Progress in Dermatology: Cutaneous Oncology in Organ Transplant Recipients: Meeting the Challenge of Squamous Cell Carcinoma

Abstract

The incidence of nonmelanoma skin cancer continues to rise with over 1.3 million cases diagnosed in the United States in 2002.[1.Geller A.C. Annas G.D. Epidemiology of melanoma and nonmelanoma skin cancer.Semin Oncol Nurs. Feb 2003; 19: 2-11Abstract Full Text PDF PubMed Scopus (103) Google Scholar] Squamous cell carcinoma (SCC), the second most common human cancer, accounts for 250,000 cancers diagnosed in the U.S. annually. In the majority of cases, cure is achieved, however there are subsets of patients in whom SCCs behave aggressively and in whom SCC can be devastating.[2.Rowe D.E. Carroll R.J. Day Jr., C.L. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.J Am Acad Dermatol. Jun 1992; 26: 976-990Abstract Full Text PDF PubMed Scopus (1160) Google Scholar] This is particularly true in the case of organ transplant recipients (OTRs).[3.Ulrich C. Schmook T. Sachse M.M. Sterry W. Stockfleth E. Comparative epidemiology and pathogenic factors for nonmelanoma skin cancer in organ transplant patients.Dermatol Surg. Apr 2004; 30: 622-627Crossref PubMed Google Scholar] There are over 100,000 OTRs currently living in the United States.[4.Berg D. Otley C.C. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management.J Am Acad Dermatol. Jul 2002; 47 (quiz 18–20): 1-17Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar] Over 25,000 transplants are performed in the U.S. annually with the large majority being renal transplants.[5.Ponticelli C. Tarantino A. Vegeto A. Renal transplantation, past, present and future.J Nephrol. Jul-Aug. 1999; 12: S105-110PubMed Google Scholar] Transplant recipients are living longer with the half life of renal grafts reaching 20 years[6.Ponticelli C. Villa M. Cesana B. Montagnino G. Tarantino A. Risk factors for late kidney allograft failure.Kidney Int. Nov 2002; 62: 1848-1854PubMed Scopus (134) Google Scholar, 7.Seron D. Arias M. Campistol J.M. Morales J.M. Late renal allograft failure between 1990 and 1998 in Spain: A changing scenario.Transplantation. 2003; 76: 1588-1594Crossref PubMed Scopus (59) Google Scholar] and the 5 – year survival rate for heart transplant recipients approaching 80%.[8.Morgan J.A. John R. Weinberg A.D. Colletti N.J. Mancini D.M. Edwards N.M. Heart transplantation in diabetic recipients: A decade review of 161 patients at Columbia Presbyterian.J Thorac Cardiovasc Surg. May 2004; 127: 1486-1492Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar] OTRs are at significantly increased risk for developing skin cancers, particularly SCC.[4.Berg D. Otley C.C. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management.J Am Acad Dermatol. Jul 2002; 47 (quiz 18–20): 1-17Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar, 9.Otley C.C. Pittelkow M.R. Skin cancer in liver transplant recipients.Liver Transpl. May 2000; 6: 253-262Crossref PubMed Scopus (112) Google Scholar, 10.Espana A. Redondo P. Fernandez A.L. et al.Skin cancer in heart transplant recipients.J Am Acad Dermatol. Mar 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (89) Google Scholar] OTRs are also at increased risk for Kaposi’s sarcoma, Melanoma, and BCC.[4.Berg D. Otley C.C. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management.J Am Acad Dermatol. Jul 2002; 47 (quiz 18–20): 1-17Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar, 9.Otley C.C. Pittelkow M.R. Skin cancer in liver transplant recipients.Liver Transpl. May 2000; 6: 253-262Crossref PubMed Scopus (112) Google Scholar, 10.Espana A. Redondo P. Fernandez A.L. et al.Skin cancer in heart transplant recipients.J Am Acad Dermatol. Mar 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (89) Google Scholar] Skin cancer is a cause of significant morbidity and even mortality in transplant patients. Seventy percent of transplant patients may eventually develop skin cancer with an increased SCC:BCC ratio.