Ann Surg Oncol DOI 10.1245/s10434-014-3597-6
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
The Clinical Behavior of Transplantable Recurrent Hepatocellular Carcinoma After Curative Resection: Implications for Salvage Liver Transplantation Hyung Soon Lee, MD1, Gi Hong Choi, MD1,2, Dong Jin Joo, MD1,2, Myoung Soo Kim, MD1,2, Jin Sub Choi, MD1,2, and Soon Il Kim, MD1,2 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea; 2The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea
1
ABSTRACT Background. This study aimed to classify transplantable recurrent hepatocellular carcinoma (HCC) after resection into subgroups according to the pattern of progression and to identify risk factors for each subgroup to select optimal candidates for salvage liver transplantation (LT). Methods. The patients that met the Milan criteria (MC) and were child-pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. A controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for C12 months or control of a recurrent tumor within the MC by active locoregional treatment. Results. After curative resection of HCC, 114 patients with transplantable recurrence were identified: 70 were classified as group 1 and 44 as group 2. Overall survival after recurrence was significantly higher in group 1 compared to group 2 (65.4 vs 35.7 %, respectively; P \ 0.003). Multiple logistic regression analysis showed that risk factors in group 1 were age [50 years and an indocyanine
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3597-6) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 13 May 2013 J. S. Choi, MD e-mail: [email protected]
green retention at 15 min [10 %. The presence of a satellite nodule (SN) and/or microscopic portal vein invasion (mPVI) was the only independent risk factor identified in group 2. Among the 15 patients that underwent salvage LT, 2 of 3 patients (66.7 %) with SN and/or mPVI at initial hepatectomy developed extrahepatic recurrence. Conclusions. The patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT, and an extended observation time is required to determine tumor biology.
INTRODUCTION Liver transplantation (LT) is the best treatment option for patients with hepatocellular carcinoma (HCC) within the Milan criteria (MC).1 However, the worldwide shortage of donor organs is problematic, and the risks from immunosuppression compromise long-term survival after LT.2 The value of primary LT for early HCC in patients with preserved liver function remains controversial.3–6 The mortality rate of liver resection at an experienced center was less than 5 %, and overall survival rates were comparable to primary LT.7,8 For this reason, liver resection may be a good alternative treatment for early HCC in patients with preserved liver function.9,10 However, after liver resection, the HCC recurrence rate can range from 60 to 100 % at 5 years.11–13 Therefore, liver resection as a first-line therapy followed by salvage LT is an attractive concept for the treatment of HCC.14 The feasibility of this strategy and the long-term outcomes appear to be comparable to primary LT.15–17 Selection criteria for salvage LT have not been established. Therefore, the MC have been widely used as the selection criteria for salvage LT in many transplantation
H. S. Lee et al.
centers.16–18 However, intrahepatic recurrent HCCs after resection originate from different mechanisms than primary tumor metastasis or multicentric occurrence.19 These intrahepatic recurrent HCCs exhibit significant variability in their clinical behavior, despite being transplantable (according to the MC).20 Further classification of these transplantable recurrent HCCs is required for the optimal selection of salvage LT candidates. In this study, we aimed to classify transplantable recurrent HCCs after curative resection into subgroups according to the pattern of progression. Additionally, we identified risk factors of each subgroup to select optimal candidates for salvage LT. METHODS Patients Selection and Study Design From January 1996–December 2007, 610 patients underwent curative resection for HCC at Severance Hospital, Yonsei University College of Medicine. Curative resection was defined as complete tumor removal with a microscopic negative surgical margin and no residual tumor by routine imaging (i.e., computed tomography (CT) and chest radiographs at 1 month after hepatectomy). Before initial resection, the diagnosis of HCC was based on consistent findings from at least two separate imaging studies including dynamic CT, magnetic resonance imaging, and hepatic angiography. If necessary, chest CT and positron emission tomography were also performed to exclude distant metastases. Additionally, intraoperative ultrasound was routinely used at our institution. If a new lesion was detected intraoperatively, we first considered including the newly detected lesion in the extent of the planned resection or it was resected separately. The patients that met the MC and were Child-Pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. Controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for C12 months or control of a recurrent tumor within the MC by active locoregional treatment. Prognosis after recurrence and clinicopathologic variables were examined in both groups. Additionally, to be able to identify risk factors in each subgroup, clinicopathologic variables were compared with those patients that did not experience HCC recurrence after initial hepatectomy. This study was approved by the Institutional Review Board of Yonsei University College of Medicine (Seoul, Republic of Korea).
Follow-Up and Treatment of HCC Recurrence Patients were followed up 1 month after hepatectomy and then every 3 months. Dynamic CT was performed at each appointment, and alpha-fetoprotein (AFP) was screened. Median duration of follow-up after initial hepatectomy was 68 months (range 4–160 months). HCC recurrence was defined as a newly developed lesion detected by CT. Patients with suspected recurrence underwent magnetic resonance imaging or hepatic angiography for diagnostic and/or therapeutic purposes. When intrahepatic recurrence was diagnosed, active treatment was immediately initiated. Repeat resection was considered the treatment of choice; however, the decision was based on tumor location, liver functional reserve, and patient performance status. Liver function was assessed using the Child-Pugh classification and indocyanine green retention at 15 min (ICG-R 15). Repeat liver resection and the combination of intraoperative local ablation therapy were performed individually and the decision was only made intraoperatively. Combination intraoperative local ablation therapy was performed instead of resection to prevent loss of functional liver parenchyma. If the patient had bilobar disease or residual tumor deep in the remaining parenchyma, intraoperative local ablation therapy was performed. Superficial lesions were resected. Local ablation therapy was considered for patients ineligible for repeat resection. Criteria for local ablation therapy included a maximum recurrent tumor diameter of 3 cm or fewer than three tumor nodules. Transarterial chemoembolization (TACE) was recommended for patients deemed unsuitable for repeat resection or local ablation therapy. The TACE was initially performed in patients with recurrent HCC for either diagnostic or therapeutic purposes. In fact, local ablation therapy was performed in patients with tumors that were not completely controlled by initial TACE and tumors that showed hypovascular features on CT or hepatic angiography.20 Since 2005, our institution has offered salvage LT for selected patients with transplantable recurrent HCC. Repeat resection could be carried out only in a small proportion of patients with HCC recurrence because of the small liver remnant and inadequate liver functional reserve. However, local ablation therapy is applicable, even in patients with borderline liver function and previous studies demonstrated that local ablation therapy has similar survival outcomes compared to repeat resection in patients with HCC recurrence after hepatectomy.21,22 Thus, repeat resection and local ablation therapy were considered curative, whereas TACE was considered palliative treatment. Patients who underwent both repeat resection and local ablation therapy were classified as repeat resection. Carcinomatosis was defined as tumor dissemination into the extrahepatic space.
