Cervical cancer screening ideally finds preinvasive lesions that can be eradicated or finds early-stage cervical cancer that can be treated successfully. Cervical cancer screening was previously limited to cervical cytology. But, during the past decade, HR HPV testing has also become an important screening tool.
In general, LGT preinvasive lesions are visible only with aided inspection. One exception is VIN, which is generally visible, palpable, or both. Only cervical lesions at either end of the neoplastic disease spectrum are grossly visible, namely, condylomata and invasive cancers. Accordingly, all symptoms suspicious for cervical neoplasia and grossly visible cervical lesions require prompt biopsy.
Cervical cytologic screening is one of modern medicine’s great success stories. It detects most cervical neoplasia during the typically prolonged premalignant or early occult invasive phases, when treatment outcomes are optimal. Conventional glass slides (traditionally called the Pap smear) and liquid-based Pap tests are considered equally acceptable for screening by all current guidelines (American College of Obstetricians and Gynecologists, 2012b; Saslow, 2012; U.S. Preventive Services Task Force, 2012).
Introduced in the 1940s, cervical cytology has never been evaluated in a randomized, controlled, or masked trial (Koss, 1989). However, countries with organized screening programs have consistently realized dramatic declines in both cervical cancer incidence and mortality rates. The Pap test’s specificity is consistently high, approximating 98 percent. However, estimates of its sensitivity for detection of CIN 2 or worse are lower, are more variable, and range from 45 to 65 percent (Whitlock, 2011). This imperfect sensitivity is balanced by recommendations for repetitive screening throughout a woman’s life. Although the incidence of cervical squamous carcinoma continues to decline, both the relative and absolute incidences of adenocarcinoma have increased, particularly in women younger than 50 (Herzog, 2007). Adenocarcinoma and adenosquamous carcinoma now account for at least 20 percent of cervical cancers. This increase may be due in part to the Pap test’s lower sensitivity for detection of adenocarcinoma than for squamous cancers and their precursor lesions.
False-negative Pap test results may follow sampling error, in which abnormal cells are not present in the Pap test, or by screening error, in which the cells are present but missed or misclassified by the screener (Wilkinson, 1990). Mandated quality assurance measures and computerized slide-screening technologies address screening errors. Suboptimal management of abnormal results by providers and failure of patient follow up also contribute to avoidable cases of cervical cancer. Clinicians can maximize the benefit of screening by obtaining an optimal cytologic specimen and by adhering to current evidence-based guidelines for the management of abnormal test results.
Ideally, Pap tests are scheduled to avoid menstruation. Patients should abstain from vaginal intercourse, douching, vaginal tampon use, and intravaginal medicinal or contraceptive creams for a minimum of 24 to 48 hours before a test. Treatment of cervicitis or vaginitis prior to Pap testing is optimal. However, Pap testing is not deferred due to unexplained discharge or unscheduled bleeding, as these may be signs of cervical or other genital tract cancers.
As shown in Figure 21-9, the appearance of cervical squamous cells varies throughout the menstrual cycle and with hormonal status. Thus, clinical information aids accurate Pap interpretation and often includes: date of last menstrual period, current pregnancy, exogenous hormone use, menopausal status, complaints of abnormal bleeding, and prior abnormal Pap test results, CIN, or other LGT neoplasia. Additionally, intrauterine devices (IUDs) can cause reactive cellular changes, and their presence is noted. Full visualization of the cervix is essential for detection of gross lesions and SCJ identification. Speculum placement should be as comfortable as possible. A thin coating of water-based lubricant can be used on the outside of the speculum blades without compromising Pap test quality or interpretation (Griffith, 2005; Harmanli, 2010). Touching the cervix prior to performing a Pap test is avoided, as dysplastic epithelium may be inadvertently removed with minimal trauma. Discharge covering the cervix may be carefully absorbed by a large swab, with care not to contact the cervix. Vigorous blotting or rubbing may cause scant cellularity or a false-negative Pap test result. When indicated, additional sampling to detect other cervical or vaginal infection may follow Pap test collection.
Sampling of the transformation zone at the SCJ is paramount to the sensitivity of the Pap test. Techniques are adapted and sampling devices chosen according to SCJ location, which varies widely with age, obstetric trauma, and hormonal status. Women known or suspected of in utero DES exposure may also benefit from a separate Pap test of the upper vagina, as these women carry an additional risk for vaginal cancer.
Three types of plastic devices are commonly used to sample the cervix: the spatula, broom, and endocervical brush (also known as a cytobrush) (Fig. 29-8). A spatula predominantly samples the ectocervix. An endocervical brush samples the endocervical canal and is used in combination with a spatula. A broom samples both endo- and ectocervical epithelia simultaneously but can be supplemented by an endocervical brush. Wooden collection devices and cotton swabs are no longer recommended due to their inferior collection and release of cells.
