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.

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.

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.

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.

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.

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.

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.

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.

Risk of Aggressive Skin Cancers After Kidney Retransplantation in Patients With Previous Posttransplant Cutaneous Squamous Cell Carcinomas: A Retrospective Study of 53 Cases.

BACKGROUND: The course of skin cancer after retransplantation in organ-transplant recipients who have already developed posttransplant skin cancer has not been assessed. METHODS: This retrospective multicentric study included 53 patients with a history of cutaneous squamous cell carcinoma (SCC) after a first kidney transplantation who received a second kidney transplantation. The primary endpoint was the occurrence of aggressive cutaneous SCC after the second transplantation. Secondary endpoints included the course of skin cancers over 3 periods (first transplantation, return to dialysis, second transplantation), the time to occurrence, and risk factors for aggressive SCC after retransplantation. RESULTS: The first SCC developed in 47 patients with a functional graft and in 6 after return to dialysis. After the first transplantation, 17 (33.3%) patients developed SCC in dialysis and 39 (73.6%) after the second transplantation, respectively. Twenty aggressive SCC developed over the study period. They occurred in 14 (26.4%) patients after retransplantation vs 5 (9.4%) after the first transplantation with a median delay of 50 months and were responsible for 5 deaths. Fair skin type, multiple tumors before retransplantation, treatment with azathioprine, T cell-depleting antibodies, and delayed revision of immunosuppression were associated with an increased risk of aggressive cutaneous SCC after retransplantation. CONCLUSIONS: Candidates to retransplantation with a history of posttransplant SCC have a high risk of aggressive SCC. Our data suggest that the risk could be reduced by a tailored immunosuppression. A wait period may be required depending on the clinicopathological characteristics of the previous SCC and discussed on an individual patient basis.

Tumour Budding Correlates with Aggressiveness of Cutaneous Squamous-cell Carcinoma.

BACKGROUND/AIM: Tumour budding (TB) is a specific pathological feature that has been found to be associated with an aggressive outcome in several cancer types; however, to our knowledge, TB has not yet been assessed in squamous-cell carcinomas of the skin (SCC). The aim of the study was to study whether TB correlates with aggressiveness in cutaneous SCC. MATERIALS AND METHODS: We examined 31 aggressive SCC (that later developed local recurrences or metastases) in comparison with 21 non-aggressive SCC (not complicated by recurrence or metastasis). TB was expressed as the mean number of tumour buds in five adjacent high-power fields of each SCC. RESULTS: Aggressive SCC had a much higher TB score compared to control SCC (1.63±1.35 vs. 0.49±0.9, p<0.001). CONCLUSION: As with other cancer types, TB seems to be a pathological marker of aggressiveness of cutaneous SCC, along with other features known to be associated with an aggressive outcome (tumour thickness, level of invasion and lymphovascular or perineural invasion). Further studies including a larger number of tumours will hopefully validate TB as a new pathological predictor of aggressiveness in cutaneous SCC and will allow its correlation with other pathological features of SCC aggressiveness to be defined.

Histopathologic features predictive of aggressiveness of post-transplant cutaneous squamous-cell carcinomas.

BACKGROUND: Squamous cell carcinomas (SCC), the commonest malignancies developing in organ-transplant recipients (OTR), may behave aggressively. We searched for pathological features of post-transplant SCC that could predict an aggressive outcome early. MATERIALS AND METHODS: We pathologically examined 34 SCC developed in OTR that developed later recurrences/metastases, and compared them with 25 non-aggressive SCC excised from the same OTRs over the same period of time for features believed to predict an aggressive outcome (tumour size and thickness, ulceration, deep tissue invasion, mitotic rate, differentiation, peritumoural infiltrate density, acantholysis, perineural and lymphovascular invasion). RESULTS: A statistically significant difference was found for the level of tumour invasion (Clark), as 58% (18/34) of aggressive SCCs (vs 24% (6/25) of non-aggressive SCCs) were of levels IV or V. CONCLUSION: Post-transplant SCCs with a Clark level of IV or V are associated with a higher risk for recurrence and metastasis and call for a close patient follow-up.

Skin cancers after liver transplantation: retrospective single-center study on 371 recipients.

