- Email: [email protected]
Pulmonary Resection of Metastatic Hepatocellular Carcinoma After Liver Transplantation
GENERAL THORACIC
Pulmonary Resection of Metastatic Hepatocellular Carcinoma After Liver Transplantation Michael J. Bates, MD, Emily Farkas, MD, David Taylor, MD, and P. Michael McFadden, MD Departments of Cardiothoracic Surgery and Pulmonary Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana
Background. The primary limitation to long-term survival after liver transplantation for hepatocellular carcinoma (HCC) is tumor recurrence. Pulmonary resection for metastatic HCC prolongs survival in patients after liver resection; this success may be extrapolated to the transplant population in the treatment of pulmonary recurrence of HCC after liver transplantation. 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. (Ann Thorac Surg 2008;85:412–5) © 2008 by The Society of Thoracic Surgeons
H
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.
epatocellular carcinoma (HCC) is one of the few cancers with increasing frequency and mortality in the United States [1]. Although HCC has always been a common cause of cancer world wide, the recent surge of cases in the western world is attributable to the increasing prevalence of hepatitis C infection. More than half of HCC cases in the United States, Europe, and Japan are due to chronic hepatitis C virus (HCV) infection and cirrhosis [2]. 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
Accepted for publication Oct 18, 2007. Address correspondence to Dr Bates, Department of Cardiothoracic Surgery, Falk Cardiothoracic Research Center, 300 Pasteur Drivem Stanford, CA 94305-5407; e-mail: [email protected].
© 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Between January 2000 and December 2006, 601 patients underwent orthotopic liver transplantation, of which 104 patients were transplanted for HCC. Five of the HCC cohort were identified on routine follow-up to have pulmonary recurrence of HCC. These patients had no other identifiable foci of disease and were in good physical condition. They all underwent resection of the pulmonary recurrence of HCC and were retrospectively studied for their respective characteristics and clinical course (see Table 1). This study was approved by the Institutional Review Board and patient consent was waived because the study was retrospective and maintained anonymity. 0003-4975/08/$34.00 doi:10.1016/j.athoracsur.2007.10.065
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Table 1. Patient Characteristics Patient 1 2 3 4 5
Gender Age Female 65 Male 58 Male 52 Male 50 Male 59
Recurrence
Second Recurrence
Resection
Immunosupression
Pretransplant Treatment
PET Scan
RLL
LLL
Lobectomy, wedge
Tacrolimus
Embolization
LUL
Rib, HCC Liver, HCC
Tacrolimus, thymo, cellcept Tacrolimus
PEG, embolization
LUL
VATS wedge, rib resection Lobectomy
RLL
No
Lobectomy
Tacrolimus
Embolization
RUL
No
Lobectomy
Tacrolimus
embolization
Positive SUV⬎2.6
PET ⫽ positron emission tomography;
RLL ⫽ right lower
HCC ⫽ hepatocellular carcinoma; lobe; RUL ⫽ right upper lobe;
LLL ⫽ left lower lobe; LUL ⫽ left upper lobe; SUV ⫽ standardized uptake value.
Patients considered for liver transplant as treatment for HCC underwent the standard clinical and psychosocial assessment for suitability. The preoperative workup also included a biopsy proven diagnosis of HCC with histologic evaluation of the tumor. Alpha fetoprotein values were obtained, as well as thoracic and abdominal computed tomography (CT) to complete the preoperative staging process. Patients received radio frequency ablation or chemoembolization of their tumors prior to transplant. Preoperative staging was repeated every three months with laboratory analysis and CT to assess for disease progression. The final HCC stage was determined based upon operative findings and the histopathology of the explanted liver. 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).
Results Five patients were identified with pulmonary recurrence of HCC after liver transplantation at Ochsner Medical Center. All recurrences were identified on routine fol-
Embolization
Positive SUV⬎6 Negative Positive SUV⬎3.7 No PET
low-up and confirmed by thoracic CT, and all of the patients identified underwent pulmonary resection of their recurrence. Four patients had a PET scan as part of their metastatic workup. Three of the PET scans were interpreted as positive for malignancy based upon increased metabolic activity with SUV greater than 2.5. One patient had a PET scan that did not demonstrate evidence of malignancy but subsequently was found to have HCC based upon fine needle aspiration. Three of the patients underwent percutaneous biopsy of the pulmonary nodule and subsequent lobectomy. The other two patients underwent surgical biopsy followed by wedge resection or formal lobectomy after confirmation of HCC in the biopsy specimen. 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
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Ann Thorac Surg 2008;85:412–5
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Ann Thorac Surg 2008;85:412–5
Table 2. Time From Transplant to Recurrence and Overall Survival Patient
Days to Transplant
Days to Recurrence
Pre Transplant AFP (ng/mL)
Days to Second Recurrence
Explant Stage
Gross Vascular Invasion
Alive, Months Post-Transplant
453 51 88 234 190
161 422 879 880 150
216 107 309 514 985
1,095 1,197 1,163 No No
III IVa IVa IVb III
Yes Yes Yes Yes No
Yes, 38 Yes, 54 No, 38 Yes, 80 Yes, 12
1 2 3 4 5
AFP ⫽ alpha feto-protein.
