Cervical Cancer Screening - The Cytology and Human Papillomavirus Report - UpToDate

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Cervical cancer screening: The cytology and human

papillomavirus report
Authors: Christopher P Crum, MD, Warner K Huh, MD, Mark H Einstein, MD, MS, FACS, FACOG
Section Editor: Barbara Goff, MD
Deputy Editor: Alana Chakrabarti, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Sep 20, 2022.
INTRODUCTION
Cervical cancer screening utilizes cervical cytology (the Pap test) and/or testing for
oncogenic subtypes of human papillomavirus (HPV) ( table 1). Results from these tests,
along with a patient's past results (if known), are used to guide further evaluation, such as
repeating cervical cytology, performing colposcopy with cervical biopsies, or less commonly,
performing an excisional procedure. Treatment decisions are then made based upon
diagnostic results from histologic examination.
Terminology for reporting cervical cytology is standardized by the Bethesda System, which
has been revised several times; the current system was developed in 2014 ( figure 1) [1-4].
This topic will discuss components of the cervical cytology and HPV report and management
of select results.
Cervical cancer screening strategies and techniques, management of cytology and HPV
results, and treatment of cervical intraepithelial neoplasia (CIN), are reviewed separately:
● Cervical cancer screening: (See "Screening for cervical cancer in resource-rich settings"
and "Cervical cancer screening tests: Techniques for cervical cytology and human
papillomavirus testing".)
● Abnormal cervical cancer screening results: (See "Cervical cancer screening:

Management of results" and "Cervical cytology: Evaluation of atypical and malignant
glandular cells".)
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● CIN: (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and

prevention" and "Cervical intraepithelial neoplasia: Management".)
Pathways:
COMPONENTS OF THE CYTOLOGY AND HPV REPORT
Overview — The cytology and HPV report consists of ( table 2) [3,4]:
● A description of specimen type and test requested – Cervical or vaginal sample,

conventional Pap smear, liquid-based cytology, and/or HPV test.
● A description of specimen adequacy. (See 'Cervical specimen adequacy' below.)
● A general categorization (optional) – Specimens are noted as "negative for

intraepithelial lesion or malignancy (NILM)," "epithelial cell abnormality," or "other."
Specimens designated as "epithelial cell abnormality" or "other" are then described in
the following section, "Interpretation/results."
● An interpretation/result – Either the specimen is NILM (although organisms or reactive

changes may be present), has an epithelial cell abnormality, or may indicate increased
risk (eg, endometrial cells in a woman ≥45 years of age).
● A description of any ancillary testing or automated review that was performed (eg, HPV,
AutoPap).
● Educational notes and suggestions by the pathologist (optional).
Cervical specimen adequacy — Evaluation of specimen adequacy is considered by experts

to be the most important quality assurance component of the Bethesda system.
Satisfactory for evaluation — Any specimen with abnormal cells (eg, atypical squamous
cells of undetermined significance [ASC-US], atypical glandular cells [AGC]) is considered
satisfactory [3]. Otherwise, adequate squamous cellularity is defined as a conventional Pap
smear with at least 8000 to 12,000 well-visualized squamous cells or a liquid-based
preparation with a minimum of 5000 well-visualized squamous cells. (See "Cervical cancer
screening tests: Techniques for cervical cytology and human papillomavirus testing", section
on 'Preparation methods'.)
Cellularity may be diminished in patients who have been treated with pelvic radiation, thus
this information should be included in the cytology requisition. Interpretation will depend on
the clinical context and ability of the laboratory to evaluate the specimen [5].
Quality indicators — If the specimen is satisfactory for evaluation, quality indicators

are described [6]:
● Absent EC/TZ component – The endocervical cell/transformation zone (EC/TZ) is an

area of squamous metaplasia that forms between the original and current
squamocolumnar junction and is the area at greatest risk for neoplasia ( picture 1)
[7,8]. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and
prevention", section on 'Cervical transformation zone'.)
An adequate EC/TZ sample requires at least 10 well-preserved endocervical or

squamous metaplastic cells. Approximately 10 to 20 percent of cytology specimens lack
this finding, and it is more common in adolescents and postmenopausal patients (likely
due to hypoestrogenism) [9,10].
The significance of an absent EC/TZ component is controversial [5,9,11-14]; patients

followed prospectively with repeat cervical cytology do not appear to be at an
increased risk of squamous cell abnormalities or cervical intraepithelial neoplasia (CIN)
[9,14-17]. However, concerns have been raised about reduced detection of glandular
cells and related abnormalities (ie, endocervical adenocarcinoma) in specimens that
lack an EC/TZ component [18,19]. There are few data to support or refute this concern,
given that glandular abnormalities are less common than squamous abnormalities
[14,20].
Increased testing for oncogenic HPV ( table 1) has not clarified this issue. While the
lack of an EC/TZ component does not appear to decrease the sensitivity of HPV testing
[10,21], studies including patients tested with both HPV and cytology do not routinely
report the rate of Pap smears without an EC/TZ component [22].
● Obscuring factors (blood, inflammation) – A specimen is considered "partially

obscured" when 50 to 75 percent of the epithelial cells cannot be visualized [2]; a
partially obscured specimen can still be satisfactory for evaluation. By contrast,
specimens in which more than 75 percent of the cells are obscured (by blood,
inflammation, or an air-drying artifact) are designated unsatisfactory [3]. (See
'Unsatisfactory for evaluation' below.)
● Interfering substances (lubricants, excessive blood) – Some lubricants or excessive

blood may impact the processing of liquid cytology specimens and may result in the
specimen being unsatisfactory for evaluation [3]. (See "Cervical cancer screening tests:
Techniques for cervical cytology and human papillomavirus testing", section on 'Gel
lubricants and other contaminants'.)
Unsatisfactory for evaluation — Cervical cytology is considered unsatisfactory for

evaluation in approximately 1 percent of samples [23,24]. Whether these patients are at
higher risk for future intraepithelial lesions or cancer is controversial [25-27].
Cervical cytology tests are designated "unsatisfactory for evaluation" for one of three
reasons [2]:
● Scant cellularity – Fewer than 8000 to 12,000 well-visualized squamous cells on

conventional smears and 5000 well-visualized squamous cells on liquid cytology
specimens. Postmenopausal patients or those who are otherwise hypoestrogenic may
have an unsatisfactory cytology result due to scant cellularity related to atrophy.
Scant cellularity may result in a false-negative HPV test [28].
● Obscuring factors – More than 75 percent of the cells are obscured.
● Unlabeled or otherwise unable to be processed by the laboratory (eg, vial or slide

broke); these specimens are distinguished from specimens determined to be
unsatisfactory after processing.
Findings
Cervical cytology — The specimen is reported as either "NILM," or an epithelial cell

abnormality is specified. Findings that are non-neoplastic (eg, infection, inflammation,
atrophy) or are related to cancers other than cervical cancer are noted as "other" [2]. The
presence of endometrial cells in a woman ≥45 years of age is also noted.
Intraepithelial cell abnormalities — Intraepithelial abnormalities are associated with

oncogenic subtypes of HPV ( table 1) and cervical precancer or cancer. They are classified
as squamous or glandular, though the term "atypical epithelial cells" may be used for cases
where a squamous versus glandular origin cannot be determined.
● Squamous cell abnormalities – Squamous cervical cytologic abnormalities are

reported as cervical squamous intraepithelial lesions (SIL) to differentiate these lesions
from anal squamous intraepithelial lesions, which use similar terminology. (See "Anal
squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis,
screening, prevention, and treatment".) SIL lesions are reported as:
• Atypical squamous cells (ASC) are categorized as either of undetermined

