Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

Management of Kaposi sarcoma after solid organ transplantation: A European retrospective study.

BACKGROUND: Systemic therapeutic management of post-transplant Kaposi sarcoma (KS) is mainly based on 3 axes: reduction of immunosuppression, conversion to mammalian target of rapamycin (mTOR) inhibitors, chemotherapy, or a combination of these. OBJECTIVE: To obtain an overview of clinical strategies about the current treatment of KS. METHODS: We conducted a multicenter retrospective cohort study including 145 solid organ transplant recipients diagnosed with KS between 1985 and 2011 to collect data regarding first-line treatment and response at 6 months. RESULTS: Overall, 95%, 28%, and 16% of patients had reduction of immunosuppression, conversion to mTOR inhibitor, and chemotherapy, respectively. Patients treated with chemotherapy or mTOR inhibitor conversion were more likely to have visceral KS. At 6 months, 83% of patients had response, including 40% complete responses. LIMITATIONS: The retrospective design of the study. CONCLUSION: Currently available therapeutic options seem to be effective to control KS in most patients. Tapering down the immunosuppressive regimen remains the cornerstone of KS management.

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study.

Organ transplant recipients (OTRs) have a 100-fold increased risk of cutaneous squamous cell carcinoma (cSCC). We prospectively evaluated the association between ß genus human papillomaviruses (ßPV) and keratinocyte carcinoma in OTRs. Two OTR cohorts without cSCC were assembled: cohort 1 was transplanted in 2003-2006 (n = 274) and cohort 2 was transplanted in 1986-2002 (n = 352). Participants were followed until death or cessation of follow-up in 2016. ßPV infection was assessed in eyebrow hair by using polymerase chain reaction-based methods. ßPV IgG seroresponses were determined with multiplex serology. A competing risk model with delayed entry was used to estimate cumulative incidence of histologically proven cSCC and the effect of ßPV by using a multivariable Cox regression model. Results are reported as adjusted hazard ratios (HRs). OTRs with 5 or more different ßPV types in eyebrow hair had 1.7 times the risk of cSCC vs OTRs with 0 to 4 different types (HR 1.7, 95% confidence interval 1.1-2.6). A similar risk was seen with high ßPV loads (HR 1.8, 95% confidence interval 1.2-2.8). No significant associations were seen between serum antibodies and cSCC or between ßPV and basal cell carcinoma. The diversity and load of ßPV types in eyebrow hair are associated with cSCC risk in OTRs, providing evidence that ßPV is associated with cSCC carcinogenesis and may present a target for future preventive strategies.

Subsequent nonmelanoma skin cancers and impact of immunosuppression in liver transplant recipients.

BACKGROUND: Nonmelanoma skin cancers (NMSCs) are the most frequent cancers in solid organ transplant recipients, with a high rate of subsequent tumors. OBJECTIVES: To describe subsequent NMSCs in a large cohort of liver transplant recipients (LTRs) with long follow-up and analyze the factors influencing it, including immunosuppressive regimen. METHODS: A total of 96 LTRs (76 male) with a personal post-transplant history of squamous cell carcinoma, basal cell carcinoma or Bowen's disease were included, with a median follow-up of 12.4 years (range, 1.5-27.8) after liver transplantation. RESULTS: The median follow-up after first NMSC was 6.4 years (range, 0.17-22.1). In all, 52 patients (53.1%) developed 141 subsequent NMSCs with a basal cell carcinoma-to-squamous cell carcinoma ratio of 1.8:1. The actuarial risk for development of a second NMSC was 13.7% at 1 year, 28.4% at 2 years, 49.4% at 5 years, 65.7% at 10 years, and 88.4% at 15 years. Multivariate analysis found that skin phototype I or II (vs III or IV) was a significant risk factor for development of a second NMSC (hazard ratio, 2.556; 95% confidence interval, 1.45-4.48; P = .001), whereas withdrawal of calcineurin inhibitors was significantly protective (hazard ratio, 0.358; 95% confidence interval, 0.142-0.902; P = .029). LIMITATIONS: Retrospective analysis. CONCLUSIONS: Subsequent NMSCs are very frequent in LTRs, and conversion from a calcineurin inhibitor-based immunosuppressive regimen to a mammalian target of rapamycin inhibitor/antimetabolite-based immunosuppressive regimen can reduce subsequent NMSCs.

Outcome of second kidney transplantation in patients with previous post-transplantation Kaposi's sarcoma: A French retrospective study.

