Dermatology Online Journal

Squamous Cell Carcinoma in Solid-Organ Transplantation
Jashin J. Wu, M.D., and Ida F. Orengo, M.D.
Dermatology Online Journal 8(2): 4

From the Department of Dermatology, Baylor College of Medicine, Houston, Texas

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Abstract

Multiple advances in the field of transplantation over the last several decades have resulted in a significant increase in the number of surgeries performed and in years of life extended. However, with the success of transplant comes the dilemma of potential complications of lifelong immunosuppressive therapy. An enormous increase in skin cancer, especially highly-aggressive squamous cell carcinoma, may affect this special population of patients. This review article discusses the main etiologic theories of squamous cell carcinoma, characteristics of skin cancer in the immunosuppressed patient, differences in skin cancer amongst three types of solid-organ transplantation (kidney, heart, and liver), and established and new treatments.

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Abbreviation and acronym list

SCC: squamous cell carcinoma HLA: : human leukocyte antigen HPV: : human papillomavirus UVR: : ultraviolet radiation BCC: : basal cell carcinoma AV: : arteriovenous SPF: : sunprotection factor

Great strides have been made in the field of solid-organ transplantation, adding many years of life to patients who suffer from end-stage failure of the kidney, heart, lungs, liver, and pancreas. However, many side effects from the chronic use of immunosuppression therapy, such as cyclosporine and azathioprine, can lead to a disproportionately high rate of malignancy, such as skin cancers, lymphoproliferative disorders, and Kaposi's sarcoma. The purpose of this review article is to summarize the etiology of, the unique characteristics of, and new treatment options for squamous cell carcinoma in solid-organ transplant recipients.

Pathophysiology

The increased frequency of skin cancers in transplant patients is believed to be caused by the interaction of multiple factors.[1] These include genetic factors such as human leukocyte antigen (HLA) and glutathione S-transferase polymorphisms, the direct effect of immunosuppression, infection by oncogenic viruses such as human papillomavirus, and exposure to ultraviolet radiation. The exact importance of each factor has yet to be determined.

Genetic factors

The role of HLA types in the predisposition of developing skin cancers in transplant recipients has been studied in depth with conflicting results.[2,3, 4,5,6,7,8,9] Transplant patients with HLA-A3, HLA-B27, HLA-DR7, and HLA-DQw2 have a predilection for skin cancer, while those with HLA-A11 are less likely to develop skin cancer.[3] An HLA-B mismatch increases the incidence of SCC, while there is no association between the incidence of SCC and the number of mismatches for HLA-A or DR.[10] In addition, it appears that as the role of ultraviolet radiation is lessened, the significance of HLA type increases.[7, 11]

The glutathione S-transferase enzymes play a major role in limiting the toxic effects of reactive oxygen species that are released by exposure to ultraviolet radiation. Polymorphisms in these genes, GSTM1, GSTT1, and GSTP1, may confer an increased risk of SCC in transplant recipients. One study showed that the GSTP1*C allele was associated with an increased risk, while there was no associated risk with the GSTM1 null genotype or the GSTT1 null genotype.[12] No association between any GST polymorphism and the development of basal cell carcinoma was found. Another study found an increased risk with GSTM1 null, which was synergistic with sun exposure.[13] GSTP1*Ile homozygotes developed greater numbers of SCC, especially in those with lower ultraviolet light exposure and cigarette use. The presence of GSTM3 and GSTT1 also showed increased risk.

The loss of function of the retinoblastoma tumor suppressor gene, which is located on chromosome 13, is common in many inherited and sporadic forms of cancer. The inactivation of its protein by oncogenic human papillomaviruses plays a major role in the initiation of cervical cancer. The retinoblastoma suppressor gene is more likely to be damaged in the SCC of transplant recipients compared with the SCC found in immunocompetent patients.[14] In addition, there is no correlation between human papillomavirus and the expression of the retinoblastoma suppressor gene in cutaneous SCC.[14]

Immunosuppressive treatment

There is considerable controversy about the increased risk of SCC using various immunosuppressive agents. Some report an increased predilection of SCC with cyclosporine,[15,16,17,18,19,20,21,22] while others report a smaller risk compared to azathioprine.[23,24,25,26,27,28] Other studies conclude that there is no significant difference in skin cancer risk between cyclosporine and azathioprine.[29,30,31,32,33]

Immunosuppressive therapy induces skin cancer by several mechanisms: decreased ability of tumor surveillance, decreased function of natural killer cell function,[34,35] and decreased density and function of Langerhans' cells in skin.[36,37] The increased risk of SCC may be the result of intense immunosuppression rather than any particicular agent.[1]

However, individual agents may contribute to the increased incidence of skin cancers. Cyclosporine promotes the progression of UV-induced skin cancers in animal models.[28] The active metabolite of azathioprine, 6-thioguanine, also has been demonstrated to promote UV-induced skin cancers.[28,38,39,40] Further, 6-mercaptopurine and nitroimidazoles, the metabolites of azathioprine, increase the SCC risk by sensitizing the skin to UVB.[38,41,42].

