P16, Ki67 and P63 staining pattern in squamous metaplasia, CIN and cervical cancer

Anu Anna Jacob; A. Sundaram

doi:10.18203/2320-6012.ijrms20180608

Authors

Anu Anna Jacob Department of of Pathology, MOSC MCH, Kolenchery, Kerala, India
A. Sundaram Department of of Pathology, MOSC MCH, Kolenchery, Kerala, India

DOI:

https://doi.org/10.18203/2320-6012.ijrms20180608

Keywords:

CIN, Cancer cervix, Ki67, p16ink4a, p63

Abstract

Background: Persistent infection with Human Papilloma Virus (HPV) has been the main cause of squamous intra epithelial neoplasia which in turn leads to cancer. The incidence is 28.0%. Early identification of dysplasia and malignancy helps early intervention.

Methods: To do Immunohistochemical staining using P16ink4a, Ki 67, and P63 in cervical squamous metaplasia, CIN I, II, III and correlate the H and E features with IHC patterns. Study was carried out in SRM Medical College Hospital and Research centre, Kattankulathur, Tamil Nadu, a descriptive study for a period of 2 years (2012 to 2014) on formalin fixed paraffin embedded tissues from cervix. H and E sections of uterine cervix were categorized into squamous metaplasia, CIN I, CIN II, CIN III and squamous cell carcinoma. 50 representative samples were subjected to Four-micrometer-thick sections and subjected to IHC using PathInsitu, using P16ink4a, Ki67 and P63. Statistics: Using SPSS for windows (V.17). Data expressed by number and percentage. Methods used were Chi square test, Screening test and ROC curve. Statistical significance was 0.05.

Results: P63 has shown to be the best marker out of the three to distinguish the progression of a lesion towards dysplasia and malignancy in cervix. Ki 67 showed a specificity of 84.2% with a negative predictive value of 59.3%, and an ROC curve area of 69.2%. In this study, Ki67 showed lesser sensitivity than that of P63.

Conclusions: P16 identifies HPV 16 infection in uterine cervix. Ki67 and P 63 are helpful in determining the nature of progression of lesion. High expression of Ki 67 indicates a neoplastic progression. P63 may be used to differentiate benign from malignant lesions. P16 with P63 showed good results in predicting the progression of a lesion.

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References

Wang JL, Zheng BY, Li XD, Ångström T, Lindström MS, Wallin KL. Predictive significance of the alterations of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen expression in the progression of cervical cancer. Clin Cancer Res. 2004;10(7):2407-14.

Kaarthigeyan K. Cervical cancer in India and HPV vaccination. Ind J Med Paediat Oncol. 2012;33(1):7-12.

Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Brit J cancer. 2003;88(1):63.

Sowjanya AP, Jain M, Poli UR, Padma S, Das M, Shah KV, et al. Prevalence and distribution of high-risk human papilloma virus (HPV) types in invasive squamous cell carcinoma of the cervix and in normal women in Andhra Pradesh, India. BMC infectious diseases. 2005;5(1):116.

Sankaranarayanan R, Nene BM, Dinshaw KA, Mahe C, Jayant K, Shastri SS, et al. A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India. Inter J Cancer. 2005;116(4):617-23.

Laikangbam P, Sengupta S, Bhattacharya P. A comparative profile of the prevalence and age distribution of human papillomavirus type 16/18 infections among three states of India with focus on northeast India. Int J Gynecol Cancer. 2005;17:107-17.

del Pino M, Garcia S, Fusté V, Alonso I, Fusté P, Torné A, et al. Value of p16INK4a as a marker of progression/regression in cervical intraepithelial neoplasia grade 1. Ame J Obst Gynecol. 2009;201(5):488-e1.

Miller RT. Utility of p16 (INK4a) immunostaining in cervical biopsies. The Focus Immunohistochemistry. 2002.

Seiz1 M, Doeberitz1 CVK. Evaluation of cervical cone biopsies for co-expression of p16INK4a and Ki-67 in epithelial cells. Svetlana Int J Cancer. 2012;130:388-94.

Carozzi FM. Combined analysis of HPV DNA and P16 Ink 4a expression to predict prognosis in ASCUS and LSIL Pap smears, coll. Antropol. 2007;31(2):103-106.

Benevolo M, Mottolese M, Marandino F. Immunohistochemical expression of p16 INK 4a is predictive of HR- HPV infection in cervical low grade lesions. Modern Pathology. 2006;19:384-91.

Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398(6729):708.

Ratovitski EA, Patturajan M, Hibi K, Trink B, Yamaguchi K, Sidransky D. p53 associates with and targets ΔNp63 into a protein degradation pathway. Proceedings National Academy of Sciences. 2001;98(4):1817-22.

Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell. 1999;99(2):143-53.

Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature. 2000;404(6773):99.

Brown CA, Bogers J, Sahebali S, Depuydt CE, De Prins F, Malinowski DP. Role of protein biomarkers in the detection of high-grade disease in cervical cancer screening programs. J oncology. 2012;2012.

Quade BJ, Yang A, Wang Y, Sun D, Park JJ, Sheets EE, et al. Expression of the p53 homologue p63 in early cervical neoplasia. Gynecologic oncology. 2001;80(1):24-9.

Hwang LY, Ma Y, Shiboski SC, Farhat S, Jonte J, Moscicki AB. Active squamous metaplasia of the cervical epithelium is associated with subsequent acquisition of human papillomavirus 16 infection among healthy young women. J Infectious Dis. 2012;206(4):504-11.

Moscicki AB, Schiffman M. Updating the natural history of human papillomavirus and anogenital cancers. Vaccine. 2012;30Suppl5:F24-33.

Hellman K, Lindquist D. Human papillomavirus, p16 (INK4A), and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina. Br J Cancer. 2014;110(6):1561-70.

Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, et al. p63 expression profiles in human normal and tumor tissues. Clinical cancer research. 2002;8(2):494-501.

Tsoumpou I, Arbyn M, Kyrgiou M, Wentzensen N, Koliopoulos G, Martin-Hirsch P, et al. p16INK4a immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer treatment reviews. 2009;35(3):210-20.

Yang A, Zhu Z, Kapranov P, McKeon F, Church GM, Gingeras TR, Struhl K. Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Molecular cell. 2006;24(4):593-602.

Pinto AP, Crum CP, Hirsch MS. Molecular markers of early cervical neoplasia. Diagnostic Histopathology. 2010;16(10):445-54.

Reuschenbach M, Seiz M, Doeberitz CV, Vinokurova S, Duwe A, Ridder R, et al. Evaluation of cervical cone biopsies for coexpression of p16INK4a and Ki‐67 in epithelial cells. Inter J cancer. 2012;130(2):388-94.

Gomez DT, Santos JL. Human papillomavirus infection and cervical cancer: pathogenesis and epidemiology. Communicating current research and educational topics and trends in applied microbiology. 2007;1:680-8.

Schlüter C, Duchrow M, Wohlenberg C, Becker MH, Key G, Flad HD, Gerdes J. The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biology. 1993;123(3):513-22.