This retrospective study concerned 8 patients with post-transplantation Kaposi's sarcoma (pt-KS) after a first kidney transplant who later had a second kidney transplantation. Pt-KS was widespread, with lymph node or visceral involvement in 7 cases. Complete remission was observed in 6 cases and partial remission in 2. After the second kidney transplantation, only 2 cases showed recurrence of skin KS, one with previous complete remission of KS and one with partial remission. The mean delay between stability or complete remission of KS and retransplantation was 2.0 and 7.3 years in patients with and without relapse, respectively. Both recurrent cases showed complete KS remission after tapering immunosuppression therapy and/or switching a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. We compared these 8 cases to 24 controls who had undergone 2 kidney transplantations but did not have KS, matching on sex, age and phototype. Cases and controls did not differ in graft function or survival. A second kidney transplantation may be possible after pt-KS and has acceptable risk, especially after a long complete remission of pt-KS.

Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.

The risk of melanoma in organ transplant recipients (OTR) is increased compared with the general population. This retrospective study registered all cases of post-transplant melanoma in kidney, heart, lung, and liver transplant recipients followed in our specialized post-transplant Dermatology Clinic since 1991. The yearly prevalence of melanoma and skin carcinoma between 2000 and 2015 was computed and compared in this population. Based on another cohort of kidney transplant recipients grafted since 2005, adjusted age- and sex-standardized incidence ratio (SIR) was calculated using a renal transplantation registry. In our overall OTR cohort, between 1991 and 2000, five melanomas occurred in 1800 OTRs (0.28%), whereas between 1991 and 2015, 53 melanomas were diagnosed in 49 of 4510 OTR (1.09%), representing a 3.9-fold increase in prevalence after 2000. Remarkably, the prevalence of nonmelanoma skin cancers remained unchanged over this period. Two deaths related to melanoma were recorded with an overall follow-up of 62 months. In our cohort of 1102 renal transplant recipients, the SIR of melanoma was 4.52. Our data suggest that contrasting with nonmelanoma skin cancer, the risk of post-transplant melanoma has considerably increased over the last decade.

Sirolimus and secondary skin-cancer prevention in kidney transplantation.

BACKGROUND: Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed. METHODS: In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus. RESULTS: Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups. CONCLUSIONS: Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).

Longitudinal study of seroprevalence and serostability of the human polyomaviruses JCV and BKV in organ transplant recipients.

The human polyomaviruses BKV and JCV cause mostly subclinical infections in childhood. Systemical immunosuppression after organ transplantation can lead to reactivation of persistent polyomavirus infections which may cause rejection of the transplanted organ. BKV and JCV seroprevalence and serostability was measured in 441 European solid organ transplanted recipients. Baseline samples were collected on average 24 days post-transplantation and sera were then collected over an 18 months follow-up period on up to six different time points. The overall seroprevalence at baseline for BKV was 97% with very little change over time. Prevalence for JCV was 76% at baseline and increased to 80% at the end of follow-up. BKV seroprevalence was highest in the youngest age group (100%) and decreased with increasing age (92% in the oldest age group; P < 0.0001), while JCV increased with age (69% vs. 81%; P = 0.020). Antibody reactivities for both BKV and JCV increased significantly with time (P = 0.0002 and P < 0.0001, respectively). Among the 406 patients with several samples, 94% were stably seropositive for BKV and 1% remained seronegative during the follow-up. JCV antibody stability was somewhat lower: 67% remained stably seropositive and 13% seronegative. While seroprevalence of BKV and JCV decrease and increase with age, respectively, both polyomaviruses showed significant increasing antibody reactivity over time in organ transplanted recipients at the onset of immunosuppression.

Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients.

There is increasing evidence of an association between human papillomaviruses (HPV) of the beta-genus (beta-PV) and the development of cutaneous squamous cell carcinoma (SCC). The viral DNA load may be an important determinant of pathogenicity, but there are currently no baseline epidemiological data relating to load in people without SCC. We investigated DNA-loads of eight beta-PV types previously associated with risk of SCC. We collected eyebrow hairs from immunocompetent people (ICP) and organ transplant recipients (OTR), determined load by quantitative PCR and obtained demographic, phenotypic, and sun exposure information. Viral loads for ICP from Australia (n = 241) and Italy (n = 223) and OTR from across Europe (n = 318) spanned seven orders of magnitude. The median loads for all types were below one viral DNA copy per 60 cells and were highest for HPV5, HPV8 and HPV20. None of the populations had consistently higher viral loads for all 8 types. However, a higher proportion of OTR were in the top deciles of viral load distributions for six of the eight beta-PV types examined. In a nested analysis of Italian OTR and ICP, this finding was significant for six beta-PV types and cumulative load. Increasing age was significantly associated with higher viral loads in Australia, and there was a weak trend for higher loads with the time elapsed since transplantation in the OTR. We observed a wide distribution of beta-PV loads with OTR significantly more likely to have the highest viral loads. Thus, viral loads may be an important contributor to the higher risk of SCC in OTR.

Basosquamous cell carcinoma in organ transplant patients: a clinicopathologic study.

