Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study

Rikke Kamp Damgaard; David Jenkins; Maurits Nc de Koning; Wim Gv Quint; Mark H Stoler; John Doorbar; Johnny Kahlert; Patti E Gravitt; Torben Steiniche; Lone Kjeld Petersen; Anne Hammer

doi:10.1136/bmjopen-2021-059593

Performance of HPV E4 and p16^INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study

BMJ Open. 2022 Jul 6;12(7):e059593. doi: 10.1136/bmjopen-2021-059593.

Authors

Rikke Kamp Damgaard^{1

2}, David Jenkins³, Maurits Nc de Koning³, Wim Gv Quint³, Mark H Stoler⁴, John Doorbar⁵, Johnny Kahlert⁶, Patti E Gravitt⁷, Torben Steiniche^{1

8}, Lone Kjeld Petersen^{9

10}, Anne Hammer^{11

2}

Affiliations

¹ Dep. Clinical Medicine, Aarhus University, Aarhus, Denmark.
² Dep. Gynecology and Obstetrics, Center for Research and Education, Gødstrup Hospital, Herning, Denmark.
³ Viroclinics-DDL, DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
⁴ Dep. Pathology, University of Virginia, Charlottesville, Virginia, USA.
⁵ Dep. Pathology, Division of Virology, University of Cambridge, Cambridge, UK.
⁶ Dep. Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
⁷ National Cancer Institute, University of Virginia Cancer Center, Charlottesville, Virginia, USA.
⁸ Dep. Pathology, Aarhus University Hospital, Aarhus, Denmark.
⁹ Dep. Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark.
¹⁰ OPEN, University of Southern Denmark, Odense, Denmark.
¹¹ Dep. Clinical Medicine, Aarhus University, Aarhus, Denmark [email protected].

Abstract

Introduction: Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16^INK4a targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16^INK4a may be valuable for risk assessment of CIN2. However, data on HPV E4/p16^INK4a as a predictor for CIN2 regression is lacking.

Methods and analysis: We will conduct a historical cohort study including 500 women aged 23-40 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000-2010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16^INK4a and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome.

Ethics and dissemination: The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings.

Trial registration number: NCT05049252.

Keywords: Community gynaecology; Histopathology; Molecular diagnostics; Risk management.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alphapapillomavirus*
Biomarkers, Tumor
Cohort Studies
Cyclin-Dependent Kinase Inhibitor p16
Female
Humans
Papillomaviridae
Papillomavirus Infections*
Uterine Cervical Dysplasia*
Uterine Cervical Neoplasms*

Substances

Biomarkers, Tumor
Cyclin-Dependent Kinase Inhibitor p16

Associated data

ClinicalTrials.gov/NCT05049252