Cervical Cytology Specimen Adequacy: Patient Management Guidelines and Optimizing Specimen Collection

Article (PDF Available)inJournal of Lower Genital Tract Disease 12(2):71-81 · May 2008with669 Reads
DOI: 10.1097/LGT.0b013e3181585b9b · Source: PubMed
Abstract
To provide updated management guidelines according to cervical cytology specimen adequacy and techniques to optimize adequacy based on literature review and expert opinion. Selected members of the American Society for Colposcopy and Cervical Pathology committee and invited experts conducted a literature review and discussed appropriate management and areas for future research emphasis. The guidelines recommend a repeat Pap test in a short interval of 2 to 4 months for most women when the cytology result is unsatisfactory. The preferred follow-up for women with a negative cytology result lacking an endocervical/transformation zone component or showing other quality indicators is a repeat Pap test in 12 months. Indications for an early repeat Pap test in 6 months are provided, and the influence of human papillomavirus testing results on management is discussed. Techniques for optimizing specimen adequacy are provided in detail. The specimen adequacy management guidelines will help promote uniform and optimal follow-up of patients receiving cervical cytology screening. The topics for future research emphasis will be helpful in promoting studies in needed areas.
Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
Cervical Cytology Specimen
Adequacy: Patient Management
Guidelines and Optimizing
Specimen Collection
Diane Davis Davey, MD,
1
J. Thomas Cox, MD,
2
R. Marshall Austin, MD, PhD,
3
George Birdsong, MD,
4
Terence J. Colgan, MD,
5
Lydia P. Howell, MD,
6
Mujtaba Husain, MD,
7
and Teresa M. Darragh, MD
8
1
Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY,
2
Student Health Service, University of California, Santa Barbara, CA,
3
Department of
Pathology, Magee-Womens Hospital of University of Pittsburgh, Pittsburgh, PA,
4
Department
of Pathology, Grady Health System and Emory University, Atlanta, GA,
5
Department of
Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada,
6
Department of Pathology, University of CaliforniaYDavis Medical Center, Sacramento, CA,
7
Department of Pathology, Detroit Medical Center and Wayne State University, Detroit, MI,
and
8
Departments of Pathology and Obstetrics/Gynecology, University of CaliforniaYSan
Francisco, San Francisco, CA
h Abstract
Objective.
To provide updated management guide-
lines according to cervical cytology specimen adequacy
and techniques to optimize adequacy based on literature
review and expert opinion.
Materials and Methods. Selectedmembersofthe
American Society for Colposcopy and Cervical Pathology
committee and invited experts conducted a literature
review and discussed appropriate management and areas
for future research emphasis.
Results. The guidelines recommend a repeat Pap
test in a short interval of 2 to 4 months for most women
when the cytology result is unsatisfactory. The preferred
follow-up for women with a negative cytology result
lacking an endocervical/transformation zone compo-
nent or showing other quality indicators is a repeat Pap
test in 12 months. Indications for an early repeat Pap
test in 6 months are provided, and the influence of
human papillomavirus testing results on management is
discussed. Techniques for optimizing specimen adequacy
are provided in detail.
Conclusion. The specimen adequacy management
guidelines will help promote uniform and optimal follow-
up of patients receiving cervical cytology screening. The
topics for future research emphasis will be helpful in
promoting studies in needed areas.
h
Key Words: cervical cytology screening, Pap test, specimen
adequacy, guidelines, management, Bethesda terminology,
unsatisfactory
I
n 2002, a task force of the American Society for
Colposcopy and Cervical Pathology (ASCCP) pub-
lished a set of guidelines related to Pap test specimen
adequacy and patient management following the
National Cancer Institute Bethesda 2001 Workshop
which updated terminology and reporting of cervical
cytology [1, 2]. The 2002 ASCCP guidelines included
recommendations on the follow-up of women with
either an unsatisfactory Pap test or a Pap test with
quality indicators including lack of an endocervical/
transformation zone (EC/TZ) component. An unsatis-
factory Pap test either shows scant cellularity or has
more than 75% of cells obscured and is considered
Correspondence to: Diane Davis Davey, MD, University of Central
Florida, College of Medicine, 12201 Research Parkway, Room 307, Orlando,
FL 32816-0116. E-mail: ddavey@mail.ucf.edu
Ó 2008, American Society for Colposcopy and Cervical Pathology
Journal of Lower Genital Tract Disease, Volume 12, Number 2, 2008, 71Y81
Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
unreliable for evaluation of epithelial abnormalities. The
absence of an EC/TZ component and partially obscuring
factors (50%Y75% of the cells obscured) are considered
quality indicators but do not make a Pap test unsatis-
factory [2]. Since the publication of these guidelines, 2
major changes have influenced cervical cancer screening.
