p16INK4a and HPV E4 immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2—A historical cohort study

Rikke Damgaard; David Jenkins; Mark H. Stoler; Miekel van de Sandt; Maurits N.C. de Koning; Wim G.V. Quint; Johnny Kahlert; Patti E. Gravitt; Torben Steiniche; Lone K. Petersen; Anne Hammer

doi:10.1002/ijc.35469

p16^INK4a and HPV E4 immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2—A historical cohort study

Rikke Damgaard, David Jenkins, Mark H. Stoler, Miekel van de Sandt, Maurits N.C. de Koning, Wim G.V. Quint, Johnny Kahlert, Patti E. Gravitt, Torben Steiniche, Lone K. Petersen, Anne Hammer^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

Cervical intraepithelial neoplasia grade 2 (CIN2) is a heterogeneous diagnosis with a high likelihood of spontaneous regression. Therefore, active surveillance for CIN2 has been implemented as an option in younger women in many countries. Yet, little is known about markers that may accurately predict the likelihood of regression to support active surveillance. Here, we aimed to assess whether p16^INK4a and HPV E4 status are associated with the likelihood of CIN2 regression. We conducted a historical cohort study on women aged 23–40 diagnosed with untreated CIN2 following cytology-based screening. Women were diagnosed at Aarhus University Hospital, Denmark from January 2000 to December 2010. Archived tissue samples were sectioned for p16^INK4a and HPV E4 immunohistochemistry and HPV genotyping. We used a modified Poisson model to estimate the relative risk of regression, adjusting for age and cytology (aRR). A total of 443 women with CIN2 were included. Most women (73.8%) were aged ≤30, and half had a high-grade cytology (48.8%). Overall, 47.6% regressed, and regression was less likely in p16^INK4a-positive compared to p16^INK4a-negative women (aRR 0.77; 95% CI 0.64–0.94). Among p16^INK4a-positive women, the risk of regression varied by HPV type and HPVE4 status, with lower risk in HPV16-positive women compared to those without (aRR 0.54; 95% CI 0.40–0.75) and in HPVE4-negative compared to HPVE4 positive women (aRR 0.73; 95% CI 0.54–0.98). When we restricted to expert-confirmed CIN2, the risk of regression did not vary by p16^INK4a or HPVE4 status, while HPV16 positive remained at a lower risk of regression compared to women without HPV16.

Originalsprog	Engelsk
Tidsskrift	International Journal of Cancer
Antal sider	10
ISSN	0020-7136
DOI	https://doi.org/10.1002/ijc.35469
Status	E-pub / Early view - 2025

Adgang til dokumentet

10.1002/ijc.35469

Biblioteksadgang?

Tjek tilgængelighed hos det Kgl. Bibliotek

Andre filer og links

Link to publication in Scopus

Citationsformater

Damgaard, R., Jenkins, D., Stoler, M. H., van de Sandt, M., de Koning, M. N. C., Quint, W. G. V., Kahlert, J., Gravitt, P. E., Steiniche, T., Petersen, L. K., & Hammer, A. (2025). p16^INK4a and HPV E4 immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2—A historical cohort study. International Journal of Cancer. Advance online publication. https://doi.org/10.1002/ijc.35469

@article{45a03a54ffca4895b917f79a5912a01f,

title = "p16INK4a and HPV E4 immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2—A historical cohort study",

abstract = "Cervical intraepithelial neoplasia grade 2 (CIN2) is a heterogeneous diagnosis with a high likelihood of spontaneous regression. Therefore, active surveillance for CIN2 has been implemented as an option in younger women in many countries. Yet, little is known about markers that may accurately predict the likelihood of regression to support active surveillance. Here, we aimed to assess whether p16INK4a and HPV E4 status are associated with the likelihood of CIN2 regression. We conducted a historical cohort study on women aged 23–40 diagnosed with untreated CIN2 following cytology-based screening. Women were diagnosed at Aarhus University Hospital, Denmark from January 2000 to December 2010. Archived tissue samples were sectioned for p16INK4a and HPV E4 immunohistochemistry and HPV genotyping. We used a modified Poisson model to estimate the relative risk of regression, adjusting for age and cytology (aRR). A total of 443 women with CIN2 were included. Most women (73.8\%) were aged ≤30, and half had a high-grade cytology (48.8\%). Overall, 47.6\% regressed, and regression was less likely in p16INK4a-positive compared to p16INK4a-negative women (aRR 0.77; 95\% CI 0.64–0.94). Among p16INK4a-positive women, the risk of regression varied by HPV type and HPVE4 status, with lower risk in HPV16-positive women compared to those without (aRR 0.54; 95\% CI 0.40–0.75) and in HPVE4-negative compared to HPVE4 positive women (aRR 0.73; 95\% CI 0.54–0.98). When we restricted to expert-confirmed CIN2, the risk of regression did not vary by p16INK4a or HPVE4 status, while HPV16 positive remained at a lower risk of regression compared to women without HPV16.",

keywords = "cervical intraepithelial neoplasia, diagnostics, HPV E4, molecular biomarkers, p16",

author = "Rikke Damgaard and David Jenkins and Stoler, \{Mark H.\} and \{van de Sandt\}, Miekel and \{de Koning\}, \{Maurits N.C.\} and Quint, \{Wim G.V.\} and Johnny Kahlert and Gravitt, \{Patti E.\} and Torben Steiniche and Petersen, \{Lone K.\} and Anne Hammer",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). International Journal of Cancer published by John Wiley \& Sons Ltd on behalf of UICC.",

year = "2025",

doi = "10.1002/ijc.35469",

language = "English",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "John Wiley \& Sons Inc.",