significance (ASC-US) or cannot exclude a high-grade squamous intraepithelial
lesion (ASC-H).
• Low-grade squamous intraepithelial lesion (LSIL).
• High-grade squamous intraepithelial lesion (HSIL).
• Squamous cell carcinoma.
The definition and incidence of each type of lesion is presented in the following tables
( table 3) and ( table 4). They are also discussed in detail separately. (See "Cervical cancer
screening: Management of results" and "Invasive cervical cancer: Epidemiology, risk factors,
clinical manifestations, and diagnosis".)
● Glandular cell abnormalities – Glandular cells usually originate from the glandular
epithelium of the endocervix or endometrium and are less common than squamous
cell abnormalities. Glandular lesions are reported as:
• AGC
• AGC, favor neoplastic
• Endocervical adenocarcinoma in situ (AIS)
• Adenocarcinoma
These terms are also defined in the table ( table 3) and discussed in detail separately. (See
"Cervical cytology: Evaluation of atypical and malignant glandular cells" and "Cervical
adenocarcinoma in situ" and "Invasive cervical adenocarcinoma".)
Benign-appearing endometrial cells — Benign-appearing endometrial cells (BEC) are

reported only in patients ≥45 years of age [3,4]. This is a change from the prior Bethesda
2001 recommendation, which set the age at ≥40 years [2]. The change in age was made to
improve the effectiveness of BEC as a predictor of endometrial hyperplasia or carcinoma;
most of the studies discussed below were compiled with a threshold of 40 years based on
the 2001 Bethesda guidelines.
BEC are noted in up to 12 percent of Pap cervical cytology tests, more commonly in
premenopausal than postmenopausal patients [29]. The prevalence is higher in liquid-based
compared with conventional cytology (0.9 versus 0.3 percent) [30].
The presence of BEC may reflect:
● Physiologic shedding – Physiologic shedding is more common in the first half of the
menstrual cycle. Combined results from two large studies showed that BEC are more
likely to be identified on cervical cytology tests in the first 10 to 12 days of the
menstrual cycle than in the remainder of the cycle (prevalence: 21 to 24 versus 2
percent) [31,32]
● A pathologic process (eg, endometrial hyperplasia or carcinoma) – Postmenopausal

patients with BEC are at an increased risk for endometrial hyperplasia or carcinoma
[29,30]. In a retrospective study including over 160 postmenopausal patients, patients
with versus without BEC had higher rates of endometrial carcinoma and its precursors
despite the presence or absence of bleeding [33]. This included patients with
postmenopausal bleeding (BEC: 16.4 versus 10.9 percent) as well as without
postmenopausal bleeding (7.6 versus 0 percent).
However, the significance of BEC in premenopausal patients is less clear [34-40]. As an

example, in a retrospective cohort study including 186 patients ≥40 years (median 48
years, menopausal status was not assessed) with abnormal uterine bleeding, patients
with versus without BEC on cervical cytology had similar rates of atypical endometrial
hyperplasia (1.6 versus 1 percent) or endometrial carcinoma (2.2 versus 2.3 percent)
[41].
A finding of BEC does not include atypical endometrial cells.
Other types of malignancy — The presence of any other types of malignant cells is
described. As an example, cervical cytology may occasionally identify malignant cells from
the fallopian tube, ovary, endometrium, peritoneum, vulva, or vagina. In these cases, referral
to a gynecologic oncologist is recommended.
Non-neoplastic findings (infection or inflammation)
● Infectious organisms – Pap tests may detect an infectious organism; however, it is not
an effective test for diagnosing a cervical or vaginal infection. When an infectious
organism is identified or suggested, the patient should be notified of the result, asked
if they are symptomatic, and evaluated further if appropriate.
• Trichomonas – Trichomonads are sometimes reported as an incidental finding on

tests performed for cervical cancer screening. (See "Trichomoniasis: Clinical
manifestations and diagnosis", section on 'Less accurate'.)
- Liquid-based cervical cytology is not a sensitive test for diagnosis of

trichomoniasis, but treatment of patients with trichomonads noted on liquid-
based cervical cytology is reasonable since specificity is high [42].
- Conventional Pap smears do not perform as well for diagnosis of

trichomoniasis [43]. Asymptomatic patients with trichomonads identified on a
conventional Pap smear need confirmation with clinical testing before
treatment.
• Bacterial vaginosis (BV) – Cervical cytology is not a reliable diagnostic method for
BV. A Pap that is suggestive of BV will show a shift in microbiota from predominantly
lactobacilli to predominantly coccobacilli with or without clue cells [44].
• Actinomyces – Actinomyces may be identified on cervical cytology tests, typically in

patients who have an intrauterine device. Cervical cytology is not the most specific
test for actinomyces. For patients who are found to have actinomyces on a Pap test,
we evaluate for symptoms of pelvic inflammatory disease and perform a cervical
culture for actinomyces. (See "Intrauterine contraception: Management of side
effects and complications", section on 'Actinomyces and related organisms'.)
• Herpes simplex – Rarely, herpes simplex may produce characteristic cytopathologic

changes (multinucleated giant cells) in a cervical cytology specimen. (See
"Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus
infection".)
• Chlamydia – Chlamydia infection cannot be reliably diagnosed by cervical cytology

tests [45]. (See "Clinical manifestations and diagnosis of Chlamydia trachomatis
infections", section on 'Diagnosis of chlamydial infections'.)
● Reactive changes/inflammation – Most patients with reactive changes due to

inflammation will not have an organism identified on their cervical cytology test;
further sampling is not required.
● Parabasal cells – Parabasal cells are most likely to be seen prior to menarche or
following menopause, when the epithelium is not fully glycogenated. They have no
clinical significance but may be confused with dysplastic cells due to their immature
appearance.
● Hyperkeratosis – Hyperkeratosis or parakeratosis on an otherwise negative cervical

cytology test is not a marker for clinically significant CIN and may be related to
infection or trauma with inflammation, such as from diaphragm use [46,47]. We do not
perform colposcopy based on this finding. We repeat the cervical cytology test in 6 to
12 months, depending upon whether the patient is at increased risk for CIN, such as
immunocompromised or age less than 30. If hyperkeratosis persists, treatment with
topical estrogen may resolve the finding, but no treatment is necessary.
HPV — The HPV report consists of the following:
● A description of specimen type and test performed (eg, cervical sample, liquid-based
specimen). There are various HPV testing systems available, and the specific test used
is recorded ( table 5).
● An interpretation/result – A positive result is reported if any one or more of a set of

high-risk types are detected ( table 1). The types that are tested have slight variation
across tests, but all test for at least the 13 most common types.
● A description of HPV genotyping results, if performed – HPV genotyping refers to

testing for individual HPV types, usually HPV 16 or 18, but some tests may also include
HPV 45.
MANAGEMENT OF RESULTS
Management of results is discussed here and an overview is shown in the algorithm.
Absent EC/TZ — Most experts agree with the American Society for Colposcopy and Cervical
Pathology (ASCCP) guidelines, which advise managing patients negative for an intraepithelial
lesion or malignancy (NILM) but with an absent or insufficient endocervical
cell/transformation zone (EC/TZ) component as follows ( algorithm 1) [48]:
● Patients age ≥30 years are managed based on the cotested high-risk HPV test results:
• HPV-positive – Options for further evaluation include:
- Genotyping for HPV types 16 and 18, or
- HPV and cytology cotesting in one year
With either option, results should be managed as appropriate. (See "Cervical cancer
screening: Management of results".)
• HPV-negative – Resume routine screening.
• No HPV or HPV-unknown – Options for further evaluation include:
- HPV testing (preferred), or
- Repeat cytology in three years (acceptable)
In our practice, for postmenopausal patients in whom the Pap test showed an absent
EC/TZ, we prescribe a six-week course of vaginal estrogen prior to performing another
Pap test. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy):
Treatment", section on 'Vaginal estrogen therapy'.)
● Patients ages 21 to 29 years may return to routine screening with no further testing.
However, based on reports of an increasing number of cervical adenocarcinoma in situ
and adenocarcinoma cases in this age group, repeating the Pap in 12 months is also
reasonable.
Unsatisfactory for evaluation — Patients with an unsatisfactory cervical cytology result are
managed based on age and high-risk HPV testing results, if available. Patients with two
consecutive unsatisfactory cervical cytology specimens are managed with colposcopy [28].
Patients ≥25 years — We follow the ASCCP management guidelines, which recommend the
following ( algorithm 2) [48]:
● HPV 16/18 positive – Colposcopy (with repeat cytology)
● HPV-positive (unknown genotype)
• Colposcopy (with repeat cytology), or
• Repeat cytology in two to four months
● HPV-negative, no HPV performed, or HPV-unknown – Repeat cytology in two to four

