Liver transplant (LT) has become the treatment of choice in patients with hepatocellular carcinoma (HCC) and cirrhosis who meet the Milan criteria (MC)[
Overall, two thirds (2/3) of patients, who develop recurrent HCC post-LT, present with extrahepatic recurrence[
In a recent report, we published our experience in LT recipients with HCC at the Johns Hopkins University Comprehensive Liver Transplant Center[
The study was approved by the institutional review board at the Johns Hopkins Hospital. HCC-related deceased donor LT recipients between January 2005 and December 2015 were evaluated. In total, 26 patients with post-LT HCC recurrence were identified among 165 recipients who were included in the study. All recipients were listed following a standard work up and discussion at the weekly selection meeting. They were within Milan criteria or downstaged into Milan criteria. The transplant was performed by piggyback technique. Postoperative HCC surveillance consisted of contrasted cross-sectional imaging with computerized tomography or magnetic resonance imaging with AFP every three months for the first year and every six months for the second and third years. There was no set therapeutic protocol for recurrence; treatment options were discussed in a multidisciplinary fashion. The Pre-LT AFP was obtained within the past three months prior to deceased donor liver transplantation (DDLT) and immediate post-LT AFP was obtained within three months post DDLT.
Data on clinical, radiologic, pathology, HCC recurrence, and survival were collected from the records, reviewed, and analyzed. Explant pathologies were reviewed retrospectively, and the following tumor parameters were collected: size, number of lesions, microvascular invasion status, and differentiation. It was determined whether patients met the Milan or University of California San Francisco (UCSF) criteria based on the number and size of HCC lesions on explant pathology. The data collected for categorical variables were reported as percentages. Data for continuous variables were reported by the mean and standard deviation. Patient survivals were analyzed using Kaplan-Meier statistics. STATA V.13 (StataCorp college station, TX) was used to perform the statistical analyses.
Among the deceased donor LT recipients, HCC was the primary indication for transplantation varying from 21% to 53% of patients
Overall, rate of deceased donor liver transplant for hepatocellular carcinoma indication at the Johns Hopkins Hospital from 2005 to 2015. HCC: hepatocellular carcinoma
Characteristics of the study population
Variable | |
---|---|
Clinical features | |
Male sex, |
23 (88.5%) |
Age (years) | 58.9 (6.8) |
Ethnicity, |
|
White | 17 (65.4%) |
African American | 7 (27.0%) |
Asian | 2 (7.6%) |
Etiology | |
HCV | 13 (50%) |
HBV | 3 (11.5%) |
ALD | 2 (7.7%) |
NAFLD | 1 (3.9%) |
HCV/ALD | 6 (23%) |
Other | 1 (3.9%) |
Explant pathology | |
Number of lesions, |
|
1 | 9 (34.6%) |
2 | 3 (11.5%) |
3 | 3 (11.5%) |
> 4 | 11 (42.4%) |
Largest lesion (cm) | 4.3 (3.8) |
Tumor location, |
|
Right lobe | 13 (50%) |
Left lobe | 1 (3.9%) |
Multi-lobar | 12 (46.1%) |
Tumor differentiation, |
|
Well | 0 (0%) |
Moderate | 14 (53.8%) |
Poor | 11 (42.3%) |
Unknown | 1 (3.9%) |
Microvascular invasion, |
|
Yes | 19 (73.1%) |
No | 6 (23%) |
Bile duct invasion | 1 (3.9%) |
Total number of loco-regional therapies, |
|
0 | 9 (34.6%) |
1 | 9 (34.6%) |
2 | 5 (19.2%) |
> 2 | 3 (11.6%) |
Patients with viable tumor, |
|
Yes | 25 (96.2%) |