[10.Espana A. Redondo P. Fernandez A.L. et al.Skin cancer in heart transplant recipients.J Am Acad Dermatol. Mar 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (89) Google Scholar, 11.Euvrard S. Kanitakis J. Pouteil-Noble C. Claudy A. Touraine J.L. Skin cancers in organ transplant recipients.Ann Transplant. 1997; 2: 28-32PubMed Google Scholar, 12.Levy M. Backman L. Husberg B. et al.De novo malignancy following liver transplantation: A single-center study.Transplant Proc. Feb 1993; 25: 1397-1399PubMed Google Scholar, 13.Lampros T.D. Cobanoglu A. Parker F. Ratkovec R. Norman D.J. Hershberger R. Squamous and basal cell carcinoma in heart transplant recipients.J Heart Lung Transplant. Jun 1998; 17: 586-591PubMed Google Scholar, 14.Veness M.J. Quinn D.I. Ong C.S. et al.Aggressive cutaneous malignancies following cardiothoracic transplantation: The Australian experience.Cancer. 1999; 85: 1758-1764Crossref PubMed Scopus (198) Google Scholar, 15.Ong C.S. Keogh A.M. Kossard S. Macdonald P.S. Spratt P.M. Skin cancer in Australian heart transplant recipients.J Am Acad Dermatol. Jan 1999; 40: 27-34Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 16.Jensen P. Hansen S. Moller B. et al.Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.J Am Acad Dermatol. Feb 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar, 17.Naldi L. Fortina A.B. Lovati S. et al.Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study.Transplantation. 2000; 70: 1479-1484Crossref PubMed Scopus (124) Google Scholar] In a study of 5356 consecutive patients transplanted between 1970 and 1994, NMSC other than BCC occurred in 172 patients.[18.Lindelof B. Sigurgeirsson B. Gabel H. Stern R.S. Incidence of skin cancer in 5356 patients following organ transplantation.Br J Dermatol. Sep 2000; 143: 513-519PubMed Google Scholar] Relative risk was ~109 for men and ~93 for women. Jensen, et al, studied skin cancer in a Norwegian cohort that included over 2500 transplant recipients.[16.Jensen P. Hansen S. Moller B. et al.Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.J Am Acad Dermatol. Feb 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar] In this study, OTRs had increased risk for cutaneous SCC (65-fold), malignant melanoma (3-fold), and SCC of the lip (20-fold). Risk for skin cancer was higher (~20:1) in patients transplanted after age 60 and for those on triple immunosuppression. Kidney transplant patients were at lower risk for skin cancer than heart transplant patients. Kidney transplant recipients on cyclosporine, azathioprine, and prednisolone had a ~3 fold increased risk for developing cutaneous SCC relative to those receiving azathioprine and prednisolone without cyclosporine. Naldi, et al, reviewed 1062 kidney transplant recipients and showed a cumulative skin cancer incidence of nearly 6% at 5 years and over 10% at 10 years.[17.Naldi L. Fortina A.B. Lovati S. et al.Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study.Transplantation. 2000; 70: 1479-1484Crossref PubMed Scopus (124) Google Scholar] Older age at transplant and male sex favored development of skin cancer. In contrast to other studies, there was no difference in risk between kidney and heart transplant recipients. The SCC:BCC ratio was 1:2.6 for kidney transplant patients. Euvrard, et al, reviewed skin cancer development in a series that included 580 kidney transplant patients.[11.Euvrard S. Kanitakis J. Pouteil-Noble C. Claudy A. Touraine J.L. Skin cancers in organ transplant recipients.Ann Transplant. 1997; 2: 28-32PubMed Google Scholar] Kidney transplant recipients were half as likely to develop skin cancer as heart transplant recipients. Kidney transplant patients were younger at transplant, received less intense immunosuppression, and had a longer interval between transplant and first skin cancer. The SCC:BCC ratio was 2.37:1 in kidney transplant recipients. In the study by Jensen, et al, heart transplant recipients were 3 times more likely to develop SCC than kidney transplant patients. Lampros, et al, reported on 248 heart transplant patients followed between 1985 and 1996.