J Nephrol DOI 10.1007/s40620-014-0098-4

REVIEW

Skin cancer in kidney transplant recipients Claudio Ponticelli • David Cucchiari PierLuca Bencini

•

Received: 20 February 2014 / Accepted: 4 April 2014 Ó Italian Society of Nephrology 2014

Abstract Morbidity and mortality due to skin cancer is excessively high in renal transplant recipients compared to the general population. This epidemiologic difference is mainly due to the severe immunosuppression that enhances ultraviolet-induced DNA damage and leads to reactivation of potential oncogenic viruses. The most common skin cancer in transplant recipients is squamous cell carcinoma followed by basal cell carcinoma, while in the general population this ratio is reversed. Melanoma and cutaneous lymphoma are relatively rare although they occur more frequently in transplant patients than in the general population. Notably some tumors, such as Kaposi’s sarcoma, are seldom encountered in the general population while they are frequently observed in transplant recipients. Local recurrences and visceral spreading are not so uncommon and pose a major issue for quality of life and overall prognosis of these patients. Timely diagnosis is essential and may be challenging, since the accuracy of clinical diagnosis is modest; thus skin biopsy is an essential tool for appropriate management. In this review, we describe the most common types of skin cancer in renal transplant recipients, with a focus on pathogenic issues that account

C. Ponticelli
D. Cucchiari Division of Nephrology, Istituto Scientifico Humanitas, Rozzano (Milano), Italy C. Ponticelli (&) Humanitas Hospital Rozzano, Via Manzoni 56, 20089 Rozzano (Milano), Italy e-mail: [email protected] P. Bencini I.C.L.I.D., Istituto di Chirurgia e Laserchirurgia In Dermatologia, Milan, Italy

for the different epidemiology and clinical expression of these neoplasms in this population. Keywords Basal cell carcinoma
Cutaneous lymphoma
Skin cancer
Squamous cell carcinoma
Transplant cancer
Transplant complications

Introduction Skin cancer represents a big issue for renal transplant recipients, who have an incidence up to 100 times higher than that in the general population, along with an increased morbidity and mortality [1]. These tumors are mainly related to the prolonged use of immunosuppressive drugs, that enhances the oncogenic properties of other risk factors, especially exposure to sunlight and viral infections [2]. Other risk factors include a past medical history of any previous skin cancer, a fair skin complexion or phototype, smoking and male sex (Table 1) [3]. Exceptionally, skin cancer may also be transmitted from donor to recipient [4]. Due to the delicate clinical context, in which immunosuppression plays a pivotal role, these tumors have a different epidemiology and pathogenesis compared to that in the general population. Indeed, the most common skin cancer in transplant recipients is squamous cell carcinoma (SCC) followed by basal cell carcinoma (BCC), while in the general population this ratio is reversed: this may reflect different pathogenic mechanisms in the development of these tumors in kidney transplant recipients. Moreover clinical presentation and treatment choices are quite heterogeneous and constitute a considerable challenge for the transplant physician. Notably, the accuracy of clinical diagnosis of suspected malignant skin lesions in renal transplant recipients is modest, so histopathological

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diagnosis is essential for diagnostic workup and for assessing prognosis. The aim of this review is to systemically describe the most common forms of skin cancers that develop in renal transplant recipients, with a focus on pathogenic issues, pathological features, clinical presentation and treatment choices.

Squamous cell carcinoma (SCC) and actin keratosis (AK) Squamous cell carcinoma and its precursor AK arise from the keratinocytes of the epidermis, which are the surveillance sensors of the skin through their expression of multiple pattern recognition receptors. Upon challenge, keratinocytes elaborate antimicrobial peptides, cytokines and chemokines that activate and recruit patrolling leukocytes. Ultraviolet (UV) radiations are the main culprit of keratinocytes’ oncogenic transformation. In animal models, it has been demonstrated that UVB is more effective to induce skin cancer than UVA [5]. The mechanisms that protect the skin from UV radiation are melanin synthesis and active DNA repair mechanisms: this explains why low pigmentation in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The importance of sunlight exposure in SCC and AK development is also highlighted by the different incidence across countries. In the Australian white population, whose sun exposure is high, there is a linear increase over time in the incidence of skin cancer, reaching 75 % at 30 years post-transplantation [6]. In less sunny areas, such as the Netherlands, incidence is around 40 % at 20 years, which is, however, 250 times higher than that in the general Dutch population [7]. In SCC the UVB may cause genomic instability in keratinocytes by inactivating p53, a protein

