Hepatocellular carcinoma is the 5th most common malignancy among men and the 9th
among women worldwide, accounting for 6% of all malignancies . The highest incidences are reported in
sub-Saharan Africa and Asia (30 or more cases per 100,000 population).Parts of Europe have intermediate
rates, followed by the United States, Canada, and the United Kingdom which have the lowest incidences of
around 3 or fewer cases per 100,000 . However, the cohort of persons infected with the hepatitis C
virus (HCV) in the 1960's and 1970's in these areas of low HCC incidence is causing a rise in the number
of cases. These patients have now been infected with HCV for as long as 20 or even 30 years, putting
them at increasing risk for HCC. Between the 1970's and 1990's, HCC incidence in the United States
increased from 1.4 per 100,000 to 3.0 per 100,000 . The incidence of HCC is predicted to continue
rising through the next decade. The epidemiology of this cohort has important implications for outcomes
of transplantation for HCC as well. Some data suggest that HCV patients, with or without HCC, have
poorer post-transplant survivals than non-HCV patients as clinically significant post-transplant
hepatitis C is of concern. Finally, HCV patients with HCC tend to be 10-20 years older than hepatitis B
patients with HCC, making them suitable candidates for transplantation.
Diagnosis of HCC
The typical symptoms of HCC include right upper quadrant pain and weight loss in a patient who may be
known to have liver disease. However, more recently an increasing number of patients have been diagnosed
with HCC when they are asymptomatic through the use of imaging studies in patients at risk and
measurement of serum alpha-fetoprotein. However, a definitive diagnosis of HCC usually requires
histological examination of tumor tissue. The tumor may be biopsied by one of several means. Simple
percutaneous biopsy may be done, particularly in advanced HCC when irregularities may be palpated on the
surface of an enlarged liver. More often, a needle biopsy must be done under ultrasound or CT guidance.
Occasionally, laparotomy may be necessary to accurately identify and biopsy a mass within the liver.
Similarly, laparoscopy may be used although its value is limited because HCC is so often found deep
within a cirrhotic liver so that it is not visible from the surface, in contrast to metastatic liver
cancer which is readily seen at laparoscopy. The risk of complications, particularly bleeding, following
needle biopsy of HCC are greater than when other non-malignant conditions are biopsied presumably because
of the vascular nature of the tumor . There are cases reported of HCC spread along track of a needle
biopsy, although the frequency of this complication is probably about 1% . Because of concern about
the risk of spreading HCC through needle biopsy, there has been some reluctance to require histologic
confirmation of HCC before offering treatment to patients, particularly in the case of potentially
curative therapies such as resection or transplantation.
For clinical purposes, a typical radiologic appearance with or without a raised serum
alpha-fetoprotein may be considered sufficient to allow the patient to be listed for liver
transplantation. Similarly, for research purposes, a recent EASL conference listed standard criteria for
diagnosis of HCC that do not involve biopsy . Radiologic criteria include two imaging techniques both
showing a focal lesion greater than 2 cm in diameter with features of arterial hypervascularization or a
single radiologic study with these features combined with a serum alpha-fetoprotein level of greater than
Because current management guidelines for hepatocellular carcinoma (HCC) do not require biopsy to
prove the diagnosis, we have evaluated our experience of patients with liver disease and hepatic lesions
suspicious for HCC who underwent both fine needle aspiration and core biopsy at Saint Louis University.
We correlated the biopsy results with various clinical, biochemical and radiologic features.
HCC was diagnosed by biopsy in 74 (63%) of 118 cases. The use of both FNA and core biopsy increased
the diagnostic yield of the procedure from 54% for FNA and 55% for core biopsy individually to 63%. On
mean follow up of 27.5 months, an additional 10 patients were found to have HCC while 26 had no further
evidence of HCC. Patients with positive biopsy results had significantly higher serum AFP levels (median
57 vs. 12, p=0.014) than those with negative biopsies, although the groups were otherwise comparable with
regard to other tests of liver function, tumor diameter and Child-Pugh class.
We compared the diagnosis of HCC from a combination of these biopsies and follow up with standard
non-invasive diagnostic criteria advocated by the European Association for the Study of the Liver
(EASL). Of 62 patients meeting the non-invasive EASL criteria for HCC, only 50 were found to have HCC on
biopsy or follow up. Thus 8 (13%) would have been falsely diagnosed with HCC as follow up data on the
remaining 4 patients was incomplete. No patient developed evidence of tumor spread along the needle
track after biopsy.
We feel therefore that image-guided biopsy of lesions clinically suspicious for HCC should be
routinely performed to allow adequate treatment planning as the risks of biopsy appear small and the
potential benefits significant.
Treatment Options for HCC
Treatment options for HCC become fewer as stage of tumor and/or cirrhosis progress.
Patients with early HCC and minimal signs of hepatic decompensation (e.g. TNM stage </= T2,
Childs-Pugh Class A), are considered for the three potentially curative options of transplantation,
surgical resection or local ablation therapies. The choice between these three is controversial and is
discussed below. Patients with TNM stage >T2 are generally not considered transplantation
candidates. Some may still qualify for surgical resection, while others may be treated with
chemoembolization or radiofrequency ablation. Advanced tumor stage in conjunction with advanced
cirrhosis (Child-Pugh Class C) limits therapeutic options significantly. Chemotherapy may be given, but
its efficacy has been disappointing and rarely curative. Unfortunately, the majority of patients present
at these later stages of disease. Indeed, those with poor functional status and advanced disease should
probably receive comfort care measure only. The Barcelona-Clinic Liver Cancer Group uses a detailed
treatment algorithm driven by stage of tumor, stage of cirrhosis, and functional status .
Liver transplantation has recently come to the fore as a favored option for those with early stage
HCC. Like local resection and ablation, transplantation offers potential for cure, but also decreases
recurrence risk and eliminates other complications of cirrhosis. The increased use of transplantation
for HCC comes at a time when there is both an increasing incidence of HCC, but also a persistent shortage
of organs. The transplant community continues to grapple with transplantation criteria and
prioritization of HCC patients to optimize both efficacy and just allocation of organs. Accurate
diagnosis, staging and optimal pre-transplant care are critical components of this ongoing process.
Several controversies remain including the roles of living donation, tumor down-staging and rescue
transplantation. A working knowledge of the current transplant option and its controversies is
essential to those caring for patients with early HCC.
- El-Serag H. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 2002;36:S74-S83.
- El-Serag H. Epidemiology of hepatocellular carcinoma. Clinics in Liver Disease 2001;5:87-107.
- McGill D, Rakela J, Zinsmeister A, Ott B. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology 1990;99:1396-1400.
- Isobe H, Imari Y, Sakai H, Sakamoto S, Nawata H. Subcutaneous seeding of hepatocellular carcinoma following fine-needle aspiration biopsy. Journal of Clinical Gastroenterology 1993;17:350-352.
- Bruix J, Sherman M, Llovet J. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. Journal of Hepatology 2001;35:421-430.
- Llovet J, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transplantation 2004;10:S115-120.