Renal transplantation is currently considered the best option for treatment of terminal renal failure. Malignancy is a well-recognized complication of renal transplantation with an estimated 10-year incidence of 20% after renal transplantation^[1], and in some population, post-transplant malignancies have even become the third leading cause of death^[2]. Previous studies reported that lung cancer accounted for only 3%-5% of all malignancies after transplantation ^[3-11], and skin malignancies and lymphoma are the most common malignancies in Western countries as compared with urological tumors in Asian countries^{[3, 12, 13]}. Due to its rather low incidence, primary lung cancer has been under-emphasized in patients receiving renal transplantation. Nonetheless, as the post-transplant survival of the recipients extends, the incidence of lung cancer increases progressively ^{[5, 14]}. The goal of this retrospective study was to analyze the clinical characteristics and the outcomes of primary lung cancer in patients after receiving renal transplantation.

This study was approved by the Ethics Committee of 309 Hospital of PLA and was performed in line with the ethical guidelines of the 2000 Declaration of Helsinki as well as the Declaration of Istanbul (2008). Because of the retrospective nature of the study, the need for informed patient consent was waived.

Between January, 1988 and April, 2015, a total of 2793 consecutive patients underwent renal transplantation at 309 Hospital of PLA, among whom 14 (0.5%) patients developed lung cancer after the transplantation. All these patients with lung cancer were followed until death or until April, 2015. The data of different variables were collected from the 14 patients, including the demographic data (age at transplantation and gender), smoking history, maintenance immunosuppressive treatment, tumor characteristics (histological results and tumor stage), therapies of tumors (surgery, chemotherapy, and radiotherapy), and outcomes of lung cancer.

The survival time of the patients in this context was defined as the period of time between tumor diagnosis and death.

The probability of survival of the patients was estimated with Kaplan-Meier method. In addition, survival was analyzed in relation to the age at transplantation, the pathological type of the tumor, tumor stage and the lymph nodes status. The patients' survival according to different modalities of these variables was assessed using the log-rank test. A P value less than 0.05 was considered to indicate a statistically significant difference.

The 14 recipients included 10 men and 4 women with an average age at transplantation of 50.2 years (range, 34-61 years). At the time of tumor diagnosis, 10 (71.4%) of the 14 patients smoked cigarettes ranging from 20 to 90 pack-years (mean 48 pack-years). They were all exposed to dialysis for 2 to 28 months (mean 8.2 months) prior to renal transplantation.

The protocols for maintenance immunosuppression were cyclosporine, azathioprine and prednisone in 6 patients, tacrolimus, mycophenolate mofetil and prednisone in 3 patients, cyclosporine, mycophenolate mofetil and prednisone in 3 patients, sirolimus, mycophenolate mofetil and prednisone in 1 patient, and cyclosporine, mizoribine and prednisone in 1 patient. The intensity of immunosuppressive therapy was reduced individually at the time of lung cancer diagnosis. Conversion from cyclosporine to sirolimus was prescribed in 2 patients. Any interruption of the immunosuppressive regimen was under nephrologic surveillance.

Before renal transplantation, all the patients underwent chest radiography, but regular postoperative chest screening was not performed as a part of follow-up. The recipients underwent chest computed tomography (CT) only as indicated by clinical symptoms. In 9 of the patients, lung cancer was detected incidentally, and the remaining 5 patients all had clinical symptoms (Tab. 1). The mean time from transplantation to diagnosis was 65.7±20.1 months (range, 27-104 months). The methods of pathological diagnosis were CT guided transthoracic biopsy in 3 cases, bronchoscopic biopsy in 6 cases, lymph node biopsy in 1 case and thoracotomy in 4 cases. The most frequent pathological types of lung cancer were squamous cell carcinoma (n=7, 50%) and adenocarcinoma (n=5, 35.7%); adenosquamous carcinoma was detected in 1 case and small cell carcinoma in another. The tumors were in stage ⅠA in 2 cases, stage ⅠB in 1 case, stage ⅡA in 1 case, stage ⅡB in 3 cases, stage ⅢA in 3 cases, stage ⅢB in 2 cases, and stage Ⅳ in 2 cases.