Clinical Behavior of Transplantable Recurrent HCC
Risk Factors of Each Subgroup
RESULTS
Fifteen clinicopathologic variables at initial hepatectomy were investigated as risk factors. The host and surgical factors included age, gender, serum albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, ICG-R 15, serum AFP, presence of cirrhosis, etiology of cirrhosis, and extent of resection. The tumor factors included tumor size, tumor number, Edmondson-Steiner grade, the presence of a satellite nodule (SN), and/or microscopic portal vein invasion (mPVI). Cirrhosis was diagnosed based on pathological findings in nontumorous regions of surgical specimens. Hepatitis B virus (HBV) was defined as positivity for HBV surface antigen, and hepatitis C virus (HCV) was defined as positivity for anti-HCV antibody. Anatomical resection was defined as segmentectomy, left lateral segmentectomy, hemihepatectomy, trisegmentectomy, or central bisegmentectomy. Nonanatomical resection was defined as wedge resection. Major hepatectomy was defined as the resection of C3 anatomical segments, as described by Couinaud. We first attempted anatomical resection at the initial operation. However, nonanatomical resection was performed for patients with superficial tumor, clinically significant portal hypertension, or ICG-R 15 [ 20 %.23,24 Early recurrence was defined as a recurrence B12 months after hepatectomy. Multiple tumors were classified using the guidelines proposed by the Japanese Liver Cancer Study Group, which are based on macroscopic and microscopic findings.25 The SN and mPVI both represent aspects of intrahepatic metastasis and are strongly correlated26; therefore, the presence of SN and/or mPVI was considered a single variable.
Patient Selection
Statistical Analysis Data are presented as percentages of patients or as medians and ranges. Categorical variables were compared using the Chi square or Fisher’s exact test, and continuous variables were compared using the Mann– Whitney U test. Overall survival was calculated using the Kaplan–Meier method, and differences in survival between groups were compared using the log-rank test. Multiple logistic regression analysis was performed using a forward stepwise method to identify risk factors, and factors with P \ 0.05 by univariate analysis were included in the multiple logistic regression analysis. The analysis was performed using SPSS version 18.0 (SPSS, Chicago, IL), and P \ 0.05 was considered statistically significant.
A total of 289 patients were excluded: HCC beyond the MC at initial hepatectomy (n = 216); Child-Pugh class B (n = 8); loss to follow-up (n = 47); and death in the hospital after hepatectomy (n = 18) (Fig. 1). The remaining 321 patients met the MC and were Child-Pugh class A at initial hepatectomy. Of these 321 patients, 146 (45.5 %) experienced HCC recurrence. Transplantable recurrence occurred in 129 of these 146 patients (88.4 %). Fifteen of these patients underwent salvage LT and were excluded from the analysis. Ultimately, 114 patients with transplantable recurrence were identified. Seventy patients were classified as group 1 (61.4 %) and 44 (38.6 %) were classified as group 2. Patient Characteristics Characteristics of the patients with transplantable recurrence are summarized in Table 1. All 114 patients with transplantable recurrence were followed up every 3 months and received active treatment. Age was significantly higher in group 1, and the presence of SN and/or mPVI and early recurrence were significantly higher in group 2. Treatment method for recurrent HCC was not significantly different in the two groups (P = 0.275). Repeat resection in combination with local ablation therapy was performed in 2 patients. One patient is included in group 1 and the other patient is included in group 2. The patient in group 1 had a 2.5-cm HCC recurrence at 24 months after initial hepatectomy and local ablation therapy was performed. However, marginal tumor recurrence was seen for which segmentectomy was performed and there was no recurrence after repeat resection. The patient in group 2 experienced a 1.0-cm HCC recurrence in segment 2 at 15 months after initial hepatectomy and TACE was performed. However, marginal tumor recurrence was detected and local ablation therapy was performed. Twelve months after local ablation therapy, a 1.0-cm recurrence developed in segment 7 and segmentectomy was performed. However, multiple HCC recurrence (more than five lesions) developed again and TACE was performed. Almost half of the patients with transplantable recurrence died during the time of the study (53 of 114). Causes of death were significantly different in the two groups (P \ 0.001). No patient died due to carcinomatosis in group 1. Of the 44 patients in group 2, there were 21 (67.7 %) patients who died due to carcinomatosis.