A. Cervical cytology collection devices: (1) Plastic spatula. (2) Endocervical brush. (3) Plastic broom. B. Pap preparations. Conventional cervical cytology is prepared by smearing collected cells directly onto a glass slide with the collection device followed by immediate fixation (upper slide). Liquid-based cytology involves transfer of collected cells from the collection device into a liquid transport medium with subsequent processing and transfer onto a glass slide. Cells are distributed over a smaller area, and debris, mucus, blood, and cell overlap are largely eliminated, allowing computer-assisted screening (lower slide). (Used with permission from Dr. Raheela Ashfaq.)
A spatula is oriented to best fit the cervical contour, straddle the squamocolumnar junction, and sample the distal endocervical canal. A clinician firmly scrapes the cervical surface, completing at least one full rotation. After the spatula sample is obtained, the endocervical brush, with its conical shape and plastic bristles, is inserted into the endocervical canal only until the outermost bristles remain visible just within the external os. This prevents inadvertent sampling of lower uterine segment cells, which can be mistaken for atypical cervical cells. To avoid obscuring blood, the brush is rotated only one-quarter to one-half turn and is used after the ectocervix has been sampled. If the cervical canal is very wide, the brush is moved so as to contact all surfaces of the endocervical canal.
Broom devices have longer central bristles that are inserted into the endocervical canal. These longer bristles are flanked by shorter bristles that splay out over the ectocervix during rotation. Five rotations in the same direction are recommended. Reversing direction may cause loss of cellular material. Broom devices are favored for liquid-based Pap testing.
Conventional slide collection requires special care to avoid air drying artifact, a leading cause of poor slide quality. The spatula sample is held while the endocervical brush sampling immediately follows. The spatula sample is then quickly spread as evenly as possible over one half to two thirds of a glass slide (see Fig. 29-8). The endocervical brush is firmly rolled over the remaining area of the slide, after which fixation is quickly carried out by spraying from a distance of 10 to 12 inches or immersing the slide in fixative.
Currently, two liquid-based cytology (LBC) Pap tests are FDA approved. Sampling and cell transfer to a liquid medium is performed according to manufacturer specifications. SurePath allows for the use of all three device types but uses modified tips that are broken off and sent to the laboratory in the liquid medium. ThinPrep requires immediate and vigorous agitation of the chosen collection device(s) in the liquid medium, after which the device is discarded.
A role for HR HPV testing in cervical cancer screening is attractive due to its improved sensitivity for CIN 3 or cervical cancer and the objectivity of its results. However, strategies for incorporation of HPV testing must compensate for a decreased specificity, particularly in young women.
Cytology with HPV Cotesting
In 2003, the FDA first approved an HPV test for use with cytology for cervical cancer screening in women 30 years and older. The combination of HR HPV testing with cytology is referred to as cotesting. This strategy is not currently endorsed for women younger than 30 due to the high prevalence of HR HPV infection in this age group and the resultant lack of test specificity. HPV testing is usually performed from the residual LBC specimen after the cytology slide is prepared. Alternatively, a cervical sampling for HPV can be sent in a specific collection device separate from the cytology specimen. Testing is performed only for HR HPV types. As noted earlier, there is no clinical role for LR HPV testing (Castle, 2014; Thomsen, 2014).
The combination of HPV testing with cytology increases the sensitivity of a single screening test for high-grade neoplasia to nearly 100 percent and leads to earlier detection and management of HSIL (Ronco, 2010). The lack of sensitivity for cervical adenocarcinoma seen with traditional cytology testing also supports HPV testing use for primary screening (Castellsagué, 2006).
Due to a high negative predictive value for high-grade neoplasia, slow progression of new HPV infection to neoplasia, and increased cost, cotesting is repeated at 5-year intervals if both cytology and HPV test are negative. Clinical guidelines have been developed for management of abnormal cotest results (Saslow, 2012). If cytology is abnormal, current cytology management guidelines are followed. Cytology-negative and HPV-positive test results will occur in less than 10 percent of screened patients (Castle, 2009a; Datta, 2008). In such cases, cotesting is repeated 12 months later. This is because the risk of high-grade neoplasia is less than that of a Pap test with an atypical squamous cell of undetermined significance (ASC-US) result, and most HPV infections will resolve during this time (Saslow, 2012). Colposcopy is recommended for persistently positive HPV DNA test results. An abnormal repeat cytology result is managed according to current guidelines regardless of concurrent HPV status.
An alternative strategy is now available for management of a negative cytology but a positive HR HPV test result. A reflex test specifically for HPVs 16 and 18, called genotyping, can be performed. If positive, immediate colposcopy is recommended (American College of Obstetricians and Gynecologists, 2012b; Saslow, 2012). This approach targets those at highest risk for significant disease, and evidence provides a sound basis for this strategy (Khan, 2005; Wright, 2015).
