Objectives: Following the first heart transplant in Ireland in 1985, there have been almost 700 deceased donor heart and lung transplants carried out in Ireland at a single institution. In this retrospective study, our aim was to assess the incidence and management of urological malignancies arising in this national cohort.
Materials and Methods: Our retrospective analysis included all heart and lung transplant recipients identified as having a urological malignancy. Primary outcome variables included incidence, management, and clinical outcomes following cancer diagnosis.
Results: A total of 28 patients (4.1%) had radiologically or histologically confirmed urological malignancies. Fourteen patients were diagnosed with prostate cancer, with 13 who underwent radical treatment. Eight renal cell carcinomas were diagnosed in heart transplant recipients, with 5 who underwent nephrectomies. Two bladder cancers and 1 upper tract urothelial carcinoma were diagnosed and managed with endoscopic resection, radiotherapy, and nephroureterectomy, respectively. Two patients were diagnosed with penile squamous cell carcinoma and managed with radical surgery and lymph node dissection/sampling, with 1 patient receiving adjuvant chemoradiotherapy.
Conclusions: Urological malignancies are not common in heart and lung transplant recipients; however, standard management options can be safely used, including radical surgery. Prospective monitoring of these patients and potential considerations for screening should be maintained.
Key words : Penile cancer, Prostate cancer, Renal cancer, Urothelial cancer, Screening
Heart transplants have been performed in Ireland since 1985; since the inclusion of lung transplants in 2005, there have been almost 700 heart and lung transplants carried out in total. All transplants have been performed at a single institution in Ireland (the Mater Misericordiae University Hospital [MMUH], Dublin, Ireland).
Organ transplantation is considered lifesaving, is associated with improved quality of life, and confers significant financial savings to health services; however, an increased incidence of cancer has been shown in Irish solid-organ transplant recipients.1 This study aimed to characterize the urological malignancies within the national heart and lung transplant group thus far and to assess their treatment to date with the hope to inform urologists and transplant physicians regarding optimal management going forward.
Materials and Methods
For this retrospective study, we analyzed all patients who underwent heart transplant since 1985 and lung transplant since 2005 at the MMUH National Heart and Lung Transplant Centre. Medical records of these recipients have been prospectively collected and maintained by the MMUH transplant data managers since the establishment of the respective transplant programs. All patient details are held securely within the hospital-based electronic medical records.
For each heart and lung transplant recipient, we used the hospital’s electronic medical records, outpatient letters, histopathology reports, theatre reports, and radiology reports to identify those who had been diagnosed with urological malignancies. Transplant details, such as date, indication, immunosuppressive regimen, and overall outcomes, were recorded. Time to diagnosis of malignancy, age at diagnosis, stage of disease (including histopathology and radiology findings), management, and outcomes specifically pertaining to cancer were also recorded. We also gathered information on complications arising from treatment of urological malignancies and outcomes at time of submission of this paper. Departmental approval was granted, although individual patient consent was not obtained due to the retrospective and noninterventional nature of the study.
Twelve heart transplant and 2 lung transplant recipients (total 2.8% of all male transplant recipients) were diagnosed with prostate cancer. Average age at diagnosis was 58 years at 9.8 years posttransplant, with average prostate-specific antigen (PSA) level at diagnosis of 16 ng/mL. Staging and treatment decisions had been based on National Cancer Control Programme guidelines for the general population diagnosed with prostate cancer in Ireland.2 Risk stratification into low, intermediate, or high risk of biochemical recurrence had been based on contemporary European Association of Urology (EAU) guidelines.3
Ten patients (71%) received radical radiotherapy, with 9 receiving external beam radiotherapy and 1 patient receiving brachytherapy. Characteristics of this subgroup are shown in Table 1. No patients experienced graft dysfunction or complications of their treatment. There were 3 deaths in this subgroup during the study period; however, no deaths were related to prostate disease. Three patients included in the radiotherapy group also received adjuvant androgen-deprivation therapy. One of these 3 patients also received adjuvant systemic therapy with enzalutamide for biochemical recurrence of high-risk prostate cancer. Characteristics of this subgroup are shown in Table 2.
Three heart transplant recipients with prostate cancer (21%) opted for radical surgery, with 1 having open radical prostatectomy and 2 having robotic-assisted laparoscopic prostatectomies. Characteristics of this subgroup are shown in Table 3. To date, none of these patients have had biochemical recurrence (PSA >0.03 ng/mL) of cancer following treatment. Functionally, all patients were fully continent, although all displayed erectile dysfunction postoperatively. One patient died 8 years after prostatectomy; however, this death was unrelated to prostate cancer (PSA of 0 ng/mL prior to death).
One patient (7%) who developed prostate cancer at age of 69 years, at 4 years after lung transplant, opted for watchful waiting. A Gleason 3+4=7 disease score with a PSA of 4.8 ng/mL was confirmed on biopsy; however, the patient died within 12 months as a result of severe respiratory disease.
