Abstract
The association between high-risk genotypes of human papillomavirus (hr-HPV) and cervical cancer is well established. As hr-HPV testing is rapidly becoming a part of routine cervical cancer screening, either in conjunction with cytology or as primary testing, the management of hr-HPV-positive women has to be tailored in a way that increases the detection of cervical abnormalities while decreasing unnecessary colposcopic biopsies or other invasive procedures. In this review, we discuss the overall utility and strategies of hr-HPV testing, as well as the advantages and limitations of potential triage strategies for hr-HPV-positive women, including HPV genotyping, p16/Ki-67 dual staining, and methylation assays.
References
1.
Renshaw
AA
, Young
NA
, Birdsong
GG
, Styer
PE
, Davey
DD
, Mody
DR
, et al Comparison of performance of conventional and ThinPrep gynecologic preparations in the College of American Pathologists Gynecologic Cytology Program
. Arch Pathol Lab Med
. 2004
Jan
;128
(1
):17
–22
.
[PubMed]
1543-21652.
Abulafia
O
, Pezzullo
JC
, Sherer
DM
. Performance of ThinPrep liquid-based cervical cytology in comparison with conventionally prepared Papanicolaou smears: a quantitative survey
. Gynecol Oncol
. 2003
Jul
;90
(1
):137
–44
.
[PubMed]
0090-82583.
Vassilakos
P
, Schwartz
D
, de Marval
F
, Yousfi
L
, Broquet
G
, Mathez-Loic
F
, et al Biopsy-based comparison of liquid-based, thin-layer preparations to conventional Pap smears
. J Reprod Med
. 2000
Jan
;45
(1
):11
–6
.
[PubMed]
0024-77584.
Walboomers
JM
, Jacobs
MV
, Manos
MM
, Bosch
FX
, Kummer
JA
, Shah
KV
, et al Human papillomavirus is a necessary cause of invasive cervical cancer worldwide
. J Pathol
. 1999
Sep
;189
(1
):12
–9
.
[PubMed]
0022-34175.
de Sanjose
S
, Quint
WG
, Alemany
L
, Geraets
DT
, Klaustermeier
JE
, Lloveras
B
, et al; Retrospective International Survey and HPV Time Trends Study Group
. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study
. Lancet Oncol
. 2010
Nov
;11
(11
):1048
–56
.
[PubMed]
1470-20456.
Zielinski
GD
, Snijders
PJ
, Rozendaal
L
, Daalmeijer
NF
, Risse
EK
, Voorhorst
FJ
, et al The presence of high-risk HPV combined with specific p53 and p16INK4a expression patterns points to high-risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix
. J Pathol
. 2003
Dec
;201
(4
):535
–43
.
[PubMed]
0022-34177.
Pirog
EC
, Lloveras
B
, Molijn
A
, Tous
S
, Guimerà
N
, Alejo
M
, et al; RIS HPV TT study group
. HPV prevalence and genotypes in different histological subtypes of cervical adenocarcinoma, a worldwide analysis of 760 cases
. Mod Pathol
. 2014
Dec
;27
(12
):1559
–67
.
[PubMed]
0893-39528.
Ho
GY
, Burk
RD
, Klein
S
, Kadish
AS
, Chang
CJ
, Palan
P
, et al Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia
. J Natl Cancer Inst
. 1995
Sep
;87
(18
):1365
–71
.
[PubMed]
0027-88749.
Ho
GY
, Bierman
R
, Beardsley
L
, Chang
CJ
, Burk
RD
. Natural history of cervicovaginal papillomavirus infection in young women
. N Engl J Med
. 1998
Feb
;338
(7
):423
–8
.
[PubMed]
0028-479310.
Rodríguez
AC
, Schiffman
M
, Herrero
R
, Wacholder
S
, Hildesheim
A
, Castle
PE
, et al; Proyecto Epidemiológico Guanacaste Group
. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections
. J Natl Cancer Inst
. 2008
Apr
;100
(7
):513
–7
.
[PubMed]
0027-887411.
Arbyn
M
, Ronco
G
, Anttila
A
, Meijer
CJ
, Poljak
M
, Ogilvie
G
, et al Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer
. Vaccine
. 2012
Nov
;30
Suppl 5
:F88
–99
.
[PubMed]
0264-410X12.
Nanda
K
, McCrory
DC
, Myers
ER
, Bastian
LA
, Hasselblad
V
, Hickey
JD
, et al Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review
. Ann Intern Med
. 2000
May
;132
(10
):810
–9
.
[PubMed]
0003-481913.
Ronco
G
, Dillner
J
, Elfstrom
KM
, Tunesi
S
, Snijders
PJ
, Arbyn
M
, et al International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomized controlled trials
. Lancet
. 2014
;383
(9916
):524
–32
.
