Department of Visceral and Transplantation Surgery Hannover Medical School, Germany
Long Term Survival Analysis of Liver Transplantation For Hepatocellular Carcinoma (HCC)
A Single- Center Experience
Thesis for the Degree of Medical Doctor Medical School, Hannover
Submitted by Zeming ZHAO From shanghai
P.R. China, 2007
Angenommen vom Senat der Medizinischen Hochschule Hannover Am 27.09.2007
Gedruckt mit Genehmigung der Medizinischen Hochschule Hannover Präsident: Prof. Dr. Dieter Bitter-Suermann
Betreuer: Prof. Dr. Jürgen Klempnauer Co-Betreuer: PD. Dr.Thomas Becker
Referent: PD. Dr. Hans-Heinrich Wedemeyer Korreferent: Prof.Dr.Ludwig Wilkens
Tag der mündlichen Prüfung:27.09.2007 Promotionsausschussmitglieder:
Prof. Dr. Michael Peter Manns Prof. Dr. Arnold Ganser Prof. Dr. Marion Haubitz
CONTENTS
ⅠTHESIS page
Abbreviation 4
1 Introduction……… 5
Hepatocellular carcinoma (HCC)……… 5
Epidemiology……….. 5
Risk factor for HCC……….…… 7
Treatment Strategy for HCC: Liver resection and Liver transplantation……….……..…………. 9
Other Treatments for HCC……….….. 11
Target Therapy: Sorafenib in the Treatment of HCC……….. 12
Current Problem of LT in HCC………... 12
LT in Germany, LT at MHH 2006………. 14
Preoperative Evaluation of liver Function……….. 16
2 Aims……….……… 19
3 Patients and Methods………. 20
4 Results………. 23
5 Review………. 36
6 Discussion……… 38
HCC………. 38
Prognosis of LT for HCC, HCC recurrence……….…… 39
Selection criteria (Milan criteria, UCSF criteria)……… 40
Preoperation treatment Neoadjuvant Therapy……….… 42
Priority Policy……….…….……… 43
CDLT and LDLT……….……… 45
Biological Tumor Marker of HCC……….. 46
Specific Immunosuppressive Agent: Sirolimus………... 47
7 Summary……….……… 48
References………... 51
ⅡAPPENDIX
Declaration……… 57Curriculum vitae………... 58
Acknowledgements……… 59
Abbreviations
HCC Hepatocellular Carcinoma
LT Liver Transplantation
CDLT Cadaveric Donor Liver Transplantation LDLT Living Donor Liver Transplantation UCSF University of California San Francisco
AFP Alpha-Feto Protein
Child classification Child-Turcotte-Pugh classification
RA Radiofrequency Ablation
TACE Transarterial Chemoembolization PEI Percutaneous Ethanol Injection
HBV Hepatitis B Virus
HCV Hepatitis C Virus
UNOS The United Network of Organ Sharing
CTP Child-Turcotte-Pugh
ICG Indocyanine Green
ICG15 ICG retention rate at 15 minutes OLT Orthotopic Liver Transplantation
MHH Medizinische Hochschule Hannover (Germany)
YSR Year Survival Rate
MELD The Model for End-stage Liver Disease
TLC Tender -Loving Care
1. INTRODUCTION
Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. With more than 1,000,000 patients diagnosed each year.1, 2 it is the fifth most common cancer worldwide3, and its incidence will increase further in the next two decades in both Europe and the United States.4, 5 This is a result of the spread of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection during the past century.4, 5 HCC now constitutes the leading cause of death in cirrhotic individuals.6
Epidemiology
The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in Non-Western Countries (regions such as central Asia, especially china;
sub-Saharan Africa, Southeast Asia). HCC is the most common cancer, generally affecting men more than women. This variability is in part due to the different patterns of Hepatitis B transmission in different populations - infection at or around birth .The period of time between hepatitis B infection and development into HCC can be years even decades, whereas the average time from the diagnosis of HCC to death is only 5.9 months, according to one Chinese study during the 1970-80s, or 3 months (median survival time) in Sub-Saharan Africa according to Manson's textbook of tropical diseases.
HCC is one of the deadliest cancers in China. Food infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxin, poses another risk factor for HCC. In developed western countries, HCC is generally seen as rare cancer, normally occurring of those with pre-existing liver disease and HCV Infection. HCC appears to be rising dramatically in incidence too. With new therapies being available for the treatment of small HCC, there is a growing emphasis on recognition of risk factors and early diagnosis.
The world age-adjusted incidence of HCC has been calculated to be 14.67 per 100,000 populations for men and 4.92 for women.7 The lowest rates are found in developed countries
(7.64 for men, 2.65 for women), and the highest rates are in developing countries (17.84 for men, 6.17 for women). (Table1).
Table1.Hepatocellular carcinoma (HCC) incidence in different regions per (100,000 populations)7
Different regions Men Women
In developing countries 17.84 6.17
In developed countries 7.64 2.65
SUM 14.67 4.92 When viewed as estimated age-adjusted incidence rates of liver cancer per 100 000 men (Table 2), in all regions, the rates recorded were two to three times higher in men than in women. The lethality of this cancer is evident by the fact that, in the above databases, mortality from HCC was virtually equivalent to the incidence figures in the same year.
Table 2 Estimated age-adjusted incidence rates of hepatocellular carcinoma in men per 100 000 population worldwide, 20003
Geographic area Region Rate/100 000
Asia Eastern South-Eastern
Western
35.5 18.3 5.6 Africa Middle
Eastern Western Southern Northern
24.2 14.4 13.5 6.2 4.9 Europe Southern
Eastern/western Northern
9.8 5.8 2.6
South America 4.8
North America 4.1
Australia/New Zealand 3.6
Central America 2.1
The most recent worldwide data on HCC come from the World Health Report, 2003 of the World Health Organization (WHO) that provides estimates of death by cause and sex in WHO regions for the year 2002 8. The estimated burden of disease by cause indicated that there was a total of 714 600 new cases of HCC (71 percent among men). Liver cancer ranked fourth in mortality due to cancer, after cancers of the trachea/bronchus/lung, stomach, and colon/rectum.
For male subjects, liver cancer ranked third; whereas for women, it ranked fifth.
Risk Factors for HCC
HCC is unusual among cancers because the specific causative factor can be identified in most patients. Common risk factors include chronic viral hepatitis and underlying liver disease in the form of cirrhosis (Table3).