Table 1 Known risk factors for the development of skin malignancies in organ-transplanted patients Immunosuppression

Intensity, duration and type of immunosuppression are linked to different risks of developing skin cancer

Cumulative UV radiation and lower latitudes

Sunlight represents the most known carcinogen

Age at the time of transplantation

Older transplanted patients have a significantly increased risk

Smoking

Smoking is a known risk factor in both the general and transplanted populations

Male sex

Males are genetically predisposed to develop skin cancer

Caucasian race

A fair phototype suffers more from UV radiations

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encoded by the TP53 gene that is crucial to maintain genomic stability by repairing damaged DNA, holding cell cycle and eventually leading to apoptosis if the damage is irreparable. p53 mutations have been found by several studies, but it is still uncertain whether p53 loss occurs prior to or after tumor invasion [8]. Human papilloma virus (HPV) appears to act as co-carcinogen. In transplant recipients SCC often coexists with viral warts caused by a wide range of HPV subtypes. The E6 oncoprotein derived from HPV binds to and induces the degradation of p53 [9], probably by recruiting ubiquitin ligase E6AP that promotes its ubiquitination and subsequent proteasomal degradation [10]. Increased expression of p53 is an immunohistochemical marker of proliferation, and SCCs of transplanted patients have a greater expression of it than their counterparts in the general population. This may account for the increased aggressiveness of these tumors in this cohort [11]. Sunlight may also have an immunosuppressant effect by impairing immune surveillance of Langerhans’ cells [12]. In kidney transplant, the risk of SCC is exponentially increased since immunosuppression impairs tumor immune surveillance and exposes recipients to potentially oncogenic viral infections. Moreover, some immunosuppressive drugs, such as calcineurin inhibitors (CNI), may promote oncogenesis in an independent way from their effect on the immune system. It has been demonstrated that intact calcineurin/nuclear factor of activated T cell (NFAT) signaling is critically required for p53 and senescence-associated mechanisms that protect against SCC development. Thus, calcineurin/NFAT inhibition caused by CNI can increase the tumorigenic potential by counteracting p53-dependent cancer cell senescence [13]. Increased transforming growth factor (TGF)-beta production may also aid cancer initiation and progression. In an experimental study, tacrolimus had a dose-dependent effect on tumor progression and TGF-beta expression, suggesting that tacrolimus-induced TGF-beta overexpression may be a pathogenic mechanism in tumor progression [14]. In another murine model, treatment with monoclonal antibodies directed at TGF-beta prevented the cyclosporine-induced increase in the number of metastases [15]. Azathioprine may also be considered carcinogenetic as it impairs the DNA mismatch repair proteins [16]. In contrast, inhibitors of mammalian target of rapamycin (mTOR) may interfere with the proliferation of cancer cells. This is accomplished both by interrupting the cascade of kinases implied in cell proliferation and by inhibiting tumor angiogenesis through interference with the vascular endothelial growth factor (VEGF) [17]. A meta-analysis on the incidence of cancer in more than 30,000 de novo renal transplant recipients showed that the relative risk of skin and solid cancer in patients receiving mTOR inhibitors, alone or in combination with CNI, was significantly lower

