Although the incidence of melanoma, Merkel cell carcinoma, and Kaposi's sarcoma is elevated in solid organ transplant recipients, squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) account for 95% of the cutaneous malignancies in this population (Carucci, 2005). The incidence of nonmelanoma skin cancer (NMSC) in organ transplant recipients increases over time, affecting 5% of patients in the United States at 2 years, 10% at 10 years, and 40% at 20 years posttransplantation. By comparison, the 20-year posttransplantation incidence is 60% in Western Europe and reaches 82% in Australia (Ulrich, Kanitakis, Stockfleth, & Euvrard, 2008). It is also important to appreciate that patients who receive heart or lung grafts tend to require higher doses of immunosuppressive medications, making them even more prone to cancer (Guba, Graeb, Jauch, & Geissler, 2004). Jensen et al. (1999) cited a 2.9 times greater incidence of SCC in heart transplant recipients compared with kidney transplant recipients because of increased requirement for immunosuppression to avoid rejection of heart transplants.

Cumulative ultraviolet radiation exposure contributes to the incidence of skin cancer. Age has also been identified as a risk factor with a 12-fold higher rate of skin cancer found in cardiac and kidney transplant patients whose grafts were received after the age of 55 years compared with grafts received before the age of 34 years. Duration of treatment with immunosuppressive medications seems to adversely affect the number of malignant lesions per patient (Ulrich et al., 2008).

There are also some clinical features of these skin cancers specific to the transplant population (Berg & Otley, 2002). The SCCs tend to be more aggressive. They may grow rapidly, and there is local recurrence in 13.4% of patients. The SCCs metastasize in 5% to 8% of transplant patients. In-transit (local cutaneous) metastases also occur more commonly in organ transplant recipients with an elevated (30%) mortality risk when compared with immunocompetent patients (Carucci et al., 2004). In some cases, skin cancer in these patients can be devastating in terms of quality of life, lost productivity, and threatened mortality.

"Catastrophic carcinogenesis" is a descriptive term that characterizes a situation in which the development of cancerous or precancerous lesions spins out of control. Catastrophic carcinogenesis has been defined by Berg and Otley (2002) as 10 or more NMSCs in a single year; evidence of in-transit, nodal, or distant metastases; or transplant patients with hundreds of actinic keratoses.

In-transit metastatic SCC lesions are usually nondescript gray to flesh-colored subcutaneous papules that are not contiguous with the primary lesion. They are likely to represent spread along lymphatic vessels and nerves, are a poor prognostic indicator, and present a diagnostic challenge. Distant metastases from skin cancers in organ transplant recipients is associated with a 29% relapse rate at 1 year and a disease-specific survival rate of 56% at 3 years (Carucci, 2005).

The NMSCs in this population are often associated with other types of skin tumors that may mimic invasive SCCs, such as actinic keratoses, Bowen's disease, keratoacanthomas, and multiple keratotic lesions. These keratotic lesions have been defined as warty or verrucose lesions that may be actinic keratoses, seborrheic keratoses, warts, flat warts, or papillomas, which are difficult to diagnose clinically (Ulrich et al., 2008). All of these lesions present as extensive areas of actinic damage with lesions of epidermal hyperplasia and may include multiple NMSCs. This is known as "field cancerization" (Figure 1).

FIGURE 1 "Field cancerization" left hand.

The first SCC in an organ transplant recipient patient should be considered a sentinel event. Euvrard et al. (2006) determined that the first SCC is predictive of subsequent multiple NMSCs within the 5 years after the first SCC. Cardiac transplant patients and renal transplant recipients developed subsequent skin cancers at a rate of 100% and 88%, respectively, with a higher number of tumors per patient in the kidney transplant population. The transplant physician may need to consider modifying the patient's immunosuppressive regimen as a result of this development.

The International Transplant Skin Cancer Collaborative (ITSCC, 2009) provides a list of immunosuppressive medications currently used to prevent the rejection of the grafted organ in solid organ transplant recipients, which includes prednisone, cyclosporine, mycophenolate mofetil (MMF), tacrolimus (TAC), azathioprine (AZA), rapamycin, daclizumab, and muromonab. Each of these agents has many possible side effects. The primary potential dermatologic adverse effect is the development of cutaneous malignancies. A brief review of the immunosuppressant medications most frequently used by solid organ transplant recipients follows, with a focus on potential adverse cutaneous effects.

