Original Clinical Science
New Pathologic Stratification of Microvascular Invasion in Hepatocellular Carcinoma: Predicting Prognosis After Living-donor Liver Transplantation Tomohiro Iguchi,1 Ken Shirabe,1 Shinichi Aishima,2 Huanlin Wang,2 Nobuhiro Fujita,3 Mizuki Ninomiya,1 Yo-ichi Yamashita,1 Toru Ikegami,1 Hideaki Uchiyama,1 Tomoharu Yoshizumi,1 Yoshinao Oda,2 and Yoshihiko Maehara1 Background. Vascular invasion of hepatocellular carcinoma (HCC) has a high incidence of recurrence after liver transplantation. Patients with microvascular invasion (MVI) show a high tumor grade; however, some show a good prognosis. This retrospective study aimed to investigate whether the degree of MVI affects prognosis after living-donor liver transplantation. Methods. A total of 142 patients with HCC who had undergone living-donor liver transplantation were histologically evaluated about the number of invaded vessels and the maximum number of invading carcinoma cells. Patients with MVI were classified into two subgroups: high MVI group (n = 38), which showed more than 50 carcinoma cells in the vessels, with multiple invaded vessels; and low MVI group (n = 17), which showed MVI, but not high MVI. Results. Analysis of recurrence-free survival showed that high MVI group had significantly poorer outcomes than the other groups (P < 0.001). High MVI group had significantly higher α-fetoprotein levels, des-γ-carboxy prothrombin levels, number of tumors, a larger tumor size, and a higher percentage of poorly differentiated HCC than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.030). Among patients exceeding the Milan criteria (n = 61), high MVI group had significantly poorer outcomes than the other groups for recurrence-free survival (P = 0.003). Patients in high MVI group had significantly higher des-γ-carboxy prothrombin levels and a larger tumor size than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.014). Conclusion. In livingdonor liver transplantation for HCC, high MVI is a novel pathologic marker for predicting prognosis.
(Transplantation 2015;99: 1236–1242)
H
epatocellular carcinoma (HCC) is the fifth most common neoplasm in the world.1-3 Despite recent development of surgical techniques and preoperative or postoperative management, a high incidence of HCC recurrence has shown an unsatisfactory outcome.4 Liver transplantation for treating cirrhosis and tumors at the same time has been established as an effective treatment for HCC.5 The Milan criteria advocated by Mazzaferro et al., who showed that patients who have a single tumor of less than 5 cm or three tumors less than 3 cm in Received 3 March 2014. Revision requested 25 March 2014. Accepted 27 August 2014. 1
Department of Surgery and Science, Kyushu University, Fukuoka, Japan.
2
Department of Anatomic Pathology, Kyushu University, Fukuoka, Japan.
3
Department of Molecular Imaging and Diagnosis, Kyushu University, Fukuoka, Japan.
T.I. participated in the study concept and design and drafting of article. K.S. participated in the study concept and critical revision of the article. S.A. participated in the pathologic examination. H.W. participated in the pathologic examination. N.F. participated in the critical revision of the article. M.N. participated in statistical analysis. Y.Y. participated in data collection. T.I. participated in the critical revision of the article. H. U. participated in data collection. T.Y. participated in the critical revision of the article. Y.O. participated in the pathologic examination. Y.M. participated in the final approval of the article. The authors declare no funding or conflicts of interest. Correspondence: Tomohiro Iguchi, MD, Department of Surgery and Science, Kyushu University, Maidashi 3-1-1, Fukuoka, Japan. ([email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9906-1236 DOI: 10.1097/TP.0000000000000489
1236
www.transplantjournal.com
diameter have a good prognosis after liver transplantation is an acceptable indication for HCC worldwide.6 However, patients exceeding the Milan criteria have been transplanted and occasionally showed a good prognosis.7 For this reason, new criteria that extend the limits have been developed in many institutions for increasing the number of patients for liver transplantation and to decrease the recurrence of HCC after liver transplantation.8 However, the optimal criteria of liver transplantation for HCC are still controversial because of HCC recurrence. Vascular invasion is a poor prognostic factor of liver transplantation for HCC.9‐13 Patients with vascular invasion preoperatively found by conventional imaging studies are contraindicated for liver transplantation.14‐16 Microvascular invasion (MVI) is generally an accidentally found histologic factor, and its presence is correlated with tumor grade.17 However, previous studies have reported that MVI does not affect HCC recurrence after liver transplantation.7,18,19 We previously reported that a high degree of portal vein invasion showing more than 50 invading carcinoma cells to the portal vein and multiple portal vein invasion was associated with a high tumor grade and poor prognosis of HCC by detailed histologic evaluation.20 Microscopic multiple-invaded portal vein invasion was also previously reported to be a poor prognostic factor in patients with HCC undergoing hepatic resection.21 Furthermore, MVI in HCC has been classified into two distinct phenotypes by microarray profiling and is a predictor for poor prognosis.22 Transplantation
