Cervical and vaginal cytology: Interpretation of resultsAuthorsChristopher P Crum, MDWarner K Huh, MDSection EditorBarbara Goff, MDDeputy EditorSandy J Falk, MD, FACOGDisclosures: Christopher P Crum, MD Nothing to disclose. Warner K Huh, MD Consultant/Advisory Boards: Merck [HPV vaccines (Gardasil)]; THEVAX [HPV vaccines (Gardasil 9)]. Barbara Goff, MD Nothing to disclose. Sandy J Falk, MD, FACOG Nothing 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.

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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Apr 15, 2015.

INTRODUCTION — Cervical cytology became the standard screening test for cervical cancer and

premalignant cervical lesions with the introduction of the Papanicolaou (Pap) smear in 1941 [1].

Liquid-based, thin layer preparation (eg, ThinPrep, SurePath) of cervical cytology specimens was a

subsequent modification in technique. Terminology for reporting cervical cytology was standardized

by the Bethesda System in 1988 [2]. This system has been revised several times, and the current

system was developed in 2001 (table 1) [3,4]. Human papillomavirus (HPV) testing has now been

incorporated into cervical cancer screening. (See "Screening for cervical cancer"and "Cervical

cancer screening tests: Techniques for cervical cytology and human papillomavirus testing".)

The cervical cytology report is presented in a standard format. Interpretation of cervical cytology

results will be reviewed here. Cervical cancer screening strategies and techniques, as well as the

follow-up of abnormal cytology results and treatment of cervical intraepithelial neoplasia (CIN), are

reviewed separately:

●(See "Screening for cervical cancer".)

●(See "Cervical cancer screening tests: Techniques for cervical cytology and human

papillomavirus testing".)

●(See "Cervical cytology: Evaluation of atypical squamous cells (ASC-US and ASC-H)".)

●(See "Cervical cytology: Evaluation of low-grade squamous intraepithelial lesions (LSIL)".)

●(See "Cervical cytology: Evaluation of high-grade squamous intraepithelial lesions (HSIL)".)

●(See "Cervical cytology: Evaluation of atypical and malignant glandular cells".)

●(See "Cervical intraepithelial neoplasia: Management of low-grade and high-grade lesions".)

ROLE OF CERVICAL CYTOLOGY — Cervical cytology can be used in combination with testing for

high-risk human papillomavirus (HPV) for cervical cancer screening. The results of cervical cytology

cannot be used to make a definitive diagnosis or initiate treatment, with the exception of high-grade

squamous intraepithelial lesion (HSIL). Rather, the test functions solely to screen for cellular

abnormalities that are associated with an increased risk for the development of cervical cancer. The

results are used to guide further evaluation, such as colposcopy and/or cervical biopsy. Treatment

decisions are then made based upon diagnostic results from histologic examination, usually from

colposcopically-directed biopsies. (See "Cervical intraepithelial neoplasia: Management of low-

grade and high-grade lesions".)

TERMINOLOGY FOR SQUAMOUS CELL ABNORMALITIES — There have been frequent

modifications in the nomenclature used for classifying cytologic and histologic cervical changes

associated with human papillomavirus (HPV) infection and precancerous lesions. The major shifts

in terminology apply to squamous cell abnormalities. The current classification system in the United

States for cervical cytology was introduced with the Bethesda 1988 System [3]. The corresponding

terms across the current and previous terminology systems for squamous cell abnormalities are

shown here (figure 1).

Squamous cervical cytologic abnormalities (those detected with Pap tests) are reported using the

term cervical squamous intraepithelial lesions (CSIL). Specifying "cervical" differentiates these

lesions from anal squamous intraepithelial lesions, which use similar terminology. (See "Anal

squamous intraepithelial lesions: Diagnosis, screening, prevention, and treatment".)

CSIL is stratified into two categories:

●Low-grade squamous intraepithelial lesion (LSIL)

●High-grade squamous intraepithelial lesion (HSIL)

The shift in terminology to LSIL and HSIL was made in the Bethesda 1988 system in recognition of

the differing clinical course of these two levels of cellular change. LSIL, especially in young women,

is generally a transient HPV infection, whereas HSIL is more likely to be associated with persistent

HPV infection and a higher risk of progression to cervical cancer [4,5].

Cytologic abnormalities must be further evaluated with colposcopy and biopsy. The finding of LSIL

versus HSIL on cytology does not constitute a diagnosis of a histologic abnormality, ie, cervical

intraepithelial lesion (CIN) 1 versus CIN 2 or 3. Cytologic findings may be associated with a

subsequent histologic finding that is either more or less severe.

In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American

Pathology and the American Society for Colposcopy and Cervical Pathology published changes in

the terminology used to describe HPV-associated squamous lesions of the anogenital tract (figure

1) [6,7]. Current terminology for histologic squamous cell abnormalities is discussed separately.