Corticosteroids

Calcineurin inhibitors include cyclosporine and TAC. Cyclosporine A (CsA) has had a major impact on the survival of solid organ transplant patients; however, it is correlated with cancers of unusually aggressive phenotypes. Several reports cited by Guba et al. (2004) have suggested that CsA promotes tumor formation in transplant recipients. Patients on TAC (oral and IV infusion) also show a similar elevation in tumor incidence. Because of an aberrant production of cytokines that regulate processes promoting tumor growth, metastasis, and angiogenesis, calcineurin inhibitors are increasingly associated with posttransplant malignancy (Wolverton, 2007).

Cyclosporine (Neoral and Sandimmune) is an immunosuppressive agent that inhibits interleukin-2 transcription and thus inhibits T-cell function (Carucci, 2005). It may be used with AZA and/or corticosteroids. The dosing is dependent on the type of transplant, ranging from 3 to 10 mg/kg/day. Cutaneous adverse reactions include skin malignancies, increased risk for opportunistic infections, hypertrichosis, hirsutism, and gingival hyperplasia.

Azathioprine (Imuran) is indicated for use in prevention ofrejection of kidney transplants, and in the treatment ofarthritis, Crohn's, and ulcerative colitis. AZA inhibits T- and B-cell proliferation by inhibiting nucleotide synthesis (Carucci, 2005). It is a mutagen and photosensitizer as well as an imunosuppressant. Renal dosing is 1 to 3 mg/kg/day. Cutaneous adverse reactions include cutaneous malignancies (SCC and lymphomas), increased risk for infections (HPV, herpes simplex) and scabies, and hypersensitivity reactions (morbilliform rash, purpura, erythema multiforme, urticaria, angioedema, and erythema nodosum).

AZA has been correlated with an increased incidence of lymphomas, SCCs, urinary bladder tumors, breast cancer, and brain tumors in studies conducted between 1971 and 1995 as cited by Guba et al. (2004). However, as AZA is used in combination with other agents in transplant patients, the effects of lower doses of AZA in this population are more difficult to assess.

Mycophenolate Mofetil

MMF has been established as an effective immunosuppressive agent in organ transplantation. It blocks the de novo purine synthesis pathway and may also possess some antineoplastic properties. A recent retrospective review of all heart transplant recipients at the Mayo Clinic from 1988 to 2006 (Brewer et al., 2009) identified a total of 1395 skin cancers in 312 patients; 1236 SCCs (89%) and 151 BCCs (11%). The review revealed an associated increased risk of BCC's in patients treated with MMF.

Rapamycin

Rapamycin (SRL) forms a binding protein complex that binds with high affinity to the mammalian target of rapamycin (mTOR). Its immunosuppressive activity is provided by subsequent actions that effectively block interleukin-2 stimulation of lymphocyte proliferation. Rapamycin seems to inhibit the development of cancer by blocking angiogenesis (Guba et al., 2004). Effective doses of rapamycin for immunosuppression coincide with doses required for the antiangiogenic effect. This potentially allows for simultaneous treatment of both organ rejection and cancer (Ulrich et al., 2008).

The mechanisms by which CsA, MMF, TAC, or SRL alone or in dual combinations influence tumor development and progression are not completely understood. A recent study compared chronically UVB-exposed mice on different regimens (Duncan et al, 2007). The mice treated with SRL alone or SRL in combination with CsA or TAC developed more tumors than the mice treated with vehicle or other immunosuppressants. However, the SRL tumors were significantly smaller and less advanced. A larger percentage of the CsA group was malignant. The addition of MMF to CsA reduced tumor size. This did not occur when MMF was combined with TAC. Immunosuppressant effects on UVB-induced inflammation and tumor angiogenesis may explain the difference in effect of different immunosuppressant agents.

