- Email: [email protected]
Lung cancer in lung transplant recipients: Experience of a tertiary hospital and literature review
Lung Cancer 74 (2011) 280–283
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Lung cancer in lung transplant recipients: Experience of a tertiary hospital and literature review Yael Raviv a,b,∗ , David Shitrit c , Anat Amital a,b , Benjamin Fox a,b , Dror Rosengarten a,b , Oren Fruchter a,b , Ilana Bakal a,b , Mordechai R. Kramer a,b a
Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Pulmonary Department, Meir Medical Center, Kfar Saba, Israel b
a r t i c l e
i n f o
Article history: Received 1 November 2010 Received in revised form 20 February 2011 Accepted 22 February 2011 Keywords: Lung transplant Bronchoalveolar carcinoma Non-small-cell lung cancer Bronchogenic carcinoma Post-transplant malignancy Lung transplant outcome
a b s t r a c t Background: Lung transplantation is a viable therapy for patients with end-stage lung disease and is being increasingly performed worldwide. The incidence of lung cancer after lung transplantation has increased concomitantly, although data are still sparse. Methods: The computerized medical records of the Pulmonary Institute of a tertiary care medical center were searched for patients who underwent lung transplantation from 1997 to 2009 and acquired lung cancer postoperatively. The prevalence, potential contributing factors, and outcome of bronchogenic cancer were determined, and the medical literature was reviewed. Results: Bronchogenic cancer developed in 7 of the 290 lung transplant recipients (2.4%). All had received a single lung transplant and in most cases, the cancer developed in the native lung. These findings were similar to reports in the literature. The indication for transplantation was chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis/interstitial lung disease. All had a history of smoking. The average interval from transplantation to development of lung cancer was 5 years (range 1–9). Five patients had stage 4 cancer at diagnosis and 2 had stage 1. Six patients died from 10 days to 1 year after diagnosis. Conclusion: Lung transplantation is associated with a relatively high prevalence of bronchogenic cancer, particularly in the native lung, in patients with primary chronic obstructive pulmonary disease/idiopathic pulmonary fibrosis, and a history of smoking. The cancer is usually diagnosed at an advanced stage with poor outcome. Efforts to improve screening are recommended, as aggressive management and treatment may be beneficial for earlier stage disease. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung transplantation is considered a viable therapy for patients with end-stage lung disease. Since the first report of successful clinical lung transplantation in 1983, the volume of procedures has progressively increased worldwide, including Israel [1,2]. However, this rise has been accompanied by an increase in the incidence of cancer in lung transplant recipients. Potential contributory factors are the increasing age of both recipients and donors [2] and the mandatory, post-transplant, high-dose, long-term, immunosuppressive treatment, particularly calcineurin inhibitors such as tacrolimus and cyclosporine [3]. According to current data, malignancies develop in about 16% of lung transplant recipients within 5 years after transplantation, and in 32% within 10 years [4].
∗ Corresponding author at: Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel. Tel.: +972 3 937 7221/50 221 6339; fax: +972 3 937 7142. E-mail address: [email protected] (Y. Raviv). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.02.012
More than 9% of lung transplant recipients will die from the malignancy. The frequency of bronchogenic carcinoma in particular in patients after lung transplantation is uncertain and is at least that of the general population or higher. The few studies conducted to date reported prevalence rates of 0.1–2.3% [5]. However, we expect to see more cases, especially in the native lung of patients with primary chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to pose a high risk of bronchogenic carcinoma [6,7]. Furthermore, COPD and IPF are strongly associated with smoking history, by itself a risk factor [8]. The aim of this study was to determine the prevalence rate, risk factors, and outcomes of bronchogenic cancer in a large population of lung transplant recipients, and to present a review of the medical literature. 2. Methods The computerized medical records of the Pulmonary Institute of Rabin Medical Center, a tertiary care university-affiliated hospital,
Y. Raviv et al. / Lung Cancer 74 (2011) 280–283
were reviewed for all patients who underwent lung transplantation from January 1997 through December 2009. Those in whom bronchogenic cancer developed after transplantation were identified. Data were collected on demographics, primary diagnosis, type of transplant and, when applicable, time and stage of cancer diagnosis, using the new staging system [9], treatment, and survival. All transplant recipients received an immunosuppression protocol that included prednisone, mycophenolate mofetil, and tacrolimus, with a target trough level of 10–15 ng/ml. If cancer was diagnosed, the mycophenolate mofetil was discontinued, the tacrolimus dose was lowered, and sirolimus or everolimus was added, aiming at levels of 4–6 ng/ml of both drugs. 3. Results A total of 312 lung transplantations were performed in our center during the 13-year study period, of which 22 were repeat procedures following chronic rejection. Bronchogenic cancer was diagnosed after transplantation in 7 of the 290 patients (2.4%). Their data are shown in Table 1. All 7 patients received a single lung transplant, accounting for 3.3% of the 211 (73%) single lung transplants performed during the study period. Five patients had a primary diagnosis of interstitial lung disease (IPF in 4, associated with scleroderma in 1), and 2 of emphysema. All had a history of smoking. Mean age of the entire sample at transplantation was 54.5 years; mean age of the 7 patients with lung cancer was 54.5 years at diagnosis. Mean time from transplantation to lung cancer diagnosis was 4.8 years (range 1–9 years). Six of the 7 cancers occurred in the native lung and one occurred in the transplanted lung. Five of the 7 patients (71%) had stage 4 bronchogenic cancer at diagnosis. One (patient 6 in Table 1) had stage 3 clinical disease, which was identified as stage 4 on pathologic study after pneumonectomy of the native involved lung. Two patients had malignant pleural effusion and the other two had bilateral lung metastases. One was treated with