Immunohistochemical expression of p16INK4a is predictive of HR-HPV infection in cervical low-grade lesions

Maria Benevolo, Marcella Mottolese, Ferdinando Marandino, Giuseppe Vocaturo, Roberto Sindico, Giulia Piperno, Luciano Mariani, Isabella Sperduti, Paola Canalini, Raffaele P. Donnorso, Amina Vocaturo

Research output: Contribution to journalArticle

Abstract

The p16INK4a is a cyclin-dependent kinase inhibitor that decelerates the cell cycle by inactivating the cyclin-dependent kinases involved in the phosphorylation of the retinoblastoma protein (RB). Expression of E6 and E7 oncogenes of high-risk (HR) human papillomavirus (HPV), affecting the RB-p16 pathway, leads to p16 upregulation. Although it is widely reported that p16 is overexpressed in a high percentage of preneoplastic lesions and in almost all carcinomas of the uterine cervix, protein upregulation and its correlation with HPV infection in low-grade lesions is still being debated. In this study, we investigated in parallel, p16 expression and HPV infection in 100 cervical biopsies (17 normal tissues, 54 CIN1, 10 CIN2, 11 CIN3, eight invasive squamous cancers). Results obtained demonstrated that none of the 17 normal cervical tissues, evaluated by immunohistochemistry, presented p16 positivity whereas, starting from CIN1 (31%) to CIN2 (90%), CIN3 (100%) and carcinomas (100%), a constant and significant increase of protein overexpression (P <0.0001) was observed. In addition, pi 6 overexpression consistently showed elevated sensitivity (84%) and specificity (98%) in detecting HR-HPV infection with a high positive predictive value (97%) and negative predictive value (86%). Of interest, 93% of the p16-positive CIN1 were also HR-HPV infected. Our findings confirmed that p16 overexpression is associated to high-grade precancerous lesions and cervical carcinomas, and further demonstrated that immunohistochemical evaluation of p16 may be a useful biomarker in identifying HR-HPV-infected low-grade lesions.

Original languageEnglish
Pages (from-to)384-391
Number of pages8
JournalModern Pathology
Volume19
Issue number3
DOIs
Publication statusPublished - Mar 2006

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Papillomavirus Infections
Retinoblastoma Protein
Cyclin-Dependent Kinases
Carcinoma
Up-Regulation
Oncogenes
Cervix Uteri
Cell Cycle
Proteins
Biomarkers
Immunohistochemistry
Phosphorylation
Biopsy
Sensitivity and Specificity
Neoplasms

Keywords

  • Cervical intraepithelial neoplasia
  • Human papillomavirus
  • p16
  • Progression risk

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Immunohistochemical expression of p16INK4a is predictive of HR-HPV infection in cervical low-grade lesions. / Benevolo, Maria; Mottolese, Marcella; Marandino, Ferdinando; Vocaturo, Giuseppe; Sindico, Roberto; Piperno, Giulia; Mariani, Luciano; Sperduti, Isabella; Canalini, Paola; Donnorso, Raffaele P.; Vocaturo, Amina.

In: Modern Pathology, Vol. 19, No. 3, 03.2006, p. 384-391.

Research output: Contribution to journalArticle

Benevolo, Maria ; Mottolese, Marcella ; Marandino, Ferdinando ; Vocaturo, Giuseppe ; Sindico, Roberto ; Piperno, Giulia ; Mariani, Luciano ; Sperduti, Isabella ; Canalini, Paola ; Donnorso, Raffaele P. ; Vocaturo, Amina. / Immunohistochemical expression of p16INK4a is predictive of HR-HPV infection in cervical low-grade lesions. In: Modern Pathology. 2006 ; Vol. 19, No. 3. pp. 384-391.
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abstract = "The p16INK4a is a cyclin-dependent kinase inhibitor that decelerates the cell cycle by inactivating the cyclin-dependent kinases involved in the phosphorylation of the retinoblastoma protein (RB). Expression of E6 and E7 oncogenes of high-risk (HR) human papillomavirus (HPV), affecting the RB-p16 pathway, leads to p16 upregulation. Although it is widely reported that p16 is overexpressed in a high percentage of preneoplastic lesions and in almost all carcinomas of the uterine cervix, protein upregulation and its correlation with HPV infection in low-grade lesions is still being debated. In this study, we investigated in parallel, p16 expression and HPV infection in 100 cervical biopsies (17 normal tissues, 54 CIN1, 10 CIN2, 11 CIN3, eight invasive squamous cancers). Results obtained demonstrated that none of the 17 normal cervical tissues, evaluated by immunohistochemistry, presented p16 positivity whereas, starting from CIN1 (31{\%}) to CIN2 (90{\%}), CIN3 (100{\%}) and carcinomas (100{\%}), a constant and significant increase of protein overexpression (P <0.0001) was observed. In addition, pi 6 overexpression consistently showed elevated sensitivity (84{\%}) and specificity (98{\%}) in detecting HR-HPV infection with a high positive predictive value (97{\%}) and negative predictive value (86{\%}). Of interest, 93{\%} of the p16-positive CIN1 were also HR-HPV infected. Our findings confirmed that p16 overexpression is associated to high-grade precancerous lesions and cervical carcinomas, and further demonstrated that immunohistochemical evaluation of p16 may be a useful biomarker in identifying HR-HPV-infected low-grade lesions.",
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AU - Benevolo, Maria

AU - Mottolese, Marcella

AU - Marandino, Ferdinando

AU - Vocaturo, Giuseppe

AU - Sindico, Roberto

AU - Piperno, Giulia

AU - Mariani, Luciano

AU - Sperduti, Isabella

AU - Canalini, Paola

AU - Donnorso, Raffaele P.

AU - Vocaturo, Amina

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AB - The p16INK4a is a cyclin-dependent kinase inhibitor that decelerates the cell cycle by inactivating the cyclin-dependent kinases involved in the phosphorylation of the retinoblastoma protein (RB). Expression of E6 and E7 oncogenes of high-risk (HR) human papillomavirus (HPV), affecting the RB-p16 pathway, leads to p16 upregulation. Although it is widely reported that p16 is overexpressed in a high percentage of preneoplastic lesions and in almost all carcinomas of the uterine cervix, protein upregulation and its correlation with HPV infection in low-grade lesions is still being debated. In this study, we investigated in parallel, p16 expression and HPV infection in 100 cervical biopsies (17 normal tissues, 54 CIN1, 10 CIN2, 11 CIN3, eight invasive squamous cancers). Results obtained demonstrated that none of the 17 normal cervical tissues, evaluated by immunohistochemistry, presented p16 positivity whereas, starting from CIN1 (31%) to CIN2 (90%), CIN3 (100%) and carcinomas (100%), a constant and significant increase of protein overexpression (P <0.0001) was observed. In addition, pi 6 overexpression consistently showed elevated sensitivity (84%) and specificity (98%) in detecting HR-HPV infection with a high positive predictive value (97%) and negative predictive value (86%). Of interest, 93% of the p16-positive CIN1 were also HR-HPV infected. Our findings confirmed that p16 overexpression is associated to high-grade precancerous lesions and cervical carcinomas, and further demonstrated that immunohistochemical evaluation of p16 may be a useful biomarker in identifying HR-HPV-infected low-grade lesions.

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KW - Progression risk

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