Screening Technologies For Cervical Cancer - Overview - PMC
Screening Technologies For Cervical Cancer - Overview - PMC
Screening Technologies For Cervical Cancer - Overview - PMC
1
Department of Gynaecological Oncology, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India,
2
Cancer Foundation of India, Kolkata, West Bengal, India,
3
Early Detection and Prevention Section/Screening Group, International Agency for Research on Cancer, Lyon, France.
Corresponding author.
*
Corresponding author: Dipanwita Banerjee, Department of Gynaecological Oncology, Chittaranjan National Cancer
Institute, Kolkata, West Bengal, India. [email protected]
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share
Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the
author is credited and the new creations are licensed under the identical terms.
Abstract
Ever since the introduction of the Papanicolaou (PAP) smear test was published in 1941 in
American Journal of Obstetrics and Gynecology, PAP test linked with definitive treatment has pre‐
vented millions of women from cervical cancer in the developed countries. Due to limited availabil‐
ity of resources, a lack of infrastructure and difficulty in getting highly trained professionals, wide‐
spread implementation of PAP test dependent cervical cancer screening program has not been es‐
tablished in low and middle income countries such as India. Therefore, after availability of non-cy‐
tological tests such as visual inspection on acetic acid (VIA) and human papillomavirus (HPV) DNA
test, there is a paradigm shift in cervical cancer screening methods. In past two decades, various
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9/12/24, 10:04 PM Screening technologies for cervical cancer: Overview - PMC
research work has convincingly established the utility of VIA and HPV test in developing countries.
The evidences were evaluated by the World Health Organization (WHO) and recommendations
have been recently published for comprehensive cervical cancer control strategies for the low and
middle income countries. For any successful screening program, achieving high coverage (>70%)
of the target population rather than frequent screening is the most important determinant. It is
also equally important to ensure appropriate investigations of the screen positive women to estab‐
lish the disease and treatment of the screen detected cases of cervical intra epithelial neoplasia
(CIN) and cancer. HPV testing is the WHO recommended test for cervical cancer screening espe‐
cially in view of widespread HPV vaccination in young population leading to lower prevalence of
CIN and other HPV related diseases.
Keywords: HPV DNA in cervix cancer, VIA, PAP, HPV in cervical screening, Cervical pre cancers
Cancer screening aims to detect preclinical disease in an apparently healthy population through
systematic administration of a simple and safe test to all men/women belonging to a specified tar‐
get age group. Since the primary objective of cervical cancer screening is to detect the premalig‐
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nant lesions (known as cervical intraepithelial neoplasia [CIN]), World Health Organization (WHO)
recommended screening of women between 30 and 49 years of age.[1] At this age, the women
have the highest possibility of harboring the CIN 2 and CIN 3 lesions that are considered as true
cervical cancer precursors or high grade lesions. Screening at younger age detects large number
of low grade lesions that regress of their own and the women are subjected to unnecessary biop‐
sies and treatment. However, screening of HIV positive women should be initiated whenever they
are sexually active. The upper age range can be extended to 55–60 years age if resources permit.
The frequency of screening in the screen negative women depends on the screening test being
used and the resources available within the program. Too frequent screening should be avoided
and the minimum interval between two rounds of screening should be 5 years. Programs with lim‐
ited resources can extend the interval to 10 years, if a highly sensitive screening test (such as HPV
DNA test) with very low possibility of missing cases can be used. Even once a lifetime screening
around the age of 40 years can reduce cervical cancer incidence by 30%.[2] Achieving high cover‐
age (>70%) of the target population rather than frequent screening is the most important deter‐
minant of success of the screening program.
Administering the screening test is only a component of cervical cancer screening that involves
community mobilization to motivate large number of women to participate, training of all levels of
service providers, ensuring further assessment of screen positive women and ensuring appropri‐
ate treatment, and follow-up of the screen detected abnormalities. It is extremely important to en‐
sure appropriate investigations of the screen positive women to establish the disease and treat‐
ment of the screen detected cases of CIN and cancer. Traditionally, colposcopy followed by di‐
rected biopsies have been used to confirm diagnosis in the screen positive women and subse‐
quent treatment decisions were made on the basis of histology report. However, this multiple visit
approach (at least three) is very inconvenient for the women and the compliance is often poor.