BACKGROUND: Basosquamous cell carcinoma (BSCC) is a poorly known tumor showing pathological features of both basal and squamous cell carcinomas. BSCC has never been specifically studied in organ transplant recipients (OTRs). OBJECTIVE: We sought to study the clinicopathologic features of BSCC in OTRs and compare them with BSCC from nongrafted patients. METHODS: Tumors diagnosed as BSCC were re-evaluated pathologically and immunohistochemically for the expression of the human epithelial antigen to confirm the diagnosis. The clinicopathologic features of BSCC in OTRs were compared with 30 BSCC obtained from nongrafted patients. RESULTS: In our cohort of 3520 OTRs, 12 patients (0.34%) developed BSCC after a mean postgraft delay of 13.2 years, ie, later than other skin carcinomas. As compared with control patients, the age of OTRs with BSCC and the tumor thickness were significantly lower. BSCC were located on the head/neck in both groups in more than 75% of cases. No metastases developed in OTRs (mean follow-up 2.8 years). During the follow-up period (mean 16 years), OTRs with BSCC developed up to 220 additional premalignant and malignant skin tumors. After the diagnosis of BSCC, two patients developed lymph node metastasis of distinct squamous cell carcinoma. LIMITATIONS: This is a single-center, retrospective study. CONCLUSIONS: BSCC is a rare tumor, even in OTRs who are at high risk of carcinomas. Its incidence (0.34%) is comparable with that of cutaneous lymphomas and melanomas, and much lower than that of other nonmelanoma skin cancers. Contrary to previous reports, BSCC do not seem to behave more aggressively than other nonmelanoma skin cancers.

Organ transplantation and skin cancer: basic problems and new perspectives.

Solid organ transplant and subsequent graft survival have increased worldwide, while immunosuppression has prevented rejection with increasing success. Side effects of cutaneous infection and neoplasm, however, affect the majority of solid organ transplant recipients (OTRs). Squamous cell carcinoma of the skin (SCC) is the most common neoplasm overall following organ transplant with a risk that is 60-100 times greater than for the immunocompetent population. This review focuses on questions of ongoing debate about SCC formation in OTRs such as viral carcinogenesis, systemic photoprotection, photosensitization by drugs, the impact of immunosuppressive drugs and inflammation as a driver of carcinogenesis.

Malignancy incidence after renal transplantation in children: a 20-year single-centre experience.

BACKGROUND: Cancer is a well-recognized complication of organ transplantation. The pattern of malignancies that occur in the paediatric graft population is different from that in the general paediatric population and in the population of adult organ transplant recipients. METHODS: We reviewed medical records from 240 consecutive paediatric renal transplantations performed in 219 children, aged less than 19 years, in our centre between April 1987 and March 2007. Data from patients who had been transferred into adult units were extracted from the French registries of dialysis and transplantation. RESULTS: Among the 219 children who underwent renal transplantation during the study period, 16 (7.3%) developed malignancy. The cumulative incidence of cancer was 1.9, 4.0, 6.9 and 10.2% at 1, 5, 10 and 15 years post-transplantation, respectively. The 10-year incidence of post-transplantation lymphoproliferative disorder (PTLD) was 4.5%. Other identified cancers were Hodgkin lymphoma, Burkitt lymphomas, renal papillary carcinoma, thyroid papillary carcinoma, recurrent ovarian seminoma and skin cancer. The mortality rate was 25% (4/16). CONCLUSION: Early detection of cancer in transplant recipients is of great importance. Regular screening for persistent Epstein-Barr virus (EBV) DNA viral load in patients at risk for developing PTLD is recommended. The occurrence of skin cancer in transplanted children is extremely rare during childhood, but cases can develop in early adulthood.

Rapidly growing orf in a renal transplant recipient: favourable outcome with reduction of immunosuppression and imiquimod.

Orf is a viral skin infection due to a poxvirus. It manifests as a nodule of the hands that heals spontaneously within 3-4 weeks, but may be persisting and difficult to treat in immunocompromised patients. Very few cases have been reported in transplant patients; therefore, management is not established. We report a renal transplant recipient with a rapidly growing orf which regressed after application of imiquimod and a reduction in immunosuppression without damage on his renal function. This case suggests that a rapidly growing orf in transplant patients behaves as an opportunistic infection and therefore minimization should be considered along with a topical treatment.

BRAF mutations in melanocytic tumors (nevi and melanomas) from organ transplant recipients.