adjuvant chemotherapy, but died 2 months after surgery. Another 3 patients with stage 4 disease died between 2 and 60 days from cancer dissemination, and the remaining, recently diagnosed, patient (no. 7) is still alive. The other 2 patients had stage 1A disease at diagnosis. One (patient 3) was treated with pneumonectomy and died one year later from recurrent disease. In the other (patient 4), surgery was performed despite the presence of bronchiolitis obliterans syndrome. She was treated with pneumonectomy of the involved native lung and retransplantation, but died soon after from postoperative complications. There were 2 additional cases of unexpected bronchogenic carcinoma in explanted lungs. The first patient was a 68-year-old man with primary pulmonary hypertension and a history of smoking who underwent heart–lung transplantation in 2003. Stage 1B squamous cell carcinoma was found in one of the explanted lungs. The patient received the regular anti-rejection regimen and is currently doing well. The second patient underwent transplantation for IPF in 2008 and had stage 2A adenocarcinoma in the explanted lung. He died from operative complications 3 days after surgery. Another 4 transplant candidates with IPF were found to have bronchoalveolar carcinoma on preoperative testing and were refused the procedure. 4. Discussion Bronchogenic carcinoma associated with lung transplantation can occur in four sites, in order of prevalence: the native lung of the single lung transplant recipient; the donor lung, after transplantation; the explanted lung of the recipient; and the donor lung,
281
diagnosed perioperatively on chest X-ray or during donor lung removal (described in only a few case reports). The prevalence of lung cancer according to these categories is not well described in the medical literature. Therefore, we combined the reports of all post-transplant lung cancers that developed either in the native lung or in the donor lung into a single group. The results are shown in Table 2. The reported prevalence ranged from 0% to 0.25% in double lung recipients [5,10], to as high as 6.9% in single lung recipients [10]. Collins et al. [10], in a multicenter study in North America of 2168 lung and heart–lung transplant recipients, found that all 24 cases of lung cancer identified (1% of the total cohort) occurred in the native lung of single lung transplant recipients (2% of all single lung transplantations). We noted a wide variation in prevalence between more recent [7,12] and earlier reports [13,14]. The higher rates in the later studies were probably a consequence of the inclusion of older recipients, given the increasing age of patients undergoing transplantation, and the increase in the intensity of the immunosuppression regimen over time (a risk factor both by itself and as a contributor to patient longevity). In the present study, the rate of development of bronchogenic carcinoma among lung transplant recipients treated over a 13-year period was 2.4%. All affected patients had received a single lung transplant. This group accounted for 3.3% of all single lung transplantations performed in our center during this time. These rates are in line with previous reports [6–9]. The interval from transplantation to diagnosis of lung cancer ranged from 4 to 52 months (mean 25 months) in the few studies in which this factor was documented [15,16], compared to 56 months in our cohort. Mathew and Kratzke [15] reported 38 patients with lung cancer associated with lung transplantation, 32 had a primary diagnosis of COPD and 6 had IPF; 35 (92%) had a history of smoking. Accordingly, in all our patients with lung cancer after transplantation, the primary diagnosis was interstitial lung disease (ILD)/IPF or COPD. Both these diseases are known to contribute to the development of bronchogenic carcinoma. We found only one report of 2 cases in which cancer in the donated lung was identified early after transplantation and proved to be of donor origin [12]. The first patient was a 25-year-old man with cystic fibrosis who was diagnosed with metastatic small cell tumor in the transplanted lung 13 months after surgery. The donor was a 50-year-old former smoker. The patient died soon after starting chemotherapy. The second patient was a 54-year-old man with stage 2 non-small-cell lung cancer who underwent lung transplantation for COPD. The donor was 55 years old and had a smoking history of 45 pack-years. This patient did well after surgical resection. In none of our patients was the lung cancer attributed to a pre-existing condition in the donated lung. The outcome of lung transplant recipients with post-transplant bronchogenic carcinoma is poor. One reason may be the advanced stage of cancer at diagnosis, perhaps due to the radiologic characteristics of native lungs with ILD, which make it difficult for the clinician to identify any changes. Furthermore, the differential diagnosis of a new radiologic shadow in lung transplant recipients is very broad. In our cohort, 5 patients (71%) had stage 4 disease at diagnosis. Minai et al. [16], in a single-center study of 12 patients with post-transplant lung cancer (2.3% of their total lung-transplant recipients), reported a mean time-to-diagnosis of 10.8 weeks and a one-year mortality rate of 75%. Historically, survival ranges from one month to one year after diagnosis. In the present study, the oneyear mortality was 85%, and the mean survival time after diagnosis was 120 days. The presence of active lung cancer other than bronchioalveolar carcinoma is considered a contraindication for lung transplantation. Nevertheless, there are some reports of lung cancer in the explanted lung of transplant recipients. In a review of 214 lung
282
Y. Raviv et al. / Lung Cancer 74 (2011) 280–283
Table 1 Prevalence of bronchogenic carcinoma in lung transplant recipients: Rabin Medial Center Experience.a Sex/ageb
Primary Dx
Interval to cancerc (years)
Involved lung
Tumor type/stage
Treatment
Outcome
1. M/54 2. F/50 3. M/58 4. F/51 5. M/60 6. M/54 7. M/55
IPF Sclero-derma IPF COPD IPF IPF COPD
8 6 1 2 5 9 3
Native Native Native Native Donor Native Native
Adeno-BAC/4 Undifferentiated/4 SCC/1A SCC/1A Adeno-BAC/4 SCC/4 Large cell/4
None None Surgery Retransplant None Surgery + chemo Surgery
Death in 2 days Death in 32 days Death in 330 days Death in 60 days Death in 60 days Death in 240 days Alive
Dx, diagnosis; adeno, adenocarcinoma; BAC, bronchioalveolar carcinoma; IPF, interstitial pulmonary fibrosis; COPD, chronic obstructive pulmonary disease; SCC, squamous cell carcinoma. a All patients had single lung transplants. b At time of transplantation (in years). c From transplantation.
