Cancer In Organ Transplant Recipients Research Articles

Incidence of melanoma in organ transplant recipients in Alberta, Canada.

Many studies have documented the increased risk of non-melanoma skin cancers in organ transplant recipients (OTRs). However, the incidence of melanoma is less well defined. To date, there have been no studies on the incidence of melanoma in Canadian OTRs. Herein, we determine the incidence and clinical features of melanoma in a cohort of OTRs in Southern Alberta, Canada. We used the Southern Alberta Transplant database to identify kidney and liver transplant recipients between the years 2000 and 2012. This population was cross-referenced with the Alberta Cancer Registry for a diagnosis of melanoma. The clinical features of all cases were obtained, and the standardized incidence rate was calculated. We identified 993 OTR patients, representing 5955 person-years. Only one patient developed a melanoma post-transplant, and this was a nodular melanoma. The age-standardized incidence rate was 11 per 100000 (0.6 per 5955), compared to 13.4 per 100000 in the general Alberta population (incidence rate ratio of 1.29, with 95% confidence interval of 0.17 to 9.82). This is the first Canadian study to investigate the association between organ transplantation and melanoma. Our study did not identify an increased risk of developing a de novo melanoma post-transplant.

Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis.

Azathioprine, a purine antimetabolite immunosuppressant, photosensitizes the skin and causes the production of mutagenic reactive oxygen species. It is postulated to increase the risk of squamous cell carcinoma (SCC) and other skin cancers in organ transplant recipients (OTRs), but evidence from multiple, largely single-center studies to date has been inconsistent. We aimed to resolve the issue of azathioprine's carcinogenicity by conducting a systematic review of the relevant literature and pooling published risk estimates to evaluate the risks of SCC, basal cell carcinoma (BCC), keratinocyte cancers (KCs) overall and other skin cancers in relation to azathioprine treatment. Twenty-seven studies were included in total, with risk estimates from 13 of these studies able to be pooled for quantitative analysis. The overall summary estimate showed a significantly increased risk of SCC in relation to azathioprine exposure (1.56, 95% confidence interval [CI] 1.11-2.18). No significant associations between azathioprine treatment and BCC (0.96, 95% CI 0.66-1.40) or KC (0.84, 95% CI 0.59-1.21) risk were observed. There was significant heterogeneity between studies for azathioprine risk estimates and the outcomes of SCC, BCC and KC. The pooled findings of available evidence support the contention that treatment with azathioprine increases the risk of SCC in OTRs.

Skin Cancer in the Crosshairs: Highlights from the Biennial Scientific Retreat of International Transplant Skin Cancer Collaborative and Skin Care in Organ Transplant Recipients Europe.

The International Transplant Skin Cancer Collaborative (ITSCC) is an organization comprising of physicians; transplant surgeons and basic science research scientists dedicated in providing optimal care and ongoing research advancements in solid organ transplant recipients to improve patient outcome and quality of life. As medical advances occur, it is anticipated that the sheer number of solid organ transplantations occurring worldwide will continue to increase. The long-term medication associated immunosuppression improves graft survival, but as a consequence, these individuals become increasingly susceptible to various cutaneous malignancies, lymphoproliferative disorders and infections. Squamous cell carcinoma is the most frequently encountered skin cancer and increases 65- to 250-fold [Jensen et al., Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177-186; Lindelöf et al., Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000; 143:513-519]. However, the rates of basal cell carcinoma, Merkel cell carcinoma and melanoma also increase in organ transplant recipients leading to significant morbidity as well as mortality [Berg and Otley. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002; 47:1-20]. In October 2014, the International Transplant Skin Cancer Collaborative and its equivalent European counterpart, Skin Care in Organ Transplant Recipients Europe held its 10th biennial meeting in Essex, MA to discuss the clinical conundrums and the evolving research pertinent to the field. This meeting report provides a synthesis of all the clinical and research data presented at the 4-day meeting.

Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients.

