- Email: [email protected]
Hepatocellular Carcinoma and Liver Transplantation: A Single-Center Experience
Hepatocellular Carcinoma and Liver Transplantation: A Single-Center Experience Kamil Yalcin Polata, Sencan Acarb,*, Genco Gencdalc, Serafettin Yazara, Ahmet Kargia, Ramazan Donmeza, Serdar Aslana, Mustafa Emre Kavlakd, Cigdem Arikane, and Murat Akyildizf a Department of General Surgery and Organ Transplantation Center, Memorial Atasehir Hospital, Istanbul, Turkey; bDepartment of Gastroenterology and Organ Transplantation Center, Sakarya University School of Medicine, Sakarya, Turkey; cDepartment of Gastroenterology and Organ Transplantation Center, Memorial Atasehir Hospital, Istanbul, Turkey; dDepartment of Anesthesiology and Intensive Care Unit and Organ Transplantation Center, Memorial Atasehir Hospital, Istanbul, Turkey; eDepartment of Pediatric Gastroenterology and Organ Transplantation Center, Koc University School of Medicine, Istanbul, Turkey; and fDepartment of Gastroenterology and Organ Transplantation Center, Koc University School of Medicine, Istanbul, Turkey
ABSTRACT Background. Liver transplantation (LT) is the best treatment in selected patients with hepatocellular carcinoma (HCC). Morphologic criteria alone are not sufficient to predict survival. In this study, we investigated the clinical, biochemical, and pathologic factors affecting survival in patients who underwent LT due to HCC. Methods. Between October 2011 and January 2018, 165 of 749 LT for HCC cases performed at the Memorial Atasehir Hospital were evaluated retrospectively. Survival, demographic characteristics and etiology, preoperative alpha-fetoprotein (AFP) level, Model for End-Stage Liver Disease (MELD) score, prognostic staging, and morphologic and histologic properties were evaluated. Results. One hundred and thirty-nine cases of 165 were living donor liver transplantation (LDLT). The mean age was 57.7 7.3 years, the mean follow-up period was 27.8 20 months, and 41 patients (24%) died before follow-up. Recurrence of HCC was detected in 23 (14%) cases. Overall survival was 85%, 71%, and 64% for 1, 3, and 5 years, respectively. In terms of 1-, 3-, and 5-year survival within vs beyond Milan criteria was 90%, 80%, and 76% vs 75%, 66%, and 44%, respectively. In the University of California San Francisco criteria, it was 86%, 76%, and 70% vs 76%, 60%, and 30% compared with 1-, 3-, and 5-year survival. While histopathological poor differentiation and AFP elevation affected the course negatively. Good differentiation did not have a significant effect on survival. It was determined that poor differentiation, lymphovascular invasion, and an increased number of nodules significantly affected survival in both within and beyond cases. Conclusion. A transplant decision is controversial in patients with HCC with other than previously defined morphologic criteria. In these cases, AFP level and histologic differentiation determine survival. The results were not satisfactory in both high and/or poorly differentiated cases.
H
EPATOCELLULAR carcinoma (HCC) constitutes over 5% of all cancer types and 80% to 90% of primary liver malignancies, causing 250,000 to 1,000,000 deaths per year worldwide. It is the sixth most common cancer type, which is the second most common cause of cancer deaths in the world [1].
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e6 (2019)
*Address correspondence to Sencan Acar, Department of Gastroenterology and Organ Transplantation Center, Sakarya University School of Medicine, Korucuk Mahh Konuralp Blv No: 81/1 Korucuk Campus, Adapazarı, Sakarya, Turkey. Tel: þ90 264 295 66 30; Fax: 90 264 295 66 29. 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.10.029
1
2
The treatment options recommended for HCC include radical treatments (surgical resection, liver transplantation, percutaneous alcohol injection/radiofrequency ablation) (30%), palliative treatments (transarterial embolization/ chemoembolization, hormonal treatment/immunotherapy, anti-proliferative agents) (40%-50%), and symptomatic treatments (20%-30%) [2]. However, despite the developments of liver transplantation, a small number of the patients with HCC may have a chance for liver transplantation. The major point is the recurrence and survival benefit for patients after liver transplantation. After vast experience with liver transplantation for HCC, it is clearly understood that not only tumor size predicts the prognosis, but histologic findings and preoperative alpha-fetoprotein (AFP) levels are important and valuable prognostic markers for HCC recurrence. There are many criteria for liver transplantation such as Milan, University of California San Francisco (UCSF), Toronto, up-to-seven, Metroticket, and others. All of those criteria are morphologic, but we do not know the biological behavior of the tumor. So, there is no obvious predictive scoring system or criteria to detect recurrence of HCC and survival after liver transplantation. In the present study, we aimed to evaluate the clinical, biochemical, and pathologic factors that affect the recurrence of HCC and the survival of patients who underwent liver transplantation due to HCC. MATERIALS AND METHODS We retrospectively studied 165 of 749 patients whose explant pathology indicated HCC and who underwent liver transplantation between October 2011 and January 2018 at Memorial Atasehir Hospital. Demographic characteristics and etiology, preoperative AFP level, Model for End-Stage Liver Disease (MELD) score, prognostic staging criteria (Milan, UCSF), and morphologic (number of nodules, diameter, largest nodule size, multifocality, presence of bilobar involvement) and histologic (vascular invasion, histologic differentiation) factors were collected from the database of Memorial Atasehir Hospital, Liver Transplantation Center. AFP and computed tomography and/or magnetic resonance imaging were performed every 3 months in the first year after liver transplantation and then every 6 months. Immunosuppressive therapy consisted of calcineurin inhibitor and rapid steroid taper with mycophenolate mofetil (MMF) combination. Prednisolone was given at a dosage of 500 mg intravenously in the operating room, followed by a taper from 100 mg to 20 mg for a period of 8 days and from 20 mg to 10 mg after 2 months. MMF was used when lower doses of calcineurin inhibitors were required due to renal dysfunction. Steroids were tapered and stopped in the sixth month; MMF was switched to everolimus, and the tacrolimus dose was reduced after the third month.