BRAF is a gene of the RAF family of kinases, frequently mutated in benign and malignant melanocytic tumors (nevi and melanomas). Organ transplant recipients are at high risk for developing various tumors, including melanocytic ones. We studied a group of 129 melanocytic tumors including various subtypes of nevi (n: 114) and melanomas (n: 15) excised from transplant (n: 63) and control (non-immunosuppressed) patients (n: 66) as to BRAF mutation status. Mutation research was performed after extraction of DNA from archival material (paraffin-embedded tissue specimens) by sequence analysis. BRAFV600E accounted for the most prevalent mutation found (94%). Melanocytic tumors from transplant patients had a lower frequency of BRAF mutations than control lesions (45.4% vs 63.5%, p<.05). The explanation for this difference is currently unknown. The possibility exists that in transplant patients, factors linked to immunosuppression (most likely immunosuppressive drugs) induce additional mutations, or activate alternative signaling pathways, which compensates for the lower rate of activating BRAF mutations in tumors developing in these patients.

Conversion from calcineurin inhibitors to sirolimus reduces vascularization and thickness of post-transplant cutaneous squamous cell carcinomas.

BACKGROUND: Immunosuppression favors the development of skin cancer. Experimental data suggest that sirolimus (SRL) has antitumoral and antiangiogenic properties. An investigation was undertaken into the effects of SRL on squamous cell carcinoma (SCC) developing in organ transplant recipients (OTR) receiving immunosuppressive treatments, with special emphasis on vascularization. MATERIALS AND METHODS: SCC that developed in eight OTR before and after conversion from calcineurin inhibitors (CNI) to SRL were compared for thickness, differentiation, ulceration, perineural invasion, density of peritumoral infiltrate, peritumoral vascularization, density of T-regulatory cells and of intratumoral Langerhans cells and growth fraction. RESULTS: SCC developing under SRL showed lower peritumoral vascularization and thickness, and higher growth fraction and density of peritumoral T-regulatory cells. CONCLUSION: Conversion from CNI to SRL at clinically relevant doses is associated in vivo with a reduced vascularization and thickness of post-transplant human cutaneous SCC. This effect could account for the beneficial effect of SRL on immunosuppression-induced skin carcinogenesis in humans.

Cutaneous Mycobacterium Marinum Infection (Fish Tank Granuloma) in a Renal Transplant Recipient: Case Report and Literature Review.

Atypical mycobacterioses are unusual infections of the skin and other organs caused by non-tuberculous mycobacteria. Fish tank granuloma and swimming pool granuloma are two forms of atypical mycobacterioses caused by Mycobacterium marinum. So far, only a few cases of these infections have been reported in organ transplant patients, and these usually are more severe when compared with atypical mycobacterioses in immunocompetent hosts. We report a kidney transplant patient with a rather mild form of atypical mycobacteriosis (fish tank granuloma) who responded well to treatment with doxycycline and will provide a review of all similar cases reported in the literature.

mTOR Signalling Pathway-protein Expression in Post-transplant Cutaneous Squamous-cell Carcinomas Before and After Conversion to mTOR-inhibitors.

BACKGROUND/AIM: Inhibitors of the mammalian target of rapamycin (mTORis) exert immunosuppressive and antitumor effects and are used in organ-transplant recipients (OTR) as immunosuppressants able to reduce skin tumor burden. This study investigated the effects of mTORis on the expression of mTOR pathway proteins in cutaneous squamous-cell carcinomas (SCC) developing in OTR, before and after switching to mTORis. MATERIALS AND METHODS: An immunohistochemical study was performed on 23 SCC sections excised from OTR with post-transplant SCC, before or after switch to mTORis, with antibodies against pAkt, pmTOR and PI3K. RESULTS: pmTOR expression was found in 8/12 SCC pre-switch, and in 8/11 SCC post-switch, to mTORis. All (but 2) SCC expressed PI3K, and all SCCs expressed pAkt. CONCLUSION: mTORis do not significantly change the immunohistochemical expression of molecules upstream of the mTOR inhibition (pmTOR, PI3K, pAkt), in cutaneous SCC.

Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results.

Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.

5% topical imiquimod tolerance in transplant recipients.

BACKGROUND: Topical imiquimod is a new immunomodulator agent approved for genital warts, actinic keratosis (AK) or carcinoma, occurring in immunocompetent patients. OBJECTIVES: This study aimed to assess the safety and efficacy of imiquimod for the treatment of warts, AK and bowenoid papulosis (BP) in transplant patients. METHODS: 24 transplant patients (18 kidney, 4 kidney-pancreas and 2 heart) were included in this retrospective study conducted between June 2000 and February 2003 at the department of dermatology of 3 hospitals. Imiquimod cream was applied 3 times a week over a median period of 9 weeks. RESULTS: Graft function was not altered under therapy. Local tolerance was excellent. Complete responses were observed in 1 patient (1/12) with cutaneous warts and 1 (1/6) with AK. Two patients of 3 with BP had total clearance of their lesions. Partial responses were observed in 3 of the 6 AK-treated patients, 5 of 12 patients with cutaneous warts and 1 of 2 patients with anogenital warts. CONCLUSIONS: Imiquimod 5% cream is a promising, well-tolerated therapy for warts, AK and BP in transplant recipients.