First, the majority of Pap tests performed in the United
States are now liquid-based preparations (LBPs) instead
of conventional smears (CSs). Second, human papillo-
mavirus (HPV) DNA testing for oncogenic/high-risk
types is increasingly used in conjunction with cervical
cytology as a primary screening test for women aged 30
years and older. Both of these developments have
influenced screening methods and frequency that impact
the adequacy issues raised in the original ASCCP
guidelines. The ASCCP Pathology Committee has
revisited and updated these guidelines and has included
emphasis on areas for future research and methods to
optimize Pap test collection. The guidelines and discus-
sion below are based on published evidence and expert
opinion of members of the ASCCP Pathology Commit-
tee and other experts in the field. The rating system for
recommendations and quality of evidence is identical to
previous ASCCP guidelines (Table 1) [3].
RESULTS
Issue 1: What Is the Recommended Follow-up for
Women With an Unsatisfactory Pap Test?
Recommendation. The recommended management
for most women undergoing cervical cancer screen-
ing who have an unsatisfactory Pap test result is a
repeat Pap test, generally within a short time
interval of 2 to 4 months (AII). This is unchanged
from previous recommendations [1]. If the unsatis-
factory result is due to obscuring inflammation and
a specific infection is identified, consider specific
treatment before repeating the Pap test. Additional
clinical evaluation is recommended in women with
symptoms, abnormal examinations, and in cases
where the Pap test is repeatedly unsatisfactory be-
cause of obscuring blood, inflammation, or necrosis
(BIII) [1]. Examples are women with visible lesions,
friable cervix, postcoital or abnormal bleeding, pel-
vic pain, and abnormal discharge; the additional eva-
luation may include colposcopy and/or biopsies, as
appropriate.
An unsatisfactory Pap test that was not indicated
according to the screening protocol in effect (e.g., the
patient was not due for her next cervical cancer
screen) does not necessarily need to be repeated.
Some women may not require continued cytology
screening. Women who have had a hysterectomy with
removal of the cervix for benign disease do not
generally benefit from screening [4Y7]. Lower cellu-
larity specimens may be acceptable in women who
have undergone hysterectomy for malignancies, che-
motherapy, or radiation therapy, as obtaining speci-
mens with higher cellularity may not be possible in
these situations [2]. Clinicians and laboratories
should exercise judgment in determining whether
the specimen is unsatisfactory and whether early
repeat cytology is indicated.
Table 1. Rating System for Recommendations
Recommended Good data to support use when only 1 option is available
Preferred Option is the best (or one of the best) when there are multiple other options
Acceptable One of multiple options when there are either data indicating that another approach is superior
or when there are no data to favor any single option
Unacceptable Good data against use
Strength of recommendation
A Both strong evidence for efficacy and substantial clinical benefit support recommendation for use
B Moderate evidence for efficacyVor strong evidence for efficacy but only
limited clinical benefitVsupports recommendation for use
C Evidence for efficacy is insufficient to support a recommendation against use, or evidence of
efficacy might not outweigh adverse consequences
D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use
E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use
Quality of evidence
I Evidence from at least 1 properly rand omized, controlled trial
II Evidence from at least 1 well-designed clinical trial without randomiza tion, from cohort or case-control
analytic studies (preferably from more than 1 center), or from multiple time-series studies, or dramatic
results from uncontrolled experiments
III Evidence from opinions of respected authorities based on clinical experience, descriptive studies,
or reports of expert committees
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Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
Issue 2: What Is the Recommended Follow-up for
Women With a Negative (for Intraepithelial Lesion
or Malignancy) Pap Test Lacking an EC/TZ
Component or Showing Other Quality Indicators
(Borderline Cellularity, Partially Obscuring (950%)
Blood or Inflammation)? Should HPV DNA Test
Results Influence Patient Management?
Recommendation. The preferred management for most
women who lack an EC/TZ component on their Pap and
are undergoing routine screening is a repeat Pap test in
12 months; this also applies to other quality indicators
(BIII). This recommendation is unchanged from the
previous guideline [1]. An early repeat (generally at 6
months) may be beneficial for some women. Indications
for considering an early repeat include (1) a previous
squamous abnormality (atypical or worse) without 2
subsequent negative Pap tests or a negative HPV test, (2)
a previous Pap with unexplained glandular abnormality,
(3) a positive high-risk/oncogenic HPV test within 12
months, (4) clinician inability to clearly visualize the
cervix or sample the endocervical canal, (5) similar
obscuring factor in consecutive Pap tests, and (6)
insufficient previous screening.
HPV test data may be available in women with
negative Pap tests that lack an EC/TZ component. If the
HPV test is negative, it may be prudent to repeat the Pap
test in 12 months rather than extend the screening
interval to 3 years in women older than 30 years.
Negative HPV status generally confers a lower risk for
abnormalities; however, only limited data are available
at this time indicating the relationship between HPV test
status and presence or absence of an EC/TZ component.
If the HPV test is positive, it is preferred to repeat the
Pap test in 6 months; if cytology is negative at 6 months,
repeat HPV testing at 12 months is suggested to check
for HPV clearance (CIII).