The role of immunosuppressive treatment in the occurrence of nonmelanoma skin cancer has been widely reported. Skin cancers result from both a decrease in immunosurveillance and from the direct oncogenic effects linked to some immunosuppressants. Patients receiving triple immunosuppression (CsA, corticosteroids, and AZA or SRL) had a threefold increased risk for NMSC as compared with patients taking two immunosuppressants (corticosteroids and AZA or SRL; Jensen et al., 1999). In addition, the effects of immunosuppressive medication seem to be reversible.

The incidence of NMSC has been shown to be proportional to the level of immunosuppression (Ulrich et al., 2008) as CD4 counts are significantly lower in organ transplant recipients with NMSC versus those patients without such malignancies. Among renal transplant patients, there is also a higher risk of skin cancer in patients with poor renal perfusion (serum creatinine >150 Vmol/L at 1 year), who require higher levels of immunosuppression. There is a lower risk in patients with a living renal donor graft, who generally receive less immunosuppression.

MANAGEMENT STRATEGIES FOR SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS

The International Transplant Skin Cancer Collaborative and the Skin Care in Organ Transplant Patients Europe (SCOPE) were established in 2002. Both organizations share similar objectives: To educate patients, scientists, primary care doctors, and specialist physicians about the unique clinical needs of the transplant population, and to integrate and support scientific and clinical research to improve the quality of care of these patients. In addition, SCOPE has developed a European Internet-based data registry to collect comprehensive epidemiological data on skin diseases in transplant recipients (Stasko et al., 2004). The groups make the following recommendations regarding screening and education, evaluation and management of warts and premalignant lesions, and evaluation and management of SCC.

Screening and Education

All transplant patients with suspected or proven SCC should have a thorough pretreatment evaluation. The provider should note the history, size, site, and histology of the lesion. Full-body skin examination should include examination of genital and mucosal areas and palpation of lymph nodes. Lymph node palpation should include the parotid gland, a frequent location for metastatic SCC originating in the facial region (Hofbauer et al., 2009).

Characteristics of less aggressive SCCs include smaller sized lesions (<0.6 cm at the mask areas of the face, genitalia, hands, and feet; <1.0 cm at the cheeks, forehead, neck, and scalp; and <2 cm at the trunk and extremities), which are static, nonulcerated, with well-defined margins, and with no satellite lesions. Histology of less aggressive SCC includes lesions that are in situ (Figure 2), keratoacanthoma (Figure 3), well differentiated (Figures 4 and 5), and limited to papillary dermis, with no perivascular or intravascular invasion, and no neural invasion (Stasko et al., 2004).

FIGURE 2. SCC in situ (Bowen's) left fifth digit.

FIGURE 3. SCC keratoacanthoma type right forearm.

FIGURE 4. Well-differentiated SCC right lateral helix.

FIGURE 5. Well-differentiated SCC right posterior ear.

Management of Less Aggressive SCC

Characteristics of aggressive SCCs include multiple or larger sized lesions (>0.6 cm at the mask areas of the face, genitalia, hands, and feet; >1.0 cm at the cheeks, forehead, neck, and scalp; and >2 cm at the trunk and extremities), which are ulcerated, have rapid growth, have indistinct margins or satellite lesions, recur after previous treatment, or occur in a scar, in an area of chronic inflammation, or in the field of prior radiation (Stasko et al., 2004). Histology of aggressive SCC includes poorly differentiated (Figure 6) deep extension of tumor into the subcutaneous fat, perineural invasion, and perivascular or intravascular invasion.

FIGURE 6. Poorly differentiated SCC right lateral lower leg.

Management of Aggressive SCC

The lack of nodal staging in cutaneous SCC leads to uncertainty among physicians regarding which patients need staging and which modality to use. However, imaging (computed tomography, magnetic resonance imaging, and positron-emission tomography) should be considered in those patients with high-risk SCC for nodal staging and for preoperative planning if deep or extensive tissue involvement is suspected (Jennings & Schmults, 2010). Appropriate excisional modalities include Mohs micrographic surgery and excision with 6- to 10-mm margins. Adjuvant radiation therapy should be considered when there is an inability to achieve margins clear of invasive tumor by surgery or in the presence of substantial perineural invasion. Sentinel lymph node biopsy may be considered in evaluation of high-risk SCC.

