Impact of incidentally found hepatocellular carcinoma on the outcome of living donor liver transplantation
2006; Springer Science+Business Media; Volume: 19; Issue: 9 Linguagem: Inglês
10.1111/j.1432-2277.2006.00338.x
ISSN1432-2277
AutoresYoji Kishi, Yasuhiko Sugawara, Sumihito Tamura, Junichi Kaneko, Norihiro Kokudo, Masatoshi Makuuchi,
Tópico(s)Liver Disease and Transplantation
ResumoTransplant InternationalVolume 19, Issue 9 p. 720-725 Free Access Impact of incidentally found hepatocellular carcinoma on the outcome of living donor liver transplantation Yoji Kishi, Yoji Kishi Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorYasuhiko Sugawara, Yasuhiko Sugawara Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorSumihito Tamura, Sumihito Tamura Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorJunichi Kaneko, Junichi Kaneko Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorNorihiro Kokudo, Norihiro Kokudo Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorMasatoshi Makuuchi, Masatoshi Makuuchi Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this author Yoji Kishi, Yoji Kishi Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorYasuhiko Sugawara, Yasuhiko Sugawara Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorSumihito Tamura, Sumihito Tamura Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorJunichi Kaneko, Junichi Kaneko Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorNorihiro Kokudo, Norihiro Kokudo Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this authorMasatoshi Makuuchi, Masatoshi Makuuchi Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, JapanSearch for more papers by this author First published: 20 June 2006 https://doi.org/10.1111/j.1432-2277.2006.00338.xCitations: 12 Yasuhiko Sugawara MD, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.Tel.: 81 3 3815 5411; fax: 81 3 5684 3989;e-mail: yasusuga-tky@umin.ac.jp AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary Hepatocellular carcinoma (HCC) nodules newly found in the explant liver have been observed, but the impact on patient prognosis is not known. Sixty HCC patients who underwent living donor liver transplantation were the subjects of the study. Radiologic findings prior to transplantation and pathologic findings of the explant liver were compared. Histologic characteristics of preoperatively overlooked tumors were examined. The influence of the discrepancy between these findings on tumor recurrence was evaluated. A total of 227 HCC nodules were found in the explant livers. Of these, 91 nodules (40%) were newly found by pathologic examination. They were smaller and more likely to be well differentiated than the others. The number and size of the tumors were underestimated in 50% (30/60) and 32% (19/60), respectively. There was no significant difference in the recurrence-free survival rate between patients who met the Milan criteria both in the pre- and post-transplant evaluation (n = 29) and those who met the Milan criteria preoperatively, but exceeded the criteria in the explant (n = 19). Nodules newly found in the explant liver had little impact on recurrence-free survival. A decision for liver transplantation according to the Milan criteria based on preoperative evaluation is valuable for securing an excellent outcome. Introduction Deceased donor liver transplantation (DDLT) is established as an effective treatment for hepatocellular carcinoma (HCC) [1-3]. Progression of the tumor before transplantation, however, strongly affects outcome. It has become accepted that DDLT should only be performed in selected cases [4, 5]. Currently, patient selection according to the Milan criteria [6] is applied world-wide with excellent results [5, 7, 8]. The existence of incidental HCCs found in the explant liver, but overlooked during the pretransplant evaluation, has been observed and recognized as not adversely affecting the outcome of transplantation [9-13]. Recently, HCC has become a major indication for living donor liver transplantation (LDLT) because the risk of dropout or tumor progression while waiting for an available organ is negligible in LDLT [14-16]. The existence of incidental HCC, however, has also become evident, even in this population which undergoes scheduled transplant surgery after strict preoperative evaluation with a shorter waiting period. The histologic nature of such incidental HCC and its effect on prognosis after LDLT, however, has not yet been described in