Does thioguanine therapy increase the risk of skin cancer?

Yes, thioguanine therapy significantly increases skin cancer risk and requires lifelong surveillance and photoprotection.

Thioguanine (a thiopurine) approximately doubles the risk of nonmelanoma skin cancer (NMSC), and this risk persists even after drug cessation due to permanent DNA damage. 1

Magnitude of Risk

• Thiopurine use for longer than 1 year increases NMSC risk 4.3-fold (adjusted OR 4.3; 95% CI 3.1–6.0) compared to non-users 1
• In a large study of 108,579 IBD patients, thiopurine use was associated with an almost 2-fold increase in NMSC development 1
• Patients with prior basal cell carcinoma have higher recurrence rates when continuing thiopurine therapy 1

Mechanism of Carcinogenesis

The skin cancer risk stems from a unique photochemical mechanism:

• 6-thioguanine (6-TG) becomes permanently incorporated into cellular DNA with maximum absorbance at 340 nm (UVA wavelength) 1, 2
• UVA photons absorbed by 6-TG-substituted DNA generate reactive oxygen species, causing lethal and mutagenic DNA damage 1, 2, 3
• This differs from normal DNA, which poorly absorbs UVA radiation 1
• The DNA damage includes transcription-blocking lesions, interstrand crosslinks, and protein oxidation that compromise DNA repair mechanisms 3, 4, 5

Critical Clinical Pitfall: Risk Persists After Drug Cessation

The DNA damage is permanent—skin cancer risk continues indefinitely after stopping thioguanine. 2 This is because:

• 6-TG remains incorporated in DNA even after drug cessation 2
• The mutagenic DNA damage persists in the genome 2
• Never reassure patients that risk normalizes immediately after stopping therapy 2

Mandatory Management Strategy

During Active Therapy

• Annual total body skin examination (TBSE) by dermatology for all patients on thiopurines 1
• Rigorous photoprotection measures (see below) 1

After Drug Cessation

• Continue annual TBSE indefinitely, particularly for patients treated longer than 1 year 1, 2
• Maintain lifelong photoprotection because DNA photosensitization persists 2
• Patients with multiple dysplastic keratoses or prior NMSCs require examination in dedicated dermatology clinics 2

Essential Photoprotection Measures

All patients on thioguanine (current or former) must implement:

• Avoid peak UV hours (10 AM to 4 PM) and seek shade whenever possible 2
• Wear protective clothing: wide-brimmed hats, long sleeves covering sun-exposed areas 2
• Apply broad-spectrum sunscreen SPF ≥30 daily to all sun-exposed skin, even on cloudy days 2
• Understand that azathioprine/thioguanine increases UVA sensitivity in normal skin, making standard sun exposure more dangerous 1, 2

Patient Counseling Points

• Discuss that skin cancer is the major exception to the otherwise favorable long-term safety profile of thiopurines 1
• Emphasize that UVA radiation (95% of solar UV) is the primary culprit, not just UVB 1
• Explain that this is a lifelong risk requiring permanent lifestyle modifications 2
• Instruct patients to immediately report any suspicious lesions (bleeding, painful, rapidly growing, or protuberant) 2

Comparison to Other Immunosuppressants

• Thiopurines carry higher NMSC risk than methotrexate, mycophenolate, or ciclosporin in IBD populations 1
• Anti-TNF agents also increase NMSC risk, but the mechanism differs from thiopurines 1
• Solid-organ transplant recipients on multiple immunosuppressants have the highest risk (>200-fold elevation), but this reflects polypharmacy 1