Management of Satellite Lesions

Transplant patients are susceptible to developing large areas of premalignant lesions, which can easily develop into cutaneous malignancies. Warts become increasingly common as the duration of immunosuppression increases, with 77% to 95% of renal transplant recipients affected within 5 years posttransplant. Viral warts may cause significant morbidity in patients unable to mount an adequate T-helper 1 cell-mediated immune response to human papillomavirus (Harwood et al., 2005). A combination of premalignant epidermal dysplastic lesions, including cutaneous viral warts, actinic keratoses, carcinoma in situ, and Bowen's disease, affects up to 40% of organ transplant recipients by 5 years after transplantation (Stockfleth, Ulrich, & Meyer, 2002). These epidermal dysplastic lesions produce a field change of skin abnormalities, which are difficult to treat, frequently recur, and are resistant to many treatment modalities. These areas have a high degree of malignant potential (Brown et al., 2005).

The ITSCC and the SCOPE underscore the importance of treating premalignant lesions aggressively at first development because many of these lesions may develop into invasive SCCs (Stasko et al., 2004). Treatment modalities include cryosurgery, topical 5-fluorouracil, and curettage and electrodesiccation. Treatment modalities that have not yet been proven safe and efficacious in the transplant population include imiquimod, topical PDT, and ablative skin resurfacing.

Imiquimod

There is a theoretical risk of allograft rejection with imiquimod because the drug will increase interferon levels. Brown et al. (2005) conducted a randomized, blinded, placebo-controlled study to assess the safety of treatment with imiquimod cream in the treatment of skin dysplasia in high-risk renal transplant patients. Twenty-one patients applied imiquimod versus placebo three times per week to affected areas for 16 weeks. The authors concluded that topical 5% imiquimod seems to be safe when applied to small (<60 cm²) areas of affected skin in renal transplant recipients. It may be effective in reducing cutaneous dysplasia and may reduce the frequency of SCC development in high-risk patients, although more intensive dosing regimens may be required.

Harwood et al. (2005) evaluated the efficacy of imiquimod cream in treating recalcitrant cutaneous warts in 12 immunosuppressed patients. The treatment course lasted 24 weeks with minimal adverse reactions. However, clearance rates were relatively low at 36%.

Topical PDT

Eight organ transplant recipients with epidermal dysplasia participated in an open-label, single-center, randomized, intrapatient comparative study conducted by Perrett et al. (2007). Each patient underwent treatment with two cycles of methyl aminolaevulinate PDT 1 week apart to one area of epidermal dysplasia and topical 5% fluorouracil twice daily for 3 weeks to another site. At 1, 3, and 6 months after treatment, methyl aminolaevulinate PDT was consistently more effective than 5% fluorouracil when evaluating complete resolution and comparing cosmetic outcome. However, as both a cytotoxic agent and a biological response modifier, Perrett et al. note that an impaired immune system may compromise the outcome of PDT over the longer term. There may also be a concern of long-term safety in patients on azathioprine who accumulate DNA thiopurines as a consequence of treatment.

Systemic Agents

Acitretin or Isotretinoin

Bouwes-Bavinck et al. (1995) observed a significant reduction in both the number of patients with new skin cancers and the cumulative number of new skin cancers in renal transplant recipients whose immunosuppressive therapy consisted of prednisone combined with AZA and/or cyclosporine when taking 30 mg/day of acitretin over 6 months. McKenna and Murphy (1999) found that the introduction of low-dose (0.3 mg/kg) acitretin offered a significant chemoprophylactic effect for up to 4 years of treatment in 16 renal transplant patients. McNamara, Muir, and Galbraith (2002) showed that five heart transplant patients who took acitretin at either 10 or 25 mg/day also had a significant reduction in both actinic keratoses and skin cancers.