transplantations performed between 1991 and 2004, Abrahams et al. [17] identified 4 cases (2%) of lung cancer in the explanted lung. Three patients had a diagnosis of adenocarcinoma and one had squamous cell carcinoma; all had stage 1 disease and survived at least one year after transplantation [18]. In a 67-center study of 8000 patients [5,19], 43 patients had bronchogenic carcinoma in the explanted lung. All the transplant recipients had a primary diagnosis of COPD or IPF and 7 patients had multifocal disease. After a median of 30 months after transplantation, 64% of patients with stage 1 disease were alive; 64% of those with stage 2–3 disease died within 8 months. Of our 2 transplant recipients with stage 1 carcinoma in the explanted lung, one died from operative complications a few days after transplantation and the other is doing well 8 years later. Therefore, we think that the prognosis of the recipients with lung cancer other than bronchioalveolar carcinoma is similar to that of other recipients, despite the potential risk of recurrent disease. Bronchioalveolar carcinoma tends to spread throughout the lungs, and metastasizes much less often. It accounts for 3–4% of all non-small-cell lung cancers [20,21]. Most patients with multifocal lung involvement die within 2 years [22,23]. Patients with bronchioalveolar carcinoma may be suitable candidates for lung transplantation. In the international 67-center study mentioned above [19], 69 patients with bronchioalveolar carcinoma in the explanted lung were identified, of whom 26 had undergone transplantation because of primary bronchioalveolar carcinoma. 13 of 22 patients (59%) developed recurrence between 5 and 49 months after LTX [19]. There is no definitive worldwide protocol for radiologic followup of lung transplantation. In our institute, chest computed
tomography (CT) is performed 1, 3, 6, and 12 months postoperatively and annually thereafter. We also perform chest X-ray every 2 months. However, a more intense imaging protocol might be necessary for high-risk patients, such as single lung recipients with primary COPD or IPF. For example, low-dose spiral chest CT, which is a sensitive tool for early lung cancer detection, might be done every 3–6 months for life, with early and aggressive treatment for positive cases [24]. Induction therapy, azathioprine, and calcineurin inhibitors (CNIs) are probably the immunosuppressive agents most linked with post-transplant malignancies. Mycophenolate mofetil (MMF) has no negative impact on the incidence of malignancies. Targets of rapamycin (mTOR) inhibitors have anti-oncogenic properties and they are associated with a lower incidence of malignancies. In addition, these agents have been recommended for use when decreasing the dose or withdrawing CNIs in patients with malignancies [24]. Immunosuppressive drugs with high carcinogenic potential should be given in the lowest possible dose. Everolimus (Certican, Novartis) is a new drug with similar effects to sirolimus. It holds promise for the reduction of chest malignancies, but studies on its anti-rejection and antitumor efficacy are still needed. Further research is also needed on the underlying causes of post-lung transplantation bronchogenic cancer of both recipient and donor origin [24]. Therefore, once the patient develops cancer our approach includes decreasing or withdrawing CNIs. In conclusion, bronchogenic carcinoma after lung transplantation, especially in the native lung, is a serious problem. It has a relatively high incidence and a poor prognosis. Improved screening
Table 2 Prevalence of lung cancer in the native lung after single lung transplantation: reports in the literature. Author
Years
Location
Cancer cases/total transplants
Pathology
Spiekerkoetter [13] Choi et al. [14] Arcasoy et al. [12]
1987–1997 1968–1997 1991–2001
Germany USA (CA) USA (PA)
1/219 (0.46%) 1/99 (1.1%) 6/251 (2.4%)
Collins et al. [9]
1981–2001
Multicenter USA
24/2168 (1.0%)a
de Perrot et al. [19,20] Dickson et al. [11]
1985–2001 1992–2005
Canada USA (NC)
1/396 (0.25%) 9/131b
Raviv et al. (present study)
1997–2009
Israel
7/290 (2.4%)
SCC SCC SCC – 2 Adenoca. – 3 Poorly diff. – 1 SCC – 8 Adenoca. – 4 Poorly diff. – 1 Anaplastic – 1 BAC – 10 BAC SCC – 6 Adenoca. – 2 Sarcoma – 1 SCC – 3 Adeno-BAC – 3 Undiff. – 1
SCC, squamous cell carcinoma; BAC, bronchoalveolar carcinoma. a 2% of single lung transplants. b All single lung transplants.