Histopathology of Explanted Liver The explanted livers were fixed in formalin and sliced as 1 cm thickness to note the number and largest size of tumor nodules. Hematoxylin-eosin stained tumor sections were analyzed routinely for the differentiation grade, growth pattern, and microscopic and larger vessel invasions as well as lymph node metastases. Tumor
POLAT, ACAR, GENCDAL ET AL differentiation was graded as moderate and poor according to Edmonson and Steiner [3].
Statistical Analyses Continuous variable results are given as means standard deviations; categorical variable results are given as percentages. Comparisons of results for categorical variables were made by c2 test or the Fisher exact test. Survival was assessed using the KaplanMeier method, with comparisons made using a log-rank test. P values of < .05 were considered statistically significant. Statistical analysis was done using SPSS for Windows version 14.0 (IBM Corp, Armonk, NY, United States).
RESULTS
One hundred and sixty-five patients were evaluated. Mean age was 57.7 7.3 years (range, 31-72 years) and 132 (80%) were male. One hundred thirty-nine had living donor liver transplantation. The average pre-transplant MELD score was 12.3 4.8 (range, 6-29), and mean AFP level was 271.8 ng/mL (1-26370 ng/mL). The mean follow-up period was 27.8 20 months, and 41 patients (24%) were lost during follow-up. Recurrence HCC was detected in 23 cases (14%). Overall survival was found as 85%, 71%, and 64% for 1, 3, and 5 years, respectively. In terms of 1-, 3-, and 5-year survival within Milan vs beyond Milan criteria was found as 90%, 80%, and 76% vs 75%, 66%, and 44%, respectively. The patients with beyond Milan had poorly differentiated survival significantly lower. According to within vs beyond, the UCSF criteria was detected as 86%, 76%, and 70% vs 76%, 60%, and 30% for 1-, 3-, and 5-year survival, respectively. The patients with beyond UCSF criteria and poorly differentiated survival significantly lower. High AFP levels affect the post-transplant course negatively according to both Milan and UCSF criteria (Fig 1). In 133 patients, the AFP level was under 100 ng/mL; in 19 patients it was between 100 ng/mL and 500 ng/mL; in 8 patients it was between 500 ng/mL and 1000 ng/mL; and in 5 patients it was >1000 ng/mL. Histologic examination revealed that poor histologic differentiation has a negative effect on survival. Criteria do not significantly affect survival in good differentiation. The survival rate was significantly lower in both inside of criteria and poorly differentiated patients. Lymphovascular invasion had a significantly negative effect on survival. Survival is negatively affected as the number of nodules increases. We classified all patients as 2 subgroups; group 1 is living patients (n ¼ 124), group 2 is patients who have died (n ¼ 41). There were 58 (35.1%) patients with HCC beyond the Milan criteria and 46 (27.8%) patients with HCC beyond the UCSF criteria. The quantitative and qualitative factors affecting the survival of the patients are shown in Tables 1 and 2. The mean preoperative AFP level in living patients was 65.29 164 ng/mL; in the loosing group it was 317 698 ng/mL. Group 2 had significantly higher levels. The mean number of nodules in group 1 was 2.27 2.6
HEPATOCELLULAR CARCINOMA AND LIVER TRANSPLANTATION
3
Fig 1. Survival rates for AFP>100, 100-500, 500-1000, and >1000. AFP, alphafetoprotein.
(range, 1-20); in group 2 it was 3.34 4 (range, 1-20). It is also significantly high in loosing group. We performed receiver operating characteristic (ROC) analysis in order to find the cutoff value for AFP by using “survival status.” The significance level for the area under the curve was higher than 0.05. Then, ROC analysis for AFP by using “recurrence status” showed the cutoff value was 11 ng/mL. The significance level for area under the curve was 0.695 (95% confidence interval: 0.619 to 0.765), P ¼ .0006 (Table 3). The mean diameter of the largest nodule in group 1 was 30.56 18 mm (range, 8-85 mm), in group 2 39.1 26 mm (range, 10-160 mm). It is also significantly higher in group 2. Of these 165 patients, 68 (41%) had multifocal nodules, 62 (37.5%) had lymphovascular invasion, 54 (32.7%) had venous invasion, and 8 (4.8%) had perineural invasion. Sixty-four patients (38.7%) had good differentiation, 85 patients (51.6%) had moderate differentiation, and 16 patients (9.7%) had poor differentiation in their explant livers. Demographic features with donors are shown in Table 4. Table 1. Quantitative Factors Affecting Patient Survival Living patients (n ¼ 124)
Age 58.6 6 MELD score 12.42 4 Preop AFP (ng/mL) 65.29 164 Number of nodules 2.27 2.6 Largest nodule diameter (mm) 30.56 18
Deceased patients (n ¼ 41)
56.87 12.29 317 3.34 39.1
9 5 698 4 26
P
.37 .90 .00 .02 .05
Abbreviations: AFP, alpha-fetoprotein; MELD, Model for End-Stage Liver Disease.
