p16INK4a immunocytochemistry versus human papillomavirus testing for triage of women with minor cytologic abnormalities

Roelens, Jolien; Reuschenbach, Miriam; Doeberitz, Magnus von Knebel; Wentzensen, Nicolas; Bergeron, Christine; Arbyn, Marc

doi:10.1002/cncy.21205

Cited by 76 publications

(63 citation statements)

References 45 publications

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“…The detection of p16 INK4a overexpression indicates cellular transformation by high-risk HPV due to cell cycle deregulation. The diagnostic evaluation of p16 INK4a as an individual biomarker was shown to be unreliable in its practical application [23,24,25,26]. An immunocytochemical detection of both p16 INK4a and Ki-67 in the same cell, however, indicates neoplastic cellular transformation [1].…”

Section: Discussionmentioning

confidence: 99%

Predictive Value of the Combined p16INK4a and Ki-67 Immunocytochemistry in Low-Grade Squamous Intraepithelial Lesions

Ziemke¹,

Marquardt

Griesser³

2014

Acta Cytologica

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Objective: The reliability of cytological diagnoses, especially for low-grade squamous intraepithelial lesions (LSIL), is limited. This leads to uncertainty in patient management. The application of adjunctive biomarkers is meant to improve this situation. Therefore, we examined the prognostic value of p16/Ki-67 immunostaining of LSIL cytology specimens. Study Design: We analyzed the p16^INK4a and Ki-67 immunocytochemistry (CINtec® PLUS, dual stain) of 260 patients with LSIL. Cytology and dual-stain results were correlated with histology at the time of treatment or with cytological follow-up. Results: After an average duration of 24.9 months (1-58) and a histology rate of 36.2% [cervical intraepithelial neoplasia, grade 2 or higher (CIN2+) as positive], the statistical evaluation for cytology and dual stain resulted in a sensitivity of 98.3 and 90.0%, respectively, a specificity of 74.5% for dual stain, a positive predictive value (PPV) of 22.8 and 51.4%, and a negative predictive value (NPV) of 96.1% for dual stain. Conclusion: The combined immunocytochemical investigation of p16^INK4a and Ki-67 leads to a significantly better PPV and a very good NPV for CIN2+ in LSIL, especially in women 30 years of age and older. An objective individualized prognosis may not be achieved with p16^INK4a/Ki-67. Statistical data from our study, however, indicate that patient management can be significantly improved by the application of combined p16/Ki-67 immunocytochemistry as an adjunct to cytology.

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Section: Discussionmentioning

confidence: 99%

Predictive Value of the Combined p16INK4a and Ki-67 Immunocytochemistry in Low-Grade Squamous Intraepithelial Lesions

Ziemke¹,

Marquardt

Griesser³

2014

Acta Cytologica

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“…However, studies that evaluated in situ hybridization to detect high-risk HPV in liquid cytology specimens from patients with cytologic diagnoses of ASC-US or greater have concluded that the test lacks sufficient sensitivity and negative predictive value to be useful in conjunction with cytology smears (87,(111)(112)(113). Similarly, studies that evaluated immunostaining for p16 tumor suppressor protein as a surrogate biomarker for the presence of highrisk HPV in cytology smears that had subsequent CIN 2ϩ or CIN 3ϩ biopsy results have shown that performance characteristics were not sufficient to add value as a triage test (87,(114)(115)(116). Other biomarkers, such Ki-67 to detect deregulated cell cycle proliferation, dual staining for Ki-67 plus p16, and BD ProEx C (Becton, Dickinson and Company, Franklin Lakes, NJ) to detect aberrant S-phase induction, genes with aberrant DNA methylation, and chromosomal aberrations in the telomerase RNA gene have not proven useful, or there is insufficient evidence related to the clinical value of the test (117)(118)(119)(120)(121)(122)(123).…”

