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a Department of Cardiothoracic Surgery, Ochsner Clinic Foundation, New Orleans, Louisiana
b Department of Pulmonary Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana
Accepted for publication October 18, 2007.
* Address correspondence to Dr Bates, Department of Cardiothoracic Surgery, Falk Cardiothoracic Research Center, 300 Pasteur Drivem Stanford, CA 94305-5407 (Email: mbates{at}stanford.edu).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentReferences |
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Methods: Between January 2000 and January 2006, five patients who underwent orthotopic liver transplantation for HCC were identified on routine follow-up with pulmonary metastases. They all underwent resection of the pulmonary recurrence of HCC and were studied retrospectively.
Results: The time from transplant to diagnosis of pulmonary recurrence ranged from 150 days to 880 days, with a mean of 500 days. All of the recurrences were amenable to complete resection. Two patients developed a second tumor. One patient had a new primary of squamous cell carcinoma. Another patient had a bony recurrence of HCC in the ninth rib. Four of the patients are still alive, and the fifth died from hepatic failure. The stage of the tumor in the explanted liver ranged from II to IVb. The average time for survival from transplant was 44 months, and the average time from pulmonary resection was 27.5 months.
Conclusions: The patients in this study demonstrate survival times similar to patients with HCC treated with liver resection. Although the size of the study population is small, the long survival times in the patients is encouraging. The advanced stage and histologically invasive nature of the primary tumors may predispose to subsequent pulmonary recurrence.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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The majority of patients with HCC have two diseases; cancer and cirrhosis. More than 80% of HCC develop in the setting of chronic liver disease due to viral diseases hepatitis B virus (HBV) and HCV, alcoholic cirrhosis, and metabolic derangements such as hemachromatosis. There are approximately three million individuals with HCV in the United States and cirrhosis will develop in 20% to 30%. It is expected the HCC will develop in patients with cirrhosis at a rate of 3% to 5% per year [3]. There is a latency period of about 20 to 40 years from infection with HCV and the occurrence of HCC.
The surgical treatment of patients with HCC includes primary resection, ablative procedures, and orthotopic liver transplantation. Liver transplantation is considered for patients with unresectable tumors due to anatomic location or limited functional reserve [4]. It is the only available treatment for both malignancy and the underlying cirrhosis. Recent studies have demonstrated an excellent long-term survival with a low incidence of recurrence. The primary limitation to long-term survival after liver transplantation for HCC is recurrence of the tumor [5, 6]. Pulmonary resection for metastatic HCC prolongs survival in patients after liver resection or in patients whose hepatic malignancy is controlled by ablative procedures [7]. This success may be extrapolated to the transplant population in the treatment of pulmonary recurrence of HCC after orthotopic liver transplantation.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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After liver transplant, immunosupression was initiated and patients were routinely evaluated with laboratory analysis, physical exams, and radiographic studies. All patients received annual thoracic and abdominal CT scans to evaluate for recurrence of HCC. Suspicious lesions were biopsied percutaneously. Once pulmonary recurrence was identified, patients were screened for other sites of recurrence with whole body positron emission tomography (PET)/CT and (or) bone scan. Patients without evidence of extrapulmonary disease underwent pulmonary resection by thoracotomy with standard anatomic lobectomy or wedge resection. After pulmonary resection they were followed for an additional recurrence and offered resection of a second occurrence as indicated.
Specific factors of each patient were reviewed. These included the final pathologic stage of the tumor in the explanted liver, including gross and microscopic features. The time from diagnosis of HCC to liver transplant and the interval from transplant to pulmonary recurrence were recorded. Other factors of treatment, including AFP levels, type of resection, immunosupression, a second recurrence, and status of the patient at the time of the study, were also reviewed (see Table 1).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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All five patients underwent a pretransplant staging and evaluation that established them as transplant candidates according to current recommendations. Clinical and anatomic factors made resection prohibitive. There was documented cirrhosis in all cases with concomitant HCC in the setting of viral hepatitis. Four patients had HCV and one had both HCV and HBV. The time from diagnosis of HCC to liver transplant ranged from 51 to 453 days, with a mean of 202. All patients received tacrolimus as immunosupression and one patient also received Thymogloblulin (Genzyme Polyclonals, Lyon, France) and Cellcept (Roche, Nutley, NJ). The stage of the tumor in the explanted liver ranged from II to IVb. Tumors in all of these patients were characterized as high grade with an infiltrative growth pattern, and four of the five patients exhibited gross vascular invasion in the surgical specimen.
The time from transplant to diagnosis of pulmonary recurrence ranged from 150 days to 880 days with a mean of 500 days. All of the recurrences were single pulmonary nodules amenable to complete resection and without evidence of any other sites of disease based upon nuclear scans, radiography, and laboratory surveillance. Two patients developed a second thoracic tumor. One of these patients had a second contralateral pulmonary recurrence at 1,095 days from the first recurrence and subsequently underwent a nonanatomic wedge resection. This lesion was found to be a new primary of squamous cell carcinoma. The second patient had a bony recurrence in the ninth rib at 1,197 days and was resected. Four of the patients are still alive and there was one late death from hepatic failure from cirrhosis and recurrence of HCC in the transplanted liver. The survival range was 12 to 80 months and the mean survival time was 44.4 months (Table 2).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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The five patients reviewed in this series underwent the standard preoperative workup, which included liver ultrasound, CT scan of the chest and abdomen, as well as biopsy confirmation of HCC in the liver nodules, and were followed for evidence of advanced disease. They all received transarterial chemoembolization of their tumors with a fall in alpha-fetoprotein levels. The imaging studies indicated stage II status; however, examination of the explanted livers resulted in upstaging of all the patients and this is the stage reported. This finding reflects the difference between image-based staging and pathologic stage. Two of the patients were stage III based upon the size and number of the nodules. The other three patients were stage IV based upon gross intrahepatic vascular invasion noted in the explanted liver. All the tumors were observed to exhibit an infiltrative growth pattern and were described as high grade HCC based on this characteristic.