}

p16^INK4a and HPV E4 immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2—A historical cohort study. / Damgaard, Rikke; Jenkins, David; Stoler, Mark H. et al.
I: International Journal of Cancer, 2025.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - p16INK4a and HPV E4 immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2—A historical cohort study

AU - Damgaard, Rikke

AU - Jenkins, David

AU - Stoler, Mark H.

AU - van de Sandt, Miekel

AU - de Koning, Maurits N.C.

AU - Quint, Wim G.V.

AU - Kahlert, Johnny

AU - Gravitt, Patti E.

AU - Steiniche, Torben

AU - Petersen, Lone K.

AU - Hammer, Anne

PY - 2025

Y1 - 2025

N2 - Cervical intraepithelial neoplasia grade 2 (CIN2) is a heterogeneous diagnosis with a high likelihood of spontaneous regression. Therefore, active surveillance for CIN2 has been implemented as an option in younger women in many countries. Yet, little is known about markers that may accurately predict the likelihood of regression to support active surveillance. Here, we aimed to assess whether p16INK4a and HPV E4 status are associated with the likelihood of CIN2 regression. We conducted a historical cohort study on women aged 23–40 diagnosed with untreated CIN2 following cytology-based screening. Women were diagnosed at Aarhus University Hospital, Denmark from January 2000 to December 2010. Archived tissue samples were sectioned for p16INK4a and HPV E4 immunohistochemistry and HPV genotyping. We used a modified Poisson model to estimate the relative risk of regression, adjusting for age and cytology (aRR). A total of 443 women with CIN2 were included. Most women (73.8%) were aged ≤30, and half had a high-grade cytology (48.8%). Overall, 47.6% regressed, and regression was less likely in p16INK4a-positive compared to p16INK4a-negative women (aRR 0.77; 95% CI 0.64–0.94). Among p16INK4a-positive women, the risk of regression varied by HPV type and HPVE4 status, with lower risk in HPV16-positive women compared to those without (aRR 0.54; 95% CI 0.40–0.75) and in HPVE4-negative compared to HPVE4 positive women (aRR 0.73; 95% CI 0.54–0.98). When we restricted to expert-confirmed CIN2, the risk of regression did not vary by p16INK4a or HPVE4 status, while HPV16 positive remained at a lower risk of regression compared to women without HPV16.

AB - Cervical intraepithelial neoplasia grade 2 (CIN2) is a heterogeneous diagnosis with a high likelihood of spontaneous regression. Therefore, active surveillance for CIN2 has been implemented as an option in younger women in many countries. Yet, little is known about markers that may accurately predict the likelihood of regression to support active surveillance. Here, we aimed to assess whether p16INK4a and HPV E4 status are associated with the likelihood of CIN2 regression. We conducted a historical cohort study on women aged 23–40 diagnosed with untreated CIN2 following cytology-based screening. Women were diagnosed at Aarhus University Hospital, Denmark from January 2000 to December 2010. Archived tissue samples were sectioned for p16INK4a and HPV E4 immunohistochemistry and HPV genotyping. We used a modified Poisson model to estimate the relative risk of regression, adjusting for age and cytology (aRR). A total of 443 women with CIN2 were included. Most women (73.8%) were aged ≤30, and half had a high-grade cytology (48.8%). Overall, 47.6% regressed, and regression was less likely in p16INK4a-positive compared to p16INK4a-negative women (aRR 0.77; 95% CI 0.64–0.94). Among p16INK4a-positive women, the risk of regression varied by HPV type and HPVE4 status, with lower risk in HPV16-positive women compared to those without (aRR 0.54; 95% CI 0.40–0.75) and in HPVE4-negative compared to HPVE4 positive women (aRR 0.73; 95% CI 0.54–0.98). When we restricted to expert-confirmed CIN2, the risk of regression did not vary by p16INK4a or HPVE4 status, while HPV16 positive remained at a lower risk of regression compared to women without HPV16.

KW - cervical intraepithelial neoplasia

KW - diagnostics

KW - HPV E4

KW - molecular biomarkers

KW - p16

UR - http://www.scopus.com/inward/record.url?scp=105004283259&partnerID=8YFLogxK

U2 - 10.1002/ijc.35469

DO - 10.1002/ijc.35469

M3 - Journal article

C2 - 40323118

AN - SCOPUS:105004283259

SN - 0020-7136

JO - International Journal of Cancer

JF - International Journal of Cancer

ER -