[PubMed]
0140-673614.
Isidean
SD
, Mayrand
MH
, Ramanakumar
AV
, Gilbert
L
, Reid
SL
, Rodrigues
I
, et al; CCCaST Study Group
. Human papillomavirus testing versus cytology in primary cervical cancer screening: end-of-study and extended follow-up results from the Canadian cervical cancer screening trial
. Int J Cancer
. 2016
Dec
;139
(11
):2456
–66
.
[PubMed]
0020-713615.
Dillner
J
, Rebolj
M
, Birembaut
P
, Petry
KU
, Szarewski
A
, Munk
C
, et al; Joint European Cohort Study
. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study
. BMJ
. 2008
Oct
;337
oct13 1
:a1754
.
[PubMed]
0959-813816.
Gage
JC
, Schiffman
M
, Katki
HA
, Castle
PE
, Fetterman
B
, Wentzensen
N
, et al Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test
. J Natl Cancer Inst
. 2014
Jul
;106
(8
):dju153
.
[PubMed]
0027-887417.
Katki
HA
, Kinney
WK
, Fetterman
B
, Lorey
T
, Poitras
NE
, Cheung
L
, et al Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice
. Lancet Oncol
. 2011
Jul
;12
(7
):663
–72
.
[PubMed]
1470-204518.
Arbyn
M
, Verdoodt
F
, Snijders
PJ
, Verhoef
VM
, Suonio
E
, Dillner
L
, et al Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis
. Lancet Oncol
. 2014
Feb
;15
(2
):172
–83
.
[PubMed]
1470-204519.
Racey
CS
, Withrow
DR
, Gesink
D
. Self-collected HPV testing improves participation in cervical cancer screening: a systematic review and meta-analysis
. Can J Public Health
. 2013
Feb
;104
(2
):e159
–66
.
[PubMed]
1920-747620.
Rebolj
M
, Lynge
E
, Bonde
J
. Human papillomavirus testing and genotyping in cervical screening
. Expert Rev Anticancer Ther
. 2011
Jul
;11
(7
):1023
–31
.
[PubMed]
1473-714021.
Muñoz
N
, Bosch
FX
, de Sanjosé
S
, Herrero
R
, Castellsagué
X
, Shah
KV
, et al; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group
. Epidemiologic classification of human papillomavirus types associated with cervical cancer
. N Engl J Med
. 2003
Feb
;348
(6
):518
–27
.
[PubMed]
0028-479322.
Kjær
SK
, Frederiksen
K
, Munk
C
, Iftner
T
. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence
. J Natl Cancer Inst
. 2010
Oct
;102
(19
):1478
–88
.
[PubMed]
0027-887423.
Khan
MJ
, Castle
PE
, Lorincz
AT
, Wacholder
S
, Sherman
M
, Scott
DR
, et al The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice
. J Natl Cancer Inst
. 2005
Jul
;97
(14
):1072
–9
.
[PubMed]
0027-887424.
Bulk
S
, Bulkmans
NW
, Berkhof
J
, Rozendaal
L
, Boeke
AJ
, Verheijen
RH
, et al Risk of high-grade cervical intra-epithelial neoplasia based on cytology and high-risk HPV testing at baseline and at 6-months
. Int J Cancer
. 2007
Jul
;121
(2
):361
–7
.
[PubMed]
0020-713625.
Vinokurova
S
, Wentzensen
N
, Kraus
I
, Klaes
R
, Driesch
C
, Melsheimer
P
, et al Type-dependent integration frequency of human papillomavirus genomes in cervical lesions
. Cancer Res
. 2008
Jan
;68
(1
):307
–13
.
[PubMed]
0008-547226.
Cook
DA
, Mei
W
, Smith
LW
, van Niekerk
DJ
, Ceballos
K
, Franco
EL
, et al Comparison of the Roche cobas® 4800 and Digene Hybrid Capture® 2 HPV tests for primary cervical cancer screening in the HPV FOCAL trial
. BMC Cancer
. 2015
Dec
;15
(1
):968
.
[PubMed]
1471-240727.
Castle
PE
, Stoler
MH
, Wright
TC
Jr, Sharma
A
, Wright
TL
, Behrens
CM
. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study
. Lancet Oncol
. 2011
Sep
;12
(9
):880
–90
.
[PubMed]
1470-204528.
Wright
TC
, Stoler
MH
, Behrens
CM
, Sharma
A
, Zhang
G
, Wright
TL
. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test
. Gynecol Oncol
. 2015
Feb
;136
(2
):189
–97
.
[PubMed]
0090-825829.
Huh
WK
, Williams
E
, Huang
J
, Bramley
T
, Poulios
N
. Cost effectiveness of human papillomavirus-16/18 genotyping in cervical cancer screening
. Appl Health Econ Health Policy
. 2015
Feb
;13
(1
):95
–107
.
