Tumor Surveillance-What Can and Should be Done?
Screening for Recurrence of Hepatocellular Carcinoma
After Liver Transplantation
John P. Roberts
1. The overall rate of recurrence of hepatocellular carci-
18% in three of the largest series, with some differences in
pre-transplant selection criteria.
2. Patients whose explant pathology is within the cur-
rently accepted criteria for transplantation have a low rate
the criteria have a 50% chance of recurrence, suggesting
that post-operative pathology should be used to stratify
3. About 10% of patients with recurrence appear to be
long-term survivors after surgical therapy for the recur-
4. Screening all patients for HCC recurrence after trans-
plantation is probably not cost effective and selecting
patients with high risk explant pathology would be more
5. Surprisingly, there is a dearth of information in the
literature that would suggest rational screening protocols.
I could not find a single article that examined protocols
for screening for recurrence after transplantation. What
follows is my interpretation of the effectiveness of screen-
ing after transplantation for HCC. (Liver Transpl 2005;
performed in patients with HCC. Over the last 2 years
performed in patients with HCC.
The selection criteria for HCC, the Milan criteria,
used for organ allocation in the United States, were
chosen to minimize the difference in outcome between
have HCC.1The Milan criteria would predict a recur-
rence free survival of 92% at 4 years in patients whose
tumors were found to be within the staging criteria on
the explanted liver. This low percentage of recurrence
would suggest that a large number of patients would
need to be screened in order to find a patient with
recurrence. Figure 1 demonstrates the time to recur-
rence of the tumor.
Unfortunately, under-staging by pre-operative radi-
ology studies occurs in about 21% of the patients.2
Milan criteria have a significant risk of recurrence of
ith the increased frequency of hepatocellular
carcinoma (HCC), more transplants are being
50%-60% at 4 years. Patients who are outside of the
criteria would be the best patients to screen in order to
find a recurrence. In addition to the patients with
tumors larger and/or more numerous than allowed by
the Milan criteria, there are other findings in the
explant that would suggest higher rate of recurrence.
For example, both vascular invasion and the tumor
recurrence and more rapid recurrence.
Mazzaferro and colleagues examined a group of 132
patients who underwent transplantation for HCC,
criteria. Twenty-one patients (16%) recurred, 71%
recurring within 18 months, with the longest time
interval being 2 years.3There was a longer interval in
patients who met the Milan criteria, (17.3 months vs.
8.7 months). Similar data was found by Roayaie from
Mt. Sinai Hospital in New York, where they followed
311 patients. Fifty-seven patients (18%) developed
75% recurring within 2 years.4It appears that the time
effective, it should be done in the early time period.
While on the surface, it might seem that screening
tation. First, the vast majority of recurrences would be
related to metastatic disease that either was present
prior to transplantation or was released during the
in studies that have examined the recurrence of tumor
Abbreviation: HCC, hepatocellular carcinoma.
From the Division of Transplant, University of California, San
Francisco, San Francisco, CA.
California at San Francisco, Liver Transplant Program, 505 Parnassus
Avenue, Box 0780, Room M-896, San Francisco, CA 94143-0780.
Telephone: 415-476-8028; FAX: 415-502-4354; E-mail: robertsj@
Copyright © 2005 by the American Association for the Study of
Published online in Wiley InterScience (www.interscience.wiley.com).
Liver Transplantation, Vol 11, No 11, Suppl 1 (November), 2005: pp S45-S46
after transplantation. Mazzaferro found that in the 21
patients who recurred, 38% initially recurred in multi-
multi-organ spread. Lung metastases were the initial
site in 19%, bone in 14%, and 19% in the liver. The
survival of these patients was limited with 17 patients
dead within 2 years. Similar data is available from Mt.
57 patients who recurred. The median survival follow-
ing recurrence was 8.7 months.
The multiple sites of recurrence would imply that
the spread of the cancer is systemic and local therapy
would be unlikely to result in cure from recurrent dis-
ease. Currently, there does not appear to be satisfactory
systemic therapy to prevent recurrence after transplan-
tation. Adriamycin given both preoperatively and post-
ized trial to prevent recurrence.5This would suggest
that treatment of recurrence would also be unlikely to
benefit from this chemotherapy regimen. Until there is
development of effective chemotherapy, it would seem
that patients with systemic recurrence will continue to
succumb to their disease.
There have been some patients with localized recur-
rence who appear to have been cured after resection.
Mazzaferro reported two patients with isolated liver
tion of localized recurrence in the transplanted liver.
Another patient with disease in the lungs was alive 41
months after systemic chemotherapy given for disease
recurrence. Roayaie reported three apparent long-term
survivors after surgical therapy; the site of recurrence of
these patients was not reported. Pichlmayer6reported
seven long-term survivors after resection of localized
disease. From these reports it appears that patients with
late recurrence may do better with resection of a local-
ized recurrence, similar to the situation with colorectal
disease metastatic to the liver.
Based upon the Mazzaferro and Roayaie studies, it
would appear that treatment is curative in only about
1% of those with HCC recurrence after liver transplan-
a cost of about $1,286 per year.7If screening was per-
that one patient would be found that could be cured of
their disease, it would be expected that the cost of
screening would be greater $100,000 per year. Screen-
ing only patients with explant pathology outside of the
Milan criteria would result in a smaller number of
patients screened, presumably with the same rate of
1. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Boz-
zetti F, et al. Liver transplantation for the treatment of small
2. Yao FY, Kinkhabwala M, LaBerge JM, Bass NM, Brown R Jr,
Kerlan R, et al. The impact of pre-operative loco-regional therapy
on outcome after liver transplantation for hepatocellular carci-
noma. Am J Transpl 2005;5:795-804.
3. Regalia E, Fassati LR, Valente U, Pulvirenti A, Damilano I, Dar-
carcinoma after liver transplantation. J Hepatobiliary Pancreat
4. Roayaie S, Schwartz JD, Sung MW, Emre SH, Miller CM, Gon-
transplant: patterns and prognosis. Liver Transpl 2004;10:534-
5. Pokorny H, Gnant M, Rasoul-Rockenschaub S, Gollackner B,
Steiner B, Steger G, et al. Does additional doxorubicin chemo-
therapy improve outcome in patients with hepatocellular carci-
noma treated by liver transplantation? Am J Transplant 2005;5:
6. Schlitt HJ, Neipp M, Weimann A, Oldhafer KJ, Schmoll E,
Boeker K, et al. Recurrence patterns of hepatocellular and fibro-
lamellar carcinoma after liver transplantation. J Clin Oncol 1999;
7. Patel D, Terrault NA, Yao FY, Bass NM, Ladabaum U. Related
Articles, Links: Cost-effectiveness of hepatocellular carcinoma
surveillance in patients with hepatitis C virus-related cirrhosis.
Clin Gastroenterol Hepatol 2005;3:75-384.
Figure 1. Time to recurrence of tumor.