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

section on 'Terminology'.)

Current terminology for glandular cell findings is described in a section below. (See 'Glandular cell

abnormalities' below.)

OVERVIEW OF THE CERVICAL CYTOLOGY REPORT — The cervical cytology report consists of

(table 1):

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

Pap smear, liquid-based cytology, and/or reflex human papillomavirus (HPV) test.

●A description of specimen adequacy.

●A general categorization (optional) – Negative, epithelial cell abnormality, or other.

●An interpretation/result – Either the specimen is negative for intraepithelial lesions and

malignancy (although organisms or reactive changes may be present) or there is an epithelial

cell abnormality as defined by the Bethesda 2001 classification or there is another finding.

This latter category may indicate some increased risk, as an example: endometrial cells in a

woman over 40 years of age [4].

●A description of any ancillary testing or automated review that was performed (eg, HPV,

AutoPap).

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

SPECIMEN ADEQUACY — Satisfactory cervical cytology is defined by the number of squamous

cells in the sample.

Satisfactory for evaluation — Criteria for "satisfactory for evaluation" are:

●Squamous cellularity – Conventional Pap smears must have at least 8000 to 12,000 well-

visualized squamous cells; liquid-based preparations must have a minimum of 5000 well-

visualized squamous cells.

●Labeled specimen.

Cellularity may be diminished in women who have been treated with pelvic radiation. This

information should be included in the cytology requisition, and the reporting of results will depend on

the clinical context and the ability of the laboratory to evaluate the specimen [8].

Cervical cytology specimens that are designated "satisfactory for evaluation" may, in addition, be

described using what are referred to as "quality indicators." Quality indicators include scant

cellularity, partially obscuring blood or inflammation, poor fixation, thickly smeared slides, and

absence of endocervical or transformation zone(EC/TZ) component [9].

Absent endocervical cell/transformation zone component — The clinical significance for

cervical cancer screening of the absence of the EC/TZ component in a cervical cytology specimen

is controversial. It appears that women with this finding are not at an increased risk of cervical

neoplasia. However, the absence of this component in a sample raises concern for a missed

diagnosis of cervical neoplasia, particularly glandular abnormalities of the endocervix.

Most experts agree with the American Society for Colposcopy and Cervical Pathology guidelines,

which advise that women with cervical cytology that is negative for an intraepithelial lesion or

malignancy but has an absent or insufficient EC/TZ component be managed as follows (algorithm

1) [10]:  

●Women age ≥30 years should be managed according to high-risk human papillomavirus

(HPV) test results:

•HPV-positive – There are two options for further evaluation: genotyping for HPV

subtypes 16 and 18 or HPV and cytology co-testing in one year. Results should be

managed as appropriate. (See 'HPV-positive' below and "Cervical cytology: Evaluation of

atypical squamous cells (ASC-US and ASC-H)" and"Cervical cytology: Evaluation of low-

grade squamous intraepithelial lesions (LSIL)" and "Cervical cytology: Evaluation of high-

grade squamous intraepithelial lesions (HSIL)".)

•HPV-negative – The patient may resume routine screening.

•HPV unknown – There are two options for further evaluation. The preferred option is

HPV testing. Alternatively, cytology may be repeated in three years.

●Women ages 21 to 29 years may return to routine screening.

The transformation zone of the cervix (junction of squamous and glandular cells, generally at the

external cervical os) is the area at greatest risk for neoplasia [11]. Approximately 10 to 20 percent of

cytology specimens lack an EC/TZ component. This finding is most common in adolescents and

women older than 30 years, particularly postmenopausal women [12,13].

The role of the transformation zone in the pathogenesis of cervical neoplasia is discussed

separately. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and

prevention", section on 'Cervical transformation zone'.)

A notation is made in the cervical cytology report regarding the presence or absence of

an EC/TZ component, but these cells are not required for a cervical cytology test to be classified as

satisfactory according to Bethesda 2001 criteria [4]. The criterion for an EC/TZ component is at

least 10 well-preserved endocervical or squamous metaplastic cells; clusters of cells are not

required as they were in Bethesda guidelines prior to 2001.

The clinical significance for cervical cancer screening of the absence of the EC/TZ component in a

cervical cytology specimen is controversial [8,12,14-17]. In specimens that lack endocervical cells,

cytologic evaluation yields a lower rate of cellular abnormalities [12,14,16]. This was best illustrated

in a prospective study of over 4000 women in whom cervical cytology specimens without

an EC/TZ component were found to have a significantly lower rate of epithelial abnormalities than

specimens with an EC/TZ component (11 versus 18 percent) [12].

Since cytologic abnormalities are the indication for further evaluation with colposcopy and cervical

biopsy, this raises the question of whether a histologic diagnosis of cervical intraepithelial neoplasia

(CIN) or cervical cancer will be missed in women in whom a Pap test lacks an EC/TZ component.

