Title: Immuno-Histochemical Study of P16INK4A in Cervical Intraepithelial Neoplasia and Cervical Cancer

Authors: Dr Sharath Kumar H.K, Dr Kokila. S

 DOI:  https://dx.doi.org/10.18535/jmscr/v5i1.37

Abstract

Background: Cervical cancer is caused by human papilloma virus (HPV) strains 16 and 18. One of the consequences of viral genomic integration into the host cell is up regulation of p16INK4A, a cyclin dependent kinase inhibitor. This implies that detection of p16INK4A may be used as a surrogate marker of integration of high risk HPV into cervical epithelium and transition to malignant transformation.

Aim: The aim of this study is to assess utility of p16INK4A immunopositivity and evaluate the usefulness of this biomarker in the diagnosis of CIN and cervical cancer.

Materials and Methods: 65 cervical biopsy/ hysterectomy specimens of LSIL, HSIL and SCC were studied for H&E and compared with IHC staining. Subsequently, the immunohistochemically stained slides were graded on a 0-3 grading scale.

Results:

·         65 evaluated cases on histopathological examination showed that 23 (35.4%) cases were LSIL, 8 (12.3%) cases were HSIL and 34 (52.3%) cases were SCC of uterine cervix

·         23 cases of LSIL were studied for p16INK4A over expression in which 20 (87%) cases showed grade 1 staining and 3 (13%) cases showed grade 2 staining

·         8 cases of HSIL were studied for p16INK4A over expression in which 1 (12.5%) case showed grade 2 staining and 7 (87.5%) cases showed grade 3 staining

·         34 cases of SCC were studied for p16INK4A over expression in which 3 (8.8%) cases showed grade 2 staining and 31 (91.2%) cases showed grade 3 staining

Conclusion: The present study concludes that p16INK4A is a specific marker for dysplastic and neoplastic alteration in the cervical epithelium and thereby significantly improves cervical pre-cancer and cancer detection.

Keywords: Dysplasia, Kinase inhibitor,  Cervical neoplasia, Biomarker.

References

1.      Kumari K, Arcot AV. p16INK4A expression in cervical intraepithelial neoplasia and cervical cancer. Brunei Int Med J. 2013;9(3):165-171.

2.      Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J of Cancer. 2001;92:276–284.

3.      Murphy N, Ring M, Killalea AG, et al. p16INK4A as a marker for cervical dyskaryosis: CIN and cGIN in cervical biopsies and thin preparation  of smears. J Cln Pathol. 2003;56:56-63.

4.      Cheah P, Looi L, Teoh K, Mun K, Nazarina AR. p16INK4A is a useful marker of  Human Papillomavirus integra-tion allowing risk stratification for cervical malignancies. APJCP. 2012;13:469-472.

5.      Kate Cuschieri, Nicolas Wentzensen. Human Papillomavirus mRNA and p16 Detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev. 2008;17:2536-2545.

6.      Raluca Balan. Immunohistochemical assessment of p16, COX-2 and EGFR in HPV-positive cervical squamous intraepithelial lesions. Rom J Morphol Embryol. 2011;52(4):1187–1194.

7.      Supriya Srivastava. P16INK4a and MIB-1: An immunohistochemical expression in preneoplasia and neoplasia of the cervix. Indian Journal of Pathology and Microbiology 2010 Jul-Sep;53(3):518-24.

8.      Rachel Redman. The Utility of P16INK4a in Discriminating Between Cervical Intraepithelial Neoplasia 1 and Nonneoplastic Equivocal Lesions of the Cervix. Arch Pathol Lab Med 2008 May;132.

9.      Han. Decreased D2-40 and increased P16INK4a immunoreactivities correlate with higher grade of cervical intraepithelial neoplasia. Diagnostic Pathology 2011; 6:59.

10.  Jian-Liu Wang, Bi-Ying Zheng, Xi-Dan Li. 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; 10:2407-14.

11.  Ines Krivak Bolana, Sreko Ciglar. Short communication Evaluation of P16INK4a in Cervical Lesion of Premenopausal and Postmenopausal Women. Coll Antropol 2007;31(2):107–11.

12.  Sangho Lee, Hyunchul Kim, Hyesun Kim, Chulhwan Kim, Insun Kim. The utility of P16INK4a and Ki-67 as a conjunctive tool in uterine cervical lesions. Korean J Pathol. 2012;46:253-260.

13.  Lulin Hu. Human papillomavirus genotyping and P16INK4a expression in cervical intraepithelial neoplasia of adolescents. Modern Pathology 2005; 18:267-73.

14.  Qi Zhang. Impact of utilizing P16INK4a immunohistochemistry on estimated performance of three cervical cancer screening tests. Int J Cancer 2006; 120:351–6.

15.  Eun Ji Nam. Expression of the P16INK4a and Ki-67 in relation to the grade of cervical intraepithelial neoplasia and high-risk human papillomavirus infection. J Gynecol Oncol 2008 Sep;19(3):162-8.

16.  Jaume Ordi. International Society of Gynecological Pathologists, P16INK4a Immunostaining Identifies Occult CIN Lesions in HPV-positive Women. International Journal of Gynecological Pathology 2008;28:90–7.

17.  Raluca Balan. Immunohistochemical assessment of p16, COX-2 and EGFR in HPV-positive cervical squamous intraepithelial lesions. Rom J Morphol Embryol 2011;52(4):1187–94.

18.  Izadi-Mood N, Asadi K, Shojaei H, Sarmadi S, Ahmadi SA, Sanii S, et al. Potential diagnostic value of P16 expression in premalignant and malignant cervical lesions. J Res Med Sci 2012;17(5):428-33.

19.  Seung-Myoung Son. Evaluation of P16INK4a, pRb, p53 and Ki-67 expression in cervical squamous neoplasia. P16INK4a Expression Correlates with Degree of Cervical Neoplasia: A Comparison with Ki-67 Expression and Detection of High- Risk HPV Types. J Biomed Res 2012;13(3):209-17.

20.  Nicholas Agoff S. P16INK4a expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types. Mod Pathol. 2003;16 (7):665–673.

21.  Márcia CM Guimarães. Immunohistoc-hemical expression of P16INK4a and bcl-2 according to HPV type and to the progression of cervical squamous intraepithelial lesions. J Histochem Cytochem. 2005;53(4):509–516.

22.  Cheah P, Looi L, Teoh K, Mun K, Nazarina AR. P16INK4a is a useful marker of Human Papillomavirus integration allowing Risk Stratification for cervical malignancies. Asian Pacific Journal of Cancer 2012;13,469-72.

23.  Qingzhu Wei. Combined detection of P16INK4a and IMP3 increase the concordance rate between cervical cytologic and histologic diagnosis. Int J Clin Exp Pathol 2013;6(8):1549-57.

24.  Volgareva G, Zavalishina L, Andreeva Y. p16 as a marker of dysplastic and neoplastic alteration in cervical epithelial cells. BMC Cancer. 2004;4:58.

25.  Iana Lesnikova, Marianne Lidang, Stephen Hamilton-Dutoit, Jørn Koch. p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens. Diagnostic Pathology 2009;4:22.

26.  Tan. Immunohistochemical study of P16INK4a and surviving expressions in cervical squamous neoplasm. Indian J Pathol Microbiol. 2010 ;53(1). 

Corresponding Author

Dr Sharath Kumar H.K

Associate Professor, Dept of Pathology,

Mysore Medical College & Research Institute, Mysore, INDIA

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