[13.Lampros T.D. Cobanoglu A. Parker F. Ratkovec R. Norman D.J. Hershberger R. Squamous and basal cell carcinoma in heart transplant recipients.J Heart Lung Transplant. Jun 1998; 17: 586-591PubMed Google Scholar] Forty one patients (17%) developed 192 SCCs or BCCs. SCC accounted for ~90% of the skin malignancies (172) with the SCC:BCC ratio approaching 9:1. Two patients in this study developed metastases from primary cutaneous SCC. Skin cancer risk was associated with increased time after transplant, use of OKT3, male sex (~20:1), blue eyes, and fair skin. In a study of heart transplant patients from Spain by Espana, et al, skin cancer was diagnosed in 14 of 92 patients between 1984 and 1993.[10.Espana A. Redondo P. Fernandez A.L. et al.Skin cancer in heart transplant recipients.J Am Acad Dermatol. Mar 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (89) Google Scholar] The risk for skin cancer rose from 4.8% in the first year after transplantation to 43.8% at seven years. Skin cancers occurred primarily in patients with skin types II and III. Interestingly the SCC:BCC ratio was 1.3:1. Four of the 14 patients developed SCC of the lip and 1 died of metastatic disease. Ong, et al, (1999), reviewed skin cancers in 455 Australian heart transplant patients and found a cumulative incidence of 31% at 5 years and 43% at 10 years.[15.Ong C.S. Keogh A.M. Kossard S. Macdonald P.S. Spratt P.M. Skin cancer in Australian heart transplant recipients.J Am Acad Dermatol. Jan 1999; 40: 27-34Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar] In this study, skin cancer accounted for 27% of 41 deaths after the fourth year following transplantation. SCCs were the most common cancers in this group outnumbering BCCs by a ratio of 3:1. Fair skin, increased age at transplant, and increased length of time after transplant were associated with greatest risk of developing skin cancer in this study. The development of aggressive cutaneous malignancy after cardiothoracic transplant (CTT) was addressed by Venes, et al, in a study of 619 patients who received heart, lung, or heart –lung transplants between 1984 and 1995.[14.Veness M.J. Quinn D.I. Ong C.S. et al.Aggressive cutaneous malignancies following cardiothoracic transplantation: The Australian experience.Cancer. 1999; 85: 1758-1764Crossref PubMed Scopus (198) Google Scholar] Aggressive skin cancer, including locally invasive SCC, recurrent SCC, poorly differentiated SCC, and regionally metastatic SCC, occurred in 27 of 66 (~41%) patients diagnosed with a malignancy. There were 10 deaths from metastatic disease. The incidence of skin cancer was 1.6% a series of liver transplant recipients by Levy[12.Levy M. Backman L. Husberg B. et al.De novo malignancy following liver transplantation: A single-center study.Transplant Proc. Feb 1993; 25: 1397-1399PubMed Google Scholar] with a single case of metastases from primary skin cancer. In a study by Frezza, et al, 50 of 1657 liver transplant recipients developed tumors.[19.Frezza E.E. Fung J.J. van Thiel D.H. Non-lymphoid cancer after liver transplantation.Hepatogastroenterology. Jul-Aug 1997; 44: 1172-1181PubMed Google Scholar] Skin cancers were most common with the SCC:BCC ratio approaching 1:1. A higher incidence of cancer was observed in patients treated with cyclosporine as opposed to tacrolimus. P53 is key in epidermal cell apoptosis following UV radiation-mediated DNA damage.[20.Brash D.E. Ziegler A. Jonason A.S. Simon J.A. Kunala S. Leffell D.J. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.J Investig Dermatol Symp Proc. Apr 1996; 1: 136-142PubMed Google Scholar, 21.Reiss M. Brash D.E. Munoz-Antonia T. et al.Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines.Oncol Res. 1992; 4: 349-357PubMed Google Scholar] Ultraviolet light (UVL) serves as an initiator as well as a tumor promoter [20.Brash D.E. Ziegler A. Jonason A.S. Simon J.A. Kunala S. Leffell D.J. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.J Investig Dermatol Symp Proc. Apr 1996; 1: 136-142PubMed Google Scholar, 22.Brash D.E. Ponten J. Skin precancer.Cancer Surv. 1998; 32: 69-113PubMed Google Scholar] and p53 dependent apoptosis of sun-damaged cells is believed to protect against SCC. Mutations in p53 including formation of thymidine dimers are seen in AKs (70%) and SCC (90%).