Journal of the National Cancer Institute Advance Access published online on August 14, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm085
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© The Author 2007. Published by Oxford University Press.
Increased Incidence of Squamous Cell Carcinoma of Eye After Kidney Transplantation
Affiliations of authors: National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia (CMV, AEG, MTvL, ML, JMK); Australia and New Zealand Dialysis and Transplant Registry, Queen Elizabeth Hospital, Adelaide, Australia (SPM, JRC, ACW); Disciplines of Medicine and Public Health, University of Adelaide, Adelaide, Australia (SPM); Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand (MREM); Centre for Transplant and Renal Research, Millennium Institute, Westmead Hospital, University of Sydney, Sydney, Australia (JRC, ACW)
Correspondence to: Claire M. Vajdic, PhD, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Level 2/376 Victoria St, Darlinghurst NSW 2010, Australia (e-mail: cvajdic{at}nchecr.unsw.edu.au).
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ABSTRACT |
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Squamous cell carcinoma (SCC) of the eye occurs at substantially increased rates in individuals with human immunodeficiency virus (HIV) infection, but it has not been reported in individuals with iatrogenic or congenital immune deficiency. In a national, population-based cohort of 10180 renal transplantation patients from Australia with 86898 person-years of follow-up, we ascertained primary incident cancers diagnosed in 1982–2003 by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. Standardized incidence ratios (SIRs) of cancer were calculated using age-, sex-, calendar year–, and state/territory–specific population cancer incidence rates. Statistical tests were two-sided. Five patients were diagnosed with ocular SCC after kidney transplantation (0.26 were expected), and the incidence was increased 20-fold (SIR = 19.5, 95% confidence interval [CI] = 6.3 to 45.5). Compared with the entire cohort, the five patients with ocular SCC after transplantation were more likely to have resided in the subtropical state of Queensland (60% versus 17%, P = .04), to have had end-stage kidney disease as a result of glomerulonephritis (100% versus 46%, P = .02), and to have a history of cutaneous SCC (100% versus 29%, P = .002). The increased incidence of ocular SCC after kidney transplantation and after HIV infection strongly suggests that this neoplasm is an immune deficiency–associated cancer. Our data also support an interaction between immune suppression and sun exposure in the development of ocular SCC after kidney transplantation.
Prior knowledge Squamous cell carcinoma of the eye occurs at increased rates in persons who are infected with human immunodeficiency virus and thus have compromised immune systems. However, this disease has not been reported to be associated with immune deficiency caused by medical treatment. Study design In this population-based cohort study, data from transplant and cancer registries were used to compare the incidence of squamous cell carcinoma in patients with end-stage kidney disease with that in the general population. Contribution A pronounced increase in the incidence of squamous cell carcinoma of the eye was observed in patients who had had kidney transplants and were therefore immunosuppressed. Implications The results of this study strongly suggest that squamous cell carcinoma of the eye is an immune deficiency–associated cancer. Limitations The results could be biased by heightened surveillance generally in this population. How this disease develops in the context of immune suppression remains to be determined.
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Squamous cell carcinoma (SCC) of the eye occurs at substantially increased rates (as much as 13 times higher) in individuals with human immunodeficiency virus (HIV) infection (1–7), but despite the association of this cancer with this immunosuppressed state, it has not been reported to be associated with iatrogenic or congenital immune deficiency, of which there have been few long-term population-based cohort studies. The increased risk of ocular SCC in HIV infection appears to be associated with exposure to high levels of solar ultraviolet radiation (6), and possibly with infection with high-risk human papillomavirus (HPV) subtypes (8,9). Sun exposure (10–13) and perhaps HPV infection (14,15) are also risk factors for the development of ocular SCC in immune-competent populations.
Ocular SCCs are believed to originate in the limbus (13), a transition zone between the bulbar conjunctival epithelium and corneal epithelium. They typically involve both the conjunctiva and cornea but are usually referred to as conjunctival SCCs.
To investigate the role of immune suppression in the etiology of this ocular SCC, we studied the incidence of this disease after kidney transplantation in an Australian population-based cohort of 10180 patients with end-stage kidney disease who were treated by kidney transplantation before January 1, 1982, and still alive at January 1, 1982, or transplanted after this date up to September 30, 2003. Patients were included regardless of their cancer history before transplantation. Data from all of these patients had been submitted to the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), a population-based registry of all patients who start maintenance dialysis or receive kidney transplantation in Australia or New Zealand (16). Ethical approval was obtained from nine institutional review boards. Patients were followed for an average of 8.5 years after transplantation.
Data on cancer in the subjects in our study were obtained from the National Cancer Statistics Clearing House, a compilation of data from all eight Australian population-based cancer registries, to which all cases of primary invasive cancer, except nonmelanoma skin cancer, are reported as required by statute (17). Data were available from 1982 to the end of 2001, 2002, or 2003, depending on the jurisdiction of cancer registration. Record linkage was performed using an established probabilistic technique, matching on each registrant's name, sex, date of birth, date of death (if deceased), and state/territory of residence. Population cancer incidence rates by 5-year age group, sex, year, and state/territory for each year from 1982 to 2001 were obtained for SCCs originating in the conjunctiva or cornea; rates for 2001 were used for later years. Skin carcinoma diagnoses of subjects in our study were obtained directly from ANZDATA, during active follow-up for each registrant.