[PubMed]
1175-565230.
Saslow
D
, Solomon
D
, Lawson
HW
, Killackey
M
, Kulasingam
SL
, Cain
J
, et al; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee
. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer
. CA Cancer J Clin
. 2012
May-Jun
;62
(3
):147
–72
.
[PubMed]
0007-923531.
Ouh
YT
, Lee
JK
. Proposal for cervical cancer screening in the era of HPV vaccination
. Obstet Gynecol Sci
. 2018
May
;61
(3
):298
–308
.
[PubMed]
2287-857232.
Al-Awadhi
R
, Chehadeh
W
, Jaragh
M
, Al-Shaheen
A
, Sharma
P
, Kapila
K
. Distribution of human papillomavirus among women with abnormal cervical cytology in Kuwait
. Diagn Cytopathol
. 2013
Feb
;41
(2
):107
–14
.
[PubMed]
8755-103933.
Tsoumpou
I
, Arbyn
M
, Kyrgiou
M
, Wentzensen
N
, Koliopoulos
G
, Martin-Hirsch
P
, et al p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis
. Cancer Treat Rev
. 2009
May
;35
(3
):210
–20
.
[PubMed]
0305-737234.
Carozzi
F
, Confortini
M
, Dalla Palma
P
, Del Mistro
A
, Gillio-Tos
A
, De Marco
L
, et al; New Technologies for Cervival Cancer Screening (NTCC) Working Group
. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial
. Lancet Oncol
. 2008
Oct
;9
(10
):937
–45
.
[PubMed]
1470-204535.
Wentzensen
N
, Fetterman
B
, Castle
PE
, Schiffman
M
, Wood
SN
, Stiemerling
E
, et al p16/Ki-67 dual stain cytology for detection of cervical precancer in HPV-positive women
. J Natl Cancer Inst
. 2015
Sep
;107
(12
):djv257
.
[PubMed]
0027-887436.
Luttmer
R
, Dijkstra
MG
, Snijders
PJ
, Berkhof
J
, van Kemenade
FJ
, Rozendaal
L
, et al p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population
. Mod Pathol
. 2016
Aug
;29
(8
):870
–8
.
[PubMed]
0893-395237.
Wright
TC
Jr, Behrens
CM
, Ranger-Moore
J
, Rehm
S
, Sharma
A
, Stoler
MH
, et al Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: results from a sub-study nested into the ATHENA trial
. Gynecol Oncol
. 2017
Jan
;144
(1
):51
–6
.
[PubMed]
0090-825838.
Bergeron
C
, Ikenberg
H
, Sideri
M
, Denton
K
, Bogers
J
, Schmidt
D
, et al; PALMS Study Group
. Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results
. Cancer Cytopathol
. 2015
Jun
;123
(6
):373
–81
.
[PubMed]
1934-662X39.
Tjalma
WA
, Kim
E
, Vandeweyer
K
. The impact on women’s health and the cervical cancer screening budget of primary HPV screening with dual-stain cytology triage in Belgium
. Eur J Obstet Gynecol Reprod Biol
. 2017
May
;212
:171
–81
.
[PubMed]
0301-211540.
Vasiljević
N
, Carter
PD
, Reuter
C
, Warman
R
, Brentnall
AR
, Carton
JR
, et al Role of quantitative p16INK4A mRNA assay and digital reading of p16INK4A immunostained sections in diagnosis of cervical intraepithelial neoplasia
. Int J Cancer
. 2017
Aug
;141
(4
):829
–36
.
[PubMed]
0020-713641.
Wajed
SA
, Laird
PW
, DeMeester
TR
. DNA methylation: an alternative pathway to cancer
. Ann Surg
. 2001
Jul
;234
(1
):10
–20
.
[PubMed]
0003-493242.
Rodríguez-Paredes
M
, Esteller
M
. Cancer epigenetics reaches mainstream oncology
. Nat Med
. 2011
Mar
;17
(3
):330
–9
.
[PubMed]
1078-895643.
Galván
SC
, Martínez-Salazar
M
, Galván
VM
, Méndez
R
, Díaz-Contreras
GT
, Alvarado-Hermida
M
, et al Analysis of CpG methylation sites and CGI among human papillomavirus DNA genomes
. BMC Genomics
. 2011
Nov
;12
(1
):580
.
[PubMed]
1471-216444.
Kalantari
M
, Calleja-Macias
IE
, Tewari
D
, Hagmar
B
, Lie
K
, Barrera-Saldana
HA
, et al Conserved methylation patterns of human papillomavirus type 16 DNA in asymptomatic infection and cervical neoplasia
. J Virol
. 2004
Dec
;78
(23
):12762
–72
.
[PubMed]
0022-538X45.