However, there appears to be no increase in the development of high-grade CIN or cancer in these

women [12,17-19].

When cervical cytology is repeated in women who have had a Pap test without

an EC/TZ component, data suggest that there is no increase in cellular abnormalities compared

with other women [12,20]. This was illustrated in the prospective study of 4000 women described in

a preceding paragraph [12]. Repeat cytology performed after a median of 60 days (range 13 to 991

days) showed no significant difference in the rate of epithelial abnormalities in women without or

with an EC/TZ component on the initial specimen.

In addition, longitudinal studies (six months to eight years of follow-up) of 40,000 to 60,000 women

with a Pap test that was reported as negative for epithelial abnormalities but lacked

an EC/TZ component found no increase in histologic diagnoses of high-grade CIN or cervical

cancer compared with women with an EC/TZcomponent (in one study, for high-grade CIN, 0.6 to

2.6 versus 2.9 per 1000 years of follow-up [17]; in the other study, for high-grade CIN, 6.2 versus

6.1 per 1000 years of follow-up and for cervical cancer, 0.53 versus 0.54 per 1000 years of follow-

up [19]).

On the other hand, the proportion of endocervical adenocarcinoma among all cervical carcinomas is

increasing. Since these cancers most commonly arise in the glandular cells of the endocervix, it is

plausible that the detection of such cancers may be reduced in specimens that lack

an EC/TZ component [21]. However, glandular abnormalities are less common than squamous

abnormalities, and there are few data to support or refute this concern [17,22].

The advent of testing for oncogenic HPV strains (table 2) has not clarified this issue. A potentially

clinically important subgroup is women with cytology that is negative, but lacks

an EC/TZ component, and a positive HPV test. It is unknown whether abnormal endocervical cells

have been missed in these women [8]. Women with a negative Pap test and positive HPV have an

increased risk of subsequent cervical neoplasia; however, studies of this issue do not report the rate

of Paps without anEC/TZ component [23]. (See "Screening for cervical cancer".)

For women with an inadequate EC/TZ component and a negative HPV test, another issue is

whether the lack of these cells decreases the sensitivity of the HPV test. Two retrospective series

from the same institution of over 26,000 negative cervical cytology specimens that were tested for

high-risk HPV found no significant difference in the prevalence of HPV in specimens without or with

an EC/TZ component (2.5 versus 2.2 percent) [13,24].

Partially obscuring blood or inflammation — A specimen is considered "partially obscured"

when 50 to 75 percent of the epithelial cells cannot be visualized [4]. Specimens in which more than

75 percent of the cells are obscured are designated unsatisfactory. (See 'Unsatisfactory for

evaluation' below.)

Women with partially obscuring blood or inflammation should have a repeat test in six months if

they are at an increased risk for cervical cancer or if they have prior incomplete testing. This

includes women whose tests are otherwise satisfactory. The criteria for repeating cervical cytology

in six months are [25]:

●A previous squamous abnormality (atypical squamous cells of undetermined significance or

worse) without three subsequent negative cervical cytology results (with at least one sample

with an EC/TZ component). This is based on a yearly screening protocol and has not been

updated for protocols that include screening every three to five years.

●A previous Pap with an unexplained glandular abnormality (eg, atypical glandular cells with

no finding of CIN or adenocarcinoma in situ on further evaluation).

●A positive high-risk HPV test within 12 months.

●Clinician’s inability to clearly visualize the cervix or sample the endocervical canal.

●Immunosuppression.

●Similar obscuring factor (blood or inflammation) in consecutive cervical cytology results.

●Insufficient previous screening. This has not been defined in the current screening

guidelines. In our practice, we define insufficient screening as: (1) for women ages 21 to 29

years with no cervical cytology for more than three years prior to the current cytology

specimen, and (2) for women age ≥30 years with no cytology for more than three years or no

cytology and HPV co-testing for more than five years prior to the current screening test.  

For pregnant patients with partially obscuring blood or inflammation, it is preferred to repeat the

cervical cytology postpartum.

For women who do not meet the criteria listed above, routine screening should be continued based

upon the recommended testing intervals (table 3).

Unsatisfactory for evaluation — An unsatisfactory cervical cytology specimen is considered

unreliable for the evaluation of epithelial abnormalities. Whether women with an unsatisfactory

cervical cytology are more likely to have intraepithelial lesions or cancer on follow-up than women

with satisfactory tests is controversial [26-28]. Scant cellularity may result in a false-negative HPV

test [10].