BACKGROUND: The increased risk of skin cancer is well known in heart and kidney transplant recipients, but fewer data exist on liver-transplant recipients (LTRs). The aim of this study was to analyze the prevalence, clinical features and risk factors of skin cancers in LTR treated mainly with tacrolimus. METHODS: We selected LTR grafted in our hospital between January 1996 and December 2008, aged 20 years or more at the time of the study. Data were collected from the patients' medical files and with a questionnaire. RESULTS: Three hundred seventy-one LTR were included. The median follow-up period was 8.2 years. The overall prevalence of skin cancers was 13.5%. The prevalence of melanoma was 1.3%. The squamous cell carcinoma to basal cell carcinoma ratio was 1:3. Both the overall cumulative patient risk of de novo skin malignancies and the squamous cell carcinoma-to-basal cell carcinoma ratio increased with time postgraft. The duration of immunosuppression was a risk factor, in addition to those common in the general population. No association was found between the primary liver disease and the development of skin cancer. CONCLUSION: Contrasting with previous data of the literature, our findings suggest that, for a similar follow-up time, the risk of skin cancer in LTR is comparable to that of kidney transplant recipients.

Transplantation: Donor-derived skin cancer in a kidney transplant recipient.

Skin carcinomas, triggered by ultraviolet light, commonly develop post-transplantation and are associated with substantial morbidity and mortality. A recent study in kidney transplant recipients has shown that some of these tumours arise from donor-derived cells. This phenomenon is interesting for the study of carcinogenesis, although its effect on clinical practice is unknown.

Differential expression of p-mTOR in cutaneous basal and squamous cell carcinomas likely explains their different response to mTOR inhibitors in organ-transplant recipients.

BACKGROUND: Mammalian Target of Rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have been shown to reduce cutaneous carcinogenesis in organ-transplant recipients requiring for immunosuppressive treatment to prevent from allograft rejection. Clinical observations suggest that cutaneous squamous cell carcinomas (SCC) are more sensitive than basal cell carcinomas (BCC) to the antitumoral effect of these inhibitors. AIM: To investigate if the different response of SCC and BCC to mTOR inhibitors can be explained by differential expression of molecules involved in the mTOR signaling pathway. MATERIALS AND METHODS: The expression of phospho-mTOR was immunohistocemically studied in specimens of cutaneous SCC and BCC. Results. All 15 SCCs expressed significant cytoplasmic phospho-mTOR immunoreactivity; by contrast, 12/13 BCC were completely negative, only one BCC exhibited weak phospho-mTOR immunoreactivity. CONCLUSION: The considerably higher expression of phospho-mTOR in SCC compared to BCC is a likely explanation for their higher sensitivity to mTOR inhibitors.

Human papillomavirus load in eyebrow hair follicles and risk of cutaneous squamous cell carcinoma.

BACKGROUND: Beta-human papillomavirus (betaPV) may play a role in the development of cutaneous squamous cell carcinoma (SCC). However betaPV is highly prevalent, and it may only be people with a higher viral load who have increased risk of SCCs. We therefore examined the association between betaPV load and SCCs. METHODS: We recruited 448 immunocompetent cases with SCCs and 464 controls from Italy and Australia and 497 immunosuppressed organ transplant recipients (OTR; 179 cases and 318 controls) from Europe. We used reverse hybridization to genotype 25 betaPV types in eyebrow hair follicles and determined the viral load for eight selected types using quantitative PCR. We used logistic regression to assess associations between type-specific and cumulative viral load and SCCs. RESULTS: Australian and OTR participants in the highest cumulative load tertile were at significantly higher risk of SCCs than those in the lowest tertile. Those with more than four betaPV types in the high load tertile were at approximately three-fold increased risk of SCCs. In Australia, HPV23 and 36 loads were significantly associated with SCCs, with borderline associations for HPV5 and 38. In OTR, HPV8 and 38 loads were significantly associated and HPV20 and 36 were borderline. We found little evidence for an association between load and SCCs in Italy. CONCLUSIONS: High viral load may be associated with risk of cutaneous SCCs, with total load seemingly more important than the load of any specific type. IMPACT: Our findings lend weight to the hypothesis that HPV plays a role in skin carcinogenesis.

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.

Longitudinal study of seroprevalence and serostability of 34 human papillomavirus types in European organ transplant recipients.

Organ transplant recipients (OTR) are at increased risk of cutaneous squamous cell carcinoma, which may be related to reactivation of human papillomavirus (HPV) infections. Measurement of change in HPV antibodies after transplantation would help to explore this hypothesis. We measured antibodies to 34 HPV types on up to six occasions over 18 months in 441 OTRs from five European countries. At baseline (mean 24 days after transplantation), 80% of all OTRs were seropositive to at least one HPV type. The beta HPV genus had the highest seroprevalence (45%). For most HPV genera baseline seroprevalence peaked between 40 and 59 years old. Most OTRs retained their serostatus over time and antibody levels were stable. Seroprevalence in immunosuppressed OTRs is stable in the 18 months immediately after transplantation. Thus there is no short-term evidence that immunosuppression leads to new or reactivated skin infection with HPV sufficient to induce antibodies.