Y. Raviv et al. / Lung Cancer 74 (2011) 280–283
efforts are recommended because aggressive management may be beneficial in patients with earlier stage disease. Conflict of interest None. References [1] Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986;314:1140–5. [2] International Society for Heart and Lung Transplantation. Available from: http://www.ishlt.org/registries/heartLungRegistry.asp; [accessed 2009]. [3] Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O’Sullivan EJ, Johnson MR, Heroux AL, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med 1990;323:1723–8. [4] Penn I. Posttransplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101–13. [5] de Perrot M, Wigle DA, Pierre AF, Tsao MS, Waddell TK, Todd TR, et al. Bronchogenic carcinoma after solid organ transplantation. Ann Thorac Surg 2003;75:367–71. [6] Bouros D, Hatzakis K, Labrakis H, Zeibecoglou K. Association of malignancy with disease causing interstitial pulmonary changes. Chest 2002;121:1278–89. [7] Tockman MS. Other host factors and lung cancer susceptibility. In: Samet JM, editor. Epidemiology of lung cancer. Lung biology in health and disease, vol. 74. New York: Marcel Dekker; 1994. p. 397–412. [8] Peto R, Lopez AD, Boreham J. Mortality from smoking in developed countries 1950–2000: indirect estimates from national vital statistics. Oxford: Oxford University Press; 1994. [9] Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009;136:260–71. [10] Collins J, Kazerooni EA, Lacomis J, McAdams HP, Leung AN, Shiau M, et al. Bronchogenic carcinoma after lung transplantation: frequency, clinical characteristics, and imaging finding. Radiology 2002;224:131–8.
283
[11] Dickson RP, Davis RD, Rea JB, Palmer SM. High frequency of bronchogenic carcinoma after single-lung transplantation. J Heart Lung Transplant 2006;25:1297–301. [12] Arcasoy SM, Hersh C, Christie JD, Zisman D, Pochettino A, Rosengard BR, et al. Bronchogenic carcinoma complicating lung transplantation. J Heart Lung Transplant 2001;20:1044–53. [13] Spiekerkoetter E, Krug N, Hoeper M, Wiebe K, Hamm M, Harringer W, et al. Prevalence of malignancies after lung transplantation. Transplant Proc 1998;30:1523–4. [14] Choi YH, Leung AN, Miro S, Poirier C, Hunt S, Theodore J. Primary bronchogenic carcinoma after heart or lung transplantation: radiologic and clinical findings. J Thorac Imaging 2000;15:36–40. [15] Mathew J, Kratzke RA. Lung cancer and lung transplantation: a review. J Thorac Oncol 2009;4:753–60. [16] Minai OA, Shah S, Mazzone P, Budev MM, Sahoo D, Murthy S, et al. Bronchogenic carcinoma after lung transplantation: characteristics and outcome. J Thorac Oncol 2008;3:1404–9. [17] Abrahams NA, Meziane M, Ramalingam P, Mehta A, DeCamp M, Farver CF. Incidence of primary neoplasms in explanted lungs: long-term follow-up from 214 lung transplant patients. Transplant Proc 2004;36:2808–11. [18] de Perrot M, Fischer S, Waddell TK, Strueber M, Harringer W, Pierre AF, et al. Management of lung transplant recipients with bronchogenic carcinoma in the native lung. J Heart Lung Transplant 2003;22:87–9. [19] de Perrot M, Chernanako S, Waddell TK, Shargall Y, Pierre AF, Hutcheon M, et al. Role of lung transplantation in the treatment of bronchogenic carcinomas for patients with end-stage pulmonary disease. J Clin Oncol 2004;22:4351–6. [20] Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer 1995;75(Suppl.):191–202. [21] Greco RJ, Steiner RM, Goldman S, Cotler H, Patchefsky A, Cohn HE. Bronchioalveolar cell carcinoma of the lung. Ann Thorac Surg 1986;41:652–6. [22] Okubo K, Mark EJ, Flieder D, Wain JC, Wright CD, Moncure AC, et al. Bronchioalveolar carcinoma: clinical, radiographic, and pathologic factors and survival. J Thorac Cardiovasc Surg 1999;118:702–9. [23] McMahon PM, Kong CY, Johnson BE, Weinstein MC, Weeks JC, Kuntz KM, et al. Estimating long-term effectiveness of lung cancer screening in the Mayo CT screening study. Radiology 2008;248:278–87. [24] Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs 2007;67:1167–88.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Lung cancer in lung transplant recipients: Experience of a tertiary hospital and literature review Yael Raviv a,b,∗ , David Shitrit c , Anat Amital a,b , Benjamin Fox a,b , Dror Rosengarten a,b , Oren Fruchter a,b , Ilana Bakal a,b , Mordechai R. Kramer a,b a
Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Pulmonary Department, Meir Medical Center, Kfar Saba, Israel b
a r t i c l e
i n f o
Article history: Received 1 November 2010 Received in revised form 20 February 2011 Accepted 22 February 2011 Keywords: Lung transplant Bronchoalveolar carcinoma Non-small-cell lung cancer Bronchogenic carcinoma Post-transplant malignancy Lung transplant outcome
a b s t r a c t Background: Lung transplantation is a viable therapy for patients with end-stage lung disease and is being increasingly performed worldwide. The incidence of lung cancer after lung transplantation has increased concomitantly, although data are still sparse. Methods: The computerized medical records of the Pulmonary Institute of a tertiary care medical center were searched for patients who underwent lung transplantation from 1997 to 2009 and acquired lung cancer postoperatively. The prevalence, potential contributing factors, and outcome of bronchogenic cancer were determined, and the medical literature was reviewed. Results: Bronchogenic cancer developed in 7 of the 290 lung transplant recipients (2.4%). All had received a single lung transplant and in most cases, the cancer developed in the native lung. These findings were similar to reports in the literature. The indication for transplantation was chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis/interstitial lung disease. All had a history of smoking. The average interval from transplantation to development of lung cancer was 5 years (range 1–9). Five patients had stage 4 cancer at diagnosis and 2 had stage 1. Six patients died from 10 days to 1 year after diagnosis. Conclusion: Lung transplantation is associated with a relatively high prevalence of bronchogenic cancer, particularly in the native lung, in patients with primary chronic obstructive pulmonary disease/idiopathic pulmonary fibrosis, and a history of smoking. The cancer is usually diagnosed at an advanced stage with poor outcome. Efforts to improve screening are recommended, as aggressive management and treatment may be beneficial for earlier stage disease. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung transplantation is considered a viable therapy for patients with end-stage lung disease. Since the first report of successful clinical lung transplantation in 1983, the volume of procedures has progressively increased worldwide, including Israel [1,2]. However, this rise has been accompanied by an increase in the incidence of cancer in lung transplant recipients. Potential contributory factors are the increasing age of both recipients and donors [2] and the mandatory, post-transplant, high-dose, long-term, immunosuppressive treatment, particularly calcineurin inhibitors such as tacrolimus and cyclosporine [3]. According to current data, malignancies develop in about 16% of lung transplant recipients within 5 years after transplantation, and in 32% within 10 years [4].
∗ Corresponding author at: Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel. Tel.: +972 3 937 7221/50 221 6339; fax: +972 3 937 7142. E-mail address: [email protected] (Y. Raviv). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.02.012
More than 9% of lung transplant recipients will die from the malignancy. The frequency of bronchogenic carcinoma in particular in patients after lung transplantation is uncertain and is at least that of the general population or higher. The few studies conducted to date reported prevalence rates of 0.1–2.3% [5]. However, we expect to see more cases, especially in the native lung of patients with primary chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to pose a high risk of bronchogenic carcinoma [6,7]. Furthermore, COPD and IPF are strongly associated with smoking history, by itself a risk factor [8]. The aim of this study was to determine the prevalence rate, risk factors, and outcomes of bronchogenic cancer in a large population of lung transplant recipients, and to present a review of the medical literature. 2. Methods The computerized medical records of the Pulmonary Institute of Rabin Medical Center, a tertiary care university-affiliated hospital,
Y. Raviv et al. / Lung Cancer 74 (2011) 280–283
were reviewed for all patients who underwent lung transplantation from January 1997 through December 2009. Those in whom bronchogenic cancer developed after transplantation were identified. Data were collected on demographics, primary diagnosis, type of transplant and, when applicable, time and stage of cancer diagnosis, using the new staging system [9], treatment, and survival. All transplant recipients received an immunosuppression protocol that included prednisone, mycophenolate mofetil, and tacrolimus, with a target trough level of 10–15 ng/ml. If cancer was diagnosed, the mycophenolate mofetil was discontinued, the tacrolimus dose was lowered, and sirolimus or everolimus was added, aiming at levels of 4–6 ng/ml of both drugs. 3. Results A total of 312 lung transplantations were performed in our center during the 13-year study period, of which 22 were repeat procedures following chronic rejection. Bronchogenic cancer was diagnosed after transplantation in 7 of the 290 patients (2.4%). Their data are shown in Table 1. All 7 patients received a single lung transplant, accounting for 3.3% of the 211 (73%) single lung transplants performed during the study period. Five patients had a primary diagnosis of interstitial lung disease (IPF in 4, associated with scleroderma in 1), and 2 of emphysema. All had a history of smoking. Mean age of the entire sample at transplantation was 54.5 years; mean age of the 7 patients with lung cancer was 54.5 years at diagnosis. Mean time from transplantation to lung cancer diagnosis was 4.8 years (range 1–9 years). Six of the 7 cancers occurred in the native lung and one occurred in the transplanted lung. Five of the 7 patients (71%) had stage 4 bronchogenic cancer at diagnosis. One (patient 6 in Table 1) had stage 3 clinical disease, which was identified as stage 4 on pathologic study after pneumonectomy of the native involved lung. Two patients had malignant pleural effusion and the other two had bilateral lung metastases. One was treated with adjuvant chemotherapy, but died 2 months after surgery. Another 3 patients with stage 4 disease died between 2 and 60 days from cancer dissemination, and the remaining, recently diagnosed, patient (no. 7) is still alive. The other 2 patients had stage 1A disease at diagnosis. One (patient 3) was treated with pneumonectomy and died one year later from recurrent disease. In the other (patient 4), surgery was performed despite the presence of bronchiolitis obliterans syndrome. She was treated with pneumonectomy of the involved native lung and retransplantation, but died soon after from postoperative complications. There were 2 additional cases of unexpected bronchogenic carcinoma in explanted lungs. The first patient was a 68-year-old man with primary pulmonary hypertension and a history of smoking who underwent heart–lung transplantation in 2003. Stage 1B squamous cell carcinoma was found in one of the explanted lungs. The patient received the regular anti-rejection regimen and is currently doing well. The second patient underwent transplantation for IPF in 2008 and had stage 2A adenocarcinoma in the explanted lung. He died from operative complications 3 days after surgery. Another 4 transplant candidates with IPF were found to have bronchoalveolar carcinoma on preoperative testing and were refused the procedure. 4. Discussion Bronchogenic carcinoma associated with lung transplantation can occur in four sites, in order of prevalence: the native lung of the single lung transplant recipient; the donor lung, after transplantation; the explanted lung of the recipient; and the donor lung,