Cervical cytology is reported as unsatisfactory for evaluation in approximately 1 percent of cases

[29,30]. Cervical cytology tests are designated "unsatisfactory for evaluation" for one of three

reasons [4]:

●Scant cellularity

●Obscuring inflammation or blood

●Unlabeled or otherwise unable to be processed by the laboratory

The reason for finding a specimen is unsatisfactory is noted in the report. The most common reason

is scant cellularity. The criteria for cellularity and obscuring inflammation or blood are noted in the

preceding sections (see 'Satisfactory for evaluation' above and 'Partially obscuring blood or

inflammation' above). Specimens that were not processed by the laboratory because they were

unlabeled or the vial or slide broke are distinguished from specimens determined to be

unsatisfactory after processing.

Most experts agree with the American Society for Colposcopy and Cervical Pathology guidelines,

which recommend that high-risk HPV testing be used to triage the management of women with

unsatisfactory cytology (algorithm 2) [10]. The results of high-risk HPV testing are managed as

follows:

●HPV-positive (age ≥30 years) – Women with unsatisfactory cytology and positive HPV

testing may be managed in one of two ways:

•Repeat cytology after two to four months.

•Alternatively, colposcopy may be performed.

●HPV-negative (age ≥30 years) – Repeat cytology after two to four months.

●HPV unknown (any age) – Repeat cytology after two to four months.

When cytology is repeated after two to four months, the results are managed as follows:

●Negative cytology

•For women who are HPV-positive, HPV and cytology co-testing should be repeated in

one year.

•For women who are HPV-negative or unknown, the patient may resume routine

screening.

●Abnormal cytology – The result should be managed as appropriate. (See "Cervical cytology:

Evaluation of atypical squamous cells (ASC-US and ASC-H)" and"Cervical cytology:

Evaluation of low-grade squamous intraepithelial lesions (LSIL)" and "Cervical cytology:

Evaluation of high-grade squamous intraepithelial lesions (HSIL)".)

●Unsatisfactory cytology – Colposcopy should be performed.

Repeating the Pap test within a short interval, even as short as 15 to 30 days, does not appear to

affect sensitivity for detection of cervical neoplasia. (See "Cervical cancer screening tests:

Techniques for cervical cytology and human papillomavirus testing", section on 'Interval between

Pap tests'.)

If the cells are obscured by inflammation and a specific infection is identified, treatment should be

given before repeating the Pap test. Therefore, in women with repeatedly unsatisfactory cytology

specimens as well as those with symptoms (eg, postcoital bleeding, pelvic pain) or physical

examination findings suggestive of cervical cancer (eg, visible cervical lesion), additional clinical

evaluation with colposcopy and/or biopsies is appropriate. (See "Invasive cervical cancer:

Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Clinical

manifestations'.)

Women with an unsatisfactory Pap test in whom the test was not indicated within an appropriate

screening protocol do not need to repeat the test. (See "Screening for cervical cancer".)

GENERAL CATEGORIZATION — This is an optional section in which specimens are noted as

"negative for intraepithelial lesion or malignancy", "epithelial cell abnormality", or "other" [4].

Specimens designated as "other" include those that contain no morphologic abnormalities, but the

findings may indicate some increased cancer risk (eg, endometrial cells).

INTERPRETATION/RESULT — The specimen is reported as either "negative for intraepithelial

lesions or malignancy" or an epithelial cell abnormality is specified. Reporting of non-neoplastic

findings (eg, infection or inflammation) is optional and is reported under the heading "other" [4].

Negative for intraepithelial lesion or malignancy — These are specimens in which no epithelial

abnormality is identified.

Intraepithelial cell abnormalities — These are intraepithelial abnormalities associated with human

papillomavirus (HPV) infection and cervical precancer or cancer (nuclear enlargement and

granulation, the presence of koilocytes, an increased nucleocytoplasmic ratio, and frequent

mitoses) as defined by the Bethesda 2001 classification.

Epithelial cell abnormalities are classified as squamous or glandular (table 1). The term "atypical

epithelial cells" may be used for cases where a squamous versus glandular origin cannot be

determined.

The categories of epithelial cell abnormalities are discussed below. The incidence of each type of

abnormality is shown in the table (table 4). Follow-up for these abnormalities can be found in the

topic reviews listed with each category.

Squamous cell abnormalities

●Atypical squamous cells (ASC) are categorized as either of undetermined significance (ASC-

US) or cannot exclude a high-grade squamous intraepithelial lesion (ASC-H). The ASC-H

category includes findings that are equivocal, but likely consist of a mixture of true high-grade

squamous intraepithelial lesions and other findings that mimic such lesions. Approximately 5

to 10 percent of ASC results are designated ASC-H [31-33]. (See "Cervical cytology:

Evaluation of atypical squamous cells (ASC-US and ASC-H)".)

●Low-grade intraepithelial lesion (LSIL). The LSIL category includes changes consistent with

HPV, mild dysplasia, or cervical intraepithelial neoplasia (CIN) 1. (See"Cervical cytology:

Evaluation of low-grade squamous intraepithelial lesions (LSIL)".)

