Metabolomic Analysis of Actinic Keratosis and SCC Suggests a Grade-Independent Model of Squamous Cancerization

SIMPLE SUMMARY: Actinic keratoses (AKs) are the most common sun-induced precancerous lesions that can progress to squamocellular carcinoma (SCC). AK I have been considered low-risk lesions, often evolving into AK II, the AK grade II and III have the potential to evolve to SCC. This research has assessed the metabolomic fingerprints of AK I, AK II, AK III and SCC by HR-MAS NMR spectroscopy, with the aim of evaluating the hypothesis of grade-association AK to SCC. The association between AKs and SCCs has also been evaluated by histopathology. Our findings support the notion that AK I are different from healthy skin and share different features with SCCs, indeed, they are metabolically active lesions with metabolic profiles similar to high-grade AKs and to SCC. The negative association of AKs with parakeratosis and the positive association with hypertrophy also suggested a similar behavior between AKs and SCCs. Therefore, all AKs should be treated independently from their clinical appearance or histological grade, since it is not possible to predict their potential evolution to SCC. ABSTRACT: Background—Actinic keratoses (AKs) are the most common sun-induced precancerous lesions that can progress to squamocellular carcinoma (SCC). Recently, the grade-independent association between AKs and SCC has been suggested; however, the molecular bases of this potential association have not been investigated. This study has assessed the metabolomic fingerprint of AK I, AK II, AK III and SCC using high resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy in order to evaluate the hypothesis of grade-independent association between AK and SCC. Association between AKs and SCCs has also been evaluated by histopathology. Methods—Metabolomic data were obtained through HR-MAS NMR spectroscopy. The whole spectral profiles were analyzed through multivariate statistical analysis using MetaboAnalyst 5.0. Histologic examination was performed on sections stained with hematoxylin and eosin; statistical analysis was performed using STATA software version 14. Results—A group of 35 patients affected by AKs and/or SCCs and 10 healthy controls were enrolled for metabolomics analysis. Histopathological analysis was conducted on 170 specimens of SCCs and AKs (including the ones that underwent metabolomic analysis). SCCs and AK I were found to be significantly associated in terms of the content of some metabolites. Moreover, in the logistic regression model, the presence of parakeratosis in AKs appeared to be less frequently associated with SCCs, while AKs with hypertrophy had a two-fold higher risk of being associated with SCC. Conclusions—Our findings, derived from metabolomics and histopathological data, support the notion that AK I are different from healthy skin and share some different features with SCCs. This may further support the expanding notion that all AKs should be treated independently from their clinical appearance or histological grade because they may be associated with SCC.