281
diagnosed perioperatively on chest X-ray or during donor lung removal (described in only a few case reports). The prevalence of lung cancer according to these categories is not well described in the medical literature. Therefore, we combined the reports of all post-transplant lung cancers that developed either in the native lung or in the donor lung into a single group. The results are shown in Table 2. The reported prevalence ranged from 0% to 0.25% in double lung recipients [5,10], to as high as 6.9% in single lung recipients [10]. Collins et al. [10], in a multicenter study in North America of 2168 lung and heart–lung transplant recipients, found that all 24 cases of lung cancer identified (1% of the total cohort) occurred in the native lung of single lung transplant recipients (2% of all single lung transplantations). We noted a wide variation in prevalence between more recent [7,12] and earlier reports [13,14]. The higher rates in the later studies were probably a consequence of the inclusion of older recipients, given the increasing age of patients undergoing transplantation, and the increase in the intensity of the immunosuppression regimen over time (a risk factor both by itself and as a contributor to patient longevity). In the present study, the rate of development of bronchogenic carcinoma among lung transplant recipients treated over a 13-year period was 2.4%. All affected patients had received a single lung transplant. This group accounted for 3.3% of all single lung transplantations performed in our center during this time. These rates are in line with previous reports [6–9]. The interval from transplantation to diagnosis of lung cancer ranged from 4 to 52 months (mean 25 months) in the few studies in which this factor was documented [15,16], compared to 56 months in our cohort. Mathew and Kratzke [15] reported 38 patients with lung cancer associated with lung transplantation, 32 had a primary diagnosis of COPD and 6 had IPF; 35 (92%) had a history of smoking. Accordingly, in all our patients with lung cancer after transplantation, the primary diagnosis was interstitial lung disease (ILD)/IPF or COPD. Both these diseases are known to contribute to the development of bronchogenic carcinoma. We found only one report of 2 cases in which cancer in the donated lung was identified early after transplantation and proved to be of donor origin [12]. The first patient was a 25-year-old man with cystic fibrosis who was diagnosed with metastatic small cell tumor in the transplanted lung 13 months after surgery. The donor was a 50-year-old former smoker. The patient died soon after starting chemotherapy. The second patient was a 54-year-old man with stage 2 non-small-cell lung cancer who underwent lung transplantation for COPD. The donor was 55 years old and had a smoking history of 45 pack-years. This patient did well after surgical resection. In none of our patients was the lung cancer attributed to a pre-existing condition in the donated lung. The outcome of lung transplant recipients with post-transplant bronchogenic carcinoma is poor. One reason may be the advanced stage of cancer at diagnosis, perhaps due to the radiologic characteristics of native lungs with ILD, which make it difficult for the clinician to identify any changes. Furthermore, the differential diagnosis of a new radiologic shadow in lung transplant recipients is very broad. In our cohort, 5 patients (71%) had stage 4 disease at diagnosis. Minai et al. [16], in a single-center study of 12 patients with post-transplant lung cancer (2.3% of their total lung-transplant recipients), reported a mean time-to-diagnosis of 10.8 weeks and a one-year mortality rate of 75%. Historically, survival ranges from one month to one year after diagnosis. In the present study, the oneyear mortality was 85%, and the mean survival time after diagnosis was 120 days. The presence of active lung cancer other than bronchioalveolar carcinoma is considered a contraindication for lung transplantation. Nevertheless, there are some reports of lung cancer in the explanted lung of transplant recipients. In a review of 214 lung
282
Y. Raviv et al. / Lung Cancer 74 (2011) 280–283
Table 1 Prevalence of bronchogenic carcinoma in lung transplant recipients: Rabin Medial Center Experience.a Sex/ageb
Primary Dx
Interval to cancerc (years)
Involved lung
Tumor type/stage
Treatment
Outcome
1. M/54 2. F/50 3. M/58 4. F/51 5. M/60 6. M/54 7. M/55
IPF Sclero-derma IPF COPD IPF IPF COPD
8 6 1 2 5 9 3
Native Native Native Native Donor Native Native
Adeno-BAC/4 Undifferentiated/4 SCC/1A SCC/1A Adeno-BAC/4 SCC/4 Large cell/4
None None Surgery Retransplant None Surgery + chemo Surgery
Death in 2 days Death in 32 days Death in 330 days Death in 60 days Death in 60 days Death in 240 days Alive
Dx, diagnosis; adeno, adenocarcinoma; BAC, bronchioalveolar carcinoma; IPF, interstitial pulmonary fibrosis; COPD, chronic obstructive pulmonary disease; SCC, squamous cell carcinoma. a All patients had single lung transplants. b At time of transplantation (in years). c From transplantation.
