans-arterial chemo-embolization) (2).

If HCC invades the portal vein, the following imaging signs are detected; first  the lumen of the portal vein is seen expanded, Second the tumor is seen enhanced within the vein, third the tumor and portal vein is fused with each other.(2)

Now let’s talk a look at sequences of MRI used to localize and characterize HCC, we should note that variable intensity of HCC depends mainly on necrosis, fibrosis and fatty changes degree:

T1 Weighted Image:

In this sequnce, HCC usually appears as a hypointense mass in compared to surroundings. As the cell increases in number, which means increase water amount. but in small HCC, it may appear hyper or iso  due to increase fat and glycogen content.(7)

T2 Weighted Image:

in T2 HCC is usually have a hyper-intense appearance to the liver density.

on the other side, the regenerative nodule usually appeared hypo-intense to the liver.

In this sequence, we can discriminate The HCC which arise inside the dysplastic nodule, as it has a pattern of (Nodule within the module) as it appears as small increase signal intensity focus within nodule of decreased intensity. (2)

T1 plus gadolinium contrast:

on this sequence, HCC appears as hyperintense heterogenous mass, associated with washout on delayed and venous phase.

To differentiate HCC from arterio-portal shunt, we should know that HCC takes fast central washout with residual capsular enhancement.(2)

A hepatobiliary contrast agent (gadoxetate):

the use of gadoxetate ( its trade names are Eovist, Primovist) after twenty minutes delay phase, reveal that Normal liver and some cirrhotic liver, brightly enhance m while HCC appears as hypo-intense masses.

some good differentiated HCC has proved to show persistent enhancement with gadoxetate. This technique is the most specific and sensitive technique for detection and location of HCC, it increases the incidence of small HCC diagnosis. (2)

Diffusion-weighted MR:

Diffusion restriction within HCC, usually detected as a bright signal in the focal lesion, it helps in increase MR sensitivity of HCC detection. (2)

Hepatocellular carcinoma (HCC) schematic diagram. HA, hepatic artery; HADP, hepatic artery–dominant phase; HBV, hepatitis B virus, IVC, inferior vena cava; PV, portal vein.(8) 

Large Complex HCC. A, The moderately T2-weighted image shows a large heterogeneously hyperintense lesion (arrow) bulging the liver capsule. The arterial phase (B) and delayed (C) images show variegated enhancement, often seen in large lesions.(8)

The Figure show DW MR of Cirrhotic liver. At dual-echo (a, b) and on T1-w.i (c), multiple nodules appear as iso- to hyperintense, while on T2-w.i (d) they show as slightly hypointense. On postcontrast dynamic study, no arterial nodular enhancement is detectable (e) as well as no wash-out is evident on the venous.and late phases (f, g). On hepatobiliary phase (h), acquired 20’ after contrast medium injection, all nodules show a significant uptake. (7)

This figure show : Different behavior of HCC and dysplastic nodule (DN) at MR. MR examination shows the oexistence of two differentiated nodules. At baseline (a, b), the HCC lesion (arrow) appears as hypointense on T1-w.i (a) and hyperintense in T2-w.i (b), while the DN (dotted arrow) shows the opposite signal behavior. At dynamic study (c–e), HCC presents the typical wash-in in arterial phase and wash-out in portal and late phases, while DN is iso–hypointense in all post-contrast phases. On hepatobiliary phase (f), HCC is hypointense due to the lack of intracellular contrast uptake, while DN is homogeneously hyperintense because of the
maintained hepatocyte function and cholestasis. (7)

Sequences are used to plan treatment, assess the completeness of treatment and detect a change in the lesion.

MR sequences have proved to be very effective in HCC treatment planning, monitoring the response of the lesion to treatment. Here we will enumerate the most important sequences used;

Diffusion-weighted MR:

has proven to be very effective in planning treatment either by surgical resection (ADC measurement before operations are very effective in measuring the risk of recurrence after surgery) or other treatment options as (TACE) transarterial chemo-embolization.(9.

In Trans-arterial Chemo-embolization (TACE), use of DWI to monitor ADC mapping measurements of the tumor response to treatment, as if poor response, it shows lower ADC measurements .(10)

ADC mapping can also together with venous enhancement of the lesion predict survival ration of the patient, by arranging them in survival classifications. (11)(12)

DWI, in general, is a very good factor in monitoring treatment effect and predicting survival rate as treatment cause local dynamic changes could be monitoring by DWI.(13)


MR Elastography.