DISCUSSION
Liver transplantation (LT) is the curative treatment option for HCC [4,5]. However, the most important risk factor among patients who undergo LT is the recurrence rate. It has been reported as 10% to 30% in selected patients [6]. It is shown that HCC recurrence significantly reduces the postLT survival [7]. Treatment options are fairly limited in patients with HCC recurrence. Therefore, the patient selection process becomes an important factor to minimize
Table 2. Qualitative Factors Affecting Patient Survival Living patients (n ¼ 124)
Histopathological Features Multifocality, yes no Differentiation good mild poor Perineural invasion no yes Lymphatic invasion no yes Lymphovascular invasion
Mortality (n ¼ 41)
P
.04 46 78
23 18
44 61 10
7 24 7
121 3
36 5
84 38
17 14
69 53
14 27
.00
.02
.02
.01
4
POLAT, ACAR, GENCDAL ET AL Table 3. ROC Analysis for AFP (Recurrence)
Criterion
>11
Sensitivity
95% CI
Specificity
95% CI
þLR
-LR
þPV
-PV
69.57
47.1-86.8
65.49
57.1-73.3
2.02
0.46
24.6
93.0
Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval; LR, likelihood ratio; PV, predictive value; ROC, receiver operating characteristic.
the recurrence risk. Most of the represented, patient selection criteria until now have been described according to the morphologic characteristics such as tumor diameter, tumor number, and vascular invasion. Recently, AFP and PIVKA II levels were suggested to combine with those morphologic criteria to decide for LT in patients with HCC. Multiple classifications have been used to select patients for LT. The Milan criteria, published by Mazzaferro et al in 1996, has been used the most frequently, described as 1 tumor with size <5 cm or up to 3 nodules, each smaller than 3 cm without major vascular invasion [8]. Five-year survival was reported to be over 70% in the patients with early stage HCC [9]. Some variables described to be the predictive factors for the risk of HCC recurrence after LT include vascular invasion, histologic differentiation, and preoperative AFP level [10e13]. Since the Milan criteria is too restrictive, new selection criteria have been studied and novel proposals were developed. The UCSF criteria was developed in 2001. It was defined as a single lesion under 6.5 cm or 2 or 3 lesions of <4.5 cm with total tumor diameter <8 cm. According to these criteria, 1-year survival was reported as 95.9%, and 5-year survival was 90% [14e16]. Similarly, Korean Asan Medical Center’s criteria (each tumor <5 cm and up to 6 nodules) and the registrybased, up-to-7 score (size of largest HCC þ number of HCCs <7), the extended Toronto criteria (any size or number of tumors provided they do not have systemic, cancer-related symptoms, extrahepatic disease, vascular invasion, or poorly differentiated tumors) were developed to increase the number of patients for LT due to HCC. In a multicenter study involving 316 patients in Japan, the 3-year survival rates for intra-Milan patients who underwent LT for HCC were 79%, and beyond Milan were 61% [17]. The 5year survival rate was 87.1% in Milan and 80% in nonMilan patients for those who received living donor liver transplantation (LDLT) for HCC in the United States [18].
Recently, Llovet et al reported a pilot study of LDLT results of 22 patients with HCC who had Barcelona Clinic Liver Cancer Extended criteria (1 tumor 8 cm, 5 tumors 3 cm, and 3 tumors 5 cm without macrovascular invasion or downstaging to Milan after locoregional therapies) [19]. In that trial, AFP level was lower than 100 ng/mL in 21of 22 patients, and at the time of transplantation, 10 of 22 patients were detected as within Milan criteria after neoadjuvant locoregional treatment with 1-, 3-, 5-, and 10-year survival reported as 95%, 86%, 80%, and 66%, respectively. In our study, 1-, 3-, and 5-year survival inside vs outside of the Milan criteria was 90%, 80%, and76% vs 75%, 66%, and 44%, respectively. According to inside vs outside of the UCSF criteria, 1-, 3-, and 5-year survival was found to be 86%, 76%, and 70% vs 76%, 60%, and 30%, respectively. The AFP cutoff value is still controversial. A pretransplant AFP level interval of 200 to 1000 ng/mL is accepted as an increased HCC recurrence risk following LT. Because of these findings, in recent years a HCC consensus group recommended that AFP can help to decide LT for HCC when it is used in combination with imaging [20]. Some studies have shown that high AFP level is a poor prognostic factor in HCC, and they suggest that the cutoff value is 200 ng/mL [21e23]. But some subsequent studies have suggested that AFP in fact has a low sensitivity (approximately 60%) and specificity (approximately 70%) [24e27]. Results from a multicenter, Italian database reported AFP and number of tumors and size were independent factors that predict the recurrence of HCC and survival on multivariate analysis. Furthermore, Duvoux et al reported the significance of AFP levels in patients with HCC who had undergone LT and illustrated the correlation between AFP levels and biologic behavior of the tumor such as tumor recurrence, vascular invasion, and tumor differentiation [28]. Finally, AFP has been accepted as a selection criteria in some centers and patients with AFP >1000 ng/mL have been excluded from
Table 4. Demographic Findings of Donors Age Cold ischemia time (min) Sex Female Male Transplant type Living Cadaveric Cause of donor Family/friend Brain death
36.49 12.660 (range, 18-75; LDLT:33, DDLT:54) 141.60 213.441 (range, 30-850; LDLT: 53 min, DDLT: 614 min)
Abbreviations: DDLT, deceased donor liver transplantation; LDLT, living donor liver transplantation.
