Treatment Hal 4

doi:10.1111/jog.14168 J. Obstet. Gynaecol. Res. Vol. 46, No.
2: 201–214, February 2020
Screening and management of preinvasive lesions of the

cervix: Good clinical practice recommendations from the
Federation of Obstetrics and Gynaecologic Societies of
India (FOGSI)
Neerja Bhatla1, Seema Singhal1, Usha Saraiya2, Shikha Srivastava3, Sarita Bhalerao4,
Saritha Shamsunder5, Niranjan Chavan6, Partha Basu7, and CN Purandare8, (on behalf of
FOGSI Expert group)
1
All India Institute of Medical Sciences, 5Vardhmaan Mahaveer Medical College & Safdarjung Hospital, New Delhi, 2Breach
Candy, Saifee, Elizabeth & Cumballa Hill Hospitals, 4Reliance HNH, Saifee and Bhatia Hospitals, 6LTMMC & LTMGH, Sion,
8
Saifee Hospital, Mumbai, 3Population Services International (PSI), Delhi, India and 7Early Detection and Prevention Section
(EDP)/Screening Group (SCR) International Agency for Research on Cancer, World Health Organization, Lyon, France
Abstract
In India, there are marked variations in resources for cervical cancer screening. For the first time, resource-
stratified screening guidelines have been developed that will be suitable for low middle-income countries
with similar diversities. The current article describes the process and outcomes of these resource stratified
guidelines for screening and treatment of preinvasive lesions of cervix. Evidence from literature was collated
and various guidelines were reviewed by an expert panel. Based on the level of evidence, guidelines were
developed for screening by human papillomavirus (HPV) testing, cytology and visual inspection after appli-
cation of acetic acid (VIA), and management of screen positive lesions in different resource settings. Expert
opinion was used for certain country-specific situations. The healthcare system was stratified into two
resource settings – good or limited. The mode of screening and treatment for each was described. HPV test-
ing is the preferred method for cervical cancer screening. VIA by trained providers is especially suitable for
low resource settings until an affordable HPV test becomes available. Healthcare providers can choose the
most appropriate screening and treatment modality. A single visit approach is encouraged and treatment
may be offered based on colposcopy diagnosis (‘see and treat’) or even on the basis of HPV test or VIA
results (‘screen and treat’), if compliance cannot be ensured. The Federation of Obsterician and Gyn-
aecologists of India Good Clinical Practice Recommendations (FOGSI) GCPR are appropriately designed for
countries with varied resource situations to ensure an acceptable cervical cancer prevention strategy.
Key words: cervical cancer screening, good clinical practice, prevention, recommendations, resource-based,
single visit approach.
Received: June 14 2019.

Accepted: November 13 2019.
Correspondence: Dr Neerja Bhatla, Department of Obstetrics & Gynaecology, Room no 3081 Teaching Block, All India Institute of
Medical Sciences, New Delhi, India. Email: [email protected]
Members of FOGSI Expert Group: Agarwal P, Arora M, Bhatla N, Basu P, Bhalerao S, Batra S, Banerjee D, Chavan N, Dhorepatil B,
Gupta B, Gandhi G, Gupta K, Ganesh P, Joshi S, Kriplani A, Khanna R, Kumar S, Maheshwari A, Meena J, Nayak B, Natarajan J,
Pai R, Pathak R, Prabhu RB, Peedicayil A, Rajaram S, Sekhon R, Shamsunder S, Srivastava S, Singh U, Singhal S, Saraiya U, Zutshi V.
© 2019 Japan Society of Obstetrics and Gynecology 201

14470756, 2020, 2, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.14168 by Nat Prov Indonesia, Wiley Online Library on [30/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
N. Bhatla et al.
Introduction
Cervical cancer is a major public health problem, distributed among the experts who reviewed the liter-
being the second most common cancer among Indian ature with reference to study designs and participants,
women.1 India contributes to one quarter of the global intervention, comparisons, outcomes (PICOS). Studies
burden with 96 922 incident cases and 60 078 deaths were evaluated for quality, and strength was assigned
in 2018.1 The age-standardized incidence and mortal- to each practice recommendation.7 Previously publi-
ity rates in India (ASR) are 14.7/100 000 and shed guidelines by major international organizations
9.2/100 000 women, respectively.1 There are regional as well as guidelines appropriate for resource-
variations in ASR, from 24.3/100 000 in Aizawl to constrained situations by the World Health Organiza-
5.6/100 000 in Dibrugarh district.2 The 5-year relative tion 2014, Government of India 2016 and the American
survival rate for cancer cervix in India continues to be Society of Clinical Oncology (ASCO) 2016 were ana-
low, approximately 46% (range 34–60%), predomi- lyzed for their applicability in the Indian context.6,8,9 A
nantly because of late detection.3 synopsis was prepared and circulated in the group.
In developed countries, establishment of national Thereafter, in a face-to-face meeting, the document
screening programs with population-based invitation with various algorithms was discussed and subse-
of eligible women and a recall system for screen posi- quent comments were circulated until unanimous
tives resulted in prevention of almost 70% of cervical agreement was reached. The draft recommendations
cancer.4 India is a land of diversity with enormous were posted online on the Federation of Obsterician
variations in sociocultural practices and healthcare and Gynaecologists of India (FOGSI) website for pub-
infrastructure.5 Shortage of trained manpower and lic comments.10,11 The final consensus document was
infrastructure has limited the establishment of effec- presented and was then approved at the FOGSI Man-
tive, standardized, cytology-based screening program, aging Committee Meeting in January 2018.
which is currently used only for opportunistic screen-
ing. Ministry of Health and Family Welfare
(MoHFW), Govt. of India has formulated operational Results and Discussion
framework for screening of cervical cancer based on
visual inspection of cervix after application of acetic Resource stratification
acid (VIA) in 2016.6 However, in urban settings the Initially the expert panel planned to stratify the
option of high-risk human papillomavirus (HPV) test- healthcare system into four groups in accordance with
ing is now available in many cities. ASCO resource stratified clinical practice guidelines,9
In the absence of national guidelines, healthcare but later for easy understanding and usability,
providers have been following different international resource stratification was simplified into two strata
recommendations, which were limited in their appli- as good and limited resource settings. Settings with-
cability to the Indian setting. Therefore, a need was out lack of facilities including trained doctors, labora-
felt for an expert group to develop evidence-based tories and equipment are considered good resource
recommendations that are suitable for diverse settings. Settings that lack any of these are termed
resource situations. The current article describes the limited resource settings.
process and outcomes of resource stratified guidelines The suggested modalities for screening and triage in
for screening and treatment of preinvasive lesions of each setting are shown in Table 1. Considering the var-
cervix. Though developed in India they are also suit- iations in cervical cancer screening practices, expert
able for low and middle income countries (LMICs) group agreed to suggest preferred and acceptable
with similar diversities. modalities for follow-up and treatment. Single visit
approach (SVA), in which screening and treatment can
be completed at the same sitting, was identified as the
Methods preferred modality for all resource settings, especially
when patient is likely to be lost to follow-up.
A panel of gynecologists, gynecologic oncologists and
public health experts with experience in cervical cancer Choosing an appropriate screening modality
prevention from all regions of the country was consti- The three main modalities of screening in use are
tuted. Relevant questions were formulated and HPV testing, cytology and visual inspection with
202 © 2019 Japan Society of Obstetrics and Gynecology

