Critical Reviews in Oncology/Hematology 56 (2005) 127136

Skin cancer and immunosuppression

Gianni Gerlini a , Paolo Romagnoli b , Nicola Pimpinelli a,
a b

Department of Dermatological Sciences, University of Florence Medical School, Via degli Alfani, 37-50121 Florence, Italy Departments of Anatomy, Histology and Forensic Medicine; University of Florence Medical School, 37-50121 Florence, Italy Accepted 4 November 2004

Contents
1. 2. 3. 4. 5. 6. 7. 8. The skin immune system and its alterations produced by immunosuppressive treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epithelial skin cancer (carcinoma) and oncogenic virus infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kaposis sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melanocytic skin cancer (melanoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphoproliferative disorders of the skin (primary cutaneous lymphoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroendocrine skin cancer (Merkel cell carcinoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rare skin cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 128 129 130 131 131 132 132 132 132 135

Abstract All immunosuppressive treatments, either pharmacological or physical, have the potential to impair the skin immune system network of cells and cytokines, thus leading to an increased incidence of skin cancer. Since skin cancer in transplant recipients may show uncommon clinical features and have an unusually aggressive course, transplant patients should be strictly followed up by experienced dermatologists in order to diagnose and treat properly any skin cancer in an early phase. Importantly, due to the fact that sun exposure increases immunosuppression in the skin, patients should be clearly informed about the additional risk of sun exposure and the preventive measures to be taken. 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Skin cancer; Immune suppression; Skin immune system; Transplant

1. The skin immune system and its alterations produced by immunosuppressive treatments Its now widely accepted that the skin is not only a passive, mechanical barrier protecting the body from outside
Abbreviations: APC, antigen presenting cells; DC, dendritic cells; SIS, skin immune system; SALT, skin associated lymphoid tissue; LC, Langerhans cells; UVB, ultraviolet-B; SCC, squamous cell carcinoma; BCC, basal cell carcinoma; AK, actinic keratosis; KS, Kaposis sarcoma; MN, melanocytic nevi; MCC, Merkel cell carcinoma Corresponding author. Tel.: +39 055 2344422; fax: +39 055 2758757. E-mail address: pimpi@uni.it (N. Pimpinelli). 1040-8428/$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2004.11.011

dangers, yet it acts as a true peripheral immunological organ [14]. Hence, the denition of skin immune system (SIS) [1] and skin-associated lymphoid tissue (SALT) [4]. The skin includes virtually all the cell types present in classic secondary lymphoid organ, such as the spleen, lymph nodes and tonsils. A network of dendritic antigen presenting cells (APC) is present throughout the skin: the CD1a positive Langerhans cells (LC), which are located in the epidermis, and different subsets of dendritic cells (DC) in the dermis. It has been shown since recently that dermal DC express all the members of the CD1 family which includes CD1a, b, c and the recently identied CD1d. This system is suitable for the presentation