In addition to its role in characterization of malignant liver tumors, as malignant tumor has higher stiffness than benign ones and it’s more viscous (14), the MR Elastography is very helpful in assessing the response of the tumor to chemotherapy and agents that cause vascular disruption. (15)

The technique of MR Elastography includes external vibrators that produce compression waves, that penetrate through tissue viscosity and elasticity of the tissues. This technique has been proved to be reliable in the liver in 22% for elasticity and 26% for viscosity.(16)


Dynamic contrast-enhanced MR imaging

in this sequence we use contrast to more visualization and detection of tumor response to treatment.

Usually, we use gadolinium contrast, then we take three phase of the liver: Arterial, Portal, and Delay (3-5 min after injection).

We can also use special hepatocyte contrast called Gadoxetate, in this case, we take additional hepato-biliary phase ( after 20 min of injection).

All phases (including arterial and portal and delayed phases) of Dynamic contrast-enhanced MR imaging should be done in routine to localize and tumor and detect its response to treatment.

so we use an especial contrast ( gadoxetate) , which in turn we get hepatobiliary phase, in which some HCC which is not good seen at classical phases of Dynamic MR imaging sequences .

and has low vascularity appears to be hypo-intense at hepato-biliary phase.Also, hyperintense lesion on these sequences predicts to prgnosed to HCC which has high vascularity. (17)

So we can say that Dynamic contrast-enhanced MR and DW MR  together can be used monitor intraarterial therapy.

There were noted survival differences between patients who their ADC level increase above 25%, their venous enhancement decrease. that’s like the difference between patients who are stable and patient who has single parameter respond, so the above text reveals the service could present the functional MR (multi-parameters) in evaluating treatment response.(18)

MRI Sequences used to grade HCC condition.

Diffusion-weighted MR:

also is useful in the grading of patients with HCC.

And almost considered the most useful sequence in this field. For example, if we had a patient with hypo-vascular liver nodule which is hyperintense on DWI. The studies proved that this nodule progress to be high vascularity HCC.

In addition, there is a correlation, but an inverse one between the level of ADC mapping and the grading of the tumor. The High differentiated tumor has more diffusion more than the poor differentiated one .(19) It’s also can predict other factors as VEGF (vascular endothelial growth factor)  (20)prognostic cell marker (21)and microvascular invasion. (22)


Tumor Grade ADC Potential association
High differentiation Good diffusion No reported association
Well differentiation Moderate diffusion No reported association
Poor differentiation Restricted diffusion presence of progenitor cell markers 1
Scarce differentiation Scarce diffusion presence of progenitor cell markers 1, vascular endothelial growth factor (VEGF) expression2-51, and microvascular invasion52.

Table, reveal the relation of ADC and HCC grading (23)

LI-RADS MR Grading system:  this system is the most common used and the most efficient to grade HCC.


This figure show LR-MR grading system of HCC. (24)

To get this we use these sequences :

MRI with extracellular contrast agents or gadobenate meglumine:

to make an HCC grading with an extra-cellular agent, we should use these sequence:

First, T1-W IP & OP sequences with no enhancement. Secondly, T2-WI (fat suppression per institutional preference).

Third Multiphase T1-WI.

Fourth Precontrast imaging.

Fifth Arterial phase, and recommended to be late.

Sixth Portal venous phase. Seventh Delayed phase.

Seventh Diffusion-weighted imaging.Eight Subtraction imaging and Multiplanar acquisition.

Lastly one to three hours hepatobiliary phase. (24)

MRI with gadoxetate disodium:

Sequenced performed with gadoxetate disodium to grade HCC.

First, T1-W IP & OP sequences with no enhancement.

Secondly, T2-WI (fat suppression per institutional preference).

Third Multiphase T1-WI.

Fourth Precontrast imaging.

Fifth Arterial phase, and recommended to be late.

Sixth Portal venous phase. Seventh Delayed phase.

Seventh Diffusion-weighted imaging.

Eight Subtraction imaging and Multiplanar acquisition.

Nine hepatobiliary phase .and we don’t forget transitional phase which we take two to five minutes after injection. (24)


Treatment options and outcomes for the patient

Treatment options of HCC vary according to the lesion and its nature and extent.