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in comparison with patients who did not receive them [18]. Apart from immunosuppressive drugs, the development of SCC may also be favored by long-term treatment with the antifungal drug voriconazole [19]. Both SCC and AK develop on sunlight damaged skin— such as backs of the hands and forearms, or the upper part of the face—but may also develop in the lower lip, particularly in smokers. Actin keratosis, characterized by thick, scaly, or crusty patches of skin, often precedes the development of SCC but can also lead to formation of basal cell carcinoma and even melanoma. The fact that these tumors arise in sun-exposed areas and that recurrences are frequent near excision areas has led to the development of the ‘‘skin field cancerization’’ concept. This means that in sun-exposed areas a network of dysplastic cells develops, due to the long-term exposure to the same carcinogen, i.e. UV radiations. On a molecular basis, these cells usually share a monoclonal origin and have a radial expansion [20]. This concept has already been observed in other clinical contexts, e.g. oral cancer, where multiple tumors arise from the oral mucosa that is exposed to the diffuse action of a carcinogen, in this case smoke [21]. These cancerization fields represent a fertile ground for carcinogenesis, with the development of multiple synchronous or metachronous tumors, when additional genetic alterations occur. Euvrard et al. [22] reported that 88 % of kidney transplant patients diagnosed with a first SCC developed multiple skin cancers in the following 5 years. The clinical appearance of SCC is variable. Initially the lesions are asymptomatic and may appear as pink macules or papules that may rapidly grow to persistent firm or scaly papules or indurated red nodules, which may eventually bleed. These lesions tend to rapidly extend and may also develop in internal organs. The presence of multiple epidermal scaling or hyperkeratotic small crusts, nodules, patches or papules that rapidly grow is highly suspicious for a diagnosis of SCC, particularly if the lesions are indurated. A useful clue to clinical diagnosis of AK are a well-preserved symmetry of the lesions and no infiltration at the base, features that are rare in SCC [23]. However, in many cases, clinical examination cannot easily differentiate AK from SCC. To have a correct diagnosis every keratotic lesion should undergo histological analysis. In SCC there are particular cytological or tissue architectural characteristics of squamous cell differentiation, such as the presence of keratin, tonofilament bundles, or desmosomes, which are specialized structures involved in cell-to-cell adhesion. On the other hand, identifying the multiple pre-neoplastic changes in the field surrounding the skin lesion may be difficult with standard histology. Today, non-invasive techniques such as optical confocal microscopy and photodiagnosis with

protoporphyrin IX-emitted fluorescence are often applied in order to identify pre-clinical malignant lesions in the field [24].

Basal cell carcinoma (BCC) This cancer is composed of pluripotential cells that form continuously during life and have the potential to form hair, and sebaceous and apocrine glands. As with SCC, sunlight exposure represents the most important risk factor for BCC development. Indeed, gene mutations usually consist in CT and CCTT transitions at dipyrimidine sequences, a signature marker of UV radiation exposure. Several genes are involved in BCC carcinogenesis, such as PTCH, SMOH and TP53 [25]. Notably, some mutations of p53 are specific only for skin cancer, supporting the hypothesis that UV may act on the p53 gene in a carcinogenic-specific fashion [26]. Accumulation and translocation to the nucleus of beta catenin, which is a powerful stimulus for cell proliferation, is another pathogenic mechanism observed in some BCC that is probably mediated by dysregulation of the Wnt pathway [27]. BCC may arise in skin exposed to sunlight, ionizing radiations or trauma. Large numbers of nevi, freckles and solar elastosis increase the risk of its development. In renal transplant recipients BCC develops in a mean of 6–7 years after transplantation. The early tumors are small, translucent and pearly, with thin epidermis and visible telangiectasia. With time, as tumor grows, ulceration can occur and may re-epithelialize and break down several times before becoming permanent. Several variants can be detected at histology, the most common being mixed subtypes (39 %), followed by nodular (21 %), superficial (17 %), and micronodular (14 %) [28]. Uncommon variants, including basosquamous, keratotic, granular-cell, adamantinoid, clear-cell, and basal-cell carcinoma with matrical differentiation, have also been described. Aggressive histologic variants include the micronodular, infiltrative, basosquamous, morpheaform and mixed subtypes. Nodular and superficial subtypes generally have a less aggressive clinical course. Apart from the histological characteristics, risk factors for spread include a tumor diameter [2 cm, location on the central part of the face or ears, long-standing duration, incomplete excision, and perineural or perivascular involvement [29].