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of lipid and glycolipid antigens to T-cells [5] in addition to the MHC system which is suitable for the presentation of highly polymorphic peptide antigens. Among the APC family, which also include B cells and macrophages, DC have the unique capacity to induce primary immune responses. They are strategically located at the body boundaries (not only skin, but also mucosae), continuously sample the antigenic content of the microenvironment, and can present peptide antigens to T-cells [6], hence the denition of sentinels of the immune system. In peripheral tissues, these cells reside as immature DC and, after encountering pathogens, they migrate to draining lymph nodes where, after full maturation, present antigens to antigen-specic naive T-cells eliciting primary immune responses [6,7]. The T-cells activated by DC migrate to sites of antigen capture, including the skin, in order to face with the antigen source-pathogens, but also tumours. DC not only elicit effective immune responses, but have many other relevant functions: induce immunological tolerance, regulate B cell proliferation, and drive the differentiation of T cells toward a Th1 or Th2 response [6], depending on the DC subtype involved and on subtle differences in the microenvironment at the time of antigen uptake and presentation [8,9]. Importantly, they also cross-talk with natural killer (NK) cells [10] and NK-T cells [11,12]. In conclusion, DC can orchestrate the entire complex of immunological responses. The SIS also includes T-cells, macrophages, and mast cells; although not members of the immune tissue in a strict sense, also broblasts, endothelial cells, and keratinocytes take part in the elicitation, action, and regulation of skin immune responses [24]. Most skin T-cells reside in the dermis, and only minor numbers in the epidermis where they are mostly represented by CD8+ T cells. The T-cell compartments can strongly increase in inammatory conditions. The entire cell repertoire of the SIS is primarily dedicated to maintain the immunologic homeostasis of the skin and, as in other lymphoid organs, is deputed to innate and adoptive immune responses. Innate immune responses are non-specic and occur in a very short time; on the contrary, adoptive immune responses are specic, need some time to be induced, and switch on a long lasting memory. Some cells of the SIS or their precursors may also be involved in tissue homeostasis and repair as blood-borne, pluripotent stem cells, but the relationships between SIS, in particular the CD34 positive DC subset, and so-called circulating brocytes needs to be further analyzed [13,14]. All immunosuppressive treatments, either pharmacological (e.g. cyclosporin, steroids, azathioprine, etc.) or physical (ultraviolet irradiation either from natural or articial sources: UVB, UVA, PUVA, etc.), can potentially impair the SIS defence capacity leading to an increased incidence of skin cancers. DC seems to be among the preferential target cells of immunosuppressive pharmacological treatment. Recent evidence has shown that immunosuppressive treatment currently used in graft recipients can impair DC function [1517]. Although cyclosporin A treatment seems to affect also the differentiation and function of LC [18,19], the exact

impact of such a treatment on these cells is not yet clear [20]. In vivo studies have conrmed these data: it has been shown that graft recipients, renal and liver transplant recipients, have a reduced number of skin DC in sun-exposed areas compared to controls [2123], and their function, as assessed by alloantigen presenting capacity, can also be reduced [24]. High dose steroid treatment also affects the differentiation of DC and the function of APC, including that of LC [2527]. Its tempting to speculate that the increased incidence of skin cancer in graft recipients, especially upon cyclosporin A-mediated immunosuppression, is at least in part related to impairment of skin DC. This would explain the selective sensitivity of skin to virus infection and tumour development which onsets dose-dependent in patients treated chronically with cyclosporin A as compared with those treated with other immunosuppressant agents [28]. However, other cells can also be affected under immunosuppressive therapy and hence, contribute to lower anti-cancer defenses. As shown for DC, kidney transplant recipients under immunosuppressive treatment have a decreased number of CD4 and CD8 T-cells [22]. Similarly, psoriatic patients under cyclosporin A and methotrexate therapy have a reduction in the number of T cells in psoriatic lesions [29]. Even NK cells have been shown to have functional defects in transplant recipients [30]. Among immunosuppressive therapy other than pharmacological, special attention is deserved to the so called phototherapy, which includes different subtypes: ultraviolet-B (UVB) or UVA therapy; photochemotherapy, i.e. oral psoralen plus UVA irradiation (PUVA); photodynamic therapy; and extracorporeal photochemotherapy (photopheresis). It is well known that sunlight exposure can cause skin cancer in certain categories of workers, such as farmers and sailors. Its also established that UVB light is by far the main cause of this phenomenon [31,32]. Among the mechanisms induced by UVB, induction of DNA gene mutations is extremely important, but also direct depression of the SIS responses play a crucial role [33]. For this reason, UV radiation has been used as immunosuppressive therapy in several skin diseases [34], but also in allograft rejection and graft-versus-host disease [3538]. In animal models, it has been shown that UV impair SIS; in particular, the application of strongly reactive haptens fails to elicit contact hypersensitivity when applied on UV-exposed skin [39], indicating that UV has a local immunosuppressive effect. Like other immunosuppressive therapies, UVB impair skin DC function through local and systemic, cytokine-mediated circuits [4045]. However, they also have systemic effects: skin exposed to UV produces IL10 [42], a well known systemic immunosuppressive cytokine which again preferentially targets DC [43,46].