Organ transplant recipients are prone to the development of non-melanoma skin cancer. Organ transplant recipients often develop multiple non-melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR-inhibitors such as everolimus or sirolimus can have an antitumor effect. In a monocentric retrospective study we evaluated organ transplant recipients who presented with non-melanoma skin cancer in the years 2008-2010. Experience with patients who were switched to an mTOR-inhibitor due to non-melanoma skin cancer are reported in detail, and recent clinical studies are reviewed. 60 organ transplant recipients with non-melanoma skin cancer were evaluated. Due to the development of multiple non-melanoma skin cancer within a few years, the immunosuppressive regimen was switched to everolimus in 7 patients and to sirolimus in 5 patients. Eight patients were evaluable for the effect of mTOR-inhibitors on the development of non-melanoma skin cancer; 4 patients had to discontinue the medication with mTOR-inhibitors early due to various side effects. In the year before the switch to mTOR-inhibitors, 8 patients developed 16 squamous cell carcinomas, 3 Basal cell carcinomas and 22 cases of Bowen's disease. All tumors were histologically confirmed. In the year after switch of immunosuppression, the rate of squamous cell carcinomas (n = 2) and Bowen's disease (n = 3), but not of basal cell carcinomas (n = 2) was significantly reduced. Moreover, 5 prospective randomized trials recently have demonstrated a reduced number of non-melanoma skin cancers in organ transplant recipients after switch of the immunosuppressive regimen to mTOR-inhibitors. Switch of the immunosuppressive regimen to mTOR-inhibitors should be considered for organ transplant recipients suffering from multiple non-melanoma skin cancers.

Voriconazole-Associated Cutaneous Malignancy: A Literature Review on Photocarcinogenesis in Organ Transplant Recipients

This article synthesizes the current data regarding the implication of voriconazole in the development of skin cancer in organ transplant recipients (OTRs) and offers suggestions for additional research. According to Organ Procurement and Transplantation Network data, 28 051 solid organ transplants were performed in 2012. Due to advancements in immunosuppression and management of infectious diseases, survival of OTRs has substantially increased. Voriconazole is a widely prescribed antifungal medication used for prophylaxis and for treatment of invasive fungal infections in OTRs. Case reports describing skin cancer associated with voriconazole exposure emerged shortly after US Food and Drug Administration approval of the drug, and it is now established that voriconazole is an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. The mechanism of voriconazole-induced skin cancer is still unknown and may involve its primary metabolite, voriconazole N-oxide. Here we discuss the current data and potential mechanisms of voriconazole-associated photosensitivity and carcinogenesis and identify areas that require further research.

Incidence of primary skin cancer after organ transplantation: An 18-year single-center experience in Korea

Skin cancer is the most common malignancy to arise after organ transplantation in Caucasians, but limited data are available on its incidence in Asian transplant recipients. We sought to assess the incidence of skin cancer after organ transplantation in a Korean cohort. A cohort study was conducted to determine the incidence and risk factors for skin cancers among kidney, liver, heart, or pancreas transplant recipients, treated at the Asan Medical Center in Seoul, Korea. The cumulative incidences of skin cancer were 0.70% at 5years, 1.66% at 10years, and 2.31% at 15years. For all skin cancers, squamous cell carcinoma, basal cell carcinoma, and Kaposi sarcoma, the standardized incidence ratios between the recipients and the Korean general population were 30.9 (95% confidence interval, 12.4-63.6), 61.9 (12.8-180.8), 11.9 (0.3-66.1), and 565.2 (68.4-2041.6) after the end of the fifth posttransplantation year, respectively. We cannot exclude the possibility of both the underestimation because of potential missing cases and the overestimation because of the ascertainment bias. The incidence of posttransplantation skin cancer is very low in Korean patients. However, the risk of skin cancer in organ transplant recipients may be considerably higher than that in the Korean general population.

Ultraviolet radiation exposure through window glass may be associated with localization of nonmelanoma skin cancer in organ transplant recipients: a study in France and the U.K

Funding sources: none. Conflicts of interest: none declared. Dear Editor, Ultraviolet (UV)B radiation is a substantial risk factor for skin cancer in both immune‐competent and immunosuppressed organ transplant recipients (OTRs). In OTRs, additional exposure to UVA through drug photosensitization may contribute to their excess risk, which is well established.1 There is some evidence for preferential lateralization of photodamage and (pre)cancers, in the general population, to the side most exposed to UV radiation while driving. Moehrle et al.2 reported that left‐sided drivers receive five times more UV to the left arm than the right arm, and 20 times more UV on the left side of the face than the right. Actinic keratoses have been reported to occur more frequently on the right side of the body in Australian drivers, where drivers sit on the right side of the car. A left‐sided bias in skin cancer was observed in the U.S.A., where drivers sit on the left side of the car.3 4 5

Nonmelanoma Skin Cancer in Organ Transplant Recipients: Increase Without Delay After Transplant and Subsequent Acceleration

Organ transplant recipients (OTRs) have a 60- to 250-fold increased risk for cutaneous squamous cell carcinoma (SCC) and a 10-fold increased risk for basal cell carcinoma (BCC).1 It is still unclear, however, how fast after transplant these tumors arise. To develop risk-adjusted clinical follow-up in OTRs, we investigated the incidence of first and subsequent nonmelanoma skin cancers (NMSCs) in OTRs.