Oncogenic viruses

The role and type of human papillomavirus (HPV) in skin cancer is controversial. Studies report the incidence of HPV to be 42% to 48% in premalignant lesions and 43% to 65% in malignant lesions.[43,44,45,46,47] The usual distribution of HPV types is switched in transplant patients: HPV types 16 and 18, which are generally found in genital lesions, are common in SCC of sun-exposed areas.[43,48] HPV types 5 and 8 are reported to be present in up to 60% of SCCs in transplant recipients.[26,49,50,51] One study which compared the prevalence and type of HPV in SCC of transplant patients and non-transplant recipients showed that the spectrum and prevalence of HPV infection was much greater in the immunosuppressed patients.[52]

The mechanism by which HPV induces carcinogenesis has yet to be established, but one model is that the viruses have a promoter effect, acting in conjunction with specific tumor initiators or other promoters, especially ultraviolet radiation.[52] Such a theory would explain why no specific HPV type has emerged as strongly associated with nonmelanoma skin cancer.

Alternatively, HPV may be a passenger virus in the skin. Studies have shown 16% to 19% of patients with nonmelanoma skin cancer had HPV in their norman skin.[44,53] In addition, the majority of hair follicles from immunosuppressed patients harbor HPV DNA.[54]

Ultraviolet radiation

Ultraviolet radiation (UVR) plays a major role in skin cancer in both immunosuppressed and immunocompetent patients. The odds ratio of skin cancer for high cumulative lifetime sunlight exposure versus low exposure is 47.6 to 2.4.[55] One study showed that high exposure to UVR before the age of 30 years is more significant for the later development of skin cancer than exposure after the age of 30 years.[55] This means there may be a long latency period between sun-damage and the appearance of SCC.

UVR causes skin cancer by direct DNA damage and by systemic immunosuppression. UVR induces DNA strands to break and to form dimers, which initiates skin cancer.[56] UVR exposure causes unrepaired cytosine dimers, which are replaced by a tandem of thymine bases.[57] The most important gene studied for the damaging effects of UVR is the p53 tumor suppresser gene, which plays an important role in apoptosis, cell proliferation, differentiation, and DNA repair.[58] Two recent studies showed that the p53 protein from immunosuppressed patients accumulates in the cells and does not function effectively as a transcriptional activator.[59,60]

The selective systemic immunosuppression that UVR exerts takes place through the disabling of Langerhans cells and the generation of cis-urocanic acid or inflammatory cytokines.[55,61] Langerhans cells process and present antigens to lymphocytes, which initiates the immune response against skin cancer and virus-infected cells.[62] Even low doses of UVR can damage the integrity of these cells.[63,64] Cis-urocanic acid is a systemic immunosuppressive mediator found close to the skin surface.[54,64] Cytokines such as interleukin-4 and interleukin-10, and immunoregulators induce immunosuppression, which allow clonal expansion and outgrowth of tumor cells.[61]

Characteristics

Prevalence

Transplant patients have an overall 5% to 6% incidence of malignancy, which is 100 times greater than the general population.[1,65] As many as 40% to 53% of all malignancies among transplant patients are skin cancers.[38,66] The incidence of skin cancer varies with the amount of sun exposure. In regions with limited sun exposure, such as the Netherlands, the risk of a skin tumor is 10% at 10 years after transplantation and 40% at 20 years.[67] In regions with high sun exposure, such as Australia, the incidence is 45% at 11 years after transplantation and 70% at 20 years.[68]

Under normal circumstances, basal cell carcinomas (BCC) are much more common than SCC. However, the incidence of SCC in transplant recipients is 40 to 250 times that of the general population, whereas the incidence of BCC is 10 times greater in transplant patients.[55,69] This results in a reversal of the BCC/SCC ratio. The normal population has a ratio of 5:1, whereas transplant patients have an average ratio of 1:1.8 to 2.3 (range of 1:1.2 to 1:15).[1,65, 69,70,71]

Risk factors

The two most important risk factors for skin cancer in the transplant population are amount of sunlight exposure and age at transplantation.[55] The degree of sun damage before age 20 years affects the SCC rate.[29] Body sites of transplant patients with high exposure to sunlight have a 21 times increase in skin cancer over the general population, compared to a 4 to 7 times increase in skin cancer in sites of limited sun exposure.[1,69] In transplant recipients, sun damage before the age of 30 is a major risk factor for SCC after transplantation,[55] and the risk is greater in those transplanted after age 35 years.[7] One study showed that after the effects of sun exposure were controlled, 60-year-old transplant patients were 3 times more likely to develop SCC compared to 30-year-old transplant patients.[72]

Other independent risk factors are the number of keratotic skin lesions, such as viral warts and actinic keratoses[55] and diabetes mellitus.[73] The male sex[74,75,76,77] and outdoor occupation[77] have also been found to be significant risk factors.