Table3. Risk Factors for HCC Infectious Chronic hepatitis C
Chronic hepatitis B Chronic delta hepatitis Metabolic diseases Hereditary hemochromatosis
α -1-antitrypsin deficiency Porphyria cutanea tarda Hereditary tyrosinemia
Toxins Alcohol
Aflatoxin B1
Hormones Anabolic steroids
Estrogens
Underlying liver disease Cirrhosis of any cause
Chronic infection with the HBV appears to account for most cases of HCC in high-incidence areas such as eastern Asia9 (excluding Japan) and sub-Saharan Africa, whereas chronic infection with the hepatitis C virus (HCV) is the underlying cause in at least two-thirds of cases in areas of intermediate incidence such as southern Europe and Japan10, 11.
The precise mechanism by which chronic viral hepatitis results in HCC is not known. HBV has a DNA genome that can become integrated within the genome of infected cells. These integration events may lead to the development of cancer, but there appears to be no unifying mechanisms of hepatocarcinogenesis12. In contrast, HCV has an RNA genome that does not become integrated with host chromosomes, and it is thought that HCV infection leads to HCC through chronic inflammation and regeneration in the presence of cirrhosis. It is likely that similar mechanisms are involved in HBV-related carcinogenesis.
Some chemical and hormonal factors may play a role in the development of HCC. Specifically, aflatoxin exposure may add to the effect of HBV infection and lead to HCC. Aflatoxin is a mycotoxin produced by molds that may contaminate stored foodstuffs and, therefore, present in the diet in some parts of the world. There is some suggestion that androgenic steroids (in men) and estrogenic steroids (in women) increase the risk of HCC. Smoking is thought to play a minor role in hepatocarcinogenesis. Chronic viral hepatitis B or C, however, overshadows all of these risk factors.
Originally Hepatocellular carcinoma (HCC) was identified as a sequel to alcoholic cirrhosis, hemochromatosis, some metabolic disorders, certain types of drug injury (such as from oral contraceptives), or exposure to environmental toxins (such as aflatoxin), the cause of the bulk of cases remained obscure for many years, although linked in most instances to cirrhosis of unknown origin. This uncertainty remained until the discovery of the hepatitis B virus (HBV) in the mid 1960s 13, and its subsequent association with HCC 14, and about 20 years later the recognition of the hepatitis C virus (HCV)15 with the subsequent evidence that it was also linked to HCC16. Thus, it became clear that the vast majority of cases of HCC were in fact a consequence of infection by one of these two viruses.
More recently, it has become apparent that obesity, with its accompanying problems of diabetes
mellitus and nonalcoholic steato hepatitis (NASH), represents a growing addition to the causes of HCC17-19.
Furthermore, evidence is accumulating that both diabetes and chronic alcoholism behave synergistically with HBV and HCV infections in the induction of HCC 20. Indeed, even past heavy alcoholism can contribute to liver disease progression in persons chronically infected with hepatitis C and can hence increase the risk of developing HCC 21.
Treatment Strategy for HCC:
Liver Resection and Liver TransplantationTreatment options of HCC and prognosis are dependent on many factors but especially on tumor size and staging. Because the vast majority of cases occur in patients with underlying liver disease, curative resection is possible in the minority. For example, even with the screening of hepatitis B surface antigen positive (HBsAg +) patients and an aggressive surgical approach, only 40% of patients in Shanghai are surgical candidates and long-term (10 years) survival rate is less than 15%22. Furthermore, the five-year survival rate of recurrence-free survival after the resection of single, small (<5cm) hepatocellular carcinomas is practically zero23.
The first human liver transplants (LT) were performed in patients with extremely large hepatic tumors.24 The role of LT in the management of HCC has evolved over three different periods.
During the 1980s, the value of orthotopic liver transplantation (OLT) in the treatment of hepatocellular carcinoma has often been debated. Although liver replacement could be curative for patients with tumors confined to the liver, the long-term results of liver transplantation in patients with hepatocellular carcinoma have been disappointing, with an overall five-year survival rate ranging from 30 to 40 percent25-32 and results from these early cases were poor.33 In the 1980s the outcomes (recurrence rate of 32-54% and 5-year survival below 40%) reflected the original acceptance of exceedingly advanced tumors with adverse prognostic factors such as macroscopic vascular invasion, lymph node involvement, and extrahepatic spread34, 35 These poor outcomes led to questioning of HCC as a transplant indication in some programs and to discarding a very aggressive and expensive treatment in patients with limited hope for long-term survival. In the past, it was tempting to conclude that liver transplantation for hepatocellular
carcinoma was futile29, 36.
The problem that optimal treatment for patients with cirrhosis who have single hepatocellular carcinomas no more than 5 cm in diameter— resection or transplantation — may become a subject of debate.
The second era started during the early 1990s.Retrospective analysis has shown that patients with cirrhosis who have stage T1 or T2 tumors (according to UICC TNM classification) do better after transplantation (five-year survival, 67-75 percent) than after hepatic resection (0-56 percent)34, 35.
Analysis of the previous experience suggested that patients with incidental tumors had the same outcome as patients with nonmalignant disease25. Following this concept, some pioneering groups selecting ‘‘optimal candidates’’ reported 70% 5-year survival with a recurrence rate below 15%37-40. This was championed by Bismuth et al41 and by Mazzaferro et al,38 who established in a landmark manuscript the so-called Milan criteria.
Mazzaferro et al.38 reported excellent 3-year survival rates for patients with a single HCC lesion
<5 cm in size or 3 or fewer lesions with the largest measuring <3 cm. These so-called Milan criteria have been accepted worldwide as identifying candidates with good prognoses and low recurrence rates. However, as documented in this study, long-term survival can be achieved with liver transplantation in carefully selected patients. During this period, transplantation was considered in most centers as the first-line option for early HCC.
Subsequently, Yao et al.42 reported that liver transplant candidates were with single tumors <6.5 cm in diameter, or <3 tumors with the largest being <4.5 cm in diameter and a total tumor burden of <8 cm (so-called UCSF criteria). (Table4).
Table 4. Milan and UCSF Staging Criteria for Hepatocellular Carcinoma
Staging Single tumor Multiple tumors
Maximum diameter Maximum
Number
Largest tumor
Size
Total tumor
Size
Milan ≦5.0 cm 3 ≦3.0 cm NA
UCSF ≦6.5 cm 3 ≦4.5 cm ≦8.0 cm
Abbreviation: NA, not available; UCSF, University of California at San Francisco.