If the patient had a small HCC, localized peripherally and has no vascular invasion; this will be ideal for surgical resection.

So surgical resection id very optimal in previously described small peripheral avascular lesions, but its effect is limited to due to the hepatic reserve will be inadequate in the majority of patients. (2)

In patients who are not suitable for surgical resection and has an HCC isolated tumor less than 4 cm, these patients will be candidates for Radio-frequency Ablation.

On the other hand, Multi-centric HCC patients who are cannot undergo resection, they are ideal for Trans-arterial Chemo-embolization (TACE) (2).

But this procedure is limited as the hepatic reserve may be insufficient. So there is an alternative to it, The radio-embolization with Yttrium-90Y-tagged microspheres. Transplantation sill a very good choice for those who have nonmetastatic HCC tumor with no vascular invasion(2).

There are criteria called Milan Criteria used to the assessment of transplantation. these criteria are; first HCC tumor should be either solitary and less than 5 cm in diameter, or it’s more than one (up to 3 HCC nodules, each less than 3 cm in diameter).

Second, it must have no extra-hepatic metastasis and had no vascular invasion. Systemic treatment is still an option, sorafenib which is tyrosine kinase inhibitor, give good survival benefit. (2)


MRI Recurrence Monitoring sequences.

Diffusion-weighted MR:

It has proven to be very effective in monitoring recurrence of HCC.

As it offers a great service in distinguishing between the recurrence of the tumor, and the effect of the treatment.

The recurrent tumor gives a low ADM mapping measurements, while the necrotic tissue or the edematous area resulting as a response to treatment give high ADC mapping measurements.and as more increasing ADC level, the more successful treatment is. (25)(26)(27)

As tumor is mixed tissue components, the necrotic part could mix with the tumor part. So it can mix up in the evaluation of recurrence, so the used of Dynamic enhanced MRI with DWI is recommended to give the best precise assessment of the recurrence.(28)

Gadoxetate Disodium–Enhanced MRI:

this sequence has proved to be very effective in the assessment of recurrence of HCC after treatment especially after radio-frequency Ablation.

HCC usually when occurring as a recurrence it appears as nodular abnormal signal intensity areas or has enhanced margins especially the ablated tumor.(29)

This figure shows  70-year-old man with locally recurrent hepatocellular carcinoma after radiofrequency ablation in an anterosuperior segment of the right liver lobe.
A T2-weighted image (TR/TE, 1600/80) shows multiple areas of nodular hyperintensity (arrows) adjacent to the ablated area (arrowhead), which was hypointense on the fat-suppressed image.
B, MR image obtained during hepatic arterial phase shows area of nodular enhancement (arrow), corresponding to one of the hyperintense areas in A, adjacent to ablated
tumor. This area of enhancement showed mild washout during the portal venous phase and was due to local tumor recurrence.
C, 3D T1-weighted gradient-echo image (TR/TR, 4.0/2.1) obtained during hepatocyte phase shows area of hypointensity (solid arrow) adjacent to ablated tumor
(arrowhead), corresponding to the area of enhancement in B. This local tumor recurrence had a signal intensity ratio of 0.61. Another area of faint hypointensity (open arrow)
corresponding to a hyperintense area in A was observed adjacent to ablate the tumor. This lesion was found to be caused by reactive response to therapy and had signal
The intensity ratio of 1.65. Note area of hypointensity (asterisk) showing another ablated tumor.(30)





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29. Gadoxetate Disodium–Enhanced MRI Useful for Detecting Local Recurrence of Hepatocellular Carcinoma After Radiofrequency Ablation Therapy , Haruo Watanabe1, Masayuki Kanematsu1 2, Satoshi Goshima1, Mariko Yoshida1, Hiroshi Kawada1, Hiroshi Kondo1 and Noriyuki Moriyama at: American Journal of Roentgenology. 2012;198: 589-595. 10.2214/AJR.11.6844.


30. Fig 1: Gadoxetate Disodium–Enhanced MRI Useful for Detecting Local Recurrence of Hepatocellular Carcinoma After Radiofrequency Ablation Therapy?

Haruo Watanabe1, Masayuki Kanematsu1 2, Satoshi Goshima1, Mariko Yoshida1, Hiroshi Kawada1, Hiroshi Kondo1 and Noriyuki Moriyama, at: American Journal of Roentgenology. 2012;198: 589-595. 10.2214/AJR.11.6844.


























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