[22.Brash D.E. Ponten J. Skin precancer.Cancer Surv. 1998; 32: 69-113PubMed Google Scholar] Mutant p53 tends to accumulate in the cytoplasm whereas wild type p53 tends to be degraded rapidly.[21.Reiss M. Brash D.E. Munoz-Antonia T. et al.Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines.Oncol Res. 1992; 4: 349-357PubMed Google Scholar] Some theorize that over expression of mutant p53 might contribute to tolerance.[23.Green C.L. Khavari P.A. Targets for molecular therapy of skin cancer.Semin Cancer Biol. Feb 2004; 14: 63-69Crossref PubMed Scopus (49) Google Scholar] Ras GTPases regulate cell proliferation, angiogenesis, apoptosis, and cellular morphology.[23.Green C.L. Khavari P.A. Targets for molecular therapy of skin cancer.Semin Cancer Biol. Feb 2004; 14: 63-69Crossref PubMed Scopus (49) Google Scholar] Ras and Raf, a downstream effector molecule, stimulate cell division, inhibit differentiation, and enhance expression of integrins, all changes characteristic of SCC.[24.Mercurio A.M. Invasive skin carcinoma--Ras and alpha6beta4 integrin lead the way.Cancer Cell. Mar 2003; 3: 201-202Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] The cascade involving Ras and downstream effector molecules might be a viable target for attacking SCC on the molecular level. The NF-kB family refers to conserved transcription factors implicated in regulation of apoptosis, differentiation and proliferation.[24.Mercurio A.M. Invasive skin carcinoma--Ras and alpha6beta4 integrin lead the way.Cancer Cell. Mar 2003; 3: 201-202Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] Blockade stimulates hyperproliferation in human epidermis in vitro. Mice with inhibited NF-kB show increased susceptibility to induction of SCC.[25.Budunova I.V. Perez P. Vaden V.R. Spiegelman V.S. Slaga T.J. Jorcano J.L. Increased expression of p50-NF-kappaB and constitutive activation of NF-kappaB transcription factors during mouse skin carcinogenesis.Oncogene. 1999; 18: 7423-7431Crossref PubMed Scopus (112) Google Scholar] Blockade along with induction of oncogenic Ras can transform human epidermis to a highly aggressive neoplasia indistinguishable from SCC.[26.Dajee M. Lazarov M. Zhang J.Y. et al.NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia.Nature. 2003; 421: 639-643Crossref PubMed Scopus (483) Google Scholar] The cDNK2A locus on 9p21 is widely mutated in a number of cancers.[23.Green C.L. Khavari P.A. Targets for molecular therapy of skin cancer.Semin Cancer Biol. Feb 2004; 14: 63-69Crossref PubMed Scopus (49) Google Scholar] It encodes a cyclin depenent kinase (CDK) inhibitor, p16[INK4A], and a p53 regulator that is translated by an alternative reading frame. The p16[INK4A] inhibits cell cycle progression in G1 by binding and inhibiting CDK4/6 kinases. CDK4/6 kinases phosphorylate retinoblastoma (Rb) proteins to remove the mid-G1 Rb block to cell cycle progression.[23.Green C.L. Khavari P.A. Targets for molecular therapy of skin cancer.Semin Cancer Biol. Feb 2004; 14: 63-69Crossref PubMed Scopus (49) Google Scholar] DNK4/6 is over expressed in SCC and is sufficient to induce SCC when co-expressed with oncogenic Ras.[27.Kubo Y. Murao K. Matsumoto K. Arase S. Molecular carcinogenesis of squamous cell carcinomas of the skin.J Med Invest. Aug 2002; 49: 111-117PubMed Google Scholar] Microarray techniques allow for analysis of differential gene expression between diseased and normal tissue. With careful interpretation investigators may be able to identify key differences in gene expression that may lead to better risk stratification and novel points for therapeutic intervention. Preliminary unique gene expression patterns have been observed in head and neck squamous cell carcinoma (HNSCC).