DISCUSSION
The guidelines in this article primarily address issues
related to primary cervical cancer screening with the Pap
test, or the combination of the Pap and HPV tests in
women aged 30 years and older. Women who are
symptomatic or have visible abnormalities or an
abnormal examination generally require additional
evaluation such as colposcopy, biopsies, or microbiolo-
gic evaluation. Due to the known false-negative rate of
cervical cytology, a negative result does not exclude an
abnormality when a lesion is present. Colposcopy is
suggested for women with repeated bloody or inflamed
unsatisfactory Pap test results [1].
Issue 1: Unsatisfactory Pap Tests
Unsatisfactory Pap tests include those that are rejected
by the laboratory (due to labeling problems, specimen
vial leakage, slide breakage, etc.) and those that are
completely processed but are unsatisfactory due to
insufficient squamous cells or obscuring (975%)
blood, inflammation, or other processes [2]. Most
processed unsatisfactory LBP specimens are related to
insufficient squamous cells. An unsatisfactory Pap test is
considered unreliable for detection of epithelial abnor-
malities, and several studies have found that women
with unsatisfactory results may be at significant risk for
disease [8, 9]. Estimating adequate cellularity of speci-
mens with cell clusters, cytolysis, and atrophy is difficult
using representative field counts, and laboratories
should exercise judgment in reporting such specimens
[2].
The numerical criteria for squamous cellularity on
Pap tests were developed for women undergoing routine
cervical cancer screening and do not apply to vaginal
specimens [2]. In posthysterectomy vaginal specimens,
laboratories should exercise judgment in evaluating
adequacy based on clinical and screening history [2].
Many cytologists accept lower cellularity in vaginal
specimens, especially if atrophy is present and the
woman is at low risk, but no peer-reviewed data have
been published to define the adequacy of vaginal
specimens. Until more data are available, laboratories
have flexibility in determining methods for cellularity
estimation in vaginal specimens.
After hysterectomy, many women may not benefit
from additional cytology screening. The American
Cancer Society (ACS) guidelines state that screening
after total hysterectomy (with removal of the cervix) is
not necessary unless the surgery was done as a treatment
for cervical cancer or precancer [7]. The American
College of Obstetricians and Gynecologists guidelines
are similar for women who have undergone hysterec-
tomy with removal of the cervix for benign indications
[4]. Both the ACS and American College of Obstetricians
and Gynecologists guidelines also state that women with
a history of cervical intraepithelial neoplasia (CIN) 2 or
worse should be screened annually until they have 3
negative vaginal Pap tests, after which screening can be
stopped; however, women treated for cervical or vaginal
cancer and women with a history of diethylstilbestrol
(DES) exposure should continue screening for as long as
Cervical Cytology Adequacy Guidelines
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they do not have a life-limiting chronic condition [4, 7].
Studies have shown that the prevalence of significant
abnormalities after total hysterectomy for benign disease
is very low and that such screening is not cost-effective
[5, 6]. However, with the growing trend to perform
supracervical hysterectomies, accurate history is critical
to decide whether a patient should still be screened.
Women who have received radiation and/or che-
motherapy for gynecological cancer frequently have
low-cellularity specimens with therapy-related changes.
The main utility of cytology specimens in this setting is
to detect recurrent malignancy. Expert opinion would
suggest that such specimens should have many well-
preserved cells or several cell groups, but there are no
data to suggest a minimum numeric threshold at this
time. Furthermore, studies have shown that cytological
screening after treatment of endometrial cancer infre-
quently detects asymptomatic vaginal recurrences and
may not be an effective surveillance tool [10]. Labora-
tories should exercise judgment in evaluating postther-
apy cytology specimens based on the clinical setting and
not rely solely on a specific numeric threshold.
The subset of women with unsatisfactory specimens
due to inadequate squamous cellularity may include
some older women with atrophic samples. If these
women do not require screening because of negative
history and risk factors, repeat screening may not be
necessary. The ACS Guidelines state that women 70
years and older who have had 3 or more consecutive
satisfactory negative Pap tests and no abnormal Pap tests
in the last 10 years may choose to stop cervical cancer
screening [7]. The positive predictive value of cervical
cytology in previously screened postmenopausal women
has been reported as low [11].
Many of the longitudinal studies of women with
unsatisfactory Pap tests that showed a higher risk of
epithelial abnormalities were performed before the
Bethesda 2001 conference or used different cellularity
criteria [8, 9]. The unsatisfactory Pap tests in these
studies included many CSs with obscuring blood and
inflammation. There are very few studies on the
significance of insufficient squamous cellularity. One
study performed using Bethesda 2001 criteria found that
women with inadequate squamous cellularity on Pap
tests do not have a significantly higher risk of
abnormalities [12]; however, this study consisted mainly
of CSs. Another study concluded that it was not possible
to define a minimum acceptable squamous cellularity
that would give an acceptable probability of detection of
all LBPs containing abnormal cells [13]. This latter study
suggested that a minimum cellularity threshold be set
pragmatically by the screening program to provide a
feasible percentage of repeat tests. The Bethesda 2001
squamous cellularity criteria provide an acceptable
threshold of unsatisfactory results for most patient
populations and laboratory settings, although additional
studies and data would be useful.
Clinicians who receive a significant number of
unsatisfactory reports from women after hysterectomy
or after therapy are encouraged to discuss the lack of
defined numeric criteria with the cytology laboratory
director.
