Progression pathways of squamous cell carcinoma associated with actinic damage: From cancer field to actinic keratosis and invasive squamous cell carcinoma.

Student thesis: Doctoral thesis


It was thought that the progression of an actinic keratosis (AK) to invasive squamous cell carcinoma (SCC) occurred as long as the intra-epidermal neoplasm occupied the entire thickness of the epidermis as in the classical pathway (PC) described in cervix cancer. However, cutaneous infiltrative squamous carcinoma can appear directly from a dysplasia that only occupies the lower third of the epidermis (AK I, differentiated pathweay or DP). This second pathway of progression has been described in SCC of the vulva and oral cavity, whose biological behavior is more aggressive. This thesis began by reviewing all cases corresponding to surgical biopsies, obtained through the BioBanco of the Germans Trias and Pujol Hospital, for three consecutive years corresponding to the period 2004-2007. We selected 503 cases of cutaneous SCC, of ​​which we finally studied 196. Most showed AK I on the surface (63.8%) or on the edges (77.9%), thus concluding that the direct invasion from AK I (DP) is the most frequent form of progression to cutaneous SCC. This study was the first one that was proposed to investigate the prevalence of CP and DP in the transformation of AK into infiltrating SCC, providing evidence of its existence. These findings were published in J Eur Acad Dermatol Venereol. 2014 Oct; 29 (5): 991-7.). The next stage of the study consisted in the realization of a tissue microarrays (TMA) of the biopsies already studied and the cases with SCC were segregated between those originated by DP and those originated by CP. In total, eight TMAs were performed, which involved 756 cores to be evaluated. Through the use of immunohistochemical techniques it was demonstrated that the epithelial-mesenchymal transition participates in the transformation of AK I into SCC (DP) while a greater proliferative capacity facilitates the intra-epidermal extension in the classical pathway and significant differences were found in to the expression of CD31 (angiogenesis) and MMP (metalloproteinases), these markers being elevated in tumors that progress through DP, which together with the epithelium-mesenchymal transition could facilitate local progression. A part of these results have been published in the journal J Eur Acad Dermatol Venereol. 2018 Apr; 32 (4): 581-586). We also proceeded to the use of CISH techniques for the study of miRNA, finding that tumors arising from DP express higher levels of miRNA31 both in their intensity and in their extension. In the next stage the extension of the keratinocyte atypia among adnexal structures was studied, being present in 25.9% of the cases and, of them, the infiltration of the squamous carcinoma directly adjacent to the follicular basal was present in 58% of the cases. Consequently, it would be highly advisable to indicate the depth of follicular extension in the histological diagnosis of incisional biopsies, given the risk of recurrence and infiltration that this implies, as well as the therapeutic derivatives that it entails. The findings have been published in the journal J Eur Acad Dermatol Venereol. 2018 Oct; 32 (10): 1657-1661). We consider that the series of studies that make up this thesis provide new knowledge about the pathways of cutaneous SCC progression and its precursor lesions. It has been established that there are at least two pathways of progression from SCC to AK, the concept of PD has been introduced in cutaneous carcinogenesis, molecular bases have been found that explain the progression through both pathways and the risk of follicular extension in the AK. All these studies have led to a paradigm shift in some areas and are relevant both in the diagnosis and treatment of AKs.
Date of Award4 Jul 2019
Original languageEnglish
SupervisorAurelio Ariza Fernandez (Tutor), Carlos Ferrandiz Foraster (Tutor), Luis Puig-Sanz (Director) & Maria Teresa Fernandez Figueras (Director)


  • Transició epiteli-mesènquima; Transición epitelio-mesénquima; Epithelial to mesenchymal transition; Via diferenciada; Differentiated pathway; Queratosis actínica; Queratosis actínica; Actinic keratosis

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