**2. Diagnosis**

Clinical features of HCC may include pain in the upper right quadrant and weight loss. Most of the patients diagnosed with HCC are patients known with liver cirrhosis. Despite this fact, there is a rare complication such as rupture of a liver tumor with intra-abdominal bleeding, which will need immediate surgical care [2]. These patients will present with acute abdominal pain, peritoneal irritation and hypotension. Other patients present with nonspecific signs such as fever, jaundice, ascites, anorexia or encephalopathy [3].

usually performed after detection of a focal lesion on standard US. The characterization of the

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Most of the HCC are characterized by arterial phase enhancement and wash-out of the contrast during the late phase. According to some studies, more the differentiated a lesion is, the

CEUS is an alternative for CT and MRI especially when there are contraindications for these investigations and it offers equivalent accuracy to CT and MRI if there is an experienced and

*CT scan* is an important investigation for the characterization of the HCC. It includes 4 phases:

HCC must be differentiated from regeneration nodules, hemangioma, focal fat, dysplastic

Factors such as injection of the contrast, tumor size and vascularity can affect the diagnostic accuracy of the HCC. In small tumors (less than 2 cm), the efficacy of CT is diminished due to the hypo-vascularization of small-sized tumors. The sensitivity of four phase CT in detecting HCC was up to 100% for tumors larger than 2 cm, 93% for tumors size between 1 and 2 cm

*Multidetector helical CT* (*MDCT*) is a new technique. which allows collection of early (18–28 s after administration of the contrast agent) and late or early parenchymal (35–45 s) arterial phase images. This new technique has improved the sensitivity and positive predictive values [23, 24]. Vascular tumors appear hypodense compared with liver parenchyma during the equilibrium phase (3–5 min after the administration of the contrast agent) and this technique

*Magnetic resonance imaging* (*MRI*) is the best technique for evaluation of the liver nodules in patients with cirrhosis. HCC aspect varies on MRI because of the following factors: hemorrhage, degree of fibrosis and necrosis and histologic pattern. MRI is more accurate than CT or ultrasonography in detecting and characterization of HCC even for patients with liver cirrhosis. HCC appears hyper-intense on T2-weighted images while in T1-weighted images it

The sensitivity of MRI depends on tumor size, and it is about 95% in tumors larger than 2 cm

Even if the MRI is the best investigation to characterize a liver nodule and to put the diagnosis of HCC, often the nodules might not be distinguished so a histological examination or

*Liver biopsy* is performed with fine needle aspiration biopsy (FNAB) under ultrasonography or CT guidance and is considered the best method for a sure diagnosis of HCC. The sensitivity and specificity are about 96 and 95%, respectively, superior to any other test [27]. Sometimes, because the HCC lesions cannot be accurately located by radiographic methods, it is necessary

hepatic lesion depends on all phases of contrast enhancement.

pre-contrast, hepatic arterial phase, portal venous and delayed phases.

is compared with MRI for early detection of small HCC (<1 cm) [24, 25].

and reduced to 30% for tumors, which are less than 2 cm in size [26].

*Angiography* can be used to define hepatic anatomy before surgical resection.

more gradually it is to washout [15, 16].

and 60% for tumors less than 1 cm [20–22].

may appear hypointense, isointense or hyperintense.

advance imaging modalities will be necessary.

skilled operator [17, 18].

nodules and peliosis [19].

Clinical examination can reveal an abdominal mass in the upper right quadrant or hepatomegaly. Obstructive jaundice can indicate tumor extension into the extrahepatic biliary structures [4].

HCC can metastasize to any organ, the most frequent being metastasis to bone, lung or other abdominal viscera; so, patients can present with various clinical signs and symptoms related to the affected organs. Watery diarrhea is more common in patients with cirrhosis and HCC because of the increased production of intestinal secretory substances such as gastrin and vasoactive intestinal peptide (VIP) [5, 6].

Alpha-1 fetoprotein is the most commonly used marker for HCC. Patients with AFP > 400 ng/ ml tend to have a greater size, bilobar involvement, portal vein thrombosis and decreased survival [7]. If the tumor producing AFP is left untreated, the AFP value will increase over the time, so this marker can be used for detecting tumor progression. APF may be increased in a variety of other malignancies and in patients with chronic liver disease without HCC, particularly in hepatitis C [8]. The sensitivity, specificity and positive predictive value of AFP range from 39 to 64%, 76 to 91% and 9 to 32% [8]. Patients with values of AFP greater than 1000 ng/ml have a higher incidence of vascular invasion (61%) compared with patients with values of AFP <1000 ng/ml [9].

Other clinical biomarkers used for the diagnosis of HCC are: microRNAs [10], des-gammacarboxyprothrombin (DCP) [11], glypican-3 (GPC3) [12], proteomic profiling [13], and alphal-fucosidase [14].