H. S. Lee et al. FIG. 1 Patient selection schematic. HCC hepatocellular carcinoma, LT liver transplantation, MC Milan criteria
Curative resection for HCC N=610
Postop. mortality, N=18 Follow - up loss, N=47 Child B cirrhosis, N=8
Primary tumor Beyond the MC N=216
Primary tumor Within the MC N=321
No recurrence N=175
Recurrence Within the MC N=129
Not performed LT N=114
Tumor controlled within the MC N=70
Overall Survival After Transplantable Recurrence Overall survival rates at 1, 3, and 5 years after recurrence were 98.6, 83.8, and 65.4 %, respectively, in group 1, and 95.5, 64.8, and 35.7 % in group 2 (P = 0.003) (Fig. 2). Overall survival rates of group 1 were significantly higher than group 2. Median duration of follow-up after transplantable recurrence was 40 months (range 2–120 months). Progression Patterns and Time to Progression in Group 2 Three progression patterns after transplantable recurrence were observed in group 2. First, recurrent HCC progressed beyond the MC without extrahepatic metastasis in 20 patients (median duration 12 months). Extrahepatic metastasis developed directly after transplantable recurrence in 10 patients (median duration 18.5 months). Transplantable recurrent HCC progressed sequentially beyond the MC and metastasized extrahepatically in 14 patients (median duration 13 months). Risk Factors of Each Subgroup By univariate analysis, risk factors in group 1 were age [50 years and an ICG-R 15 [ 10 %. Risk factors in group 2 were extent of resection, presence of multiple tumors, and
Recurrence beyond the MC N=17
LT N=15
Tumor progression beyond the MC N=44
the presence of an SN and/or mPVI at initial hepatectomy (Supplementary Table 1). Multiple logistic regression analysis showed that age [50 years and an ICG-R 15 [ 10 % at initial hepatectomy were risk factors in group 1. However, the presence of an SN and/or mPVI at initial hepatectomy was the only independent risk factor identified in group 2 (Table 2). Patients who Underwent Salvage LT After Transplantable Recurrence Salvage LT was performed in 15 patients with transplantable recurrence (Table 3). No patient underwent salvage LT for deteriorating liver function after resection. Five patients underwent prior major hepatectomy and 10 patients underwent prior minor hepatectomy. Median duration between initial hepatectomy and transplantable recurrence was 13 months (range 2–58 months), and median duration between transplantable recurrence and LT was 11 months (range 2–65 months). An SN and/or mPVI in resected specimens at initial hepatectomy occurred in 3 patients, and 2 (66.7 %) of these patients had extrahepatic recurrence develop after salvage LT. In addition, one patient that received TACE before initial hepatectomy had extrahepatic recurrence develop after salvage LT. However, it was not possible to determine whether an SN and/or
Clinical Behavior of Transplantable Recurrent HCC TABLE 1 Characteristics of patients with transplantable recurrence Variables
Group 1 (n = 70)
Group 2 (n = 44)
Age (years)a
58.5 (24–73)
50.5 (33–70)
0.021
60 (85.7)
38 (86.4)
0.923
8.5 (1.5–33.8)
0.082
42 (0.76–7,402)
0.086
3.0 (0.9–5.0)
0.722
Male gender (n [%]) ICG-R 15 (%)a AFP (IU/mL)
10.6 (1.8–37.5)
a
21.5 (1.6–30,676)
Tumor size (cm)a
3.0 (1.3–5.0)
Multiple tumors (n [%])
6 (8.6)
P Value
7 (15.9)
0.230
Edmondson-Steiner grade (n [%])
0.871
I
9 (15.8)
5 (12.5)
II
33 (57.9)
25 (62.5)
III
15 (15.5)
10 (10.3)
3 (4.3) 18 (25.7)
19 (43.2) 20 (45.5)
\0.001 0.030
6 (8.6)
5 (11.4)
0.275
SN and/or mPVI (n [%]) Early recurrence (n [%]) (B12 months) Type of treatment (n [%]) Re-resection Local ablation therapy
8 (11.4)
2 (4.5)
Local ablation therapy ? TACE
16 (22.9)
16 (36.4)
TACE
40 (57.1)
21 (47.7)
Carcinomatosis
0 (0.0)
21 (67.7)
Hepatic failure
13 (59.1)
4 (12.9)
UGI bleeding
4 (18.2)
3 (9.7)
Infection
5 (22.7)
2 (6.5)
Cause of death (n [%]) \0.001
This data represents patients characteristics at initial hepatectomy, except early recurrence and type of treatment AFP alpha-fetoprotein, ICG-R 15 indocyanine green retention at 15 min, IU international units, mPVI microscopic portal vein invasion, SN satellite nodule, TACE transarterial chemoembolization, UGI upper gastrointestinal a
Results are presented as medians and range
98.6%
100
P=0.003
83.8%
95.5%
TABLE 2 Multiple logistic regression analysis of risk factors in the two groups Variable
Overall survival (%)
80
65.4%
Coefficient Standard P Value Odds ratio (95 % CI) error
Group 1
64.8%
Age [50 years
60
0.778
0.358
0.030
2.178 (1.080–4.395)
ICG-R 15 [ 10 % 0.741
0.305
0.015
2.097 (1.153–3.814)
0.427
\0.001
Group 2
Group 1 (n=70)
40
20
Group 2 (n=44)
0 12
24
36
48
60
2.057
7.819 (3.389–18.042)
CI confidence interval, ICG-R 15 indocyanine green retention at 15 min, mPVI microscopic portal vein invasion, SN satellite nodule
35.7%
0
SN and/or mPVI
72
84
96
108 120
Time after recurrence (months) FIG. 2 Overall survival rates after transplantable recurrence
mPVI were present in this patient because pathological examination of the initial tumor revealed complete necrosis.
DISCUSSION The present study demonstrates that subgroups defined by the progression pattern after transplantable recurrence had different clinical characteristics, risk factors, and prognoses. Of the 114 patients with transplantable recurrence, 70 (61.4 %) showed controlled tumors within the MC, and these patients showed a high incidence of late recurrence and were associated with host factors (age [50 years and ICG-R 15 [ 10 %). None of the patients
H. S. Lee et al. TABLE 3 Patients who underwent salvage liver transplantation after transplantable recurrence Patient Age Time to (years)/sex recurrence after initial hepatectomy (months)
Time to Bridge LT after therapy transplantable (number) recurrence (months)
1
50/M
23
22
RFA (1), Living TACE (1)
2
62/M
11
18
RFA (1)
Living
No
No
No
3
47/M
13
11
TACE (1)
Living
No
No
Yes
4
51/F
3
31
TACE (5)
Deceased No
No
No
5
44/M
16
15
TACE (2)
Living
No
No
No
22
6 7
62/M 42/M
30 58
3 2
No No
Deceased No Living No
No No
No No
50 43
8
41/M
39
11
TACE (3)
Deceased No
No
No
9
50/M
8
38
RFA (1), Living TACE (4)
No
No
Yes
10
44/M
12
8
TACE (1)
Living
Yes (SN)
No
No
11
58/F
2
2
No
Deceased Yes (SN, mPVI)
Lung (11)
Yes
12
57/M
13
4
No
Living
No
No
No
37
13 14
57/M 53/M
21 3
65 2
TACE (4) No
Living Living
No Yes (SN)
No Adrenal (49)
No No
31 57
15
55/M
13
17
TACE (5)
Living
Noa
Lung (10)
No
21
LT type
SN and/or Post-transplant Death Cause of mPVI recurrence death (at initial (months) hepatectomy)
Survival after LT (months)
No
24
No
No
46 Biliary sepsis
5 82
91 Postoperative bleeding
0 32
Carcinomatosis 40
F female, LT liver transplantation, M male, mPVI microscopic portal vein invasion, RFA radiofrequency ablation, SN satellite nodule, TACE transarterial chemoembolization a