Prevention of nonmelanoma skin carcinomas Due to the high risk of developing skin cancer, preventive measures should be recommended in renal transplant

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recipients. The primary carcinogen for the genesis of skin cancers is UV light. Therefore, minimizing the exposure to sun and avoiding tanning beds are mandatory to prevent skin cancer in transplant recipients [30]. Patients should cover up with long sleeved shirts and pants, wear a hat and sunglasses when outdoors. The so-called broad-spectrum sunscreen may protect against UVA as well as UVB radiation. Frequent self-examination of the skin is recommended. Whenever possible, a picture of any cutaneous lesion, even with a smartphone, should be taken. This may be very helpful for early detection and monitoring of skin tumors. Moreover, transplant caretakers should perform a baseline skin examination at the time of transplant and should organize strict follow-up dermatologic assessments. In the recent past, despite education, transplant patients showed poor compliance with the advice given for protecting their skin from the sun [31]. More recently, however, there has been a significant improvement in compliance, at least in some countries [32].

Treatment of nonmelanoma skin carcinomas Early skin biopsy and management of premalignant and malignant lesions is essential for treating these patients successfully. Considering how these lesions appear on cancerization fields, it is mandatory that treatment is performed for the entire field and not only for the lesion itself. After initial treatment, frequent monitoring is needed in transplant recipients for timely detection both of possible recurrences and of development of de novo malignancies. Local treatments have been used depending on the adverse events and cosmetic effects. Topical 5-fluorouracil and imiquimod are efficacious and safe for the treatment of superficial BCC but not for more severe BCC subtypes or SCC. To be successful they have to be self-administered twice daily for several weeks. Topical diclofenac and ingenol mebutate have also been used, but there are insufficient data to validate their therapeutic index [33]. Topical photodynamic therapy is a therapeutic option effective for treating field cancerization and non-melanocytic skin cancers such as AK, early SCC, Bowen’s disease and superficial BCC. It implies the administration of a photosensitizing drug and its subsequent activation by light at wavelengths matching the absorption spectrum of the photosensitizer. Recently, a new treatment combining photodynamic therapy with needling has been successfully tried in kidney transplant recipients in order to treat the entire cancerization field and to prevent recurrences [34]. However, all these treatments do not constitute a first-line therapy for BCC or SCC, since they are not as effective as surgery. Prompt excision or Mohs micrographic surgery is the standard of care for primary uncomplicated SCC and

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BCC. A systematic review of 118 observational studies estimated that the risk of SCC recurrence was lowest after cryotherapy (0.8 %) and curettage and electrodessication (1.7 %) but most cancers were small and at low risk. After Mohs micrographic surgery, the pooled estimate of local recurrence during variable follow-up periods was 3.0 %, which was non-significantly lower than the pooled average local recurrence of 5.4 % after standard surgical excision and 6.4 % after external radiotherapy. Of note, the recurrence was significantly higher (26 %) after photodynamic therapy [35]. Retinoids are metabolites of vitamin A that have been proposed for chemoprevention of nonmelanoma skin cancer. Topical retinoids—such as tretinoin, tazarotene or adapalene–have been used to treat AK and also BCC and SCC, with conflicting results. A small number of randomized controlled trials reported that acitretin may have a role in the management of solid organ transplant recipients with skin cancers [36]. Tolerability of the drug is a major factor limiting its use. More common adverse events include unusual fatigue, headache, nausea and vomiting. Of main concern is the possible development of liver dysfunction, pseudotumor cerebri and/or depression [36]. In view of the anti-neoplastic activity of mTOR inhibitors, replacing calcineurin inhibitors with an mTOR inhibitor is a promising approach for preventing recurrence of skin cancer in transplant recipients, especially in SCC where an increased expression of mTOR has been noted [37]. In a controlled trial, survival time free of cutaneous SCC was significantly longer in transplant recipients who converted to sirolimus than in those who continued immunosuppression with calcineurin inhibitors. Overall, new SCC developed in 14 patients (22 %) of the sirolimus group and in 22 (39 %) of the calcineurin-inhibitor group, with a relative risk in the sirolimus group of 0.56. However, the benefit was restricted to renal transplant patients with only one previous invasive SCC, and there were more serious adverse events in the sirolimus group, particularly when conversion was rapid [38]. Similarly, a recent study showed that in renal transplant recipients with biopsy-confirmed SCC, conversion to sirolimus-based immunosuppression was effective in terms of SCC-free survival at 1 year only in patients with one tumor at inclusion. However, at 2 years there was no significant difference in cancer-free survival between patients who converted to sirolimus and those continuing the original immunosuppressive regimen [39]. For patients with in-transit or metastatic SCC, adjuvant radiation, chemotherapy, and staging by sentinel lymph node dissection may be employed. If these treatments fail, epidermal growth factor receptor (EGFR) inhibition by the monoclonal antibody cetuximab associated with tyrosine kinase or insulin-like receptor inhibitors may represent an alternative therapeutic option [40].