2. Epithelial skin cancer (carcinoma) and oncogenic virus infection Several skin cancers can develop as a consequence of the immune system suppression induced in patients under

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different therapeutical regimens. The most striking example is represented by transplant recipients, which often receive associations of heavily immunosuppressive drugs for a long time. Among all malignancies, non-melanoma skin cancers are the most frequent in transplanted patients, who show a very high incidence of squamous (SCC) and basal cell carcinomas (BCC), as well as of actinic keratoses (AK), which are considered the precursor lesions to SCC and BCC, but they also can be regarded as true in situ SCC [4751]. Very often skin cancers in transplant recipients show clinical aspects unusual in the general population: they may be highly aggressive and invasive [52], and may develop, particularly SCC, in a very short time; even AK progress more rapidly and frequently than normal into SCC, which in turn exhibits a stronger tendency to metastasize. Clinically, early SCC may often simulate benign keratotic lesions. For this reason excisional or punch biopsies are strongly recommended. AK has been calculated to appear 15 years earlier in average in transplant recipients than in a control population (55 versus 70 years) [53]. Among the different solid organ transplant recipients, AK is more frequent in heart than in kidney or liver recipients [51]. Importantly, the risk of developing skin cancer is proportional to the length of immunosuppression: in a recent study, it has been observed that within the rst 5 years from transplantation 40% of patients develop precancerous skin lesions (AK), in situ malignancies (Bowens disease), and invasive cancers, i.e. BCC and SCC [54]. Other studies have shown that in the rst 10 years after transplantation the risk of developing skin cancer is around 14%, and increases to 40% after 20 years in comparison to a 6% cumulative risk in a control population [51,55]. Interestingly, this percentage raises to 45 and 70% after 11 and 20 years, respectively, in Australia. This suggests that sun exposure has a great inuence on carcinogenesis in these patients [56], as it has been conrmed by other studies [5759]. This holds true particularly for SCC, which is often located on sun-exposed areas in contrast to BCC that can often develop also on the trunk. Its worth to mention that the SCC/BCC ratio is inverted in transplant recipients (SCC > BCC), while the opposite (SCC BCC) occurs in the general population [56]. Jensen et al. [60] have calculated a 65-fold increase over the non-immunosuppressed general population in the risk for cutaneous SCC and a 20fold increase in that for lip SCC in a total of 2561 kidney and heart transplant patients, with a signicantly higher risk (2.9 times) in heart than in kidney graft recipients. A prospective study by Fuente et al. [61] on 174 kidney transplant recipients, with a median follow-up of 72 months, has shown that 25.3% developed skin cancer, with a BCC/SCC ratio of 1.4:1. The cumulative incidence of skin cancer was 13 at 3 years, 27.5 at 6, and 48% at 10 years. These data are in line with those reported by another Australian group, as mentioned above [56], but are in contrast with those reported by an Italian group that found a cumulative incidence of 9.7% at 10 years [62]; this last retrospective study was in line with other reports from Northern Europe countries, which show cumu-

lative incidences varying from 4.8 to 16% at 10 years [6366]. Once again, this conrms the great concausative role of sun exposure (occupational and, at a lesser extent, recreational) and genetic traits (Australian white population is mostly of celtic origin) in the development of epithelial skin cancer in organ transplant recipients. Another important clinical consequence of immunosuppression is represented by a high incidence of HPV-related skin lesions [67]. Its well known that HPV may play important role in the pathogenesis of skin cancer. This is conrmed by the presence of HPV DNA in skin cancers of these patients [68]. Viral warts are frequent in those same patients, and these lesions much frequently occur before the onset of skin cancers. In transplant recipients, warts appear as numerous, keratotic, at lesions that often degenerate in skin cancer (epidermodysplasia verruciformis). Virus infection and UVB exposure seem to be synergic in the induction of HPVassociated skin cancer [69].