It could not be determined whether an SN or mPVI were present in this patient because the tumor showed complete necrosis by pathology
with controlled tumors died from carcinomatosis. Additionally, the overall survival rates after the recurrence of controlled tumors were significantly greater than those for progressive tumors. These results suggest that controlled tumors tend to originate from multicentric occurrence. By contrast, 44 (38.6 %) patients showed progressive tumors, despite active treatment, and these patients showed a higher incidence of early recurrence and greater likelihood of SN and/or mPVI. Thirty-one of the 44 patients in group 2 died, and of these, 67.7 % died of carcinomatosis. It is suggested by our results that progressive recurrent tumors likely originated from metastasis of the primary tumor. The origin of intrahepatic recurrence after resection can be predicted based on the time to recurrence and type of recurrence. Early recurrence suggests primary tumor metastasis, whereas late recurrence indicates multicentric occurrence.19 Three types of recurrence are described after resection: intrahepatic nodular, intrahepatic multiple, and extrahepatic.27 Extrahepatic and intrahepatic multiple type recurrence have been linked to primary tumor metastasis, whereas the intrahepatic nodular type is more frequently associated with multicentric occurrence.28,29 However, several authors have suggested that the intrahepatic nodular type recurrence could originate from primary tumor metastasis or
multicentric occurrence.11,19,20 Therefore, even when intrahepatic recurrent HCC seems transplantable, there is a risk of including tumors originating from the primary tumor metastasis. Park et al.28 concluded that portal vein tumor thrombi and intrahepatic metastases are risk factors of early intrahepatic multiple recurrences after resection, and concluded intrahepatic metastasis occurs primarily via the portal vein. Our analysis shows that the presence of an SN and/or mPVI at initial hepatectomy was the only independent risk factor for a progressive tumor. Furthermore, the incidence of a progressive tumor was higher in patients with early recurrence, which suggests recurrent tumor originates from primary tumor metastasis in these patients. The present study shows that the methods used to treat recurrent HCC were not significantly different in the two groups. However, overall survival rates after the recurrence of controlled tumors were significantly greater than progressive tumors. Arii et al.30 and Yang et al.31 concluded that repeat resection and local ablation therapy are more effective in patients with multicentric occurrence than in those with recurrence originating from primary tumor metastasis. This finding indicates that the origin of recurrent tumor should be considered when patients are enlisted
Clinical Behavior of Transplantable Recurrent HCC
as candidates for salvage LT. In the present study, controlled tumors showed a high incidence of late recurrence and were associated with host factors (age [50 years and ICG-R 15 [ 10 %). Our results suggest that controlled tumors have a low probability of HCC dissemination because they tend to originate from multicentric occurrence. None of the patients with controlled tumors died from carcinomatosis. Thus, patients with controlled tumors may be optimal candidates for salvage LT. Previous studies have recommended salvage LT before recurrence in patients at high pathological risk of recurrence.32,33 Sala et al.34 first recommended salvage LT before recurrence and performed salvage LT in 5 patients with a high pathological risk of recurrence (microvascular invasion and/or additional nodules). However, one patient who received salvage LT developed extrahepatic recurrence. Two patients that refused LT developed large multinodular recurrence. Unfortunately, these authors did not report the long-term outcomes of salvage LT before recurrence in patients at high pathological risk. Fuks et al.35 also recommended performing salvage LT before recurrence in patients with at least three or more than three of five poor histological factors (i.e., microscopic vascular invasion, SN, tumor [3 cm, poorly differentiated tumor, and liver cirrhosis). However, it seems paradoxical to recommend salvage LT in the presence of these factors, which are also predictors of recurrence after transplant.8 Recently, Fan et al.36 demonstrated that circulating HCC stem cells in the blood can predict recurrence post-hepatectomy. Marubashi et al.37 found that the presence of AFP messenger ribonucleic acid-expressing cells in peripheral blood preoperatively can predict HCC recurrence after LT. In other words, tumor cell migration into the blood is an important factor in HCC recurrence after hepatectomy or LT. These findings suggest that the probability of posttransplant recurrence is high due to systemic tumor cell dissemination, despite the removal of the diseased liver by salvage LT in patients at high pathological risk of recurrence. Accordingly, salvage LT should not be encouraged in patients with high pathological risk of recurrence (presence of SN and/or mPVI in this study). Limitations of this article included a relatively small sample size and a higher percentage of patients with HBV than those reported in Western and Japanese studies. Additionally, SN or mPVI, or both were identified in 10.9 % of patients that did not recur after resection and in 4.3 % of patients with controlled tumors. These results indicate that time is required to observe patients with SN and/or mPVI at initial hepatectomy to determine tumor biology. In the present study, the median duration between transplantable recurrence and recurrent tumor progression beyond the MC or extrahepatic metastasis were 12 and 18.5 months, respectively.
Accordingly, based on our results, we suggest that an observation time of at least 12 months is required. In conclusion, the present study shows that transplantable recurrent HCCs have different risk factors and prognoses that ultimately depend on patterns of tumor progression. Controlled tumors were associated with multicentric occurrence. Thus, patients with controlled tumors may be the best candidates for salvage LT. On the other hand, progressive tumors had poorer prognoses, and these recurrences were associated more with primary tumor metastasis, and SN or mPVI, or both are risk factors for progressive tumors. Thus, patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT. Additionally, an extended observation time is required to determine tumor biology in patients with SN and/or mPVI at initial hepatectomy. Increased observation times may reduce recurrence after salvage LT and facilitate effective organ use in this era of organ donor shortage. DISCLOSURE
The authors declare no conflict of interest.
