p16INK4a immunocytochemistry in liquid-based cervical cytology: is it feasible for clinical use?

Abstract

Abstract.A consecutive series of 118 samples from patients referred to colposcopy assessment and follow-up with cytology and biopsies were analysed with immunocytochemical staining to determinate the expression of p16 INK4a . Accumulation of p16INK4a antigen has been proposed as a biomarker helpful for the identification of dysplastic cervical cells. In our study all benign cases were negative for p16 INK4a , while more than half of the high grade lesions showed moderate or strong reactivity. There was a correlation between CIN grade and p16INK4a expression levels with more advanced lesions showing stronger reactivity. The correlation between p16INK4a immunoreactivity and the severity of cytological abnormality was stronger, when the diagnosis was based on simultaneous routine cytology (p<0.001, χ 2 exact test for trend). There was no or weak reactivity in benign cases, as well as almost all low-grade lesions, while two thirds of high-grade lesions showed moderate or strong staining for p16 INK4a antigen. Thus p16INK4a expression analysis yielded information which is consistent with results from the histopathology and is a simple way of emphasizing the presence of premalignant cell reactive atypias. This staining can be applied to cytological samples, and might be a complement prognostic procedure in order to find women at risk for cervical cancer. IntroductionPreinvasive lesions of the cervix are frequent in young women, with a peak in incidence between the age of 25 and 40 years (1). Cytopathological screening for precancerous cervical lesions has achieved a considerable reduction in cervical cancer incidence and mortality in industrialized nations (2). Nevertheless, it remains the principle female cancer in developing countries, mainly due to lack of screening (3).Human papillomavirus (HPV) of high-risk types have been identified as the causative agent in cervical cancers (4). The presence of HPV has however a low predictive value since most infections are transient and only a small fraction of women positive for oncogenic types of HPV develop cervical cancer (5-7).In Sweden, a combination of organized and opportunistic screening has reduced the incidence of squamous carcinoma substantially during the last decades (1,8). All abnormal samples are followed-up with colposcopy, biopsy and ultimately conization. Both cytological and histopathological assessment rely on defined morphological criteria, but are also associated with intra-and interobserver variation (9-11), and could therefore benefit from complementary, more objective procedures.Various screening strategies have been proposed in which HPV testing is combined with the cytological examination to increase sensitivity. HPV testing has shown satisfying sensitivity, but it lacks specificity to be used as a primary screening tool (12,13). The ideal would be an objective test distinguishing women with non-progressive mild neoplasia from those with oncogenic transformation and at risk of developing invasive cancer, to facilitate decision on therapy and nee...

Human papillomavirus, p16INK4A, and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina

“…Furthermore, Ki-67 and/or p16 INK4A expression have been found to be markers of progression for intraepithelial neoplastic lesions in cervix, vulva, vagina, and anus ( Cameron et al , 2002 ; Norman et al , 2007 ). We observed a correlation between HPV positivity, lower histopathological grade, and high p16 INK4A expression.…”

“…Studies in other SCCs have shown that p16 INK4A expression measured by immunohistochemistry correlates well with HPV positivity ( Mellin Dahlstrand et al , 2005 ; Santos et al , 2006 ; Reimers et al , 2007 ; Fuste et al , 2010 ), making it a useful biomarker for HPV-related oncogenic activity and malignant transformation in cervix, vulva, and vagina ( Klaes et al , 2001 ; O'neill and Mccluggage, 2006 ; Fuste et al , 2010 ). In the cervix p16 INK4A has proven as useful in identifying dysplasia, and correlates with the severity of dysplasia ( Norman et al , 2007 ). In the cervix and other sites, it has also been demonstrated to be of prognostic significance ( Masoudi et al , 2006 ; Reimers et al , 2007 ; Schwarz et al , 2012 ).…”