A growing body of evidence supports HR HPV testing alone without initial cytology as an option for primary cervical cancer screening (Castle, 2011; Cuzick, 2006; Dillner, 2013). In late 2014, the cobas HPV test was the first HPV test approved by the FDA for primary cervical cancer screening in women 25 years and older. This test gives simultaneous results for the presence or absence of HPVs 16 and 18 and for a group of 12 other oncogenic HPV types. This represents a profound paradigm shift in cervical cancer screening, in which Pap testing assumes a secondary role for the triage of HPV positive results.
HPV testing alone is approximately twice as sensitive (>90 percent) as a single Pap test and leads to earlier detection of high-grade neoplasias. The very high negative-predictive value of a single negative HPV test was shown by Sankaranarayanan (2009). During this 8-year study, a single round of HPV testing outperformed cytology, with no cervical cancer deaths within 8 years of a negative HR HPV test result. Recent evaluations show that cotesting does not perform any better than HPV testing alone (Dillner, 2013; Whitlock, 2011). However, specificity declines with HPV testing, particularly in younger women (Mayrand, 2007; Ronco, 2006, 2010). This could lead to excessive numbers of colposcopies, biopsies, and treatments. Triaging women with positive non-HPV16/18 HPV test results to reflex cytology is a viable counterbalance to the decreased specificity. Overall, this strategy is expected to result in more colposcopic referrals but yield higher and earlier HSIL detection rates.
Suggested interim guidelines for primary HPV test screening are recently published and will no doubt be debated and revised in coming years (Huh, 2015). These propose that screening with a HR HPV test can be used as an alternative to cytology alone or cotesting in women 25 years and older and at intervals no less than 3 years. Immediate colposcopy is recommended if HPV 16/18 is identified. If other HR HPV types are found, then triage to reflex cytology is proposed. Colposcopy is recommended for any cytologic abnormality. Importantly, as of mid-2015, major cervical cancer screening guidelines do not include this screening option.
Cervical Cancer Screening Guidelines
Perspective on Guidelines
Notably, all approved cervical cancer screening strategies, including the use of periodic cytology alone, dramatically reduce a woman’s lifetime risk of developing or dying from cervical cancer. Since most women with positive HR HPV test results will not develop significant disease, the choice of screening strategy should be a shared decision by the provider and individual patient. Reviewed by the National Cancer Institute (2015a), the balance of benefits and harms of each screening strategy warrants careful consideration by both health care providers and health care policy agencies. With that perspective, guidelines are subsequently presented.
Evidence-based cervical cancer screening guidelines continue to evolve. In 2012, all major professional societies updated these. The American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology (ACS/ASCCP/ACP) jointly issued guidelines (Saslow, 2012). The U.S. Preventive Services Task Force (USPSTF) (Moyer, 2012) and the American College of Obstetricians and Gynecologists (2012b) each published guidelines as well. These three sets of guidelines agree with few exceptions and pertain only to average-risk women, that is, immunocompetent women with no history of HSIL or cervical cancer. All agree on the acceptability of both conventional and liquid-based Paps, the age of initiation and cessation of screening, screening intervals, and continued screening after HPV vaccination. Adherence to current guidelines should not preclude or delay other indicated gynecologic care. In particular, provision of contraception is never contingent on compliance with cervical cancer screening recommendations or the evaluation of cytologic abnormalities.
Cervical cancer screening ideally begins at age 21 in average-risk women. This is true regardless of sexual history, sexual orientation, or other risks. In young women, most Pap abnormalities represent transient HPV infection, and the spontaneous regression of even high-grade lesions is common (Moscicki, 2005). Most high-grade lesions are CIN 2 rather than CIN 3 in young women (Moscicki, 2008). Cervical cancer is exceedingly rare in adolescents and not as preventable by screening as for older women (Saslow, 2012). Additionally, treatment of high-grade CIN in adolescents is often followed by persistence of Pap abnormalities, and theoretically may have adverse reproductive consequences (Case, 2006; Moore, 2007).
Whether to begin screening earlier in the presence of significant immune compromise, as with HIV infection, use of immunosuppressive medications, and organ transplantation, is uncertain and not addressed by current guidelines. The Centers for Disease Control and Prevention (CDC) (2015) recommends initiation of screening soon after HIV diagnosis, even if before age 21, and repeat Pap testing in 6 months. As for other such conditions, clinician judgment is exercised, taking into consideration age and severity of immune compromise. In general, initial screening at age 21 seems reasonable (American College of Obstetricians and Gynecologists, 2012a).