Imaging has an important role in the diagnosis of HCC. Even if over the past decades the imaging technology has improved and the hepatic lesions are better characterized, detection of the small tumors continues to be difficult especially in patients with liver cirrhosis whose parenchymal architecture is abnormal. The most common imaging techniques used for evaluation of the liver parenchyma are as follows: ultrasound scanning (US), CT scan, MRI, and angiography.

*Ultrasound scanning* is the most used technique, and it is performed as a routine test for screening focal hepatic lesions. Ultrasound imaging has now been replaced in diagnosis by CT scan and MRI. Contrast-enhanced ultrasound (CEUS) uses contrast agents such as intra-arterial dioxide carbon and helium. Also, application of color Doppler sonography can be useful in the assessment of intrahepatic vascular flow and the Doppler of the portal vein can differentiate bland thrombus from tumor invasion.

*Contrast-enhanced ultrasonography* (*CEUS*) can offer information about the nature of the liver tumor which cannot be obtained with conventional ultrasonography. CEUS is safe, and it is usually performed after detection of a focal lesion on standard US. The characterization of the hepatic lesion depends on all phases of contrast enhancement.

**2. Diagnosis**

138 Liver Research and Clinical Management

Clinical features of HCC may include pain in the upper right quadrant and weight loss. Most of the patients diagnosed with HCC are patients known with liver cirrhosis. Despite this fact, there is a rare complication such as rupture of a liver tumor with intra-abdominal bleeding, which will need immediate surgical care [2]. These patients will present with acute abdominal pain, peritoneal irritation and hypotension. Other patients present with nonspecific signs

Clinical examination can reveal an abdominal mass in the upper right quadrant or hepatomegaly. Obstructive jaundice can indicate tumor extension into the extrahepatic biliary structures [4]. HCC can metastasize to any organ, the most frequent being metastasis to bone, lung or other abdominal viscera; so, patients can present with various clinical signs and symptoms related to the affected organs. Watery diarrhea is more common in patients with cirrhosis and HCC because of the increased production of intestinal secretory substances such as gastrin and

Alpha-1 fetoprotein is the most commonly used marker for HCC. Patients with AFP > 400 ng/ ml tend to have a greater size, bilobar involvement, portal vein thrombosis and decreased survival [7]. If the tumor producing AFP is left untreated, the AFP value will increase over the time, so this marker can be used for detecting tumor progression. APF may be increased in a variety of other malignancies and in patients with chronic liver disease without HCC, particularly in hepatitis C [8]. The sensitivity, specificity and positive predictive value of AFP range from 39 to 64%, 76 to 91% and 9 to 32% [8]. Patients with values of AFP greater than 1000 ng/ml have a higher incidence of vascular invasion (61%) compared with patients with

Other clinical biomarkers used for the diagnosis of HCC are: microRNAs [10], des-gammacarboxyprothrombin (DCP) [11], glypican-3 (GPC3) [12], proteomic profiling [13], and alpha-

Imaging has an important role in the diagnosis of HCC. Even if over the past decades the imaging technology has improved and the hepatic lesions are better characterized, detection of the small tumors continues to be difficult especially in patients with liver cirrhosis whose parenchymal architecture is abnormal. The most common imaging techniques used for evaluation of the liver parenchyma are as follows: ultrasound scanning (US), CT scan, MRI, and angiography. *Ultrasound scanning* is the most used technique, and it is performed as a routine test for screening focal hepatic lesions. Ultrasound imaging has now been replaced in diagnosis by CT scan and MRI. Contrast-enhanced ultrasound (CEUS) uses contrast agents such as intra-arterial dioxide carbon and helium. Also, application of color Doppler sonography can be useful in the assessment of intrahepatic vascular flow and the Doppler of the portal vein can differenti-

*Contrast-enhanced ultrasonography* (*CEUS*) can offer information about the nature of the liver tumor which cannot be obtained with conventional ultrasonography. CEUS is safe, and it is

such as fever, jaundice, ascites, anorexia or encephalopathy [3].

vasoactive intestinal peptide (VIP) [5, 6].

values of AFP <1000 ng/ml [9].

ate bland thrombus from tumor invasion.

l-fucosidase [14].

Most of the HCC are characterized by arterial phase enhancement and wash-out of the contrast during the late phase. According to some studies, more the differentiated a lesion is, the more gradually it is to washout [15, 16].

CEUS is an alternative for CT and MRI especially when there are contraindications for these investigations and it offers equivalent accuracy to CT and MRI if there is an experienced and skilled operator [17, 18].

*CT scan* is an important investigation for the characterization of the HCC. It includes 4 phases: pre-contrast, hepatic arterial phase, portal venous and delayed phases.

HCC must be differentiated from regeneration nodules, hemangioma, focal fat, dysplastic nodules and peliosis [19].