Cervical Cancer Screening & Management of CIN
Table 1 Resource-based strategies for cervical cancer screening and management of CIN
Good Resource settings Limited Resource settings
Screening modality HPV testing VIA (visual inspection of cervix with acetic
•Primary HPV testing acid)
•Co-testing (HPV and cytology) Affordable HPV test (if available),
Cytology including self-sampling, can be used
VIA
Triage tool For ASCUS cytology: Colposcopy if available
High-risk HPV test Biopsy‡
For HPV test:

Cytology newer modalities†
Or HPV Genotyping for types 16/18
Or colposcopy and biopsy‡
Or VIA and biopsy‡
Management options All CIN2 and CIN3 can be treated by LEEP. All grades of CIN fulfilling the criteria for
for histopathology CKC can be performed for AIS or if early ablation§ should be treated by cryotherapy
proved CIN invasive cancer is suspected. or thermal ablation.
CIN1 can be followed up and be treated All grades of CIN not fulfilling the criteria
if it progresses or persists after should be treated by LEEP.
2 years. CKC can be performed for AIS or if early
Cryotherapy or thermal ablation can be invasive cancer is suspected.
performed for all grades of CIN as an
alternative to LEEP, provided the
criteria for ablation are fulfilled.§
Approaches to reduce the ‘See-and-Treat’ strategy is preferred to treat ‘See-and-Treat’ strategy should be followed,
number of visits women with colposcopically suspected if colposcopy facilities are available.
high-grade lesions. Treatment with If colposcopy is not available, VIA or HPV
LLETZ/LEEP or ablation depending on positive women may be offered imme-
suitability of lesion for ablative treatment. diate treatment (‘Screen-and-Treat’). All
Histopathology report should be reviewed cases should initially be assessed for
at follow-up. suitability of ablative treatment
(cryotherapy or thermal ablation).
Eligibility of HPV positive women to be
assessed after applying 5% acetic acid
(VIA). A punch biopsy should be
obtained prior to ablative treatment and
the report reviewed at follow-up.
LLETZ/LEEP, large loop excision of transformation zone/loop electrosurgical excision procedure; CKC, cold knife colonization; CIN, cer-
vical intra epithelial lesion.; †Newer modalities (p16, Ki 67 testing, mRNA testing, E6, E7 protein testing).; ‡Biopsy from any abnormal
area(s). and §Criteria for ablation: (i) Lesion should be entirely visible and not occupy more than two quadrants of cervix, (ii) The entire
lesion should be located on ecto cervix without any vaginal or endo-cervical extension, (iii) Lesion should be entirely covered by largest
cryotherapy probe available, (iv) No suspicion of invasive disease, (v) Contraindicated in cases with post coital or postmenopausal bleed-
ing, obvious cervical growth, irregular surface or bleeds on touch.
acetic acid (VIA). Figure 1 describes the algorithm to is expensive and not widely available. It is rec-
choose the most appropriate screening modality. Vali- ommended for women aged over 30 years using vali-
dated primary HPV screening, the most effective dated tests. Validated tests are those that have
method, was recommended for screening in good demonstrated efficacy in randomized controlled trials
resource settings. However, the centers with an or have shown test accuracy comparable to a vali-
established cytology program with good quality con- dated test. The results of such tests are generally
trol may continue with cytology. In limited resource reported as detected/not detected for a pool of 13 or
settings one may screen with VIA. 14 high-risk HPV genotypes; some also report indi-
There is ample evidence that HPV testing is the vidual genotypes for the most oncogenic types (HPV
most sensitive modality, suitable for screening in all 16/18). Example of validated tests are Hybrid Cap-
resource settings.12,13 In an Indian study, even a single ture 2, careHPV, Cobas, Xpert, Cervista, APTIMA etc.
round of HPV testing was shown to significantly HPV tests based on routine polymerase chain reaction
reduce the incidence of cervical cancer.14 However, it (PCR) detecting only a few genotypes should not be