detail. We retrospectively analyzed the discrepancy between pre- and post-transplantation tumor evaluation in our series and report the results herein. Patients and methods Patients A total of 68 patients underwent LDLT for HCC either as a primary or secondary indication with decompensated liver cirrhosis at our center between June 1998 and December 2004, including 13 cases that exceeded the Milan criteria. Of these, two patients with more than 10 tumors and six patients with only completely necrotic tumors in the explanted liver were excluded, and the other 60 patients were the subjects of the study. Mean and SD of the follow-up period was 31 ± 20 months. The etiology of liver cirrhosis was hepatitis C virus-related in 38 (63%), hepatitis B virus-related in 14 (23%), alcoholism in three (5%), primary biliary cirrhosis in two (3%), cryptogenic in two (3%), and hepatitis B and C virus-related in one (2%). The mean and SD of the Child-Pugh score was 9.6 ± 1.9. Twenty-two (38%) and 31 (53%) patients were classified as Child-Pugh B and C, respectively. Preoperative therapy for HCC included percutaneous ethanol injection therapy or radio-frequency ablation in 29 patients and transarterial chemoembolization in 28, and both in seven patients. Preoperative evaluation of HCC The preoperative diagnosis of HCC was based on helical computed tomography (CT) of multi-phase dynamic study with contrast enhancement taken within 1 month before LDLT. Triple-phase contiguous CT scans with 7-mm-thick sections were obtained. First, nonenhanced CT scans were obtained. Early (arterial)-phase CT scans were obtained 30 s after the initiation of the bolus injection of 100 ml of 65% iopamidol; late (portal)-phase scans were obtained 120 s after the initiation of the injection. The lesions with typical radiologic characteristics or classical HCC, i.e. stained in the arterial phase and detected as low-density lesion in the portal phase, were diagnosed as HCC. The lesions with early staining and not low in the portal phase or low-density lesions in the portal phase without enhancement in the arterial phase were diagnosed as regenerative or dysplastic nodules. Evaluation of the explant liver Immediately following explantation of the diseased liver, the location of each tumor identified prior to transplantation was confirmed by ex situ hepatic ultrasound (SS-6500; Aloka Co., Tokyo, Japan) at the side table in the operation theater. Tumors newly detected at this stage were recorded and assigned for further study. The liver was then sliced approximately 1-cm thick along the axial plane to check for tumors on the cut surface. Pathologic features, including histologic differentiation, capsular formation, growth pattern (expansive or infiltrative), intrahepatic metastasis, and microvascular invasion were evaluated. Comparison of pre- and post-transplant staging Comparison of the number and size of HCC nodules recognized by preoperative radiologic evaluation and pathologic analysis of the explant liver were performed in each case. According to the discrepancy between the pre- and post-transplant findings concerning the number of tumors, the patients were classified into the following three groups: NU, the number of tumors was underestimated; NO, the number was overestimated; NC, the number was correctly diagnosed. According to the discrepancy in tumor size, the patients were classified into three groups: SU, the size of the tumor was underestimated; SO, the size was overestimated; SC, the size was correctly diagnosed. The over- or underestimation of tumor size was defined as a mismatch of the tumor diameter of 5 mm or more in diameter between the preoperative and postoperative diagnosis. Follow-up of the patient after transplantation All patients were followed-up at our department after transplantation according to the following protocol; monthly measurement of alpha-feto protein and protein-induced-by-vitamin-K absence II, abdominal ultrasound performed every 3 months, and dynamic CT every 6 months. Recurrence was defined as the emergence of radiologic findings compatible with classical HCC. To assess the influence of the discrepancy between pre- and post-transplantation evaluation on recurrence-free survival, patients were stratified into four groups as follows: M, those who satisfied the Milan criteria in both the pre- and post-transplant evaluation; E1, those with extra-Milan HCC in both pre- and postoperative evaluations; E2, those