Factors such as injection of the contrast, tumor size and vascularity can affect the diagnostic accuracy of the HCC. In small tumors (less than 2 cm), the efficacy of CT is diminished due to the hypo-vascularization of small-sized tumors. The sensitivity of four phase CT in detecting HCC was up to 100% for tumors larger than 2 cm, 93% for tumors size between 1 and 2 cm and 60% for tumors less than 1 cm [20–22].

*Multidetector helical CT* (*MDCT*) is a new technique. which allows collection of early (18–28 s after administration of the contrast agent) and late or early parenchymal (35–45 s) arterial phase images. This new technique has improved the sensitivity and positive predictive values [23, 24]. Vascular tumors appear hypodense compared with liver parenchyma during the equilibrium phase (3–5 min after the administration of the contrast agent) and this technique is compared with MRI for early detection of small HCC (<1 cm) [24, 25].

*Magnetic resonance imaging* (*MRI*) is the best technique for evaluation of the liver nodules in patients with cirrhosis. HCC aspect varies on MRI because of the following factors: hemorrhage, degree of fibrosis and necrosis and histologic pattern. MRI is more accurate than CT or ultrasonography in detecting and characterization of HCC even for patients with liver cirrhosis. HCC appears hyper-intense on T2-weighted images while in T1-weighted images it may appear hypointense, isointense or hyperintense.

The sensitivity of MRI depends on tumor size, and it is about 95% in tumors larger than 2 cm and reduced to 30% for tumors, which are less than 2 cm in size [26].

Even if the MRI is the best investigation to characterize a liver nodule and to put the diagnosis of HCC, often the nodules might not be distinguished so a histological examination or advance imaging modalities will be necessary.

*Angiography* can be used to define hepatic anatomy before surgical resection.

*Liver biopsy* is performed with fine needle aspiration biopsy (FNAB) under ultrasonography or CT guidance and is considered the best method for a sure diagnosis of HCC. The sensitivity and specificity are about 96 and 95%, respectively, superior to any other test [27]. Sometimes, because the HCC lesions cannot be accurately located by radiographic methods, it is necessary to perform open surgical biopsy. The most important complications are the risk of tumor spreading along the needle tract, estimated at up 3%, important bleeding or infectious complications [7] [28–30]. Contraindications for liver biopsy are platelet count <50,000 per mm3 or the international normalizing ratio (INR) > 2 [7].

HCC include: pathologic tumor-node-metastasis (pTNM) [36], Okuda [37], Cancer of the Liver

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BCLC staging system seems to be the best for selection of early-stage HCC that should benefit from orthotopic liver transplantation, hepatic resection or local ablation while the CLIP score may be more useful at stratifying patients who are not candidates for resection or transplantation.

Nowadays, many of the patients with HCC are diagnosed at an early stage when there are no signs of an advanced cancer. In the past, most of the patients were diagnosed only when they became symptomatic and no treatment had a chance of being effective or to improve the survival rates. There are a number of treatments available which seems to improve the survival rates, but to achieve the best results a careful selection of the patients is needed. Liver transplantation is the best option treatment for the patients with solitary HCC in the setting of decompensated cirrhosis and for those with early multifocal disease (up to 3 lesions, none larger than 3 cm) [40, 41], while for the patients with solitary tumors in well-compensated cirrhosis the best treatment strategy is under debate [42]. Treatments which offer the best survival rate are surgical resection, liver transplantation, percutaneous ablation and transarterial chemoembolization [40, 43]. Systemic chemotherapy has been demonstrated that has no benefits on survival rates [44, 45], while agents like tamoxifen [43], anti-androgens [46] or octreotide [47] are completely ineffective. *Hepatic resection* is the treatment of choice in non-cirrhotic patients who have been diagnosed with HCC (**Figure 1a** and **b**). Patients with cirrhosis have to be very well selected for surgical resection due to the high risk of postoperative liver failure which can lead to death after the surgery. Cirrhotic patients have a higher rate of decompensation if they are operated with right hepatectomy than if a left hepatectomy is performed; however, the 5-year survival rate after resection can exceed 50%

[42, 48, 49]. Before the surgery there are some specific factors which need to be considered:

• Quality and volume of the future functional liver remnant.

• Presence/absence of a chronic liver disease and portal hypertension assessed clinically or by hepatic vein catheterization. If the upper endoscopy shows varices or diuretic treatment is necessary, the portal hypertension is severe and there is no need for catheterization of

The most important causes of death after liver resections are postoperative hemorrhages, liver failure and sepsis, but all these complications have a lower incidence due to the improvements of the surgical techniques (Pringles maneuver), the development of ultrasonic dissec-

To perform a *right hepatic resection*, you have to mobilize completely the right lobe of the liver to have control on the right hepatic vein before the parenchymal transection. Sometimes the

Italian Program (CLIP) [38] and Barcelona Clinic Liver Cancer (BCLC) [39].

**5. Treatment**

• Stage of the tumor; • Size of the tumor;

the hepatic veins;

tors and vascular staplers.