[28.Sok J.C. Kuriakose M.A. Mahajan V.B. Pearlman A.N. DeLacure M.D. Chen F.A. Tissue-specific gene expression of head and neck squamous cell carcinoma in vivo by complementary DNA microarray analysis.Arch Otolaryngol Head Neck Surg. Jul 2003; 129: 760-770Crossref PubMed Scopus (49) Google Scholar] Such a molecular fingerprint has yet to be established for cutaneous SCC however this is the subject of ongoing collaborative efforts involving the Laboratory of Investigative Dermatology at the Rockefeller University and the Section of Mohs Micrographic and Dermatologic Surgery at the Weill Medical College of Cornell. Presently, several studies support the importance of differential expression of key genes in SCC and SCC cell lines. In one pilot study, p16[INK4A] was 85% sensitive and 96% specific in distinguishing Bowen’s disease from AK.[29.Salama M.E. Mahmood M.N. Qureshi H.S. Ma C. Zarbo R.J. Ormsby A.H. p16INK4a expression in actinic keratosis and Bowen's disease.Br J Dermatol. Nov 2003; 149: 1006-1012Crossref PubMed Scopus (51) Google Scholar] Dazard, et al, studied the response of normal keratinocytes and SCC to UVB and found up-regulation of CXC/CC chemokines, growth factors, pro-inflammatory mediators including S100A9, DNA repair genes, and proteases including MMP1 and MMP 10.[30.Dazard J.E. Gal H. Amariglio N. Rechavi G. Domany E. Givol D. Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: Implications for skin and epithelial cancer.Oncogene. 2003; 22: 2993-3006Crossref PubMed Scopus (85) Google Scholar] They found that Delta Np63 and PUMILIO, potential markers for maintenance of keratinocytes stem cells, were down-regulated. Gariboldi, et al, found that the serpin like SCCA2 was associated with younger onset in 2 series of patients with cutaneous SCC.[31.Gariboldi M. Peissel B. Fabbri A. et al.SCCA2-like serpins mediate genetic predisposition to skin tumors.Cancer Res. 2003; 63: 1871-1875PubMed Google Scholar] The pathogenesis of skin cancer in the general population and in organ transplant recipients involves ultraviolet light (UVL).[32.Grossman D. Leffell D.J. The molecular basis of nonmelanoma skin cancer: New understanding.Arch Dermatol. Oct 1997; 133: 1263-1270Crossref PubMed Google Scholar] Tumor initiation occurs through UV induced genetic changes in keratinocytes DNA.[20.Brash D.E. Ziegler A. Jonason A.S. Simon J.A. Kunala S. Leffell D.J. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.J Investig Dermatol Symp Proc. Apr 1996; 1: 136-142PubMed Google Scholar, 32.Grossman D. Leffell D.J. The molecular basis of nonmelanoma skin cancer: New understanding.Arch Dermatol. Oct 1997; 133: 1263-1270Crossref PubMed Google Scholar] In addition, UV specific changes take place in tumor suppressor p53. Thus UVL acts as both tumor initiator and tumor promoter.[20.Brash D.E. Ziegler A. Jonason A.S. Simon J.A. Kunala S. Leffell D.J. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.J Investig Dermatol Symp Proc. Apr 1996; 1: 136-142PubMed Google Scholar, 32.Grossman D. Leffell D.J. The molecular basis of nonmelanoma skin cancer: New understanding.Arch Dermatol. Oct 1997; 133: 1263-1270Crossref PubMed Google Scholar] HPV is involved in the pathogenesis of SCC.[33.Viac J. Chardonnet Y. Chignol M.C. Schmitt D. Papilloma viruses, warts, carcinoma and Langerhans cells.In Vivo. May-Jun 1993; 7: 207-212PubMed Google Scholar] HPV types 6, 11, 16 and 18 have been associated with cervical cancers.[34.Bosch F.X. Munoz N. The viral etiology of cervical cancer.Virus Res. Nov 2002; 89: 183-190Crossref PubMed Scopus (167) Google Scholar] HPV types 5 and 8 are associated with epidermodysplasia verruciformis.[35.Orth G. Favre M. Majewski S. Jablonska S. Epidermodysplasia verruciformis defines a subset of cutaneous human papillomaviruses.J Virol. May. 2001; 75: 4952-4953Crossref PubMed Scopus (33) Google Scholar] HPV 16 has been implicated in SCC occurring on the digits.[36.Alam M. Caldwell J.B. Eliezri Y.D. Human papillomavirusassociated digital squamous cell carcinoma: Literature review and report of 21 new cases.J Am Acad Dermatol. Mar 2003; 48: 385-393Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar] HPV 16 and 18 have associated E6 and E7 proteins that inhibit tumor suppressor p53.[37.Jackson S. Storey A. E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage.Oncogene. 