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Eur J Cardiothorac Surg 2008;34:196-199. doi:10.1016/j.ejcts.2008.03.056
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Surgical outcomes for pulmonary metastases from hepatocellular carcinoma

Masafumi Kawamuraa,*, Jun Nakajimab, Haruhisa Matsugumac, Hirotoshi Horiod, Shinichiro Miyoshie, Ken Nakagawaf, Takehiko Fujisawag, Koichi Kobayashia, The Metastatic Lung Tumor Study Group of Japan

a Division of General Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan
b Department of Cardiothoracic Surgery, University of Tokyo, Tokyo, Japan
c Department of Chest Surgery, Tochigi Prefectural Cancer Center, Tochigi, Japan
d Department of General Thoracic Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
e Department of Cardiothoracic Surgery, Dokkyo Medical University, Tochigi, Japan
f Department of Chest Surgery, Cancer Institute Hospital, Tokyo, Japan
g Department of Thoracic Surgery, Chiba University, Chiba, Japan

Received 27 September 2007; received in revised form 24 March 2008; accepted 31 March 2008.

* Corresponding author. Address: Division of General Thoracic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 Japan. Tel.: +81 3 5363 3806; fax: +81 3 5363 3499. (Email: kawamura{at}sc.itc.keio.ac.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods and materials
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Although favourable prognosis following aggressive treatment of extrahepatic metastases from hepatocellular carcinoma (HCC) has been reported, surgical outcomes for pulmonary metastases are unclear. Methods and materials: Sixty-one patients (2.6%) of 2297 registered with the Metastatic Lung Tumor Study Group of Japan between 1990 and 2006, who underwent surgery for pulmonary metastases from HCC, were retrospectively reviewed from the registry. Results: The overall 5-year survival rate was 32.2%. The prognosis was significantly better for ≤2 lesions than for ≥3 lesions (p = 0.046), for ≤3 lesions than for ≥4 lesions (p = 0.0070), and for ≤4 lesions than for ≥5 lesions (p = 0.029). No other factors that influence outcomes were identified. A stepwise regression analysis showed three or less pulmonary metastases to be an independent factor for better prognosis (p = 0.048). Conclusion: With careful patient selection, comparatively good outcomes can be expected following surgical resection of pulmonary HCC metastases. Among them, patients with multiple metastases, if number of metastases is small such as four or less, can be expected to survive long after surgery.

Key Words: Hepatocellular carcinoma • Pulmonary metastasis • Extrahepatic metastasis • Surgery • Metastasectomy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods and materials
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Advances in localised treatments for hepatocellular carcinoma (HCC) have seen better local control achieved in recent years. The prognosis remains poor for extrahepatic recurrence however, although some studies have reported improved outcomes following aggressive treatment of extrahepatic metastases [1]. Pulmonary metastases account for over 50% of extrahepatic HCC metastases [2,3]. The primary lesion in more than 80% of HCC with extrahepatic HCC metastases is advanced, stage III or IVa, so there are few opportunities for aggressive surgical treatment of extrahepatic metastases [3]. Surgical resection is contraindicated in most cases of pulmonary HCC metastases due to the number of lesions. There have accordingly been few studies of the results of surgical treatment of pulmonary metastases. In this study we analysed the results of surgical procedures on pulmonary HCC metastases in 61 patients to determine prognostic factors.


   2. Methods and materials
Top
 Abstract
 1. Introduction
 2. Methods and materials
3. Results
 4. Discussion
 5. Conclusions
 References
 
From 2297 patients registered with the Metastatic Lung Tumor Study Group of Japan from January in 1990 to May in 2006 who underwent resection of metastatic lung tumours, the subjects of this study were the 61 patients (2.6%) who underwent surgery for pulmonary HCC metastases. Information regarding subject gender, date of birth, date and time of hepatic surgery, date of detection of pulmonary metastases, number of lesions on right and left, maximum tumour diameter, date and time of resection of pulmonary metastases, and the type of procedure performed, were recorded in the registration form. Detection of pulmonary metastases was performed by CT scan. Multi-detector CT scan has become available since late 1990s. Video-assisted thoracic surgery (VATS) has been undergone since 1996. Choice of surgical procedure was left to each surgeon. Although the patients were required to have sufficient liver function for pulmonary resection, information of their liver condition was not mandatory for registration because of chest surgeons’ registration. Patients were followed-up basically with chest CT scan twice a year for the recurrence of pulmonary metastases. Outcome surveys were subsequently conducted at 1-year intervals. In general, we followed the indications for surgical resection of pulmonary HCC metastases proposed by Thomfold et al. [4], that the primary lesion is under control or is planned to be under control, there are no metastases to other organs, and the patient's general condition is good enough to withstand surgery [4]; we also included patients with bilateral disease. We counted two stage procedures for bilateral pulmonary metastases as a single procedure, and we defined re-do surgery for recurrent pulmonary metastases as surgery for pulmonary metastases newly detected after the initial procedure. The disease-free interval (DFI) was defined as the time between the day of hepatic surgery and the day of detection of pulmonary metastases, giving a DFI of 0 if pulmonary metastases were discovered prior to or at the time of the initial hepatic surgery. Cumulative survival rates were calculated using the Kaplan–Meier method, and comparisons among the survival curves were made using the log-rank test. Multivariate analysis for prognostic factors was assessed using a stepwise regression. A p value <0.05 were considered as a statistically significant difference. Statistical analysis was performed using the SPSS Base 11.0J software package (SPSS Inc., IL, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods and materials
 3. Results
4. Discussion
 5. Conclusions
 References
 