3. Kaposis sarcoma Kaposis sarcoma (KS) is a vascular neoplasm consisting of slowly growing, spindle shaped endothelial cells expressing endothelial and macrophage markers, mainly localized in the skin [7072]. It can be divided into four different clinical variants, i.e., the classical or sporadic form described by Moritz Kaposi, which affects elderly people and is characterized by an indolent course; the endemic form, observed in Africa and Mediterranean area and two immune-depression related forms, namely the epidemic AIDS-related form and the post-transplant form [71]. This tumour is crucially related to a specic virus, the so-called Kaposi sarcoma-associated human herpes virus (KSHV) also known as HHV-8. This virus has been detected in KS tumor cells by molecular biology techniques and morphologically characterised by electron microscopy studies [7175]. Although more than 95% of lesions are infected by KSHV and the virus is crucial for KS development, immunosuppression is very important for clinical manifestation [71]. It seems that KS lesions develop as the result of a reactivation and/or replication of the virus, but in a few cases they may represent a consequence of primary infection [7678]. The seroprevalence of KSHV in blood donors is highly variable among different populations: it is 0.2% in Japan, raises to 10% in the United States, and peaks to 50% in certain African populations [71]. Clinically, early lesions of KS are macules or small plaques, reddish, blue or purple, that grow progressively and can coalesce to form large plaques or nodules. The preferred sites are the lower limbs, at a lesser extent the trunk, last the upper limbs. KS can also involve oral mucosa, in particular the palate, and extracutaneous organs, such as lymph nodes, stomach and duodenum. Less frequently it can affect the lung, liver, and heart. KS in transplant recipients is usually quite aggressive, and often involves extracutaneous sites, such as

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mucosae, lymph nodes and visceral organs, with or without skin lesions [70]. Barozzi et al. [79] have shown that HHV-8 infected neoplastic cells in post-transplant KS from ve out of eight renal transplant patients contained genetic (as detected by singlecell PCR, microsatellite analysis and in situ hybridization) or antigenic markers (as detected by immunohistochemistry and double immunouorescence) of their donors. In particular, among six females with KS developed after receiving organ trasplantation from a male donor, Y-chromosome markers and donor-derived microsatellite sequences were found in HHV-8 infected tumour cells from four patients. These data suggest that KS could originate from progenitor cells derived from organ donor, and that the tumour is likely to develop because of the state of immunosuppression of transplanted patients. In fact, the incidence of KS in transplant recipients is 400500 times higher than in the general population in USA (1 out of 200 transplanted patients) [70], while in Saudi Arabia, where KSHV is endemic, the percentage of transplant patients with KS raises to 5% [80]. Jensen et al. [60] have calculated a 84-fold increased risk for KS in a Norwegian population of kidney and heart transplant patients. The incidence of KS increases with duration of immunosuppressive treatment, with actually more than 5% of all de novo tumours in this group of patients being KS [70]. Similar to the other forms of KS, also in transplant recipients this tumour is more frequent in males. Treatment of post-trasplant KS depends on the extension of the diseases. In case of a few and small lesion, surgical excision or physical destruction by electrodessication or cryotherapy are recommended. When the disease is more severe or localized to different areas, the treatment is more problematic: interruption or reduction of the immunosupressive regimen can lead to regression of the lesions, but is burdened by the loss of the graft in a considerable percentage of patients [71,81]. While in kidney transplanted patients developing severe KS the cessation of immunosupressive therapy is a possible option because of the possibility to practice dialysis, in heart or liver transplants the therapy can only be dose-reduced. In case of no response to immunosupressive therapy modication, a chemotherapy protocol with a single agent, such as vinblastine or vincristine or a combination protocol with doxorubicin, bleomycin and vincristine are recommended [81]. Unfortunately, however, the latter option can worsen the immunosuppression. In recent years, new, less immunosuppressive antiblastic agents like gemcitabin or liposomal doxorubicin are increasingly recommended [81]. Another therapeutical option is represented by biological agents, such as interferon alfa, used either alone or in combination with antiretroviral therapy [71,81].

4. Melanocytic skin cancer (melanoma) Melanoma is a relatively common type of cancer in Caucasians, and its incidence is increasing in the general popu-