We calculated the standardized incidence ratio (SIR) of SCC with exact (Poisson) 95% confidence intervals (CIs) using Stata software (version 8; Stata Corporation, College Station, TX). Person-years were accrued from 1982, included all follow-up time after transplantation, and were terminated at death, loss to follow-up, December 31 of the last year for which National Cancer Statistics Clearing House records were available, or the date of cancer diagnosis. Cancer incidence before transplantation was also examined (18). Characteristics of patients diagnosed with ocular SCC were compared with those for the entire cohort, and differences were tested for statistical significance using the chi-square test and Fisher exact test or the Student t test. All statistical tests were two-sided.
Based on 86898 person-years of follow-up, we observed a 20-fold increase in the incidence of SCC of the eye after kidney transplantation (SIR = 19.5, 95% CI = 6.3 to 45.5) when immunosuppressive regimens are used. Five patients were diagnosed with ocular SCC (Table 1), whereas 0.26 were expected. The tissue of origin was recorded as conjunctiva in three cases and cornea in two cases. In contrast, there were no cases of ocular SCC during dialysis (0.43 expected) and one case in the 5 years before renal replacement therapy (survival-adjusted 0.60 expected, SIR = 1.66, 95% CI = 0.04 to 9.25).
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Compared with the entire cohort of patients who received one or more kidney grafts (n = 10180), the patients with ocular SCC after transplantation (n = 5; Table 1) tended to reside in the subtropical state of Queensland, Australia (60% versus 17%, P = .04) and to have progressed to end-stage kidney disease as a result of glomerulonephritis (100% versus 46%, P = .02). Mean age at transplantation and proportions that were male and born in Australia or of Caucasian ethnicity were not statistically significantly different. All ocular SCC patients had a functioning graft at the time of SCC diagnosis, and three of five were taking a triple-therapy immunosuppressant drug combination consisting of a corticosteroid, cytostatic drug, and calcineurin inhibitor (Table 1). In addition, all patients with ocular SCC were diagnosed with one or more skin carcinomas, either before (n = 2) or after (n = 3) their ocular SCC diagnosis. In contrast, only 29% of the cohort had a skin carcinoma diagnosis (P = .002).
The striking increase in the incidence of ocular SCC after kidney transplantation, together with the increased incidence of ocular SCC in HIV infection (1–7), strongly suggests that this neoplasm is an immune deficiency–associated cancer. The association of indirect measures of history of high sun exposure—residence in a subtropical location and personal history of cutaneous SCC—support an interaction between immune suppression and sun exposure in carcinogenesis. The fact that all patients who developed SCC had a history of glomerulonephritis may be explained by receipt of immunosuppressive agents before transplantation. An increased incidence of eye cancer or ocular SCC after transplantation has not, to our knowledge, been reported previously; however, it is likely that prior studies had limited power to detect such an association because of the rarity of the neoplasm (0.03 per 100000 among whites in the United States) (13).
A possible source of bias in our study is heightened surveillance for cancer generally in this population, but when the incidence of all cancer types was examined, there was no evidence that increased surveillance played a major role (18). Another potential source of bias is misclassification error; however, our linkage methodology was highly sensitive and specific in identifying cases of AIDS-related non-Hodgkin lymphoma (19). Furthermore, the accuracy and completeness of end-stage kidney disease registration is routinely verified by active follow-up, and Australian cancer registration was reported to be of high quality (20).
The observation from large-scale population-based registry studies that the incidence of ocular SCC is markedly increased during HIV infection and, now in our study, during iatrogenic immune suppression indicates a strong association with immune deficiency. The carcinogenic mechanism is not known, but the available evidence suggests an effect of solar ultraviolet radiation and possibly HPV infection.
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Funding |
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Cancer Council New South Wales (RG 47/03); National Health and Medical Research Council (Postdoctoral Research Fellowship ID 209668 to C.M.V., Postgraduate Scholarship ID 401131 to M.T.v.L.); Cancer Institute New South Wales Research Scholar Award (06/RSA/1/28 to M.T.v.L.); Australian Government Department of Education, Science and Training (International Postgraduate Research Scholarship to A.C.W.); University of Sydney (International Postgraduate Research Award to A.C.W.). The ANZDATA Registry administrative office is supported by funding from the Australian Government Department of Health and Ageing, the New Zealand Ministry of Health and Kidney Health Australia; data collection costs are borne by contributing renal units.