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
June 2015
■
Volume 99
■
Number 6
Iguchi et al
© 2014 Wolters Kluwer
This retrospective study aimed to investigate whether the degree of MVI affects the prognosis of patients with HCC after living-donor liver transplantation. RESULTS Patient Characteristics
The selected patients’ status is shown below. The age of the patients ranged from 40 to 73 years, with a mean of 57.6 years. The male-to-female ratio was 84:58. Twentyone patients (14.8%) had hepatitis B virus surface antigen, 114 patients (80.1%) had hepatitis C virus antibody, and 12 patients (5.1%) had neither hepatitis C virus antibody nor hepatitis B virus surface antigen. The Child-Pugh score classification, commonly used as a means to determine the necessity for liver transplantation was C for 75 patients (52.8%), B for 57 patients (40.1%), and A for 10 patients (7.1%). The mean (± standard deviation) preoperative αfetoprotein levels and des-γ-carboxy prothrombin levels were 994.2 ± 4671.6 ng/mL and 515.4 ± 1797.1 mAU/mL, respectively. The mean preoperative neutrophil-to-lymphocyte ratio, largest tumor size, and number of tumors were 7.1 ± 8.0, 2.5 ± 1.2, and 4.7 ± 7.7, respectively. Forty-one patients (29.1%) were histologically diagnosed with poorly differentiated HCC. Ninety-four patients (66.2%) with recurrent HCC, 71 patients with bilobar distribution of HCC (50.0%), and 61 patients exceeding the Milan criteria (43.0%) were included in this study. Clinical Comparison and Outcome Among the Non-MVI, Low MVI, and High MVI Groups
Of the 142 patients, MVI was observed in 55 (38.7%) patients. Based on histologic evaluation, there were 17 patients in the low MVI group and 38 patients in the high MVI group (Fig. 1). The recurrence-free survival rates in the non-MVI group (n = 87) at 1, 3, and 5 years were 97.6%, 92.6%, and 92.6%, those for the low MVI group were 94.1%, 94.1%, and 94.1%, and those for the high MVI group were 72.5%, 60.1%, and 56.1%, respectively (Fig. 2). Analysis of recurrence-free survival also showed that the high MVI group had significantly poorer outcomes than the low MVI and non-MVI groups (P
New Pathologic Stratification of Microvascular Invasion in Hepatocellular Carcinoma: Predicting Prognosis After Living-donor Liver Transplantation Tomohiro Iguchi,1 Ken Shirabe,1 Shinichi Aishima,2 Huanlin Wang,2 Nobuhiro Fujita,3 Mizuki Ninomiya,1 Yo-ichi Yamashita,1 Toru Ikegami,1 Hideaki Uchiyama,1 Tomoharu Yoshizumi,1 Yoshinao Oda,2 and Yoshihiko Maehara1 Background. Vascular invasion of hepatocellular carcinoma (HCC) has a high incidence of recurrence after liver transplantation. Patients with microvascular invasion (MVI) show a high tumor grade; however, some show a good prognosis. This retrospective study aimed to investigate whether the degree of MVI affects prognosis after living-donor liver transplantation. Methods. A total of 142 patients with HCC who had undergone living-donor liver transplantation were histologically evaluated about the number of invaded vessels and the maximum number of invading carcinoma cells. Patients with MVI were classified into two subgroups: high MVI group (n = 38), which showed more than 50 carcinoma cells in the vessels, with multiple invaded vessels; and low MVI group (n = 17), which showed MVI, but not high MVI. Results. Analysis of recurrence-free survival showed that high MVI group had significantly poorer outcomes than the other groups (P < 0.001). High MVI group had significantly higher α-fetoprotein levels, des-γ-carboxy prothrombin levels, number of tumors, a larger tumor size, and a higher percentage of poorly differentiated HCC than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.030). Among patients exceeding the Milan criteria (n = 61), high MVI group had significantly poorer outcomes than the other groups for recurrence-free survival (P = 0.003). Patients in high MVI group had significantly higher des-γ-carboxy prothrombin levels and a larger tumor size than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.014). Conclusion. In livingdonor liver transplantation for HCC, high MVI is a novel pathologic marker for predicting prognosis.
(Transplantation 2015;99: 1236–1242)
H
epatocellular carcinoma (HCC) is the fifth most common neoplasm in the world.1-3 Despite recent development of surgical techniques and preoperative or postoperative management, a high incidence of HCC recurrence has shown an unsatisfactory outcome.4 Liver transplantation for treating cirrhosis and tumors at the same time has been established as an effective treatment for HCC.5 The Milan criteria advocated by Mazzaferro et al., who showed that patients who have a single tumor of less than 5 cm or three tumors less than 3 cm in Received 3 March 2014. Revision requested 25 March 2014. Accepted 27 August 2014. 1
Department of Surgery and Science, Kyushu University, Fukuoka, Japan.