lation [82]. Its not clear whether the incidence of melanoma and its potential precursors, melanocytic naevi (MN), is increased in transplant recipients. There are some reports indicating that MN develop in high number in transplant recipients [8386]. In particular, it has been reported that the mean total number of MN was signicantly higher in renal transplant patients than in a control group [83]. The same study also indicated palms, soles, back and buttocks as the places where the increase occurred. In a kidney transplant recipient, an eruption of clinically atypical MN has been reported [84]. McGregor et al. [85] have described the development of numerous MN in an identical twin following kidney transplantation, whereas no increase in naevi occurred in the other twin. However, these reports have not been conrmed univocally. Gulec et al. [87] did not nd any difference in the number of MN between kidney transplant recipients and controls, and Andreani et al. [88] reported that the overall number of MN was not signicantly increased in a group of allogenic bone marrow transplantation patients as compared with controls. However, also in this latter study a signicantly higher number of MN was reported for the palms and legs compared to general population. Given the reported higher incidence of MN in children receiving organ transplants, Kanitakis et al. [89] analysed the proliferative capacity of MN in this group of patients in comparison to non-immunosuppressed subjects: they found that the proliferation rate of MN was not different between children with organ transplants and controls. Melanoma is one of the few cancers which are immunogenic, and the importance of the immune system to control this tumour is well known [90]. Conicting data are available in the literature about melanoma and immunosuppressive treatment. From a series of reports, melanoma incidence in transplant recipients seems to be higher than in the general population, with a 210-fold increase in the risk [56,63,91,92]. However, no signicant increase in the risk of melanoma was observed in another study [59]. Noticeably, histopathological analysis of the primary tumour, when available, has shown that in several cases of transplant recipients melanoma originates from a precursor naevus [91,92]. Transplant recipients who experienced melanoma prior to transplantation are at high risk of relapse according to a study published by Penn [93]. This author reported that among 31 patients treated for melanoma before transplantation (30 cutaneous and 1 ocular lesions), six patients (19%) had recurrences post transplantation and died. Among these patients, three had been treated less than 2 years pre-transplantation, two between 2 and 5 years pre-transplantation, and one 10 years pre-transplantation. This same study also reported the striking nding that 20 patients had received inadvertently an organ from 11 donors, containing undiagnosed metastatic melanoma. Among the 20 recipients, three patients never developed clinically evident melanoma, one had a local spread of melanoma beyond the transplant boundary, and 16 developed metastatic melanoma. Among these last patients, 11 died of melanoma. In four patients, transplant

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nephrectomy and cessation of immunosuppressive therapy resulted in complete remission. Recently, the inadvertent transplant of malignant melanoma from a single donor (of heart, liver, and two kidneys) into four recipients has been described [94]. The donor had no clinical history or evidence of melanoma. All the recipients developed metastatic melanoma within 1 year after transplantation and died of metastatic melanoma [94]. Since in these cases melanoma can be very aggressive, retransplantation can be a valuable therapeutic option, as shown in some patients who inadvertently received kidney and cardiac transplants from a donor found to have metastatic melanoma and then underwent successful retransplantation [95,96] Melanoma can develop de novo in transplant recipients. The Cincinnati Transplant Tumour Registry (CTTR), based on 7192 grafts, reported that 177 patients developed melanoma after transplantation: among those patients, cutaneous melanoma occurred in 164 patients, ocular melanoma in 5, and melanoma of unknown origin in 8 patients. In this study, melanomas represented 5.2% of skin tumours after transplantation, a gure which should be compared with 2.7% in the general population. The importance of immunosuppression is stressed by the fact that cutaneous melanoma occurred even in 6 (4%) children, a group of patients that is usually not affected by melanoma, and 9 (5%) occurred in patients receiving bone marrow transplantation as part of a treatment for leukemia. In children receiving transplants, melanoma represented 14% of skin cancer while the corresponding percentage in adults is 5%; however, it should be considered that BCC and SCC are rare in children. Forty-four patients (27%) with cutaneous melanoma also experienced other skin cancers. Among the 177 patients with melanoma, 56 died of their malignancy. Melanoma represented 410% of skin cancer in solid organ transplanted patients, while it was 60% in bone marrow transplanted, but in this group many were children in whom BCC and SCC are rare [93]. The relative risk of melanoma among transplant recipients has been calculated to range between 2 and 5 [56,60,92,97,98]. Detailed data on the type and site of cutaneous melanoma have been given by a French study on 12,477 graft recipients, followed up for 5 years [92]. Seventeen (0.14%) patients developed melanoma, precisely 14 kidney and 3 heart recipients, with a mean interval between transplantation and melanoma excision of 63 months. Among the 17 melanoma cases, 14 were cutaneous melanoma; among them, two developed on Hutchinsons lentigo, two were in situ melanoma, seven were supercial spreading melanoma, and three were ulcerated nodular melanoma. Two patients had mucosal melanoma: one on the glans penis and the other on anorectal mucosa. No clinical data were available for one patient. Similar to the general population, women developed melanoma preferentially on the lower limb and men on the trunk. The patients with ulcerated nodular melanoma and the one with anorectal melanoma died of metastatic melanoma after a mean of 15 months from excision. Interestingly, a patient who had lymph node metastasis was treated with inter-