●High-grade intraepithelial lesion (HSIL). HSIL includes changes consistent with moderate or

severe dysplasia, CIN 2 or 3, and carcinoma in situ (CIS) and should indicate if there are

features suspicious for invasive disease. (See "Cervical cytology: Evaluation of high-grade

squamous intraepithelial lesions (HSIL)".)  

●Squamous cell carcinoma. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical

manifestations, and diagnosis".)

LSIL-H — LSIL cervical cytologic specimens occasionally contain a few cells that are suspicious for

but not diagnostic of HSIL. Retrospective studies have found that these women have a significantly

higher likelihood of a high-grade lesion on biopsy than other women with LSIL (approximately 30

versus 15 percent) [34,35].

Although this is not included in the Bethesda classification, some pathologists report such cytology

as LSIL with a statement regarding the presence of a possible high-grade abnormality (eg, cannot

exclude a high-grade lesion, some cells suggestive of high-grade intraepithelial lesion, or LSIL-H).

There is no standard approach to the evaluation of this finding. These women should undergo

colposcopy and endocervical sampling. One of the authors follows up the results in the same

manner as LSIL cytology, unless there is a concern that the patient will not follow up. The other

author follows up in the same manner as HSIL cytology. (See "Cervical cytology: Evaluation of low-

grade squamous intraepithelial lesions (LSIL)" and "Cervical cytology: Evaluation of high-grade

squamous intraepithelial lesions (HSIL)".)

Glandular cell abnormalities — Glandular abnormalities on cytology are reported in the Bethesda

2001 classification as follows [4]:

●Atypical glandular cells (AGC). Endocervical, endometrial, or not otherwise specified is

noted. Upon further evaluation, either high-grade squamous or glandular abnormalities are

found in 10 to 39 percent of women with a finding of AGC on cytology [36]. This replaces the

previous term "atypical glandular cells of undetermined significance."

●Atypical glandular cells, favor neoplastic. Endocervical or not otherwise specified is noted.

This designation is for specimens that show features suggestive of but not sufficient for an

interpretation of adenocarcinoma.

●Endocervical adenocarcinoma in situ (AIS).

●Adenocarcinoma.

The follow-up of glandular cervical abnormalities is discussed separately. (See "Cervical cytology:

Evaluation of atypical and malignant glandular cells".)

When glandular cell abnormalities are present, it should be noted whether there are changes

favoring neoplasia.

Other — Findings that are non-neoplastic or are related to cancers other than cervical cancer are

noted as "other." The presence of endometrial cells in a woman ≥40 years of age should be noted.

Specimens may have additional findings that should be described, such as infectious organisms or

cellular changes associated with infection, reactive cellular changes, atrophy, or glandular cells after

hysterectomy.

Benign-appearing endometrial cells in a woman ≥40 years — The Bethesda 2001 system

reports the presence of normal, cytologically benign-appearing exfoliated endometrial glandular

cells only in women ≥40 years of age (these are not reported for women younger than 40 years) [4].

These are reported regardless of the date of the last menstrual period. Their presence may reflect

physiologic shedding (especially in the first half of the menstrual cycle) or shedding in response to a

pathological process. The cells are reported so that the clinician can determine the significance of

the finding in an individual patient.

Benign-appearing endometrial cells are noted in up to 12 percent of Pap cervical cytology tests

performed over one year, more commonly in premenopausal than postmenopausal women [37].

The frequency of this finding in women who are older than 40 years or postmenopausal is 0.4

percent of specimens [38]. The prevalence is significantly higher in liquid-based than conventional

cytology (0.9 versus 0.3 percent).

The prevalence of a finding of benign-appearing endometrial cells varies with the menstrual cycle.

Combined results from two large studies showed that benign-appearing endometrial cells are more

likely to be identified on cervicovaginal cytology tests in the first 10 to 12 days of the menstrual

cycle (prevalence 21 to 24 percent) than in the remainder of the cycle (prevalence 2 percent)

[39,40].

Large reviews of benign-appearing endometrial cells in women over age 40 have reported that 7 to

16 percent of cervical cytology specimens with this finding were associated with significant

endometrial pathology (hyperplasia or carcinoma) upon further evaluation [37,38]. In one of these

reviews that included 22 studies, among women with significant pathology, 79 percent also had

abnormal bleeding [38].

Women over age 40 encompass both pre- and postmenopausal women. If symptoms of

endometrial cancer are present (abnormal uterine bleeding), the patient should undergo

endometrial sampling regardless of menopausal status (table 5). For women with abnormal

bleeding, the presence of benign endometrial cells on cervical cytology does not appear to further

increase the risk of endometrial hyperplasia or carcinoma. As an example, a retrospective cohort

study including 186 women ≥40 years with abnormal bleeding found no significant difference in the

rate of atypical endometrial hyperplasia (1.6 versus 1.0 percent) or endometrial carcinoma (2.2

verus 2.3 percent) in women with versus without benign endometrial cells on cervical cytology [41].  