A Surveillance Model for Skin Cancer in Organ Transplant Recipients: A 22-Year Prospective Study in an Ethnically Diverse Population

Skin cancer is a frequent complication of organ transplantation. Current guidelines advise specialist skin surveillance but there are limited data on how these should be implemented. This study determines overall burden of cancer and relevant intervals for strategic surveillance in an ethnically diverse transplant population. Prospective data on time to first and subsequent cancers and cumulative burden with respect to defined risk factors were analyzed in a cohort of 1010 patients in a UK center over 22 years. Among 931 individuals transplanted >6 months (mean 10.3 years), 1820 skin cancers occurred in 267 (29%) individuals and were multiple in 66%. Cumulative incidence at 5, 10, 20 and 30 years was 11%, 25%, 54% and 74%, with median time to second, third and fourth cancers of 24, 14.7 and 8.4 months, respectively. Tumors were overwhelmingly squamous and basal cell carcinomas (73% and 24%, respectively). Skin phototype, ultraviolet radiation exposure, age at transplant and duration of transplant were significant risk predictors and were used to construct clinically relevant surveillance intervals. This study provides a comprehensive, prospective analysis of skin cancer morbidity and risk in an ethnically diverse transplant population from which we derive an evidence-based skin cancer surveillance program.

The development of squamous cell carcinoma in a patient after kidney transplantation: a

In patients with organ transplantation as compared to the general population the risk of cancer is significantly increased. The most common changes are malignant tumors of the skin, constituting 30-65% of malignant tumors found in recipients. Potential risk factors for skin cancer after a transplant operation are: solar radiation, immunosuppressive therapy, genetic factors, infection with HPV and skin cancer transmission before transplantation. In contrast to the immunocompetent population, skin cancers in transplant recipients are dominated by squamous cell carcinoma, followed by basal cell carcinoma. Squamous cell carcinoma in patients after transplantation is characterized by a strong tendency to give local recurrences and distant metastases. Due to the high risk of developing skin cancer in transplant recipients, preventive oncology plays an important role in the long-term care of patients after transplantation. This includes: sun protection, education, and early treatment of patients with precancerous lesions. It is also stressed that systematic dermatologic studies need to be carried out in patients after transplantation surgery. The paper contains basic information about skin cancers in organ transplant recipients: epidemiology, potential risk factors, treatment and prognosis. The paper presents also a case of patient who developed squamous cell carcinoma of the skin 3 years after renal transplantation.

Incidence, Risk Factors, and Preventative Management of Skin Cancers in Organ Transplant Recipients: A Review of Single- and Multicenter Retrospective Studies from 2006 to 2010

Organ transplant recipients (OTRs) taking immunosuppressants are at high risk of skin cancer, which is the most common malignant condition in OTRs, so dermatologic surveillance is important for OTRs. To characterize the most common skin cancers arising from chronic immunosuppression in OTRs. A PubMed search for retrospective single- and multicenter studies reporting skin cancer incidence from 2006 to 2010 was undertaken. Data regarding each study's immunosuppressive regimen, affected skin cancer cohort, and associated risk factors were extracted. Thirty-six articles that met our inclusion criteria reported incidences of nonmelanoma skin cancer (NMSC), Kaposi's sarcoma, melanoma, and Merkel cell carcinoma. NMSC was the most commonly reported cancer of all skin cancers after transplantation. Common risk factors were sex, age, sunlight exposure, and immunosuppressive agent-related (duration, type). Sun education programs and frequent screenings in organ transplant clinics have provided the best preventative strategies after transplantation, although the characteristics of the immunosuppressive regimen also play an important role. Thus, the adjuvant strategy of modifying immunosuppression may be effective when confronting severe transplant-associated skin cancer. Although the decision-making process for curbing levels of immunosuppression is difficult, further long-term, randomized controlled studies should assess the effect of using less immunosuppressant medication while preserving graft function.