The United Network of Organ Sharing (UNOS)43 has adopted the criteria proposed by the group from Milan, Italy, solitary tumor <5 cm, or three or fewer lesions none >3 cm (the Milan criteria38)—as selection guidelines for OLT.
Other Treatments for HCC
At detection or over time, hepatocellular carcinoma (HCC) is multicentric in origin, against a background of chronic hepatic disease at different stages. Orthotopic liver transplantation (OLT) is the only therapy able to definitely cure both diseases. When OLT is not feasible, all other options can be only palliative44.
Transarterial chemoembolization (TACE), Radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) were the first regional and local ablative techniques that came into use for irresectable HCC. The selection of an appropriate treatment strategy for patients with HCC depends on careful tumor staging and assessment of the underlying liver disease. RFA and PEI are now considered as the local ablative techniques of choice for the treatment of, preferably small, HCC. When tumors are located close to bile ducts or large vessels, PEI remains a valuable therapy45. For larger tumors, their association with other techniques, such as TACE, seems
adequate46.
Local ablative therapies such as PEI, RFA, and TACE offer palliation for patients for whom
surgical approaches are contraindicated. Percutaneous alcohol injection and RFA are minimally invasive and can be used on an outpatient basis, usually for tumor nodules smaller
than 3 cm. When these therapies are used for small tumors, the survival rates can be similar to those achieved by partial hepatectomy. TACE may be used as an interim treatment for patients waiting for OLT. Although TACE is often used for the palliation of large tumors, significant survival benefits have not yet been demonstrated for this indication47. In carefully selected patients, The combination of limited TACE with PEI or RFA may lead to improved survival and decreased risk of liver failure48.
Target Therapy: Sorafenib in the Treatment of HCC
Improvements in our understanding of the molecular basis of cancer have led to the clinical development of protein kinase inhibitors, which target pivotal molecules involved in intracellular signaling pathways implicated in tumorigenesis and progression49.
Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib is the first oral multi-kinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. Liu L, et al proved that the antitumor activity of sorafenib in HCC models might be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival50.
Abou-Alfa GK, et al reported that although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents Target therapy sorafenib in the treatment of HCC.
Current Problem of LT in HCC
After 20 years, despite the fact that transplantation has changed the treatment strategy for HCC,
some of the greatest challenges still remain.
1. Liver transplantation is the main option for patients with early HCC who are not optimal candidates for surgical resection.
2. Shortage of donors is its main limitation, as waiting for a liver allows the tumor to progress and induce exclusion from the waiting list and death.
3. The absence of randomized controlled trials hinders the establishment of the most effective therapy to prevent tumor progression while waiting.
4. Live donation may be a cost-effective approach if optimal results are expected and the mortality risk for the donor is kept low.
5. Priority policies have to be developed and refined to provide a fair and effective distribution of cadaveric organs.51
LT in Germany, LT at MHH 2006
Figure 1. Liver transplantation 2006, Germany (971 CDLT and 82 LDLTwere performed at 23 centers in 2006, Germany)52
151 144 91
86 84 61
Hannover Berlin/Charite Essen Hamburg Heidelberg Mainz Regensburg Leipzig Tubingen Jena Münster Kiel Frankfurt München/Großhadern Bonn München/r.d.isar Göttingen Erlangen-Nürnberg Magdeburg Rostock Homburg/Saar Köln Würzburg
Table5. Indication of liver transplantation in 2005,Germany
Cryptogenic cirrhosis 537
Posthepatitische cirrhosis 237
Other liver disease 169
Hepatocellular carcinoma 119
Acute liver failure 87
Sclerosis cholangitis 77
Primary biliary cirrhosis 43
Autoimmuncirrhosis 34
Bile duct atresia 30
Metabolic disease 27
Budd-Chiari-Syndrom 15
Secondary biliary cirrhosis 10
Bile duct carcinoma 6
Other malignant liver disease 4
Benign liver mass 3
liver metastasis 2
Obstructive bile duct disease 1 Acute or sub acute hepatitis 0 Congenital bile duct disease 0
Gallbladder carcinoma 0
Polycystic liver disease 0
SUM 1401
Figure2. 119 cases of LT with HCC accounted for 8% all Liver transplantations 2005 in Germany,
119
537 237
169
From 1975 to 2006, 2344 liver transplantations were performed at Hannover Medical School, included Cadeveric Liver Transplantation (CDLT), Living Donor Liver Transplantation (LDLT), split liver transplantation and domino liver transplantation. Of them, split liver transplantation, which was first successfully performed by Hannover Medical School in 1988, has become a mature surgical technique to expand the donor pool.53
Figure 3. 2344 liver transplantations we performed at Hannover Medical School.
Preoperative Evaluation of Liver Function
Worldwide, preoperative liver function is generally evaluated by the Child-Pugh classification,
1975-2005.11 LT at MHH ( n=2176)
1 2 3 1 7 8 25 31 30 38 46 83 65 92 104 98 102 66 94 102 91 93 98 90 94 121 106 99 129 137 137 151
0 20 40 60 80 100 120 140 160
1975.1.1- 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005
1975-2006 LT at MHH (n=2344)
re
(Table 6), which was originally designed for predicting the prognosis of patients with portal hypertension undergoing shunting operations.
Table 6. Child–Pugh System for Grading the Severity of Liver Disease. *
VARIABLE POINTS SCORED
None 1
1–2 2
3–4 3
Absent 1 Slight 2
1.0–2.0 1
2.1–3.0 2
3.1 3 umin
>35 1
8–35 2
<28 3 Encephalopathy
Ascites
Moderate 3 Serum bilirubin (mg/dl) †
Serum alb (g/liter)
2
Prolongation of prothrombin
Time (sec)
1–3 1
4–10 2
>10 3
*Child–Pugh class A (a total of 5 to 6 points) indicates good hepatic function; class B (7 to 9 points),
87
The MELD score replaces the Child-Turcotte-Pugh (CTP) score as a disease severity index54, 55. sur
MELD score is calculated using a relatively simple formula that relies on three readily available
• Serum creatinine (Scr; mg/dL)
• Total bilirubin (Tbil; mg/dL)
• INR (international normalized ratio) The Formula & the Calculator:
MELD Score = 10 [0.957 Ln(Scr) + 0.378 Ln(Tbil) + 1.12 Ln(INR) + 0.643]
However, the amount of hepatic parenchyma that can be resected safely by MELD score and
s
Moderate hepatic function; and class C (10 to 12 points), poor hepatic function.