who satisfied the Milan criteria preoperatively, but had HCCs in the explant exceeding the criteria. In addition, patients' preoperative profiles and pathologic tumor characteristics were analyzed to specify the risk factors of tumor recurrence. Statistics Each value was expressed as mean and SD. Statistical comparisons were made by Wilcoxon signed rank test for quantitative variables and Pearson's chi-squared test or Fisher's exact test for qualitative variables. Recurrence-free survival was estimated using the Kaplan–Meyer method and compared by log-rank test. Multivariate analysis for the risk factors of tumor recurrence was performed by logistic regression test. A P-value <0.05 was considered to be statistically significant. Results Discrepancy between pre- and post-transplantation evaluation The NC, NO, and NU consisted of 27, 3, and 30 cases, respectively (Table 1). There were no statistical differences in age, sex, or severity of cirrhosis as represented by the Child-Pugh score. When treatment modalities against HCC prior to transplantation were analyzed, however, percutaneous ethanol injection therapy or radio-frequency ablation were performed more frequently in NU patients, although transarterial chemoembolization seemed to have little influence over such discrepancies. In contrast, 26, 15, and 19 patients were classified as group SC, SO, and SU, respectively. Table 1. Profiles of the patients stratified by the tumor numbers. Groups NC (n = 27) NO (n = 3) NU (n = 30) P-value* Age 54 ± 6.7 57 ± 4.5 55 ± 5.4 0.86 Men/women 20/7 1/2 27/3 0.10 Child-Pugh class (A/B/C) 1/9/17 2/1/0 2/13/15 0.80† Preoperative treatment TACE 8 2 12 0.79 PEIT/RFA 4 1 14 0.03 Both 1 0 6 0.10 TACE, transarterial chemoembolization; PEIT, percutaneous ethanol injection therapy; RFA, radio-frequency ablation; NU, the number of tumors was underestimated; NO, the number was overestimated; NC, the number was correctly diagnosed. *Comparison between NC + NO and NU. †Comparison between Child A + B and C. Histologic grade of incidentally found HCCs A total of 227 HCC nodules were found in the explant livers. Of these, 91 nodules (40%) were newly found by pathologic examination (Table 2). None were poorly differentiated. Among them, 15 were preoperatively detected, but diagnosed as dysplastic nodules. Table 2. Differentiation of preoperatively detected or undetected tumors. Preoperative diagnosis Hepatocellular carcinoma (n = 136) Benign nodule (n = 15) Undetected (n = 76) Well 52 12 43 Moderate 45 3 14 Poor 3 0 0 Combined* 1 0 0 Necrosis 35 0 19 *Hepatocellular carcinoma and cholangiocellular carcinoma. Of the 227 HCC nodules, 54 nodules could not be histologically analyzed because they were essentially necrotic (Table 3). The morphologic characteristics of the other 173 HCCs indicated that the preoperatively undetected HCCs were significantly smaller and more likely to be well differentiated. A total of 47 nodules were 1 cm or less in diameter and 30 (64%) of them were preoperatively undetected. Table 3. Histological characters of hepatocellular carcinoma nodules. Preoperative diagnosis Hepatocellular carcinoma Benign nodule or undetected P-value n 101 72 Size 2.1 ± 1.4 1.1 ± 0.5 0.9999 Im‡ 7 (7%) 0 0.04 *Tumor infiltration to the capsule. †Infiltrative growth pattern. ‡Intrahepatic metastasis. Analysis of recurrence-free survival Groups M, E1, and E2 consisted of 29, 12, and 19 patients, respectively. Group E2 included 11 number underestimation, four number underestimation and microvascular invasion, three microvascular invasion (both number and size were correctly estimated), and one underestimation in both number and size. Recurrence occurred in three patients in group E1 at 3, 6, and 14 months after LDLT. In group E2, two patients presented with recurrent HCC at 9 and 16 months after LDLT. No recurrence occurred in group M patients. There was a statistically significant difference between M and E1. There were no significant differences, however, between groups M and E2 (Fig. 1). Figure 1Open in figure viewerPowerPoint Recurrence-free survival of each group. There was no tumor recurrence during the follow-up period in patients of group M. Significant difference was seen between group M and group E1. Thick line, group M; thin gray line, group E1; thin black line, group E2. An alpha-feto protein level over 300 ng/ml and poorly differentiated HCC negatively affected tumor-free survival rate (Table 4). Multivariate analysis