Keratoacanthoma of the Lip

The PI3K-PTEN-mTOR is one of the most important pathways involved in cancer development and progression; however, its role in keratoacanthoma (KA) is poorly understood. In this study, we investigated the activation of key proteins in the PI3K-mTOR pathway in lip KA. We analyzed the activation of the PI3K-PTEN-mTOR pathway using human tumor samples stained for well-established protein markers in this pathway, including pS6 and pAKT phosphoproteins. We assessed proliferation using Ki-67 and performed additional morphological and immunohistochemical analysis using anti-PTEN and anti-p16 antibodies. We found that the majority of KA labeled to pS6 and not pAKT. PTEN expression was inversely correlated with Ki-67 expression. In addition to PTEN expression, KA cells were positive for p16 senescence marker. PI3K-PTEN-mTOR pathway is activated in lip KA, leading to downstream activation of mTORC1, but not mTORC2. This pathway plays an important role in KA progression by promoting proliferation and activation of oncogenic-induced senescence. (Medicine 94(38):e1552) Abbreviations: c = cytoplasm, CGH = comparative genomic hybridization, DAB = 3,3-diaminobenzidine, H&E = hematoxylin and eosin, IHC = Immunohistochemistry, KA = keratoacanthoma, LI gues Martins, DDS eurer, MD, PhD, Cristiane Helena Squarize, DDS, MS, PhD mammalian target of rapamycin mTOR, PIP3 = phosphatidylinositol 3,4,5-trisphosphate, pS6 = phosphorylation of S6, PTEN = Phosphatase and tensin homolog, r = Spearman correlation coefficient, SCC = squamous cell carcinoma. INTRODUCTION K eratoacanthoma (KA) is an epithelial tumor that frequently occurs in sun-exposed areas, including the face and lip. It may arise from the derived from pilosebaceous unit, particularly the outer root sheath cells. KA is classically described as rapid proliferation of epithelial cells that molds a crateriform architecture containing a central plug of keratin. The clinical progression of KA is characterized by rapid enlargement, maturation of the lesion, and spontaneous regression. The involution phase of KA can take months, resulting in surgical excision of the majority of KAs. KA cells proliferate rapidly and contain dyskeratosis that is similar to keratin pearls; its histopathological features resemble those of a well-differentiated squamous cell carcinoma (SCC), suggesting it may have the potential for malignant transformation. Because the histopathological aspects of KA and SCC are similar, clinical history may be necessary for the correct diagnosis. The most part of studies have focused on the identification of markers that distinguish KA from SCC, but the mechanisms underlying KA pathways are poorly understood. Molecular biology profiling using comparative genomic hybridization (CGH) revealed that KA and SCC rarely share genomic aberrations. Indeed, genomic aberrations are found in 30% to 40% of KAs and 80% of SCCs. The phosphatidylinositol 3-kinase-mammalian target of rapamycin mTOR (PI3K-mTOR) pathway is one of the most common pathways implicated in tumor development and progression, particularly in tumors of epithelial origin. PI3KmTOR signaling leads to the activation of mTORC1 and mTORC2 complexes, which are regulated by the tumor suppressor PTEN (Phosphatase and tensin homolog). PTEN protein, also known as MMAC1 and TEP1, acts as a phosphatase and blocks activation of PI3K-mTOR signaling. Therefore, PTEN functions as a master regulator of tumor proliferation, aggressiveness, and survival. The role of the PI3K-mTOR pathway in the pathobiology of KA is poorly understood. In the present study, we investigated the role of PI3K-PTEN-mTOR pathway in lip KA with immunohistochemistry analysis of pathway representative markers PTEN, pS6, and pAKT. In addition, we analyzed the activation of evidenced by expression of the p16 and the proliferation profile using www.md-journal.com | 1 TABLE 2. Descriptive Attributes of the Cases Case A. Location Sex Age Race A Lower lip M 67 W B Lip F N/A W C Lower lip M 48 W D Lower lip F 77 W E Lower lip M 71 W F Lower lip F 53 W G Lower lip F 68 W H Lower lip M 63 W Medicine Volume 94, Number 38, September 2015 MATERIALS AND METHODS