Section: Commercially Available Test Systems For Hpv Detection In Thementioning

confidence: 99%

Human Papillomavirus Laboratory Testing: the Changing Paradigm

2016

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SUMMARYHigh-risk human papillomaviruses (HPVs) cause essentially all cervical cancers, most anal and oropharyngeal cancers, and some vaginal, vulvar, and penile cancers. Improved understanding of the pathogenesis of infection and the availability of newer tests are changing the approach to screening and diagnosis. Molecular tests to detect DNA from the most common high-risk HPVs are FDA approved for use in conjunction with cytology in cervical cancer screening programs. More-specific tests that detect RNA from high-risk HPV types are now also available. The use of molecular tests as the primary screening tests is being adopted in some areas. Genotyping to identify HPV16 and -18 has a recommended role in triaging patients for colposcopy who are high-risk HPV positive but have normal cytology. There are currently no recommended screening methods for anal, vulvar, vaginal, penile, or oropharyngeal HPV infections. HPV testing has limited utility in patients at high risk for anal cancer, but p16 immunohistochemistry is recommended to clarify lesions in tissue biopsy specimens that show moderate dysplasia or precancer mimics. HPV testing is recommended for oropharyngeal squamous cell tumors as a prognostic indicator. Ongoing research will help to improve the content of future guidelines for screening and diagnostic testing.

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“…The reprogramming of p16INK4a and Hox has been attributed to viral oncoproteins (McLaughlin-Drubin et al 2011). In fact, the accumulation of p16INK4a is one of the validated biomarkers for HPV-induced highgrade dysplasias and cancers (Roelens et al 2012) along with S-phase biomarkers such as Ki-67, MCM7, and PCNA in the suprabasal cells of a squamous epithelium. Furthermore, HPV oncoproteins also affect the expression of oncogenic or tumor suppressive miRNAs (Martinez et al 2008;Wang et al 2008Wang et al , 2009bWald et al 2011).…”

Section: Human Papillomavirus Infectionsmentioning

confidence: 99%

Human Papillomavirus Infections: Warts or Cancer?

Chow

Broker

2013

Cold Spring Harbor Perspectives in Biology

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Human papillomaviruses (HPVs) are prevalent pathogens of mucosal and cutaneous epithe-lia. Productive infections of squamous epithelia lead to benign hyperproliferative warts, condylomata, or papillomas. Persistent infections of the anogenital mucosa by high-risk HPV genotypes 16 and 18 and closely related types can infrequently progress to high-grade intraepithelial neoplasias, carcinomas-in-situ, and invasive cancers in women and men. HPV-16 is also associated with a fraction of head and neck cancers. We discuss the interactions of the mucosotropic HPVs with the host regulatory proteins and pathways that lead to benign coexistence and enable HPV DNA amplification or, alternatively, to cancers that no longer support viral production. H uman papillomaviruses (HPVs) are ubiquitous small DNA viruses that comprise a family of more than 150 genotypes. Closely related types show a predilection for particular epithelial tissues and have similar pathogenic properties (de Villiers et al. 2004; Bravo et al. 2010). The mucosotropic HPVs can be sexually transmitted. Infections are frequently asymp-tomatic and are cleared by the immune systems. Active cases are manifested as hyperproliferative lesions but often regress into subclinical persis-tency within a year. Latent infections can reactivate following immunosuppression or upon undergoing repeated cycles of wounding and healing (Fig. 1). A small fraction of persistent infections by the high-risk (HR) HPV genotypes leads to cancers (reviewed by zur Hausen 2009). Worldwide, each year there are about 500,000 new cases of cervical cancer and 275,000 deaths. More than 99% of cervical cancers are caused by high-risk (HR) HPVs, and types 16 and 18 are responsible for about 70% of the cases (Wal-boomers et al. 1999). The HR HPVs are also responsible for a high percentage of cancers of other anogenital sites in men and women. Moreover, HPV-16 is associated with a fraction of the head and neck neoplasias, in particular tonsillar and oro-pharyngeal cancers (reviewed by Syrjänen 2010). In contrast, infections by the low-risk (LR) types 6 and 11 cause 90% of genital warts and essentially all laryngeal papillomas (recurrent respiratory papillomatosis or RRP) (reviewed by Derkay and Wiatrak 2008) but they rarely result in carcinomas. Juvenile-onset RRP results from transmission in utero or during passage through the birth canal of mothers with active condylomata, yet infections may become symptomatic years later. Recent studies

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p16^INK4a immunocytochemistry versus human papillomavirus testing for triage of women with minor cytologic abnormalities

Cited by 76 publications

References 45 publications

Predictive Value of the Combined p16<sup>INK4a</sup> and Ki-67 Immunocytochemistry in Low-Grade Squamous Intraepithelial Lesions

Predictive Value of the Combined p16<sup>INK4a</sup> and Ki-67 Immunocytochemistry in Low-Grade Squamous Intraepithelial Lesions

Human Papillomavirus Laboratory Testing: the Changing Paradigm

Human Papillomavirus Infections: Warts or Cancer?

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