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The pathogenesis of skin cancer in the immunosuppressed: does it differ?

Hofbauer, G.

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doi: 10.1097/
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Although the origin of post-transplant skin cancer is multifactorial, immunosuppressive treatments play a key role in most cases, and trigger the special clinical and progressive aspects observed in OTRs. All immunosuppressants allow cancer growth while inducing a decrease of immunosurveillance. In addition, some immunosuppressants have specific oncogenic properties. Most recently, ATF3 was recognized as a transcription factor upregulated by cyclosporin A in keratinocytes, thus driving keratinocytes to SCC formation.

In summary, all immunosuppressive agents contribute to skin cancer formation in OTRs. The most effective measure in reducing the incidence of SCC is lowering the total immunosuppression. Within a given band of immunosuppression, introducing mTOR inhibitors, or substituting them for calcineurin inhibitors, or switching antimetabolites away from azathioprine may further reduce SCC formation.

Inflammation caused by the immune system was long assumed to be beneficial in fighting cancer, as local immunosurveillance increases and therefore seemed likely to contribute to early elimination of proliferating malignant cells. Current evidence, however, suggests that inflammation may be a double-edged sword. Especially at a low grade, inflammation may simultaneously initiate and promote cancer formation. This phenomenon has been well documented for other cancers such as colon cancer, but there is scant data on SCC, which is less well studied than other cancers in general and even less so in the setting of organ transplant. Nevertheless, the findings from several current and pre-publication studies are relevant to SCC, suggesting that a chronic smouldering inflammation may well contribute to tumour formation in SCC.

Knowledge continues to evolve regarding SCC in OTRs, with promising treatment implications. HPV-induced hyperkeratotic lesions may help to identify OTRs at increased risk for SCC in need of more intensive dermatological surveillance. Drugs contributing to photosensitivity of the skin such as Aza may be replaced with alternatives less damaging to DNA such as mycophenolate. The systemic availability of melanocortin receptor ligands may allow more complete photoprotection. Immunosuppressive medication may be modulated to reduce SCC formation and to control Kaposi sarcoma by the introduction of mTOR inhibitors. If research bears out the suspicion that low-grade inflammation may drive carcinogenesis, then anti-inflammatory agents may prove helpful in preventing SCC development. Each of these possibilities deserves careful exploration in the coming years, with good cause to hope for greater clarity for the physician and a decreased burden upon OTRs and indeed all sufferers of SCC.

Further details can be found within the review article ‘Organ transplantation and skin cancer: Basic problems and new perspectives’ by Bouwes Bavinck, Euvrard, Hofbauer in press with Exp Dermatol.

© 2010 Lippincott Williams & Wilkins, Inc.