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Melanoma The prevalence of melanoma in renal transplant recipients is higher than in the sex- and age-matched general population [41]. Although few cases of melanoma transmitted by the donor have been reported [42], most cases are related to UV light exposure and immunosuppressive therapy. Immunosuppression plays a pivotal role in melanocytes proliferation, although little is known about pathogenic mechanisms of melanoma development in transplant recipients. As in other types of skin cancer, also in melanoma overexpression of p53 has been reported, probably related to mutations of the TP53 gene caused by UV or other additional damage [43]. UV may also induce mutations of genes that regulate two major signaling pathways, the RAS/RAF/MEK/ERK (i.e. mitogen-activated protein kinase, MAPK) and the PI3 K/PTEN/AKT [44, 45]. The genes of the rapidly accelerated fibrosarcoma (RAF) family, such as BRAF, encode kinases regulated by genes of RAS, such as KRAS, and mediate cellular responses. Mutations of BRAF have been proposed to contribute to melanoma development. Increased activity of the MAPK pathway prevents apoptosis and induces cell cycle progression. PTEN is the physiological regulator of the activity of AKT/PI3 k (phosphatidyl-inositol-3-kinase) family. A deficient expression of PTEN results in Akt activation with phosphorylation and inactivation of RAF. This decrease in downstream MEK and ERK activation may contribute to anti-apoptosis, abnormal proliferation, angiogenesis, and melanoma development and progression. However, transplant recipients with melanoma had a lower frequency of BRAF mutations in comparison with nonimmuno suppressed patients. It has been postulated that in transplant patients immunosuppressive drugs might induce additional mutations, or activate alternative signaling pathways, which compensates for the lower rate of activating BRAF mutations in tumors developing in these patients [46]. This view may be supported by the recent descriptions of mutations in the promoter of the telomerase reverse transcriptase gene (TERT) in patients with melanoma [47, 48]. A physician who observes a pigmented lesion rapidly changing size, color, margins and overall symmetry should always suspect melanoma. The diagnosis requires experience, as early stages may look identical to harmless moles or not have any color at all. The mnemonic ABCDE is useful for the practitioner: asymmetry, irregular borders, multiple colors, diameter [6 mm, and enlarging or evolving lesions. However, the diagnosis should always be confirmed by a skin biopsy. The prognosis depends on the timeline of diagnosis. Le Mire et al. [49] noted that Breslow thickness of melanomas in renal transplant recipients

is usually \1 mm and this may be explained by a faster recognition of these lesions. Treatment is based on wide surgical excision of the tumor and chemotherapy. Good results in unresectable or metastatic melanoma have been reported with vemurafenib, a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase [50, 51]. Dacarbazine has also been used for the treatment of metastatic melanoma for many years. Single-agent chemotherapy is well tolerated but is associated with a very low rate of response in metastatic disease. On the other hand, a combination of chemotherapy and biochemotherapy may improve objective response rates but does not extend survival and is associated with greater toxicity. Immunotherapy with high-dose interleukin (IL)-2 is associated with a durable response in a small subset of patients, but it is still unclear which patients would benefit more from this treatment [52]. Recently, other new promising drugs have been used in patients with metastatic disease. Ipilimumab is a monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), an inhibitor of the co-stimulation pathway necessary for T cell activation. Ipilimumab improved overall survival in metastatic melanoma but it was loaded by a number of adverse events including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis [53]. Dabrafenib, a reversible inhibitor of mutant BRAF kinase, improved response rates and median progression-free survival in patients with V600E BRAFmutant metastatic melanoma. The drug is well tolerated and is effective when given as a monotherapy; however, resistance developed in most patients [54] and other drugs are currently under investigation to overcome this issue. For example, trametinib is an oral agent that targets the MEK kinase, a member of the MAPK signaling cascade that resulted to be activated in melanomas which become resistant to dabrafenib [54]. It improves rates of progression-free and overall survival among patients with metastatic disease with a BRAF V600E or V600 K mutation in comparison with chemotherapy [55]. Notably, combining BRAF and MEK inhibition with dabrafenib and trametinib resulted valuable in improving progression-free survival in patients with metastatic disease [56] and the U.S. Food and Drug Administration recently approved the use of this combination therapy for treating these patients.