The primary limitation to long-term survival after liver transplantation for HCC is recurrence of the tumor in any location. Tumor recurrence after liver resection for HCC most often occurs in the liver; however, after transplantation recurrence follows a different pattern and must be due to the presence of micrometastases present preoperatively or during the transplant procedure. The sites of recurrence vary due to the major route of recurrence, hematogenous spread. These sites are most often the liver (62%), lung (52%), and bone (18%). The timing to recurrence exhibits a wide range with a median of 441 days from transplantation. These recurrences were associated with male gender, pointing to a hormonal influence. Other factors predisposing to recurrence are absence of cirrhosis, size greater than 5 cm, more than five nodules, and vascular invasion [5]. Recurrence of HCC after liver transplantation has been observed in 18% of patients in one large, single center study. In this population the five year survival was significantly reduced from 64% to 22% and the median time to recurrence was observed at 12.3 months. Despite shortened survival there was significant benefit to patients who underwent surgical resection for recurrence. In this study a similar pattern of recurrences occurred with liver (47%), lung (43%), and bone (33%) [6]. Due to the small population sizes in these studies it is difficult to demonstrate a benefit due to surgical resection. It may be that the tumors amenable to surgical resection play a role in the increased survival; however, these studies do suggest a survival advantage in the patients who undergo surgical resection of tumor recurrences [5, 6, 10].
The patients in the present series demonstrated large tumors with vascular invasion in the milieu of a cirrhotic liver. There were also four male and one female patients. All of these factors have been associated with tumor recurrence after resection or transplantation [9]. The average time for recurrence was noted to be 16.6 months, which compares favorably with the reported time of 12.3 months stated above. This raises the question of whether adjuvant therapy may be warranted in patients who are transplanted with tumors that demonstrate these aggressive characteristics.
The presence of pulmonary recurrence was detected based upon biochemical and radiographic evidence. Alpha fetoprotein levels were measured posttransplant and were found to be elevated in four of the five patients. Radiographic studies demonstrated a pulmonary nodule in all patients. The PET scan was performed in four of the patients and was suggestive of metastatic disease in three patients; PET scan has been shown to be useful in the evaluation of extrahepatic HCC. In lesions larger than 1 cm the detection rate for PET was 83% and only 13% in nodules less than 1 cm [11]. Another study demonstrated a detection rate of 89% for PET scan for extrahepatic disease and a 98% rate for PET plus CT fusion [12]. In this study the detection rate was 75% for the presence of HCC on PET scan for the four patients imaged prior to resection. The one patient who did not have a PET scan was diagnosed with pulmonary HCC by CT guided needle biopsy.
The surgical treatment of pulmonary metastases after liver resection for HCC is an established therapeutic modality, and survival has been reported in between 24% to 78% at three years, with median survival from 21 months to 29 months. When compared with similar patients who did not undergo resection of pulmonary recurrences, the patients undergoing resection had significantly longer survival times with a low rate of another pulmonary recurrence. It has been surmised from these studies that the surgical resection of pulmonary metastasis from HCC results in improved outcomes for selected patients [7, 13, 14].
Patients transplanted for HCC may present with an analogous situation and may derive a similar benefit from resection of a pulmonary recurrence. The type of resection performed on patients in this study was based upon anatomic and physiologic considerations. Patients with good pulmonary function and tumors located within the lung parenchyma were treated with lobectomy as a more complete anatomic resection. Patients with peripheral tumors, a second recurrence, or decreased pulmonary function underwent wedge resection. The patients in this study demonstrate similar survival times to the studies mentioned above. The average time for survival from transplant was 44 months and the average time from pulmonary resection was 27.5 months. The range of survival was from 3 months in the most recent patient resected to 52 months. The one patient death in the series occurred 8.5 months after pulmonary resection. Although the size of the study population is small the long survival times in the patients is encouraging.
Hepatocellular carcinoma is an increasingly prevalent disease. Orthotopic liver transplantation is one of the treatment modalities for this difficult problem. Long-term survival has been demonstrated in this population of patients, and with this success comes the inevitable challenge of treating recurrences. Pulmonary recurrence of HCC is the most common site of metastasis after liver resection for HCC as well as transplantation. In the small cohort of transplant patients presented in this study, survival times are similar to the survival of patients with HCC undergoing metastasectomy after liver resection for HCC. This suggests that resection of pulmonary recurrence of HCC after liver transplantation is a reasonable and safe treatment and should result in survival similar to the nontransplant population.
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  F. Shoji, D. Kawano, T. Ikegami, Y. Soejima, A. Taketomi, T. Yano, and Y. Maehara Surgical resection of pulmonary malignant tumors after living donor liver transplantation. Ann. Thorac. Surg., July 1, 2009; 88(1): 206 - 211. [Abstract] [Full Text] [PDF]
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 C. Zhang, J. Rao, Z. Tu, and Y. Ni Surgical resection of resectable thoracic metastatic hepatocellular carcinoma after liver transplantation J. Thorac. Cardiovasc. Surg., July 1, 2009; 138(1): 240 - 241. [Full Text] [PDF]
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