months. While a negative HPV test is often adequate despite cytology cellularity being
insufficient, there is a possibility, albeit small, of a false-negative HPV test [28].
When a repeat Pap is performed, recommendations regarding when to start HPV testing
vary by professional organization, with some starting HPV testing at age 25 and others
starting HPV testing at age 30 ( table 6).
Patients <25 years — HPV testing is not recommended for patients <25 years; thus,
management of such patients with an unsatisfactory cytology result in whom screening for
HPV was inadvertently performed is unclear and practice patterns differ. In our practice, we
perform the following:
● HPV 16/18 positive or HPV-positive (unknown genotype)
• Colposcopy (with repeat cytology), or
• Repeat cytology in two to four months
● HPV negative – Some contributors repeat cytology in two to four months; other
contributors delay repeat cytology until one year as patients with a negative HPV result
are at low risk for developing cervical cancer.
● HPV unknown or not performed – Repeat cytology in two to four months.
Special considerations
● Patients with infection – Patients with an unsatisfactory result in whom a specific

infection is identified on the Pap test report or through other testing (eg, microscopy
[wet prep]) should be treated prior to repeating the Pap test. (See 'Non-neoplastic
findings (infection or inflammation)' above.)
● Postmenopausal patients – Postmenopausal patients with an unsatisfactory result

(who have no contraindications to estrogen therapy) may be treated with a short
course of vaginal estrogen (eg, at least five days or up to six to eight weeks) prior to
repeating the Pap test [49]. (See "Genitourinary syndrome of menopause (vulvovaginal
atrophy): Treatment", section on 'Vaginal estrogen therapy'.)
● Patients who have been inadvertently screened – In some cases, a Pap test has
been performed even though cervical cancer screening test was not indicated.
Typically, the Pap test was performed too soon after a previous test. This may happen if
a clinician does not have access to previous results or does not follow guidelines. If a
patient with previous normal cervical cancer screening who is not due for a Pap test
has an unsatisfactory specimen, the test does not have to be repeated and the patient
should continue with routine screening. (See "Screening for cervical cancer in resource-
rich settings".)
Benign-appearing endometrial cells — For patients with benign-appearing endometrial

cells (BEC) on a cervical cytology specimen, evaluation for endometrial hyperplasia or
carcinoma is performed for all postmenopausal patients with this finding and for
premenopausal patients with risk factors (eg, prior endometrial hyperplasia, tamoxifen use,
chronic anovulation, obesity, diabetes) ( table 7) or symptoms (eg, abnormal uterine
bleeding) of endometrial carcinoma [48]. This is discussed in detail elsewhere. (See
"Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'
and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology,
evaluation, and approach to diagnosis" and "Approach to the patient with postmenopausal
uterine bleeding".)
Patients for whom menopausal status is uncertain are evaluated as if they are
postmenopausal. (See "Clinical manifestations and diagnosis of menopause", section on
'Diagnosis'.)
HPV-positive results — A patient with a positive high-risk HPV result is at an increased risk
of cervical neoplasia. These patients are managed based on the combination of HPV and
cytology results, according to standard guidelines, which are discussed in detail separately.
(See "Cervical cancer screening: Management of results".)
General considerations include:
● HPV 16/18 – HPV 16 or 18 positivity is the highest risk clinical scenario and is an
indication for immediate referral to colposcopy and, if combined with a high-grade
squamous intraepithelial lesion (HSIL), expedited treatment with an excisional
procedure [48]. (See "Cervical cancer screening: Management of results", section on
'Immediate risk >60 percent: Expedited treatment'.)
● First positive result – This is a common finding and, if there is no prior HPV-positive
testing, most likely represents a new infection. Most new infections will revert to a
negative result within 6 to 12 months [50-52]. Importantly, a subsequent negative HPV
test in this setting does not mean the patient has cleared the HPV virus, but rather that
the virus is dormant and below the threshold of a positive test.
● Recurrent positive result – Positive HPV testing may recur after reversion to HPV-
negative status [53-55]. Often, it is the same HPV type as a past infection, suggesting a
"reactivation" from a latent infection, but it can also be a new infection.
Patients are counseled that most infections detected over the years of screening are
reactivations of latent infections that are acquired at or near sexual debut [53,54].
Reactivation of a latent infection could imply waning immunity, and the patient might
be at increased risk of persistence. This is particularly common in
immunocompromised individuals [53,54].
● Persistent positive result – Persistent HPV infection (defined as consecutively positive

HPV results at least 12 months apart [56]) is a necessary pathogenetic step for
progression to clinically relevant disease. Most, if not all, patients with persistent HPV
infection will be diagnosed with cervical intraepithelial neoplasia 2 or more (CIN 2+)
within five to seven years, many in as few as two years [57].
Patients with persistent positive results, but in whom further work-up (with cytology
and colposcopic biopsies) is reassuring, are evaluated with vaginal colposcopy. If
vaginal colposcopy is negative, continued surveillance with cervical cytology and
colposcopy is prudent as the patient remains at risk for cervical cancer.
All other results — Management of all other results obtained from cytology and HPV
testing are discussed in detail elsewhere. (See "Screening for cervical cancer in resource-rich
settings" and "Cervical cancer screening: Management of results".)
SPECIAL CONSIDERATIONS
Vaginal cytology — If vaginal cytology is performed, the findings are reported in the same
manner as cervical cytology. The sample should be labeled as a vaginal sample because
pathology evaluation cannot typically differentiate between vaginal and cervical squamous
cells. If endocervical columnar or benign glandular cells are present, this is mentioned in the
pathology report. Benign glandular cells are seen in fewer than 2 percent of vaginal cytology
specimens following hysterectomy [58]. They are presumed to be the consequence of either
columnar metaplasia or reactive phenomena, and do not require further evaluation.
Indications for obtaining vaginal cytology are discussed in detail separately:

● Cervical intraepithelial neoplasia (CIN) 2,3 or cervical adenocarcinoma in situ prior to or

diagnosed at the time of total hysterectomy. (See "Cervical intraepithelial neoplasia:
Choosing excision versus ablation, and prognosis and follow-up after treatment",
section on 'Type and duration of testing'.)
● Prior vaginal cancer. (See "Vaginal cancer", section on 'Post-treatment surveillance'.)
● Prior cervical, vulvar, or anal cancer. (See "Invasive cervical cancer: Patterns of
recurrence and post-treatment surveillance", section on 'Surveillance strategies' and
"Treatment of anal cancer", section on 'Post-treatment surveillance and assessing the
local response to primary chemoradiotherapy'.)
● In-utero exposure to diethylstilbestrol (DES). (See "Outcome and follow-up of

diethylstilbestrol (DES) exposed individuals", section on 'Vaginal or cervical clear cell
adenocarcinoma'.)
● Immunosuppression (eg, human immunodeficiency infection, history of solid organ or