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25. Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer, 4th edition. Tokyo, Japan: Kanehara; 2000. 26. Yamamoto J, Kosuge T, Takayama T, Shimada K, Yamasaki S, Ozaki H, et al. Recurrence of hepatocellular carcinoma after surgery. Br J Surg. 1996;83:1219–22. 27. Shimada M, Takenaka K, Gion T, Fujiwara Y, Kajiyama K, Maeda T, et al. Prognosis of recurrent hepatocellular carcinoma: a 10-year surgical experience in Japan. Gastroenterology. 1996;111:720–6. 28. Park JH, Koh KC, Choi MS, Lee JH, Yoo BC, Paik SW, et al. Analysis of risk factors associated with early multinodular recurrences after hepatic resection for hepatocellular carcinoma. Am J Surg. 2006;192:29–33. 29. Matsumata T, Kanematsu T, Takenaka K, Yoshida Y, Nishizaki T, Sugimachi K. Patterns of intrahepatic recurrence after curative resection of hepatocellular carcinoma. Hepatology. 1989;9:457– 60. 30. Arii S, Teramoto K, Kawamura T, Okamoto H, Kaido T, Mori A, et al. Characteristics of recurrent hepatocellular carcinoma in Japan and our surgical experience. J Hepatobiliary Pancreat Surg. 2001;8:397–403. 31. Yang W, Chen MH, Yin SS, Yan K, Gao W, Wang YB, et al. Radiofrequency ablation of recurrent hepatocellular carcinoma after hepatectomy: therapeutic efficacy on early- and late-phase recurrence. AJR Am J Roentgenol. 2006;186:S275–83. 32. Scatton O, Zalinski S, Terris B, Lefevre JH, Casali A, Massault PP, et al. Hepatocellular carcinoma developed on compensated cirrhosis: resection as a selection tool for liver transplantation. Liver Transpl. 2008;14:779–88. 33. Muscari F, Foppa B, Carrere N, Kamar N, Peron JM, Suc B. Resection of a transplantable single-nodule hepatocellular carcinoma in Child-Pugh class A cirrhosis: factors affecting survival and recurrence. World J Surg. 2011;35:1055–62. 34. Sala M, Fuster J, Llovet JM, Navasa M, Sole´ M, Varela M, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl. 2004;10:1294–300. 35. Fuks D, Dokmak S, Paradis V, Diouf M, Durand F, Belghiti J. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology. 2012;55:132–40. 36. Fan ST, Yang ZF, Ho DW, Ng MN, Yu WC, Wong J. Prediction of posthepatectomy recurrence of hepatocellular carcinoma by circulating cancer stem cells: a prospective study. Ann Surg. 2011;254:569–76. 37. Marubashi S, Dono K, Nagano H, Sugita Y, Asaoka T, Hama N, et al. Detection of AFP mRNA-expressing cells in the peripheral blood for prediction of HCC recurrence after living donor liver transplantation. Transpl Int. 2007;20:576–82.
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
The Clinical Behavior of Transplantable Recurrent Hepatocellular Carcinoma After Curative Resection: Implications for Salvage Liver Transplantation Hyung Soon Lee, MD1, Gi Hong Choi, MD1,2, Dong Jin Joo, MD1,2, Myoung Soo Kim, MD1,2, Jin Sub Choi, MD1,2, and Soon Il Kim, MD1,2 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea; 2The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea
1
ABSTRACT Background. This study aimed to classify transplantable recurrent hepatocellular carcinoma (HCC) after resection into subgroups according to the pattern of progression and to identify risk factors for each subgroup to select optimal candidates for salvage liver transplantation (LT). Methods. The patients that met the Milan criteria (MC) and were child-pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. A controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for C12 months or control of a recurrent tumor within the MC by active locoregional treatment. Results. After curative resection of HCC, 114 patients with transplantable recurrence were identified: 70 were classified as group 1 and 44 as group 2. Overall survival after recurrence was significantly higher in group 1 compared to group 2 (65.4 vs 35.7 %, respectively; P \ 0.003). Multiple logistic regression analysis showed that risk factors in group 1 were age [50 years and an indocyanine
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3597-6) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 13 May 2013 J. S. Choi, MD e-mail: [email protected]
green retention at 15 min [10 %. The presence of a satellite nodule (SN) and/or microscopic portal vein invasion (mPVI) was the only independent risk factor identified in group 2. Among the 15 patients that underwent salvage LT, 2 of 3 patients (66.7 %) with SN and/or mPVI at initial hepatectomy developed extrahepatic recurrence. Conclusions. The patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT, and an extended observation time is required to determine tumor biology.
INTRODUCTION Liver transplantation (LT) is the best treatment option for patients with hepatocellular carcinoma (HCC) within the Milan criteria (MC).1 However, the worldwide shortage of donor organs is problematic, and the risks from immunosuppression compromise long-term survival after LT.2 The value of primary LT for early HCC in patients with preserved liver function remains controversial.3–6 The mortality rate of liver resection at an experienced center was less than 5 %, and overall survival rates were comparable to primary LT.7,8 For this reason, liver resection may be a good alternative treatment for early HCC in patients with preserved liver function.9,10 However, after liver resection, the HCC recurrence rate can range from 60 to 100 % at 5 years.11–13 Therefore, liver resection as a first-line therapy followed by salvage LT is an attractive concept for the treatment of HCC.14 The feasibility of this strategy and the long-term outcomes appear to be comparable to primary LT.15–17 Selection criteria for salvage LT have not been established. Therefore, the MC have been widely used as the selection criteria for salvage LT in many transplantation
H. S. Lee et al.
centers.16–18 However, intrahepatic recurrent HCCs after resection originate from different mechanisms than primary tumor metastasis or multicentric occurrence.19 These intrahepatic recurrent HCCs exhibit significant variability in their clinical behavior, despite being transplantable (according to the MC).20 Further classification of these transplantable recurrent HCCs is required for the optimal selection of salvage LT candidates. In this study, we aimed to classify transplantable recurrent HCCs after curative resection into subgroups according to the pattern of progression. Additionally, we identified risk factors of each subgroup to select optimal candidates for salvage LT. METHODS Patients Selection and Study Design From January 1996–December 2007, 610 patients underwent curative resection for HCC at Severance Hospital, Yonsei University College of Medicine. Curative resection was defined as complete tumor removal with a microscopic negative surgical margin and no residual tumor by routine imaging (i.e., computed tomography (CT) and chest radiographs at 1 month after hepatectomy). Before initial resection, the diagnosis of HCC was based on consistent findings from at least two separate imaging studies including dynamic CT, magnetic resonance imaging, and hepatic angiography. If necessary, chest CT and positron emission tomography were also performed to exclude distant metastases. Additionally, intraoperative ultrasound was routinely used at our institution. If a new lesion was detected intraoperatively, we first considered including the newly detected lesion in the extent of the planned resection or it was resected separately. The patients that met the MC and were Child-Pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. Controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for C12 months or control of a recurrent tumor within the MC by active locoregional treatment. Prognosis after recurrence and clinicopathologic variables were examined in both groups. Additionally, to be able to identify risk factors in each subgroup, clinicopathologic variables were compared with those patients that did not experience HCC recurrence after initial hepatectomy. This study was approved by the Institutional Review Board of Yonsei University College of Medicine (Seoul, Republic of Korea).
