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P16 has emerged as a valuable surrogate marker for high-risk human papillomavirus infection and shows increased immunoexpression with worsening grades of cervical intraepithelial neoplasia

The p16 gene product normally acts to inhibit progression through the cell cycle by binding to cyclin dependent kinase, thereby preventing the phosphorylation and subsequent inactivation of oncogene supressors. Several studies have shown a large percentage of low-grade squamous intraepithelial lesion (LSIL) cytology and histologic specimens to be positive for HPV types (80% to 83%). The majority of which will regress if left untreated. In all grades of CIN, and the fact that many of these lesions will ultimately regress spontaneously, other methods for detecting the potential for persistent infection and subsequent progression to higher grades of cervical neoplasia are needed. Indeed, integration of high-risk HPV sequences into the cell genome is considered to be an important event in the progression of cervical neoplasia. In addition, and likely closely

related, p16 has been shown to be a surrogate marker of infections by HPV and is proposed to be a possible prognostic marker in the progression of CIN. The direct relationship between the grade of cervical dysplasia and the intensity of p16 staining is well established. Most studies report negative p16 staining in normal or reactive cervical biopsies. Many recent studies support that p16 is a specific marker of high-grade CIN, reporting a positive predictive value of 100%. In low grade CIN (mild dysplasia), the positivity is about 30%. However, it was found that those positive low grade lesions are the one that are more likely to progress into higher grades. All studies concluded that p16 was one of the best markers for detecting CIN. In postmenopausal patients, epithelial atrophy can mimic carcinoma in Pap smears and high-grade CIN in cervical biopsies. In fact, CIN 3 may coexist with atrophy. p16. Can help to confirm CIN in this setting

Summary: p16 immunohistochemistry has emerged as a valuable diagnostic aid in the diagnosis of CIN. It has proven benefit in distinguishing high-grade cervical dysplasia from its benign mimics such as cervical atrophy, immature squamous metaplasia, reactive inflammatory lesions, and radiation induced changes. Overexpression of p16 is a useful biomarker of HPV related carcinogenesis. P16, when it is positive in low grade CIN, can predict its progression to higher CIN grade

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Dr. Hussam Abu-Farsakh

American Boards of Anatomic and Clinical pathology and Cytopathology