N. Bhatla et al.
Figure 1 : How to choose the most appropriate screening modality?
advised as they are of high analytical sensitivity and a and high false positivity.16 Currently it is the only
positive result has little clinical relevance. Affording test that can be used in low resource settings with
centers/individuals, can consider co-testing with both considerable accuracy and safety but in future, the
cytology and HPV test or switch over to primary availability of affordable HPV testing may change
HPV testing.15 The incremental benefit of co-testing this paradigm.
over HPV test alone is, however, small. Whenever possible, colposcopy should be used to
Cytology facilities are available in most cities and obtain a guided biopsy; if not available, biopsy can be
tertiary hospitals, but cytology has an inherent fal- guided by VIA too. It is advisable to link screening
lacy of low sensitivity (60–70%), which therefore with treatment by minimizing the number of visits to
necessitates frequent rounds of testing.13,14,16 Its the clinics, especially when there is a risk of loss to
major advantage lies in its high specificity (93.5%). follow up. When screening and treatment can be com-
Liquid based cytology (LBC) does not improve the pleted in the same sitting, the strategy is known as
sensitivity of conventional cytology, though it does the single visit approach (SVA). Biopsy can be
decrease the rates of unsatisfactory smears and also reviewed post-hoc for adequacy of treatment and to
allows the same sample to be used for HPV test- rule out invasive cancer. Women with high-grade
ing.17 Centers with established cytology programs abnormalities on cytology (ASC-H or HSIL) and an
should assess quality indicators including diagnostic abnormal colposcopy can be treated without waiting
accuracy, training, coverage, etc. If these are found for histopathological verification.18 Such an approach
adequate they may continue with the same. If not, is known as ‘See-and-Treat’. It is also applicable to
they should consider switching to primary HPV women who are HPV or VIA positive and are
screening or even substitute or supplement with referred for colposcopy. In low resource settings
VIA. VIA has sensitivity comparable to cytology but where colposcopy facilities are not available, treat-
poorer specificity.16 It can be used in all resource ment by cryotherapy or thermal ablation based on
settings by all levels of healthcare providers. How- abnormal HPV test or VIA is also admissible and is
ever, a larger number of women will require further known as a ‘Screen-and-Treat’ strategy. This will
triage by colposcopy because of its low specificity ensure that women with cervical intraepithelial

neoplasia (CIN) lesions that fulfill the criteria do not feasible, it should be targeted at women between the
remain untreated. With this there is an acceptable risk age of 35–40 years.14
of over-treatment and the referral is minimized to The upper age limit is decided based on life expec-
only those with large, suspicious or endocervical tancy. If screening was continued till 90 years, the
lesions. estimated chance of preventing cervical cancer was
only 1.6 cases per 1000 women with substantial bur-
Age of screening den of colposcopies.20 Therefore, women over
To be most cost-effective, the age of starting and stop- 65 years with previously adequate negative screening
ping screening is determined by the age-specific can- and no history of CIN2+ within the last 20 years need
cer burden. In India, the burden of cervical cancer not be screened further.20,21 Adequate negative prior
under the age of 30 years is very low and it is negligi- screening is defined as three consecutive negative
ble under the age of 25 years.19 According to cytology or two consecutive negative co-tests within
Globocan 2018, the age standardized incidence rate 10 years, with the last test having taken place within
below 29 years is 0.46/100 000 women and below the last 5 years.20,21 In women who have undergone
24 years, is as low as 0.06 per 100 000 women.1 There- hysterectomy with a report of CIN2+ lesions, screen-
fore, screening should not be initiated before 25 years ing should be continued for 20 years from the age of
in asymptomatic women, regardless of the age of ini- surgery. Women who underwent hysterectomy for
tiation of sexual activity/resources. In limited any other benign disease need not continue screening.
resource settings, screening is recommended after the The screening age and periodicity recommenda-
age of 30 years. If only one round of screening is tions for each resource setting are depicted in Table 2.
Table 2 Resource-based cervical cancer screening recommendations

Good resource settings Limited resource settings
Target age group (years) 25–65 years 30–65 years (NB: In post-menopausal
women, screening with VIA may not
be as effective)
Age to start (years) Cytology at 25 years
Primary HPV testing/co-testing VIA at 30 years
at 30 years
Frequency Primary HPV testing or co-testing – Every 5 years (at least 1–3 times in a
every 5 years lifetime)
Cytology alone – every 3 years
Age to stop (years) 65 years, with consistent negative results in last 15 years
Women with no prior screening should undergo tests once at 65 years and, if
negative, they should exit screening
Follow up after treatment (method HPV testing (preferred) or cytology or VIA, 12 months
and interval) colposcopy, 12 months
Screening following abnormal 20 years
reports ≥ CIN 2+, irrespective of
method of treatment
Screening in hysterectomized Following hysterectomy in which cervix was removed for benign causes: no
women need for screening, unless there is history of previous cervical intraepithelial
neoplasia.
Absence of cervix must be confirmed by clinical records or examination.
If indications for hysterectomy unclear, screening may be performed at
clinician’s discretion.
Follow up in women with CIN in Need to be screened with HPV at 6 months and 18 months.
hysterectomy HPE report
Screening of immunocompromised Start within 1 year of initiation of Start within 1 year of initiation of
women sexual activity or as soon as HIV is sexual activity or as soon as HIV is
detected in sexually active women detected in sexually active women
HPV testing/co-testing/cytology/ VIA/affordable HPV testing
VIA (if available)
Every 2–3 years Every 3 years (at least twice as often
as general population)