Issue 2: EC/TZ Component, Quality Indicators, and
HPV Testing
The importance of the EC/TZ component in defining
adequacy is controversial: research studies on the
significance are conflicting [1]. While abnormal cells
are more commonly found in specimens with an EC/TZ
component [14], longitudinal studies have not shown
that women with Pap smears lacking an EC/TZ
component are at increased risk for developing high-
grade squamous lesions and cancer [15]. Women with
Pap smears lacking an EC/TZ component may represent
a lower risk group as a whole because this group is
skewed toward older ages [14, 16]. This may explain the
apparent inconsistency between longitudinal studies,
which suggest no increase in risk, and cross-sectional
studies, which report more abnormalities in samples that
contain an EC/TZ component. The proportion of
endocervical adenocarcinoma among all cervical carci-
noma cases is increasing, however [17]. Thus, the
absence of an EC/TZ component may have greater
significance in defining a Pap test_sadequacyin
detection of adenocarcinoma. Therefore, the committee
opinion is that some women with Pap tests lacking an
EC/TZ component may benefit from a shorter screening
interval (CIII).
Women with a positive HPV test and a concurrent
negative Pap test are at increased risk for future abnor-
malities [18]. In women with a positive HPV test, but
lacking an EC/TZ component, there is the additional
possibility of an increased risk of a false-negative cyto-
logy result in the presence of an endocervical adenocar-
cinoma or a squamous lesion high in the canal.
When the HPV test is negative, there may be more
uncertainty regarding optimal management. Although
the negative predictive value for women with a negative
HPV test is high, most studies have not evaluated
adequacy of HPV samples. Currently, there are little
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published data from which to develop a morphological
definition of an adequate sample for HPV testing.
Inadequate samples may be due to lack of any cellular
material (the specimen was inadvertently not transferred
to the vial) or to samples showing low cellularity. There
are currently very few studies examining the HPV status
of women with negative cytology with, versus without,
an EC/TZ component [19]. There are some data
suggesting that hypocellular specimens in patients with
high-grade lesions may have false-negative HPV results
[20, 21]. Whether this may possibly reflect lack of
sampling of the transformation zone is unknown.
Conversely, HPV DNA may be detected in hypocellular
specimens. Additional considerations include specific
HPV types not included in the Hybrid Capture 2 (HC2)
assay, DNA quantities below the threshold of the test,
and other mechanisms. Both HPV prevalence and the
reporting of EC/TZ component are inversely correlated
with patient age, so that older women are more likely to
be negative for both EC/TZ component and HPV [16].
Nevertheless, data from individual laboratories and a
single published abstract appear to suggest that EC/TZ
status and HPV DNA positivity appear to be indepen-
dent variables [19]. Given the current uncertainty
regarding the relationship between specimen adequacy
parameters and HPV status, it is prudent to repeat the
Pap test in 12 months in women older than 30 years with
negative HPV and cytology lacking an EC/TZ compo-
nent, rather than extending the interval to 3 years as
recommended for women who are negative on both test
results [4, 7].
Areas for Additional Research
The following topics represent areas in which significant
clinical questions arise related to each of the issues
above, but where there is little published evidence on
which to base guidelines or recommendations.
Borderline Cellularity and Ensuring Adequate Sampling
for HPV Testing. The current guidelines defining
unsatisfactory specimens on the basis of low cellularity
have been in use for several years. Whether lesser degrees
of hypocellularity (5,000Y20,000 squamous cells) are of
clinical significance remains uncertain. In addition, the
rising use of HPV testingVwhether used as a follow-up
test, coscreening test, or as a single primary screening
testVhas raised new issues regarding the degree of
cellularity, specimen adequacy, and reliability of results
for both Pap and HPV testing. These issues represent
fertile ground for future investigation.
There are many physiological, anatomic, and clinical
situations in which Pap test cellularity may be low or
adequacy is considered compromised. These include
mature and postmenopausal women, women who have
undergone treatment for cervical disease, menstruating
women, and others. In these clinical scenarios, how can
the laboratory and the clinician ensure that there is
adequate sampling for the HC2 HPV test or other HPV
testing method if the test does not include a verification
of specimen adequacy? Is a negative HPV result truly
negative, or is there significant potential for false-
negative results if there are few cells, questionable
sampling of the EC/TZ, or other factors that may
interfere with the test? When HPV testing without any
internal adequacy validation step is performed in the
absence of any morphological evaluation, as is the case
in some follow-up situations, can one safely assume that
the result is from an adequate sample? A few studies
have begun to address these questions, but there is not
yet a body of knowledge for definitive recommendations
or practice guidelines. Nonetheless, cellularity, and
endocervical cellularity, in particular, does appear to
be a factor that influences reliability of HPV test results.