Screening Interval and Strategy
Between ages 21 and 29, all guidelines recommend screening with cytology alone at 3-year intervals. Women aged 30 to 65 can continue screening with cytology alone at 3-year intervals or can begin cotesting at 5-year intervals. The risk of cancer is approximately the same using either strategy. USPSTF sees both strategies as equally effective, and cotesting is available to women wishing to extend their screening interval. However, both the ACS/ASCCP/ACP (Saslow, 2012) and American College of Obstetricians and Gynecologists (2012b) have deemed cotesting the preferred screening strategy in women 30 years and older. Women with HIV infection and other immune suppression should receive annual cytology screening (Centers for Disease Control and Prevention, 2015; American College of Obstetricians and Gynecologists, 2012a).
Screening may be stopped in women older than 65 if they have an average risk for cervical cancer and have undergone adequate screening, regardless of sexual history. Adequate screening is three consecutive, negative Pap results or two consecutive, negative cotest results in the prior 10 years, with the most recent within the past 5 years. Women with prior treatment for CIN 2, CIN 3, AIS, or cervical cancer should continue routine screening for at least 20 years, as they remain at increased long-term risk of cervical cancer (Saslow, 2012; Strander, 2007). It is uncertain when HIV-positive women can discontinue screening or whether this should continue annually and indefinitely for as long as there is reasonable life expectancy.
Vaginal cancers are rare and account for less than 2 percent of cancers in women. All guidelines recommend against Pap screening in women who have undergone total hysterectomy for benign disease if there is no past history of high-grade CIN or cervical cancer. The absence of a cervix should be confirmed by examination or pathology report as many women are inaccurate in their reporting of hysterectomy type. Women who have undergone supracervical hysterectomy should continue routine screening. Recommendations for vaginal cytology after hysterectomy in women with histories of high-grade cervical neoplasia or cancer are less clear, as vaginal cancer is still rare, and screening is of uncertain benefit (Saslow, 2012). The American College of Obstetricians and Gynecologists (2012b) recommends cytology of the vaginal cuff every 3 years for 20 years after the initial posttreatment surveillance, which is generally a schedule of three Pap tests in the first 2 years posthysterectomy. HPV testing is not FDA-approved in the absence of a cervix but remains common. Evidence-based recommendations for managing vaginal HPV test results are nonexistent (Chappell, 2010). Such testing should be avoided.
Cervical cytology reporting is standardized by the Bethesda System nomenclature (National Cancer Institute Workshop, 1989; Nayar, 2015; Solomon, 2002). Clinically, the key elements reported are specimen adequacy and epithelial cell abnormalities (Tables 29-3 and 29-4). An overview of evidence-based guidelines for the initial management of cervical cytology abnormalities for nonpregnant women follows in the next paragraphs (American College of Obstetricians and Gynecologists, 2013; Massad, 2013). Full guidelines should be reviewed and applied on an individualized basis. Guidelines cannot address all clinical situations or prevent all cervical cancers.
TABLE 29-3The 2014 Bethesda System Cytology Report Components ||Download (.pdf) TABLE 29-3 The 2014 Bethesda System Cytology Report Components
| Specimen type |
Conventional (Pap smear)
Liquid-based (Pap test)
|Specimen adequacy |
|General categorization (optional) |
Negative for intraepithelial lesion or malignancy
Epithelial cell abnormality (see Table 29-4)
Other (see Interpretation/Results)
Negative for intraepithelial lesion or malignancy
Epithelial cell abnormalities (see Table 29-4)
Nonneoplastic findings (optional)
Cellular variations (atrophy, keratosis, metaplasia)
Reactive cellular changes (inflammation, repair, radiation)
Glandular cells status posthysterectomy
Fungal organisms consistent with Candida spp
Shift in flora suggestive of bacterial vaginosis
Cellular changes consistent with herpes simplex virus
Cellular changes consistent with cytomegalovirus
Bacteria consistent with Actinomyces spp
Other nonneoplastic findings (optional)
|Adjunctive testing |
|Computer-assisted interpretation |
|Educational notes and comments (optional) |
TABLE 29-4The 2014 Bethesda System: Epithelial Cell Abnormalities ||Download (.pdf) TABLE 29-4 The 2014 Bethesda System: Epithelial Cell Abnormalities
| Squamous cell |
|Atypical squamous cells (ASC): of undetermined significance (ASC-US) cannot exclude HSIL (ASC-H) |
|Low-grade squamous intraepithelial lesion (LSIL) |
|High-grade squamous intraepithelial lesion (HSIL) |
|Squamous cell carcinoma |
| Glandular cell |
|Atypical glandular cells (AGC): |
| Endocervical, endometrial, or not otherwise specified |
|Atypical glandular cells, favor neoplastic: |
| Endocervical or not otherwise specified |
|Endocervical adenocarcinoma in situ (AIS) |
This is reported as satisfactory or unsatisfactory for evaluation and is based primarily on criteria for slide cellularity and the presence of obscuring blood or inflammation. The presence or absence of TZ components, that is, endocervical and/or squamous metaplastic cells, is also reported. A TZ component is not required for test adequacy. Although its presence is associated with increased detection of cytologic abnormalities, its absence is not associated with failure to diagnose CIN. Pap tests lacking TZ components are repeated in 3 years. For women 30 years and older, HPV testing is preferred and further testing is guided by results.