hematopoietic cell transplant). (See "Screening for cervical cancer in resource-rich
settings", section on 'Screening in higher risk patients'.)
Patients who have undergone a total hysterectomy (removal of the uterus and cervix) and
have no history of gynecologic neoplasia do not require continued screening. Vaginal cancer
is rare in these patients (<1 per 100,000 women). If screening is performed (despite
guidelines against this practice), and an abnormality is found, follow-up is determined based
upon severity of the cytologic findings and clinical estimation of risk of vaginal cancer [59].
(See "Screening for cervical cancer in resource-rich settings", section on 'Prior benign
hysterectomy' and "Colposcopy", section on 'Vaginal colposcopy' and "Vaginal intraepithelial
neoplasia".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Cervical cancer
screening, prevention, and management".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Cervical cancer screening tests (The Basics)")
● Beyond the Basics topic (see "Patient education: Cervical cancer screening (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● Components of the cytology and HPV report – Cervical cancer screening utilizes
cervical cytology (the Pap test) and/or testing for human papillomavirus (HPV) subtypes
that are high risk for causing cervical cancer ( table 1). Results are reported in a
standardized format ( table 2). (See 'Overview' above.)
● Absent EC/TZ – Patients in whom cytology is negative for an intraepithelial lesion but
have no endocervical cell/transformation zone (EC/TZ) component are managed
according to the algorithm ( algorithm 1). (See 'Absent EC/TZ' above.):
● Unsatisfactory for evaluation – Patients in whom cytology is unsatisfactory for

evaluation (typically due to scant cellularity in the specimen) are managed based on
age and HPV testing results, if available. (See 'Unsatisfactory for evaluation' above.)
• Patients ≥25 years are managed according to the algorithm ( algorithm 2). (See
'Patients ≥25 years' above.)
• HPV testing is not recommended for patients <25 years; thus, management of such
patients with an unsatisfactory cytology result in whom screening for HPV was
inadvertently performed is unclear and practice patterns differ. (See 'Patients <25
years' above.)
● Benign-appearing endometrial cells – Benign-appearing endometrial cells (BEC) are

reported only in patients ≥45 years. Evaluation for endometrial hyperplasia or
carcinoma is performed for all postmenopausal patients with this finding and for select
premenopausal patients (eg, risk factors ( table 7) or symptoms [ie, abnormal uterine
bleeding] of endometrial carcinoma) ( table 8). (See 'Benign-appearing endometrial

cells' above.)
● HPV-positive results – Patients with a positive high-risk HPV result are at an increased
risk of cervical neoplasia. (See 'HPV-positive results' above.)
• HPV 16 or 18 positivity is the highest risk clinical scenario and is an indication for
immediate referral to colposcopy and, if combined with other high-risk history (eg,
high-grade squamous intraepithelial lesion [HSIL]), immediate treatment.
• A first positive result most likely represents a new infection. Most new infections will
revert to a negative result within 6 to 12 months. However, a negative HPV test does
not mean the patient has cleared the virus, but rather that the virus is dormant and
below the threshold of a positive result.
• A recurrence of HPV-positive testing after a period of negative testing is often a

"reactivation" from a latent infection but may also be a new infection.
• Persistent HPV infection (HPV-positive results at least 12 months apart) reflects an

increased risk of development of or progression to clinically relevant disease
(cervical intraepithelial neoplasia 2 or more severe [CIN 2+]).
● Intraepithelial cell abnormalities – Patients with squamous or glandular

abnormalities on cervical cytology ( table 3) require further assessment to exclude
cancer or a precancerous lesion. (See 'Intraepithelial cell abnormalities' above.)
● Vaginal cytology – Following total hysterectomy, vaginal cytology is not required for
most patients, particularly those with documented benign cervical findings in the
hysterectomy specimen. If vaginal cytology is performed and abnormalities are found,
the indications for further evaluation with vaginal colposcopy are the same as for
abnormal cervical cytology findings. (See 'Vaginal cytology' above.)
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transformation zone component: should clinicians worry? Obstet Gynecol 2002;
99:1053.
10. Zhao C, Austin RM. Adjunctive high-risk human papillomavirus DNA testing is a useful
option for disease risk assessment in patients with negative Papanicolaou tests without
an endocervical/transformation zone sample. Cancer 2008; 114:242.
11. Vooijs PG, Elias A, van der Graaf Y, Veling S. Relationship between the diagnosis of
epithelial abnormalities and the composition of cervical smears. Acta Cytol 1985; 29:323.
12. Kivlahan C, Ingram E. Papanicolaou smears without endocervical cells. Are they
inadequate? Acta Cytol 1986; 30:258.
13. Martin-Hirsch P, Lilford R, Jarvis G, Kitchener HC. Efficacy of cervical-smear collection

devices: a systematic review and meta-analysis. Lancet 1999; 354:1763.
14. Mitchell HS. Longitudinal analysis of histologic high-grade disease after negative
cervical cytology according to endocervical status. Cancer 2001; 93:237.
15. Mitchell H, Medley G. Longitudinal study of women with negative cervical smears
according to endocervical status. Lancet 1991; 337:265.
16. Bos AB, van Ballegooijen M, van den Akker-van Marle ME, et al. Endocervical status is
not predictive of the incidence of cervical cancer in the years after negative smears. Am
J Clin Pathol 2001; 115:851.
17. Tacken MA, Braspenning JC, Mulder J, et al. Loss to follow-up of cervical smears without
endocervical columnar cells is not disturbing. Eur J Gynaecol Oncol 2006; 27:42.
18. van der Horst J, Siebers AG, Bulten J, et al. Increasing incidence of invasive and in situ
cervical adenocarcinoma in the Netherlands during 2004-2013. Cancer Med 2017; 6:416.
19. Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma
relative to squamous cell carcinoma of the uterine cervix in the United States--a 24-year
population-based study. Gynecol Oncol 2000; 78:97.
20. Mitchell H, Hocking J, Saville M. Cervical cytology screening history of women diagnosed
with adenocarcinoma in situ of the cervix: a case-control study. Acta Cytol 2004; 48:595.
21. Bansal M, Austin RM, Zhao C. High-risk HPV DNA detected in less than 2% of over 25,000
cytology negative imaged liquid-based Pap test samples from women 30 and older.
Gynecol Oncol 2009; 115:257.
22. Castle PE, Wacholder S, Sherman ME, et al. Absolute risk of a subsequent abnormal pap
among oncogenic human papillomavirus DNA-positive, cytologically negative women.
Cancer 2002; 95:2145.
23. Moriarty AT, Clayton AC, Zaleski S, et al. Unsatisfactory reporting rates: 2006 practices of
participants in the college of american pathologists interlaboratory comparison
program in gynecologic cytology. Arch Pathol Lab Med 2009; 133:1912.
24. Hoda RS, Loukeris K, Abdul-Karim FW. Gynecologic cytology on conventional and liquid-
based preparations: a comprehensive review of similarities and differences. Diagn
Cytopathol 2013; 41:257.
25. Hock YL, Ramaiah S, Wall ES, et al. Outcome of women with inadequate cervical smears
followed up for five years. J Clin Pathol 2003; 56:592.
26. Ransdell JS, Davey DD, Zaleski S. Clinicopathologic correlation of the unsatisfactory
Papanicolaou smear. Cancer 1997; 81:139.
27. Adams AL, Gidley J, Roberson J, et al. Clinical significance of unsatisfactory conventional
pap smears owing to inadequate squamous cellularity defined by the Bethesda 2001
criterion. Am J Clin Pathol 2005; 123:738.
28. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the
management of abnormal cervical cancer screening tests and cancer precursors. J Low
Genit Tract Dis 2013; 17:S1.
29. Fadare O, Ghofrani M, Chacho MS, Parkash V. The significance of benign endometrial
cells in cervicovaginal smears. Adv Anat Pathol 2005; 12:274.
30. Canfell K, Kang YJ, Clements M, et al. Normal endometrial cells in cervical cytology:
systematic review of prevalence and relation to significant endometrial pathology. J Med
Screen 2008; 15:188.
31. Vooijs GP, van der Graaf Y, Vooijs MA. The presence of endometrial cells in cervical
smears in relation to the day of the menstrual cycle and the method of contraception.
Acta Cytol 1987; 31:427.
32. LIU W, BARROW MJ, SPITLER MF, KOCHIS AF. NORMAL EXFOLIATION OF ENDOMETRIAL
CELLS IN PREMENOPAUSAL WOMEN. Acta Cytol 1963; 7:211.
33. Aslan DL, Crapanzano JP, Harshan M, et al. The Bethesda System 2001 recommendation
for reporting of benign appearing endometrial cells in Pap tests of women age 40 years
and older leads to unwarranted surveillance when followed without clinical qualifiers.
Gynecol Oncol 2007; 107:86.
34. Bean SM, Connolly K, Roberson J, et al. Incidence and clinical significance of
morphologically benign-appearing endometrial cells in patients age 40 years or older:
the impact of the 2001 Bethesda System. Cancer 2006; 108:39.
35. Greenspan DL, Cardillo M, Davey DD, et al. Endometrial cells in cervical cytology: review
of cytological features and clinical assessment. J Low Genit Tract Dis 2006; 10:111.
36. Thrall MJ, Kjeldahl KS, Savik K, et al. Significance of benign endometrial cells in
papanicolaou tests from women aged >or=40 years. Cancer 2005; 105:207.
37. Simsir A, Carter W, Elgert P, Cangiarella J. Reporting endometrial cells in women 40
years and older: assessing the clinical usefulness of Bethesda 2001. Am J Clin Pathol
2005; 123:571.
38. Ashfaq R, Sharma S, Dulley T, et al. Clinical relevance of benign endometrial cells in
postmenopausal women. Diagn Cytopathol 2001; 25:235.
39. Chang A, Sandweiss L, Bose S. Cytologically benign endometrial cells in the