N. Bhatla et al.
VIA every 5 years, starting from 30 upto 65 years is countries including Australia and some parts of
the recommended screening modality by Government Europe.24,25 In an RCT the detection rates of high-
of India.6 The accuracy of VIA in postmenopausal grade precancer/cancer (CIN2+) lesions in the initial
women decreases as the transformation zone rounds were higher in the HPV arm than cytology
(TZ) recedes into the endocervical canal. Other but were either same or lower in the subsequent
resource-based guidelines have recommended screen- rounds of screening with greater sensitivity
ing at least one to three times till the age of (ratio = 1.29, 95% CI, 1.18–1.39) and lower specificity
50 years.8,9 In a randomized trial in India, a single (ratio = 0.94, 95% CI 0.92–0.96).26 Another study
round of VIA based screening led to 30% reduction observed the cumulative incidence rates of CIN3 and
in cervical cancer incidence and a 42% reduction in cancer in HPV negative women aged >25 years as
cervical cancer mortality. The maximum reduction in low as 0.34% (95% CI, 0.10–0.65), in cytology-negative
the incidence of cervical cancer was seen among women 0.78%(95% CI, 0.53–1.09) and least in co-test
women aged 30–39 years.21 Another study demon- negative women 0.30% (95% CI, 0.05–0.62).27 How-
strated 25–31% reduction in the lifetime risk of invasive ever, this small decrease in cancer risk associated with
cervical cancer with VIA, 30–36% reduction with HPV co-testing may not be affordable in developing coun-
DNA testing, carried out once at the age of 35 years. tries with important competing health priorities. HPV
Two rounds of screening done at the age of 35 and test also provides better reassurance that high-grade
40 years reduced lifetime risk by 40%.22 lesion is currently absent and thus provides an oppor-
tunity to safely extend the screening intervals to
Screening paradigms 5 years or even 10 years. Compared to Pap test, HPV
The efficacy of the cervical cancer screening modali- test misses fewer adenocarcinomas or adenocarci-
ties; co- testing, primary HPV testing, cytology and nomas in situ.28
VIA are investigated in large clinical trials and based The specificity and positive predictive value of
on the generated evidence, clinical practice points are HPV test are low. To reduce referral to colposcopy,
formulated as shown in Table 3. HPV positive women may be triaged with another
test (cytology or VIA or HPV 16/18 genotyping), and
Co-testing with HPV testing and cytology triage positive cases may then be referred to colpos-
The combination of a highly sensitive validated HPV copy.29 The risk of CIN3+ in HPV 16/18 positive
test with highly specific cytology every 5 years is the cases is 21.1% while it is 5.4% with other non-16/18
most effective and preferred screening modality in strains.27 Hence HPV 16,18 positive women may be
India. Co-testing can detect 51% more cases of immediately referred to colposcopy and those with
CIN2/3 or invasive cancer than cytology alone.23 other strains may have cytology or VIA.12 In good
Schiffman et al. investigated the relative performance resource settings, women should be screened every
of each component and found that the first co-test 5 years with an approved HPV test or co-test. FOGSI
could detect 67.9% cases likely to progress in next Good Clinical Practice Recommendations (GCPR) rec-
10 years. Only a small fraction, i.e., 3.5% cases of ommends VIA as a feasible option to triage HPV posi-
preinvasive and 5.9% cases of invasive disease were tive cases where genotyping or good quality cytology
detected in women who were HPV−/cytology+ are not available. Direct colposcopy is acceptable for
results and were actually benefited by adding cytol- noncompliant cases (Fig. 2).
ogy to HPV test.15 Although this number may be
small (five cases/million women/year) and the com- Cytology as the primary screening modality
bination is costly but considering that in India major- Cytology-based programs have reduced the burden
ity of the women will be possibly having infrequent of cervical cancer in developed countries. The sensi-
screening or even once in a life-time screening, it is tivity of a single Pap test for detection of CIN2/3
prudent to use co-testing. Management of women reportedly ranges from 51% to 53% but the specificity
with abnormal co-testing based on specific abnormal- is as high as 96.3%.30 Therefore, currently cytology is
ity and resource availability is depicted in Figure 2. best used as a triage tool for HPV positive cases to
reduce unnecessary colposcopy.12 The GCPR provide
Primary HPV testing algorithms for the management of women with both
Primary HPV testing alone has replaced cytology in squamous and glandular abnormalities in different
the cervical cancer screening programs in various age groups.10,11

