Abstract
Introduction: A causal link between infection with a high-risk strain of human papilloma virus (hrHPV) and the development of cervical squamous cell carcinoma (SCC) is well established. However, a small number of SCCs are hrHPV-negative by either HPV co-DNA testing and/or HPV-in situ hybridization (HPV-ISH) at the time of diagnosis. These apparently hrHPV-negative lesions are poorly understood, specifically whether hrHPV-positive precursor lesions exist, which would be detected through hrHPV-based screening. Methods: A search of the pathology archives at the Johns Hopkins Hospital identified women with a diagnosis of hrHPV-negative cervical SCC on surgical specimen. All prior pathologies, including cervical cytology and surgical pathology specimens, and associated hrHPV DNA test results, p16 immunohistochemistry, and HPV-ISH were reviewed. Results: A total of 25 women were identified having a surgical specimen diagnosed as SCC with either negative or equivocal HPV-ISH. Fifteen had a Pap test in the 6 months preceding a diagnosis of SCC, with cytology diagnoses as follows: high-grade squamous intraepithelial lesion n = 14/15; atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion n = 1/15. hrHPV co-testing was performed for 5 of these 15 women and was negative in 2/5 cases. Cervical biopsy was performed for 24 women. HPV-ISH testing, performed on 14 of the biopsy specimens, was negative for 11/14 patients. Of 15 specimens stained for p16, 14 were positive. Conclusion: A subset of patients exist in whom hrHPV is not detectable at or near the time of progression to SCC. Additional research is necessary to further describe this population and determine whether maintaining cytological screening would provide benefit.
References
2.
American Cancer Society
. Cancer Facts and Figures 2018
. Atlanta
: American Cancer Society
; 2018
.3.
Evans
MF
, Adamson
CS
, Papillo
JL
, St John
TL
, Leiman
G
, Cooper
K
. Distribution of human papillomavirus types in ThinPrep Papanicolaou tests classified according to the Bethesda 2001 terminology and correlations with patient age and biopsy outcomes
. Cancer
. 2006
Mar
;106
(5
):1054
–64
.
[PubMed]
0008-543X4.
Samimi
SA
, Mody
RR
, Goodman
S
, Luna
E
, Armylagos
D
, Schwartz
MR
, et al. Do Infection Patterns of Human Papillomavirus Affect the Cytologic Detection of High-Grade Cervical Lesions on Papanicolaou Tests?
Arch Pathol Lab Med
. 2018
Mar
;142
(3
):347
–52
.
[PubMed]
0003-99855.
Sundström
K
, Eloranta
S
, Sparén
P
, Arnheim Dahlström
L
, Gunnell
A
, Lindgren
A
, et al. Prospective study of human papillomavirus (HPV) types, HPV persistence, and risk of squamous cell carcinoma of the cervix
. Cancer Epidemiol Biomarkers Prev
. 2010
Oct
;19
(10
):2469
–78
.
[PubMed]
1055-99656.
Li
Z
, Austin
RM
, Guo
M
, Zhao
C
. Screening test results associated with cancer diagnoses in 287 women with cervical squamous cell carcinoma
. Arch Pathol Lab Med
. 2012
Dec
;136
(12
):1533
–40
.
[PubMed]
0003-99857.
Tao
X
, Griffith
CC
, Zhou
X
, Wang
Z
, Yan
Y
, Li
Z
, et al. History of high-risk HPV and Pap test results in a large cohort of patients with invasive cervical carcinoma: experience from the largest women’s hospital in China
. Cancer Cytopathol
. 2015
Jul
;123
(7
):421
–7
.
[PubMed]
1934-662X8.
Curry
SJ
, Krist
AH
, Owens
DK
, Barry
MJ
, Caughey
AB
, Davidson
KW
, et al.; US Preventive Services Task Force
. Screening for Cervical Cancer: US Preventive Services Task Force Recommendation Statement
. JAMA
. 2018
Aug
;320
(7
):674
–86
.
[PubMed]
0098-74849.
Schwarz
JK
, Lewis
JS
Jr, Pfeifer
J
, Huettner
P
, Grigsby
P
. Prognostic significance of p16 expression in advanced cervical cancer treated with definitive radiotherapy
. Int J Radiat Oncol Biol Phys
. 2012
Sep
;84
(1
):153
–7
.
[PubMed]
0360-301610.
Toll
AD
, Kelly
D
, Maleki
Z
. Utility of P16 expression and Ki-67 proliferation index in ASCUS and ASC-H pap tests
. Diagn Cytopathol
. 2014
Jul
;42
(7
):576
–81
.
[PubMed]
8755-103911.
Darragh
TM
, Colgan
TJ
, Cox
JT
, Heller
DS
, Henry
MR
, Luff
RD
, et al.; Members of LAST Project Work Groups
. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology
. Arch Pathol Lab Med
. 2012
Oct
;136
(10
):1266
–97
.
[PubMed]
0003-998512.
Boshart
M
, Gissmann
L
, Ikenberg
H
, Kleinheinz
A
, Scheurlen
W
, zur Hausen
H
. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer
. EMBO J
. 1984
May
;3
(5
):1151
–7
.
[PubMed]
0261-418913.
Austin
RM
, Onisko
A
, Zhao
C
. Enhanced Detection of Cervical Cancer and Precancer Through Use of Imaged Liquid-Based Cytology in Routine Cytology and HPV Cotesting
. Am J Clin Pathol
. 2018
Oct
;150
(5
):385
–92
.
[PubMed]
0002-917314.