Several alternate strategies have been recommended and adopted to reduce the number of visits
and improve compliance of the women. The positive predictive value of colposcopy is reasonably
high to detect CIN 2/CIN 3 disease and treatment can be done on the basis of colposcopy diagno‐
sis alone. Such strategy of “colposcopy and treat, also known as see and treat” improves compli‐
ance to treatment and is convenient to the women though some over-treatment is unavoidable.
Over-treatment is acceptable as the treatment methods are simple and safe and the treated
women with negative histology will require less intensive follow-up. In more basic settings where
organizing colposcopy and histopathology is challenging, a more simpler approach like direct
treatment of the screen positive women (“screen and treat”) is also recommended.[1] This will be
further discussed in the subsequent sections.
A second screening test is sometimes recommended for the women positive on the primary
screening test. The second test is called triaging test and the women positive on both the tests are
only referred for colposcopy. Such triaging strategy is used if the primary screening test is less
specific and/or if the colposcopy services are insufficient and expensive.
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To achieve desired effectiveness of program to reduce cervical cancer burden, the screen detected
CIN 2/CIN 3 lesions must be treated appropriately. CIN lesions can be treated by ablation or by ex‐
cision. Ablative techniques are simpler, less expensive, can be performed by trained nonclinicians
and have very low complication rates. Two different ablative techniques are available –
Cryotherapy and Thermocoagulation; both of them are equally effective and safe even when per‐
formed by nurses.[3] A major advantage of ablative therapies is that the treatment can be done in
primary care or secondary care settings. The excision methods of treatment include large loop ex‐
cision of transformation zone (LLETZ) and cold knife conization (CKC). In both the techniques, the
entire transformation zone (TZ) is excised and submitted for histopathological evaluation. While
LLETZ is much simpler, requires local anesthesia only and has low complication rate, CKC has to
be done under regional or general anesthesia, requires higher level of technical expertise and has
higher complication rates.
All the screen positive women need to be assessed for suitability of treatment by ablative tech‐
niques using the following criteria (with colposcopy or with naked eye after application of 3–5%
acetic acid):
If suitable, the lesions may be treated by Cryotherapy or Thermocoagulation without waiting for
histopathological verification. Only the women with lesions not suitable for Cryotherapy should be
referred for treatment by exciscion.[4]
Follow-up of the women after treatment is also important. Women treated for CIN 2 or CIN 3 have
much higher risk of developing cervical cancer even after 10 years of treatment compared to the
normal women.[5] Post-treatment initial follow-up should be done after 1 year either by the
screening test or by colposcopy. The protocol for subsequent checkups varies from program to
program. Usually, the women are sent back to routine screening if they are normal on 2–3 consec‐
utive rounds of yearly screening.
Cervical screening tests such as conventional cytology (PAP smear), liquid based cytology (LBC),
human papillomavirus (HPV) testing, and visual inspection on acetic acid (VIA) can detect cervical
precancerous lesions in apparently healthy, asymptomatic women.
Cytology
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The most widely used cervical screening test is cytology. High-income countries have integrated
cytology screening services in medical and public health services and have achieved high coverage
through better program organization. This has resulted in substantial declines in cervical cancer
incidence and mortality over time.[6] Some of the middle-income countries in South and Central
America and in Asia also implemented population-based cervical cancer screening using cytology
for a few decades. However, these programs were largely ineffective in reducing cervical cancer
burden due to poor coverage with screening, treatment and follow-up care and lack of quality as‐
surance.[7] Majority of the low middle income countries (LMICs) have neither initiated nor have
the capacity to initiate and sustain quality assured cytology screening programs in their underde‐
veloped and fragmented health services with several competing priorities, lack of resources, and
trained manpower. Cytology needs good quality laboratory infrastructure, rigorous monitoring
and supervision, highly skilled technicians or pathologists and a good system of recalling the
screen positives. All these are very challenging to implement in the low resourced countries.