Follow-Up and Treatment of HCC Recurrence Patients were followed up 1 month after hepatectomy and then every 3 months. Dynamic CT was performed at each appointment, and alpha-fetoprotein (AFP) was screened. Median duration of follow-up after initial hepatectomy was 68 months (range 4–160 months). HCC recurrence was defined as a newly developed lesion detected by CT. Patients with suspected recurrence underwent magnetic resonance imaging or hepatic angiography for diagnostic and/or therapeutic purposes. When intrahepatic recurrence was diagnosed, active treatment was immediately initiated. Repeat resection was considered the treatment of choice; however, the decision was based on tumor location, liver functional reserve, and patient performance status. Liver function was assessed using the Child-Pugh classification and indocyanine green retention at 15 min (ICG-R 15). Repeat liver resection and the combination of intraoperative local ablation therapy were performed individually and the decision was only made intraoperatively. Combination intraoperative local ablation therapy was performed instead of resection to prevent loss of functional liver parenchyma. If the patient had bilobar disease or residual tumor deep in the remaining parenchyma, intraoperative local ablation therapy was performed. Superficial lesions were resected. Local ablation therapy was considered for patients ineligible for repeat resection. Criteria for local ablation therapy included a maximum recurrent tumor diameter of 3 cm or fewer than three tumor nodules. Transarterial chemoembolization (TACE) was recommended for patients deemed unsuitable for repeat resection or local ablation therapy. The TACE was initially performed in patients with recurrent HCC for either diagnostic or therapeutic purposes. In fact, local ablation therapy was performed in patients with tumors that were not completely controlled by initial TACE and tumors that showed hypovascular features on CT or hepatic angiography.20 Since 2005, our institution has offered salvage LT for selected patients with transplantable recurrent HCC. Repeat resection could be carried out only in a small proportion of patients with HCC recurrence because of the small liver remnant and inadequate liver functional reserve. However, local ablation therapy is applicable, even in patients with borderline liver function and previous studies demonstrated that local ablation therapy has similar survival outcomes compared to repeat resection in patients with HCC recurrence after hepatectomy.21,22 Thus, repeat resection and local ablation therapy were considered curative, whereas TACE was considered palliative treatment. Patients who underwent both repeat resection and local ablation therapy were classified as repeat resection. Carcinomatosis was defined as tumor dissemination into the extrahepatic space.
Clinical Behavior of Transplantable Recurrent HCC
Risk Factors of Each Subgroup
RESULTS
Fifteen clinicopathologic variables at initial hepatectomy were investigated as risk factors. The host and surgical factors included age, gender, serum albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, ICG-R 15, serum AFP, presence of cirrhosis, etiology of cirrhosis, and extent of resection. The tumor factors included tumor size, tumor number, Edmondson-Steiner grade, the presence of a satellite nodule (SN), and/or microscopic portal vein invasion (mPVI). Cirrhosis was diagnosed based on pathological findings in nontumorous regions of surgical specimens. Hepatitis B virus (HBV) was defined as positivity for HBV surface antigen, and hepatitis C virus (HCV) was defined as positivity for anti-HCV antibody. Anatomical resection was defined as segmentectomy, left lateral segmentectomy, hemihepatectomy, trisegmentectomy, or central bisegmentectomy. Nonanatomical resection was defined as wedge resection. Major hepatectomy was defined as the resection of C3 anatomical segments, as described by Couinaud. We first attempted anatomical resection at the initial operation. However, nonanatomical resection was performed for patients with superficial tumor, clinically significant portal hypertension, or ICG-R 15 [ 20 %.23,24 Early recurrence was defined as a recurrence B12 months after hepatectomy. Multiple tumors were classified using the guidelines proposed by the Japanese Liver Cancer Study Group, which are based on macroscopic and microscopic findings.25 The SN and mPVI both represent aspects of intrahepatic metastasis and are strongly correlated26; therefore, the presence of SN and/or mPVI was considered a single variable.
Patient Selection
Statistical Analysis Data are presented as percentages of patients or as medians and ranges. Categorical variables were compared using the Chi square or Fisher’s exact test, and continuous variables were compared using the Mann– Whitney U test. Overall survival was calculated using the Kaplan–Meier method, and differences in survival between groups were compared using the log-rank test. Multiple logistic regression analysis was performed using a forward stepwise method to identify risk factors, and factors with P \ 0.05 by univariate analysis were included in the multiple logistic regression analysis. The analysis was performed using SPSS version 18.0 (SPSS, Chicago, IL), and P \ 0.05 was considered statistically significant.
A total of 289 patients were excluded: HCC beyond the MC at initial hepatectomy (n = 216); Child-Pugh class B (n = 8); loss to follow-up (n = 47); and death in the hospital after hepatectomy (n = 18) (Fig. 1). The remaining 321 patients met the MC and were Child-Pugh class A at initial hepatectomy. Of these 321 patients, 146 (45.5 %) experienced HCC recurrence. Transplantable recurrence occurred in 129 of these 146 patients (88.4 %). Fifteen of these patients underwent salvage LT and were excluded from the analysis. Ultimately, 114 patients with transplantable recurrence were identified. Seventy patients were classified as group 1 (61.4 %) and 44 (38.6 %) were classified as group 2. Patient Characteristics Characteristics of the patients with transplantable recurrence are summarized in Table 1. All 114 patients with transplantable recurrence were followed up every 3 months and received active treatment. Age was significantly higher in group 1, and the presence of SN and/or mPVI and early recurrence were significantly higher in group 2. Treatment method for recurrent HCC was not significantly different in the two groups (P = 0.275). Repeat resection in combination with local ablation therapy was performed in 2 patients. One patient is included in group 1 and the other patient is included in group 2. The patient in group 1 had a 2.5-cm HCC recurrence at 24 months after initial hepatectomy and local ablation therapy was performed. However, marginal tumor recurrence was seen for which segmentectomy was performed and there was no recurrence after repeat resection. The patient in group 2 experienced a 1.0-cm HCC recurrence in segment 2 at 15 months after initial hepatectomy and TACE was performed. However, marginal tumor recurrence was detected and local ablation therapy was performed. Twelve months after local ablation therapy, a 1.0-cm recurrence developed in segment 7 and segmentectomy was performed. However, multiple HCC recurrence (more than five lesions) developed again and TACE was performed. Almost half of the patients with transplantable recurrence died during the time of the study (53 of 114). Causes of death were significantly different in the two groups (P \ 0.001). No patient died due to carcinomatosis in group 1. Of the 44 patients in group 2, there were 21 (67.7 %) patients who died due to carcinomatosis.