In premenopausal women without abnormal bleeding, benign-appearing endometrial cells are

rarely associated with significant pathology [42-48]. Thus, the 2006 Bethesda recommendations

suggest no further work-up for these patients [43]. In our practice, we perform endometrial sampling

in asymptomatic premenopausal women with benign-appearing endometrial cells only if they are at

increased risk for endometrial cancer (eg, family or personal history of ovarian, breast, colon, or

endometrial cancer; tamoxifen use; chronic anovulation; obesity [9]; estrogen therapy; prior

endometrial hyperplasia; diabetes) (table 6). (See "Endometrial carcinoma: Epidemiology and risk

factors", section on 'Risk factors'.)

On the other hand, asymptomatic postmenopausal women with benign endometrial cells are at

higher risk of endometrial cancer. Therefore, endometrial assessment is recommended for this age

group [49].

Other types of malignancy — The presence of any other types of malignant cells should be

described. As an example, the cervical cytology test may occasionally identify malignant cells from

the fallopian tube, ovary, peritoneal cavity, vulva, or vagina. This should be kept in mind, especially

in women with persistent AGC that remains unexplained after cervical and endometrial evaluation.

In these cases, referral to a gynecologic oncologist is recommended.

Infectious organisms — The presence of infection does not preclude further evaluation of an

epithelial cell abnormality. When an infectious organism is identified or suggested, the patient

should be contacted to determine if she is symptomatic. Antibiotic therapy is indicated for any

symptomatic infection [50]. (See "Approach to women with symptoms of vaginitis".)

●Trichomonas – Asymptomatic trichomonas infection should be treated if the diagnosis is

reasonably certain. Liquid-based cervical cytology for diagnosis of trichomoniasis is more

accurate than conventional Pap smears. The sensitivity, specificity, and positive and negative

predictive values of liquid-based cervical cytology tests for trichomonas infection are 61, 99,

96, and 91 percent, respectively [51]. Conventional Pap smears have a high false-positive rate

for trichomonads. Therefore, the diagnosis should be confirmed by wet prep in asymptomatic

women. However, if the wet prep is negative, then culture is indicated because of the low

sensitivity of wet prep for this organism. (See "Trichomoniasis".)

●Bacterial vaginosis – Cervical cytology is not a reliable diagnostic method for bacterial

vaginosis (BV), and women with a cytologic report of BV need confirmation with clinical testing

before treatment. Further, clinical diagnosis of BV is not associated with CIN [52]. However, a

cytologic report of BV occurs 10 times more commonly in women with versus without HSIL

[53]. The clinical significance of this finding is unknown. (See "Bacterial vaginosis", section on

'Diagnosis'.)

●Herpes simplex – Herpes simplex may produce characteristic cytopathologic changes

(multinucleated giant cells). (See "Epidemiology, clinical manifestations, and diagnosis of

genital herpes simplex virus infection".)

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

who have an intrauterine device. (See "Intrauterine contraception: Management of side effects

and complications", section on 'Actinomyces on cervical cytology'.)

●Chlamydia – Chlamydia infection cannot be reliably diagnosed by cervical cytology tests [54].

Other non-neoplastic findings

Reactive changes/inflammation — Most patients with only reactive changes due to inflammation

will not have an organism identified on their cervical cytology test. The cervical cytology sampling

does not need to be repeated unless the patient is HIV positive (or has a history of

immunosuppression), in which case it should be repeated in four to six months. (See "Screening for

cervical cancer in HIV-infected women".)

Parabasal cells — Parabasal cells are most likely to be seen prior to menarche or following

menopause, when the epithelium is not fully glycogenated. They carry no significance other than

being occasionally 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 significant CIN [50,55] and may be related to infection or trauma with

inflammation, such as from use of a diaphragm. 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.

(See "Cervical cytology: Evaluation of atypical squamous cells (ASC-US and ASC-H)".)

FOLLOW-UP OF CYTOLOGIC RESULTS

Normal cytology — Follow-up of patients with a normal result on cervical cytology is discussed

separately. (See "Screening for cervical cancer".)

HPV-positive — Women with negative cytology and positive high-risk human papillomavirus (HPV)

testing have an increased risk of cervical precancer or cancer than women with negative HPV

testing. High-risk HPV testing refers to testing for a panel of high-risk HPV subtypes; the results are

reported as positive or negative and no individual subtype is identified (table 7). Genotyping for HPV

16 and 18 tests solely for these two subtypes.