No | 1 (3.8%) |
Within Milan, |
|
Yes | 10 (38.4%) |
No | 16 (61.6%) |
Downstaged to Milan, |
4 (15.4%) |
Within UCSF, |
|
Yes | 11 (42.3%) |
No | 15 (57.7%) |
Downstaged to UCSF, |
3 (11.5%) |
Laboratory | |
Pre-LT AFP (ng/mL) | 27,578 (133,183) |
Post-LT AFP (ng/mL) | 23,586 (81,707) |
MELD | 13(7) |
WBC (109/L) | 6 (2.2) |
Hgb (g/dL) | 12.9 (2.7) |
MCV (fL) | 91(6) |
PLT (103/μL) | 116(67) |
BUN (mg/dL) | 15(6) |
Creatinine (mg/dL) | 1.1 (0.6) |
TP (g/dL) | 7.2 (0.8) |
Alb (g/dL) | 3.6 (0.7) |
ALP (U/L) | 141(58) |
AST (U/L) | 109(167) |
ALT (U/L) | 71(122) |
T.Bili (mg/dL) | 2.2 (2.4) |
PT (sec) | 14 (4.1) |
INR | 1.3 (0.4) |
Clinical and pathological characteristics of the 26 recipients with hepatocellular carcinoma recurrence following liver transplant. Quantitative data are expressed as mean and categorical variables are reported as percentages. AFP: alpha fetoprotein; ALD: alcoholic liver disease; Alb: albumin; ALP: alkaline phosphatase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; BUN: blood urea nitrogen; HBV: hepatitis B virus; HCV: hepatitis C virus; Hgb: hemoglobin; INR: international normalized ratio; LT: liver transplant; MCV: mean corpuscular volume; MELD: model for end-stage liver disease; NAFLD: non-alcoholic fatty liver disease; PLT: platelet count; PT: prothrombin time; TP: total protein; T.Bili: total bilirubin; UCSF: University of California San Francisco; WBC: white blood cell count
The average model for end-stage liver disease (MELD) score was 13, ranging from 6 to 35. Mean AFP was 27.6 ng/mL for pre-LT
Alpha fetoprotein levels pre and post-liver transplant
Patient | Pre-LT AFP | Initial post-LT AFP | AFP at recurrence |
---|---|---|---|
1 | 9 | 7 | 2019 |
2 | 28,139 | 365,210 | NA |
3 | 135 | 4.1 | 15 |
4 | 3.6 | 0.6 | 1.7 |
5 | 27 | 3864 | NA |
6 | 488 | 57 | 86 |
7 | 22 | 2 | 26 |
8 | 23 | 12 | 1416 |
9 | 162 | 6.4 | 7 |
10 | 169 | 682 | 3342 |
11 | 34 | 3 | 389 |
12 | 48 | 4 | 12 |
13 | 323 | 76 | 157 |
14 | 7 | 21 | NA |
15 | 23 | 10 | 51 |
16 | 4659 | 25,154 | NA |
17 | 304 | 35 | 5.4 |
18 | 3.3 | 4.3 | 210 |
19 | 1707 | 100 | 47,304 |
20 | 34 | 2 | 3.7 |
21 | 680,000 | 217,576 | 120,848 |
22 | 22 | 2 | 17 |
23 | 4 | 2 | NA |
24 | 207 | 317 | 40.9 |
25 | 486 | 104 | 3677 |
26 | 5.2 | 5.5 | 4 |
Alpha fetoprotein levels (ng/mL) pre- and post-liver transplant in 26 liver transplant recipients with hepatocellular carcinoma recurrence. AFP: alpha fetoprotein; LT: liver transplant; NA: data not available
Overall, nine (34.6%) patients were treated with mammalian target of rapamycin (mTOR) treatment with sirolimus in eight and everolimus in one patient. Seventeen patients received Tacrolimus-based therapy.
In the explant pathologies of LT recipients, 9 (34.6%) patients had only one lesion and 11 (42.4%) had 4 or more lesions. The average for the largest lesion size was 4.3 cm. In total, 12 patients (46.1%) had multi-lobar tumors and 13 (50%) had tumors that were located in the right lobe. Overall, 10 patients (38.4%) were within MC criteria and 11 patients (42.3%) were within UCSF criteria. Four patients (15.4%) were downstaged to MC with locoregional treatment. Seventeen (65.4%) patients underwent locoregional therapy before transplant. None of the tumors were well-differentiated. Overall, 14 (53.8%) patients had moderately differentiated HCC. Eleven (42.3%) patients had HCC with poor differentiation. Microvascular invasion was detected in 19 of the 26 cases (73.1%) while one patient had bile duct invasion only.