H. S. Lee et al. FIG. 1 Patient selection schematic. HCC hepatocellular carcinoma, LT liver transplantation, MC Milan criteria
Curative resection for HCC N=610
Postop. mortality, N=18 Follow - up loss, N=47 Child B cirrhosis, N=8
Primary tumor Beyond the MC N=216
Primary tumor Within the MC N=321
No recurrence N=175
Recurrence Within the MC N=129
Not performed LT N=114
Tumor controlled within the MC N=70
Overall Survival After Transplantable Recurrence Overall survival rates at 1, 3, and 5 years after recurrence were 98.6, 83.8, and 65.4 %, respectively, in group 1, and 95.5, 64.8, and 35.7 % in group 2 (P = 0.003) (Fig. 2). Overall survival rates of group 1 were significantly higher than group 2. Median duration of follow-up after transplantable recurrence was 40 months (range 2–120 months). Progression Patterns and Time to Progression in Group 2 Three progression patterns after transplantable recurrence were observed in group 2. First, recurrent HCC progressed beyond the MC without extrahepatic metastasis in 20 patients (median duration 12 months). Extrahepatic metastasis developed directly after transplantable recurrence in 10 patients (median duration 18.5 months). Transplantable recurrent HCC progressed sequentially beyond the MC and metastasized extrahepatically in 14 patients (median duration 13 months). Risk Factors of Each Subgroup By univariate analysis, risk factors in group 1 were age [50 years and an ICG-R 15 [ 10 %. Risk factors in group 2 were extent of resection, presence of multiple tumors, and
Recurrence beyond the MC N=17
LT N=15
Tumor progression beyond the MC N=44
the presence of an SN and/or mPVI at initial hepatectomy (Supplementary Table 1). Multiple logistic regression analysis showed that age [50 years and an ICG-R 15 [ 10 % at initial hepatectomy were risk factors in group 1. However, the presence of an SN and/or mPVI at initial hepatectomy was the only independent risk factor identified in group 2 (Table 2). Patients who Underwent Salvage LT After Transplantable Recurrence Salvage LT was performed in 15 patients with transplantable recurrence (Table 3). No patient underwent salvage LT for deteriorating liver function after resection. Five patients underwent prior major hepatectomy and 10 patients underwent prior minor hepatectomy. Median duration between initial hepatectomy and transplantable recurrence was 13 months (range 2–58 months), and median duration between transplantable recurrence and LT was 11 months (range 2–65 months). An SN and/or mPVI in resected specimens at initial hepatectomy occurred in 3 patients, and 2 (66.7 %) of these patients had extrahepatic recurrence develop after salvage LT. In addition, one patient that received TACE before initial hepatectomy had extrahepatic recurrence develop after salvage LT. However, it was not possible to determine whether an SN and/or
Clinical Behavior of Transplantable Recurrent HCC TABLE 1 Characteristics of patients with transplantable recurrence Variables
Group 1 (n = 70)
Group 2 (n = 44)
Age (years)a
58.5 (24–73)
50.5 (33–70)
0.021
60 (85.7)
38 (86.4)
0.923
8.5 (1.5–33.8)
0.082
42 (0.76–7,402)
0.086
3.0 (0.9–5.0)
0.722
Male gender (n [%]) ICG-R 15 (%)a AFP (IU/mL)
10.6 (1.8–37.5)
a
21.5 (1.6–30,676)
Tumor size (cm)a
3.0 (1.3–5.0)
Multiple tumors (n [%])
6 (8.6)
P Value
7 (15.9)
0.230
Edmondson-Steiner grade (n [%])
0.871
I
9 (15.8)
5 (12.5)
II
33 (57.9)
25 (62.5)
III
15 (15.5)
10 (10.3)
3 (4.3) 18 (25.7)
19 (43.2) 20 (45.5)
\0.001 0.030
6 (8.6)
5 (11.4)
0.275
SN and/or mPVI (n [%]) Early recurrence (n [%]) (B12 months) Type of treatment (n [%]) Re-resection Local ablation therapy
8 (11.4)
2 (4.5)
Local ablation therapy ? TACE
16 (22.9)
16 (36.4)
TACE
40 (57.1)
21 (47.7)
Carcinomatosis
0 (0.0)
21 (67.7)
Hepatic failure
13 (59.1)
4 (12.9)
UGI bleeding
4 (18.2)
3 (9.7)
Infection
5 (22.7)
2 (6.5)
Cause of death (n [%]) \0.001
This data represents patients characteristics at initial hepatectomy, except early recurrence and type of treatment AFP alpha-fetoprotein, ICG-R 15 indocyanine green retention at 15 min, IU international units, mPVI microscopic portal vein invasion, SN satellite nodule, TACE transarterial chemoembolization, UGI upper gastrointestinal a
Results are presented as medians and range
98.6%
100
P=0.003
83.8%
95.5%
TABLE 2 Multiple logistic regression analysis of risk factors in the two groups Variable
Overall survival (%)
80
65.4%
Coefficient Standard P Value Odds ratio (95 % CI) error
Group 1
64.8%
Age [50 years
60
0.778
0.358
0.030
2.178 (1.080–4.395)
ICG-R 15 [ 10 % 0.741
0.305
0.015
2.097 (1.153–3.814)
0.427
\0.001
Group 2
Group 1 (n=70)
40
20
Group 2 (n=44)
0 12
24
36
48
60
2.057
7.819 (3.389–18.042)
CI confidence interval, ICG-R 15 indocyanine green retention at 15 min, mPVI microscopic portal vein invasion, SN satellite nodule
35.7%
0
SN and/or mPVI
72
84
96
108 120
Time after recurrence (months) FIG. 2 Overall survival rates after transplantable recurrence
mPVI were present in this patient because pathological examination of the initial tumor revealed complete necrosis.