A study of approximately one million cervical cytology specimens in women in the Kaiser

Permanente Medical Program, a large healthcare practice in the United States, evaluated the five-

year risk of cervical neoplasia in women ages 30 to 64 [56,57]. The risks were as follows:

●Negative cytology alone (regardless of HPV results) – Cervical intraepithelial neoplasia grade

2 or more severe (CIN 2+) (0.68 percent), CIN 3+ (0.26 percent), cervical cancer (0.025

percent)

●Cytology negative, HPV-negative – CIN 2+ (0.27 percent), CIN 3+ (0.08 percent), cervical

cancer (0.011 percent)

●Cytology negative, HPV-positive – CIN 2+ (10 percent), CIN 3+ (4.5 percent), cervical cancer

(0.34 percent)

Most experts agree with the American Society for Colposcopy and Cervical Pathology guidelines,

which advise that patients with normal cytology and positive high-risk HPV testing be evaluated in

one of two ways (algorithm 3) [10]:

●Cytology and HPV co-testing at 12 months

●Alternatively, genotyping for HPV 16 and 18 (the subtypes that are associated with the

highest risk of cervical cancer):

•Positive for HPV 16 or 18 – Colposcopy should be performed. In our practice, we also

do an endocervical curettage in these patients because normal cytology with persistent

HPV infection can be associated with endocervical/glandular abnormalities, which are

less reliably detected by colposcopy alone [58].

•Negative for HPV 16 or 18 – Repeat cytology and HPV co-testing in one year.

If co-testing or colposcopy results are positive, the patient should be managed as appropriate.

(See "Cervical intraepithelial neoplasia: Management of low-grade and high-grade

lesions" and "Cervical cytology: Evaluation of atypical squamous cells (ASC-US and ASC-

H)" and "Cervical cytology: Evaluation of low-grade squamous intraepithelial lesions

(LSIL)" and "Cervical cytology: Evaluation of high-grade squamous intraepithelial lesions (HSIL)".)

Some patients with normal cytology will have persistent high-risk HPV-positive testing with no

HPV 16/18 genotyping or negative HPV 16/18 genotyping. This is not a clinical scenario that is

included in the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines and

there are no longitudinal data regarding how to further evaluate these patients. Women with

persistent HPV infection are at a higher risk of cervical neoplasia than those with transient infection

[57,59]. In our practice, for these women, we perform HPV 16/18 genotyping if it has not yet been

performed, and then perform colposcopy if positive, as advised by the ASCCP guidelines. If the

patient has had two results that are cytology-negative, high-risk HPV-positive, and

HPV 16/18 genotyping-negative, we perform colposcopy.  

Persistent HPV infection is discussed in detail separately. (See "Cervical cytology: Evaluation of

atypical squamous cells (ASC-US and ASC-H)", section on 'Persistent HPV-positive ASC-US'.)

Abnormal cytology — Patients with significant cytological abnormalities need further evaluation,

which may include repeat cytology, HPV testing, or colposcopy. Evaluation of the results of cervical

cytology is discussed in detail separately. (See "Cervical cytology: Evaluation of atypical squamous

cells (ASC-US and ASC-H)" and"Cervical cytology: Evaluation of low-grade squamous

intraepithelial lesions (LSIL)" and "Cervical cytology: Evaluation of high-grade squamous

intraepithelial lesions (HSIL)".)  

VAGINAL CYTOLOGY — Following total hysterectomy (removal of the uterus and cervix), vaginal

cytology is not required for most women, particularly those with documented benign cervical

findings in the hysterectomy specimen. Vaginal cancer is rare (1 per 100,000 women), and vaginal

cytology should be performed only in women who are at increased risk. (See "Screening for cervical

cancer", section on 'Prior hysterectomy'.)

The risk of vaginal intraepithelial neoplasia (VAIN) or vaginal cancer is extremely low in women who

have undergone total hysterectomy for benign disease (excluding cervical intraepithelial neoplasia

[CIN] 2,3), and for this reason, screening guidelines in the United States from the US Preventive

Services Task Force (USPSTF), the American Cancer Society (ACS), and the American College of

Obstetricians and Gynecologists (ACOG) concur that these women do not need post-hysterectomy

vaginal cytology. (See "Cervical intraepithelial neoplasia: Treatment and follow-up", section on

'Post-hysterectomy' and "Screening for cervical cancer", section on 'Prior hysterectomy'.)