transplantations performed between 1991 and 2004, Abrahams et al. [17] identified 4 cases (2%) of lung cancer in the explanted lung. Three patients had a diagnosis of adenocarcinoma and one had squamous cell carcinoma; all had stage 1 disease and survived at least one year after transplantation [18]. In a 67-center study of 8000 patients [5,19], 43 patients had bronchogenic carcinoma in the explanted lung. All the transplant recipients had a primary diagnosis of COPD or IPF and 7 patients had multifocal disease. After a median of 30 months after transplantation, 64% of patients with stage 1 disease were alive; 64% of those with stage 2–3 disease died within 8 months. Of our 2 transplant recipients with stage 1 carcinoma in the explanted lung, one died from operative complications a few days after transplantation and the other is doing well 8 years later. Therefore, we think that the prognosis of the recipients with lung cancer other than bronchioalveolar carcinoma is similar to that of other recipients, despite the potential risk of recurrent disease. Bronchioalveolar carcinoma tends to spread throughout the lungs, and metastasizes much less often. It accounts for 3–4% of all non-small-cell lung cancers [20,21]. Most patients with multifocal lung involvement die within 2 years [22,23]. Patients with bronchioalveolar carcinoma may be suitable candidates for lung transplantation. In the international 67-center study mentioned above [19], 69 patients with bronchioalveolar carcinoma in the explanted lung were identified, of whom 26 had undergone transplantation because of primary bronchioalveolar carcinoma. 13 of 22 patients (59%) developed recurrence between 5 and 49 months after LTX [19]. There is no definitive worldwide protocol for radiologic followup of lung transplantation. In our institute, chest computed
tomography (CT) is performed 1, 3, 6, and 12 months postoperatively and annually thereafter. We also perform chest X-ray every 2 months. However, a more intense imaging protocol might be necessary for high-risk patients, such as single lung recipients with primary COPD or IPF. For example, low-dose spiral chest CT, which is a sensitive tool for early lung cancer detection, might be done every 3–6 months for life, with early and aggressive treatment for positive cases [24]. Induction therapy, azathioprine, and calcineurin inhibitors (CNIs) are probably the immunosuppressive agents most linked with post-transplant malignancies. Mycophenolate mofetil (MMF) has no negative impact on the incidence of malignancies. Targets of rapamycin (mTOR) inhibitors have anti-oncogenic properties and they are associated with a lower incidence of malignancies. In addition, these agents have been recommended for use when decreasing the dose or withdrawing CNIs in patients with malignancies [24]. Immunosuppressive drugs with high carcinogenic potential should be given in the lowest possible dose. Everolimus (Certican, Novartis) is a new drug with similar effects to sirolimus. It holds promise for the reduction of chest malignancies, but studies on its anti-rejection and antitumor efficacy are still needed. Further research is also needed on the underlying causes of post-lung transplantation bronchogenic cancer of both recipient and donor origin [24]. Therefore, once the patient develops cancer our approach includes decreasing or withdrawing CNIs. In conclusion, bronchogenic carcinoma after lung transplantation, especially in the native lung, is a serious problem. It has a relatively high incidence and a poor prognosis. Improved screening
Table 2 Prevalence of lung cancer in the native lung after single lung transplantation: reports in the literature. Author
Years
Location
Cancer cases/total transplants
Pathology
Spiekerkoetter [13] Choi et al. [14] Arcasoy et al. [12]
1987–1997 1968–1997 1991–2001
Germany USA (CA) USA (PA)
1/219 (0.46%) 1/99 (1.1%) 6/251 (2.4%)
Collins et al. [9]
1981–2001
Multicenter USA
24/2168 (1.0%)a
de Perrot et al. [19,20] Dickson et al. [11]
1985–2001 1992–2005
Canada USA (NC)
1/396 (0.25%) 9/131b
Raviv et al. (present study)
1997–2009
Israel
7/290 (2.4%)
SCC SCC SCC – 2 Adenoca. – 3 Poorly diff. – 1 SCC – 8 Adenoca. – 4 Poorly diff. – 1 Anaplastic – 1 BAC – 10 BAC SCC – 6 Adenoca. – 2 Sarcoma – 1 SCC – 3 Adeno-BAC – 3 Undiff. – 1
SCC, squamous cell carcinoma; BAC, bronchoalveolar carcinoma. a 2% of single lung transplants. b All single lung transplants.