feron for 18 months with clinical remission for 2 years before a relapse. 5. Lymphoproliferative disorders of the skin (primary cutaneous lymphoma) In addition to the reduced immune surveillance and direct oncogenic effect caused by immunosuppressive drugs, chronic antigen stimulation of skin-homing (CLA+) lymphocytes caused by grafts may have a specic role in the development of lymphoproliferative disorders of the skin. The possible role of chronic antigenic stimulation in the development of primary cutaneous lymphoma is witnessed by the progression to lymphoma from lymphoid reactive hyperplasia due to known stimuli-tattoo [99] and specic immune therapy [100]. Generally speaking, transplant recipients often develop lymphoproliferative disorders, with a relative risk estimated between 28- and 49-fold [101]. These disorders are predominantly, but not exclusively, related to Epstein-Barr virus (EBV) infection [102]. Primary cutaneous B-cell lymphoma occurs more frequently than T-cell lymphoma, which is rare [103]. The issue of primary cutaneous T-cell lymphoma related to immunosuppression is extensively dealt with in another chapter of this issue. 6. Neuroendocrine skin cancer (Merkel cell carcinoma) In addition to SCC and BCC, other rarer skin cancer, such as Merkel cell carcinoma (MCC) may have an increased frequency [104115]. MCC is a rare, aggressive cutaneous malignancy of neuroendocrine origin, that usually affects the head, neck and extremities of elderly patients. According to the Cincinnati Transplant Tumor Registry, MCC is not so uncommon in transplant recipients. Forty-one cases have been reported by Penn et al. [115], and many other cases, single or in small groups, have been described [104115]. As mentioned above, MCC generally affects elderly people in the general population; on the contrary, in transplant recipients the mean age at diagnosis was 53 years, and the tumour appeared a mean of 91 months after the transplant. The sites involved are mainly the head, neck and upper extremities, as in the general population, although the trunk and lower extremities can also be involved. The importance of immunosuppression is shown by the fact that approximately 50% of these patients had experienced other skin cancers. As observed for other skin cancers, MCC in transplant patients have the tendency to be more aggressive than in the general population: the incidence of lymph node metastases (68%) and mortality (56%) are signicantly high. According to the largest report, the mean follow-up of surviving patients was only 18 months and one third was still suffering of MCC, therefore the incidence of mortality may have further increased [115]. Similar to MCC in the general

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population, therapeutic options include wide surgical excision, lymph node dissection, radiotherapy and chemotherapy. When possible, decrease of immunosuppressive therapy is also recommended. Coexistence of multiple tumours has emerged from a study performed in the United States by the Surveillance, Epidemiology, and End Results programme (SEER): six patients with melanoma and MCC have been reported among transplant recipients [112]. Also this report suggests an increased tumour aggressiveness due to immunosuppression [112].

7. Rare skin cancers Uncommon tumours, such as sarcoma also seem to occur at increased rate in transplant recipients [114]. A case of locally invasive dermatobrosarcoma protuberans (DFSP) has been described in a kidney transplant recipient 4 years after successful renal transplantation [116]. Another case of DFSP has been described at the site of an arteriovenus stula in a renal recipient [117]. A report on a cohort of 642 renal transplant recipients suggests an elevated incidence of cutaneous malignant brous histiocytoma and atypical broxanthoma in renal transplant recipients [118]. Atypical broxanthoma has usually an indolent behaviour, but may be aggressive in transplant recipients, with relapse after excision and destruction of large vessels [119]. The treatment schedule may require multiple excisions and re-excisions and the reduction of the immunosupprerssive therapy [120]. A cutaneous angiosarcoma has been diagnosed in a kidney transplant recipient, with several violaceous nodules surrounded by reddish/purple macule on the scalp [121]. A wide surgical excision was followed by local radiotherapy and a short-term immunotherapy with systemic interleukin-2. The patient remained tumour-free for 15 months after radiotherapy, but eventually died of lung metastases. Other rare tumours of the skin reported in transplant recipients include brosarcoma, liposarcoma, rhabdomyosarcoma [122], sweat gland carcinoma [123], and syringomatous carcinoma [124].