Table 3 Resource-based good clinical practice recommendations for cervical cancer screening and treatment of
preinvasive lesions†
FOGSI good clinical practice recommendation
1. In limited resource settings, women should be screened with VIA, at least one to three times in a lifetime, every
5 years (Level A).
In good resource settings, women should be screened every 5 years with a validated HPV test or co-test
(HPV + cytology) (Level A).
2. HPV positive cases should be triaged with either HPV genotyping or cytology. Referral to colposcopy if HPV
16/18 positive or cytology result is abnormal (ASCUS or worse). Others should have a repeat HPV test after
1 year. Colposcopy referral if the HPV test is persistently positive (Level A).
In limited resource settings, VIA can be used to triage HPV positive women. Direct colposcopy is an
acceptable option where compliance is an issue (Level B).
3. Women with co-testing (HPV + cytology)
Women with both HPV positive and cytology abnormal report should be advised colposcopy and directed
biopsy (Level A).
Women with HPV positive and cytology negative report should be advised HPV genotyping or repeat
co-testing after 1 year, depending on the availability of resources (Level B).
Women with HPV negative and cytology abnormal report should be advised further follow-up depending on
the type of cytological abnormality. All cases with ASC-H, HSIL, atypical glandular cells or suspected
cancer on cytology should be referred to colposcopy irrespective of HPV test result (Level A).
4. Women with ASCUS cytology:
Women aged 30–64 years with ASCUS cytology should be triaged preferably with HPV test, or if not
available with repeat cytology at 1 year (Level A).
Younger women should be followed up with annual cytology for 2 years (Level A).
If compliance is a concern, or HPV test is not available, colposcopy/VIA and directed biopsy is an acceptable
option for all age groups (Level C).
Women with LSIL cytology:
Women with LSIL cytology should be managed preferably with colposcopy (Level A).
If compliance is an issue, ‘See-and-Treat’ approach is an acceptable option (Level C).
Colposcopy in younger women with LSIL cytology should be done only when cytology results are persistent
or severe (Level B).
In postmenopausal women, LSIL cytology should be triaged with either colposcopy or reflex HPV or repeat
cytology (Level B).
Women with ASC-H or HSIL cytology:
Colposcopy should be done with special emphasis on visualization of the transformation zone (TZ) and
endocervical evaluation for managing women with ASC-H or HSIL (Level A).
Women with atypical glandular cells with any of the sub-categories should be evaluated with colposcopy
and directed biopsy along with endocervical sampling. Cold knife colonization or LEEP is required if the
cytology is repeatedly showing glandular abnormalities (Level A).
If colposcopy normal endometrial and adnexal pathology should be ruled out (Level B).
5. VIA based screening
VIA based screening is the most feasible modality in low resource settings and also in good resource settings
with high volume of patients (Level B).
VIA positive cases, depending on their compliance and need, can be either managed with colposcopy and
biopsy or can be treated in the same sitting with ablation if eligibility criteria for ablative treatment are
fulfilled (Level C).
6. HIV positive women can be screened with any available modality (Level A).
Screen positive HIV positive women should be managed in the same way as general population (Level A).
7. In women with CIN1 preceded by ASCUS or LSIL cytology treatment in form of excision or ablation is
warranted if it persists for 2 years (Level A).
In women with CIN1 preceded by ASC-H or HSIL cytology should be followed up either with yearly co-
testing or with 6-monthly cytology for 2 years. If the abnormality persists, a diagnostic excisional procedure
should be advised. Alternatively, if the patient cannot follow up, a diagnostic excisional procedure can be
recommended (Level B).
Patients with CIN2/3 who have type I transformation zone on colposcopy should be managed by either
excision (LEEP) or ablation of the TZ (cryotherapy or thermal ablation). Conversely, if TZ is type II or III on
colposcopy or endocervical sampling shows CIN2/3 or in recurrent CIN, excisional procedure (either cold
knife conization or LEEP) should be performed (Level B).
†Level A: Recommendations are based on good and consistent scientific evidence; Level B: Recommendations are based on limited or
inconsistent scientific evidence; Level C: Recommendations are based primarily on consensus and expert opinion.

N. Bhatla et al.
Figure 2 (a) Management of abnormal primary HPV testing. HR HPV, high-risk HPV; VIA, visual inspection after appli-
cation of acetic acid; NILM, negative for intra epithelial lesion or malignancy; CIN, cervical intra epithelial neoplasia.
(b) Management of abnormal co-testing. ASCUS, atypical squamous cells of undetermined significance; HSIL, high-
grade squamous intra epithelial lesion.
Management of cytology showing atypical squamous cells reflex HPV or repeat cytology at 6 months or immedi-
with undetermined significance Atypical squamous ate colposcopy. The detection of cumulative cases of
cells with undetermined significance (ASCUS) cytol- CIN3+ was highest in HPV triage group (72.3%),
ogy is seen in 2.8% of women between 30 and followed by conservative management (55%), and
64 years and 23–74% of these women are HPV posi- least(54.6%) in immediate colposcopy group. HPV tri-
tive.31,32 The ASCUS/LSIL Triage Study (ALTS) age could detect 92.4% of the CIN3 cases. Repeat
investigated triage of ASCUS cytology either with cytology needed two visits to demonstrate similar

sensitivity (95.4%) and would have to refer a large the accuracy of cytology is uncertain, HPV testing
number of cases (67.1%) for colposcopy and thus was may be used for triage. If compliance is an issue, ‘See-
not cost-effective compared to HPV testing.33 There- and-Treat’ approach is acceptable (Fig. 3). Colposcopy
fore, HPV triage is equally sensitive as immediate col- and treatment may do more harms than benefits in
poscopy and also reduces unnecessary colposcopy women aged <30 years because of higher regression
referrals.32 Women aged 30–64 years with ASCUS (70% with CIN2) and lower progression (0.5% with
should be triaged preferably with HPV test or if not CIN3) rates.35 Therefore, colposcopy should be done
available with repeat cytology at 1 year and women with severe/persistent cytology results. Immediate
≤30 years with ASCUS or low grade squamous intra- colposcopy is also preferred in post-menopausal
epithelial lesion (LSIL) should be followed with women. However, due to likelihood of regression of
annual cytology for 2 years. However, where compli- transformation zone (TZ), use of endocervical specu-
ance is a concern or HPV testing is not available, col- lum for clear delineation is highly desirable.
poscopy/VIA and directed biopsy is acceptable for all
age groups (Fig. 3).
Management of women with ASC-H (atypical squamous
cells: Cannot exclude high-grade squamous intraepithelial
Management of LSIL cytology In the ALTS trial, 1572 lesion) or high-grade squamous intraepithelial lesion
women with LSIL were followed either with colpos- cytology HPV triage is not advisable because 65.8%
copy or HPV or with repeat cytology at 6 months. of ASC-H and 89–97% of high-grade squamous intra-
More than 80% were HPV positive thus obviating the epithelial lesion (HSIL) cytology are HPV positive and
need for HPV triage in women with LSIL.34 Thus col- are managed with immediate colposcopy with endo-
poscopy is preferred for managing women with LSIL cervical evaluation.35 If TZ is not visualized, diagnostic
cytology. If colposcopy is not readily available or if excisional procedure is preferred except during
Figure 3 Management of abnormal cytology test. (a) Management of ASCUS. ASCUS, atypical squamous cells of un
determined significance; LSIL, low grade squamous intra epithelial lesion; VIA, visual inspection after application of
acetic acid; HSIL, high-grade squamous intra epithelial lesion. (b) Management of LSIL. (c) Management of ASC-H/
HSIL. ASC-H, atypical squamous cells cannot exclude HSIL. (d) Management of HSIL.