papanicolaou smears of postmenopausal women. Gynecol Oncol 2001; 80:37.
40. Beal HN, Stone J, Beckmann MJ, McAsey ME. Endometrial cells identified in cervical
cytology in women > or = 40 years of age: criteria for appropriate endometrial
evaluation. Am J Obstet Gynecol 2007; 196:568.e1.
41. Moatamed NA, Le LT, Levin MR, et al. In Papanicolaou smears, benign appearing
endometrial cells bear no significance in predicting uterine endometrial
adenocarcinomas. Diagn Cytopathol 2013; 41:335.
42. Lara-Torre E, Pinkerton JS. Accuracy of detection of trichomonas vaginalis organisms on

a liquid-based papanicolaou smear. Am J Obstet Gynecol 2003; 188:354.
43. Wiese W, Patel SR, Patel SC, et al. A meta-analysis of the Papanicolaou smear and wet
mount for the diagnosis of vaginal trichomoniasis. Am J Med 2000; 108:301.
44. Greene JF 3rd, Kuehl TJ, Allen SR. The papanicolaou smear: inadequate screening test for
bacterial vaginosis during pregnancy. Am J Obstet Gynecol 2000; 182:1048.
45. Pandit AA, Klhilnani PH, Powar HS, et al. Value of Papanicolaou smear in detection of
Chlamydia trachomatis infection. Diagn Cytopathol 1993; 9:164.
46. Zahn CM, Askew AW, Hall KL, Barth WH Jr. The significance of
hyperkeratosis/parakeratosis on otherwise normal Papanicolaou smears. Am J Obstet
Gynecol 2002; 187:997.
47. Cecchini S, Iossa A, Ciatto S, et al. Colposcopic survey of Papanicolaou test-negative

cases with hyperkeratosis or parakeratosis. Obstet Gynecol 1990; 76:857.
48. Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus
Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low
Genit Tract Dis 2020; 24:102.
49. Bateson DJ, Weisberg E. An open-label randomized trial to determine the most effective
regimen of vaginal estrogen to reduce the prevalence of atrophic changes reported in
postmenopausal cervical smears. Menopause 2009; 16:765.
50. Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection
and low-grade squamous intraepithelial lesion development in young females. JAMA
2001; 285:2995.
51. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human
papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001;
357:1831.
52. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus
infection in young women. N Engl J Med 1998; 338:423.
53. Markt SC, Rodriguez AC, Burk RD, et al. Longitudinal analysis of carcinogenic human
papillomavirus infection and associated cytologic abnormalities in the Guanacaste
natural history study: looking ahead to cotesting. J Infect Dis 2012; 205:498.
54. Castle PE, Schiffman M, Herrero R, et al. A prospective study of age trends in cervical
human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect
Dis 2005; 191:1808.
55. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin
Sci (Lond) 2006; 110:525.
56. Einstein MH, Burk RD. Persistent Human Papillomavirus Infection: definitions and
clinical implications. Papillomavirus Report 2001; 12:119.
57. Elfgren K, Elfström KM, Naucler P, et al. Management of women with human
papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J
Obstet Gynecol 2017; 216:264.e1.
58. Tambouret R, Pitman MB, Bell DA. Benign glandular cells in posthysterectomy vaginal
smears. Acta Cytol 1998; 42:1403.
59. Khan MJ, Massad LS, Kinney W, et al. A common clinical dilemma: Management of
abnormal vaginal cytology and human papillomavirus test results. Gynecol Oncol 2016;
141:364.
Topic 3205 Version 52.0
GRAPHICS
Human papillomavirus: High- and low-risk types for causing cervical

cancer
High-risk (oncogenic or cancer-associated) types
Common types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82
Low-risk (non-oncogenic) types
Common types: 6, 11, 40, 42, 43, 44, 54, 61, 72, 81
Data from: Centers for Disease Control and Prevention. National Cancer Institute Factsheet. Human papillomavirus and
cancer: Questions and answers (Accessed on June 11, 2012).
Graphic 76394 Version 7.0
Terminology and histology of cervical intraepithelial neoplasia
Terminology regarding cytologic and histologic precancerous changes of the uterine cervix.
The corresponding terminology from the previous classification systems is shown. Images of
the histologic correlates for each category are also shown.
LAST: lower anogenital squamous terminology; LSIL: low-grade squamous intraepithelial

lesions; HSIL: high-grade squamous intraepithelial lesions; CIN: cervical intraepithelial
neoplasia.
* CIN 2 that is p16-positive is classified as HSIL. CIN 2 that is p16-negative is classified as

LSIL.
References:
1. Darragh TM, Colgan TJ, Thomas Cox J, et al. The Lower Anogenital Squamous Terminology Standardization
project for HPV-associated lesions: background and consensus recommendations from the College of
American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol
Pathol 2013; 32:76.
2. Nayar R, Wilbur DC. The Pap Test and Bethesda 2014: "The reports of my demise have been greatly
exaggerated. (after a quotation from Mark Twain)". J Low Genit Tract Dis 2015; 19:175.
Bethesda 2014 classification system for cervical cytology
Specimen type
Indicate conventional smear (Pap smear), liquid-based preparation (Pap test), versus other
Specimen adequacy
Satisfactory for evaluation (describe presence or absence of endocervical/transformation

zone component and any other quality indicators, eg, partially obscuring blood,
inflammation, etc)
Unsatisfactory for evaluation (specify reason)
Specimen rejected/not processed (specify reason)
Specimen processed and examined, but unsatisfactory for evaluation of epithelial
abnormality because of (specify reason)
General categorization (optional)
Negative for intraepithelial lesion or malignancy

Other: see "Interpretation/results" (eg, endometrial cells in a woman older than 45 years)
Epithelial cell abnormality: see "Interpretation/results" (specify "squamous" or "glandular,"
as appropriate)
Interpretation/results
Negative for intraepithelial lesion or malignancy
(When there is no cellular evidence of neoplasia, state this in the "General categorization"
above and/or in the "Interpretation/results" section of the report—whether there are
organisms or other non-neoplastic findings)
Non-neoplastic findings (optional to report)
Non-neoplastic cellular variations:

Squamous metaplasia
Keratotic changes
Tubal metaplasia
Atrophy
Pregnancy-associated changes
Reactive cellular changes associated with:
Inflammation (includes typical repair)
Lymphocytic (follicular) cervicitis
Radiation
Intrauterine contraceptive device (IUD)
Glandular cells status posthysterectomy
Organisms
Trichomonas vaginalis
Fungal organisms morphologically consistent with Candida spp
Shift in flora suggestive of bacterial vaginosis
Bacteria morphologically consistent with Actinomyces spp

Cellular changes consistent with herpes simplex virus
Cellular changes consistent with cytomegalovirus
Other
Endometrial cells (in a woman older than 45 years)