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NOTES |
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Professor J. R. Chapman is on advisory boards and speaker panels for Astellas, Novartis, Wyeth, and Hoffmann la Roche, and he has received research support from the National Health and Medical Research Council, Juvenile Diabetes Foundation International, Novartis, Wyeth, Jannsen-Cilag, and Hoffmann la Roche. Associate Professor A. E. Grulich is on the advisory board for the Gardasil HPV vaccine for the Commonwealth Serum Laboratories. The National Centre in HIV Epidemiology and Clinical Research is supported by the Australian Government Department of Health and Aging. No other authors reported financial disclosures.
The authors gratefully acknowledge the dedication and care with which dialysis and transplantation units throughout Australia have regularly submitted the information on which this analysis has been performed and the ANZDATA staff who have created and maintained the database so accurately. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the Australia and New Zealand Dialysis and Transplant Registry. The authors are also grateful to the staff of the state and territory cancer registries for the use of their data. The authors also acknowledge assistance by the Australian Institute of Health and Welfare and the Cancer Council Victoria in the conduct of this study.
The authors take full responsibility for the study design, data collection, analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.
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REFERENCES |
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(1) Kestelyn P, Stevens AM, Ndayambaje A, Hanssens M, van de Perre P. HIV and conjunctival malignancies. Lancet (1990) 36:51–2.
(2) Ateenyi-Agaba C. Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda. Lancet (1995) 345:695–6.[CrossRef][ISI][Medline]
(3) Goedert JJ, Cote TR. Conjunctival malignant disease with AIDS in USA. Lancet (1995) 346:257–8.[ISI][Medline]
(4) Newton R. A review of the aetiology of squamous cell carcinoma of the conjunctiva. Br J Cancer (1996) 74:1511–3.[ISI][Medline]
(5) Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA (2001) 285:1736–45.
(6) Newton R, Ziegler J, Ateenyi-Agaba C, Bousarghin L, Casabonne D, Beral V, et al. The epidemiology of conjunctival squamous cell carcinoma in Uganda. Br J Cancer (2002) 87:301–8.[CrossRef][ISI][Medline]
(7) Mbulaiteye SM, Katabira ET, Wabinga H, Parkin DM, Virgo P, Ochai R, et al. Spectrum of cancers among HIV-infected persons in Africa: the Uganda AIDS-Cancer Registry Match Study. Int J Cancer (2006) 118:985–90.[CrossRef][ISI][Medline]
(8) Ateenyi-Agaba C, Dai M, Le Calvez F, Katongole-Mbidde E, Smet A, Tommasino M, et al. TP53 mutations in squamous-cell carcinomas of the conjunctiva: evidence for UV-induced mutagenesis. Mutagenesis (2004) 19:399–401.
(9) Ateenyi-Agaba C, Weiderpass E, Smet A, Dong W, Dai M, Kahwa B, et al. Epidermodysplasia verruciformis human papil-lomavirus types and carcinoma of the conjunctiva: a pilot study. Br J Cancer (2004) 90:1777–9.[ISI][Medline]
(10) Lee GA, Williams G, Hirst LW, Green AC. Risk factors in the development of ocular surface epithelial dysplasia. Ophthalmology (1994) 101:360–4.[ISI][Medline]
(11) Kraemer KH, Lee M, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. Arch Dermatol (1994) 130:1018–21.[Abstract]
(12) Newton R, Ferlay J, Reeves G, Beral V, Parkin DM. Effect of ambient solar ultraviolet radiation on incidence of squamous cell carcinoma of the eye. Lancet (1996) 347:1450–1.[CrossRef][ISI][Medline]
(13) Sun EC, Fears TR, Goedert JJ. Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiol Biomarkers Prev (1997) 6:73–7.[Abstract]
(14) McDonnel JM, Mayr AJ, John Martin W. DNA of human papillomarivurs type 16 in dysplastic and malignant lesions of the conjunctiva and cornea. N Engl J Med (1989) 320:1442–6.[Abstract]
(15) Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F. WHO International Agency for Research on Cancer. Carcinogenicity of human papillomaviruses. Lancet Oncol (2005) 6:204.[CrossRef][ISI][Medline]
(16) McDonald SP, Excell L, eds. ANZDATA Registry Report 2005 (2005) Adelaide (South Australia): Australia and New Zealand Dialysis and Transplant Registry.
(17) Australian Institute of Health and Welfare (AIHW). Australasian Association of Cancer Registries (AACR). In: Cancer in Australia 2001. AIHW Cat. No. CAN 23. Canberra (Australia): Australian Institute of Health and Welfare. 2004 Cancer Series No. 28.
(18) Vajdic CM, McDonald SP, McCredie MRE, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA (2006) 296:2823–31.
(19) Grulich AE, Wan X, Coates M, Day P, Kaldor JM. Validation of a non-identifying method of linking cancer and AIDS register data. J Epidemiol Biostat (1996) 1:207–12.
(20) Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, eds. Cancer incidence in five continents, volume VIII. IARC Scientific Publication No. 155 (2002) Lyon (France): IARC Press.
Manuscript received November 6, 2006; revised June 13, 2007; accepted June 26, 2007.
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