Unsatisfactory Pap tests are unreliable for the detection of cervical neoplasia and also for HR HPV by some HPV tests. Unsatisfactory Pap tests are repeated in 2 to 4 months. If atrophy or a specific infection is present, treatment before repeat cytology may be helpful. If the result is unsatisfactory again, colposcopy is recommended as this persistent result confers increased CIN risk. Rarely, obscuring blood or inflammation on cervical cytology may indicate invasive cancer. Therefore, unexplained vaginal discharge, abnormal bleeding, or abnormal physical findings should prompt immediate evaluation rather than waiting for repeat Pap testing.
Epithelial Cell Abnormality Management
A cytology report is a medical consultation that interprets a screening test and does not provide a diagnosis. A final diagnosis is determined clinically, often with results from histologic evaluation. Pap tests are interpreted as either being negative for intraepithelial lesion or malignancy (NILM) or demonstrating one or more epithelial cell abnormalities.
Atypical Squamous Cells of Undetermined Significance
The most common cytologic abnormality is ASC-US. This term indicates cells that suggest SIL but do not fulfill all the criteria. An ASC-US result often precedes the diagnosis of CIN 2 or 3, but this risk approximates only 5 to 10 percent. Cancer is found in only 1 to 2 per thousand (Solomon, 2002).
Management of ASC-US without HPV cotesting is repeat cytology in 1 year, and this is preferred for women aged 21 to 24. If the repeat Pap test result is abnormal, colposcopy is recommended. Reflex HPV testing is preferred in women 25 years and older and acceptable in those age 21 to 24 years. Reflex testing refers to HPV testing in response to a specific result and is not performed if cytology is negative. With an ASC-US Pap result, reflex HPV testing is a good discriminator of those with high-grade CIN and those without. ASC-US, HPV-positive test results have a risk profile similar to LSIL results and thus are evaluated with colposcopy. ASC-US, HPV-negative results are followed up with a cotest in 3 years or with cytology alone in women under age 25.
Low-grade Squamous Intraepithelial Lesion
LSIL encompasses the cytologic features of HPV infection and CIN 1 but carries a 15 to 30 percent risk of CIN 2 or 3, similar to ASC-US, HPV-positive. Therefore, colposcopy is generally indicated for LSIL cytology.
Specifically, for LSIL with no HPV testing or with HPV-positive results, colposcopy is indicated in women aged 25 years and older. If a negative HPV test result is obtained due to cotesting, a repeat cotest in 1 year is preferred, but colposcopy is acceptable. Reflex HPV testing with an LSIL result is not useful in reproductive-aged women, as 75 to 85 percent will test positive for HR HPV. In women aged 21 to 24 years with an LSIL result, cytology follow-up is preferred to immediate colposcopy due to high rates of resolution. For postmenopausal women with LSIL and no HPV cotest, options include repeat cytology at 6 and 12 months, HPV testing, or colposcopy.
Atypical Squamous Cells, Cannot Exclude HSIL
Five to 10 percent of ASC is designated as atypical squamous cells, cannot exclude HSIL (ASC-H). This finding should not be confused with ASC-US. ASC-H describes cellular changes that do not fulfill criteria for HSIL cytology, but a high-grade lesion cannot be excluded. Histologic HSIL is found in upward of 25 percent of these cases, which is a higher rate than seen with ASC-US or LSIL. Thus, colposcopy is indicated regardless of age or concurrent HPV test result. Reflex HPV testing is not helpful due to a high rate of HPV-positivity. If colposcopy is inadequate, a diagnostic excision procedure is recommended.
High-grade Squamous Intraepithelial Lesion
HSIL cytology encompasses features of CIN 2 and CIN 3 (Fig. 29-9). It carries an elevated risk of underlying histologic HSIL (at least 70 percent) or invasive cancer (1 to 2 percent) (Kinney, 1998). Colposcopic evaluation is warranted for all HSIL cytology regardless of age or HPV status. Alternative management of HSIL cytology in women 25 years and older includes immediate loop electrosurgical excision procedure (LEEP), which is referred to as a see-and-LEEP approach. This strategy is reasonable because colposcopy may miss a high-grade lesion, and most HSIL cytologies eventually result in excision for diagnosis or treatment. Inadequate colposcopy should prompt excision unless initial biopsies show invasive cancer.