†To convert values for bilirubin to micromoles per liter, multiply by 17.1.
This change is designed to improve the organ allocation system in liver transplantation to en e that available organs are directed to transplant candidates based on the severity of their liver disease rather than the length of time they have been on the waiting list56. These efforts have been prompted by the so-called "final rule" issued in 1998 by the US Department of Health and Human Services55. This rule states that organs should be allocated to appropriate transplant candidates based on medical urgency.
objective variables:
CTP cannot be determined. Instead, in Japan indocyanine green (ICG) clearance has been used to assess liver dynamic function. Makuuchi M et al,57 established the criteria for decision making for surgical treatment based on three parameter : the presence or absence of ascites, total bilirubin level, and the ICG retention rate at 15 minutes (ICG15). Operability is assessed by the former two parameters and the maximum resectable liver volume is restricted by the last:
patients with ICG15 less than 10%, 10– 20%, 20– 30%, and more than 30% are subjected to hepatectomy extended to tri- or bi-sectoriectomy, one sectori ectomy, one segmentectomy, and limited resection,respectively. 37
33
2. AIMS
The role of orthotopic liver transplantation (OLT) in the treatment of patients with hepatocellular carcinoma (HCC) and cirrhosis is well established, but there is still a debate regarding accepted criteria, and specific data regarding long-term survival (10 years) are rarely available.
To evaluate treatment of hepatocelular carcinoma (HCC) and the selection of recipients, we evaluated the outcome of consecutive patients with HCC and cirrhosis who underwent OLT over a 12-year period at Hannover medical school.
The primary aim of our study was to further analyse the impact of traditional TNM and pathologic tumor stage on survival rate and tumor recurrence-free survival rate after OLT in patients with HCC, and to re-evaluate selection criteria (Milan criteria and UCSF criteria) regarding the upper limits of size and number of tumor nodules upon which an appropriate selection policy can be based for OLT of HCC.
Current selection criteria of liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) were derived from the outcomes of cadaveric donor LT (CDLT). To evaluate the efficacity of living donor liver transplantation
(LDLT) to overcome organ shortage particularly with respect to the tumor growth
during the waiting time, we tried to expand the applicability of such criteria to
living donor LT (LDLT). The principal aims of this thesis were to define thelimitations of current transplant criteria for HCC, and to identify potential areas for
improvement.
3. PATIENTS AND METHODS
Between November 1, 1993 and May 21, 2006, 119 cases of Liver Transplantation for adult patients with HCC were carried out at Hannover Medical School, 2 patients were lost for follow-up; This case number accounted for more than 8% unicenter of LTs during the study period. In 117 adult patients HCC was diagnosed preoperatively or found incidentally in the explanted livers. Information regarding the survival status of all patients could be obtained from LTX document center and ALIDA, AMIS software information center. The inquired items included profiles of the recipients (age, sex, cause of liver cirrhosis, viral hepatitis B, viral hepatitis C, serum alpha-fetoprotein, Child-Turcotte-Pugh classification, serum bilirubin, creatinine, INR, MELD score, donor and LT operation (CDLT, LDLT, and graft type), primary HCC lesion (timing of diagnosis, pretransplant treatment, Tumor size, number, micro vascular invasion, invasion [hepatic vein and portal vein], tumor distribution, and histological differentiation), tumor recurrence (timing, site, alpha-fetoprotein, and treatment), and patient survival (perioperative mortality, causes of death, and survival period).
The mean age of the 117 adult recipients was 53.3±9.49 years (range, 19-69) and 96 were male (82.05%). Viral infection was associated with liver cirrhosis in 74 (63.24%) patients (hepatitis B, n = 28 [23.9%]; hepatitis C, n =37[31.6%]; both hepatitis B and C, n=9 [7.7%]). Non-viral cause was alcoholism and others (n=39 [33.3%]). Without liver cirrhosis (n=4 [3.4%])
4 patients were incidentally diagnosed as HCC after detection of HCC lesions at the explanted livers. 113 patients had been preoperatively diagnosed with HCC. 28(23.9%) did not receive any specific treatment for HCC before OLT, primarily because they had incidental HCC and because of poor liver function or organ available before scheduled anticancer therapy. Treatment was directed at the hepatic lobe involved by one or more tumor nodules. If the lesions involved both the right and left hepatic lobes, chemoembolization of the entire liver was performed. Another 89 patients underwent PEI (percutaneous ethanol injection) (n =34 [29.1%]), TACE (transarterial chemoembolization) (n=37 [31.6%]), PEI and TACE (n =13 [11.1%]), systemic chemotherapy (n
= 5 [4.3%]).
TNM pathologic staging of 108 patients could be obtained. The tumor extents of HCC lesions were classified as T1 (n = 31 [28.7%]), T2 (n =31 [28.7%]), T3 (n =35 [32.4%] and T4 (n = 11[10.2%])) (according to the pathologic staging system American Joint Committee on Cancer /International Union Against Cancer).
In the TNM system,
T1 a single tumor ≤2 cm in diameter without vascular invasion;
T2 a single tumor ≤2 cm with vascular invasion,
a single tumor >2 cm without vascular invasion, or multiple single-lobed tumors ≤2 cm without vascular invasion;
T3 a single tumor >2 cm with vascular invasion, multiple single-lobed tumors >2 cm without vascular invasion, or multiple single-lobed tumors of any size with vascular invasion;
T4 indicates multiple two-lobed tumors of any size, with or without vascular invasion..
In the explanted livers with HCC, the diameter of single or largest lesion was 3.83±2.79cm (range, 0.5– 20 cm). The distribution of nodules number and single or largest lesion size of HCC lesions was drawn in Figure 11.
Mean waiting time for transplantation was 218days,range(2-1007days). 103 patients received cadaveric liver grafts (whole liver, n = 97; split right trisegment, n = 6) and 14 patients received living donor grafts (domino LTX 2; left lobe, right lobe, n= 12). There were 7 (6%) cases of retransplantation due to primary no function of the first graft.