Higher detection of oncogenic HPV viral load and
increased detection of abnormalities have been demon-
strated in cervical samples with larger numbers of
endocervical cells [22]. Reports show that false-negative
HPV tests occur more often in samples that contain few
abnormal cells [20, 21]. Anatomic factors, such as a
large cervical os, have also been noted to be associated
with false-negative HPV tests, suggesting that this
anatomic variation may adversely influence HPV sample
adequacy [23]. The frequency of positive HPV tests by
HC2 does not appear to vary with the date of last
menstrual period, although there is a slightly higher
frequency of HPV positivity in specimens collected at
midcycle [24]. Although multiple studies have docu-
mented a very high negative predictive value of HC2 for
high-grade lesions in various patient populations, these
studies have not generally addressed sample adequacy.
To provide optimal management guidelines for indivi-
dual patients, studies addressing specimen adequacy for
HPV testing are needed. For this to occur, future HPV
testing methods will need to include an internal control.
Management of Women With Negative Cytology and
HPV Results Which Lack an EC/TZ Component.
Additional follow-up studies are needed to more
rigorously determine if the presence or absence of an
EC/TZ warrants different follow-up strategies in women
Cervical Cytology Adequacy Guidelines
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who have both negative Pap and HPV results. The most
appropriate protocol may be age-dependent, so specific
consideration of the following scenarios would poten-
tially be beneficial as future areas of investigation:
Women 30 years or older with no EC/TZ component
and negative cytology and HPV cotest
Can women lacking an EC/TZ component, but with
multiple negative cytology results and negative HPV
results, be returned to routine screening?
In women younger than 30 years with no EC/TZ
component present in repeated Pap tests, is there a
role for HPV testing?
In pregnant women with no EC/TZ component and
negative cytology, would HPV testing of any value?
Sampling Adequacy for the Detection of Adenocarci-
noma. Pap testing was originally designed for detection
of cervical squamous cell carcinoma and its precursors;
however, there is now an increased interest and
expectation for the early detection and treatment of
adenocarcinoma in situ (AIS) in the prevention of
cervical adenocarcinoma. Until recently, the Pap test
had not been demonstrated to have a major impact on
the incidence of invasive adenocarcinoma [17, 25Y31].
This had been attributed to suboptimal sampling of
endocervical lesions and difficulties in recognition of the
cytological features of the precursor lesion, AIS [32].
Several studies have reported either a rising incidence of
adenocarcinoma in absolute numbers or a rising
incidence relative to that of squamous carcinoma as
the incidence of squamous carcinoma continues to
decline [17, 28, 33Y37]. Recent evidence suggests that
modification in the sampling and technique of the Pap
test may decrease the incidence of invasive adenocarci-
noma [38Y40]. For example, one large opportunistic
screening program has reported a decline in the
incidence of adenocarcinoma over a 10-year period
(following a lengthy period of rising incidence) after the
adoption of a dual sampling technique, appropriate
terminology, and quality assurance efforts [38]. The use
of LBP may be another factor in improving the detection
of AIS and of adenocarcinoma. Although classic
morphological features of AIS may not be as pro-
nounced on LBP, a few studies suggest that LBP may
have higher sensitivity in the detection of adenocarci-
noma in comparison to conventional cytology [41, 42].
Current adequacy criteria have been largely defined with
reference to the detection of squamous lesions only. It
may be appropriate in the future to consider whether
these current criteria are also optimal for the detection of
glandular neoplasia or whether modification of these
criteria is desirable. Finally, data are needed on the
utility of HPV screening in the detection of AIS and
adenocarcinoma as well.
Adequacy of Vaginal Pap Tests. Approximately 15% of
US Pap tests are vaginal samples [43]. As discussed, the
Bethesda System allows laboratories to exercise judge-
ment in reporting cellularity of vaginal Pap tests and of
those obtained after cancer therapy [2]. No peer-
reviewed published studies are currently available to
precisely establish what constitutes an adequate vaginal
Pap sample. Most studies have concluded that vaginal
screening after hysterectomy for benign disease is not
cost-effective [5], but reliability of patient history and
the risk of development of new vaginal lesions in
sexually active posthysterectomy women have received
little study. Most literature recommends continued
cytological surveillance in women who have had
hysterectomy for CIN or cervical cancer [4]. A recent
review concluded that the value of vaginal cytology is
largely unproven but that Binconsistency of study design
and limited methodological quality mean that the value
of vaginal vault smears could not be established[ [44].
There is also a need to assess the possible utility of
cytology and high-risk HPV DNA cotesting in this
population because HPV types prevalent in vaginal
intraepithelial neoplasia parallel those prevalent in CIN
[45]. Additional research is needed on the value of
vaginal cytology in patients with a benign history, what
constitutes an adequate posthysterectomy vaginal speci-
men, an adequate posttherapy cervical/vaginal speci-
men, and the role of HPV cotesting in vaginal and
posttherapy specimens.
Sampling Techniques to Improve Adequacy and
Decrease False-Negative Rate
False-negative cytology is the term applied when the Pap
test result does not accurately reflect the state of disease
present in the cervix. False-negative cytology comprises
Btrue[ false-negatives (70%Y80%) and laboratory
errors (20%Y30%) [46]. True false-negative Pap smears
are free of abnormal cells, even on review of the slide, yet
there is a histological evidence of cervical disease. These
are classified as Bsampling errors.[ Sampling errors may
have multiple possible etiologies: inadequate patient
preparation, sampling technique errors, and intermittent
or inadequate shedding of abnormal cells. There is a
general agreement that optimizing both patient prepara-
tion and sampling techniques is one strategy that will
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Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
reduce but not completely eliminate false-negative
cytology results.