表 1(Table 1)

Table 1 Tumor characteristics and survival data in each case Case No. Symptom TNM Stage Histology Treatment Survival (month) Current Status 1 Cough T3 N2 M0 ⅢA Squamous cell carcinoma Biolobectomy 6 Deceased 2 Blood stained sputum T3 N2 M0 ⅢA Squamous cell carcinoma Wedge resection 10 Deceased 3 Asymptomatic T1a N0 M0 ⅠA Squamous cell carcinoma Lobectomy 36 Alive 4 Asymptomatic T3 N0 M0 ⅡB Squamous cell carcinoma Lobectomy 38 Alive 5 Asymptomatic T2b N1 M0 ⅡB Squamous cell carcinoma Lobectomy+radiotherapy 15 Deceased 6 Asymptomatic T4 N2 M0 ⅢB Small cell carcinoma Chemotherapy 3 Deceased 7 Asymptomatic T1b N0 M0 ⅠA Adenocarcinoma Lobectomy 53 Deceased 8 Asymptomatic T2b N1 M0 ⅡB Adenocarcinoma Lobectomy+chemotherapy 22 Deceased 9 Asymptomatic T2a N0 M0 ⅠB Adenocarcinoma Lobectomy 65 Deceased 10 Fever T2b N1 M1a Ⅳ Squamous cell carcinoma Palliative radiotherapy 3 Deceased 11 Asymptomatic T2a N1 M0 ⅡA Adenocarcinoma Lobectomy+chemotherapy 41 Alive 12 Asymptomatic T1a N2 M0 ⅢA Adenocarcinoma Lobectomy+chemo-radiotherapy 17 Deceased 13 Cough T3 N3 M0 ⅢB Adenosquamous carcinoma Palliative radiotherapy 7 Deceased 14 Back pain T3 N1 M1b Ⅳ Squamous cell carcinoma None 2 Deceased

Table 1 Tumor characteristics and survival data in each case

Ten (71.4%) of 14 patients were treated with thoracic surgery. The surgical procedure was complete resections in 9 cases (8 lobectomies and 1 bilobectomy with complete mediastinal lymphadenectomy) and palliative resection in another (the patient underwent wedge resection for poor pulmonary function). No patient died during the perioperative period. Two patients developed bacterial pneumonia and recovered uneventfully after improved anti-inflammatory treatment.

All the 14 patients contributed data to the survival analysis (Tab. 2). The patients showed a survival time ranging from 2 to 65 months after the diagnosis of lung cancer. The survival time differed significantly among patients with different tumor stages at diagnosis (P= 0.001) and with different lymph nodes status (P=0.02). We observed a mean survival time of 47.4 months in recipients with lung cancer in stage ⅡB or lower, 11 months in recipients with stage ⅢA disease, and only 2.8 months in patients with stage ⅢB or Ⅳ disease. The patients with negative lymph nodes had significantly longer mean survival time than those with positive lymph nodes (53.3 months vs 12.6 months). Nevertheless, we found no association of age at transplantation (P=0.68) or pathological types of the tumors (P=0.11) with the survival time of the patients.

表 2(Table 2)

Table 2 Survival analysis in the study population (estimated by the Kaplan-Meier method) Characteristics n Mean survival (Mean±SD, month) Log-rank test (P value) Histology   Squamous cell carcinoma 7 21.4±2.8 0.11   Adenocarcinoma 5 43.2±15.3   Other 2 5.0±5.4 Age group (yr)   34-49 6 43.7±12.5 0.68   50-61 8 27.8±10.0 Tumor stage   Ⅰ-Ⅱ 7 47.4±12.2 0.001   ⅢA 3 11.0±6.4   ⅢB-Ⅳ 4 2.8±1.0 N (lymph node) status   N- 4 53.3±0 0.02   N+ 10 12.6±2.5

Table 2 Survival analysis in the study population (estimated by the Kaplan-Meier method)

During the follow-up, 11 patients died from lung cancer metastasis (n=8) or organ failure (n=3). The remaining 3 patients were alive without tumor recurrence at the time of this current report. The patients showed a median survival time of 15 months, with 2-year and 5-year survival rates of 35.7% and 17.9%, respectively.

In renal transplant recipients, the incidence of primary lung cancer was rather low, ranging from 0.1% to 0.8% in different reports^{[3-11, 14-20]}(Tab. 3). According to findings from National Central Cancer Registry (NCCR) in 2010, the estimated rate of lung cancer was 46.08 per 100 000 in the general population in China ^[21], much lower than the incidence of 0.5% after renal transplantation we report herein. We found a mean time from transplantation to lung cancer diagnosis of 65.7 months, similar to the previously published data^{[15, 17, 22]}.

表 3(Table 3)

Table 3 Incidence of primary lung cancer reported in the literature First author (Ref.) Year of publication Total renal transplant recipients No. of patients Incidence (%) Zhang et al [3] 2014 30 632 28 0.09 Tessari et al[4] 2013 3537 18 0.51 Sampaio et al [5] 2012 123 380 608 0.49 Engels et al [14] 2011 102 654 517 0.5 Ju et al [6] 2011 2630 6 0.23 Genebes et al [15] 2010 1993 10 0.5 Padilla et al [16] 2009 1539 10 0.65 Vegso et al [7] 2007 2852 15 0.53 Webster et al [8] 2007 15 183 104 0.68 Ahmed et al [17] 2004 3750 8 0.21 De Perrot et al [18] 2003 1735 3 0.17 Pedotti et al [9] 2003 3521 7 0.2 Birkeland et al [l0] 2000 1821 15 0.82 Delcambre et al [19] 1996 564 2 0.35 Kehinde et al [20] 1994 492 4 0.81 Barrett et al [11] 1993 876 3 0.34 Current study - 2793 14 0.5