(also specify if "negative for squamous intraepithelial lesion")
Epithelial cell abnormalities
Squamous cell
Atypical squamous cells
Of undetermined significance (ASC-US)
Cannot exclude HSIL (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
(encompassing: HPV/mild dysplasia/CIN-1)
High-grade squamous intraepithelial lesion (HSIL)
(encompassing: moderate and severe dysplasia, CIS; CIN-2 and CIN-3)
With features suspicious for invasion (if invasion is suspected)
Squamous cell carcinoma
Glandular cell
Atypical
Endocervical cells (NOS or specify in comments)
Endometrial cells (NOS or specify in comments)
Glandular cells (NOS or specify in comments)
Atypical
Endocervical cells, favor neoplastic
Glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
Endocervical
Endometrial
Extrauterine
Not otherwise specified (NOS)
Other malignant neoplasms (specify)
Adjunctive testing
Provide a brief description of the test method(s) and report the result so that it is easily
understood by the clinician
Computer-assisted interpretation of cervical cytology

If case examined by an automated device, specify the device and result
Educational notes and comments appended to cytology reports (optional)

Suggestions should be concise and consistent with clinical follow-up guidelines published by
professional organizations (references to relevant publications may be included)
Pap: Papanicolaou; HPV: human papillomavirus; CIN: cervical intraepithelial neoplasia; CIS:
carcinoma in situ.
From: Nayar R, Wilbur DC. The Pap Test and Bethesda 2014: "The reports of my demise have been greatly exaggerated.
(after a quotation from Mark Twain)". J Low Genit Tract Dis 2015; 19:175. DOI: 10.1097/LGT.0000000000000115.
Copyright © 2015 American Society for Colposcopy and Cervical Pathology, The International Society for the Study of
Vulvovaginal Disease, and The International Federation of Cervical Pathology and Colposcopy. Reproduced with
permission from Lippincott Williams & Wilkins. Unauthorized reproduction of this material is prohibited.
Cervical transformation zone at colposcopy
A cervical transformation zone with mature metaplasia and active immature metaplasia.
Reproduced with permission from Kenneth Hatch, MD, University of Arizona, Department of Obstetrics and Gynecology. Copyrigh
2016.
Cervical cytology: Terminology of normal and abnormal results [1,2]
Normal cytology result:
Negative intraepithelial A specimen that is adequate for evaluation and in which no

lesions or malignancy epithelial abnormality is identified.
(NILM)
Squamous lesions:
Atypical squamous cells Cells that display abnormalities more marked than simple
(ASC): reactive changes but qualitatively or quantitatively do not fulfill
Atypical the criteria for a squamous intraepithelial lesion; in some cases,
squamous cells of these lesions are associated with cervical intraepithelial
undetermined neoplasia (CIN).
significance (ASC- Cells that alone (or in combination with low-grade squamous
US) intraepithelial lesions [LSIL]) share cytologic features with high-
Atypical grade squamous intraepithelial lesions (HSIL). Cytologies termed
squamous cells ASC-H can reflect the presence of true high-grade squamous
cannot exclude intraepithelial lesion and other entities that mimic such lesions.
high-grade
squamous
intraepithelial
lesion (ASC-H)
Low-grade squamous Lesions associated with human papillomavirus (HPV) infection.

intraepithelial lesions These tend to be associated with transient changes that regress
(LSIL) over time.
High-grade squamous Lesions associated with high-risk types of HPV and that have a
intraepithelial lesions high risk of a CIN 2,3 outcome, persistence, or progression to
(HSIL) cancer.
Glandular lesions:
Atypical glandular cells Either endocervical (AEC), endometrial, or not otherwise

(AGC) specified (NOS) is noted as a subcategory. This replaces the
previous term "atypical glandular cells of undetermined
significance (AGUS)."
Atypical glandular cells, Endocervical is the only subcategory. This designation is for
favor neoplastic specimens that show features suggestive of, but not sufficient
for, an interpretation of adenocarcinoma.
Endocervical The normal glandular architecture of the endocervical glands

adenocarcinoma in situ may be preserved, but the glands are lined by atypical columnar
(AIS) epithelial cells similar to those of invasive cervical
adenocarcinoma but without stromal invasion.
References:
1. Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: Terminology for reporting results of cervical
cytology. JAMA 2002; 287:2114.
2. Katki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 3+ and cervical cancer among women with HPV-
positive and HPV-negative high-grade Pap results. J Low Genit Tract Dis 2013; 17(5 Suppl 1):S50.
Relative incidence of cervical cytology results
Cytology Incidence (percent)
Negative 96
Atypical squamous cells of undetermined significance (ASC-US) 2.8
Low-grade squamous intraepithelial lesion (LSIL) 0.97
High-grade squamous intraepithelial lesion (HSIL) 0.21
Atypical glandular cells (AGC) 0.21
Atypical squamous cells: cannot exclude high-grade squamous 0.17

intraepithelial lesion (ASC-H)
Squamous cell cervical carcinoma 4.5 per 100,000
Data from: Katki HA, Schiffman M, Castle PE, et al. Benchmarking CIN 3+ Risk as the Basis for Incorporating HPV and
Pap Cotesting into Cervical Screening and Management Guidelines. J Low Genit Tract Dis 2013; 17:S28.
HPV tests used for cervical cancer screening and surveillance [1,2]
Approved Commercial
Assay target* DNA/RNA
indication name
Cotest or Aptima ¶ Pooled detection of 14 high-risk HPV subtypes Δ RNA

reflex
Aptima HPV 16 Specifically reports on the presence or absence of
testing (use
and 18/45 ¶ HPV 16 and 18/45
only in
combination Cervista HPV Pooled detection of 14 high-risk HPV subtypes Δ DNA
with cervical HR ¶
cytology)
Cervista HPV Pooled detection of 14 high-risk HPV subtypes Δ
16/18 ¶ and specifically reports on the presence or
absence of HPV 16 and 18
Hybrid Pooled detection of 13 high-risk HPV subtypes ◊

Capture 2
(HC2) ¶
Primary Cobas HPV ¶ Pooled detection of 12 high-risk HPV subtypes § DNA

test (use and specifically reports on the presence or
without absence of HPV 16 and 18
concurrent
BD Onclarity ¶ Specifically reports on the presence or absence of
cervical
14 high-risk HPV subtypes Δ (individual results for
cytology)
6 HPV subtypes [16, 18, 31, 45, 51, and 52] and
grouped results for the remaining subtypes
[33/58, 35/39/68, and 56/59/66])
Cepheid Xpert Pooled detection of 11 high-risk HPV subtypes ‡

HPV ¥ and specifically reports on the presence or
absence of HPV 16 and 18/45
Qiagen Pooled detection of 14 high-risk HPV subtypes Δ

careHPV ¥
HPV: human papillomavirus; HR: high-risk.
* A positive pooled result indicates that at least one high-risk HPV subtype was detected. The test
cannot identify the HPV subtype or whether one or more HPV subtypes are present, unless
otherwise indicated.
¶ US Food and Drug Administration approval.
Δ The 14 high-risk HPV subtypes include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68.
◊ The 13 high-risk HPV subtypes include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.
§ The 12 high-risk HPV subtypes include 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68.
¥ World Health Organization prequalified.
‡ The 11 high-risk HPV subtypes include 31, 33, 35, 39, 51, 52, 56, 58, 59, 66, and 68.
References:
1. Integrating HPV testing in cervical cancer screening program: a manual for program managers, Pan American
Health Organization 2016.
2. Fontham ET, Wolf AM, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 guideline
update from the American Cancer Society. CA Cancer J Clin 2020.
Clinical management of cytology that is negative for