Mortality

SCCs in transplant patients are much more aggressive and deadly.[78,79] They tend to recur locally even after surgical excision.[80] Cancer that spread to lymph nodes occurred in 5.8% of patients. Seventy-five percent of these were caused by SCC.[69] Of the 5.1% of transplant patients who die from skin cancer, 60% had SCC and 33% had melanoma,[69] which represents a 10-fold increase in mortality from SCC.[81] This is in stark contrast to the mortality of skin cancer in the general population, where melanoma is the most common cause of death.

SCC in different solid-organ transplant patients

Kidney Versus Heart

Most of the literature concerning skin cancer in transplant patients describes kidney recipients, and there are very few studies about liver, lung, and pancreas recipients. However, there are several differences in the SCCs that develop in each type of patient population. Heart transplant patients are twice as likely to develop skin cancer compared to kidney recipients.[75,82,33,84] This can be explained by two reasons.[75] The intensity of immunosuppressive therapy is much greater in heart transplant recipients, as many patients undergo triple-drug therapy compared to the usual double-drug therapy in kidney recipients. The second factor is that heart transplant recipients are about 15 years older at transplantation.

The location of the skin cancers also differed between the two populations. A cephalic location occurred in 70% of heart transplant recipients compared to 40% of kidney transplant recipients.[75] The difference in age at transplantation may account for this observation. If the transplant recipient received the organ before age 40 years, the skin cancer was mostly extracephalic. However, if the transplant recipient received the organ after age 40 years, the skin cancer was mostly cephalic, as is seen in the normal population.

Although the BCC/SCC ratio was reversed for both transplant populations, the reversal was more salient in the kidney recipient versus the heart recipient (1:2.3 versus 1:1.08).[75] This is due to the older age of heart transplant patients, which would increase the incidence of BCC.

The time interval between transplantation and development of skin cancer was much shorter in the heart transplant patients compared to the kidney transplant patients (3.9 years versus 8.6 years).[75] This is also due to the more intense immunosuppression seen in heart transplant patients.

Because of donor shortage, heart transplant recipients were less likely to be HLA-matched before transplantation, as the majority of kidney transplant patients were. However, HLA-A, -B, or -DR mismatches were not found to be risk factors for skin cancer.[85]

One study hypothesized that the distribution of upper limb skin cancers in renal transplant recipients was related to the side of the arteriovenous (AV) fistula placed in the arm for hemodialysis before transplantation.[86] It is possible that the presence of an AV fistula impairs local immune response secondary to the increased lymphatic workload or that HPV-related skin cancers may be induced secondary to surgical trauma. However, the study could not demonstrate any association of increased skin cancer on the side of the AV fistula.

Liver

There is sparse literature concerning skin cancers in liver transplant recipients, and there are no studies comparing the features of skin cancers that develop in liver transplant recipients versus other solid-organ transplant recipients. Transplant-associated immunosuppressive regimens used in liver transplant recipients differ from those developed for kidney and heart transplantation.[87] Many liver transplant centers prefer the use of tacrolimus rather than cyclosporine.[88] Because the liver may be a less immunogenic organ, the immunosuppression of this population may be less profound than that used in kidney and heart transplantation.

A large case series reported an overall incidence of 4.5% malignancy in liver transplant recipients, with an overall incidence of skin cancer of 1.6%, including one metastatic SCC.[89] Because of the limited patient sample size and short follow-up, the authors could not generalize reliably the specific risk of skin cancer in this population.

A 6.5-year follow-up of patients treated with tacrolimus showed a 2.2% incidence of skin cancer, with a 3-year survival rate of 86%.[90] Another report showed a low incidence of skin cancer in a large liver transplant population, but the authors felt that there was a bias of under-recognition of skin cancer.[91] This report also found that tacrolimus-treated patients seemed to have a significantly lower risk of malignancy, including skin cancer, compared to cyclosporine-treated patients. However, another study showed similar cancer risk for both populations.[92]

Treatment

Primary Prevention

The definition of primary prevention is prevention aimed at influencing factors that are known or thought to promote disease. The factors that physicians can target include UVR protection, intensity of immunosuppressive treatment, HPV infections, and HLA mismatching.