N. Bhatla et al.
Figure 4 Management of abnormal VIA test. VIA, visual inspection of cervix after application of acetic acid; CIN, cervical
intra epithelial neoplasia.
pregnancy. In noncompliant cases, SVA with cervical from 16% to 82.6%, and 82.1% to 96.8%, respec-
ablation is acceptable if criteria is fulfilled, but without tively.19 VIA when compared with cytology has
a diagnostic specimen (Fig. 3). In younger women higher sensitivity (90% vs 50%) but lower specificity
with normal colposcopy and Type-I TZ after a high- (37% vs 93.5%) thus raising the burden of false posi-
grade smear, regular follow-up is emphasized and a tive cases.19,40,41 VIA permits an SVA for screening
diagnostic excisional procedure is recommended when in LMICs because of instant results and linkage
an abnormal screening test persists for 2 years. with treatment.7,8,16 VIA-positive cases can be either
managed with colposcopy and biopsy or can be
Management of women with glandular cell treated in the same sitting with ablation, if criteria
abnormalities About 30% women aged >40 years with are fulfilled (Fig. 4).
atypical glandular cytology will have preinvasive or
invasive disease.36,37 Majority of these lesions are squa-
mous lesions but the probability of finding endometrial
Screening in HIV Infected Women
malignancy is 2–3%, cervical adenocarcinoma in situ is
3–4%, invasive adenocarcinoma cervix is 2% and cervi- Infection with HIV increases a woman’s lifetime
cal squamous cell carvcinoma is 1%.38 Hence, a thor- risk of developing cervical cancer and approxi-
ough evaluation to rule out endometrial, ovarian or mately 10% HIV positive women develop CIN2+
cervical malignancy is essential.38 Women with atypi- each year compared to 1–2% HIV negative
cal glandular cells with any of the sub-categories women.42 The prevalence of invasive cervical can-
should be evaluated with colposcopy and directed cer was 4% and CIN2+ lesions was 8.5% among
biopsy along with endocervical sampling (Fig. 3). HIV positive women.42,43 Women who are HIV pos-
itive should begin screening with any of the screen-
VIA as the primary screening modality ing modalities as soon as they are diagnosed with
VIA is a promising tool for screening in low- HIV. The expert group has endorsed the recommen-
resource settings because it is economical, with dations by WHO and ASCO that the screening
minimal loss to follow up.39,40 The pooled sensitiv- frequency in HIV+ women should be twice as often
ity and specificity of VIA to detect CIN2+ ranged as the general population.7,9 ART(antiretroviral

Figure 5 Management of women with CIN on histology. CIN, cervical intraepithelial neoplasia; ASC-H, atypical squa-
mous cells cannot exclude HSIL; HSIL, high-grade squamous intra epithelial lesion. (a) Management of women with
CIN-1. (b) Management of women with CIN2/3
therapy) services should be integrated with cervical Management of CIN

cancer screening program.44 Screen positive cases
should be managed in the same way as general The aim of CIN management is to prevent progression
population (Tables 2 and 3). of disease while avoiding over-treatment of lesions that

N. Bhatla et al.
might otherwise regress.45 CIN1 preceded by ASCUS or Contributions of PSI (Population Services Interna-
LSIL cytology is likely to progress to CIN2/3 in 4–13% tional India) are appreciated for arranging the expert
cases in next 2 years. Thus treatment by ablation or exci- group meeting.
sion is warranted if the abnormality persists for
2 years.46 The risk of progression of CIN1 when pre-
ceded by ASC-H or HSIL is more than 15%, thus imme- Disclosure
diate colposcopy examination is advised.46 About
40–58% of CIN2 will regress and only 22% will progress None declared.
to CIN3; the cumulative incidence of invasive disease in
untreated CIN3 is 31% after 10 years.47 Patients with References
CIN2/3 with type-I or type-II TZ on colposcopy may be
treated by excision or ablation. Risk of invasive cancer is 1. Cancer Today-Global cancer observatory. [Cited 12 Oct
as high as 7% in women with type-III TZ on colposcopy 2018]. Available from URL: https://gco.iarc.fr/today/home.
2. Sreedevi A, Javed R, Dinesh A. Epidemiology of cervical
or in recurrent CIN, therefore excisional procedures with cancer with special focus on India. Int J Women’s Health
either LLETZ/LEEP (large loop excision of TZ) or cold 2015; 7: 405–414.
knife colonization are performed and ablation should be 3. Sankaranarayanan R, Swaminathan R, Lucas E. Cancer Sur-
avoided in such situation.47 vival in Africa, Asia, Caribbean and Central America: Survcan.
In women ≤30 years the probability of regression is Lyon: IARC scientific publication International Agency for
Research on Cancer, 2010.
higher and 70% of CIN2 lesions would regress. There- 4. Labeit A, Peinemann F, Kedir A. Cervical cancer screening
fore, conservative management is preferred and treat- service utilization in UK. Sci Rep 2013; 3: 2362.
ment is advisable when CIN2 persists for over 5. Bhatla N, Dar L, Patro AR et al. Can human papilloma virus
24 months.45,47 The management of CIN depending DNA testing of self collected vaginal samples compare with
physician collected cervical samples and cytology for cervi-
on the severity and age group is depicted in Figure 5
cal cancer screening in developing countries? Cancer
and summarized in Table 3. Epidemiol 2009; 33: 10.
The FOGSI recommendations have been drafted to 6. Ministry of Health and Family Welfare, Government of
empower healthcare professionals with evidence-based India. Operational framework. Management of common
simplified algorithms applicable in daily practice regard- cancers. 2016. [Cited 1 Feb 2019.] Available from URL:
less of available resources. However, dissemination http://cancerindia.org.in/cp/images/PDF/Operational
Framework Management of Common Cancers.pdf/.
to remote areas still remains a challenge. Expanding 7. Harris RP, Helfand M, Woolf SH et al. Current methods of
access through newer technologies such as mHealth the US preventive services task force: A review of the pro-
is being considered. cess. Am J Prev Med 2001; 20: 21–35.
8. WHO. Guidelines for Screening and Treatment of Precancerous
Lesions for Cervical Cancer Prevention. Geneva: World Health
Organization, 2013.
Conclusion and Perspective 9. Jeronimo J, Castle PE, Temin S et al. Secondary prevention of
cervical cancer: ASCO resource-stratified clinical practice
Implementation of universal screening for cervical can- guideline. J Global Oncol 2016; 3: 635–657.
cer irrespective of resources is the need of the hour. 10. FOGSI GCPR on Screening and Treatment of Preinvasive
lesions of the cervix and HPV vaccination. [30 Jan 2019.]
The screening effort should be linked with optimum
Available from URL https://www.fogsi.org/fogsi-gcpr-on-
treatment and follow-up. The FOGSI recommenda- screening-mangement-of-cervical-precancerous-lesions/
tions not only empower clinicians with the option of 11. FOGSI GCPR on Screening and Treatment of Preinvasive
using any available modality, but also provide a com- lesions of the cervix and HPV vaccination – Summary flow-
prehensive overview of follow-up and treatment. Thus charts. [1 Feb 2019.] Available from URL: http://www.fogsi.
they are suitable not only for India but also for many org/wp=content/uploads/2018/03/FOGSI-GCPR-Final-March-
2018.pdf.
LMICs with similar diverse practices and inequality. 12. Tota JE, Bentley J, Blake J et al. Introduction of molecular
HPV testing as the primary technology in cervical cancer
screening: Acting on evidence to change the current para-
Acknowledgments digm. Prev Med 2017; 98: 5–14.
13. Isidean SD, Mayrand MH, Ramanakumar AV et al. Human
papillomavirus testing versus cytology in primary cervical
The contributions of Sankaranarayanan R, Ahuja M, cancer screening: End-of-study and extended follow-up
Joshi R, Purandare N and Natarajan J to development results from the Canadian cervical cancer screening trial. Int
of the GCPR are deeply appreciated. J Cancer 2016; 139: 2456–2466.