Primary cutaneous lymphoma Post-transplant lymphoproliferative disorders (PTLD) are frequent after transplantation. They can have a bimodal presentation. PTLD developing within the first year after transplantation usually affect children, while in adults they

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usually develop years after transplantation. Most PTLD are of B cell origin and associated with Epstein-Barr virus (EBV) infection. On the other hand, primary cutaneous lymphomas are rare and derive from cells of T origin. There are two types of cutaneous T cell lymphoma, mycosis fungoides and Sezary syndrome. Mycosis fungoides is a slow-growing condition that usually affects only the skin. Over time, in a small number of people, it may spread to other parts of the body. Treatments can often keep mycosis fungoides under control for many years, and in the early stage this type of lymphoma is relatively benign. Sezary syndrome is an advanced type of T cell lymphoma. Large areas of the skin are affected with redness and scaling. The skin can be very itchy and may look thicker in parts. The lymph nodes are swollen and there are abnormal lymphocytes in the blood. In the advanced phase there is generalized erythrodermia, leukemia and hepatosplenomegaly [57, 58]. The diagnosis of cutaneous PTLD can be difficult. In the early phase the lesions consist in pruritic and scaling erythema, which may be confounded with eczema or psoriasis. With time, rash-like patches and infiltrative plaques appear. A skin biopsy is needed to confirm the clinical suspicion. Histology shows a polymorphous inflammatory infiltrate in the dermis that contains a small number of frankly atypical lymphoid cells. Most reports in the literature discussed anecdotal cases. In a Turkish multicenter study 35 cases were collected. The median interval between transplantation and diagnosis was 85 months. About 70 % were classified as primary cutaneous T cell lymphoma and 30 % as B cell PTLD often associated with EBV. Half of the cases presented with a picture of mycosis fungoides. Sixteen (45.7 %) patients died after a median follow-up of 19.5 months, the prognosis being worse in patients with T cell lymphoma [59]. There is little information about treatment of Mycosis fungoides and Sezary syndrome in renal transplant recipients. In the Turkish study, most patients reduced or discontinued the immunosuppressive treatment, which is a logical first-step approach; however, the following treatment choices were heterogeneous and the authors could not deduce which one was most effective [59]. But it seems reasonable to start topical therapy in patients with a limited and indolent disease and to use systemic treatments when lymph nodes or visceral spreading occur. Some indications can be drawn from the experience in non-transplant patients. Topical treatment with steroids, nitrogen mustard or bischloroethylnitrosourea may be effective in the early stages of mycosis fungoides. Ultraviolet B or ultraviolet A treatment, enhanced with psoralen, or total body electron beam radiation are used in the patch or plaque phase. In patients with advanced mycosis fungoides or Sezary syndrome, photopheresis, interferon alpha, bexartotene and

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lenalinomide have been attempted. Emerging agents include: the histone deacetylase inhibitors; a novel antifolate agent, pralatrexate; the proteasome inhibitor, bortezomib; the purine nucleoside phosphorylase inhibitor, forodesine; and the anti-CD52 monoclonal antibody, alemtuzumab [60, 61]. In a systematic review of the randomized controlled trials on different treatments of mycosis fungoides, the Cochrane group concluded that owing to the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution [62].