Optimal sample collection and adequate fixation are
the most important factors in improving the reliability of
cytology and reducing sampling errors. Steps taken by
the clinician, from patient education to improved
sampling technique, may help ensure that the sample
collected maximizes the potential of the Pap test.
Cervical cytology specimens are smeared directly onto
a glass slide in the office (CS) or transferred to a liquid-
based Pap medium (LBP). Most issues related to
optimizing the sample are shared by each technique,
but there are some differences that will be discussed.
General Recommend ations
for Optimal Sample Colle ction
Patient Preparation. When possible, patient education
regarding preparation for obtaining an optimal Pap test
should begin before the patient_s office visit [47, 48].
This could be in the form of advice given over the phone
at the time the appointment is scheduled, materials sent
to the patient before the scheduled examination, or an
information Balert[ that Bpops up[ when online appoint-
ments are scheduled by the patient. The woman should
be counseled to refrain from intercourse, douching,
using tampons, or using intravaginal medication, for at
least 48 hours before the examination to decrease the
possibility that the number of exfoliated cells will be
diminished or obscured by lubricants or spermicides
[7, 47]. In addition, the patient should avoid scheduling
her appointment during heavy menstrual bleeding, but
should not defer for abnormal bleeding [7].
Labeling and Documentation. The first criterion for
accurate assessment and reporting is the correct identi-
fication of the patient_s specimen. When the slide or
liquid-based vial is not labeled appropriately, the Pap
will not be processed and will be reported as Brejected
due to lack of patient identification[ [2]. In this
circumstance, the Pap test specimen must be repeated,
as it cannot be labeled retrospectively. For a CS, the
frosted end of the slide must be clearly labeled in pencil
or indelible marker before the specimen is collected. For
LBP, the vial should be clearly labeled before obtaining
the specimen. In either case, 2 unique patient identifiers
(name and either date of birth or patient identification
number) should be included on the label for proper
specimen identification. Before taking the sample for a
CS, the collection device(s) and either spray or liquid-
pour fixative or an open bottle of 95% ethanol should be
ready for immediate fixation of the slide; rapid fixation
reduces the possibility of drying artifact which may
reduce the quality of the Pap test [47]. Air-drying artifact
typically does not occur with liquid-based cytology.
Pertinent Clinical History. In addition to patient age and
date of last menstrual period, other relevant clinical
history and observations should be provided (e.g., a
history of prior abnormal Pap smears, suspicious
findings, prior cervical treatment, or other factors that
increase the risk for cervical neoplasia) [48]. These
Bhigh-risk[ Pap smears are typically rescreened by
another cytologist as a quality control measure. Addi-
tional history that may prove helpful includes current
pregnancy, use of hormonal contraceptives or estrogen
replacement therapy, or presence of an intrauterine
device [47].
Choosing the Optimal Collection Device. There are
numerous sampling devices available to collect Pap
tests. In general, these can be referred to as spatulas,
brushes, swabs, and brooms. A recent meta-analysis of
numerous studies on collection devices and specimen
adequacy supported the use of the extended-tip spatula
and devices that effectively collect endocervical cells
[14]. However, the cotton swab traps cells and results in
the greatest number of Pap smears with cellular
distortion and the fewest endocervical cells [49, 50].
With liquid sampling, one should use the sampling
device(s) approved for that particular LBP.
Because the goal of the Pap is to sample the entire
transformation zone, the choice of collection device
should be tailored to the clinical appearance of the
cervix. For example, a large broom device may provide a
more representative sample when the patient has a large
ectopy with a peripheral or large transformation zone.
In contrast, in postmenopausal women and in women
with prior cervical excisional or ablative treatment, the
squamocolumnar junction is usually located within the
endocervical canal and the cervical os may be narrow;
sampling with an endocervical brush plus spatula may
be more appropriate. Women after cervical laser
sampled with an endocervical brush plus an Ayre spatula
were shown to have better quality Pap results than those
sampled with the broom alone, in regard to both
adequacy and the presence of endocervical cells [51].
Optimal Technique. The cytology specimen should be
taken before the bimanual examination [47]. An
Cervical Cytology Adequacy Guidelines
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77
Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
appropriately sized speculum should be inserted with
either water or sparing use of a lubricant gel applied to
facilitate insertion. Water-soluble gel lubricant sparingly
applied to the posterior blade of the speculum to ease
insertion does not result in an increased rate of unsatis-
factory CS [52, 53]. However, lubricants can cause an
unsatisfactory LBP, especially the ThinPrep Pap [54].