DISCUSSION The present study demonstrates that subgroups defined by the progression pattern after transplantable recurrence had different clinical characteristics, risk factors, and prognoses. Of the 114 patients with transplantable recurrence, 70 (61.4 %) showed controlled tumors within the MC, and these patients showed a high incidence of late recurrence and were associated with host factors (age [50 years and ICG-R 15 [ 10 %). None of the patients
H. S. Lee et al. TABLE 3 Patients who underwent salvage liver transplantation after transplantable recurrence Patient Age Time to (years)/sex recurrence after initial hepatectomy (months)
Time to Bridge LT after therapy transplantable (number) recurrence (months)
1
50/M
23
22
RFA (1), Living TACE (1)
2
62/M
11
18
RFA (1)
Living
No
No
No
3
47/M
13
11
TACE (1)
Living
No
No
Yes
4
51/F
3
31
TACE (5)
Deceased No
No
No
5
44/M
16
15
TACE (2)
Living
No
No
No
22
6 7
62/M 42/M
30 58
3 2
No No
Deceased No Living No
No No
No No
50 43
8
41/M
39
11
TACE (3)
Deceased No
No
No
9
50/M
8
38
RFA (1), Living TACE (4)
No
No
Yes
10
44/M
12
8
TACE (1)
Living
Yes (SN)
No
No
11
58/F
2
2
No
Deceased Yes (SN, mPVI)
Lung (11)
Yes
12
57/M
13
4
No
Living
No
No
No
37
13 14
57/M 53/M
21 3
65 2
TACE (4) No
Living Living
No Yes (SN)
No Adrenal (49)
No No
31 57
15
55/M
13
17
TACE (5)
Living
Noa
Lung (10)
No
21
LT type
SN and/or Post-transplant Death Cause of mPVI recurrence death (at initial (months) hepatectomy)
Survival after LT (months)
No
24
No
No
46 Biliary sepsis
5 82
91 Postoperative bleeding
0 32
Carcinomatosis 40
F female, LT liver transplantation, M male, mPVI microscopic portal vein invasion, RFA radiofrequency ablation, SN satellite nodule, TACE transarterial chemoembolization a
It could not be determined whether an SN or mPVI were present in this patient because the tumor showed complete necrosis by pathology
with controlled tumors died from carcinomatosis. Additionally, the overall survival rates after the recurrence of controlled tumors were significantly greater than those for progressive tumors. These results suggest that controlled tumors tend to originate from multicentric occurrence. By contrast, 44 (38.6 %) patients showed progressive tumors, despite active treatment, and these patients showed a higher incidence of early recurrence and greater likelihood of SN and/or mPVI. Thirty-one of the 44 patients in group 2 died, and of these, 67.7 % died of carcinomatosis. It is suggested by our results that progressive recurrent tumors likely originated from metastasis of the primary tumor. The origin of intrahepatic recurrence after resection can be predicted based on the time to recurrence and type of recurrence. Early recurrence suggests primary tumor metastasis, whereas late recurrence indicates multicentric occurrence.19 Three types of recurrence are described after resection: intrahepatic nodular, intrahepatic multiple, and extrahepatic.27 Extrahepatic and intrahepatic multiple type recurrence have been linked to primary tumor metastasis, whereas the intrahepatic nodular type is more frequently associated with multicentric occurrence.28,29 However, several authors have suggested that the intrahepatic nodular type recurrence could originate from primary tumor metastasis or
multicentric occurrence.11,19,20 Therefore, even when intrahepatic recurrent HCC seems transplantable, there is a risk of including tumors originating from the primary tumor metastasis. Park et al.28 concluded that portal vein tumor thrombi and intrahepatic metastases are risk factors of early intrahepatic multiple recurrences after resection, and concluded intrahepatic metastasis occurs primarily via the portal vein. Our analysis shows that the presence of an SN and/or mPVI at initial hepatectomy was the only independent risk factor for a progressive tumor. Furthermore, the incidence of a progressive tumor was higher in patients with early recurrence, which suggests recurrent tumor originates from primary tumor metastasis in these patients. The present study shows that the methods used to treat recurrent HCC were not significantly different in the two groups. However, overall survival rates after the recurrence of controlled tumors were significantly greater than progressive tumors. Arii et al.30 and Yang et al.31 concluded that repeat resection and local ablation therapy are more effective in patients with multicentric occurrence than in those with recurrence originating from primary tumor metastasis. This finding indicates that the origin of recurrent tumor should be considered when patients are enlisted
Clinical Behavior of Transplantable Recurrent HCC
as candidates for salvage LT. In the present study, controlled tumors showed a high incidence of late recurrence and were associated with host factors (age [50 years and ICG-R 15 [ 10 %). Our results suggest that controlled tumors have a low probability of HCC dissemination because they tend to originate from multicentric occurrence. None of the patients with controlled tumors died from carcinomatosis. Thus, patients with controlled tumors may be optimal candidates for salvage LT. Previous studies have recommended salvage LT before recurrence in patients at high pathological risk of recurrence.32,33 Sala et al.34 first recommended salvage LT before recurrence and performed salvage LT in 5 patients with a high pathological risk of recurrence (microvascular invasion and/or additional nodules). However, one patient who received salvage LT developed extrahepatic recurrence. Two patients that refused LT developed large multinodular recurrence. Unfortunately, these authors did not report the long-term outcomes of salvage LT before recurrence in patients at high pathological risk. Fuks et al.35 also recommended performing salvage LT before recurrence in patients with at least three or more than three of five poor histological factors (i.e., microscopic vascular invasion, SN, tumor [3 cm, poorly differentiated tumor, and liver cirrhosis). However, it seems paradoxical to recommend salvage LT in the presence of these factors, which are also predictors of recurrence after transplant.8 Recently, Fan et al.36 demonstrated that circulating HCC stem cells in the blood can predict recurrence post-hepatectomy. Marubashi et al.37 found that the presence of AFP messenger ribonucleic acid-expressing cells in peripheral blood preoperatively can predict HCC recurrence after LT. In other words, tumor cell migration into the blood is an important factor in HCC recurrence after hepatectomy or LT. These findings suggest that the probability of posttransplant recurrence is high due to systemic tumor cell dissemination, despite the removal of the diseased liver by salvage LT in patients at high pathological risk of recurrence. Accordingly, salvage LT should not be encouraged in patients with high pathological risk of recurrence (presence of SN and/or mPVI in this study). Limitations of this article included a relatively small sample size and a higher percentage of patients with HBV than those reported in Western and Japanese studies. Additionally, SN or mPVI, or both were identified in 10.9 % of patients that did not recur after resection and in 4.3 % of patients with controlled tumors. These results indicate that time is required to observe patients with SN and/or mPVI at initial hepatectomy to determine tumor biology. In the present study, the median duration between transplantable recurrence and recurrent tumor progression beyond the MC or extrahepatic metastasis were 12 and 18.5 months, respectively.
Accordingly, based on our results, we suggest that an observation time of at least 12 months is required. In conclusion, the present study shows that transplantable recurrent HCCs have different risk factors and prognoses that ultimately depend on patterns of tumor progression. Controlled tumors were associated with multicentric occurrence. Thus, patients with controlled tumors may be the best candidates for salvage LT. On the other hand, progressive tumors had poorer prognoses, and these recurrences were associated more with primary tumor metastasis, and SN or mPVI, or both are risk factors for progressive tumors. Thus, patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT. Additionally, an extended observation time is required to determine tumor biology in patients with SN and/or mPVI at initial hepatectomy. Increased observation times may reduce recurrence after salvage LT and facilitate effective organ use in this era of organ donor shortage. DISCLOSURE
The authors declare no conflict of interest.
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