The degree of liver cirrhosis and extent of HCC lesions were routinely investigated before LDLT or CDLT operation. The primary reason for LT in HCC patients with liver cirrhosis of Child-Turcotte-Pugh class C was treatment of the liver cirrhosis and tumor resection; for patients with Child-Turcotte-Pugh class A, the primary reason was treatment of the unresectable or refractory HCC lesion.
Alpha-fetoprotein (AFP) levels obtained within 3 months before OLT were available in 83 of 117patients. The AFP level ranged from 1.0 to 214975 ng /mL,with a median level of 42 ng/mL.
Twenty-six of 117 (22.2%) patients had normal AFP levels (<10 ng/mL).
The explanted liver was examined by an experienced histopathologist. The removed livers at the time of total hepatectomy were fixed in formalin and were cut into slices. The number of tumors,
diameter, maximal tumor diameter, anatomical location, and microscopical appearance of each tumor were recorded (T stage), as well as micro vascular invasion. The total tumor diameter for patients with multiple tumor nodules was calculated as the sum of the maximal diameter of each lesion in centimeters. Histological grade based on the modified Edmondson criteria for the degree of tumor differentiation (grade 1: well-differentiated; grade 2: moderately differentiated;
grade 3: poorly differentiated), The individual HCC was retrospectively staged according to the traditional TNM criteria, the Milan criteria,38 and the UCSF criteria.42
The lymph nodes of the hepatic hilum were removed and studied separately for possible tumor spread (N stage). An autopsy was always performed in patients who died after transplantation, and the possible recurrence of cancer was investigated.
Peri-operative mortality was defined as death before hospital discharge and included in Statistical analysis of patient survival. Mean values with standard deviation and median values with ranges were used for numeric data.
LT was performed whenever a compatible liver became available, regardless of any scheduled anticancer therapy. After transplantation neither medical therapy nor radiation treatment was given unless recurrence of the cancer was detected. In addition to regular post-transplantation follow-up, all patients were checked every three months (by ultrasonography, chest radiography, and measurement of serum alpha-fetoprotein); abdominal and thoracic computed tomography (CT) scans were obtained regularly.
The relationship between each of the clinicopathologic variables and survival was assessed by the Kaplan-Meier method and compared with log-rank test (SPSS 13.0 software, Inc, Chicago, IL). Patient death (include Perioperative death) unrelated to HCC recurrence was regarded as censored case during the statistical analysis of HCC recurrence-free survival. The Fishers exact test was used in the analysis, and two-sided P values were reported. Differences of P< 0.05 were considered to be statistically significant.
4. RESULTS
Cases of LT with HCC performed in every year at MHH (from 1993.11.1 to 2006.5.21) were drawn in figure 4.
2
7 7 8
6 7
14
6 12
11 7
14 12
6
0 2 4 6 8 10 12 14 16
1993. 11.1- 1994
1995 1996
1997 1998
1999 2000
2001 2002
2003 2004
2005
2006. 1. 1- 5. 21
Figure4. Cases of LTs with HCC performed in every year at MHH (from 1993.11.1 to 2006-5-21).
The overall actuarial one, three, five and ten-year cumulative survival rate was 79 %, 71 %, 62%and 45%, the recurrence-free survival at one, three, five and ten-year was79 %, 73%, 68 % and 49% respectively (Fig.5, 6). After three years, recurrence-free survival became higher than overall survival, because recurrence of cancer was excluded at autopsy in some patients who died or because data were censored earlier in the calculation of recurrence free survival. During first two years and ten years later hazard of LT with HCC was rapidly ascending. (Fig.7)
Figure5. Overall Survival Rate after LT in 117(1993.11.1-2006.5.21) Patients with HCC.
Years/after LT 0 1 2 3 4 5 6 7 8 9 10 Recurrence-free survival 100% 79% 74% 73% 71% 68% 66% 66% 62% 62% 49%
Patients at risk 117 78 57 52 43 37 27 21 15 9 4
Data on the three patients who died within one month after transplantation were included in the calculation of recurrence-free survival.
Figure 6. Recurrence-free Survival after Liver Transplantation in 117 Patients with HCC.
Figure 7. Cumulative hazard curve after Liver Transplantation of 117(1993.11.1-2006.5.21) Patients with HCC.
During the period of 1993.11-1998 and 1999-2006.5.21, 35 and 82 cases of LT for Adult patients with HCC were carried out respectively; they were shown in Figure 8. The outcome of the
latter was better than the previous, but by Log-Rank test P=0.081, no significance.
Figure 8. Overall Survival after LT of Patients with HCC. N=82(1999-2006.5.21) vs. n=35(1993.11.1-1998) , P=0.081; by Log-Rank test. Solid line indicates the period 1999-2006.5.21.
Figure 9. Cumulative hazard curve after Liver Transplantation in Patients with HCC; N=82(1999-2006.5.21) vs.
n=35(1993.11.1-1998) Solid line indicates the period 1999-2006.5.21.
The influence of several variables on overall survival is shown in Table 7. Survival was not affected by the patient’s age or sex or by common variables of chronic liver disease, such as the
type of hepatitis virus and the MELD score at the time of transplantation. Of particular importance was the fact that, classic prognostic factors such as the number of tumors (single vs.
multi), serum alpha-fetoprotein concentration were not statistically significant predictors of survival.