A. Normal Pap test. A fragment of benign endocervical epithelium with the characteristic “honeycomb” appearance conferred by the presence of cytoplasmic mucin is seen (arrow). Benign parabasal, intermediate, and superficial squamous cells are present in the background. B. Pap test reflecting high-grade squamous intraepithelial lesion. The dysplastic squamous cells have nuclear membrane irregularities and coarse chromatin. The increased nuclear to cytoplasmic size ratio would classify this as a moderate squamous dysplasia (CIN 2). (Used with permission from Ann Marie West, MBA, CT[ASCP].)
Glandular Cell Abnormalities
This group includes atypical glandular cells (AGC); AGC, favor neoplasia; and AIS. This category carries an increased risk of neoplasia (Zhao, 2009). Paradoxically, squamous neoplasia is more frequently diagnosed than glandular neoplasia upon evaluation of AGC cytology (Schnatz, 2006). There is also an elevated risk of endometrial and other reproductive tract cancers and cancers at other sites such as breast and colon. Approximately half of the neoplasia diagnosed subsequent to an AGC Pap is endometrial.
Accordingly, initial evaluation of a glandular abnormality includes colposcopy and endocervical sampling. It also includes endometrial sampling in patients 35 years and older or in younger women with risk factors for endometrial disease, which include abnormal bleeding or history suggesting chronic anovulation. If atypical endometrial cells are specified in the report, then initial endometrial and endocervical sampling is acceptable with subsequent colposcopy if these are negative.
Reflex HPV testing is not recommended for the triage of glandular cytologic abnormalities. Indeed, a negative reflex HPV test result may dissuade appropriate evaluation of AGC cytology. However, HPV testing at the initial evaluation of AGC may help distinguish cervical from endometrial disease (Castle, 2010; de Oliveira, 2006).
If initial evaluation of glandular cytologic abnormalities is negative, management and surveillance are generally aggressive due to the significant risk of occult disease. Current guidelines should be followed (American College of Obstetricians and Gynecologists, 2013; Massad, 2013). Diagnostic excision is indicated following AGC, favor neoplasia and AIS Paps if initial evaluation does not result in a cancer diagnosis.
Cytologies suspicious for squamous cell carcinoma or adenocarcinoma carry the highest risk of invasive cancer and are evaluated promptly. If initial evaluation fails to reveal invasive cancer, a diagnostic excision procedure is indicated.
Pregnant patients 21 years and older are screened and their abnormal cytologies managed according to guidelines for the general population. However, deferred evaluation of ASC-US and LSIL cytologies until at least 6 weeks postpartum is acceptable (Massad, 2013). When indicated, the goal of colposcopy is to exclude invasive cancer. Colposcopy and ectocervical biopsy are safe and accurate during pregnancy (Economos, 1993). Endocervical and endometrial sampling are not performed during pregnancy to avoid amnionic membrane rupture and infection. Preinvasive neoplasia is not treated but rather is reevaluated postpartum. This is because lesion progression is typically slow and lesion grade may change during delivery and puerperal remodeling (Yost, 1999). Although cervical conization is infrequently performed during pregnancy, indications for this are discussed in Chapter 30.
Certain nonneoplastic findings may be reported, and these include findings consistent with, but not conclusively diagnostic of, certain organisms. These findings include Trichomonas vaginalis, Candida species, Actinomyces species, herpes simplex virus, or shift in flora consistent with bacterial vaginosis. Sensitivity is generally limited, and accuracy of diagnosis varies (Fitzhugh, 2008). For this reason, confirmatory tests or clinical correlation should dictate any actions related to these findings. Other nonneoplastic findings are reactive changes associated with inflammation or repair, radiation changes, atrophy, and posthysterectomy benign glandular cells. None of these require a clinical response.
Benign endometrial cells seen in the cervical cytology of a postmenopausal woman confer an increased risk of endometrial hyperplasia and cancer. Because menstrual history and menopausal status are often unknown to the cytologist, benign endometrial cells are reported on cervical cytology for all women 45 years and older (Nayar, 2015). Premenopausal women do not require endometrial evaluation in the absence of abnormal bleeding.
This outpatient procedure examines the lower anogenital tract with a binocular microscope affixed to a stand and requires skills that encompass colposcopic terminology, lesion identification and grading, and biopsy techniques. Its primary goal is to identify invasive or preinvasive neoplastic lesions for directed biopsy and subsequent management. It remains the gold standard evaluation of patients with abnormal cervical cytology. However, its sensitivity, interobserver agreement, and reproducibility are less than previously thought. Sensitivity estimates range between 50 and 80 percent (American College of Obstetricians and Gynecologists, 2013; Ferris, 2005; Jeronimo, 2007). This highlights the need for further evaluation or surveillance when initial colposcopy fails to reveal high-grade neoplasia.