Mirabello
L
, Schiffman
M
, Ghosh
A
, Rodriguez
AC
, Vasiljevic
N
, Wentzensen
N
, et al Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia
. Int J Cancer
. 2013
Mar
;132
(6
):1412
–22
.
[PubMed]
0020-713646.
Piyathilake
CJ
, Macaluso
M
, Alvarez
RD
, Chen
M
, Badiga
S
, Edberg
JC
, et al A higher degree of methylation of the HPV 16 E6 gene is associated with a lower likelihood of being diagnosed with cervical intraepithelial neoplasia
. Cancer
. 2011
Mar
;117
(5
):957
–63
.
[PubMed]
0008-543X47.
Kim
JH
, Choi
YD
, Lee
JS
, Lee
JH
, Nam
JH
, Choi
C
. Assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens
. Gynecol Oncol
. 2010
Jan
;116
(1
):99
–104
.
[PubMed]
0090-825848.
Virmani
AK
, Muller
C
, Rathi
A
, Zoechbauer-Mueller
S
, Mathis
M
, Gazdar
AF
. Aberrant methylation during cervical carcinogenesis
. Clin Cancer Res
. 2001
Mar
;7
(3
):584
–9
.
[PubMed]
1078-043249.
van Baars
R
, van der Marel
J
, Snijders
PJ
, Rodriquez-Manfredi
A
, ter Harmsel
B
, van den Munckhof
HA
, et al CADM1 and MAL methylation status in cervical scrapes is representative of the most severe underlying lesion in women with multiple cervical biopsies
. Int J Cancer
. 2016
Jan
;138
(2
):463
–71
.
[PubMed]
0020-713650.
Hesselink
AT
, Heideman
DA
, Steenbergen
RD
, Coupé
VM
, Overmeer
RM
, Rijkaart
D
, et al Combined promoter methylation analysis of CADM1 and MAL: an objective triage tool for high-risk human papillomavirus DNA-positive women
. Clin Cancer Res
. 2011
Apr
;17
(8
):2459
–65
.
[PubMed]
1078-043251.
Verhoef
VM
, van Kemenade
FJ
, Rozendaal
L
, Heideman
DA
, Bosgraaf
RP
, Hesselink
AT
, et al Follow-up of high-risk HPV positive women by combined cytology and bi-marker CADM1/MAL methylation analysis on cervical scrapes
. Gynecol Oncol
. 2015
Apr
;137
(1
):55
–9
.
[PubMed]
0090-825852.
Hesselink
AT
, Heideman
DA
, Steenbergen
RD
, Gök
M
, van Kemenade
FJ
, Wilting
SM
, et al Methylation marker analysis of self-sampled cervico-vaginal lavage specimens to triage high-risk HPV-positive women for colposcopy
. Int J Cancer
. 2014
Aug
;135
(4
):880
–6
.
[PubMed]
0020-713653.
Luttmer
R
, De Strooper
LM
, Dijkstra
MG
, Berkhof
J
, Snijders
PJ
, Steenbergen
RD
, et al FAM19A4 methylation analysis in self-samples compared with cervical scrapes for detecting cervical (pre)cancer in HPV-positive women
. Br J Cancer
. 2016
Aug
;115
(5
):579
–87
.
[PubMed]
0007-092054.
De Strooper
LM
, Verhoef
VM
, Berkhof
J
, Hesselink
AT
, de Bruin
HM
, van Kemenade
FJ
, et al Validation of the FAM19A4/mir124-2 DNA methylation test for both lavage- and brush-based self-samples to detect cervical (pre)cancer in HPV-positive women
. Gynecol Oncol
. 2016
May
;141
(2
):341
–7
.
[PubMed]
0090-825855.
Lorincz
AT
, Brentnall
AR
, Scibior-Bentkowska
D
, Reuter
C
, Banwait
R
, Cadman
L
, et al Validation of a DNA methylation HPV triage classifier in a screening sample
. Int J Cancer
. 2016
Jun
;138
(11
):2745
–51
.
[PubMed]
0020-713656.
Verhoef
VM
, Heideman
DA
, van Kemenade
FJ
, Rozendaal
L
, Bosgraaf
RP
, Hesselink
AT
, et al Methylation marker analysis and HPV16/18 genotyping in high-risk HPV positive self-sampled specimens to identify women with high grade CIN or cervical cancer
. Gynecol Oncol
. 2014
Oct
;135
(1
):58
–63
.
[PubMed]
0090-825857.
Luttmer
R
, De Strooper
LM
, Berkhof
J
, Snijders
PJ
, Dijkstra
MG
, Uijterwaal
MH
, et al Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study)
. Int J Cancer
. 2016
Feb
;138
(4
):992
–1002
.
[PubMed]
0020-7136© 2019 S. Karger AG, Basel
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