Table 7. Prognostic Variables Related to Survival after Liver Transplantation in Patients with HCC
Variable Number
of petients
percent P
(by log-rank test)
Demographic
sex 117 0.879
Female male
21 96
17.9%
82.1%
Age 53±9.49(19-69) 117 0.165
≤53 47 40.2%
>53 70 59.8%
Cirrhosis-related 117 0.886
HBV HCV HBV+HCV Alkoholic Other without Cirrhosis
28 37 9 7 32 4
23.9%
31.6%
7.7%
5.9%
27.4%
3.4%
Mel d scor e
>15
10-15
<10
73 18 23 32
24.7%
31.5%
43.8%
0.212
Tumor-related T stage
T1-2 T1 T2 T3-4
T3 T4
108 62
31 31 46
35 11
57.4%
42.6%
0.138
No. of t umor nodul es 1
≥2
Ser um al pha- f et opr ot ei n
≤20 ng/ mL
>20 ng/ mL ≤200 ng/ mL
>200 ng/ mL≤1000 ng/ mL
108 46 62 83 34 25 10
42.6%
57.4%
0.345
0.993
>1000 ng/ mL 14
Mi cr o i nvasi on Wi t h Wi t hout
108 17 91
15.7%
84.3%
0.041
G G1 G2 G3
108 26 61 21
24.1%
56.5%
19.4%
0.434
Selection criteria
Mi l an cr i t er i a Wi t hi n Beyond
108 63 45
58.3%
41.7%
0.033
UCSF cr i t er i a Wi t hi n Beyond
108 73 35
67.6%
32.4%
0.034
Donor t ype CDLT LDLT
117 103 14
88.0%
22.0%
0.911(Fig 17)
Preoperation treatment 117 0.008
with treatment PEI TACE PEI+TACE Chemo without treatment
89 34 37 13 5 28
76.1%
29.1%
31.6%
11.1%
4.3%
23.9%
Table8. Comparison between the two groups: LTs (during1999-2006) vs. the ones (during 1993-1998)
Variable 1993-1998 1999-2006 p
n 35 82
Age 54.65± 8.13(31-66) 52.73± 10.01(19-69) 0.474*
Tumor recurrence 3 7 0.623 Sex
M F
31 4
65 17
0.175
Milan criteria W B
21 12
42 33
0.458
UCSF W B
27 6
46 29
0.036
P TNM
T1-2 21 41
0.535
T3-4 13 33
G G1 G2-3
12 23
14 59
0.086
Micro invasion With Without
4 32
13 59
0.350
*t –test, the others use Crosstab test;M:male;F:female;W:within;B:beyond
In this selected group of patients with HCC, preoperative treatment (PEI, TACE, PEI+TACE, Chemo) proved effective (Fig. 10), even though these treatments were not randomly assigned, but rather were used only if liver function was not seriously impaired. In the 89 pretreated patients (76.1 % of the total) one, three and five -YSR was 83 %, 78%, and 69%. Higher than one, three, five -YSR 67%, 51%, 43% of the 28 patients who received no treatment before transplantation respectively.
The selection of patients (single or largest tumor size and tumor number) was the main factor affecting survival after transplantation, as was confirmed by pathological examination of the explanted livers, which revealed a median of 2 tumor massesper liver (range, 1 to 7) and a diameter of 3.83±2.79cm(range, 0.5– 20 cm).Fig11.
Figure 10. Overall Survival after LT in Patients with preoperative treatments. N=89 vs. without preoperative treatments N =28, P=0.008; by Log-Rank test. Solid line indicates. with preoperative treatments.
Figure 11. Patients’ information was plotted on the graph showing tumor number and the largest size.
The distribution shows at a glance how far the patients were outside traditional Milan criteria.
Since a tumor stage at the time of transplantation was the predictor factor associated with greater rates of recurrence-free survival, we attempted a more exact definition of all cancers (either single or multiple) that could be cured by liver transplantation. Although there were no differences in overall or recurrence-free survival after transplantation between patients who had single tumors and those with multiple tumors (Table 7), the particular criteria (tumor size as well as nodules number) for tumor stage that we used in selecting patients proved effective in predicting outcome after transplantation (Fig. 12).
Patient Selection Criteria
On pathological examination of the explanted livers, 63 patients (58.3%) were found to have tumors that met Milancriteria(single tumors 5 cm in diameter or no more than three tumors, <3 cm in diameter),whereas 45 patients (41.7%) had tumors that exceeded those limits of Milan.
within UCSF criteria and Beyond UCSF criteria were 73(67.6%) and 35(32.4%), respectively.
Comparisons between the two groups Milan criteria and Beyond Milan criteria, the overall one, three, five and ten-YSR was 90 %, 85 %, 72%and 65%; 74 %, 66 %, 60%and 37%, respectively.
(Fig. 12) P=0.033 by Log-Rank test.
Figure12. Overall Survival after LT in Patients with HCC, Within Milan criteria; n=63 vs. Beyond Milan criteria; n=45;
P=0.033 by Log-Rank test, Solid line indicates Within Milan criteria
Comparisons between the two groups Milan criteria and Beyond milan criteria, the recurrence-free survival at one, three, five and ten-YSR was91 %, 87%, 77 % and 71%; 72 %, 66%, 66 % and 30%; respectively. (Fig.13).P=0.031 by Log-Rank test.
Figure13. Recurrence-free survival after LT in Patients with HCC, Within Milan criteria; n=63 vs. Beyond Milan criteria; n=45; P=0.031 by Log-Rank test, Solid line indicates Within Milan criteria
Years after LT 0 1 2 3 4 5 6 7 8 9 10 63 52 39 35 29 23 19 16 11 7 3 within Milan n
Recurrence-freeYSR 100% 91% 89% 87% 84% 77% 77% 77% 71% 71% 71%
Beyond Milan n n 45 24 17 16 13 13 7 5 4 2 1 Recurrence-freeYSR 100% 72% 66% 66% 66% 66% 60% 60% 60% 60% 30%
Comparisons between the two groups UCSF criteria and Beyond UCSF criteria, the overall one, three, five and ten-YSR was 88 %, 83 %, 73%and 63%; 71 %, 64 %, 53%and 27%, respectively.
(Fig. 14) P=0.034 by Log-Rank test.
Figure14. Overall Survival after LT in Patients with HCC, Within UCSF criteria; n=73 vs. Beyond UCSF criteria; n=35;
P=0.034. By Log-Rank test, Solid line indicates Within UCSF criteria
Years after LT 0 1 2 3 4 5 6 7 8 9 10 73 60 45 41 34 28 22 18 13 7 3 Within UCSF criteria
Survival rate 100% 88% 85% 83% 79% 73% 71% 71% 66% 66% 66%
35 23 16 15 11 8 4 3 2 2 1 Beyond UCSF criteria
Survival rate 100% 71% 64% 64% 59% 53% 53% 53% 53% 53% 27%
Comparisons between the two groups UCSF criteria and Beyond UCSF criteria, the recurrence-free survival at one, three, five and ten-YSR was88 %, 83%, 75 % and 67%; 71 %, 67%, 67 % and 33%; respectively. (Fig. 15) P=0.165 by Log-Rank test.
Figure15. Recurrence-free survival after LT in Patients with HCC, Within UCSF criteria; n=73 vs. Beyond UCSF Criteria; n=35; P=0.165, by Log-Rank test, Solid line indicates Within UCSF criteria.