SCC occur in sun exposed area, such as the face, hands and forearms. Therefore, the patients should be offered full informations on the additional risks of sun exposure. This latter should be avoided as much as possible, and strict sunprotective measures have to be taken, i.e. avoiding or at least drastically reducing the time of sun exposure, wearing appropriate clothes, and using a total block sunscreen. Early treatment of pre-cancer lesions should include topical retinoids (tretionin, tazarotene, adapalene), but also topical application of 5-uorouracil, diclofenac, and immune response modier, such as imiquimod [125,126]. In addition, physical measures, such as cryotherapy, lasertherapy and electrodessication may be used. In the experience of Fuente et al. [61], none of the patients suffered from metastases or local relapses of the skin cancer thanks to strict follow up. It should, therefore be proposed that dermatological consultation should be made on a regular basis as an integral part of the long-term follow up schedule for these patients.

Reviewers Friedrich Breier, Dr., Univ.-Doz., Departments of Dermatology, Lainz Municipal Hospital Woldersbergenstr. 1, A-1130, Vienna, Austria. Guenter Burg (M.D.), Professor and Chairman, Departments of Dermatology, University Hospital of Zuerich, CH8091 Zuerich, Switzerland.

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8. Conclusions Since skin cancer in transplant recipients may have uncommon clinical features and a more aggressive course than in non-immunosuppressed subjects, transplant patients should be followed up regularly and strictly by experienced dermatologists in order to identify and treat any skin cancer in an early phase. Additionally, as tumours which are generally rare in the general population have a higher incidence in transplant recipients, total excision or punch biopsy followed by histological analysis of any suspicious lesion are recommended. As discussed above, sun exposure increases immunosuppression in the skin, and most pre-cancer lesions and

G. Gerlini et al. / Critical Reviews in Oncology/Hematology 56 (2005) 127136 [12] Vincent MS, Gumperz JE, Brenner MB. Understanding the function of CD1-restricted T cells. Nat Immunol 2003;4(6):51723. [13] Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R. Circulating brocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol 2004;36(4):598606. [14] Gilmour TK, Wilkinson B, Breit SN, Kossard S. Analysis of dendritic cell populations using a revised histological staging of morphoea. Br J Dermatol 2000;143(6):118392. [15] Chen T, Guo J, Yang M, et al. Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression. Blood 2004;103(2):413 21. [16] Tajima K, Amakawa R, Ito T, Miyaji M, Takebayashi M, Fukuhara S. Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets. Immunology 2003;108(3):321 8. [17] Duperrier K, Farre A, Bienvenu J, et al. Cyclosporin A inhibits dendritic cell maturation promoted by TNF-alpha or LPS but not by double-stranded RNA or CD40L. J Leukoc Biol 2002; 72(5):95361. [18] Dupuy P, Bagot M, Michel L, Descourt B, Dubertret L. Cyclosporin A inhibits the antigen-presenting functions of freshly isolated human Langerhans cells in vitro. J Invest Dermatol 1991;96(4): 40813. [19] Borghi-Cirri MB, Riccardi-Arbi R, Bacci S, et al. Inhibited differentiation of Langerhans cells in the rat epidermis upon systemic treatment with cyclosporin A. Histol Histopathol 2001;16(1): 10712. [20] Peguet-Navarro J. Does cyclosporin A directly affect human Langerhans cell function? J Invest Dermatol 1991;97(5):9534. [21] Bedani PL, Risichella IS, Strumia R, et al. Kaposis sarcoma in renal transplant recipients: pathogenetic relation between the reduced density of Langerhans cells and cyclosporin-A therapy. J Nephrol 1999;12(3):1936. [22] Galvao MM, Sotto MN, Kihara SM, Rivitti EA, Sabbaga E. Lymphocyte subsets and Langerhans cells in sun-protected and sunexposed skin of immunosuppressed renal allograft recipients. J Am Acad Dermatol 1998;38(1):3844. [23] Bergfelt L. Langerhans cells, immunomodulation and skin lesions. A quantitative, morphological and clinical study. Acta Derm Venereol Suppl (Stockh) 1993;180:137. [24] Sontheimer RD, Bergstresser PR, Gailiunas Jr P, Helderman JH, Gilliam JN. Perturbation of epidermal Langerhans cells in immunosuppressed human renal allograft recipients. Transplantation 1984;37(2):16874. [25] Woltman AM, Massacrier C, de Fijter JW, Caux C, van Kooten C. Corticosteroids prevent generation of CD34+-derived dermal dendritic cells but do not inhibit Langerhans cell development. J Immunol 2002;168(12):61818. [26] Matasic R, Dietz AB, Vuk-Pavlovic S. Dexamethasone inhibits dendritic cell maturation by redirecting differentiation of a subset of cells. J Leukoc Biol 1999;66(6):90914. [27] Cumberbatch M, Dearman RJ, Kimber I. Inhibition by dexamethasone of Langerhans cell migration: inuence of epidermal cytokine signals. Immunopharmacology 1999;41(3):23543. [28] Dantal J, Hourmant M, Cantarovich D, et al. Effect of longterm immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 1998;351(9103):6238. [29] Piskin G, Heydendael VM, de Rie MA, Bos JD, Teunissen MB. Cyclosporin A and methotrexate are equally effective in reducing T cell numbers in psoriatic skin lesions but have no consistent effect on IFN-gamma and IL-4 expression in psoriatic skin in situ. Arch Dermatol Res 2003;294(12):55962. [30] Legendre CM, Guttmann RD, Yip GH. Natural killer cell subsets in long-term renal allograft recipients. A phenotypic and functional study. Transplantation 1986;42(4):34752.