43.6% (n ¼ 72, LDLT:63, DDLT:9) 56.4% (n ¼ 93, LDLT:76, DDLT:17) 84.2% (n ¼ 139) 15.8% (n ¼ 26) 84.2% (n ¼ 139) 15.8% (n ¼ 26)
HEPATOCELLULAR CARCINOMA AND LIVER TRANSPLANTATION
LT due to poor outcomes [28,29] . Similarly, we have shown that AFP level is a negative independent risk factor for both recurrence and survival in the present study. In addition to that, some studies have suggested that pathologic markers such as tumor differentiation and microvascular invasion may be more important than tumor size [30,31]. Presence of vascular invasion and grade of tumor has been demonstrated to be a significant predictor of recurrence and survival after LT [8,32,33]. Similarly, the present study showed that poor differentiation decreased survival, even if it was within the criteria. So, there is no problem in the transplant decision of patients with HCC within the criteria and low AFP levels. The main issue of discussion is the answer to the question of in which cases to or not to make a transplant decision. AFP level and histologic differentiation determine survival with morphologic criteria. Even beyond the criteria, if the AFP level is low or histologically well differentiated, LT can be performed easily. However, it should be kept in mind that in the presence of both the beyond criteria and the high AFP levels, the outcome of LT will not be satisfactory. In conclusion, LT is the only curative treatment for HCC and offers satisfactory long-term survival. The present study shows that AFP level and tumor differentiation are independent factors that affect recurrence and patient survival.
REFERENCES [1] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359e86. [2] Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519e24. [3] Edmonson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer 1954;7: 462e503. [4] Müller V, Fortsch T, Gundel M, et al. Long-term outcome of liver transplantation as treatment modality in patients with hepatocellular carcinoma in cirrhosis: a single-center experience. Transplant Proc 2013;45:1957e60. [5] Doyle MB, Vachharajani N, Maynard E, et al. Liver transplantation for hepatocellular carcinoma: long-term results suggest excellent outcomes. J Am Coll Surg 2012;215:19e28. [6] Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534e40. [7] Welker MW, Bechstein WO, Zeuzem S, Trojan J. Recurrent hepatocellular carcinoma after liver transplantation; an emerging clinical challenge. Transpl Int 2013;26:109e18. [8] Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693e9. [9] Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020e2. [10] Tamura S, Kato T, Berho M, et al. Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg 2001;136:25e30 [discussion: 31]. [11] De Carlis L, Giacomoni A, Lauterio A, et al. Liver transplantation for hepatocellular cancer: should the current indication criteria be changed? Transpl Int 2003;16:115e22.
5 [12] Herrero JI, Sangro B, Quiroga J, et al. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001;7:631e6. [13] Shetty K, Timmins K, Brensinger C, et al. Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 2004;10: 911e8. [14] Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007;246:502e9. [15] Chen JW, Kow L, Verran DJ, et al. Poorer survival in patients whose explanted hepatocellular carcinoma (HCC) exceeds Milan or UCSF criteria. An analysis of liver transplantation in HCC in Australia and New Zealand. HBP (Oxford) 2009;11:81e9. [16] Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large volume center. Liver Transpl 2008;14: 935e45. [17] Todo S, Furukawa H, Japanese Study Group on Organ Transplantation. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240:451e61. [18] Vakili K, Pomposelli JJ, Cheah YL, et al. Living donor liver transplantation for hepatocellular carcinoma: increased recurrence but improved survival. Liver Transpl 2009;15:1861e6. [19] Llovet JM, Pavel M, Rimola J, et al. Pilot study of living donor liver transplantation for patients with hepatocellular carcinoma exceeding Milan criteria (Barcelona Clinic Liver Cancer extended criteria). Liver Transpl 2018;24:369e79. [20] Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13: 11e22. [21] Forner A, Reig M, Bruix J. Alpha-fetoprotein for hepatocellular carcinoma diagnosis: the demise of a brilliant star. Gastroenterology 2009;137:26e9. [22] Margarit C, Charco R, Hidalgo E, Allende H, Castells L, Bilbao I. Liver transplantation for malignant diseases: selection and pattern of recurrence. World J Surg 2002;26:257e63. [23] Nomura F, Ohnishi K, Tanabe Y. Clinical features and prognosis of hepatocellular carcinoma with reference to serum alpha-fetoprotein levels. Analysis of 606 patients. Cancer 1989;64: 1700e7. [24] Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35e43. [25] Jonas S, Bechstein WO, Steinmüller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080e6. [26] Cescon M, Ravaioli M, Grazi GL, et al. Prognostic factors for tumor recurrence after a 12-year, single-center experience of liver transplantations in patients with hepatocellular carcinoma. J Transplant 2010;2010:904152. [27] Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008;8:2547e57. [28] Duvoux C, Roudot-Thoraval F, Decaens T, et al. Liver transplantation for hepatocellular carcinoma: a model including afetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:986e94. [29] Sapisochin G, Goldaracena N, Laurence JM, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology 2016;64:2077e88.