Using the same statistical analysis, When the University of California San Francisco (UCSF) criteria were applied58, 73(67.59%) recipients met the selection criteria. It could expand the indication population by 9.26% comparing with the Milan criteria. Their 1, 3, 5, 10- overall survival rate (within or beyond the UCSF criteria) was significant. P=0.034 by Log-Rank test.
but recurrence-free survival within UCSF criteria and Beyond UCSF criteria showed no significance. P=0.165 by Log-Rank test.
Ten patients who all were male developed tumor recurrence after LT and demonstrated in Table (9, 10). Among these, the patient with the largest tumor (20 cm size) and 7 nodules died 10 months after LT because of multifocal tumor recurrence in lungs 3 months after LT.
The sites of the recurrence were only the liver in 4 patients, only the lungs in 1 patient, the liver and spine in 1 patient, and the adrenal gland in 2 patients, the lungs and the liver in 1 patient, and the bone in1 patient.
Treatment for the recurrent tumor included adrenalectomy and resection of lung metastasis, resection of liver metastases, systemic chemotherapy. At the end of follow-up, three patients are still alive in good general condition with pulmonary metastases and transplant liver recurrence and bone metastases.
Table 9. Type of tumor recurrence after LT for HCC
patient sex age Time after LT (months)
Type of tumor recurrence
pT* G Milan UCSF outcome Survival (months)
1 M 59 11 Multiple liver lesions T2 G3 W W D 16 2 M 58 7 Multiple liver lesions T2 G 3 B B D 10 3 M 59 6 in adrenal T4 G 2 B B D 22 4 M 62 43 in liver and spine T4 G 2 B B D 52 5 M 58 21 in adrenal T4 G 2 B B A 58 6 M 60 8 in bone T4 G 2 B B A 49 7 M 46 3 in liver and lungs T3 G 3 W W A 14 8 M 65 36 Multiple liver lesions T3 G 3 W W D 38 9 M 60 3 in lungs T3 G 3 B B D 10 10 M 54 32 Multiple liver lesions T3 G 3 B B D 37 M:male, W: Within ,B: beyond;D :Dead; A: Alive.
*In the TNM system,
T1 a single tumor ≤2 cm in diameter without vascular invasion;
T2 a single tumor ≤2 cm with vascular invasion,
a single tumor >2 cm without vascular invasion, or multiple single-lobed tumors ≤2 cm without vascular invasion;
T3 a single tumor >2 cm with vascular invasion, multiple single-lobed tumors >2 cm without vascular invasion, or multiple single-lobed tumors of any size with vascular invasion;
T4 indicates multiple two-lobed tumors of any size, with or without vascular invasion..
None of the patients had positive lymph nodes, metastases, or major vascular invasion; their tumors were therefore classified as N0 and M0.
Table 10. Prognostic Variables Related to Recurrence after LT in Patients with HCC
Variable Num.of recurrence Num of No recurrence
n P
(by fish exact test)
Age
<53
>53 1 9
46 61
47 70
0.048
AFP
<200 ng/ mL
>200 ng/ mL
5 5
54 19
59 24
0.144
Milan criteria
(W) (B)
3 7
60 38
63 45
0.090
UCSF criteria
(W) (B)
3 7
70 28
73 35
0.013
pT
T2 2 29 31
0.300
T3-4 8 38 46 G
G2 G3
4 6
57 15
61 21
0.015
Micro vascular invasion
Yes no
6 4
11 87
17 91
0.001
W: Within ,B: beyond .with Fisher exact test, two-sided P values were reported.
Recurrence after LT in Patients with HCC was significantly associated with the Age, presence of micro vascular invasion, presence of beyond UCSF criteria, and degree of tumor differentiation (G3 vs. G2).
Figure15. Comparison between the two groups no recurrence (n=107) vs. recurence (n=10), P=0.029 by Log-Rank test.Solid line indicates no recurrence.
Figure17. Comparison between the two groups CDLT (n=103) vs. LDLT (n=14), P=0.911, by Log-Rank test, Solid line indicates CDLT.
Figure18. Survival analysis after excluding peri-operative mortality
5. REVIEW
Table 11 Evidence-Based Benefits in the Treatment of Hepatocellular Carcinoma According to the Strength of Study Design and of Endpoints as Defined by the National Cancer Institute (NCI)59
Treatments Assessed Benefit Evidence Endpoint
Surgical treatments Surgical resection LT
CDLT LDLT
Increase survival Increase survival
non–population based, consecutive non–population based, consecutive
Survival Survival
Locoregional treatments Percutaneous treatments PEI
RA TACE
Arterial chemotherapy Internal radiation (131I,
90Y)
Increase survival
Increase survival Treatment R Treatment R
non–population based, consecutive
no blinded
non–population based, consecutive non–population based, consecutive
Survival
Survival tumor response tumor response
Systemic treatments Tamoxifen
Systemic chemotherapy Interferon
No benefit No benefit No benefit
double blinded no blinded no blinded
Survival Survival Survival Treatment R: Treatment response
Classification of evidence adapted from NCI: www.cancer.gov60
Table 12 Main Series from the Last 10 Years Reporting Outcomes of Cirrhotic Patients with HCC Treated by Resection, Liver Transplantation, and Living Donor Liver Transplantation59.
Actuarial Survival (%)
Treatmentr N 1 Years 3 Years 5 Years
Surgical Resection Takayama et al, 199861
Very early HCC Overt HCC Fong et al, 199962 Llovet et al, 199937 –
No Portal HT, normal bilirubin
Arii et al, 200063
15 52 100 77 35
100 92 83 85 91
––
––
––
––
––
93 54 42 51 74
Stage I, HCC <2 cm HCC 2–5 cm Zhou et al, 200164 Poon et al, 200265 Wayne et al, 200266 Kianmanesh et al, 200367 Ercolani et al, 200368 Ikai et al, 200469
HCC <2 cm HCC 2.1–5 cm HCC 5.1–10 cm HCC >10 cm
767 587 1000 161 249 301 224 12118 2320 (21%) 5956 (54%) 1946 (17%) 819 (7%)
96 95
— 79 83 82 83 85 83 70 53 44
––
––
––
––
––
––
––
––
––
––
––
––
54 38 62 44 41 39 43 50 66 53 37 32 CDLT
Mazzaferro et al, 199638 – Bismuth et al, 199939 – Llovet et al, 199937 – Jonas et al, 200140 – Yao et al, 200142 – Adam et al, 200370 – Hwang et al 71
Within Milan criteria Beyond Milan criteria
48 45 79 120 64 195 42 19
84 82 86 90 87 80
––
––
––
––
––
––
89.9 66.4
74*
74 75 71 73 61
LDLT
Mt Sinai (follow-up, Gondolesi, 2004)72
Within Milan criteria Beyond Milan criteria Todo, 200473
Within Milan criteria Beyond Milan criteria Hwang et al 71
Within Milan criteria Beyond Milan criteria
15 27 316 137 172 151 62
––
––
––
––
––
––
86 42 79 60 91.4 62.6
––
––
––
––
––
––
*: 4 YSR
6. DISCUSSION
HCC
Hepatocellular carcinoma (HCC) is a well-established indication for liver transplantation (LT)37-40, 74.