When de Sevaux, Smit, de Jong, van de Kerkhof, and Hoitsma (2003) compared two different low-dose acitretin regimens (0.2-0.4 mg/kg/day) in 26 renal transplant recipients over 1 year, both groups had a nearly 50% decrease in the number and thickness of actinic keratoses; however, there was no decrease in the number of new malignant tumors. Most of these patients were then included in a study by de Sevaux et al. later in 2003 in which 33 patients who were at least 10 years posttransplant underwent biopsies both before and after a 90-day treatment course of acitretin. Acitretin reduced the hypertrophy of the stratum corneum of actinic keratoses, thereby producing a clinical softening of the skin. However, there was no significant decrease in proliferation or dysplasia, which might explain why there is often recurrence of actinic keratoses after cessation of acitretin treatment.

The benefit of acitretin is present only during treatment. Unfortunately, complications and intolerance of long-term systemic retinoid therapy is common. Most patients require a decrease in the retinoid dose or discontinuation because of the frequent occurrence of significant mucocutaneous side effects. The most frequent systemic side effect of oral retinoid therapy is an increase in plasma triglycerides. Patients must also be monitored for increases of total and LDL cholesterol levels and abnormalities of liver function tests. Other adverse effects include mucocutaneous xerosis, arthralgias, and alopecia. Retinoids are highly teratogenic if taken during embryogenesis, and there is continued controversy over isotretinoin's link to psychiatric disorders. Long-term treatment risks with retinoids at high doses includes calcifications of tendons and ligaments around joints, hyperostosis of the spine, and osteoporosis. There is also a theoretical concern for rejection of the transplanted organ because of the possible immune-stimulatory effect of retinoids, requiring monitoring of the transplant organ function (De Graaf, Euvrard, & Bouwes-Bavinck, 2004).

In addition, transplant patients who are severely affected by skin cancer may be less able to tolerate systemic retinoid therapy in actual clinical practice than patients in formal clinical trials (Martinez et al., 2004). Therapeutic doses of acitretin are 10 to 50 mg/day at an average of 25 mg/day and isotretinoin at 10 to 70 mg/day. Treatment modifications might include starting at a low dose and titrating upward to effect, reducing the dose for 4 to 24 weeks until adverse symptoms subside, or using an intermittent treatment schedule with treatment-free periods.

Rapamycin or Everolimus

mTOR inhibitors including SRL and everolimus may have antitumoral properties by blocking angiogenesis (Guba et al., 2004) and may reduce tumor size (Duncan et al., 2007). Early clinical trials indicate that mTOR inhibitors may have a preventative action on the development of cutaneous malignancies (Lebbe, Euvrard, & Barrou, 2006). Euvrard, Ulrich, and Lefrancois (2004) reviewed the most significant publications on the role of the main immunosuppressants in the pathogenesis of skin cancers. Data of these preliminary studies suggest that rapamycin (Sirolimus) could have a protective effect against skin cancer.

A total of 1671 renal transplant recipients were enrolled in five multicenter studies reported by Matthew, Kreis, and Friend (2004). Patients receiving SRL-based therapy without cyclosporine or SRL maintenance therapy after cyclosporine withdrawal had lower rates of malignancy in the first 2 years after transplantation. Therefore, SRL immunotherapy may be beneficial in protecting renal transplant patients from skin cancer even when given in combination with cyclosporine.

Kauffman, Cherikh, Cheng, Hanto, and Kahan (2005) performed a multivariate analysis of posttransplant malignancies in 33,249 renal transplant recipients from July 1996 to December 2001. Maintenance immunosuppression with mTOR inhibitors was associated with a significantly reduced risk of developing any posttransplant de novo malignancy and nonskin solid tumors. The authors note that the favorable results found with the use of mTOR inhibitors both alone and in combination with calcineurin inhibitors (cyclosporine, TAC) are significant because combination immunosuppression is used more often clinically to reduce the toxicity of individual drugs.

Although the use of mTOR inhibitors appears to be an attractive alternative to commonly used immunosuppressants, the drugs seem to be difficult for transplant recipients to tolerate. The main side effects of SRL are asthenia (loss of strength), headache, arthralgia, lymphocele, interstitial pneumonitis, and delayed wound healing. Mahe et al. (2005) conducted a study of 80 renal transplant recipients to evaluate the dermatologic adverse effects of the drug. Nearly all study participants (99%) experienced cutaneous adverse events. Patients who took SRL for an average of 18 months developed cutaneous events, including acne-like eruptions, scalp folliculitis, hidradenitis suppurativa, chronic edema, angioedemas, aphthous ulceration, epistaxis, chronic gingivitis, chronic lip fissures, chronic onychopathy, and periungual infections. These adverse reactions are often the reason for stopping SRL therapy. In addition, long-term use of SRL may prove problematic as Ulrich et al. (2008) suggested that drug resistance may develop because of acquired mutations to mTOR preventing rapamycin from binding to mTOR.