6 [30] Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 2002;8: 765e74. [31] Kakodkar R1, Soin AS. Liver transplantation for HCC: a review. Indian J Surg 2012;74:100e17.
POLAT, ACAR, GENCDAL ET AL [32] Ankeny JS, Court CM, Hou S, et al. Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer. Br J Cancer 2016;114:1367e75. [33] Wang Z, Luo L, Cheng Y, et al. Correlation between postoperative early recurrence of hepatocellular carcinoma and mesenchymal circulating tumor cells in peripheral blood. J Gastrointest Surg 2018;22:633e9.
ABSTRACT Background. Liver transplantation (LT) is the best treatment in selected patients with hepatocellular carcinoma (HCC). Morphologic criteria alone are not sufficient to predict survival. In this study, we investigated the clinical, biochemical, and pathologic factors affecting survival in patients who underwent LT due to HCC. Methods. Between October 2011 and January 2018, 165 of 749 LT for HCC cases performed at the Memorial Atasehir Hospital were evaluated retrospectively. Survival, demographic characteristics and etiology, preoperative alpha-fetoprotein (AFP) level, Model for End-Stage Liver Disease (MELD) score, prognostic staging, and morphologic and histologic properties were evaluated. Results. One hundred and thirty-nine cases of 165 were living donor liver transplantation (LDLT). The mean age was 57.7 7.3 years, the mean follow-up period was 27.8 20 months, and 41 patients (24%) died before follow-up. Recurrence of HCC was detected in 23 (14%) cases. Overall survival was 85%, 71%, and 64% for 1, 3, and 5 years, respectively. In terms of 1-, 3-, and 5-year survival within vs beyond Milan criteria was 90%, 80%, and 76% vs 75%, 66%, and 44%, respectively. In the University of California San Francisco criteria, it was 86%, 76%, and 70% vs 76%, 60%, and 30% compared with 1-, 3-, and 5-year survival. While histopathological poor differentiation and AFP elevation affected the course negatively. Good differentiation did not have a significant effect on survival. It was determined that poor differentiation, lymphovascular invasion, and an increased number of nodules significantly affected survival in both within and beyond cases. Conclusion. A transplant decision is controversial in patients with HCC with other than previously defined morphologic criteria. In these cases, AFP level and histologic differentiation determine survival. The results were not satisfactory in both high and/or poorly differentiated cases.
H
EPATOCELLULAR carcinoma (HCC) constitutes over 5% of all cancer types and 80% to 90% of primary liver malignancies, causing 250,000 to 1,000,000 deaths per year worldwide. It is the sixth most common cancer type, which is the second most common cause of cancer deaths in the world [1].
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e6 (2019)
*Address correspondence to Sencan Acar, Department of Gastroenterology and Organ Transplantation Center, Sakarya University School of Medicine, Korucuk Mahh Konuralp Blv No: 81/1 Korucuk Campus, Adapazarı, Sakarya, Turkey. Tel: þ90 264 295 66 30; Fax: 90 264 295 66 29. 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.10.029
1
2
The treatment options recommended for HCC include radical treatments (surgical resection, liver transplantation, percutaneous alcohol injection/radiofrequency ablation) (30%), palliative treatments (transarterial embolization/ chemoembolization, hormonal treatment/immunotherapy, anti-proliferative agents) (40%-50%), and symptomatic treatments (20%-30%) [2]. However, despite the developments of liver transplantation, a small number of the patients with HCC may have a chance for liver transplantation. The major point is the recurrence and survival benefit for patients after liver transplantation. After vast experience with liver transplantation for HCC, it is clearly understood that not only tumor size predicts the prognosis, but histologic findings and preoperative alpha-fetoprotein (AFP) levels are important and valuable prognostic markers for HCC recurrence. There are many criteria for liver transplantation such as Milan, University of California San Francisco (UCSF), Toronto, up-to-seven, Metroticket, and others. All of those criteria are morphologic, but we do not know the biological behavior of the tumor. So, there is no obvious predictive scoring system or criteria to detect recurrence of HCC and survival after liver transplantation. In the present study, we aimed to evaluate the clinical, biochemical, and pathologic factors that affect the recurrence of HCC and the survival of patients who underwent liver transplantation due to HCC. MATERIALS AND METHODS We retrospectively studied 165 of 749 patients whose explant pathology indicated HCC and who underwent liver transplantation between October 2011 and January 2018 at Memorial Atasehir Hospital. Demographic characteristics and etiology, preoperative AFP level, Model for End-Stage Liver Disease (MELD) score, prognostic staging criteria (Milan, UCSF), and morphologic (number of nodules, diameter, largest nodule size, multifocality, presence of bilobar involvement) and histologic (vascular invasion, histologic differentiation) factors were collected from the database of Memorial Atasehir Hospital, Liver Transplantation Center. AFP and computed tomography and/or magnetic resonance imaging were performed every 3 months in the first year after liver transplantation and then every 6 months. Immunosuppressive therapy consisted of calcineurin inhibitor and rapid steroid taper with mycophenolate mofetil (MMF) combination. Prednisolone was given at a dosage of 500 mg intravenously in the operating room, followed by a taper from 100 mg to 20 mg for a period of 8 days and from 20 mg to 10 mg after 2 months. MMF was used when lower doses of calcineurin inhibitors were required due to renal dysfunction. Steroids were tapered and stopped in the sixth month; MMF was switched to everolimus, and the tacrolimus dose was reduced after the third month.
