**8. Outcomes of liver transplantation for HCC**

The outcomes of Liver Transplantation for HCC have improved dramatically due to the introduction of tumor size criteria. In the 1990's, inferior outcomes after transplant were experienced due to recurrence of HCC leading to patient death. An influential observation was made by the Milan group in 1996 and resulted in the *Milan criteria* (Mazzaferro, 1996).This study showed that patients with pretransplant radiological evidence of 2 to 3 tumors ≤ 3 cm in diameter or a single tumor ≤ 5 cm in diameter had a 4 year recurrence free survival of 92% when the explant confirmed the presence of these criteria. The United Network for Organ Sharing in the United States adopted the Milan criteria for transplantation and many publications have confirmed the validity of restricting the tumor size and number. Increasing the number and/or size of transplantable tumors has raised the concern of transplanting a higher incidence of tumors with microvascular invasion, microsatellitosis and poor differentiation (Table 3). In 2001, The UCSF reported outcomes for 70 consecutive patients transplanted at their center and followed for 12 years (Yao et al, 2001). They identified poor survival in patients with pT4 tumors, total tumor diameter ≥ 8 cm, age > 55 years, poorly differentiated histological grade and an - fetoprotein level > 1000 ng/ml. The survival rates after liver transplantation of patients meeting *the UCSF criteria* (solitary tumor < 6.5 cm, or < 3 nodules with the largest lesion < 4.5 cm and total tumor diameter < 8 cm) on pretransplant imaging was 90% and 75.2%, at 1 and 5 years, respectively. There has been some criticism to the original Milan criteria due to its restrictive nature and for disallowing other potential candidates with HCC who may benefit from transplant. In addition to the UCSF report, another study has demonstrated reasonable outcomes after liver transplantation for HCC. The Metroticket Study group has described the *Up-to Seven criteria*: seven is the result of the sum of size (in cm) and number of tumors for any given HCC (Mazzaferro, 2009). This complex statistical analysis demonstrated that patients who fulfilled the up-to seven criteria but had no microvascular invasion, achieved overall 5-year survivals of 71%. At the present time, the expected survival of Liver Transplantation for HCC at 5 years is 70% and most current allocation systems work under this goal (which equals transplantation for non HCC indications). The future may bring less restrictive allocation rules, as long as the long term benefit is not inferior to the current standards and as long as patients awaiting transplantation for other indications are not disadvantaged.

> Macro and Microvascular invasion Poor differentiation Microsatellitosis - fetoprotein level > 1000 ng/ml Tumors exceeding standard criteria (Milan, UCSF, Up-to-seven)

Table 3. Poor prognostic factors in Transplantation for HCC

#### **9. Future therapies and challenges**

Primary prevention and detection via sophisticated imaging studies, such as MRI and CT, are imperative for the elimination and minimization of HCC. Further research is also necessary in regards to bridging therapy. The development of molecular signatures which predict the natural behavior of HCCs is being explored, and this includes gene arrays which have already shown some promise. We can predict somewhat more accurately now than ever the propensity of tumors to metastasize and recur after transplant with certain markers such as micro vascular invasion or microsatellitosis on the explant speciments. The grade of HCCs, as characterized by an experienced pathologist on biopsy or explant, has gained importance over the years in prognosticating the natural history of the cancer and its risk of recurrence after resection or transplant. Immunohistochemical markers are being constantly developed- and some have already been tested– regarding the presence of positive CK7 and CK 17 staining in HCCs, which portends a more aggressive cancer with higher recurrence rates. The use of systemic chemotherapy in the form of multikinase inhibitors such as sorafenib in combination with ablative procedures such as TACE, RFA or radioembolization has been used with success and is likely to gain momentum in the future. Furthermore, systemic chemotherapy is more frequently employed after surgery or even after transplantation in patients with high risk tumors. An important consideration for bridging therapy is that it is difficult to completely eradicate tumors >3 cm in size or multifocal HCC, and this area especially merits further exploration. Finally, in the era of organ shortage, alternative curative modalities to transplant are certainly a need of the hour. With advances in laparoscopic surgical techniques, use of portal vein embolization, and adequate and aggressive ablative techniques pre-operatively, more patients than in the previous years can be made suitable for surgical resection safely and effectively. On the vanguard of medicine is the phenomenon of stem cell research and a discussion on HCC is incomplete without its mention- like other solid tumors- it is believed though not completely elucidated that cancer stem cells may have an important role to play in the natural history and response to treatment of HCCs. Although these stem cells in the liver have not been accurately identified, there is intensive investigation in this area (Wen Xu, 2009). The further development of these stem cells has boundless potential in the prognostication and treatment of this cancer.

### **10. References**

294 Liver Transplantation – Basic Issues

cm, age > 55 years, poorly differentiated histological grade and an - fetoprotein level > 1000 ng/ml. The survival rates after liver transplantation of patients meeting *the UCSF criteria* (solitary tumor < 6.5 cm, or < 3 nodules with the largest lesion < 4.5 cm and total tumor diameter < 8 cm) on pretransplant imaging was 90% and 75.2%, at 1 and 5 years, respectively. There has been some criticism to the original Milan criteria due to its restrictive nature and for disallowing other potential candidates with HCC who may benefit from transplant. In addition to the UCSF report, another study has demonstrated reasonable outcomes after liver transplantation for HCC. The Metroticket Study group has described the *Up-to Seven criteria*: seven is the result of the sum of size (in cm) and number of tumors for any given HCC (Mazzaferro, 2009). This complex statistical analysis demonstrated that patients who fulfilled the up-to seven criteria but had no microvascular invasion, achieved overall 5-year survivals of 71%. At the present time, the expected survival of Liver Transplantation for HCC at 5 years is 70% and most current allocation systems work under this goal (which equals transplantation for non HCC indications). The future may bring less restrictive allocation rules, as long as the long term benefit is not inferior to the current standards and as long as patients awaiting transplantation for other indications are not

Tumors exceeding standard criteria (Milan, UCSF, Up-to-seven)

Primary prevention and detection via sophisticated imaging studies, such as MRI and CT, are imperative for the elimination and minimization of HCC. Further research is also necessary in regards to bridging therapy. The development of molecular signatures which predict the natural behavior of HCCs is being explored, and this includes gene arrays which have already shown some promise. We can predict somewhat more accurately now than ever the propensity of tumors to metastasize and recur after transplant with certain markers such as micro vascular invasion or microsatellitosis on the explant speciments. The grade of HCCs, as characterized by an experienced pathologist on biopsy or explant, has gained importance over the years in prognosticating the natural history of the cancer and its risk of recurrence after resection or transplant. Immunohistochemical markers are being constantly developed- and some have already been tested– regarding the presence of positive CK7 and CK 17 staining in HCCs, which portends a more aggressive cancer with higher recurrence rates. The use of systemic chemotherapy in the form of multikinase inhibitors such as sorafenib in combination with ablative procedures such as TACE, RFA or radioembolization has been used with success and is likely to gain momentum in the future. Furthermore, systemic chemotherapy is more frequently employed after surgery or even after transplantation in patients with high risk tumors. An important consideration for bridging therapy is that it is difficult to completely eradicate tumors >3 cm in size or multifocal HCC, and this area especially merits further exploration. Finally, in the era of organ shortage,

disadvantaged.

Macro and Microvascular invasion


Table 3. Poor prognostic factors in Transplantation for HCC

Poor differentiation Microsatellitosis

**9. Future therapies and challenges** 


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