Cervical cancer screening: The cytology and human papillomavirus report

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: Risk assessment, evaluation, and management after screening" and "Cervical cytology: Evaluation of atypical and malignant glandular cells".)

●CIN: (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention" and "Cervical intraepithelial neoplasia: Management".)

●(Related Pathway(s): Cervical cancer screening: Follow-up of a Pap test with an absent endocervical transformation zone and Cervical cancer screening: Follow-up of a Pap test showing partially obscuring blood or inflammation.)

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: Risk assessment, evaluation, and management after screening" 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: Risk assessment, evaluation, and management after screening".)

•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].

(Related Pathway(s): Cervical cancer screening: Follow-up of a Pap test reported as "unsatisfactory".)

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: Risk assessment, evaluation, and management after screening".)

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: Risk assessment, evaluation, and management after screening", section on 'Expedited treatment: Immediate risk >60 percent'.)

●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: Risk assessment, evaluation, and management after screening".)

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 5^th to 6^th 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 10^th to 12^th 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.)