Seven heart transplant recipients and 1 lung transplant recipient were diagnosed with renal masses on average 12 years posttransplant (1.17% of all transplant recipients). Average age at transplant was 49 years. All patients (100%) who developed renal tumors following heart or lung transplant had biochemical chronic kidney disease (CKD) at diagnosis. Mean follow-up for this group was 74 months.
Five patients (63%) opted for nephrectomy as the treatment of choice. Histology confirmed papillary renal cell carcinoma (RCC) in 3 patients and unspecified RCC in the remaining 2 patients. All tumors ranged from 24 to 50 mm and were classified as pT1a/b. All patients had preexisting CKD (stage 3-5) at the time of surgery, with 1 patient on dialysis preoperatively. Two patients developed end-stage CKD requiring dialysis in the years after nephrectomy, with 1 of these patients proceeding to renal transplant. Although 3 patients in this subgroup died, no deaths were related to renal malignancy.
One patient (12.5%) opted for radiofrequency ablation of a biopsy that was confirmed to be clear cell RCC on a background of preexisting CKD stage 3 (glomerular filtration rate of 30-59 mL/min/1.73 m2). This patient ultimately died from complicated diverticular disease 4 years later; however, the renal lesion had remained stable following ablation.
Two patients (25%) opted for surveillance, with stability seen after an average of 22 months. Significant medical comorbidities have precluded radical surgery in both of these patients. A summary of these findings is shown in Table 4.
Two transplant recipients (0.3% of all heart and lung transplant recipients) were diagnosed during the study period with bladder cancer during workup for hematuria as shown in Table 5. Average age at time of transplant was 56 years, and interval from transplant to bladder cancer diagnosis was 17 years. Both patients underwent transurethral resection of bladder tumor. One patient required multiple subsequent fulgurations of recurrent low-grade tumors on surveillance cystoscopies; however, this patient was shown to be disease free at a recent follow-up of 36 months. The remaining patient was diagnosed with aggressive T4 transitional cell carcinoma. The patient succumbed to progressive bladder cancer following palliative radiotherapy after 11 months of follow-up.
A further transplant recipient (0.15% of all heart and lung transplant recipients) was diagnosed with upper tract urothelial carcinoma of the ureter following multiple episodes of visible hematuria and recurrent urinary tract infections at 4 years posttransplant. The patient proceeded to have an uncomplicated robot-assisted laparoscopic nephroureterectomy without any interruption to his immunosuppression. Histopathological analysis confirmed high-grade ureteric transitional cell carcinoma, pT3, with carcinoma in situ. The patient has not had any adverse outcomes or complications at a 3-month follow-up.
Three male patients were diagnosed with penile cancer posttransplant (0.6% of male heart and lung transplant recipients). Two were diagnosed with invasive penile cancer an average of 10 years posttransplant. Both patients developed clinically apparent tumors of the glans penis with palpable inguinal lymphadenopathy and proceeded to have partial penectomy with bilateral inguinal lymph node dissection. One patient developed pulmonary metastases and subsequently died within 6 months of diagnosis. The other patient had positive inguinal lymph node disease and proceeded to pelvic lymph node dissection as well as adjuvant chemotherapy (carboplatin and paclitaxel) with radiotherapy to the lymph node beds. A local stump recurrence required revision distal penectomy. At 15-month follow-up, this patient showed no clinical recurrence of disease. The final patient was diagnosed with penile intraepithelial neoplasia at 3 years after lung transplant at circumcision and was managed with topical 5-fluorouracil. At 48-month follow-up, the patient showed no further clinically appreciable disease. A summary of these findings is shown in Table 6.
