Browse > Article
http://dx.doi.org/10.7314/APJCP.2012.13.2.469

p16INK4a is a Useful Marker of Human Papillomavirus Integration Allowing Risk Stratification for Cervical Malignancies  

Cheah, Phaik-Leng (Department of Pathology, Faculty of Medicine, University of Malaya)
Looi, Lai-Meng (Department of Pathology, Faculty of Medicine, University of Malaya)
Teoh, Kean-Hooi (Department of Pathology, Faculty of Medicine, University of Malaya)
Mun, Kein-Seong (Department of Pathology, Faculty of Medicine, University of Malaya)
Nazarina, Abdul Rahman (Department of Pathology, Faculty of Medicine, University of Malaya)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.13, no.2, 2012 , pp. 469-472 More about this Journal
Abstract
The present study was conducted to assess utility of $p16^{INK4a}$ immunopositivity as a surrogate marker for genomic integration of high-risk human papillomavirus infection (hrHPV). A total of 29 formalin-fixed, paraffin-embedded cervical low-grade squamous intraepithelial lesions (LSILs), 27 high-grade squamous intraepithelial lesions (HSILs) and 53 invasive squamous cell carcinomas (SCCs), histologically-diagnosed between 1st January 2006 to 31st December 2008 at the University of Malaya Medical Centre were stained for $p^{16INK4a}$ (CINtec Histology Kit (REF 9511, mtm laboratories AG, Heidelberg, Germany). Immunopositvity was defined as diffuse staining of the squamous cell cytoplasm and or nucleus (involving > 75% of the intraepithelial lesions or SCCs). Staining of basal and parabasal layers of intraepithelial lesions was pre-requisite. One (3.4%) LSIL, 24 (88.9%) HSIL and 46 (86.8%) SCC were $p^{16INK4a}$ immunopositive. All normal squamous epithelium did not express $p16^{INK4a}$. $p16^{INK4a}$ expression was significantly lower (p<0.05) in LSIL compared with HSIL and SCC with no difference in expression between HSIL and SCC. The increased $p16^{INK4a}$ immunopositivity in HSIL and SCC appears in line with the integrated existence of the hrHPV and may provide more insightful information on risk of malignant transformation of cervical squamous intraepithelial lesions than mere hrHPV detection.
Keywords
$p^{16INK4a}$ immunohistochemistry; high risk human papillomavirus; cervix; invasive squamous carcinoma;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Benevolo M, Mottolese M, Marandino F, et al (2006). Immunohistochemical expression of p16(INK4a) is predictive of HR-HPV infection in cervical low-grade lesions. Mod Pathol, 19, 384-91.   DOI
2 Bergeron C, Ordi J, Schmidt D, et al (2010). Conjunctive p16INK4a testing significantly increases accuracy in diagnosing high-grade cervical intraepithelial neoplasia. Am J Clin Pathol, 133, 395-406.   DOI
3 Cheah PL, Looi LM, Sivanesaratnam V (2011). Human papillomavirus in cervical cancers of Malaysians. J Obstet Gynaecol Res, 37, 489-95   DOI
4 Cheah PL, Looi LM, Mun KS, Nazarina AR, Teoh KH (2011). Implications of continued upregulation of p16INK4a through the evolution from high-grade squamous intraepithelial lesion to invasive squamous carcinoma of the cervix. Malaysian J Pathol, 33, 83-7.
5 Doorbar J (2005). The papillomavirus life cycle. J Clin Virol, 32, 7-15
6 Eleuterio J Jr, Giraldo PC, Goncalves AK, et al (2007). Prognostic markers of high-grade squamous intraepithelial lesions: the role of p16INK4a and high-risk human papillomavirus. Acta Obstet Gynecol Scand, 86, 94-8.   DOI
7 Klaes R, Friedrich T, Spitkovsky D, et al (2001). Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer, 92, 276-84.   DOI   ScienceOn
8 Kong CS, Balzer BL, Troxell ML, Patterson BK, Longacre TA (2007). p16INK4A immunohistochemistry is superior to HPV in situ hybridization for the detection of high-risk HPV in atypical squamous metaplasia. Am J Surg Pathol, 31, 33-43   DOI
9 Kurshumliu F, Thorns C, Gashi-Luci L (2009). p16INK4A in routine practice as a marker of cervical epithelial neoplasia. Gynecol Oncol, 115, 127-31   DOI
10 Lesnikova I, Lidang M, Hamilton-Dutoit S, Koch J (2009). p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens. Diagn Pathol, 4, 22-?.   DOI
11 Lim GCC, Rampal S, Halimah Y (Eds) (2008). Cancer Incidence in Peninsular Malaysia 2003-2005. The Third Report of the National Cancer Registry. National Cancer Registry, Ministry of Health Malaysia. Kuala Lumpur.
12 Missaoui N, Trabelsi A, Hmissa S, et al (2010). p16INK4A overexpression in precancerous and cancerous lesions of the uterine cervix in Tunisian women. Pathol Res Pract, 206, 550-5   DOI
13 Murphy N, Ring M, Heffron CC, et al (2005). p16INK4A, CDC6, and MCM5: predictive biomarkers in cervical preinvasive neoplasia and cervical cancer. J Clin Pathol, 58, 525-34   DOI
14 Nishino HT, Tambouret RH, Wilbur DC (2011). Testing for human papillomavirus in cervical cancer screening: a review of indications and methodology. Cancer Cytopathol, 119, 219-27   DOI
15 Reuschenbach M, Vinokurova S, von Knebel Doeberitz M (2011). HPV-associated carcinomas of the female genital tract : Molecular mechanisms of development. Pathologe, 32, 451-60.   DOI
16 Rodríguez AC, Schiffman M, Herrero R, et al (2008). Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst, 100, 513-7   DOI
17 Schiffman M, Wentzensen N, Wacholder S, et al (2011). Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst, 103, 368-83   DOI
18 Sherr CJ, Roberts JM (2004). Living with or without cyclins and cyclin-dependent kinases. Genes Dev, 18, 2699-711   DOI   ScienceOn
19 Stanley M (2010). Pathology and epidemiology of HPV infection in females. Gynecol Oncol, 117, 5-10   DOI   ScienceOn
20 Syrjanen K (2011). Persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease. Potential new endpoint for efficacy studies with new-generation (non-HPV 16/18) prophylactic HPV vaccines. Eur J Gynaecol Oncol, 32, 17-33
21 Ukpo OC, Flanagan JJ, Ma XJ, et al (2011). High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma. Am J Surg Pathol, 35, 1343-50.   DOI
22 Van Niekerk D, Guillaud M, Matisic J, et al (2007). p16 and MIB1 improve the sensitivity and specificity of the diagnosis of high grade squamous intraepithelial lesions: methodological issues in a report of 447 biopsies with consensus diagnosis and HPV HCII testing. Gynecol Oncol, 107, 233-40   DOI
23 Walboomers JM, Jacobs MV, Manos MM, et al (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 189, 12-9   DOI   ScienceOn