Cytology results are most widely reported using The Bethesda system (TBS); the major categories
of 2014 TBS is given in [Table 1].[8] The threshold for positive cytology for referral for
triaging/diagnostic investigations such as colposcopy may be at atypical squamous cells of unde‐
termined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) in various set‐
tings. All women with atypical squamous cells, cannot rule out high-grade squamous intraepithe‐
lial lesion (ASC-H), LSIL or high-grade squamous intraepithelial lesion (HSIL) report on cytology
must have further evaluation with colposcopy. The management options for ASCUS smears are ei‐
ther repeat smear after 6 months or HPV test (triaging) or direct colposcopy.
Cytology smears are prepared by spreading the cervical cell specimen collected using a spatula
and cervical brush on to a glass slide which is then fixed and stained using Papanicolaou (PAP)
staining. Cytology is a highly subjective and provider dependent test with varying performance be‐
tween laboratories and cytologists reading the smears.
LBC
LBC offers an improved test specimen collection with lower frequency of unsatisfactory smears,
lower debris, and shorter time needed for interpretation compared to conventional cytology. It is
the first technical advancement in cervical cytology in more than 50 years. For LBC, the cervical
cell specimen is washed into a vial of liquid transport medium and filtered and a random sample is
presented as a thin layer on a slide avoiding overlapping of cells. LBC samples may be used for re‐
flex HPV and other molecular testing (for triaging in case of ASCUS report). However, LBC has
more or less equivalent sensitivity and specificity as compared to cytology for the detection of CIN
2 or worse lesions.[11]
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HPV testing
HPV testing involves detecting HPV DNA or mRNA of two oncoproteins (E6 and E7) in cervical cell
samples collected by pelvic examination or by self-sampling. HPV testing is the most accurate, re‐
producible and provider independent cervical screening test. Its sensitivity to detect CIN2+ lesions
exceeds 90% and CIN3+ exceeds 95%; it is more sensitive but less specific than cytology.[12]
If available, HPV testing is the most suitable test to screen women above the age of 30 years, since
HPV negative women can be left alone for at least 7–10 years in view of the high Negative
Predictive Value of a negative HPV test for CIN3 and cervical cancer.[13,14] Characteristics of some
selected clinical HPV tests are given in the [Table 2].
HPV tests have been widely evaluated and compared with cytology in several randomized con‐
trolled trials. A cluster randomized trial in India involving around 135,000 women aged 30–59
years demonstrated that following a single round of HPV testing, a significant 53% reduction in
the incidence of advanced cancer (stage II+) and a 48% reduction in cervical cancer mortality
could be achieved.[14] In four European randomized trials involving 176,464 women aged 20–64
years, HPV testing was compared with cytology screening. These women were followed up for a
median 6.5 years and the relative efficacy of HPV- versus cytology-screening for prevention of in‐
vasive cancer was compared. HPV testing provided 60–70% greater protection against invasive
cervical carcinomas compared with cytology.[15] Data from the randomized trials in Europe and
India[14,15] support initiation of HPV based screening and extension of screening intervals to at
least 5 years. The WHO recommends repeat screening after 10 years in HPV negative women in
resource limited countries.[16]
Cervical cell samples are collected with a brush in a liquid medium for HPV test. The test positive
women need further evaluation by colposcopy. In some settings, HPV positivity may be high and
sending all HPV positive women to colposcopy may overburden the services. Reflex cytology test‐
ing or genotyping for HPV 16 or 18 may be used to triage HPV positive women before referral for
colposcopy; In LMICs, HPV positive women may be triaged by VIA screening in a two-visit “screen
and treat” approach.
