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p16^INK4A as a marker for cervical dyskaryosis: CIN and cGIN in cervical biopsies and ThinPrep^TM smears

¹ Department of Pathology, Coombe Women’s Hospital, Dublin 8, Ireland
² Trinity College Dublin, Dublin 2, Ireland
³ Department of Obstetrics and Gynaecology, The Coombe Women’s Hospital
⁴ Department of Genitourinary Medicine, St James’s Hospital, Dublin, Ireland
⁵ Department of Histopathology, St James Hospital

Correspondence to:
Ms N Murphy, Department of Pathology, Coombe Women’s Hospital, Dublin 8, Ireland;
ncmurphy{at}tcd.ie Aim: To examine the potential of p16^INK4A as a biomarker for dysplastic squamous and glandular cells of the cervix in tissue sections and ThinPrep^TM smears.

Methods: Immunocytochemical analysis of p16^INK4A expression was performed on 22 normal cervical tissue samples, five cervical glandular intraepithelial neoplasia (cGIN), 38 cervical intraepithelial neoplasia 1 (CIN1), 33 CIN2, 46 CIN3, and 10 invasive cancer cases (eight squamous and two adenocarcinomas). All samples were formalin fixed and paraffin wax embedded, and immunohistochemical analysis was carried out using a mouse monoclonal anti-p16^INK4A antibody after antigen unmasking. The staining intensity was assessed using a 0 to 3 scoring system. In addition, the expression status of p16^INK4A was examined in 12 normal ThinPrep smears, one smear exhibiting cGIN, and a total of 20 smears exhibiting mild, moderate, and severe dyskaryosis. Human papillomavirus (HPV) detection was carried out using a modified SYBR green assay system. Fluorogenic polymerase chain reaction (PCR) and solution phase PCR were used for specific HPV typing.

Results: p16^INK4A immunoreactivity was absent in all normal cervical tissues examined. Dysplastic squamous and glandular cells were positive for p16^INK4A expression in all cases included in this study, except for one CIN3 case. p16^INK4A expression was mainly nuclear in CIN1 cases, and both nuclear and cytoplasmic in CIN2, CIN3, cGIN, and invasive cases. All cases positive for HPV expressed the p16^INK4A protein, although not all cases found positive for p16^INK4A were HPV positive. In general, the p16^INK4A staining intensity was lower in cases negative for HPV or those containing a low risk HPV type.

Conclusion: This pattern of overexpression demonstrates the potential use of p16^INK4A as a diagnostic marker for cervical squamous and also glandular neoplastic lesions. In addition, the technique can be used to identify individual dyskaryotic cells in ThinPrep smears. Thus, p16^INK4A is a useful marker of cervical dyskaryosis.

Keywords: p16; dyskaryosis; marker

Abbreviations: BSA, bovine serum albumin; cdk, cyclin dependent kinase; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; Pap, Papanicolaou test; PBST, phosphate buffered saline/Tween 20; PCR, polymerase chain reaction; pRb, retinoblastoma protein; TBS, Tris buffered saline

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