UVA photosensitization of thiopurines and skin cancer in organ transplant recipients

The thiopurines azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) are important medications for cancer and inflammatory disorders. They are also widely prescribed as immunosuppressants in organ transplant patients. Their metabolism results in the incorporation of 6-TG into patients' DNA, and this increases skin sensitivity to incident UVA. Unlike the canonical DNA bases, which do not absorb UVA to a significant degree, DNA 6-TG is a strong UVA chromophore. It acts as a Type II UVA photosensitizer, and the combination of 6-TG and UVA treatment induces a synergistic toxicity in cultured human cells. Here, we review some of the damage that this interaction causes. Photochemical activation of DNA 6-TG triggers DNA and protein oxidation; it induces DNA breakage, DNA crosslinking, oxidation of DNA bases and the covalent attachment of proteins to DNA. Many of these photochemical DNA lesions are difficult for cells to deal with, and we review the evidence linking thiopurine immunosuppression with genome instability and the high incidence of skin cancer in organ transplant recipients.

Squamous cell carcinoma of the skin induces considerable sustained cost of care in organ transplant recipients

Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTR). We retrospectively analyzed the cost of dermatologic care in our OTR specialty clinic. We collected billing data for OTR (n = 198) seen at the Dermatology Department of Zurich University Hospital over 4 years (2004-2007). Grouping by histology yielded the groups: SCC (n = 70), with SCC occurring within the observation period; past SCC (n = 40), with SCC before the observation period; in situ SCC (n = 13), when only in situ SCC had been diagnosed; biopsy negative (n = 49) for SCC and in situ SCC; and no biopsy ever (n = 26) within the observation period. Median annual costs for dermatologic care were US$1398 for SCC; US$776 for past SCC; US$308 for in situ SCC; US$211 for biopsy negative; and US$156 for no biopsy ever. Median cost per case of invasive SCC (US$1830) was higher than cost per case of in situ SCC (US$603). Regression analysis showed male sex (P = .006), age at transplantation (P = .001), and time since transplantation (P < .001) as independent cost factors. This was an open, retrospective, single-center study with limited patient numbers. Dermatologic care for OTR is costly, and the majority of the costs are associated with SCC. Once SCC occurs, costs increase in a pronounced and sustained fashion. Interventions reducing the progression from in situ SCC to SCC could lead to considerable financial savings. We advocate sun protection, early diagnosis, and intervention to minimize the costs associated with SCC.

Skin cancer in organ transplant recipients

Cancer development is one of the most important late complications in organ transplant recipients. Skin cancer represents 40–50% of post-transplant malignancies and is the most common cancer. Within the first 10 years post-transplantation, 15–40% of graft recipients develop skin cancer, mainly cancers of epithelial origin induced by UV irradiation, infection with certain human papillomaviruses or other viruses that either promote or even directly induce various skin cancers. These cancers frequently grow rapidly with an increased risk of metastasis, and dermatologists have a prominent position in managing these patients. Management of skin cancer comprises primary prevention, more frequently secondary prophylaxis and appropriate treatment of established cancers. In high-risk skin cancer patients or metastatic disease, reduction of immunosuppression and change of calcineurin inhibitors to mTOR inhibitors may substantially improve the prognosis.

Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non‐melanoma skin cancer in an at‐risk population: A cohort study

The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure. We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007. We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non-Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3-67.4). Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.

Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair

UV-induced skin cancers comprise a major problem in organ transplant recipients (OTRs). Cyclosporin A, a calcineurin inhibitor, is used as a standard immunosuppressant and clearly increases the skin cancer risk. Azathioprine does not appear to result in such an increase in skin cancer risk, and mTOR inhibitors are associated with an even lesser skin cancer risk. The underlying molecular mechanisms of these clinically important differences among immunosuppressants are still unclear and may relate to other than immunological effects. Insights may be gained by the multistep skin cancer theory and xeroderma pigmentosum, where defective nucleotide excision repair (NER) results in a cellular mutator phenotype and cutaneous carcinogenesis. This viewpoint assay summarizes current knowledge about the influence of the most commonly used immunosuppressive drugs in OTRs on DNA repair. Calcineurin inhibition results in a 200-fold increased skin cancer risk compared with the normal population and inhibits NER. The skin cancer risk under azathioprine is threefold less compared with calcineurin inhibitors, which may relate to inhibition of only the last step of NER, i.e. gap filling. mTOR inhibitors do not reduce NER in the global genome and can inhibit the growth of already initiated tumors, which may account for the markedly reduced skin cancer risk compared with calcineurin inhibitors. We conclude that OTRs may benefit from treatment regimens other than calcineurin inhibitors and speculate that a targeted modulation of calcineurin-dependent signalling may prevent UV-induced tumor formation by enhancing NER not only in OTRs but also in the general population, at least in part.