Histopathology of Explanted Liver The explanted livers were fixed in formalin and sliced as 1 cm thickness to note the number and largest size of tumor nodules. Hematoxylin-eosin stained tumor sections were analyzed routinely for the differentiation grade, growth pattern, and microscopic and larger vessel invasions as well as lymph node metastases. Tumor
POLAT, ACAR, GENCDAL ET AL differentiation was graded as moderate and poor according to Edmonson and Steiner [3].
Statistical Analyses Continuous variable results are given as means standard deviations; categorical variable results are given as percentages. Comparisons of results for categorical variables were made by c2 test or the Fisher exact test. Survival was assessed using the KaplanMeier method, with comparisons made using a log-rank test. P values of < .05 were considered statistically significant. Statistical analysis was done using SPSS for Windows version 14.0 (IBM Corp, Armonk, NY, United States).
RESULTS
One hundred and sixty-five patients were evaluated. Mean age was 57.7 7.3 years (range, 31-72 years) and 132 (80%) were male. One hundred thirty-nine had living donor liver transplantation. The average pre-transplant MELD score was 12.3 4.8 (range, 6-29), and mean AFP level was 271.8 ng/mL (1-26370 ng/mL). The mean follow-up period was 27.8 20 months, and 41 patients (24%) were lost during follow-up. Recurrence HCC was detected in 23 cases (14%). Overall survival was found as 85%, 71%, and 64% for 1, 3, and 5 years, respectively. In terms of 1-, 3-, and 5-year survival within Milan vs beyond Milan criteria was found as 90%, 80%, and 76% vs 75%, 66%, and 44%, respectively. The patients with beyond Milan had poorly differentiated survival significantly lower. According to within vs beyond, the UCSF criteria was detected as 86%, 76%, and 70% vs 76%, 60%, and 30% for 1-, 3-, and 5-year survival, respectively. The patients with beyond UCSF criteria and poorly differentiated survival significantly lower. High AFP levels affect the post-transplant course negatively according to both Milan and UCSF criteria (Fig 1). In 133 patients, the AFP level was under 100 ng/mL; in 19 patients it was between 100 ng/mL and 500 ng/mL; in 8 patients it was between 500 ng/mL and 1000 ng/mL; and in 5 patients it was >1000 ng/mL. Histologic examination revealed that poor histologic differentiation has a negative effect on survival. Criteria do not significantly affect survival in good differentiation. The survival rate was significantly lower in both inside of criteria and poorly differentiated patients. Lymphovascular invasion had a significantly negative effect on survival. Survival is negatively affected as the number of nodules increases. We classified all patients as 2 subgroups; group 1 is living patients (n ¼ 124), group 2 is patients who have died (n ¼ 41). There were 58 (35.1%) patients with HCC beyond the Milan criteria and 46 (27.8%) patients with HCC beyond the UCSF criteria. The quantitative and qualitative factors affecting the survival of the patients are shown in Tables 1 and 2. The mean preoperative AFP level in living patients was 65.29 164 ng/mL; in the loosing group it was 317 698 ng/mL. Group 2 had significantly higher levels. The mean number of nodules in group 1 was 2.27 2.6
HEPATOCELLULAR CARCINOMA AND LIVER TRANSPLANTATION
3
Fig 1. Survival rates for AFP>100, 100-500, 500-1000, and >1000. AFP, alphafetoprotein.
(range, 1-20); in group 2 it was 3.34 4 (range, 1-20). It is also significantly high in loosing group. We performed receiver operating characteristic (ROC) analysis in order to find the cutoff value for AFP by using “survival status.” The significance level for the area under the curve was higher than 0.05. Then, ROC analysis for AFP by using “recurrence status” showed the cutoff value was 11 ng/mL. The significance level for area under the curve was 0.695 (95% confidence interval: 0.619 to 0.765), P ¼ .0006 (Table 3). The mean diameter of the largest nodule in group 1 was 30.56 18 mm (range, 8-85 mm), in group 2 39.1 26 mm (range, 10-160 mm). It is also significantly higher in group 2. Of these 165 patients, 68 (41%) had multifocal nodules, 62 (37.5%) had lymphovascular invasion, 54 (32.7%) had venous invasion, and 8 (4.8%) had perineural invasion. Sixty-four patients (38.7%) had good differentiation, 85 patients (51.6%) had moderate differentiation, and 16 patients (9.7%) had poor differentiation in their explant livers. Demographic features with donors are shown in Table 4. Table 1. Quantitative Factors Affecting Patient Survival Living patients (n ¼ 124)
Age 58.6 6 MELD score 12.42 4 Preop AFP (ng/mL) 65.29 164 Number of nodules 2.27 2.6 Largest nodule diameter (mm) 30.56 18
Deceased patients (n ¼ 41)
56.87 12.29 317 3.34 39.1
9 5 698 4 26
P
.37 .90 .00 .02 .05
Abbreviations: AFP, alpha-fetoprotein; MELD, Model for End-Stage Liver Disease.