2
Department of Anatomic Pathology, Kyushu University, Fukuoka, Japan.
3
Department of Molecular Imaging and Diagnosis, Kyushu University, Fukuoka, Japan.
T.I. participated in the study concept and design and drafting of article. K.S. participated in the study concept and critical revision of the article. S.A. participated in the pathologic examination. H.W. participated in the pathologic examination. N.F. participated in the critical revision of the article. M.N. participated in statistical analysis. Y.Y. participated in data collection. T.I. participated in the critical revision of the article. H. U. participated in data collection. T.Y. participated in the critical revision of the article. Y.O. participated in the pathologic examination. Y.M. participated in the final approval of the article. The authors declare no funding or conflicts of interest. Correspondence: Tomohiro Iguchi, MD, Department of Surgery and Science, Kyushu University, Maidashi 3-1-1, Fukuoka, Japan. ([email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9906-1236 DOI: 10.1097/TP.0000000000000489
1236
www.transplantjournal.com
diameter have a good prognosis after liver transplantation is an acceptable indication for HCC worldwide.6 However, patients exceeding the Milan criteria have been transplanted and occasionally showed a good prognosis.7 For this reason, new criteria that extend the limits have been developed in many institutions for increasing the number of patients for liver transplantation and to decrease the recurrence of HCC after liver transplantation.8 However, the optimal criteria of liver transplantation for HCC are still controversial because of HCC recurrence. Vascular invasion is a poor prognostic factor of liver transplantation for HCC.9‐13 Patients with vascular invasion preoperatively found by conventional imaging studies are contraindicated for liver transplantation.14‐16 Microvascular invasion (MVI) is generally an accidentally found histologic factor, and its presence is correlated with tumor grade.17 However, previous studies have reported that MVI does not affect HCC recurrence after liver transplantation.7,18,19 We previously reported that a high degree of portal vein invasion showing more than 50 invading carcinoma cells to the portal vein and multiple portal vein invasion was associated with a high tumor grade and poor prognosis of HCC by detailed histologic evaluation.20 Microscopic multiple-invaded portal vein invasion was also previously reported to be a poor prognostic factor in patients with HCC undergoing hepatic resection.21 Furthermore, MVI in HCC has been classified into two distinct phenotypes by microarray profiling and is a predictor for poor prognosis.22 Transplantation
■
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
June 2015
■
Volume 99
■
Number 6
Iguchi et al
© 2014 Wolters Kluwer
This retrospective study aimed to investigate whether the degree of MVI affects the prognosis of patients with HCC after living-donor liver transplantation. RESULTS Patient Characteristics
The selected patients’ status is shown below. The age of the patients ranged from 40 to 73 years, with a mean of 57.6 years. The male-to-female ratio was 84:58. Twentyone patients (14.8%) had hepatitis B virus surface antigen, 114 patients (80.1%) had hepatitis C virus antibody, and 12 patients (5.1%) had neither hepatitis C virus antibody nor hepatitis B virus surface antigen. The Child-Pugh score classification, commonly used as a means to determine the necessity for liver transplantation was C for 75 patients (52.8%), B for 57 patients (40.1%), and A for 10 patients (7.1%). The mean (± standard deviation) preoperative αfetoprotein levels and des-γ-carboxy prothrombin levels were 994.2 ± 4671.6 ng/mL and 515.4 ± 1797.1 mAU/mL, respectively. The mean preoperative neutrophil-to-lymphocyte ratio, largest tumor size, and number of tumors were 7.1 ± 8.0, 2.5 ± 1.2, and 4.7 ± 7.7, respectively. Forty-one patients (29.1%) were histologically diagnosed with poorly differentiated HCC. Ninety-four patients (66.2%) with recurrent HCC, 71 patients with bilobar distribution of HCC (50.0%), and 61 patients exceeding the Milan criteria (43.0%) were included in this study. Clinical Comparison and Outcome Among the Non-MVI, Low MVI, and High MVI Groups
Of the 142 patients, MVI was observed in 55 (38.7%) patients. Based on histologic evaluation, there were 17 patients in the low MVI group and 38 patients in the high MVI group (Fig. 1). The recurrence-free survival rates in the non-MVI group (n = 87) at 1, 3, and 5 years were 97.6%, 92.6%, and 92.6%, those for the low MVI group were 94.1%, 94.1%, and 94.1%, and those for the high MVI group were 72.5%, 60.1%, and 56.1%, respectively (Fig. 2). Analysis of recurrence-free survival also showed that the high MVI group had significantly poorer outcomes than the low MVI and non-MVI groups (P