2000; 19: 592-598Crossref PubMed Scopus (175) Google Scholar] In addition it has been shown that E6 may inhibit UV induced apoptosis by a p53 independent mechanism thus acting as a p53 independent tumor promoter by allowing propagation of atypical keratinocytes. Furthermore it has been shown that EDV associated HPV types are found in SCCs from OTRs.[38.Bouwes Bavinck J.N. Feltkarmp M. Struijk L. ter Scheggett J. Human papillomavirus infection and skin cancer risk in organ transplant recipients.J Investig Dermatol Symp Proc. Dec 2001; 6: 207-211Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar] This is in agreement with Stockfleth, et al, who recently showed that HPV DNA was detected more frequently in SCCs from OTRs compared to non-OTRs (75% vs 37%) and that HPV 5 and 8 were detected most frequently in SCCs from transplant recipients.[39.Stockfleth E. Nindl I. Sterry W. Ulrich C. Schmook T. Meyer T. Human papillomaviruses in transplant-associated skin cancers.Dermatol Surg. Apr 2004; 30: 604-609Crossref PubMed Scopus (123) Google Scholar] Euvrard, et al, examined warts, actinic keratoses and SCCs from renal transplant recipients for the presence of HPV types 1a, 2a, 5, 16, and 18.[40.Euvrard S. Chardonnet Y. Pouteil-Noble C. et al.Association of skin malignancies with various and multiple carcinogenic and noncarcinogenic human papillomaviruses in renal transplant recipients.Cancer. 1993; 72: 2198-2206Crossref PubMed Scopus (120) Google Scholar] HPV DNA was detected in 44 of 86 specimens overall including 14 of 17 warts, 4 of 17 actinic keratoses, and 14 of 30 SCC. Benign types 1 and 2 were detected in 5 SCC. Opinion differs as to whether certain HLA types confer protection or risk.[10.Espana A. Redondo P. Fernandez A.L. et al.Skin cancer in heart transplant recipients.J Am Acad Dermatol. Mar 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (89) Google Scholar, 15.Ong C.S. Keogh A.M. Kossard S. Macdonald P.S. Spratt P.M. Skin cancer in Australian heart transplant recipients.J Am Acad Dermatol. Jan 1999; 40: 27-34Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 16.Jensen P. Hansen S. Moller B. et al.Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.J Am Acad Dermatol. Feb 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar] There was no association with haplotypes HLA-A3, HLA-A11, HLA-DR and mismatches for HLA-B in the study of heart transplant patients by Espana, et, al. In contrast, HLA-DR homozygosity was associated with skin cancer and HLA-DR7, HLA-A1 and HLA-A11 seemed to be protective in a study by Ong. Major factors associated with increased risk for skin cancer are summarized in Table 1.Table 1Factors Associated with SCC in Organ Transplant RecipientsRisk FactorReferenceSun ExposureLindelof, et al. (18.Lindelof B. Sigurgeirsson B. Gabel H. Stern R.S. Incidence of skin cancer in 5356 patients following organ transplantation.Br J Dermatol. Sep 2000; 143: 513-519PubMed Google Scholar)HPV 5 and 8Euvrard, et al., (40.Euvrard S. Chardonnet Y. Pouteil-Noble C. et al.Association of skin malignancies with various and multiple carcinogenic and noncarcinogenic human papillomaviruses in renal transplant recipients.Cancer. 1993; 72: 2198-2206Crossref PubMed Scopus (120) Google Scholar) Stockfelth, et al. (39.Stockfleth E. Nindl I. Sterry W. Ulrich C. Schmook T. Meyer T. Human papillomaviruses in transplant-associated skin cancers.Dermatol Surg. Apr 2004; 30: 604-609Crossref PubMed Scopus (123) Google Scholar)Fair skinLampros, et al., (10.Espana A. Redondo P. Fernandez A.L. et al.Skin cancer in heart transplant recipients.J Am Acad Dermatol. Mar 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (89) Google Scholar) Espana, et al. (13.Lampros T.D. Cobanoglu A. Parker F. Ratkovec R. Norman D.J. Hershberger R. Squamous and basal cell carcinoma in heart transplant recipients.J Heart Lung Transplant. Jun 1998; 17: 586-591PubMed Google Scholar)Heart transplantJensen, et al., (16.Jensen P. Hansen S. Moller B. et al.Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.J Am Acad Dermatol. Feb 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar) Euvrard, et al. (11.Euvrard S. Kanitakis J. Pouteil-Noble C. Claudy A. Touraine J.L. Skin cancers in organ transplant recipients.Ann Transplant. 