DISCUSSION
Liver transplantation (LT) is the curative treatment option for HCC [4,5]. However, the most important risk factor among patients who undergo LT is the recurrence rate. It has been reported as 10% to 30% in selected patients [6]. It is shown that HCC recurrence significantly reduces the postLT survival [7]. Treatment options are fairly limited in patients with HCC recurrence. Therefore, the patient selection process becomes an important factor to minimize
Table 2. Qualitative Factors Affecting Patient Survival Living patients (n ¼ 124)
Histopathological Features Multifocality, yes no Differentiation good mild poor Perineural invasion no yes Lymphatic invasion no yes Lymphovascular invasion
Mortality (n ¼ 41)
P
.04 46 78
23 18
44 61 10
7 24 7
121 3
36 5
84 38
17 14
69 53
14 27
.00
.02
.02
.01
4
POLAT, ACAR, GENCDAL ET AL Table 3. ROC Analysis for AFP (Recurrence)
Criterion
>11
Sensitivity
95% CI
Specificity
95% CI
þLR
-LR
þPV
-PV
69.57
47.1-86.8
65.49
57.1-73.3
2.02
0.46
24.6
93.0
Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval; LR, likelihood ratio; PV, predictive value; ROC, receiver operating characteristic.
the recurrence risk. Most of the represented, patient selection criteria until now have been described according to the morphologic characteristics such as tumor diameter, tumor number, and vascular invasion. Recently, AFP and PIVKA II levels were suggested to combine with those morphologic criteria to decide for LT in patients with HCC. Multiple classifications have been used to select patients for LT. The Milan criteria, published by Mazzaferro et al in 1996, has been used the most frequently, described as 1 tumor with size <5 cm or up to 3 nodules, each smaller than 3 cm without major vascular invasion [8]. Five-year survival was reported to be over 70% in the patients with early stage HCC [9]. Some variables described to be the predictive factors for the risk of HCC recurrence after LT include vascular invasion, histologic differentiation, and preoperative AFP level [10e13]. Since the Milan criteria is too restrictive, new selection criteria have been studied and novel proposals were developed. The UCSF criteria was developed in 2001. It was defined as a single lesion under 6.5 cm or 2 or 3 lesions of <4.5 cm with total tumor diameter <8 cm. According to these criteria, 1-year survival was reported as 95.9%, and 5-year survival was 90% [14e16]. Similarly, Korean Asan Medical Center’s criteria (each tumor <5 cm and up to 6 nodules) and the registrybased, up-to-7 score (size of largest HCC þ number of HCCs <7), the extended Toronto criteria (any size or number of tumors provided they do not have systemic, cancer-related symptoms, extrahepatic disease, vascular invasion, or poorly differentiated tumors) were developed to increase the number of patients for LT due to HCC. In a multicenter study involving 316 patients in Japan, the 3-year survival rates for intra-Milan patients who underwent LT for HCC were 79%, and beyond Milan were 61% [17]. The 5year survival rate was 87.1% in Milan and 80% in nonMilan patients for those who received living donor liver transplantation (LDLT) for HCC in the United States [18].
Recently, Llovet et al reported a pilot study of LDLT results of 22 patients with HCC who had Barcelona Clinic Liver Cancer Extended criteria (1 tumor 8 cm, 5 tumors 3 cm, and 3 tumors 5 cm without macrovascular invasion or downstaging to Milan after locoregional therapies) [19]. In that trial, AFP level was lower than 100 ng/mL in 21of 22 patients, and at the time of transplantation, 10 of 22 patients were detected as within Milan criteria after neoadjuvant locoregional treatment with 1-, 3-, 5-, and 10-year survival reported as 95%, 86%, 80%, and 66%, respectively. In our study, 1-, 3-, and 5-year survival inside vs outside of the Milan criteria was 90%, 80%, and76% vs 75%, 66%, and 44%, respectively. According to inside vs outside of the UCSF criteria, 1-, 3-, and 5-year survival was found to be 86%, 76%, and 70% vs 76%, 60%, and 30%, respectively. The AFP cutoff value is still controversial. A pretransplant AFP level interval of 200 to 1000 ng/mL is accepted as an increased HCC recurrence risk following LT. Because of these findings, in recent years a HCC consensus group recommended that AFP can help to decide LT for HCC when it is used in combination with imaging [20]. Some studies have shown that high AFP level is a poor prognostic factor in HCC, and they suggest that the cutoff value is 200 ng/mL [21e23]. But some subsequent studies have suggested that AFP in fact has a low sensitivity (approximately 60%) and specificity (approximately 70%) [24e27]. Results from a multicenter, Italian database reported AFP and number of tumors and size were independent factors that predict the recurrence of HCC and survival on multivariate analysis. Furthermore, Duvoux et al reported the significance of AFP levels in patients with HCC who had undergone LT and illustrated the correlation between AFP levels and biologic behavior of the tumor such as tumor recurrence, vascular invasion, and tumor differentiation [28]. Finally, AFP has been accepted as a selection criteria in some centers and patients with AFP >1000 ng/mL have been excluded from
Table 4. Demographic Findings of Donors Age Cold ischemia time (min) Sex Female Male Transplant type Living Cadaveric Cause of donor Family/friend Brain death
36.49 12.660 (range, 18-75; LDLT:33, DDLT:54) 141.60 213.441 (range, 30-850; LDLT: 53 min, DDLT: 614 min)
Abbreviations: DDLT, deceased donor liver transplantation; LDLT, living donor liver transplantation.