HPV testing is the most promising test for cervical screening in the future including LMICs, in view
of the inevitability of widespread HPV vaccination leading to lower prevalence of CIN. In such a
scenario, an objective test such as HPV testing will be the most suitable screening test. Already
many European countries, Australia and some Latin American countries have introduced HPV test
as the primary screening test. Collection of high vaginal samples by the women themselves (self-
collection) is feasible and has almost same accuracy as that of provider collected cervical samples.
[17] Such a strategy can significantly improve the compliance of the women and improve the logis‐
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VIA involves naked eye visualization of the cervix 1 min after the application of 3–5% dilute acetic
acid under bright light. Test results are reported as negative, positive or suspicious of invasive can‐
cer and their criteria[18] are given in the [Table 3].
A positive test is defined by the appearance of well-delineated, dense acetowhite area abutting the
SCJ in the TZ of the cervix. It is a suitable test in premenopausal women under 50 years of age
when the TZ is fully visualized on the ectocervix. Interpretation of test is difficult in post‐
menopausal and older women. VIA is not ideal for women above 50 years of age or when the SCJ
is not fully visible. [Figure 1] shows images of cervix for different VIA outcome categories.
VIA is a simple, feasible and affordable point of care test, providing immediate results enabling di‐
agnosis and/or treatment to be carried out in the same visit for screen positive women. Wide
range of health professionals including doctors, nurses, midwives and primary health care work‐
ers can be trained to perform VIA after a short period of training. The infrastructural need is mini‐
mal and the consumables are universally available.
VIA has been extensively evaluated in a variety of settings. Although the pooled sensitivity and
specificity of VIA to detect CIN 2 + lesions were 80–92%, respectively, in a pooled analysis,[19]
these values varied widely in different settings due to the subjective and provider dependent na‐
ture of the test, varying quality of reference standard investigations and differing age groups in‐
cluded in the studies. VIA also suffers from high false positive rates.
VIA screening was followed by a 31% reduction in cervical cancer mortality in a randomized trial
in Mumbai[5] In a randomized trial in South India, VIA screening was associated with 25% decline
in cervical cancer incidence and 35% reduction in mortality.[20] This evidence culminated in the
launching of a population based VIA screening program in the state of Tamil Nadu in India. Large
number of nurses have been trained in providing VIA throughout the primary health centers in
the state and 55% of targeted 15 million have been screened through the first round of a VIA
screening program during 2012–2014.
The visual tests seem to perform better in HIV-infected women than in the general population due
to the increased prevalence of large high-grade lesions.[21,22]
The safety, acceptability and effectiveness of a single visit “screen and treat” approach (SVA) in
which VIA positive women eligible for cryotherapy, are treated in the same sitting has been well
established.[23-25] Women with precancerous lesions not eligible for Cryotherapy may be referred
for loop electrosurgical excision procedure for diagnosis and treatment. The SVA paradigm repre‐
sents a major innovation for scaling up cervical cancer screening in LMICs and has been adopted
by many countries in subSaharan Africa and Asia.[26] Primary care practitioners should utilize ev‐
ery opportunity in routine health care interactions to screen women aged 30 years and above
with VIA and investigate and treat screen positive women.
Despite all its limitations, implementing VIA screening in low-income countries provides a realistic
approach to build up infrastructure and human resources that may facilitate the introduction of
affordable HPV screening in future.
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Visual inspection after application of Lugol’s iodine (VILI) is another simple inexpensive visual
screening technique. The test relies on identification of Iodine negative areas on the cervix after
application of Lugol’s Iodine [Figure 2]. VILI has not been widely evaluated and has high false
positivity. The consumables are expensive and are not readily available. The test is not yet recom‐
mended by WHO for routine screening.
The ultimate aim of cervical cancer screening is to reduce the disease burden by detecting the pre‐
cancerous lesions early and managing them appropriately.
There is no single definitive strategy for management of HPV positive women. The management
approaches generally depend on factors such as available resources, logistics, and program guide‐
lines. As cervical cancer is a rare outcome of high risk-HPV infections, management strategies are
based on assessment of risk thresholds that identifies the small percentage of women who are
likely to develop cervical precancer or cancer. To allow risk stratification and subsequent identifi‐
cation of at-risk women, additional tests (Triage tests) are indicated depending on availability of
the tests and feasibility of doing it. Triage tests like Cytology, HPV genotyping for HPV 16/18, test
for E6/E7 mRNA, p16/Ki-67 dual staining and VIA may be used for risk-based management.