There are many styles of colposcopes, but they all operate similarly. The colposcope contains a stereoscopic lens or digital imaging system that has magnification settings ranging from 3- to 20-fold. Its stand allows positioning, and a high-intensity light provides illumination. A green (red-free) light filter adds contrast to aid vascular pattern evaluations (Fig. 29-10).
Evaluation of surface vessels. A. Benign surface vessels viewed through a colposcope using usual white light source. B. Use of a blue-green (red-free) light filter provides higher contrast and definition of vascular patterns.
Prior to colposcopic examination, a woman’s medical history and record are reviewed and indications for colposcopy confirmed (Table 29-5). Urine pregnancy testing is performed if clinically indicated. Colposcopic examination is optimally timed to avoid menses. However, it is not delayed in the patient with a visible lesion, abnormal bleeding, or poor appointment compliance. In cases of severe cervicitis or other pelvic infection, treatment may be indicated before performing biopsies or endocervical curettage. Notably, abnormal cervical discharge in the absence of an identified pathogen may be a cancer indicator. A Pap test performed at the time of colposcopy is of questionable value, may obscure colposcopic findings, and should be performed on an individualized basis.
TABLE 29-5Clinical Considerations Directing Colposcopy ||Download (.pdf) TABLE 29-5 Clinical Considerations Directing Colposcopy
| Clinical objectives |
Provide a magnified view of LGT
Identify cervical squamocolumnar junction
Detect lesions suspicious for neoplasia
Direct lesion biopsy
Monitor patients with current or past LGT neoplasia
|Clinical indications |
Grossly visible LGT lesion
Abnormal cervical cancer screening
In utero diethylstilbestrol exposure
|Contraindications: none |
|Relative contraindications |
Upper or lower reproductive tract infection
Uncontrolled severe hypertension
Uncooperative or overly anxious patient
Solutions may aid colposcopic examination and are applied by gently dabbing a saturated swab or sponge or by spray-bottle misting so as not to traumatize the cervical epithelium. High-grade cervical lesions are particularly fragile. To begin, normal saline can help remove cervical mucus and allows initial assessment of vascular patterns and surface contours. Abnormal vessels, especially when viewed with green-filtered light, may be more prominent before acetic acid application.
Acetic acid in a 3- to 5-percent solution is a mucolytic agent thought to exert its effect by reversibly clumping nuclear chromatin. This causes neoplastic lesions to assume a thicker density and hues of white depending on the degree of abnormal nuclear density. Applying acetic acid to abnormal epithelium results in the acetowhite change characteristic of neoplastic lesions and of some benign conditions. Several minutes may be needed for this effect to become fully developed.
Dilute Lugol iodine solution stains mature squamous epithelial cells a dark purple-brown color in estrogenized women as a result of high cellular glycogen content. Due to incomplete cellular differentiation, dysplastic cells have lower glycogen content, fail to fully stain, and appear various shades of yellow (Fig. 29-11). This solution is particularly useful when abnormal tissue cannot be found using acetic acid alone. It is also used to define the limits of the active TZ, as immature squamous metaplasia does not stain as strongly as mature (fully differentiated) squamous epithelium. Lugol solution should not be used in patients allergic to iodine, radiographic contrast, or shellfish.
Solutions used for colposcopy. A. Cervix after application of acetic acid. Several areas of acetowhite change adjacent to the squamocolumnar junction are apparent. B. Same cervix after application of Lugol iodine solution. Nonstaining of the lesions at the 10 to 11 o’clock positions is seen (black arrow), while there is partial iodine uptake of acetowhite areas along the posterior SCJ (white arrow).
Two major components of colposcopic examination are general assessment and specific colposcopic findings. Careful description of these aids diagnosis and management of abnormalities. For this, standard colposcopic terminology used in the United States differs somewhat from that proposed by the International Federation for Cervical Pathology and Colposcopy (IFCPC) (Bornstein, 2012).
General colposcopic assessment has three components: cervical visualization, SCJ visibility, and TZ classification. First, every examination is characterized by whether the cervix is fully seen or whether the evaluation is limited by inflammation, bleeding, scarring, or other obscuring causes. The IFCPC labels full cervix visualization as “adequate” and otherwise as “inadequate.” However, current guidelines for management of abnormal cervical cytology and precancers issued by the ASCCP and standard U.S. practice reserve these descriptors for visibility of the SCJ and any lesions present (Massad, 2013).