There were 46 male and 15 female subjects, ages ranging from 27 to 80 (mean 60 years). Patient background characteristics are shown in Table 1 . There were no operation related deaths. Preoperative evaluation of hilar and mediastinal lymph node metastasis was recorded in 44 cases. Among them actual lymphatic metastases were proven histologically in four cases. Pulmonary metastases were already present at the time of diagnosis of HCC in six patients, of whom pulmonary surgery was performed first in one patient. The cumulative 1-year survival rate after the initial pulmonary surgery was 69.8%, the 3-year survival rate 46.9%, and the 5-year survival 32.2%. The cumulative 1-year survival rate after hepatic surgery was 93.2%, the 3-year survival rate 74.0%, the 5-year survival 50.3%, and the 8-year survival 33.3% (Fig. 1 ). Of the eight subjects who survived at least 5 years following pulmonary surgery, three survived as cancer bearers.


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  		Table 1 Clinical characteristics of subjects with pulmonary metastases from hepatocellular carcinoma
 

Figure 1
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  		Fig. 1. Cumulative survival curves after hepatectomy and after initial pulmonary resection. Five-year survival rate after initial pulmonary metastasectomy is 32.2% and 5-year survival rate after hepatectomy is 50.3%.

 
We examined outcomes according to each parameter: gender, age (<60 vs ≥60), DFI (≤12 m vs ≥13 m, ≤24 m vs ≥25 m), number of pulmonary metastases at time detection (solitary vs multiple, n = 1–2 vs ≥3, n = 1–3 vs ≥4, n = 1–4 vs ≥5), maximum tumour diameter (<2 cm vs ≥2 cm), procedure (wedge resection vs segment resection/lobectomy), and number of pulmonary procedures (single vs multiple). As shown in Table 2 , no significant difference was seen between solitary metastasis and multiple lesions (p = 0.203), whereas the prognosis was significantly worse for ≥3 lesions than for ≤2 lesions (p = 0.046), for ≥4 lesions than for ≤3 lesions (p = 0.007) (Fig. 2 ) and for ≥5 lesions than for ≤4 lesions (p = 0.029). No other factors that influence outcomes were identified. A stepwise regression analysis showed three or less pulmonary metastases to be an independent factor for better prognosis (p = 0.048) (Table 3 ).


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  		Table 2 Cumulative overall survival results using log-rank analysis (Kaplan–Meier method)
 

Figure 2
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  		Fig. 2. Cumulative survival curves of patients with 1–3 metastases and with four or more metastases.

 

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  		Table 3 Relationships of individual variables to patient prognosis (stepwise regression model)
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods and materials
 3. Results
 4. Discussion
5. Conclusions
 References
 
Treatment outcomes for HCC hepatic primary lesions have improved remarkably with recent advances in a variety of therapeutic modalities, including resection, hepatic artery injection sclerotherapy, ethanol injections and ablation therapy. This has led to consideration of more aggressive treatments for extrahepatic metastases. There have been some reports of prolonged life expectancy following aggressive therapy, including localised treatments, for extrahepatic metastases [1]. Pulmonary lesions are the most common extrahepatic HCC metastases, accounting for 50–60% of the total [2,3]. In most cases, surgery is contraindicated due to multiple lesions, so surgical treatment for pulmonary HCC metastases has yet to be fully evaluated.

Tomimaru et al. reported a series of 615 patients who underwent radical resection for HCC, 34 of whom developed pulmonary metastases during the postoperative follow-up period. Pulmonary metastases were resected in eight of the 14 patients with one or two pulmonary lesions, and outcomes were markedly better in the resection group than in the nonresection group [5]. This result indicates that surgical resection is effective in this highly selected group of patients with 1–2 pulmonary metastases, but at the same time leaves us with the suspicion that surgical resection may be indicated only in patients with no more than two pulmonary HCC metastases. Lam et al. reported a favourable 5-year survival rate of 67% in patients (n = 9) who underwent resection of solitary lesions [6]. Our analysis did not show any significant difference in the 5-year survival rate between subjects with solitary lesions (n = 32) and with multiple lesions (n = 29) (p = 0.203). On the other hand, there were significant differences in prognosis between ≥3 lesions and ≤2 lesions (p = 0.046), between ≥4 lesions and ≤3 lesions (p = 0.0070), and between ≥5 lesions and ≤4 lesions (p = 0.029). These data suggest that there is a relationship between metastatic number and prognosis and some patients with multiple metastases, if number of metastases is small such as four or less, can be expected to survive long after surgery. Actually about 90% of subjects had no more than three pulmonary metastases in this study. Multivariate analysis also showed that three or less pulmonary metastases was an independent better prognostic factor for surgical treatment (p = 0.027).