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Lancet 1989;1(8630):1249. de Jong-Tieben LM, Berkhout RJ, ter Schegget J, et al. The prevalence of human papillomavirus DNA in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer. Transplantation 2000; 69(1):449. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 2000;14(23):306573. Mendez JC, Paya CV. Kaposis sarcoma and transplantation. Herpes 2000;7(1):1823. Antman K, Chang Y. Kaposis sarcoma. N Engl J Med 2000; 342(14):102738. [72] Boshoff C, Schulz TF, Kennedy MM, et al. Kaposis sarcomaassociated herpesvirus infects endothelial and spindle cells. Nat Med 1995;1(12):12748. [73] Chang Y, Cesarman E, Pessin MS, et al. Identication of herpesvirus-like DNA sequences in AIDS-associated Kaposis sarcoma. Science 1994;266(5192):18659. 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Biographies Gianni Gerlini was born in Florence on 19/02/1967. He graduated in Medicine and Surgery with a rst-class honours degree at the University of Florence Medical School in 1993 (thesis entitled Distribution and possible patogenetic role of IgE binding dermal dendritic cells in atopic dermatitis). Research fellow at the Department of Dermatology, University of Zuerich (Switzerland) in the eld of dendritic cell vaccination in melanoma (19992000). He obtained the specialisation in Dermatology and Venereology cum laude at the Department of Dermatological Sciences, University of Florence in November 1999, with a thesis entitled Specic active immune-therapy with dendritic cell in melanoma. He is currently working in Florence at the Regional Referral Centre for Surgical and Immunologic Therapy of Melanoma and in the Laboratory of Skin Immunology and Cell Cultures at the Department of Dermatological Sciences of Florence. Paolo Romagnoli graduated M.D. in 1974 and is full professor of Histology in the Medical Faculty of the University of Florence (Italy) since 1986. He has been research fellow of the Alexander von Humboldt Foundation in Hannover, Munich and Bonn (Germany), and visiting scientist at the Schepens Eye Research Institute in Boston (Massachusetts). His main research topics have been the behaviour of the Golgi apparatus and plasma membrane along the secretory cycle and the differentiation and intercellular relationships of cells of the skin immune system and of keratinocytes in

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physiology and pathology; he has authored 134 scientic papers (70 in indexed journals) until now. Nicola Pimpinelli was born in Florence on 24 may, 1957. Graduated M.D. in 1983 and Ph.D. in 1986. Specialist in Dermatology and Venreology since 1986. Associate professor of Dermatology in the Medical Faculty of the Uni-

versity of Florence (Italy) since 2001. His main clinical and research interests are in dermatoncology (current president of the International Society for Cutaneous Lymphomas; vice-coordinator of the Skin Cancer group of the Oncology Department in Florence) and skin immunology. He has authored more than 119 scientic papers (71 in indexed journals) to date.