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).
Comment Evaluation of potential liver transplant candidates with HCC includes a full metastatic workup with bone scan and thoracic and abdominopelvic CT scans or magnetic resonance imaging. Autopsy studies demonstrated that thoracic metastases are the most common site of spread, followed by abdominal and bone metastases. Liver transplantation is considered for patients with unresectable tumors due to anatomic location or poor functional reserve, tumors less than 5 cm, or three tumors less than 3 cm and absence of extrahepatic disease [4, 8]. The detection of extrahepatic disease precludes resection or transplantation and portends a shorter survival for these patients. Up to 42% of patients may have metastases at the time of presentation. The most common location of metastasis is the thorax [9]. 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 preop-
eratively 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. Longterm 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
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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.
References 1. EL-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1990;340:745–50. 2. Hoofnagle JH. Hepatocellular carcinoma: summary and recommendations. Gastroenterology 2004;127:S319 –23. 3. Carr BI. Hepatocellular carcinoma: current management and future trends. Gastroenterology 2004;127:S218 –24. 4. Olthoff KM. Surgical options for hepatocellular carcinoma: resection and transplantation. Liver Transpl Surg 1998;5: S98 –104. 5. Schlitt HJ, Neipp M, Weimann A, et al. Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncology 1999;17:324 –31. 6. Roayaie S, Schwartz ME, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534 – 40. 7. Tomimaru Y, Sasaki Y, Yamada T, et al. The significance of surgical resection for pulmonary metastasis from hepatocellular carcinoma. Am J Surg 2006;192:46 –51. 8. Lee YT, Greer DA. Primary liver cancer: pattern of metastasis. J Surg Oncol 1987;36:26 –31. 9. Si MS, Amersi F, Golish SR, et al. Prevalence of metastases in hepatocellular carcinoma: risk factors and impact on survival. Am Surg 2003;69:879 – 85. 10. Regalia E, Fassati LR, Valente U, et al. Pattern and management of recurrent hepatocellular carcinoma after liver transplantation. J Hepatobiliary Pancreat Surg 1998;5:29 –34. 11. Sugiyama M, Nakamura S, Torizuka T, et al. 18F-FDG PET in the detection of extrahepatic metastases from hepatocellular carcinoma. J Gastroenterol 2004;39:961– 8. 12. Nagaoka S, Itano S, Ishibashi M, et al. Value of fusing PET plus CT images in hepatocellular carcinoma and combined hepatocellular and cholangiocarcinoma patients with extrahepatic metastases: preliminary findings. Liver Int 2006;26: 781– 8. 13. 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;85:1198 –1200. 14. 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;29:715– 8.
GENERAL THORACIC
Ann Thorac Surg 2008;85:412–5
Pulmonary Resection of Metastatic Hepatocellular Carcinoma After Liver Transplantation Michael J. Bates, MD, Emily Farkas, MD, David Taylor, MD, and P. Michael McFadden, MD Departments of Cardiothoracic Surgery and Pulmonary Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana
Background. The primary limitation to long-term survival after liver transplantation for hepatocellular carcinoma (HCC) is tumor recurrence. Pulmonary resection for metastatic HCC prolongs survival in patients after liver resection; this success may be extrapolated to the transplant population in the treatment of pulmonary recurrence of HCC after liver transplantation. 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. (Ann Thorac Surg 2008;85:412–5) © 2008 by The Society of Thoracic Surgeons
H
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.
epatocellular carcinoma (HCC) is one of the few cancers with increasing frequency and mortality in the United States [1]. Although HCC has always been a common cause of cancer world wide, the recent surge of cases in the western world is attributable to the increasing prevalence of hepatitis C infection. More than half of HCC cases in the United States, Europe, and Japan are due to chronic hepatitis C virus (HCV) infection and cirrhosis [2]. 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
Accepted for publication Oct 18, 2007. Address correspondence to Dr Bates, Department of Cardiothoracic Surgery, Falk Cardiothoracic Research Center, 300 Pasteur Drivem Stanford, CA 94305-5407; e-mail: [email protected].