As majority of the HPV infections are transient, most of the HPV positive women will not have any
clinically detectable disease on colposcopy. Referral of all HPV positive women for colposcopy will
lead to over burdening of the system, particularly in context of LMICs with limited colposcopy fa‐
cility. This approach is also likely to increase the cost of public health programs and should be con‐
sidered for situations where performing triage tests are not feasible or ensuring follow-up of posi‐
tive women is challenging.
Direct treatment of HPV positive women has been widely promoted, especially in LMICs, to ensure
a linkage between screening and treatment and minimize loss to follow-up. In settings where col‐
poscopy and histopathology services are not available, the WHO recommendation of “screen and
treat” strategy has strongly encouraged treatment of HPV positive women by ablative treatment
methods such as cryotherapy, provided the lesion suits the eligibility criteria for ablation.[4]
Various management strategies for HPV positive women is summarized in [Figure 3].
VIA is a real time test that allows for taking treatment decisions in the same sitting as screening. In
the context of LMICs where there is no or limited facility for colposcopy and histology, the WHO
guidelines for “screen and treat” strategies recommend immediate treatment of VIA positive cases
by ablative method if the lesion characteristic fulfills the criteria for ablative treatment.[4] In situa‐
tions where Colposcopy and biopsy facilities are available, the VIA positive women can be referred
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for evaluation by Colposcopy. Treatment can be done either in the same sitting as Colposcopy
(“See and treat”) or based on histopathology report. The management options for VIA positive
women are given in [Figure 4].
The management options for women with cytological abnormalities are presented in [Figure 5]
and discussed in details in the chapter “Role of colposcopy in management of women with abnor‐
mal cytology.”
CONCLUSION
Accumulated evidence on all cervical screening tools available shows that HPV testing is an accept‐
able, safe and highly efficacious procedure for detecting cervical cancer precursors. Sampling de‐
pendency and quality control is also favorable for HPV testing as compared to cytology. In middle
income countries like India with lack of infrastructure and non availability of trained professionals,
non cytological screening tests like VIA and HPV test are a viable alternative to cytologic screening.
From the perspective of health policy, though at present HPV test as the primary screening test
may have high upfront cost but because of its high sensitivity, specificity and negative predictive
value, there is net cost saving in HPV detection based screening program due to high and pro‐
longed protection that allows screening interval to be increased. HPV testing will be most suitable
in the post vaccination era in view of low prevalence of HPV infection and neoplasia, when subjec‐
tive tests like cytology and VIA will be more challenging with poor accuracy. Along with awareness
and education change from a cellular to viral test will be more effective in controlling the huge
burden of cervical cancer.
ACKNOWLEDGMENTS
None.
Footnotes
How to cite this article: Banerjee D, Mittal S, Mandal R, Basu P. Screening technologies for cervical cancer: Overview.
CytoJournal 2022;19:23.