Tao
X
, Zheng
B
, Yin
F
, Zeng
Z
, Li
Z
, Griffith
CC
, et al. Polymerase Chain Reaction Human Papillomavirus (HPV) Detection and HPV Genotyping in Invasive Cervical Cancers With Prior Negative HC2 Test Results
. Am J Clin Pathol
. 2017
May
;147
(5
):477
–83
.
[PubMed]
0002-917315.
15Cancer Genome Atlas Research N, Albert Einstein College of M, Analytical Biological S, Barretos Cancer H, Baylor College of M, Beckman Research Institute of City of H, Buck Institute for Research on A, Canada's Michael Smith Genome Sciences C, Harvard Medical S, Helen FGCC, Research Institute at Christiana Care Health S, HudsonAlpha Institute for B, Ilsbio LLC, Indiana University School of M, Institute of Human V, Institute for Systems B, International Genomics C, Leidos B, Massachusetts General H, McDonnell Genome Institute at Washington U, Medical College of W, Medical University of South C, Memorial Sloan Kettering Cancer C, Montefiore Medical C, NantOmics, National Cancer I, National Hospital AN, National Human Genome Research I, National Institute of Environmental Health S, National Institute on D, Other Communication D, Ontario Tumour Bank LHSC, Ontario Tumour Bank OIfCR, Ontario Tumour Bank TOH, Oregon H, Science U, Samuel Oschin Comprehensive Cancer Institute C-SMC, International SRA, St Joseph's Candler Health S, Eli, Edythe LBIoMIoT, Harvard U, Research Institute at Nationwide Children's H, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins U, University of B, University of Texas MDACC, University of Abuja Teaching H, University of Alabama at B, University of California I, University of California Santa C, University of Kansas Medical C, University of L, University of New Mexico Health Sciences C, University of North Carolina at Chapel H, University of Oklahoma Health Sciences C, University of P, University of Sao Paulo RaPMS, University of Southern C, University of W, University of Wisconsin School of M, Public H, Van Andel Research I, Washington University in St L: Integrated genomic and molecular characterization of cervical cancer. Nature 2017;543:378-384.
16.
Madrigal
E
, Bishop
JA
, Faquin
WC
. Head and Neck Cytopathology: Human Papillomavirus-Positive Carcinomas, Including Diagnostic Updates, Testing Modalities, and Recommendations
. Surg Pathol Clin
. 2018
Sep
;11
(3
):501
–14
.
[PubMed]
1875-918117.
Mills
AM
, Dirks
DC
, Poulter
MD
, Mills
SE
, Stoler
MH
. HR-HPV E6/E7 mRNA In Situ Hybridization: Validation Against PCR, DNA In Situ Hybridization, and p16 Immunohistochemistry in 102 Samples of Cervical, Vulvar, Anal, and Head and Neck Neoplasia
. Am J Surg Pathol
. 2017
May
;41
(5
):607
–15
.
[PubMed]
0147-518518.
Horn
LC
, Reichert
A
, Oster
A
, Arndal
SF
, Trunk
MJ
, Ridder
R
, et al. Immunostaining for p16INK4a used as a conjunctive tool improves interobserver agreement of the histologic diagnosis of cervical intraepithelial neoplasia
. Am J Surg Pathol
. 2008
Apr
;32
(4
):502
–12
.
[PubMed]
0147-518519.
Klaes
R
, Benner
A
, Friedrich
T
, Ridder
R
, Herrington
S
, Jenkins
D
, et al. p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia
. Am J Surg Pathol
. 2002
Nov
;26
(11
):1389
–99
.
[PubMed]
0147-518520.
Moyer
VA
, Force
USPST
: Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012
;156:880-891, W312.21.
Murphy
N
, Ring
M
, Killalea
AG
, Uhlmann
V
, O’Donovan
M
, Mulcahy
F
, et al. p16INK4A as a marker for cervical dyskaryosis: CIN and cGIN in cervical biopsies and ThinPrep smears
. J Clin Pathol
. 2003
Jan
;56
(1
):56
–63
.
[PubMed]
0021-974622.
Petry
KU
, Schmidt
D
, Scherbring
S
, Luyten
A
, Reinecke-Lüthge
A
, Bergeron
C
, et al. Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology
. Gynecol Oncol
. 2011
Jun
;121
(3
):505
–9
.
[PubMed]
0090-825823.
Samarawardana
P
, Dehn
DL
, Singh
M
, Franquemont
D
, Thompson
C
, Gaido
L
, et al. p16(INK4a) is superior to high-risk human papillomavirus testing in cervical cytology for the prediction of underlying high-grade dysplasia
. Cancer Cytopathol
. 2010
Jun
;118
(3
):146
–56
.
[PubMed]
1934-662X24.
Rooper
LM
, Gandhi
M
, Bishop
JA
, Westra
WH
. RNA in-situ hybridization is a practical and effective method for determining HPV status of oropharyngeal squamous cell carcinoma including discordant cases that are p16 positive by immunohistochemistry but HPV negative by DNA in-situ hybridization
. Oral Oncol
. 2016
Apr
;55
:11
–6
.
[PubMed]
1368-837525.
Beauséjour
CM
, Krtolica
A
, Galimi
F
, Narita
M
, Lowe
SW
, Yaswen
P
, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways
. EMBO J
. 2003
Aug
;22
(16
):4212
–22
.
[PubMed]
0261-418926.
Wheeler
CM
, Hunt
WC
, Joste
NE
, Key
CR
, Quint
WG
, Castle
PE
. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States
. J Natl Cancer Inst
. 2009
Apr
;101
(7
):475
–87
.
[PubMed]
0027-8874© 2019 S. Karger AG, Basel
2019
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