Since the first heart transplant in 1985 conducted at MMUH, over 400 heart transplants and almost 300 lung transplants have been performed.4 With improving perioperative treatment and optimized immunosuppressive regimens and aftercare, life expectancy of transplant recipients continues to improve, with recent data showing that 60% and 40% of Irish patients are alive 10 years after their heart and lung transplants, respectively.5 Because these patients are immunosuppressed, they may be more likely to develop malignancies and at a younger age.1,6,7 Tacrolimus or cyclosporine is used in all patients, as well as prednisolone and/or mycophenolate mofetil for immunosuppression; however, no patients in this series required immunosuppression interruption during cancer treatment. In transplant recipients, bladder, renal, and prostate cancers have been specifically implicated as having a worse disease-specific survival compared with outcomes in the general population.8
Data on urological cancers in heart and lung transplant recipients are sparse. Nevertheless, surgical management of any organ-confined malignancy should be offered to transplant recipients where suitable. An expected survival of >50% at 5 years to justify surgery and thorough multidisciplinary team meetings involving the treating oncologist (surgical/medical/radiation) with the primary transplant physician are general guidelines to assist in decision making.9
On average, heart and lung transplant recipients are diagnosed with prostate cancer at age 68 years, which is comparable to the national average of 67 years; stage of disease has also been favorable in heart and lung transplant recipients, with 86% diagnosed with T2 tumors.10 Irish demographics from 2000 to 2014 showed a decrease in all patients opting for surgery, with a corresponding increase in radiotherapy. This trend has also been seen in Irish renal transplant recipients, with radiotherapy being the preferred method of treatment for 53%, and also in patients presented in our study, with 71% receiving radiotherapy.10,11 However, in a systematic review of kidney transplant recipients with prostate cancer, 82% of patients underwent surgery for organ-confined prostate cancer.12 Surgery clearly allows maximum control in avoiding the nearby renal graft in the iliac fossa, as opposed to radiotherapy, which may inadvertently subject the graft to radiation, potentially increasing the risk of graft loss, although this is clearly not of significance in heart and lung transplant recipients. No treatment-specific complications or prostate cancer deaths were observed in the patients actively treated in our series; thus, all options appear safe for heart and lung transplant recipients.
Data from the United Kingdom have suggested that heart and lung transplant recipients are 2.5 and 4.4 times more likely to be diagnosed with kidney cancer compared with the general population, respectively, with highest incidence among male patients and those over 60 years of age.13 In kidney transplant recipients, increasing age and acquired renal cystic disease specifically are thought to be behind the increase in RCC.13 Furthermore, it must be considered that a certain proportion of transplant recipients will develop chronic renal impairment, a well-recognized complication of immunosuppression after organ transplant and an independent risk factor for development of renal malignancies.14 In our series, all patients with renal tumors had some degree of chronic renal impairment.
Partial nephrectomy is the standard of care in T1 (<7 cm) tumors and has been shown to have a more favorable overall survival over radical nephrectomy in patients under 65 years of age, although there are limited reports in transplant recipients.15 In a study from Tollefson and colleagues,16 partial nephrectomy was successfully performed in 3 transplant recipients with T1 tumors as well as 8 radical nephrectomies. In a study of 5 patients with RCC after heart transplant, Peled and colleagues17 also showed safety in performing radical nephrectomies in 3 patients, with the remaining 2 managed with surveillance. Although interventional procedures such as radiofrequency ablation appear feasible and safe without compromising oncological outcomes in renal transplant recipients, they should be reserved for frail patients or those with significant comorbidities that preclude surgery.3,15 In our series, no patients experienced perioperative complications and there were no cancer-specific deaths, although 2 patients progressed to end-stage renal disease. We have also demonstrated that surveillance is safe in appropriately selected patients.
Bladder cancer, although uncommon, has been noted to be particularly aggressive following heart transplant.18 Diagnostic transurethral resection of bladder tumor is the mainstay of obtaining a tissue diagnosis and can be therapeutic in nonmuscle-invasive bladder tumors.19,20 There is a risk of BCG (Bacillus Calmette-Guérin) infection in immunosuppressed patients with its use; therefore, this treatment is used mainly for high-grade tumors, multifocal tumors, recurrences, or those with carcinoma in situ disease.9,19,20 Treatment of muscle-invasive bladder cancer, when the patient is deemed fit for surgery and in the absence of metastatic disease, relies on radical cystectomy and an appropriate diversion method for curative intent. Although no patients in our series were appropriate, radical cystectomy has been reported to be successful in heart and lung transplant recipients.19,21 Currently, EAU recommendations include neoadjuvant cisplatin-containing chemotherapy, if suitable, because of the demonstrated improved overall survival of 5% to 8% at 5 years.8 In unsuitable patients, immunotherapy in programmed death-ligand 1-positive patients in a trial setting can be considered.8 Outcomes are of course variable and based on disease stage but appear comparable with outcomes in the nontransplanted population when early, aggressive therapy is initiated.20
Testicular malignancies are rare in organ transplant recipients and in most papers account for 1 to 2 cases per series.6,7,22 Because of the inherent risk of developing testicular cancer with cryptorchidism, some authors have advocated orchidectomy in an atrophic, undescended testicle in immunosuppressed patients due to the potential for accelerated malignant growth.23 Because there were no
patients with testicular tumors in our series and surgical management is generally straightforward, patients with a suspicious lump should obtain a definitive histological diagnosis via inguinal radical orchidectomy, as recommended by the EAU.24 Because of the risk of secondary non-germ cell malignancies in patients treated with radiotherapy who are already at risk because of immunosuppression, chemotherapy, if suitable, should likely be considered as adjuvant treatment where required.24
Although rare, most reported cases of penile cancer in organ transplant recipients have been managed with conventional methods of wide local excision of the tumor for treatment and diagnosis with good success.25 Human papillomavirus (HPV) is known
to be associated with the development of approximately one-third of invasive penile cancers and up to 100% of intraepithelial neoplasia with HPV-related malignancies known to occur in excess in solid-organ transplant recipients.26,27 In our series, we had 2 patients with invasive penile carcinoma, resulting in an incidence of 0.4%, which is notably higher than quoted figures in other series of 0.004%.25 In terms of management, there are several effective modalities under local, regional, or general anesthesia, making surgical treatment suitable for virtually all transplant recipients regardless of fitness for anesthesia. Radical lymphadenectomy in clinically apparent nodes can be lifesaving and therefore should performed in all patients, including pelvic lymphadenectomy, if inguinal nodes are positive during initial sentinel lymph node biopsy.28 In our series, we demonstrated the success and safety of multimodality therapy with surgery, chemoradiotherapy, and topical treatment in penile intraepithelial neoplasia in immunosuppressed transplant recipients.