© 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Between January 2000 and December 2006, 601 patients underwent orthotopic liver transplantation, of which 104 patients were transplanted for HCC. Five of the HCC cohort were identified on routine follow-up to have pulmonary recurrence of HCC. These patients had no other identifiable foci of disease and were in good physical condition. They all underwent resection of the pulmonary recurrence of HCC and were retrospectively studied for their respective characteristics and clinical course (see Table 1). This study was approved by the Institutional Review Board and patient consent was waived because the study was retrospective and maintained anonymity. 0003-4975/08/$34.00 doi:10.1016/j.athoracsur.2007.10.065
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Table 1. Patient Characteristics Patient 1 2 3 4 5
Gender Age Female 65 Male 58 Male 52 Male 50 Male 59
Recurrence
Second Recurrence
Resection
Immunosupression
Pretransplant Treatment
PET Scan
RLL
LLL
Lobectomy, wedge
Tacrolimus
Embolization
LUL
Rib, HCC Liver, HCC
Tacrolimus, thymo, cellcept Tacrolimus
PEG, embolization
LUL
VATS wedge, rib resection Lobectomy
RLL
No
Lobectomy
Tacrolimus
Embolization
RUL
No
Lobectomy
Tacrolimus
embolization
Positive SUV⬎2.6
PET ⫽ positron emission tomography;
RLL ⫽ right lower
HCC ⫽ hepatocellular carcinoma; lobe; RUL ⫽ right upper lobe;
LLL ⫽ left lower lobe; LUL ⫽ left upper lobe; SUV ⫽ standardized uptake value.
Patients considered for liver transplant as treatment for HCC underwent the standard clinical and psychosocial assessment for suitability. The preoperative workup also included a biopsy proven diagnosis of HCC with histologic evaluation of the tumor. Alpha fetoprotein values were obtained, as well as thoracic and abdominal computed tomography (CT) to complete the preoperative staging process. Patients received radio frequency ablation or chemoembolization of their tumors prior to transplant. Preoperative staging was repeated every three months with laboratory analysis and CT to assess for disease progression. The final HCC stage was determined based upon operative findings and the histopathology of the explanted liver. 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).
Results Five patients were identified with pulmonary recurrence of HCC after liver transplantation at Ochsner Medical Center. All recurrences were identified on routine fol-
Embolization
Positive SUV⬎6 Negative Positive SUV⬎3.7 No PET
low-up and confirmed by thoracic CT, and all of the patients identified underwent pulmonary resection of their recurrence. Four patients had a PET scan as part of their metastatic workup. Three of the PET scans were interpreted as positive for malignancy based upon increased metabolic activity with SUV greater than 2.5. One patient had a PET scan that did not demonstrate evidence of malignancy but subsequently was found to have HCC based upon fine needle aspiration. Three of the patients underwent percutaneous biopsy of the pulmonary nodule and subsequent lobectomy. The other two patients underwent surgical biopsy followed by wedge resection or formal lobectomy after confirmation of HCC in the biopsy specimen. 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
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Table 2. Time From Transplant to Recurrence and Overall Survival Patient
Days to Transplant
Days to Recurrence
Pre Transplant AFP (ng/mL)
Days to Second Recurrence
Explant Stage
Gross Vascular Invasion
Alive, Months Post-Transplant
453 51 88 234 190
161 422 879 880 150
216 107 309 514 985
1,095 1,197 1,163 No No
III IVa IVa IVb III
Yes Yes Yes Yes No
Yes, 38 Yes, 54 No, 38 Yes, 80 Yes, 12
1 2 3 4 5
AFP ⫽ alpha feto-protein.
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).
Comment Evaluation of potential liver transplant candidates with HCC includes a full metastatic workup with bone scan and thoracic and abdominopelvic CT scans or magnetic resonance imaging. Autopsy studies demonstrated that thoracic metastases are the most common site of spread, followed by abdominal and bone metastases. Liver transplantation is considered for patients with unresectable tumors due to anatomic location or poor functional reserve, tumors less than 5 cm, or three tumors less than 3 cm and absence of extrahepatic disease [4, 8]. The detection of extrahepatic disease precludes resection or transplantation and portends a shorter survival for these patients. Up to 42% of patients may have metastases at the time of presentation. The most common location of metastasis is the thorax [9]. 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 preop-
eratively 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. Longterm 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
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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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GENERAL THORACIC
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