Beyond p16 immunostaining: an overview of biomarkers in anal squamous intraepithelial lesions.

Histological grading of squamous intraepithelial lesions or intraepithelial neoplasia is fundamental for clinical management and for assessment of the risk of progression. Biomarkers are important for assisting correct grading of these lesions, reducing inter and intraobserver variability and most promising, for prognosis. Although p16 is the most studied biomarker in this setting, there are several other biomarkers that have been studied, reflecting also the need to find a better single or association option that can be more suitable, especially for classification purposes. A PubMed and Embase search was conducted from their inception until April 2018, aiming to identify biomarkers evaluated in histological samples of anal squamous intraepithelial lesions, other than p16. Information on "Ki-67", "ProExTM C", "p53", "human papillomavirus L1 capsid protein", "stathmin-1", "minichromosome maintenance protein", "p21", "proliferating cell nuclear antigen", "histones", "human papillomavirus E4", "chromosomal abnormalities" and "methylation" was collected and reviewed. From these, the most studied biomarker was by far Ki-67. In many cases there were few studies performed for each biomarker, with no clear standardized interpretation of the immunostaining. An increased positive rate with more severe grades of lesions was shown in many cases. Prognostic data are limited and need to be further validated.