Y. Raviv et al. / Lung Cancer 74 (2011) 280–283
efforts are recommended because aggressive management may be beneficial in patients with earlier stage disease. Conflict of interest None. References [1] Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986;314:1140–5. [2] International Society for Heart and Lung Transplantation. Available from: http://www.ishlt.org/registries/heartLungRegistry.asp; [accessed 2009]. [3] Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O’Sullivan EJ, Johnson MR, Heroux AL, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med 1990;323:1723–8. [4] Penn I. Posttransplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101–13. [5] de Perrot M, Wigle DA, Pierre AF, Tsao MS, Waddell TK, Todd TR, et al. Bronchogenic carcinoma after solid organ transplantation. Ann Thorac Surg 2003;75:367–71. [6] Bouros D, Hatzakis K, Labrakis H, Zeibecoglou K. Association of malignancy with disease causing interstitial pulmonary changes. Chest 2002;121:1278–89. [7] Tockman MS. Other host factors and lung cancer susceptibility. In: Samet JM, editor. Epidemiology of lung cancer. Lung biology in health and disease, vol. 74. New York: Marcel Dekker; 1994. p. 397–412. [8] Peto R, Lopez AD, Boreham J. Mortality from smoking in developed countries 1950–2000: indirect estimates from national vital statistics. Oxford: Oxford University Press; 1994. [9] Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009;136:260–71. [10] Collins J, Kazerooni EA, Lacomis J, McAdams HP, Leung AN, Shiau M, et al. Bronchogenic carcinoma after lung transplantation: frequency, clinical characteristics, and imaging finding. Radiology 2002;224:131–8.
283
[11] Dickson RP, Davis RD, Rea JB, Palmer SM. High frequency of bronchogenic carcinoma after single-lung transplantation. J Heart Lung Transplant 2006;25:1297–301. [12] Arcasoy SM, Hersh C, Christie JD, Zisman D, Pochettino A, Rosengard BR, et al. Bronchogenic carcinoma complicating lung transplantation. J Heart Lung Transplant 2001;20:1044–53. [13] Spiekerkoetter E, Krug N, Hoeper M, Wiebe K, Hamm M, Harringer W, et al. Prevalence of malignancies after lung transplantation. Transplant Proc 1998;30:1523–4. [14] Choi YH, Leung AN, Miro S, Poirier C, Hunt S, Theodore J. Primary bronchogenic carcinoma after heart or lung transplantation: radiologic and clinical findings. J Thorac Imaging 2000;15:36–40. [15] Mathew J, Kratzke RA. Lung cancer and lung transplantation: a review. J Thorac Oncol 2009;4:753–60. [16] Minai OA, Shah S, Mazzone P, Budev MM, Sahoo D, Murthy S, et al. Bronchogenic carcinoma after lung transplantation: characteristics and outcome. J Thorac Oncol 2008;3:1404–9. [17] Abrahams NA, Meziane M, Ramalingam P, Mehta A, DeCamp M, Farver CF. Incidence of primary neoplasms in explanted lungs: long-term follow-up from 214 lung transplant patients. Transplant Proc 2004;36:2808–11. [18] de Perrot M, Fischer S, Waddell TK, Strueber M, Harringer W, Pierre AF, et al. Management of lung transplant recipients with bronchogenic carcinoma in the native lung. J Heart Lung Transplant 2003;22:87–9. [19] de Perrot M, Chernanako S, Waddell TK, Shargall Y, Pierre AF, Hutcheon M, et al. Role of lung transplantation in the treatment of bronchogenic carcinomas for patients with end-stage pulmonary disease. J Clin Oncol 2004;22:4351–6. [20] Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer 1995;75(Suppl.):191–202. [21] Greco RJ, Steiner RM, Goldman S, Cotler H, Patchefsky A, Cohn HE. Bronchioalveolar cell carcinoma of the lung. Ann Thorac Surg 1986;41:652–6. [22] Okubo K, Mark EJ, Flieder D, Wain JC, Wright CD, Moncure AC, et al. Bronchioalveolar carcinoma: clinical, radiographic, and pathologic factors and survival. J Thorac Cardiovasc Surg 1999;118:702–9. [23] McMahon PM, Kong CY, Johnson BE, Weinstein MC, Weeks JC, Kuntz KM, et al. Estimating long-term effectiveness of lung cancer screening in the Mayo CT screening study. Radiology 2008;248:278–87. [24] Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs 2007;67:1167–88.