In their studies of outcomes following surgical treatment of pulmonary HCC metastases, Koide et al. reported a 5-year survival rate (overall survival) of 26.8% for 14 subjects [7], and Nakajima et al. reported 23.8% for 20 subjects [8]. These are both single center therapeutic results. Our data, although collected from multiple institutions, yield a similar 5-year survival rate of 32%. All of the published studies to date have had insufficient patient numbers to properly assess the therapeutic effect of surgical resection for pulmonary HCC metastases. Koide and Nakajima both used roughly the same indications for surgery as we did, however, indicating that a 5-year survival rate of around 30% can be achieved with patients selected in this way.

Of the 12 subjects who underwent repeat surgery for recurrent pulmonary metastatic disease, only one survived for 5 years. This study does not demonstrate any efficacy for re-do surgery. There were no surgery-related deaths, however, and a number of studies have shown better outcomes for aggressive treatment of extrahepatic metastases [9–12], so there are no convincing reasons why repeat surgical resection should be contraindicated for recurrent pulmonary metastases.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods and materials
 3. Results
 4. Discussion
 5. Conclusions
References
 
With careful patient selection, comparatively good outcomes can be expected following surgical resection of pulmonary HCC metastases. Among them, patients with multiple metastases, if number of metastases is small such as four or less, can be expected to survive long after surgery.


   References
Top
 Abstract
 1. Introduction
 2. Methods and materials
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Imamura I. Prognostic efficacy of treatment for extrahepatic metastasis after surgical treatment of hepatocellular carcinoma. Kurume Med J 2003;50(1–2):41-48.[Medline]
  2. Natsuizaka M, Omura T, Akaike T, Kuwata Y, Yamazaki K, Sato T, Karino Y, Toyota J, Suga T, Asaka M. Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol 2005;20(11):1781-1787.[CrossRef][Medline]
  3. Katyal S, Oliver JH, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastasis of hepatocellular carcinoma. Radiology 2000;216(3):698-703.[Abstract/Free Full Text]
  4. Thomford NR, Woolner LB, Clagett OT. The surgical treatment of metastatic tumors in the lung. J Thorac Cardiovasc Surg 1965;49:357-363.[Medline]
  5. Tomimaru Y, Sasaki Y, Yamada T, Eguchi H, Takami K, Ohigashi H, Higashiyama M, Ishikawa O, Kodama K, Imaoka S. The significance of surgical resection for pulmonary metastasis from hepatocellular carcinoma. Am J Surg 2006;192(July (1)):46-51.[CrossRef][Medline]
  6. Lam CM, Lo CM, Yuen WK, Liu CL, Fan ST. Prolonged survival in selected patients following surgical resection for pulmonary metastasis from hepatocellular carcinoma. Br J Surg 1998;85(Sept. (9)):1198-1200.[CrossRef][Medline]
  7. Koide N, Kondo H, Suzuki K, Asamura H, Shimada K, Tsuchiya R. Surgical treatment of pulmonary metastasis from hepatocellular carcinoma. Hepatogastroenterology 2007;54(Jan.–Feb. (73)):152-156.[Medline]
  8. Nakajima J, Tanaka M, Matsumoto J, Takeuchi E, Fukami T, Takamoto S. Appraisal of surgical treatment for pulmonary metastasis from hepatocellular carcinoma. World J Surg 2005;29(June (6)):715-718.[CrossRef][Medline]
  9. Chen YJ, Hsu HS, Hsieh CC, Wu YC, Wang LS, Hsu WH, Huang MH, Huang BS. Pulmonary metastasectomy for hepatocellular carcinoma. J Chin Med Assoc 2004;67(Dec. (12)):621-624.[Medline]
  10. Gwak GY, Jung JO, Sung SW, Lee HS. Long-term survival after pulmonary metastasectomy of hepatocellular carcinoma; treatment outcome or natural history?. Hepatogastroenterology 2004;51(Sep.–Oct. (59)):1428-1433.[Medline]
  11. Kitayama D, Yoshidome H, Mitsuhashi N, Ito H, Kimura F, Shimizu H, Ohtsuka M, Miyazaki M. Aggressive surgical resection for hepatocellular carcinoma with tumor thrombus extending to inferior vena cava and synchronous pulmonary metastasis. Hepatogastroenterology 2004;51(Sept.–Oct. (59)):1326-1329.[Medline]
  12. Aramaki M, Kawano K, Sasaki A, Matsumoto T, Kai S, Iwashita Y, Himeno Y, Kitano S. Prolonged survival after repeat resection of pulmonary metastasis from hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 2002;9(3):386-388.[CrossRef][Medline]



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This Article
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