Kaposi’s sarcoma (KS) KS is a multifocal, vascular, malignant tumor that accounts for more than 5 % of malignancies in transplant recipients. KS occurs endemically in tropical Africa, in some Mediterranean areas, among Jews and Arabs, while it occurs sporadically in Europe and North America and is rare in India. The incidence of KS is 400–500 times greater in renal transplant patients compared to controls of the same ethnic origin [63]. In transplant recipients, the male to female ratio is 2.8:1, far less than the 10–15:1 ratio seen in the general population. KS is associated with the presence of human herpes virus-8 (HHV-8) also called Kaposi sarcoma-associated herpes virus (KSHV). HHV8 has been regularly found by polymerase chain reaction in all forms of KS (classic KS, AIDS-KS, endemic KS and organ transplant KS), in certain types of Castleman’s disease, in primary effusion lymphoma and in EBV-negative PTLD [64]. HHV-8 genome contains potential oncogens able to regulate cell proliferation and apoptosis. Several encoded genes, e.g. bcl-2, IL-6, cyclin D, G-protein-coupled receptor, and interferon regulatory factor, provide key functions of cellular proliferation and survival, resulting in a hyperplastic polyclonal lesion with predominant spindle cells derived from lymphoid endothelia. Emerging evidence now points to a single gene, ORF74, encoding for the viral G protein-coupled receptor (vGPCR), as essential for KS development. This viral receptor, which is expressed in only a fraction of KS cells, induces tumorigenesis by promoting cell proliferation, enhancing cell survival, modulating cell migration, stimulating angiogenesis, and recruiting inflammatory cells [65]. HHV8 can escape antigen presentation to cytotoxic T lymphocytes [66], can modulate pro-proliferative pathways such as the PI3 k family of kinases, can inhibit pro-apoptotic signals and interfere with innate immunity [67]. These mechanisms

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allow prolonged survival of the infected cell following primary infection, and during viral latency. Although infection with HHV8 is necessary for the development of Kaposi sarcoma, it is not sufficient. Both HIV coinfection and immunosuppression significantly increase the risk of KSHV-associated disease [68]. After transplantation, HHV8 can reactivate quickly, the risk being higher in patients with strong immunosuppression and in the endemic areas. Increased HHV8 DNA levels in peripheral blood lymphocytes are associated with the progression of KS [69]. HHV8 can be also transmitted through renal allografts, representing a potential risk factor for transplantation-associated KS. However, reactivation of the virus remains the main factor responsible for the development of post-transplant KS [70]. Kaposi’s sarcoma generally occurs between 12 and 30 months after transplantation. However, the more aggressive the immunosuppression, the earlier the development of the tumor is [71]. In the skin, KS lesions have a dark blue or purplish color, being initially almost macular and progressively more tumid. These lesions may be firm or compressible, and may even appear initially as a dusky stain. Lesions usually begin on the extremities, most commonly on the feet, with multifocal and asymptomatic development. The rate of spread is remarkably variable but lesions become nodular and with advanced disease they may become confluent with large plaques and remarkable spreading, particularly in the legs [72]. Lymphatic involvement is not unusual and KS may present as lymphadenopathy. In its more severe manifestations the lesions may also diffuse to visceral mucosa and involve trachea, lungs, and the gastrointestinal tract. Extensive parenchymal or pleural involvement of the lung may result as lifethreatening. About 60 % of patients have a nonvisceral KS confined to the skin, conjunctiva, or oropharyngolaryngeal mucosa. Only 10 % of patients do not have skin disease. The diagnosis of KS can be suspected in the presence of the above reported skin or mucosal lesions. However, it should be confirmed by histology. A wide spectrum of histological variants of KS have been reported. Although there is no officially accepted system for staging KS, the typical cutaneous KS progresses from patch, to plaque and finally nodular stages [73]. The patch stage is characterized by a subtle vasoformation process that may protrude into the lumen of ectasic neoplastic channels. This early lesion may be confused with an inflammatory dermatosis. In the plaque stage there are diffuse dermal vascular and cellular infiltrates, which may extend into the underlying subcutaneous adipose tissue. The infiltrating cells tend to be more spindled and arranged in short fascicles, which may cut in cross-section showing a sieve-like appearance. Mitotic figures are sparse and there is no significant nuclear or cytological pleomorphism.