43.6% (n ¼ 72, LDLT:63, DDLT:9) 56.4% (n ¼ 93, LDLT:76, DDLT:17) 84.2% (n ¼ 139) 15.8% (n ¼ 26) 84.2% (n ¼ 139) 15.8% (n ¼ 26)
HEPATOCELLULAR CARCINOMA AND LIVER TRANSPLANTATION
LT due to poor outcomes [28,29] . Similarly, we have shown that AFP level is a negative independent risk factor for both recurrence and survival in the present study. In addition to that, some studies have suggested that pathologic markers such as tumor differentiation and microvascular invasion may be more important than tumor size [30,31]. Presence of vascular invasion and grade of tumor has been demonstrated to be a significant predictor of recurrence and survival after LT [8,32,33]. Similarly, the present study showed that poor differentiation decreased survival, even if it was within the criteria. So, there is no problem in the transplant decision of patients with HCC within the criteria and low AFP levels. The main issue of discussion is the answer to the question of in which cases to or not to make a transplant decision. AFP level and histologic differentiation determine survival with morphologic criteria. Even beyond the criteria, if the AFP level is low or histologically well differentiated, LT can be performed easily. However, it should be kept in mind that in the presence of both the beyond criteria and the high AFP levels, the outcome of LT will not be satisfactory. In conclusion, LT is the only curative treatment for HCC and offers satisfactory long-term survival. The present study shows that AFP level and tumor differentiation are independent factors that affect recurrence and patient survival.
REFERENCES [1] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359e86. [2] Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519e24. [3] Edmonson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer 1954;7: 462e503. [4] Müller V, Fortsch T, Gundel M, et al. Long-term outcome of liver transplantation as treatment modality in patients with hepatocellular carcinoma in cirrhosis: a single-center experience. Transplant Proc 2013;45:1957e60. [5] Doyle MB, Vachharajani N, Maynard E, et al. Liver transplantation for hepatocellular carcinoma: long-term results suggest excellent outcomes. J Am Coll Surg 2012;215:19e28. [6] Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534e40. [7] Welker MW, Bechstein WO, Zeuzem S, Trojan J. Recurrent hepatocellular carcinoma after liver transplantation; an emerging clinical challenge. Transpl Int 2013;26:109e18. [8] Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693e9. [9] Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020e2. [10] Tamura S, Kato T, Berho M, et al. Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg 2001;136:25e30 [discussion: 31]. [11] De Carlis L, Giacomoni A, Lauterio A, et al. Liver transplantation for hepatocellular cancer: should the current indication criteria be changed? Transpl Int 2003;16:115e22.
5 [12] Herrero JI, Sangro B, Quiroga J, et al. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001;7:631e6. [13] Shetty K, Timmins K, Brensinger C, et al. Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 2004;10: 911e8. [14] Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007;246:502e9. [15] Chen JW, Kow L, Verran DJ, et al. Poorer survival in patients whose explanted hepatocellular carcinoma (HCC) exceeds Milan or UCSF criteria. An analysis of liver transplantation in HCC in Australia and New Zealand. HBP (Oxford) 2009;11:81e9. [16] Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large volume center. Liver Transpl 2008;14: 935e45. [17] Todo S, Furukawa H, Japanese Study Group on Organ Transplantation. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240:451e61. [18] Vakili K, Pomposelli JJ, Cheah YL, et al. Living donor liver transplantation for hepatocellular carcinoma: increased recurrence but improved survival. Liver Transpl 2009;15:1861e6. [19] Llovet JM, Pavel M, Rimola J, et al. Pilot study of living donor liver transplantation for patients with hepatocellular carcinoma exceeding Milan criteria (Barcelona Clinic Liver Cancer extended criteria). Liver Transpl 2018;24:369e79. [20] Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13: 11e22. [21] Forner A, Reig M, Bruix J. Alpha-fetoprotein for hepatocellular carcinoma diagnosis: the demise of a brilliant star. Gastroenterology 2009;137:26e9. [22] Margarit C, Charco R, Hidalgo E, Allende H, Castells L, Bilbao I. Liver transplantation for malignant diseases: selection and pattern of recurrence. World J Surg 2002;26:257e63. [23] Nomura F, Ohnishi K, Tanabe Y. Clinical features and prognosis of hepatocellular carcinoma with reference to serum alpha-fetoprotein levels. Analysis of 606 patients. Cancer 1989;64: 1700e7. [24] Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35e43. [25] Jonas S, Bechstein WO, Steinmüller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080e6. [26] Cescon M, Ravaioli M, Grazi GL, et al. Prognostic factors for tumor recurrence after a 12-year, single-center experience of liver transplantations in patients with hepatocellular carcinoma. J Transplant 2010;2010:904152. [27] Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008;8:2547e57. [28] Duvoux C, Roudot-Thoraval F, Decaens T, et al. Liver transplantation for hepatocellular carcinoma: a model including afetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:986e94. [29] Sapisochin G, Goldaracena N, Laurence JM, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology 2016;64:2077e88.
6 [30] Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 2002;8: 765e74. [31] Kakodkar R1, Soin AS. Liver transplantation for HCC: a review. Indian J Surg 2012;74:100e17.
POLAT, ACAR, GENCDAL ET AL [32] Ankeny JS, Court CM, Hou S, et al. Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer. Br J Cancer 2016;114:1367e75. [33] Wang Z, Luo L, Cheng Y, et al. Correlation between postoperative early recurrence of hepatocellular carcinoma and mesenchymal circulating tumor cells in peripheral blood. J Gastrointest Surg 2018;22:633e9.