Roles of the immune system in skin cancer

Over the past several decades, there has been increasing interest in understanding the roles of the immune system in the development and progression of cancer. The importance of the immune system in human skin cancer has been long recognized based primarily upon the increased incidence of skin cancers in organ transplant recipients and mechanisms of ultraviolet (UV) radiation-mediated immunomodulation. In this review, we integrate multiple lines of evidence highlighting the roles of the immune system in skin cancer. First, we discuss the concepts of cancer immunosurveillance and immunoediting as they might relate to human skin cancers. We then describe the clinical and molecular mechanisms of skin cancer development and progression in the contexts of therapeutic immunosuppression in organ transplant recipients, viral oncogenesis, and UV radiation-induced immunomodulation with a primary focus on basal cell carcinoma and squamous cell carcinoma. The clinical evidence supporting expanding roles for immunotherapy is also described. Finally, we discuss recent research examining the functions of particular immune cell subsets in skin cancer and how they might contribute to both antitumour and protumour effects. A better understanding of the biological mechanisms of cancer immunosurveillance holds the promise of enabling better therapies.

Dermatologic Care of the Transplant Patient

The goal of this article is to build on the earlier review "Dermatologic Care of the Transplant Patient: Part I" by offering a detailed analysis of the immunosuppressive medications and management strategies used in the current approach to the transplant patient. The incidence of nonmelanoma skin cancer in organ transplant recipients increases over time as immunosuppressive therapy continues. The International Transplant Skin Cancer Collaborative provides a list of immunosuppressive medications currently used to prevent the rejection of the grafted organ in solid organ transplant recipients, which includes prednisone, cyclosporine, mycophenolate mofetil, tacrolimus, azathioprine, rapamycin, daclizumab, and muromonab. Each of these agents has many possible side effects. The longer the patient's immune system is suppressed, the greater the risk for the development of malignant skin lesions. The transplant recipient is at particular risk for developing aggressive squamous cell carcinomas. The first squamous cell carcinoma in an organ transplant recipient patient should be considered a sentinel event. The current challenge is to determine if a change to a different class of immunosuppressive medication is a better option than minimizing current medication regimens for transplant patients who develop skin cancer. Several randomized clinical trials are underway to test these theories.

Immunosuppression Affects CD4+ mRNA Expression and Induces Th2 Dominance in the Microenvironment of Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients

Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTRs). The immune system plays a major role in the fight against SCC, however, little is known about the local inflammatory response in SCC at all. We analyzed quantity and quality of the perineoplastic inflammatory SCC microenvironment in immunocompetent patients and immmunosuppressed OTRs. RNA expression profile of SCC patients was analyzed for 8 different sets of genes relating to Th1 versus Th2 response using Gene Set Enrichment Analysis. SCC from immunocompetent patients and OTRs were analyzed by real-time polymerase chain reactions for CD4, CD8, TBET, GATA-3, FOXP3, RORC, IFN-gamma, IL-4, TGF-beta, IL-10, and IL-17A mRNA expression. Immunohistochemistry was carried out in SCC for CD3, CD4, CD8, and FOXP3 expression. Considerable inflammation was seen in both patient groups. SCC in immunocompetent patients and OTRs was associated with a mixed Th1 and Th2 gene expression signature. CD4(+) mRNA was diminished in immunosuppression. Skin adjacent to SCC in OTRs showed Th2 expression pattern as compared with immunocompetent patients. T-BET and IFN-gamma mRNA expression were decreased in the OTR group. Although Th17-weighted inflammation was unchanged, IL-17A mRNA level was markedly decreased with immunosuppression. Regulatory T cells, characterized by FOX-P3 and TGF-beta mRNA level, were decreased in OTRs. Our findings support the hypothesis that nontumor-bearing skin adjacent to SCC in OTRs is not necessarily normal and that the local microenvironment may contribute to a field effect contributing to higher recurrence rates and more aggressive behavior observed in these patients.

Dermatologic management, sun avoidance and vitamin D status in organ transplant recipients (OTR)

It is well known that skin cancer, especially cutaneous squamous cell carcinoma (SCC), in organ transplant recipients (OTRs) has higher incidence rates, behaves more aggressively and has higher rates of metastasis. OTRs who have been treated for many years with immunosuppressive medication are at the highest risk for developing malignant skin tumors. Protection against solar and artificial UV-radiation is crucial to prevent skin cancer in OTRs. However, investigations have revealed that solar UV-B-exposure and serum 25(OH)D levels positively correlate with decreased risk for various internal malignancies (e.g. breast, colon, prostate, and ovarian cancer) and other severe diseases. Therefore, it is important to detect and treat vitamin D deficiency in OTRs. This review discusses guidelines for the optimal management of these patients, that require communication between the transplant teams, the treating dermatologist and other clinicians.