Human papillomavirus (HPV) is the etiologic agent of most vaginal cancers, as well as other

anogenital malignancies. Women who are immunosuppressed have decreased rates of clearance

of HPV infection. In addition, women exposed to diethylstilbestrol (DES) in utero are at risk of

developing vaginal clear cell adenocarcinoma. Thus, vaginal cytology for vaginal cancer screening

is advisable for women who have undergone total hysterectomy who have the following

characteristics:

●Prior vaginal cancer (see "Vaginal cancer", section on 'Posttreatment surveillance')

●Prior cervical, vulvar, or anal cancer (see "Invasive cervical cancer: Patterns of recurrence

and posttreatment surveillance", section on 'Surveillance strategies' and"Vulvar cancer:

Staging, treatment, and prognosis", section on 'Posttreatment surveillance' and "Clinical

features, staging, and treatment of anal cancer", section on 'Posttreatment surveillance')  

●CIN 2,3 or cervical adenocarcinoma in situ prior to, or diagnosed at, the time of total

hysterectomy (see "Cervical intraepithelial neoplasia: Treatment and follow-up", section on

'Post-hysterectomy')

●In utero exposure to DES (see "Outcome and follow-up of diethylstilbestrol (DES) exposed

individuals", section on 'Clear cell adenocarcinoma')

●Immunosuppression (eg, human immunodeficiency infection, history of solid organ or

hematopoietic cell transplant) (see "Screening for cervical cancer", section on

'Immunocompromised women')

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 squamous cervical cells. If endocervical columnar or benign

glandular cells are present, this is mentioned in the pathology report.

Benign glandular cells are seen in less than 2 percent of vaginal cytology specimens following

hysterectomy [60]. They are presumed to be the consequence of either columnar metaplasia or

reactive phenomena. They do not require further evaluation.

If abnormalities are found in a vaginal cytology sample, the indications for further evaluation with

vaginal colposcopy are the same as for abnormal cervical cytology findings. (See "Cervical

cytology: Evaluation of atypical squamous cells (ASC-US and ASC-H)" and "Cervical cytology:

Evaluation of low-grade squamous intraepithelial lesions (LSIL)" and "Cervical cytology: Evaluation

of high-grade squamous intraepithelial lesions (HSIL)" and "Cervical cytology: Evaluation of atypical

and malignant glandular cells" and "Colposcopy", section on 'Vaginal colposcopy'.)  

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.)

●Beyond the Basics topic (see "Patient information: Cervical cancer screening (Beyond the

Basics)")

SUMMARY AND RECOMMENDATIONS

●Cervical cytology (Pap test) is a standard part of cervical cancer screening. Cervical cytology

may detect squamous or glandular abnormalities. (See 'Introduction'above.)

●The management of a patient whose cytology is negative for an intraepithelial lesion but has

no endocervical/transformation zone component can be based on the results of high-risk

human papillomavirus (HPV) testing (see 'Absent endocervical cell/transformation zone

component' above):

•Women ages ≥30 years:

-HPV-positive – There are two options: genotyping for HPV types 16 and 18 or

HPV and cytology co-testing in one year.

-HPV-negative – The patient may resume routine screening.

-HPV status unknown – There are two options: HPV testing (preferred) or cytology

may be repeated in three years.

•Women ages 21 to 29 years may return to routine screening.

●The evaluation of unsatisfactory cytology (typically due to scant cellularity in the specimen) is

based upon HPV testing (see 'Unsatisfactory for evaluation' above):

•Women ages ≥30 years:

-HPV-positive – Cytology should be repeated in two to four months or colposcopy

may be performed.

-HPV-negative – Cytology should be repeated in two to four months.

•If HPV testing has not been performed (as per cervical cancer screening guidelines in

women ages 21 to 29 (table 3)), cytology should be repeated in two to four months.  

●Squamous or glandular abnormalities require further assessment to exclude cancer or a

precancerous lesion. (See 'Intraepithelial cell abnormalities' above.)

●For patients who are ≥40 years and have a cervical cytology test showing benign-appearing

endometrial cells, we suggest an endometrial biopsy only in those who have symptoms of

endometrial cancer (abnormal uterine bleeding) or risk factors for endometrial cancer (eg,

postmenopausal; family or personal history of ovarian, breast, colon, or endometrial

cancer; tamoxifen use; chronic anovulation; obesity; estrogen therapy; prior endometrial

hyperplasia); women without these factors may continue routine gynecologic care.

(See 'Benign-appearing endometrial cells in a woman ≥40 years' above.)

●Patients with normal cytology and positive HPV testing may be further evaluated either with

cytology and HPV co-testing at 12 months or with genotyping for HPV 16 and 18, the types

that are associated with the highest risk of cervical cancer (algorithm 3). (See 'HPV-

positive' above.)

●For asymptomatic or symptomatic women with trichomonas infection detected on cervical

cytology, we suggest treatment (Grade 2C). The sensitivity and specificity of liquid-based

cervical cytology tests for trichomonas infection are 61 and 99 percent, respectively.

(See 'Infectious organisms' above.)

●Following total hysterectomy, vaginal cytology is not required for most women, particularly

those with documented benign cervical findings in the hysterectomy specimen. If vaginal

cytology is indicated 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.)Use of UpToDate is subject to the Subscription and License Agreement.

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