1997; 2: 28-32PubMed Google Scholar)Intense immunosuppressionPreciado, et al. (69.Preciado D.A. Matas A. Adams G.L. Squamous cell carcinoma of the head and neck in solid organ transplant recipients.Head Neck. Apr 2002; 24: 319-325Crossref PubMed Scopus (54) Google Scholar) Euvrard, et al. (11.Euvrard S. Kanitakis J. Pouteil-Noble C. Claudy A. Touraine J.L. Skin cancers in organ transplant recipients.Ann Transplant. 1997; 2: 28-32PubMed Google Scholar)Older age at transplantJensen, et al., (16.Jensen P. Hansen S. Moller B. et al.Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.J Am Acad Dermatol. Feb 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar) Euvrard, et al. (11.Euvrard S. Kanitakis J. Pouteil-Noble C. Claudy A. Touraine J.L. Skin cancers in organ transplant recipients.Ann Transplant. 1997; 2: 28-32PubMed Google Scholar)Male sexNaldi, et al., (17.Naldi L. Fortina A.B. Lovati S. et al.Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study.Transplantation. 2000; 70: 1479-1484Crossref PubMed Scopus (124) Google Scholar) Lampros, et al. (13.Lampros T.D. Cobanoglu A. Parker F. Ratkovec R. Norman D.J. Hershberger R. Squamous and basal cell carcinoma in heart transplant recipients.J Heart Lung Transplant. Jun 1998; 17: 586-591PubMed Google Scholar) Open table in a new tab Immunosuppression is key to preventing graft rejection and optimizing graft survival. However, immunosuppressive regimens have been associated with increased rates of skin cancer. Studies suggest that both azathioprine and cyclosporine contribute to increased risk for skin cancer through direct carcinogenic effects as well as decreased immunosurveillance.[4.Berg D. Otley C.C. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management.J Am Acad Dermatol. Jul 2002; 47 (quiz 18–20): 1-17Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar, 41.Stockfleth E. Ulrich C. Meyer T. Christophers E. Epithelial malignancies in organ transplant patients: Clinical presentation and new methods of treatment.Recent Results Cancer Res. 2002; 160: 251-258Crossref PubMed Scopus (123) Google Scholar, 42.Penn I. De novo tumors in pediatric organ transplant recipients.Transplant Proc. Feb 1994; 26: 1-2PubMed Google Scholar, 43.Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients.Clin Transpl. 1994; : 99-109PubMed Google Scholar, 44.Penn I. Posttransplantation de novo tumors in liver allograft recipients.Liver Transpl Surg. Jan 1996; 2: 52-59Crossref PubMed Scopus (128) Google Scholar] Intensity and duration of immune suppression appear to correlate with risk of aggressive SCC.[4.Berg D. Otley C.C. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management.J Am Acad Dermatol. Jul 2002; 47 (quiz 18–20): 1-17Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar] Azathioprine inhibits T and B cell proliferation by inhibiting nucleotide synthesis.[45.Hong J.C. Kahan B.D. Immunosuppressive agents in organ transplantation: past, present, and future.Semin Nephrol. Mar 2000; 20: 108-125PubMed Google Scholar] It is a mutagen, a photosensitizer and an immunosuppressant. A metabolite of azathioprine, 6-thioguanine has been found in higher concentrations in red blood cells from renal transplant recipients with skin cancer.[46.Chan G.L. Erdmann G.R. Gruber S.A. Matas A.J. Canafax D.M. Azathioprine metabolism: Pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients.J Clin Pharmacol. Apr 1990; 30: 358-363Crossref PubMed Scopus (107) Google Scholar] Azathioprine has been associated with high numbers of UV induced tumors in animals.[47.Harvey J.J. East J. Katz F.E. Azathioprine-induced lymphocytic neoplasms of NZB mice lack ecotropic murine leukaemia virus.Int J Cancer. Feb 1979; 23: 217-223Crossref PubMed Scopus (5) Google Scholar] Cyclosporine inhibits IL-2 transcription, enhances TGF-β expression and thus inhibits T cell function.[48.Flechner S.M. Cyclosporine: A new and promising immunosuppressive agent.Urol Clin North Am. May 1983; 10: 263-275PubMed Google Scholar] Anima