14. Sankaranarayanan R, Nene BM, Shastri SS et al. HPV screen- primary cervical cancer screening. Int J Cancer 2006; 119:
ing for cervical cancer in rural India. NEJM 2009; 360: 1095–1101.
1385–1394. 31. Katki HA, Schiffman M, Castle PE et al. Benchmarking Cin 3
15. Schiffman M, Kinney WK, Cheung LC et al. Relative perfor- + risk as the basis for incorporating HPV and pap cotesting
mance of HPV and cytology components of co-testing in cer- into cervical screening and management guidelines. J Low
vical screening. J Natl Cancer Inst 2017; 110: 501–508. Genit Tract Dis 2013; s28: 17.
16. Arbyn M, Sankaranarayanan R, Muwonge R et al. Pooled 32. Katki HA, Schiffman M, Castle PE et al. Five year risks of
analysis of the accuracy of five cervical cancer screening Cin 2+ and Cin 3+ among women with HPV positive and
tests assessed in eleven studies in Africa and India. Int J Can- HPV negative LSIL pap results. J Low Genit Tract Dis 2013;
cer 2008; 123: 153–160. s43: 17.
17. Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, 33. ASCUS LSIL Triage Study (ALTS) Group. Results of a ran-
Siebers AG, Bulten J. Liquid compared with conventional domized trial on the management of cytology interpreta-
cervical cytology: A systematic review and meta-analysis. tions of atypical squamous cells of undetermined
Obstet Gynecol 2008; 111: 167–177. significance. Am J Obstet Gynecol 2003; 188: 1383.
18. Guducu N, Sidar G, Bassullu N, Turkmen I, Dunder I. 34. ASCUS LSIL Triage Study (ALTS) group. A randomized
Three-step approach versus see-and-treat approach in trial on the management of low-grade squamous intra-
patients with cytological abnormalities. Int J Clin Exp Med epithelial lesion cytology interpretations. Am J Obstet Gynecol
2013; 6: 372–376. 2003; 188: 1393–1400.
19. Bobdey S, Sathwara J, Jain A, Balasubramaniam G. Burden 35. Castle PE, Fetterman B, Cox JT et al. The age-specific rela-
of cervical cancer and role of screening in India. Indian J Med tionships of abnormal cytology and human papillomavirus
Paediatr Oncol 2016; 37: 278–285. DNA results to the risk of cervical precancer and cancer.
20. Kulasingam SL, Havrilesky L, Ghebre R, Myers ER. Screen- Obstet Gynecol 2010; 116: 76–84.
ing for Cervical Cancer: A Decision Analysis for the US Preven- 36. Marques JP, Costa LB, Pinto AP et al. Atypical glandular
tive Services Task Force. Rockville, MD: Agency for cells and cervical cancer: Systematic review. Rev Assoc Med
Healthcare Research and Quality, 2011. Bras 2011; 57: 234–238.
21. Sankaranarayanan R, Esmy PO, Rajkumar R et al. Effect of 37. Zhao C, Florea A, Onisko A, Austin RM. Histologic follow-
visual screening on cervical cancer incidence and mortality up results in 662 patients with pap test findings of atypical
in Tamil Nadu, India: A cluster-randomised trial. Lancet glandular cells: Results from a large academic womens hos-
2007; 370: 398–406. pital laboratory employing sensitive screening methods.
22. Goldie SJ, Gaffikin L, Goldhaber-Fiebert JD et al. Cost- Gynecol Oncol 2009; 114: 383–389.
effectiveness of cervical-cancer screening in five developing 38. Schnatz PF, Guile M, O’sullivan DM, Sorosky JI. Clinical sig-
countries. NEJM 2005; 353: 2158–2168. nificance of atypical glandular cells on cervical cytology.
23. Naucler P, Ryd W, Törnberg S et al. Human papillomavirus Obstet Gynecol 2006; 107: 701–708.
and papanicolaou tests to screen for cervical cancer. New 39. Shastri SS, Mittra I, Mishra GA et al. Effect of VIA screen-
Engl J Med 2007; 357: 1589–1597. ing by primary health workers: Randomized controlled
24. Australian Government Department of Health. Overview of study in Mumbai, India. J Natl Cancer Inst 2014; 106:
the Renewal. 2017. [Cited 14 Sept 2018.] Available from dju009.
URL: http://www.cancerscreening.gov.au/internet/screening/ 40. Mustafa RA, Santesso N, Khatib R et al. Systematic reviews
publishing.nsf/Content/overview-of-the-renewal. and meta-analyses of the accuracy of HPV tests, visual
25. Ponti A, Anttila A, Ronco G, Senore C. Cancer Screening in inspection with acetic acid, cytology, and colposcopy. Int J
the European Union (2017). Report on the implementation Gynecol Obstet 2016; 132: 259–265.
of the Council Recommendation on cancer screening. [Cited 41. Poli UR, Bidinger PD, Gowrishankar S. Visual inspection
14 Sept 2018.] Available from URL: https://ec.europa.eu/ with acetic acid (VIA) screening program: Seven years
health/sites/health/files/major_chronic_diseases/docs/2017_ experience in early detection of cervical cancer and pre-
cancerscreening_2ndreportimplementation_en.pdf cancers in rural South India. Indian J Community Med 2015;
26. Richardson L, Tota J, Franco E. Optimizing technology for 40: 203–207.
cervical cancer screening. Expert Rev Obstet Gynecol 2011; 6: 42. Joshi S, Sankaranarayanan R, Muwonge R, Kulkarni V,
343–353. Somanathan T, Divate U. Screening of cervical
27. Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, neoplasia in HIV-infected women in India. AIDS 2013; 27:
Wright TL. The ATHENA human papillomavirus study: 607–615.
Design, methods, and baseline results. Am J Obstet Gynecol 43. Clifford GM, Tully S, Franceschi S. Carcinogenicity of
2012; 206: 46–e1. human papillomavirus (HPV) types in HIV-positive women:
28. Gage JC, Schiffman M, Katki HA et al. Reassurance against A meta-analysis from HPV infection to cervical cancer. Clin
future risk of precancer and cancer conferred by a negative Infect Dis 2017; 64: 1228–1235.
human papillomavirus test. J Natl Cancer Inst 2014; 44. Sahasrabuddhe VV, Bhosale RA, Kavatkar AN et al. Com-
106: 1–4. parison of visual inspection with acetic acid and cervical
29. Bhatla N, Puri K, Kriplani A et al. Adjunctive testing for cer- cytology to detect high-grade cervical neoplasia among
vical cancer screening in low resource settings. Aust N Z J HIV-infected women in India. Int J Cancer 2012; 130:
Obstet Gynaecol 2012; 52: 133–139. 234–240.
30. Cuzick J, Clavel C, Petry KU et al. Overview of the 45. Elit L, Levine MN, Julian JA et al. Expectant management
European and north American studies on HPV testing in versus immediate treatment for low-grade cervical