UVR exposure appears to be the most significant factor. All transplant patients should see a dermatologist before and after transplantation so that they can be taught about the importance of sun protection.[93] Essentials of sun protection include the use of sunscreens with a sun protection factor (SPF) of at least 15, the use of protective clothing such as hats or commercially available clothing (Solumbra), and avoidance of sun, especially during the hours of 10AM to 4PM.[80]

It appears that transplant patients are not particularly aware of the importance of sun protection. One study found that 91% of patients knew of the danger of UVR exposure, and 77% knew they were more likely to develop skin cancers.[94] However, 31% were not changing their lifestyle to decrease UVR exposure. Another study found that 72% of surveyed patients examine their skin regularly, but only 67% use sunscreen routinely.[95] Forty-one percent of these patients were unable to recall any specific skin education, and only 52% showed an interest in skin cancer screening. Discouragingly, only 27% had seen a dermatologist since their transplant surgery, and only 14% were followed regularly by a dermatologist. The primary care physician and dermatologist must work together to change this trend. One group in Italy has made a strong commitment by offering free clinical consultations for all patients on a walk-in basis. All kidney transplant patients are scheduled for annual dermatologic check-ups.[96] Keeping the level of immunosuppressive treatment as low as possible is also very important.[1] As seen by the increased incidence of skin cancers in heart transplant recipients compared to kidney transplant recipients, the intensity of suppression plays a major role in the development of skin cancers.[75,85]

As HPV infection has a very likely role in skin cancers in transplant recipients, prevention of viral infection should also decrease the incidence of tumor formation. Sexually transmitted HPV can be prevented by using barrier contraception such as condoms.[1] Multiple warts can be treated with new topical immodulators such as imiquimod.

It is controversial whether HLA mismatching increases the risk for developing skin cancer. A recent study showed that an increase of HLA mismatching in heart transplant recipients did not increase the risk of skin cancer compared to kidney transplant recipients.[85]

Secondary Prevention

The definition of secondary prevention is prevention aimed at early detection and treatment. Older patients with high levels of sun exposure should be examined frequently by a dermatologist. Patients should be seen every 2 to 3 months if they already have multiple viral warts and precancerous lesions.[80] Patients with stable cutaneous lesions may be seen every 6 months. During each office visit, patients should be asked whether they are taking sun protection precautions, and they should be educated to notify the medical staff of any new lesions.

Aggressive therapy of viral warts and precancerous lesions should be initiated in this population.[80] Cryotherapy is an appropriate treatment if there are only a few lesions. Chemical peels may be used for multiple lesions. Light peels can be achieved with α-hydroxy acid or β-hydroxy acid. Medium-depth peels can be performed by with trichloroacetic acid. Carbon dioxide laser or dermabrasion can be used for deep peels.

Since SSCs are more likely to behave aggressively, more aggressive therapy may be warranted as soon as the diagnosis is established.[97] For small skin cancers less than 0.5 cm, curettage and desiccation three times followed by cryotherapy may be an option.[80] For lesions larger than 0.5 cm, complete excision is mandatory and may be performed by Mohs' micrographic technique.

For extensive involvement of skin cancers, some suggest careful reduction in the intensity of immunosuppressive therapy.[97,98,99] Etretinate and acitretin, a free acid of etretinate, have been shown to decrease the number of viral warts and keratotic skin lesions while decreasing the risk of skin cancer in transplant patients.[6,100,101,102,103] There is some concern that these medications may potentiate graft rejection,[6,104,105] but many studies do not show changes in graft function or immunologic parameters.[6,100,102,103] The results and relapse profile of isotretinoin is similar to etretinate,[105,106, 107] but it appears to be associated with less risk of graft rejection.[104, 108] Another safe alternative is topical tretinoin, either alone or in combination with low-dose oral retinoids.[108] Two studies have shown that renal transplant patients using topical tretinoin have significantly less keratotic skin lesions.[107,109] Further, the discontinuation of etretinate and acitretin tends to allow relapse of premalignant and malignant lesions, so long-term use of retinoids should be considered in these patients.

In a phase II, open-label study of 16 non-transplant patients, imiquimod 5% cream achieved a 93% positive treatment response in Bowen's disease, a form of squamous cell carcinoma in-situ.[110] Imiquimod cream, which is approved for the treatment of genital warts, is a topical immune response modifier that has been shown to have indirect anti-viral and anti-tumor effects through the stimulation of cell-mediated immune responses and local cytokine production.[111,112] Further investigation of the use of imiquimod 5% cream in transplant recipients is needed.

Summary

Immunosuppressed transplant recipients are a special population of patients with a significantly increased risk of development and death from skin cancer, particularly SCC. Close monitoring of these patients by dermatologists, combined with sun protection and early, aggressive treatment of pre-cancerous lesions and early cancers are all essential features of the proper care of transplant patients.

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