Skin malignancies are the only formal screening programs in transplant recipients that have been advocated; therefore, prudent monitoring and guidelines for detection of urological cancers should be considered on a case-by-case basis by the treating physician when there is clinical suspicion.1 In line with recommendations, PSA results are checked yearly in all male transplant recipients >40 years old at our center, with patients referred directly to a urologist if results are persistently elevated or if patients have an abnormal digital rectal examination.29 For bladder cancer, no specific screening recommendations exist, with the exception of yearly cytology and imaging for patients who have undergone renal transplant and who have a history of analgesia abuse.29 Renal transplant recipients are generally recommended to have yearly native kidney ultrasonographic eval-uations to monitor for development of RCC, and this could be considered for any heart or lung transplant recipients with coexisting renal impairment.30 All male transplant recipients should be encouraged to self-examine their testicles for abnormalities, particularly those with a history of cryptorchidism.23
Our study had limitations because of limited availability of certain data that predated electronic medical records, as the national heart transplant program commenced in 1985. Data are retrospective and were collected primarily by transplant physicians; therefore, data pertaining to the patient’s urological issues may be scant in some records. Selection bias of a small number of transplant recipients with a urological malignancy in over 700 transplant recipients in total may also apply. These small numbers practically only suffice for a narrative review rather than possibly more meaningful statistical analyses. Furthermore, although all patients underwent follow-up at a single national center from a transplant perspective, their urological care was often performed in other hospitals; therefore, some details may be unavailable. With the consideration that this study spanned many years, there have clearly been significant developments in management of cancer and outcomes over this period (eg, neoadjuvant chemotherapy for muscle invasive bladder cancer, use of robot technology for minimally invasive surgery). Thus, there may be some heterogeneity of histopathological reporting, treatment modalities, and outcomes.
Urological cancer in the transplant population is uncommon in terms of isolated figures; however, this population is clearly at higher risk of developing malignancy, which must be considered in follow-up. The striking finding in this study is that 100% of heart and lung transplant recipients who developed malignant renal masses had underlying chronic renal impairment, although this may be a sequelae of immunosuppressive therapy. This specific subgroup may benefit from routine surveillance with ultrasonography in follow-up posttransplant. Otherwise, no findings in this national cohort study were shown that might advocate for additional screening programs within the heart and lung transplant recipient group, although each patient must be assessed on individual risks. Surgery, radiotherapy, and systemic therapy options were all performed in all patient subgroups, in line with treatment options in the standard population, with equitable success, safety, and outcomes. We do advocate that these patients undergo treatment in specialist transplant centers shared by a uro-oncologist with multidisciplinary facilities available to ensure contemporary and individualized specialist management.
Volume : 19
Issue : 10
Pages : 1069 - 1075
DOI : 10.6002/ect.2021.0206
From the 1Department of Urology, Mater Misericordiae University Hospital, Dublin; the 2Department of Urology, Beaumont Hospital, Dublin; and the 3Department of Urology, St. Vincent’s University Hospital, Dublin, Ireland
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Robert A. Keenan, Department of Urology, Mater Misericordiae University Hospital, Eccles St., Dublin 7, Ireland
Phone: +353 01 803 2000
Table 1. Characteristics of Patients Who Underwent Only Radical Radiotherapy for Localized Prostate Cancer
Table 2. Characteristics of Patients Who Underwent Androgen Deprivation Therapy for High-Risk, Locally Advanced, or Metastatic Prostate Cancer
Table 3. Characteristics of Patients Who Underwent Radical Surgery for Localized Prostate Cancer
Table 4. Characteristic and Management of Patients Diagnosed With Renal Tumors Following Heart and Lung Transplant
Table 5. Characteristic and Management of Patients Diagnosed With Bladder and Upper Tract Urothelial Malignancy Following Heart and Lung Transplant
Table 6. Characteristic and Management of Patients Diagnosed With Penile Malignancy Following Heart and Lung Transplant