Table 3 Incidence of primary lung cancer reported in the literature

The role of immunosuppression in lung cancer development after renal transplantation remains controversial, although it was found to clearly associate with some primary neoplasms in transplant recipients^{[13, 23, 24]}. Genebes et al^[15]presumed that immunosuppression may induce lung cancer independent of a smoking history, but Anyanwu et al ^[25] demonstrated that in heart transplant recipients, immunosuppression was not a causative factor while smoking and advanced age were identified as the causative risks, which was consistent with the findings in others studies^{[24, 26]}.

Prolonged duration of dialysis has been considered as a potential risk for malignancy. Several studies^{[10, 27, 28]} demonstrated that the increased time on dialysis was significantly and independently associated with lung cancer in renal transplant recipients. In this present study, all the 14 recipients underwent dialysis before transplantation. The cumulative exposure to toxins on dialysis needs to be evaluated for its potential risk for malignancies in renal transplant recipients.

For recipients with early-stage lung cancer (stage Ⅰ-Ⅱ), complete resection is considered as the standard surgical treatment, but in patients in stage ⅢA, the role of surgery is questionable. In our patients, 3 patients with stage ⅢA disease underwent operation, and their mean survival time (11 months) was longer than that of patients with stage ⅢB-Ⅳ disease (mean 2.8 months). For patients with stage ⅢB-Ⅳ disease, the benefits of chemotherapy and radiotherapy should be carefully weighed against their severe adverse effects, which can be potentially fatal in these patients.

Intense immunosuppression results in accelerated disease progression and a lowered survival of the patients^{[11, 29, 30]}. Reduction of immunosuppression reduction appeared to have a positive effect on tumor progression and on the prognosis. In our cases, we reduced the immunosuppression to about half of the original dose in patients with early-stage tumors. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, are known to have both immunosuppressive and anti-neoplastic activities ^{[1, 13, 31]}. Several studies demonstrated that mTOR inhibitor was associated with a significantly lowered incidence of primary malignancies including lung cancer ^{[32, 33-36]}. In our patients, only 1 patient received sirolimus-based regimen in the maintenance treatment with a duration of 6 years from the transplantation to the diagnosis. Two patients had conversion from cyclosporine to sirolimus for tumor metastases, but their survival time was only 6 and 3 months. Due to the small sample size in this study, we could not draw a definite conclusion regarding the protective effect of sirolimus.

The cumulative intense immunosuppression disrupts the antitumor surveillance and accelerates tumor progression ^{[11, 17, 18, 22]}. Ahmed et al ^[17]reported that 75% of the renal transplant recipients with stage ⅢB-Ⅳ lung cancer had a mean survival of only 2 months, but the early-stage patients had significantly better prognoses: half of the patients with stage Ⅰ-Ⅱ disease survived for a mean of 47.4 months after radical resection. Early diagnosis and surgical treatment may obtain favorable prognosis in the recipients with early-stage lung cancer.

Malignancies are reported to account for 18% of all deaths in renal transplant recipients ^[37]. Such malignancies are found often incidentally in chest examinations, as was the case in 9 (64.3%) of our patients. Most of the asymptomatic cancers might have been detected by systematic surveillance of the chest after renal transplantation.

So far no clear recommendations are available for lung cancer surveillance in renal transplant recipients. Screening with chest roentgenograms, as stated by several investigators, is inadequate^{[17, 22, 25, 26]}. Chest CT markedly enhances the detection rate (especially for lung nodules) ^[38]. In the current study, 71.4% of the patients reported tobacco use, and the nonsmokers showed a longer interval before the diagnosis of lung cancer (mean 86.5 months) than the smokers (mean 57.4 months). We thus recommend annual chest CT examination for the recipients or biannual examination for heavy former smokers.

This study has several limitations. Firstly, the retrospective nature of the study may result in underestimation of the actual incidence of primary lung cancer in the renal recipients. Secondly, we did not examine the possibility that lung cancer was derived from the organ donors as previous studies suggested^[39]. Thirdly, due to the small sample size in this single-center study, we could not perform a multivariate analysis of the patients' survival to fully interpret the survival differences.

The incidence of primary lung cancer might be much higher in renal transplant recipients compared with the general population in China. Lung cancer can develop late in the post-transplant period and is often associated with a poor prognosis. Nevertheless, early diagnosis and surgeries may obtain more favorable outcomes in these patients. We recommend annual chest CT monitoring of the renal transplant recipients especially the heavy smokers and those with dialysis prior to the transplantation.