The overall rate of HCC recurrence following LT in our series was 15%. The rate of HCC recurrence has improved over the years with a recurrence rate of 10% in 2015
Overall, per year rate of hepatocellular carcinoma recurrence in deceased donor liver transplant recipients at the Johns Hopkins Hospital from 2005 to 2015. HCC: hepatocellular carcinoma
A range of different treatment modalities was used for recurrences
Survival analysis for 26 liver transplant recipients with hepatocellular carcinoma recurrence: A: Kaplan-Meier curve for recurrence-free survival; B: Kaplan-Meier curve for overall survival
Specific characteristics of the tumors, treatment, and outcomes
Patient | Number of lesions | Largest lesion (cm) | Within Milan criteria | Downstaged | MVI | Differentiation | Diagnosis of recurrence following LT (in days) | Site of recurrence | Survival | Time of death following LT (days) | Treatment of recurrence |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | 5 | 4 | No | No | Yes | Moderate | 984 | Gastro-hepatic ligament, mediastinal | Died | 1466 | Sorafenib |
2 | 1 | 8 | No | Yes | Yes | Poor | 314 | Liver | Died | 369 | Supportive care |
3 | 5 | 8.5 | No | Yes | Yes | Moderate | 950 | Brain | Died | 1062 | Brain metastasis resection |
4 | Infiltrative | 1.1 | No | No | Yes | Moderate | 536 | Liver | Died | 780 | Y90 |
5 | 1 | 1 | Yes | No | No | Moderate | 80 | Porta-hepatis | Died | 366 | Chemotherapy with capecitabine |
6 | 1 | 7.5 | No | No | Yes | Poor | 102 | Perihilar, lung | Died | 222 | Supportive care |
7 | Infiltrative | 2 | No | No | Yes | Poor | 224 | Brain, liver, adrenal | Died | 1459 | Brain metastasis resection and radiation, cryoablation of adrenal metastasis, Y90 in liver |
8 | 3 | 1 | Yes | No | No | Moderate | 490 | Humerus, brain | Died | 663 | Bone resection and radiation, brain met resection |
9 | 8 | 4.3 | No | No | Yes | Poor | 291 | Ribs, spine | Died | 602 | Sorafenib |
10 | 2 | 1.5 | Yes | No | No | Moderate | 94 | Portal nodes, mediastinal, lung | Died | 253 | Sorafenib, external radiation |
11 | 2 | 1.6 | Yes | No | Yes | Poor | 464 | Bone, lung | Died | 547 | Supportive care |
12 | 1 | 5 | Yes | No | Yes (bile duct) | Poor | 482 | Bile ducts | Died | 1131 | Whipple surgery, Sorafenib |
13 | 5 | 6 | No | No | Yes | Moderate | 111 | Lung, peritoneal carcinomatosis | Died | 332 | Supportive care |
14 | Infiltrative | 2.8 | No | No | Yes | Moderate | 544 | Pelvic bone | Died | 1079 | External radiation, Sorafenib |
15 | 1 | 2.3 | Yes | No | No | Moderate | 795 | Spine | Died | 1319 | Spine surgery and radiation |
16 | 1 | 7.2 | No | No | Yes | Poor | 93 | Pelvic bone, lung | Died | 493 | External radiation |
17 | 5 | 3.5 | No | No | Yes | Poor | 261 | Liver | Alive | - | TACE |
18 | 3 | 3.5 | No | Yes | Yes | Moderate | 713 | Lung, liver | Died | 861 | TACE |
19 | 1 | 2.9 | Yes | No | Yes | Poor | 346 | Liver | Died | 407 | Supportive care |
20 | 1 | 2.8 | Yes | No | Yes | Moderate | 1502 | Liver | Alive | - | RFA, TACE, Sorafenib |
21 | Infiltrative | 19 | No | No | Yes | Poor | 78 | Lung, bone, liver | Died | 178 | Chemotherapy with Gemcitabine/Cisplatin, external radiation |
22 | 2 | 2.6 | Yes | No | Yes | Poor | 199 | Liver | Died | 260 | Supportive care |
23 | 5 | 2 | No | No | No | Moderate | 594 | Brain | Died | 1156 | Brain metastasis resection |
24 | 3 | 7.5 | No | Yes | Yes | Moderate | 147 | Mediastinal lymph nodes, pleura | Died | 697 | Sorafenib |
25 | Infiltrative | 4 | No | No | Yes | Moderate | 34 | Spine, mediastinal | Died | 1065 | Spine radiation |
26 | 1 | 2.2 | Yes | No | No | No viable tissue | 917 | Lung, mediastinal | Died | 1359 | External radiation |
Specific characteristics of the tumors, treatment, and outcomes in 26 liver transplant recipients with a recurrence of hepatocellular carcinoma following liver transplant. LT: liver transplant; MVI: microvascular invasion; RFA: radiofrequency ablation; TACE: transarterial chemoembolization
