**4.1.4 Other imaging studies**

284 Liver Transplantation – Basic Issues

as the intravenous contrast material used in these studies, has improved the detection of this hepatic malignancy (B.I. Choi, 2010). The use of multidetector CT scans, for example has markedly highlighted the hypervascular characteristics of hepatomas which were not as evident in earlier CT scan technology (K.H. Lee, 2004). The sensitivity of CT scans has increased due to these advances. However, some studies have shown that the improved accuracy of this imaging technique is more apparent in the detection of larger tumors with classic radiographic features, and when the studies are interpreted by more experienced radiologists (Addley, 2011). It seems that in the setting of cirrhosis and when the lesions are smaller than 1 centimeter in diameter, CT has difficulties over and underestimating the diagnosis of hepatocellular carcinoma (Luca, 2010; Ronzoni, 2007). Similar observations have been shown in large and experienced liver transplant centers were the false positive diagnosis rate of primary liver cancer has been reported as high as 8%, and predominantly seen in lesions that were between 0.75 and 1.5 centimeters in diameter (Brancatelli, 2003). Perhaps the continued progress in the field of computed tomography might some day better

Magnetic resonance imaging provides another suitable option in the staging of hepatocellular carcinoma during the liver transplantation workup. There is ample evidence that attests the important role of MR in the diagnosis and description of hepatomas. The development of faster MR techniques has contributed to obtaining multiphase intravenous contrast-enhanced images that capture with more detail the hypervascular characteristics of this cancer. One of its most important attributes is its superior ability for the detection of small liver tumors, particularly those less than 2 centimeters in diameter (Burrel, 2003; Colli, 2006; Golfieri,2009, D.H. Lee, 2009,). Given the reported higher sensitivities and accuracy detecting these malignant lesions with the newer MR techniques and contrast agents, many transplant centers have adopted MR as their study of choice when evaluating potential transplant recipients with cirrhosis. One cannot forget that as in the case of CT scans and other imaging modalities, the detection and characterization of hepatocellular carcinoma could also be in part influenced by the experience of the radiologists interpreting these studies. MR use is limited in the setting of patients that have certain types of metallic medical implants or other devices, and on those who are claustrophobic or cannot hold their breath. Recently, gadolinium contrast has also been linked to nephrogenic systemic sclerosis which also limits the use contrast-enhanced MR in patients with significant renal failure, a not uncommon situation in the cirrhotic patient population (Idee, 2009). Nonetheless, the current available evidence has MR as the clear frontrunner in the search for the best imaging

Contrast-enhanced ultrasonography's (CEUS) capability of detecting vascular liver lesions, particularly hepatomas, has been studied and shown some promise (Forner, 2008; Jang, 2007). This modality has even demonstrated remarkable sensitivities and accuracy of 87 and 93% respectively, for diagnosing liver cancer in lesions less than 2 centimeters in diameter (Jang, 2009). Other studies have looked at its utility characterizing portal vein thrombosis as malignant or benign. This differentiation is critical as it has major implications for those

modality for diagnosing and characterizing hepatocellular carcinoma.

**4.1.3 Contrast enhanced ultrasound (CEUS)** 

characterize these small lesions.

**4.1.2 Magnetic resonance (MR)** 

Extrahepatic metastasis is not common in early stage hepatocellular carcinoma (Si, 2003). Nevertheless, physicians working at transplant centers fear to miss its presence in a liver cancer patient who is potentially going to be listed for liver transplantation. The United Network for Organ Sharing (UNOS) implemented a policy in which all centers need to include a chest CT to their protocol to evaluate for lung and lymph node metastasis of hepatoma patients being considered for transplantation (United Network for Organ Sharing [UNOS], 2010). Bone is the other preferred site of spread, and although UNOS had included bones scans in the policies implemented in the 1990s, in light recent evidence provided by several studies, this decision was amended in their most recent liver allocation statements. The significant number of false positive or indeterminate results obtained with this modality is a major disadvantage, as well as the costs incurred for a study that has little impact in the selection of patients given its negligible true-positive yield (Koneru, 2005; Sheth, 2005).

The role of positron emission tomography (PET) has also been studied in patients with hepatocellular carcinoma. In general, the sensitivity of this modality for detection of hepatoma that is less than 5 centimeters in diameter has been low (Trojan, 1999; Wolfort, 2010). PET may have some utility identifying extrahepatic metastasis, but the data available is not strong and sufficient enough to widely recommend this practice (Yoon et al., 2007).

### **4.2 Biopsy**

The use of liver biopsies in the setting of hepatocellular carcinoma is controversial. The radiological advances that have taken place over the past decade have markedly improved detection and characterization of this malignancy, thus reducing the need for liver biopsies to confirm the diagnosis. The United Network for Organ Sharing has stated in its liver allocation policy that biopsy is not mandatory in cirrhotic liver transplant candidates with hepatoma as long as the lesion meets imaging criteria (UNOS, 2010). As a result, liver biopsies are now reserved to situations in which the lesion's radiographic studies are not showing the typical features of enhancement in arterial phase and washout in portal venous phase. This rule applies to tumors greater than 2 centimeters in diameter lacking classic features in one imaging modality, and to lesions between 1 and 2 centimeters in diameter with atypical radiographic characteristics in two different imaging modalities (Bruix & Sherman, 2010).

Pathologic staging of hepatocellular carcinoma is established the majority of the time after surgery (resection or transplantation), whereas clinical staging predominantly relies on imaging studies and is done before the treatment is decided. Some groups advocate obtaining a pretransplant liver biopsy to exclude candidates with poorly differentiated tumors and to identify patients that might need more aggressive bridging therapy. Dubay and colleagues evaluated this and found that in patients exceeding Milan criteria (single tumor not greater than 5 centimeters in diameter or up to 3 tumors none larger than 3 centimeters in diameter) there was a significant increase in overall 5-year survival (61% versus 79%, p=0.03) after the introduction of pretransplant liver biopsies and the use of aggressive bridging therapies (Dubay, 2011). The authors of this study conclude that tumor differentiation might be a more important predictor of biologic behavior than other factors such as size, total tumor diameter, multifocality, and microvascular invasion.

Performing liver biopsies in any patient population carries risks that although small, are not negligible. While pain is the most common complication, bleeding is the most feared and important complication. Severe bleeding events requiring hospitalization and other interventions occur anywhere from 1 in 2,500 to 1 in 10,000 in patients with diffuse, nonfocal liver disease (Rockey, 2009). However, the bleeding risk may be higher in cirrhotic patients, who usually have some degree of coagulopathy and thrombocytopenia. Similar increased risk could be expected in cirrhotic individuals in whom a highly vascular lesion such as hepatocellular carcinoma is being percutaneously biopsied (Huang, 1996). Tumor seeding along the needle track after biopsy has also been reported as a complication in this population (Dubay, 2011; Huang, 1996; Schotman, 1999; Sood, 2002). A recent systematic review and meta-analysis showed that the overall incidence of needle track tumor seeding is 2.7%, or 0.9% per year (M.A. Silva, 2008). These statistics are probably not too high because biopsy of primary hepatic cancer is not a common practice nowadays. However, the risks and benefits of biopsying a liver lesion must always be carefully weighed. This procedure should be reserved to instances when there is reasonable doubt about the diagnosis of hepatoma.