With more than 1,000,000 new cases diagnosed worldwide75 and the incidence rising4. The prognosis for patients with the disease is poor, because the number of new cases roughly equals the number of deaths per year. Hepatocellular carcinoma (HCC) has the potential to change the liver transplant system in very short order. Because the vast majority arise in cirrhotic livers, thereby limiting surgical resection to the few cases whose functional hepatic synthetic reserve is sufficient to tolerate removal of hepatic parenchyma. Patients with cirrhosis are at substantial risk for hepatocellular carcinoma; and cirrhosis itself may be a preneoplastic condition, even though the incidence of hepatocellular carcinoma is not related to the severity of liver disease.76The yearly incidence of HCC in such patients with cirrhosis is 3 percent.76Liver transplantation remains the only curative option for the majority of early stage cases.
Furthermore, orthotopic liver transplantation (OLT) is a rational therapeutic option for patients with hepatocellular carcinoma (HCC), because it addresses the multifocal potential of HCC in many patients that limits the success and applicability of resection, and also treats the underlying liver disease. In fact, a few of our patients with hepatocellular carcinoma underwent liver transplantation although they had good hepatic function and general condition; those patients could not be treated without transplantation because their cancer was multiple or centrally located in the organ.
The early (During the 1980s) experience of OLT for HCC in unselected patients included those with extensive and bulky tumors, and was associated with a dismal outcome primarily as a result of aggressive tumor recurrence after OLT.32,77 The observation that small HCC discovered incidentally at the time of pathologic examination of the explanted liver had a much lower recurrence rate after OLT32,77 provided the impetus for subsequent studies evaluating OLT
mainly for patients with small HCC.38, 41, 78, 79
In a study by Bismuth et al41, the subgroup of patients with no more than 3 tumor nodules and none greater than 3 cm in greatest diameter had a 3-year disease-free survival of 83% with OLT, compared with only 18% treated by resection.
In a subsequent study by Mazzaferro et al.,38 35 patients with a solitary tumor not exceeding 5 cm or no more than 3 tumors with none greater than 3 cm had excellent overall and recurrence-free survival rates of 85% and 92%, respectively, at 4 years after OLT. In the report by Figueras et al79., the 5-year survival rate for OLT in 38 patients with small HCC not exceeding 5 cm in maximal diameter was 75%, essentially identical to the survival rate in patients without HCC.
In our study, the overall one, three, five and ten-year cumulative survival rate was 79 %, 71 %, 62%and 45%, the recurrence-free survival at one, three, five and ten-year was79 %, 73%, 68 % and 49% respectively .Our cases included a few bulky tumors. Such as the patient with the largest tumor (20 cm size) and 7 nodules died 10 months after LT because of multifocal tumor recurrence in lungs 3 months after LT.
Prognosis of LT for HCC, HCC recurrence
In our study, ten patients of 117 cases with HCC occurred tumor recurrence after LT, Comparison between the two groups no recurrence (n=107) vs recurence (n=10), P=0.029 by Log-Rank test.
(Fig.16) tumor recurrence affected years survival rate heavily. Recurrence after LT in Patients with HCC was significantly associated with the Age (>53years), presence of micro vascular invasion, presence of beyond UCSF criteria, degree of tumor differentiation (G3 vs. G2).
Both size and number of tumors were important factors predicting survival rate in patients with HCC after LT. Among the variables that are easy to assess preoperatively, tumor size appears to correlate most closely with vascular invasion. Small, encapsulated HCCs (<3 cm diameter) rarely demonstrate vascular invasion.80 The identification of multiple small lesions on pretransplant imaging studies, particularly in view of the increasing sensitivity of such tests, probably has no great significance. On the other hand, in patients with a large (>5 cm) tumor, the presence of multiple other smaller tumors, particularly in the same or adjacent liver segments (satellites),81 is
evidence of vascular invasion with metastasis. In such cases the risk of unrecognized spread outside the liver is increased.
Although several factors may contribute to a poor prognosis after liver transplantation, vascular invasion is one of the most important. 40, 82-84 microscopic vascular invasion is a prerequisite for lymphatic and hematogenous spread. While major vascular invasion can be identified preoperatively in the majority of cases, microscopic vascular invasion is impossible to rule out before transplantation, only after pathologic result. Tumor size is an important predictor of outcome after surgical treatment for HCC most likely because tumor size acts as surrogate marker for the presence of microscopic vascular invasion.40, 85 Pawlik TM et al reported the incidence of microscopic vascular invasion increased with tumor size. Both size and number of tumors were important factors predicting vascular invasion. The high incidence of occult vascular invasion and advanced histological grade in HCC tumors larger than 5 cm, as well as biologic predictors of poor prognosis, should be considered before criteria for transplantation are expanded to include these patients86.
According to our study, 17 of 108 patients with HCC were examined by pathologic check with micro vascular invasion after LT, Comparison between the two groups no micro vascular invasion (n=91) vs with micro vascular invasion (n=17), P=0.041 by Log-Rank test.
Lymph node metastasis is a contraindication to transplantation.35 Caution should be exercised in interpreting scans, however, as many patients with chronic liver disease (in particular hepatitis C) have large lymph nodes, often up to 2– 3 cm, in the porta hepatis. In patients with HCC, hilar lymph nodes are routinely examined by frozen section at the time of transplant; right now, if metastatic HCC is found, the procedure is aborted and the donor liver is instead transplanted into the next recipient.
Selection criteria (Milan criteria, UCSF criteria )
Even if recent advances in imaging techniques have consented more precise definition of extension of HCC, appropriate preoperative staging of the tumor is not always possible. In patients with HCC, biological properties of the tumor are more accurate than radiological criteria