Intra- and extracellular hyaline globules are often seen. The histologic differential diagnosis includes tufted angioma, targetoid hemosiderotic hemangioma, microvenular hemangioma and acroangiodermatitis. Nodular KS is characterized by dermal expansion with variable cellular proliferation of neoplastic spindled cells arranged in fascicles. Erythrocytes are contained within slit-like channels between the individual spindled cells. Although careful inspection may reveal occasional mitoses, the lesional cells are relatively monomorphic. The periphery of some nodular KS lesions may show more dilated vascular spaces, imparting a pattern that is strikingly reminiscent of a cavernous hemangioma. Large cutaneous nodules may frequently undergo ulceration. Superficial shave biopsies of such lesions may be diagnostically challenging to the pathologist, as most of the specimen may contain only an inflammatory exudate with underlying granulation tissue which may be misinterpreted as a pyogenic granuloma [73, 74]. A number of other variants have been recently described, demonstrating that KS can develop into lesions of varying morphologic appearance. It is important to be able recognize these variants in order to avoid potential misdiagnosis and improper management of afflicted patients. Although the KS tumor may remain localized to the skin, widespread dissemination with mucocutaneous or visceral organ involvement is common in immuno suppressed patients [75]. The prognosis depends on timely diagnosis and treatment. Early diagnosis and appropriate reduction of immunosuppressive therapy may obtain a resolution of disease and rescue of the allograft. A late diagnosis with visceral involvement has usually a poor prognosis.

Treatment of KS Different therapeutic approaches may be employed in treating renal transplant recipients with KS. In the presence of initial cutaneous lesions, imiquimod, a topically applied immunomodulator without significant systemic absorption, may represent a promising treatment for early cutaneous KS [76]. Alitretinoin gel and radiotherapy are also effective in treating cutaneous KS [77]. More recently, electrochemical therapy has been proposed as a first-line treatment for treatment of cutaneous KS [78]. However, the most important measure to take is the reduction or withdrawal of immunosuppression [79, 80]. This measure may allow the immune system to recover sufficiently to reduce viral replication to a level that coincides with clinical remission of the KS lesions. As a consequence of this strategy, some patients may develop an irreversible graft rejection, while others may maintain stable graft function

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with a mild immunosuppression or with small doses of prednisone alone. The risk of rejection may be minimized by switching treatment from calcineurin inhibitors to an mTOR inhibitor. Some investigators have documented the possibility of complete reversal of KS in renal transplant patients switched from cyclosporine to sirolimus [81, 82] or everolimus [83]. The improvement of lesions may be probably attributed to the anti-angiogenic effect of these drugs that impairs endothelial cell proliferation mediated by VEGF. In fact, VEGF activates a cascade of kinases mediated by mTOR, a complex of serine-threonine kinases and other proteins, that is inhibited by sirolimus and its derivate, everolimus. In patients with visceral involvement or rapidly progressive course, a number of treatments have been tried, including polyethylene glycol (PEG)-liposomal doxorubicin, vincristine, cyclophosphamide, vinblastine, bleomycin, thalidomide, actinomycin, gemcitabine, bortezomib and lenalinomide. When required, treatment options can also include excision or radiotherapy of single lesions.

Merkel cell carcinoma (MCC) Merkel cell carcinoma is a rare but highly aggressive neuroendocrine tumor of the skin with a propensity for distant metastatic spread. MCC most commonly affects elderly Caucasians, its incidence being approximately 3 cases per million per year. The mortality rate ranges between 36 and 46 % at 5 years, considerably higher than melanoma [84, 85]. In about 80 % of cases MCC is associated with Merkel cell polyomavirus [86]. These viruses are able to evade the immune system and produce oncoproteins that play a critical role in tumor progression [87]. Usually the tumor manifests as a solitary painless erythematous nodule, sometimes ulcerated, located on the head or neck. A little more than half of the patients develop local lymph node metastases while just under half develop distant metastases. The incidence of MCC is greatly increased among subjects who have received a kidney transplant and in this population the clinical course is particularly aggressive, frequently resulting in a fatal outcome [88–90]. Treatment consists of surgical excision with 2-cm margins or Mohs surgery. Lymphadenectomy with radiotherapy and chemotherapy is recommended. Temporary regression of MCC metastases after cessation of cyclosporine has been reported [91]. Acknowledgments All the authors participated in the preparation of the manuscript. None of them reported any conflict of interest. Conflict of interest

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