N. Bhatla et al.
intraepithelial neoplasia : A randomized trial in Canada and 47. McCredie MR, Sharples KJ, Paul C et al. Natural
Brazil. Cancer 2011; 117: 1438–1445. history of cervical neoplasia and risk of invasive
46. Katki HA, Gage JC, Schiffman M et al. Follow-up testing post- cancer in women with cervical intraepithelial neoplasia
colposcopy: Five-year risk of CIN2+ after a colposcopic diag- 3: A retrospective cohort study. Lancet Oncol 2008; 9:
nosis of CIN1 or less. J Lower Genit Tract Dis 2013; 17: S69. 425–434.

Treatment Hal 4

Uploaded by

Document Informationclick to expand document information

Document Informationclick to expand document information

Copyright:

Available Formats

Treatment Hal 4

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Treatment Hal 4

Uploaded by

Copyright:

Available Formats

doi:10.1111/jog.14168 J. Obstet. Gynaecol. Res. Vol. 46, No.

2: 201–214, February 2020

Screening and management of preinvasive lesions of the

Received: June 14 2019.

© 2019 Japan Society of Obstetrics and Gynecology 201

202 © 2019 Japan Society of Obstetrics and Gynecology

For HPV test:

© 2019 Japan Society of Obstetrics and Gynecology 203

Figure 1 : How to choose the most appropriate screening modality?

204 © 2019 Japan Society of Obstetrics and Gynecology

Table 2 Resource-based cervical cancer screening recommendations

© 2019 Japan Society of Obstetrics and Gynecology 205

206 © 2019 Japan Society of Obstetrics and Gynecology

© 2019 Japan Society of Obstetrics and Gynecology 207

208 © 2019 Japan Society of Obstetrics and Gynecology

© 2019 Japan Society of Obstetrics and Gynecology 209

210 © 2019 Japan Society of Obstetrics and Gynecology

therapy) services should be integrated with cervical Management of CIN

© 2019 Japan Society of Obstetrics and Gynecology 211

212 © 2019 Japan Society of Obstetrics and Gynecology

© 2019 Japan Society of Obstetrics and Gynecology 213

214 © 2019 Japan Society of Obstetrics and Gynecology

You might also like