In this series, we report a rate of 15% HCC recurrence following deceased donor LT at our transplant program. This rate is consistent with the literature report of 15%-20% post-LT HCC recurrence[
Our sites of recurrence findings are very similar to the recent reports[
Within our series, 54% of the HCC recurrences were diagnosed within 1 year post-OLT, while 81% and 96% of recurrences occurred within 2 and 3 years following OLT, respectively. The average time to HCC recurrence within our series was 427 days (range 34-1502 days). It is shown by others that early versus late recurrence is a predictor of post-LT survival[
The selection of an ideal treatment for post LT HCC recurrence is a matter of debate, and the evidence is mainly based on expert opinion and non-randomized cohort studies[
Surgical options including extrahepatic resection, liver graft resection, and liver re- transplant have also been considered for patients presenting with HCC recurrence. In 2004, the Mount Sinai group reported resection of the liver allograft in five out of 18 recipients with HCC recurrence[
Sorafenib, a multikinase inhibitor, has been approved as first-line treatment for the management of advanced-stage HCC following two clinical trials in 2008 and 2009[
Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, has been shown to be upregulated in 40%-50% of HCCs. mTOR is involved in the regulation of cell metabolism and growth[
HCC recurrence following LT is an unfortunate event and associated with poor outcomes. In a recent meta-analysis, the median overall survival was 13 months following the diagnosis of HCC recurrence post-LT[
In conclusion, HCC recurrence post liver transplant is an unfortunate event associated with extremely poor survival. The majority of the cases are early recurrence occurring 1-2 years following liver transplantation. More than 50% of HCC recurrences are extrahepatic. Therefore, post-liver transplant imaging confined to the liver may not be enough to detect all of the recurrences. In patients with AFP producing tumors, this marker may also be helpful to diagnose the HCC recurrence. There is no general consensus on the treatment for post liver transplant hepatocellular carcinoma recurrence. The current reports are mainly based on single-center retrospective experience.
Acquisition of data, analysis and interpretation of data, drafting of the manuscript: Simsek C
Interpretation of the data, Final Editing and Critical Review of the manuscript for important intellectual content: Kim A
Acquisition of data, analysis and interpretation of data, drafting of the manuscript: Ma M
Review of the data, drafting of the manuscript and editing: Danis N
Analysis and interpretation of data, statistical analysis: Gurakar M
Study concept and design, interpretation of data, critical revision manuscript for important intellectual content: Cameron AM
Study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content: Philosophe B
Study concept and design, interpretation of data, statistical analysis, critical revision of the manuscript for important intellectual content: Garonzik-Wang J
Study concept and design, critical revision of the manuscript for important intellectual content: Ottmann S
Study concept and design, acquisition of data, drafting of the manuscript, analysis and interpretation of data, revision of the manuscript for important intellectual content study supervision: Gurakar A
Study concept and design, acquisition of data, drafting of the manuscript, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, study supervision: Saberi B
Data source has been the Electronic Medical System. Please contact the corresponding author for unidentified data availability
This Research is partially supported by NIH Grants: R44 CA165312 - Development of a urine test for the early detection of liver cancer. U01 CA230690 - Pathway Specific Functional Biomarkers for the Early Detection of Liver Cancer.
All authors declared that there are no conflicts of interest.
This retrospective study was approved by Johns Hopkins IRB NA_00028034.
Not applicable.
© The Author(s) 2020.