The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report

Abstract

Background: Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer.

Case presentation: Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma.

Conclusion: The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.

Figure 1

Macroscopic, microscopic and immune histological appearance of an oral lichen planus and a subsequently arising squamous cell carcinoma. Macroscopic (A) and microscopic (B) picture of the squamous cells carcinoma. p53 expression (C to E, single positive cells are indicated by arrows), Erk 1/2 phosphorylation (F to H, increased expression is indicated by closed triangles) and Bax expression (I to K, reduced expression is indicated by open triangles) in mucosa before (C, F, I) and after (D, G, J) tacrolimus treatment, as well as in the arising squamous cell carcinoma (E, H, K); magnification: A 5×, C to K 20×. All lesions were obtained by surgical excision, fixed in formalin and embedded in paraffin. Five μm sections of tumor lesions were fixed in acetone and air dried for 30 min. Slides were incubated for 30 min with the indicated specific primary antibodies (anti-p53 [clone D07] and anti-Bax [polyclonal], DAKO, Hamburg, Germany; anti-pErk 1/2 [clone E10], Cell Signalling, BioLabs New England, Frankfurt, Germany) at predetermined dilutions ranging from 1:200 to 1:800.

Figure 2

Hypothetical effects of tacrolimus in keratinocytes promoting oncogenic transformation.