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9/12/24, 10:04 PM Screening technologies for cervical cancer: Overview - PMC
TZ – Transformation zone
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India. Int J Cancer. 2012;130:234–40. doi: 10.1002/ijc.25971. [PMCID: PMC3516675] [PubMed: 21387289] [CrossRef:
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acceptability of 'see and treat' with cryotherapy by nurses in a cervical screening study in India. Br J Cancer. 2007;96:738–
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24. Mwanahamuntu MH, Sahasrabuddhe VV, Kapambwe S, Pfaendler KS, Chibwesha C, Mkumba G, et al. Advancing cervical
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25. Parham GP, Mwanahamuntu MH, Kapambwe S, Muwonge R, Bateman AC, Blevins M, et al. Population-level scale-up of
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cancer prevention program in Zambia. PLoS One. 2015;10:e0122169. doi: 10.1371/journal.pone.0122169. [PMCID:
PMC4401717] [PubMed: 25885821] [CrossRef: 10.1371/journal.pone.0122169]
26. Sankaranarayanan R, Nessa A, Esmy PO, Dangou JM. Visual inspection methods for cervical cancer prevention. Best
Pract Res Clin Obstet Gynaecol. 2012;26:221–32. doi: 10.1016/j.bpobgyn.2011.08.003. [PubMed: 22075441] [CrossRef:
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Table 1:
Specimen adequacy
Interpretation/results
• ASCUS or ASC-H
• (HSIL, encompassing moderate and severe dysplasia, CIS; CIN 2 and CIN 3); (if invasion is
suspected), with features suspicious for invasion
• Atypica
• Adenocarcinoma
ASCUS: Atypical squamous cells of undetermined significance, LSIL: Low-grade squamous intraepithelial lesion, ASC-H:
Atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesion, HSIL: High-grade squamous intraep‐
ithelial lesion, TBS: The Bethesda System, CIN: Cervical intra epithelial neoplasia, HPV: Human papillomavirus
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Table 2:
Hybrid capture 2 HPV DNA of types 16, 18, 31, 33, 35, 39, 45, • Robust and relatively simple technology
(HC2) HR HPV 51, 52, 56, 58, 59, and 68 • Semi-quantitative viral load estimation
possible
• Cross-react with non-targeted nononcogenic
types
• Genotype information not obtained
CareHPV HPV DNA of types 16, 18, 31, 33, 35, 39, 45, • Does not require elaborate laboratory
51, 52, 56, 58, 59, 66 and 68 infrastructure
• Flexible temperature ranges
• Minimal training needs
• Run time 2.5 h
• Less expensive
• Genotype information not obtained
GeneExpert HPV DNA of types 16, 18, 31, 33, 35, 39, 45, • Results are available in 1–2 h
51, 52, 56, 58, 59, and 68 (+ concurrent • The test platform is available in many low
genotype information for HPV 16, 18 and 45) resourced countries (used to detect MDR TB)
• Sample preparation very simple
• Still expensive
Cervista HPV HPV DNA of types 16, 18, 31, 33, 35, 39, 45, • Less cross-reactivity to low risk types
51, 52, 56, 58, 59, 66 and 68 • Internal control to assess DNA content and
integrity
• Genotype information not obtained
Abbott Concurrent individual genotyping for types • Simultaneous detection of types 16/18 allows
16/18 and pooled detection of types 31, 33, triaging
35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
Cobas HPV HR Concurrent individual genotyping for types • Simultaneous detection of types 16/18 allows
16/18 and pooled detection of types 31, 33, triaging
35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
PreTect HPV mRNA of E6/E7 of types 16, 18, 31, 33, 45 • More predictive of lesions with potential for
progression
• Less sensitive due limited genotype detection
• Sample storage conditions more stringent
Aptima HPV mRNA of E6/E7 of types 31, 33, 35, 39, 45, 51, • More predictive of lesions with potential for
52, 56, 58, 59, 66 and 68 progression
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Table 3:
VIA is reported Negative when any of the following features are seen
• Thin transparent acetowhite lesions or faint patchy lesions or lesions without definite
margins
• Streak-like acetowhitening
• Dot like areas in the endocervix, which are due to grape-like columnar epithelium
transiently staining with acetic acid
VIA is reported Positive when any of the following features are seen:
• Distinct, well defined, dense, opaque or dull white or oyster white acetowhite areas
touching the SCJ or touching the external os (if SCJ not seen)
• The lesion should have a well-defined margin may or may not be raised from the surface
VIA is reported Suspicious of Invasive Cancer when any of the following features are seen:
• The growth or ulcer may or may not be acetowhite after acetic acid application
Figure 1:
Visual inspection on acetic acid outcome categories. (a) VIA – Negative, (b) VIA – Positive, (c) VIA - Suspicious of invasive
cancer.
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Figure 2:
Figure 3:
Figure 4:
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Figure 5:
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