intraepithelial lesion or malignancy, but with absent
transformation zone or endocervical cells
This algorithm describes the steps involved in clinical management of cytology that is
negative for intraepithelial lesion or malignancy, but with absent transformation
zone or endocervical cells.
HPV: human papillomavirus; ASCCP: American Society for Colposcopy and Cervical
Pathology.
* Triage using HPV testing is not recommended for age <30 years.
From: Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines
for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis 2020; 24:102.
DOI: 10.1097/LGT.0000000000000525. Copyright © 2020 the American Society for Colposcopy and
Cervical Pathology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction
of this material is prohibited.
Clinical management of unsatisfactory cervical cytology
This algorithm describes the steps involved in clinical management of unsatisfactory

cytology. Note that "unknown genotype" refers to both HPV testing without genotyping
and HPV testing where genotyping is negative for HPV 16 and 18 but positive for other
high-risk HPV types.
Patients <25 years inadvertently screened for HPV may be managed differently; see
related UpToDate content.
HPV: human papillomavirus; ASCCP: American Society for Colposcopy and Cervical
Pathology.
From: Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for
Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis 2020; 24:102. DOI:
10.1097/LGT.0000000000000525. Copyright © 2020 the American Society for Colposcopy and Cervical
Pathology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this
material is prohibited.
Cervical cancer screening recommendations from United States

professional organizations* [1-6]
Post-
hysterectom
Age to Age to
Recommended screening (with cervix
Organization initiate discontinue
test and frequency removed) fo
(years) ¶ (years)
benign
disease
In our practice, we use the following guidelines, in order of preference:
USPSTF (2018) 21 65 Δ Age 21 to Age ≥30 years Not indicated §

29 years
One of these
Pap test methods:
every 3 Pap test
years every 3
years
Primary
HPV
testing ◊
alone
every 5
years
Co-testing
(Pap test
and HPV
testing)
every 5
years
ACS (2020) 25 65 ¥ Age ≥25 years Not indicated ‡
One of these methods:

Primary HPV testing ◊
every 5 years (preferred)
Co-testing (Pap test and
HPV testing) every 5
years
Pap test every 3 years
Other expert group recommendations:
Age 21 to Age ≥30 years

29 years
ACOG (2021) 21 65 Δ Pap test One of these Not indicated §

every 3 methods:
years
Pap test
every 3
years
Primary
HPV
testing ◊
alone
every 5
years
Co-testing
(Pap test
and HPV
testing)
every 5
years
ACP (2015) 21 65 Δ Pap test One of these Not indicated §

every 3 methods:
years Pap test
every 3
years
Alternative:
Co-testing
(Pap test
and HPV
testing)
every 5
years
ASCCP/SGO 21 N/A Can Can consider N/A

(2015 interim consider primary HPV
guidelines) primary testing ◊ every 3
HPV years
testing ◊
every 3
years for
patients
age ≥25
ACS/ASCCP/ASCP 21 ¶ 65 † Pap test One of these Not indicated**

(2012) every 3 methods:
years Co-testing
(preferred) (Pap test
and HPV
testing)
every 5
years
(preferred)
Pap test
every 3
years
HPV: human papillomavirus; ACS: American Cancer Society; ASCCP: American Society for
Colposcopy and Cervical Pathology; ASCP: American Society for Clinical Pathology; SGO: Society
of Gynecologic Oncology; USPSTF: United States Preventive Services Task Force; ACOG: American
College of Obstetricians and Gynecologists; ACP: American College of Physicians; DES:
diethylstilbestrol; HIV: human immunodeficiency virus; CIN: cervical intraepithelial neoplasia;
FDA: US Food and Drug Administration.
* These guidelines are intended for the general population and are not intended for patients
with a history of cervical cancer, high-grade cervical precancers, DES in utero exposure, or who
are immunocompromised (eg, HIV infection).
¶ Regardless of the age of initiation of sexual activity.
Δ For patients with no history of CIN 2 or higher with evidence of prior adequate screening (3 or
more negative cytology test results in a row or 2 consecutive negative co-tests in the past 10
years, with the most recent within the past 5 years).
◊ Only certain HPV tests are approved by the FDA for primary HPV testing (ie, Cobas, BD
Onclarity).
§ For patients who have had a benign hysterectomy with removal of the cervix who do not have a
history of CIN 2 or higher.
¥ For patients with evidence of adequate negative prior screening (2 consecutive negative
primary HPV tests or co-tests within the past 10 years, with the most recent test within the
previous 5 years, or 3 consecutive negative Pap tests within the past 10 years, with the most
recent test within the previous 3 years) and no history of CIN 2 or greater within the last 25 years.
Screening should not be resumed for any reason, even if a woman has a new sexual partner.
‡ For patients who have had a benign hysterectomy with removal of the cervix who do not have a
history of CIN 2 or 3 in the past 25 years, or a history of cervical cancer ever.
† For patients with evidence of adequate negative prior screening (consecutive negative cytology
results or 2 consecutive negative co-tests within the previous 10 years, with the most recent test
within the previous 5 years) and no history of CIN 2 or greater within the last 20 years. Screening
should not be resumed for any reason, even if the patient has a new sexual partner.
** For patients who have had a benign hysterectomy with removal of the cervix who do not have
a history of CIN 2, CIN 3 in the past 20 years, or a history of cervical cancer ever.
References:
1. Curry SJ. Screening for cervical cancer: United States Preventive Services Task Force recommendation statement.
JAMA 2018; 320:674.
2. Fontham ETH, Wolf AMD, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020
guideline update from the American Cancer Society. CA Cancer J Clin 2020.
3. Updated Cervical Cancer Screening Guidelines. The American College of Obstetricians and Gynecologists.
Available at: www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2021/04/updated-cervical-cancer-
screening-guidelines (Accessed on February 16, 2023).
4. Sawaya GF, Kulasingam S, Denberg TD, et al. Cervical Cancer Screening in Average-Risk Women: Best Practice
Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2015;
162:851.
5. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer
screening: Interim clinical guidance. Gynecol Oncol 2015; 136:178.
6. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical
Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early
detection of cervical cancer. CA Cancer J Clin 2012; 62:147.
Risk factors for endometrial cancer
Relative risk (RR)

Risk factor
(other statistics are noted when used)
Increasing age 1 to 2% cumulative incidence of endometrial

cancer in females age 50 to 70 years
Unopposed estrogen therapy 2 to 10
Tamoxifen therapy 2
Early menarche NA
Late menopause (after age 55) 2
Nulliparity 2
Polycystic ovary syndrome (chronic 3

anovulation)
Obesity For type I endometrial cancer: OR 1.5 for

overweight (BMI 25.0 to <30 kg/m 2 ), 2.5 for
class 1 obesity (30.0 to <35 kg/m 2 ), 4.5 for class
2 obesity (35.0 to 39.9 kg/m 2 ), and 7.1 for class
3 obesity (≥40.0 kg/m 2 ).
For type II: OR 1.2 for overweight (BMI 25.0 to

<30 kg/m 2 ), 1.7 for class 1 obesity (30.0 to <35
kg/m 2 ), 2.2 for class 2 obesity (35.0 to 39.9
kg/m 2 ), and 3.1 for class 3 obesity (≥40.0
kg/m 2 ).
Diabetes mellitus 2
Estrogen-secreting tumor NA
Lynch syndrome (hereditary nonpolyposis 13 to 71% lifetime risk

colorectal cancer)
Cowden syndrome 13 to 28% lifetime risk
Family history of endometrial, ovarian, breast, NA

or colon cancer
NA: RR not available; OR: odds ratio; BMI: body mass index.
Data from:
1. Heald B, Mester J, Rybicki L, et al. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a
prospective series of PTEN mutation carriers. Gastroenterology 2010; 139:1927.
2. Pilarski R, Stephens JA, Noss R, et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and
Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet 2011; 48:505.
3. Ramsoekh D, Wagner A, van Leerdam ME, et al. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different
risk profiles may influence clinical management. Hered Cancer Clin Pract 2009; 7:17.
4. Riegert-Johnson DL, Gleeson FC, Roberts M, et al. Cancer and Lhermitte-Duclos disease are common in Cowden
syndrome patients. Hered Cancer Clin Pract 2010; 8:6.
5. Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin
Oncol 2013; 31:2607.
6. Smith RA, von Eschenbach AC, Wender R, et al. American Cancer Society guidelines for the early detection of
cancer: Update of early detection guidelines for prostate, colorectal, and endometrial cancers. CA Cancer J Clin
2001; 51:38.
7. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer
Res 2012; 18:400.
8. Ten Broeke SW, van der Klift HM, Tops CMJ, et al. Cancer risks for PMS2-associated Lynch syndrome. J Clin Oncol
2018; 36:2961.
Patients who should undergo evaluation for endometrial hyperplasia or