revealed that poorly differentiated HCC was a significant risk factor for recurrence (Table 5). Table 4. Recurrence-free survival. Factors No Recurrence-free survival (%) P-value 1 year 3 year Age ≥60 12 91 91 0.97 0.9999 Women 12 91 91 Preoperative RFA/PEIT Yes 19 90 84 0.20 No 41 95 95 Preoperative TACE Yes 22 95 90 0.90 No 38 94 91 AFP* ≥300 ng/ml 12 83 74 0.02 <300 ng/ml 48 98 95 PIVKA II† ≥200 mAu/ml 7 100 80 0.54 <200 mAu/ml 53 94 92 Maximum tumor size ≥5 cm 5 80 80 0.26 <5 cm 55 96 92 Tumor numbers ≥5 9 89 89 0.78 <5 51 96 91 Histological differentiation* Well/moderate 50 100 95 <0.0001 Poor 3 33 33 Vascular invasion Yes 14 100 85 0.45 No 46 93 93 Intrahapteic metastasis Yes 6 100 100 0.47 No 54 94 90 AFP, alpha-feto protein; PIVKA II, protein-induced-by-vitamin-K-deficiency II; TACE, transarterial chemoembolization; PEIT, percutaneous ethanol injection therapy; RFA, radio-frequency ablation. *Lowest among the tumors. Table 5. Multivariate analysis for the risk factors of tumor recurrence. Factors Odds ratio 95% CI P-value AFP (≥300 ng/ml vs. <300 ng/ml) 5.63 −0.96 to 4.93 0.2 Histological differentiation (poor versus well/moderate) 56.94 1.20–7.78 0.0097 AFP, alpha-feto protein; CI, confidential interval. Discussion Several articles emphasize the inconsistency of radiologic and pathologic estimation of HCC in cirrhotic liver [8, 10, 17-19]. These studies revealed that 7–60% of HCC are undetected preoperatively, although most of the reports did not discuss the influence of undetected HCC on exceeding the Milan criteria or on tumor recurrence rate in the context of liver transplantation. Our results indicate that 40% of HCCs were missed or underestimated as dysplasia or adenomatous hyperplasia. This might be due, at least in part, to preoperative local treatment such as radio-frequency ablation or percutaneous ethanol injection therapy. These results are similar to another report showing the low sensitivity of CT (36%) for detecting residual or recurrence after radio-frequency ablation [20]. Sotiropoulos et al. [21] reported that the sensitivity of radiologic detection of HCC of 1–2 cm and <1 cm in diameter was only 21% and 0%, respectively. Zancherl et al. [22] described that preoperative CT was inferior in staging HCC in cirrhosis versus intraoperative ultrasonography. The present analysis indicated that even if patients with extra-Milan criteria were falsely estimated to satisfy Milan criteria preoperatively, their tumor-free survival rate does not significantly change compared with patients who fulfill the criteria. Similar to that were reported by Ravaioli et al. [8]. In their analysis of 63 HCC patients who survived more than 1 year after liver transplantation, the rate of exceeding the Milan criteria as assessed by postoperative staging (29%) was significantly higher than that assessed by preoperative staging (13%) because of small nodules undetected preoperatively. Comparison of the recurrence and survival rates between patients meeting and not meeting the Milan criteria, however, revealed a significant difference only in the preoperative staging and not in the postoperative staging. This might be due to the preoperatively undetected nodules being histologically less aggressive. In the present analysis, in 11 of the 19 Group E2 patients, number of the tumors was underestimated. That is, the tumor size underestimation had little influence on the prognosis. Multivariate analysis revealed that only poorly differentiated HCC was a significant risk factor for tumor recurrence. Unexpectedly, vascular invasion or intrahepatic metastasis, which are recognized as risk factors of tumor recurrence in several previous reports [7, 17, 23, 24], did not significantly affect recurrence rate in our study. This discrepancy might be partly due to the small number of episodes of HCC recurrence. In our five cases of HCC recurrence, there was microvascular invasion in only two. Of 14 cases with microvascular invasion in the explanted liver, 10 survived without recurrence for 8–45 months. Two other patients with macroscopic vascular invasion survived 19 and 60 months without recurrence. In conclusion, the present analysis indicates that nodules newly found in the explant liver had little impact on recurrence-free survival. A decision for LDLT according to the Milan criteria based on preoperative evaluation is valuable for securing an excellent outcome. 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