Carcinoma cuniculatum in course of etanercept: blocking autoimmunity but propagation of carcinogenesis?

Carcinoma cuniculatum (CC) or verrucous squamous cell carcinoma is a rare variant of squamous cell carcinoma with low incidence of metastasis. It mainly affects men during the fifth-sixth decade of life, arising mostly on the weight-bearing surface of the foot, but it can also be found in other body areas. The favorable effects on the psoriatic, rheumatoid, juvenile polyarthritis as well as the ankylosing spondylitis after the application of Tumour Necrosis Factor (TNF)-alpha inhibitors, like etanercept, presume the availability of similarity between the etiopathogenetic mechanisms which are responsible for the generation of the inflammatory cascade. According to the latest studies, the sensitivity of the patients to TNF-alpha inhibitors could be genetically determined and may also be due to certain genetic polymorphisms of the NLP3 and CARD8 zones of the inflammasome. The blocking of the inflammatory reaction within the borderlines of the psoriatic arthritis could also be accepted as something of a double edged sword. There is a growing volume of literary data which informs us of the clinical manifestation, not only of skin, but also of other types of tumors after the application of TNF-alpha inhibitors. This inevitably generates the hypothesis that within a certain group of patients the TNF-alpha inhibitors have some additional, and currently obscure, effects on presumably key regulatory proteins of the so-called extrinsic apoptotic pathway. Other proteins of the human inflammasome could be also implicated in the regulation of the programmed cell death and the carcinogenesis - there are speculations, that the adapter protein, ASC/TMS1, could be one of these. The present study describes the case of a patient who developed a rare form of skin tumor - epithelioma cuniculatum - whilst undergoing etanercept therapy for psoriatic arthritis. Under discussion are the possible critical connections in the complex regulatory networks of the inflammatory processes, the programmed cell death (apoptosis) and the carcinogenesis which, in the near or distant future, could become the objects of a targeted therapy.