Capecitabine (Xeloda)

Another treatment that may prove beneficial is capecitabine. This oral chemotherapeutic agent used for treatment of colon cancer and metastatic breast cancer is a precursor to 5-fluorouracil. Endrizzi and Lee (2009) investigated the use of capecitabine in three organ transplant recipients. In the 6 months before treatment, a total of 35 skin cancers were excised from the three participants; only one of the patients required a single surgical excision during the 6 months of treatment. There was also a dramatic reduction of precancerous lesions. All three patients experienced transient erythema and pain and later desquamation of the palms of the hands and soles of the feet (palmar-plantar erythrodysesthesia) after receiving capecitabine.

Epidermal Growth Factor Receptor Inhibitors (Cetuximab)

Epidermal growth factor receptor is expressed in the basal layers and epidermal appendages of human epidermis. Its activation is responsible for cell cycle progression, proliferation, survival, angiogenesis, and metastasis (Shimizu et al., 2001). Of the epidermal growth factor receptor inhibitors, cetuximab has had reported success in several case reports: unresectable SCC, in-transit recurrent SCC, and metastatic SCC in epidermolysis bullosa (Bauman, Eaton, & Martins, 2007).

Modification of Immunosuppression

Although most primary skin cancers are easily managed, some transplant patients develop over 100 skin cancers per year (Otley & Maragh, 2005). In addition, the cancers may be particularly aggressive, with a 7% rate of metastasis of SCCs in this population. When faced with such a situation, transplant physicians may need to consider a reduction of the number or dosage of immunosuppressants, an approach called "minimization." Reduction of immunosuppression is associated with a lower incidence of skin cancer but yields a higher risk for rejection of the transplant organ.

There are currently no guidelines available defining which threshold of cancer development necessitates modification of immunosuppressive medications. However, Ulrich et al. (2008) suggested that it seems reasonable to consider minimization as an adjuvant therapy not only in patients with multiple and/or aggressive SCC but also at the occurrence of the first SCC because of the high rate of subsequent skin cancers.

The first SCC in a transplant recipient is considered to be a sentinel event. The influence of immunosuppressive treatments on the occurrence of subsequent tumors was assessed by Euvrard et al. (2006) by comparing control patients with patients who took a decreased dose of immunosuppressants within the first year after the first SCC posttransplantation. A 20% decrease in the dose of AZA or cyclosporine or a 25% reduction of corticosteroid, MMF, or TAC was considered to constitute a reduced dosage. Despite the dosage reduction, subsequent skin cancers developed in 100% of cardiac transplant patients and in 88% of renal transplant recipients, with a higher number of tumors per patient in the kidney transplant population.

These results suggest that new immunosuppressive strategies should be considered in an effort to reduce the number of subsequent skin cancers after a first SCC in transplant patients. A survey conducted by Otley et al. (2007) concluded that transplant physicians are willing to accept an increased risk of allograft compromise when confronted by severe or extensive skin cancer.

CONCLUSION

The current challenge in clinical management strategies of skin cancer in organ transplant recipients is to determine if the conversion to mTOR inhibitors is a better option than minimization for patients who have developed skin cancer. The promising results of SRL may be hampered by its side effects, which seem to be more frequent when SRL is given to patients who have been immunosuppressed for several years. Several randomized clinical trials are underway to test the potential antineoplastic effects of mTOR inhibitors on NMSCs in organ transplant recipients, and new studies have been initiated in France and Germany for heart transplant recipients with NMSCs (Ulrich et al., 2008). The ITSCC is currently pursuing research to clarify the optimal use of reduction of immunosuppression as an adjuvant therapeutic strategy in patients severely affected by skin cancer (Otley & Maragh, 2005).

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