endometrial cancer
Abnormal uterine bleeding
Postmenopausal patients – Any uterine bleeding, regardless of volume (including spotting

or staining). Pelvic ultrasound to evaluate endometrial thickness is an alternative to
endometrial sampling in appropriately selected patients. A thickened endometrium should
be further evaluated with endometrial sampling.
Age 45 years to menopause – In any patient, bleeding that is frequent (interval between the
onset of bleeding episodes is <21 days), heavy, or prolonged (>8 days). In patients who are
ovulatory, this includes intermenstrual bleeding.
Younger than 45 years – Any abnormal uterine bleeding in patients with BMI ≥30 kg/m 2 . In
patients with BMI <30 kg/m 2 , abnormal uterine bleeding that is persistent and occurs in the
setting of one of the following: chronic ovulatory dysfunction, other exposure to estrogen
unopposed by progesterone, failed medical management of the bleeding, or patients at
high risk of endometrial cancer (eg, Lynch syndrome, Cowden syndrome).
In addition, endometrial neoplasia should be suspected in premenopausal patients who are

anovulatory and have prolonged periods of amenorrhea (six or more months).
Cervical cytology results
Presence of AGC-endometrial.
Presence of AGC-all subcategories other than endometrial – If ≥35 years of age or at risk
for endometrial cancer (risk factors or symptoms).
Presence of benign-appearing endometrial cells in patients ≥40 years of age who also have
abnormal uterine bleeding or risk factors for endometrial cancer.
Other indications
Monitoring of patients with endometrial pathology (eg, endometrial hyperplasia).
Screening in patients at high risk of endometrial cancer (eg, Lynch syndrome).
These recommendations are based on an average age of menopause of 51 years. Evaluation of

patients who undergo menopause earlier should be individualized based on gynecologic history
and risk of endometrial neoplasia.
BMI: body mass index; AGC: atypical glandular cells.
Contributor Disclosures
Christopher P Crum, MD Equity Ownership/Stock Options: Multiclonal Therapeutics [Stem cell
research]. Patent Holder: P63 [Diagnostics]. Grant/Research/Clinical Trial Support: NCI [Ovarian
cancer]. All of the relevant financial relationships listed have been mitigated. Warner K Huh,
MD Consultant/Advisory Boards: AstraZeneca [Ovarian cancer management]; Inovio [DSMB]; SeaGen
[Cervical cancer]. All of the relevant financial relationships listed have been mitigated. Mark H
Einstein, MD, MS, FACS, FACOG Grant/Research/Clinical Trial Support: Astra Zeneca [Ovarian Cancer];
Imvax [Endometrial cancer ]; Inovio [Cervical dysplasia therapeutic]; Iovance [Cervical Cancer]; J&J
[Ovarian Cancer]; Pfizer [Ovarian Cancer]. Consultant/Advisory Boards: Becton Dickinson [Screening
marker development]; Douglas Pharmaceuticals [Investigational therapeutic]; Merck [Cost of Care
Analysis Cervix]; Papivax [investigational therapeutic vaccines]; PDS Biotechnologies [investigational
therapeutic vaccines]; Proimmune [Cervical intraepithelial neoplasia]. All of the relevant financial
relationships listed have been mitigated. Barbara Goff, MD No relevant financial relationship(s) with
ineligible companies to disclose. Alana Chakrabarti, MD No relevant financial relationship(s) with
ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Cervical Cancer Screening - The Cytology and Human Papillomavirus Report - UpToDate

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6/3/23, 10:53 Cervical cancer screening: The cytology and human papillomavirus report - UpToDate

Official reprint from UpToDate®

Cervical cancer screening: The cytology and human

● Abnormal cervical cancer screening results: (See "Cervical cancer screening:

● CIN: (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and

COMPONENTS OF THE CYTOLOGY AND HPV REPORT

Overview — The cytology and HPV report consists of ( table 2) [3,4]:

● A description of specimen type and test requested – Cervical or vaginal sample,

● A description of specimen adequacy. (See 'Cervical specimen adequacy' below.)

● A general categorization (optional) – Specimens are noted as "negative for

● An interpretation/result – Either the specimen is NILM (although organisms or reactive

● Educational notes and suggestions by the pathologist (optional).

Cervical specimen adequacy — Evaluation of specimen adequacy is considered by experts

Quality indicators — If the specimen is satisfactory for evaluation, quality indicators

● Absent EC/TZ component – The endocervical cell/transformation zone (EC/TZ) is an

An adequate EC/TZ sample requires at least 10 well-preserved endocervical or

The significance of an absent EC/TZ component is controversial [5,9,11-14]; patients

● Obscuring factors (blood, inflammation) – A specimen is considered "partially

● Interfering substances (lubricants, excessive blood) – Some lubricants or excessive

Unsatisfactory for evaluation — Cervical cytology is considered unsatisfactory for

● Scant cellularity – Fewer than 8000 to 12,000 well-visualized squamous cells on

Scant cellularity may result in a false-negative HPV test [28].

● Obscuring factors – More than 75 percent of the cells are obscured.

● Unlabeled or otherwise unable to be processed by the laboratory (eg, vial or slide

Cervical cytology — The specimen is reported as either "NILM," or an epithelial cell

Intraepithelial cell abnormalities — Intraepithelial abnormalities are associated with

● Squamous cell abnormalities – Squamous cervical cytologic abnormalities are

• Atypical squamous cells (ASC) are categorized as either of undetermined

• Low-grade squamous intraepithelial lesion (LSIL).

• High-grade squamous intraepithelial lesion (HSIL).

• Squamous cell carcinoma.

Benign-appearing endometrial cells — Benign-appearing endometrial cells (BEC) are

The presence of BEC may reflect:

● A pathologic process (eg, endometrial hyperplasia or carcinoma) – Postmenopausal

However, the significance of BEC in premenopausal patients is less clear [34-40]. As an

A finding of BEC does not include atypical endometrial cells.

Non-neoplastic findings (infection or inflammation)

• Trichomonas – Trichomonads are sometimes reported as an incidental finding on

- Liquid-based cervical cytology is not a sensitive test for diagnosis of

- Conventional Pap smears do not perform as well for diagnosis of

• Actinomyces – Actinomyces may be identified on cervical cytology tests, typically in

• Herpes simplex – Rarely, herpes simplex may produce characteristic cytopathologic

• Chlamydia – Chlamydia infection cannot be reliably diagnosed by cervical cytology

● Reactive changes/inflammation – Most patients with reactive changes due to

● Hyperkeratosis – Hyperkeratosis or parakeratosis on an otherwise negative cervical

HPV — The HPV report consists of the following:

● An interpretation/result – A positive result is reported if any one or more of a set of

● A description of HPV genotyping results, if performed – HPV genotyping refers to

Management of results is discussed here and an overview is shown in the algorithm.

• HPV-positive – Options for further evaluation include:

- Genotyping for HPV types 16 and 18, or

- HPV and cytology cotesting in one year

• HPV-negative – Resume routine screening.

• No HPV or HPV-unknown – Options for further evaluation include:

- HPV testing (preferred), or

- Repeat cytology in three years (acceptable)

● HPV 16/18 positive – Colposcopy (with repeat cytology)

● HPV-positive (unknown genotype)

• Colposcopy (with repeat cytology), or

• Repeat cytology in two to four months

● HPV-negative, no HPV performed, or HPV-unknown – Repeat cytology in two to four

● HPV 16/18 positive or HPV-positive (unknown genotype)

• Colposcopy (with repeat cytology), or