It is critical to fully expose the cervix by manipulation
of the speculum or the cervix to obtain the most direct
frontal view of the portio and cervical canal before
collecting the Pap sample; otherwise, taking the endo-
cervical sample may be compromised. Excessive mucus,
discharge, or menstrual blood can be gently removed or
blotted from the cervix before taking the sample. When
there is an evidence of significant infection or inflam-
mation, consideration should be given to treatment
before taking the Pap, unless there are findings
suspicious for cervical neoplasia or the patient cannot
be relied on to return [47].
Previously, it has been recommended that the Pap
sample should be collected before the collection of
samples for sexually transmitted infection [47]. How-
ever, recent studies have documented that when more
than 1 cervical specimen is collected for sexually
transmitted infections and for cervical cytology, the
proportion of inadequate CS and LBP are independent
of specimen order [55Y57].
When 2 sampling devices are used to collect the Pap,
the exocervical sample is obtained first, followed by the
endocervical sample. This minimizes contamination by
bleeding that may accompany the use of the endocervi-
cal brush. The spatula should be rotated at least 360
degrees around the ectocervix as per the manufacturer_s
instructions; the broom should be rotated 5 times. To
fully sample the entire transformation zone in some
women, passing the sampling device across areas of the
transformation zone that fall outside the area covered
by the central 360-degree rotation may also be required
as well [47].
Lesion size and location have been reported to be
important determinants in sampling error [58, 59].
Lesions on a women_s right ectocervix have been shown
to be associated with more frequent false-negative
results than lesions on left [59]. This may be secondary
to the tendency of the sampling device to lift off the
cervix during the part of the rotation in which the
rotating hand necessarily inverts. That this more often
occurs on the right side of the cervix is due to the
majority of the population being right-handed. For left-
handed clinicians, lesions on the left-hand side of the
cervix would be at greatest risk of poor sampling.
Hence, care must be taken by right-handed individuals
to pass a second sweep of the spatula over the right
portio of the cervix and by those left-handed to do the
same over the left portio.
Another study demonstrated that the location of the
squamocolumnar junction, the size of the transforma-
tion zone area, the size of the acetowhite area, and the
ratio of the acetowhite area to the area of the trans-
formation zone influenced the accuracy of cytology [58].
In particular, women with large transformation zone
areas (930.03 mm
2
) and/or small acetowhite lesions
(G7.01 mm
2
) are more likely to have an inaccurate
cytology report than women with small transformation
zones and women with larger acetowhite areas. These
data confirm the importance of clinically evaluating the
architecture of the cervix before taking the Pap
specimen to optimally tailor the sample collection for
each individual patient. Some individuals have used
additional sampling devices or prepared split CSs and
LBPs in women who have a history of unsatisfactory
results due to low squamous cellularity, especially in
the setting of atrophy or postpartum state. Such ap-
proaches may help minimize repeat unsatisfactory
reports.
The endocervical brush, if used, should not be
inserted into the endocervix beyond the full length of
the brush and should be turned in the canal no more
than 180 degrees to minimize bleeding [47]. If the
cervix is shortened because of prior surgery, clinicians
should be aware that sampling of the endometrium can
lead to cytological interpretation challenges and should
refrain from deep brush insertion. The use of the brush
during pregnancy has been shown to be safe and
effective [60, 61].
Each specimen collected for an LBP should be
immediately immersed in the liquid medium as soon as
it is obtained. In contrast, when 2 sampling devices are
used for a CS, the spatula sample should be held until the
endocervical specimen is obtained and each then is
sequentially smeared on the slide, followed by immedi-
ate fixation [47]. Prevention of drying artifact is critical
and is best achieved by rapid fixation in 95% ethanol
solution or by quickly spraying or covering the slide with
a poured-on liquid fixative. A spray fixative is best
applied by holding the spray nozzle approximately 9 to
12 inches from the slide. A single-slide technique for CS,
rather than 2 slides, is preferable; it does not result in a
diminished detection rate, and it uses less laboratory
materials and screening time [62, 63].
78
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DAVEY ET AL.
Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
Rarely, a separate vaginal Pap specimen is needed for
the follow-up of women with a previous history of
vaginal lesions or for DES-exposed women. In these
circumstances an Ayre spatula or cervical brush can be
used to obtain vaginal samples for either CS or LBPs. For
DES-exposed women, a sample from each lateral
vaginal wall should be collected [47]. The speculum is
then rotated, and the procedure repeated on the anterior
and posterior vaginal walls. Specimens should be placed
on separate slides or containers if the specific anatomic
location of the sampling is desired. Gynecological
cytology is no longer recommended for hormonal
evaluation.
CONCLUSION
Specimen adequacy management guidelines should help
promote uniform and optimal follow-up of patients
receiving Pap tests. However, data to determine recom-
mendations are lacking or conflicting in many areas, and
research studies are needed to define future management
options. Clinicians performing Pap tests are encouraged
to adopt optimal sampling techniques tailored to the
individual patient to minimize false-negative results.
