Level of UV Exposure, Skin Type, and Age Are More Important than Thiopurine Use for Keratinocyte Carcinoma Development in IBD Patients



Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort.


Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire.


A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%, p = 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61 years old versus less than 30 years old (OR 6.76; 95% CI 2.38–19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6–6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4–10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9–16.0).


Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.

This is a preview of subscription content, access via your institution.

Fig. 1


  1. 1.

    Fransen M, Karahalios A, Sharma N, English DR, Giles GG, Sinclair RD. Non-melanoma skin cancer in Australia. Med J Aust. 2012;197:565–568.

    Article  Google Scholar 

  2. 2.

    Annese V, Beaugerie L, Egan L, et al. European evidence-based consensus: inflammatory bowel disease and malignancies. J Crohns Colitis. 2015;9:945–965.

    Article  Google Scholar 

  3. 3.

    Kricker A, Armstrong BK, English DR, Heenan PJ. Pigmentary and cutaneous risk factors for non-melanocytic skin cancer—a case–control study. Int J Cancer. 1991;48:650–662.

    CAS  Article  Google Scholar 

  4. 4.

    Bulliard JL, Cox B, Elwood JM. Latitude gradients in melanoma incidence and mortality in the non-Maori population of New Zealand. Cancer Causes Control. 1994;5:234–240.

    CAS  Article  Google Scholar 

  5. 5.

    Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol. 1995;131:157–163.

    CAS  Article  Google Scholar 

  6. 6.

    Nambour Study Group, Green A, Battistutta D, Hart V, Leslie D, Weedon D. Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. Am J Epidemiol. 1996;144:1034–1040.

    Article  Google Scholar 

  7. 7.

    Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002;50:485–489.

    CAS  Article  Google Scholar 

  8. 8.

    Dubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol. 2004;2:731–743.

    CAS  Article  Google Scholar 

  9. 9.

    Timmer A, Patton PH, Chande N, McDonald JW, MacDonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016;5:CD000478.

    Google Scholar 

  10. 10.

    Gomollon F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management. J Crohns Colitis. 2017;11:3–25.

    Article  Google Scholar 

  11. 11.

    O’Donovan P, Perrett CM, Zhang X, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 2005;309:1871–1874.

    Article  Google Scholar 

  12. 12.

    Parrish JA. Immunosuppression, skin cancer, and ultraviolet A radiation. N Engl J Med. 2005;353:2712–2713.

    CAS  Article  Google Scholar 

  13. 13.

    Jensen P, Moller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42:307.

    CAS  Article  Google Scholar 

  14. 14.

    Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–1691.

    Article  Google Scholar 

  15. 15.

    Annese V, Beaugerie L, Egan L, et al. European evidence-based consensus: inflammatory bowel disease and malignancies. J Crohn’s Colitis. 2015;9:945–965.

    Article  Google Scholar 

  16. 16.

    Abbas AM, Almukhtar RM, Loftus EV, Lichtenstein GR, Khan N. Risk of melanoma and non-melanoma skin cancer in ulcerative colitis patients treated with thiopurines: a nationwide retrospective cohort. Am J Gastroenterol. 2014;109:1781–1793.

    CAS  Article  Google Scholar 

  17. 17.

    Armstrong RG, West J, Card TR. Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study. Am J Gastroenterol. 2010;105:1604–1609.

    CAS  Article  Google Scholar 

  18. 18.

    Van Schaik FD, van Oijen MG, HM Smeets, van der Heijden GJ, Siersema PD, Oldenburg B. Risk of nonmelanoma skin cancer in patients with inflammatory bowel disease who use thiopurines is not increased. Clin Gastroenterol Hepatol. 2011;9:449e1–450e1. author reply 450–451.

    Google Scholar 

  19. 19.

    Setshedi M, Epstein D, Winter TA, Myer L, Watermeyer G, Hift R. Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study. J Gastroenterol Hepatol. 2012;27:385–389.

    CAS  Article  Google Scholar 

  20. 20.

    Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141:1621–28e1–5.

    Article  Google Scholar 

  21. 21.

    Ariyaratnam J, Subramanian V. Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2014;109:163–169.

    CAS  Article  Google Scholar 

  22. 22.

    Cust AE, Pickles KM, Goumas C, et al. Accuracy of self-reported nevus and pigmentation phenotype compared with clinical assessment in a population-based study of young Australian adults. Cancer Epidemiol Biomark Prev. 2015;24:736–743.

    Article  Google Scholar 

  23. 23.

    Lin AN, Carter DM. Skin cancer in the elderly. Dermatol Clin. 1986;4:467–471.

    CAS  Article  Google Scholar 

  24. 24.

    Green A, Beardmore G, Hart V, Leslie D, Marks R, Staines D. Skin cancer in a Queensland population. J Am Acad Dermatol. 1988;19:1045–1052.

    CAS  Article  Google Scholar 

  25. 25.

    Harvey I, Lear JT, Szeimies RM. Non-melanoma skin cancer. BMJ. 1989;299:1118–1120.

    CAS  Article  Google Scholar 

  26. 26.

    Long MD, Herfarth HH, Pipkin CA, Porter CQ, Sandler RS, Kappelman MD. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2010;8:268–274.

    Article  Google Scholar 

  27. 27.

    Camus M, Seksik P, Bourrier A, et al. Long-term outcome of patients with Crohn’s disease who respond to azathioprine. Clin Gastroenterol Hepatol. 2013;11:389–394.

    CAS  Article  Google Scholar 

  28. 28.

    Singh H, Nugent Z, Demers AA, et al. Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. Gastroenterology. 2011;141:1612–1620.

    Article  Google Scholar 

  29. 29.

    Cockburn M, Hamilton A, Mack T. Recall bias in self-reported melanoma risk factors. Am J Epidemiol. 2001;153:1021–1026.

    CAS  Article  Google Scholar 

  30. 30.

    Parr CL, Hjartåker A, Laake P, Lund E, Veierød MB. Recall bias in melanoma risk factors and measurement error effects: a nested case-control study within the Norwegian Women and Cancer Study. Am J Epidemiol. 2009;169:257–266.

    Article  Google Scholar 

  31. 31.

    Morze CJ, Olsen CM, Perry SL, et al. Good test-retest reproducibility for an instrument to capture self-reported melanoma risk factors. J Clin Epidemiol. 2012;65:1329–1336.

    Article  Google Scholar 

  32. 32.

    Australian Institute of Health and Welfare. 2016. Skin cancer in Australia. Cat. no. CAN 96. Canberra: AIHW.

Download references


This work was supported by an educational grant from Abbvie. David Whiteman has received Research Fellowship (APP1058522) from the National Health and Medical Research Council of Australia (NHMRC).

Author information



Corresponding author

Correspondence to Yang Wu.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2406 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, Y., Ghaly, S., Kerr, S. et al. Level of UV Exposure, Skin Type, and Age Are More Important than Thiopurine Use for Keratinocyte Carcinoma Development in IBD Patients. Dig Dis Sci 65, 1172–1179 (2020). https://doi.org/10.1007/s10620-019-05818-w

Download citation


  • Immunosuppression
  • Inflammatory bowel disease
  • Skin cancer