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Cervical Cytology Adequacy Guidelines
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    • "Given the proportion of absence of EC/TZ component in a large population receiving Pap smears, correct management must be re- emphasized [4]. According to the American Society for Colposcopy and Cervical Pathology guidelines [15], women with a routine Pap Table 1 Predictive factors for satisfactory but absence of endocervical/transformation component by univariate analysis. Variables Absence (n) Reference (n) p smear with absence of EC/TZ component should have yearly followup . "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To study clinical factors predicting the absence of endocervical/transformation zone (EC/TZ) components of conventional cervical Papanicolaou (Pap) smears. Materials and methods: The medical charts of patients who received Pap smears between March 2006 and August 2006 in the hospital were reviewed. The results of their Pap smears were retrieved while their demographic and clinical information were obtained from the medical charts. After excluding 378 cases with incomplete demographic data and 1397 cases with a history of pelvic irradiation, pelvic malignancy, and hysterectomy, 5662 cases were enrolled for data analysis. The relationship between clinical parameters and the absence of EC/TZ component was analyzed by Pearson Chi-square tests with Yates continuity correction and binary logistic regression tests. Results: The incidence of satisfactory but absence of EC/TZ component was 8.7% (491/5662). Pregnancy increased the absence of EC/TZ component [odds ratio (OR}: 2.84, 95% confidence interval (CI): 2.14-3.77, p. <. 0.0001]. Postpartum status and endocervical polyps decreased incidence (OR: 0.61, 95% CI: 0.38-0.98, p = 0.043 and OR: 0.33, 95% CI: 0.25-0.44, p. <. 0.0001, respectively). Conclusions: Pregnancy is the only clinical factor associated with increased incidence of absence of EC/TZ cells. For these pregnant women undergoing a Pap smear, a more effective strategy may be needed to get a satisfactory smear with adequate EC/TZ components.
    Full-text · Article · Feb 2016
    • "cytolgy.org.hk/.../Final%20Draft2.pdf. Davey et al. [10] and the Clinical and Laboratory Standards Institute [11] only recommend that the secretion is removed gently, but do not pro-sion procedure conization for cervical intraepithelial neoplasia (CIN). The laboratory is a private practice, serving a low-risk population in Mexico City, Mexico. "
    [Show abstract] [Hide abstract] ABSTRACT: Sensitivity of cervical cytology is suboptimal, especially in developing countries such as Mexico, despite available guidelines aimed at improving this. When obtaining cervical samples, whether the samples are taken from the transformation zone and whether abnormal cells are missing must be considered. Cervical secretions (CS) are always present in variable proportions, and when cleaning the cervix, better samples may be obtained. In this study, we analyzed samples obtained with or without cleaning the cervix, and compared their contents in order to determine the sensitivity and specificity of these two methods. Methods: Of 500 patients who underwent cytology and colposcopy, 271 (54.2%) required a second opinion due to a diagnosis of cervical intraepithelial neoplasia (CIN). CS was removed and compared with the clean, second sample (SS) using in both liquid-based cytology. The quality of samples according to the Bethesda System, the presence of CIN, and inflammatory reactions were recorded. The sensitivity and specificity were calculated using biopsy as the gold standard. Results: The SS resulted in a higher proportion of adequate samples being obtained (97.6% vs. 44.8%), and in increased sensitivity (88.2% vs. 58.8%). CIN was detected in the SS 26% more often than in the CS (34 vs. 27 samples), whereas inflammatory reactions were noted more often in the CS (91.4% vs. 74%). Conclusion: Cervical sampling including CS results in lower sensitivity and CIN detection rates, and in more inflammatory reactions. By excluding CS from cervical samples, the sensitivity could be improved and the false negative rate could be reduced.
    Full-text · Article · Sep 2014
    • "In this way, the subjects have to wait until the local environment returns to a stable state to repeat the screening [1]. In this manner, identifying new cervical cancer victims is usually delayed by two to four months [2]. Considering the emergency room as a nodal point where female patients, who neglected primary prophylaxis, have a second chance, we tried to find an alternative option to a conventional based Pap test (CBP), in order to identify more significant cells, needed for a clean cytological diagnostic. "
    [Show abstract] [Hide abstract] ABSTRACT: The importance of screening to detect early lesions that may soon turn into cervical carcinoma is well known. The Romanian contribution to the diagnosis of these lesions dates back over a century ago and is due to A. Babes (1926 and later in the standardization of the Papanikolaou 1928). The experience of the Cytology Compartment of the University Emergency Hospital in Bucharest increased permanently regarding smears made conventionally and those in liquid medium. We believe that this experience should be statistically analyzed and compared with the histological results, especially for the cases of high-grade intraepithelial neoplastic lesions. The article scholastically presents the activity of SUUB's Cytology Compartment, our cases arising mostly from Departments of Gynecology and from medical or surgical emergency cases that were considered at risk by SUUB's clinicians. Our study is based on conventional based Pap test cervico-vaginal cytology activity reports of SUUB's Pathology Department from the past 23 months - 9730 cases -, using Bethesda 2001 system, including descriptive statistics parameters by age, year period, and diagnostic categories. The authors make a detailed description of the pool, enumerating its epidemiological attributes for a future comparative analysis CBP versus LBP - the current technical procedure in SUUB's Cytology Compartment.
    Full-text · Article · Jan 2009
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