Second, SCJ visibility is important, as nearly all cervical neoplasia is located within the TZ and at or adjacent to the SCJ. Within a neoplastic lesion, the most severe disease tends to be at the proximal (cephalad or upper) limit of the lesion. Therefore, the ability to see the entire SCJ and the upper limits of all lesions is essential to exclude invasive cancer and to determine disease severity. The IFCPC terminology characterizes the SCJ separately as completely, partially, or not visible. Current ASCCP guidelines define full visualization of both the SCJ and upper limits of all lesions present as “adequate.” Otherwise, the examination is “inadequate” (Fig. 29-12). Finally, the IFCPC classifies the TZ location as types 1, 2, or 3. A type 1 TZ is entirely ectocervical and visible; a type 2 has an endocervical component that is fully visible; and a type 3 TZ has an endocervical component that cannot be completely visualized. Types 2 and 3 may have ectocervical TZ components of varying extent. If treatment is indicated, the size and location of the SCJ, TZ, and visible lesions are important determinants of the modality chosen.
In colposcopic cases in which the squamocolumnar junction is initially inadequately seen, an endocervical speculum can aid in viewing the endocervical canal.
Colposcopically, normal squamous epithelium of the cervix appears as a featureless, smooth, pale-pink surface. Blood vessels lie below this layer and therefore are not visible or are seen only as a fine capillary network. The mucin-secreting columnar epithelium appears red due to its thinness and the close proximity of blood vessels to the surface. It has a polypoid appearance due to infoldings that form peaks and clefts (see Fig. 29-3). Against this normal colposcopic landscape, colposcopists discern abnormal tissue and choose for biopsy the sites most likely to harbor the most severe neoplasia. Several colposcopic grading systems quantify lesion qualities to improve diagnostic accuracy (Coppleson, 1993; Reid, 1985). Best known, the Reid Colposcopic Index is based on four lesion features, which are margin, color, vascular pattern, and Lugol solution staining. Each category is scored from 0 to 2, and the summation provides a numeric index that correlates with histology (Table 29-6).
TABLE 29-6Reid Colposcopic Index ||Download (.pdf) TABLE 29-6 Reid Colposcopic Index
|Colposcopic Sign ||Zero Points ||1 Point ||2 Points |
|Margin ||Condylomatous ||Smooth ||Rolled |
| ||Micropapillary ||Straight ||Peeling |
| ||Feathery || ||Internal border |
| ||Satellite lesions || || |
|Color: acetowhitening ||Shiny ||Duller white ||Dull white |
| ||Snowy || ||Gray |
| ||Translucent || || |
| ||Transient || || |
|Vessels ||Fine patterns ||Absent ||Coarse patterns |
| ||Uniform caliber and patterns || ||Dilated with variable caliber and intercapillary distances |
|Iodine staining ||Positive ||Partial ||Negative |
The IFCPC has proposed a standardized nomenclature for lesion grading and recommends that it replace prior terminologies (Bornstein, 2012). Lesions with low-grade characteristics are labeled grade 1 (minor) lesions, whereas higher-grade characteristics are grade 2 (major) findings.
Of Reid index features, lesion margins and color are best assessed following application of acetic acid. The color or degree of whiteness obtained, rapidity and duration of acetowhitening, and sharpness of lesion borders are observed. Grade 2 (major or high-grade) lesions demonstrate a more persistent, duller shade of white, whereas grade 1 (minor or low-grade) lesions are translucent or bright white and fade quickly. Generally, grade 1 lesions have feathery or irregular “geographic” margins, whereas grade 2 lesions have straighter, sharper outlines (Figs. 29-13 and 29-14). Other lesion features suggestive of a high-grade lesions are: internal borders (inner border sign), an opaque protuberance within a lesion (ridge sign), and cuffed crypt openings.
Low-grade squamous intraepithelial lesion (LSIL). After 5-percent acetic acid application, LSIL is often multifocal and bright white with irregular borders.
High-grade squamous intraepithelial lesion (HSIL). After 5-percent acetic acid application, HSIL demonstrates off-white dull color and coarse vascular pattern.
Abnormal vascular patterns include punctation, mosaicism, and atypical vessels. Punctate and mosaic patterns are graded on the basis of vessel caliber, intercapillary distance, and the uniformity of each of these. Fine punctation and mosaicism, which are created by narrow vessels and short, uniform intercapillary distances, typify low-grade (grade 1) lesions. A coarse pattern results from wider and more variable vessel diameters and spacing and indicates high-grade (grade 2) abnormalities. Atypical vessels are irregular in caliber, shape, course, and arrangement and raise suspicion for invasive cancer (Fig. 29-15).
Colposcopy shows a large high-grade lesion with cuffed crypt openings (arrow) and atypical vessels (arrowheads) that are worrisome for invasive cancer.
Under direct colposcopic visualization, suspicious lesions are biopsied using cervical biopsy forceps (Fig. 29-16). Generally, cervical biopsy does not require an anesthetic. Thickened Monsel solution (ferric subsulfate) or a silver nitrate applicator are applied with pressure to the biopsy site, providing hemostasis if needed. Heavier bleeding is rare and can be controlled with direct pressure or brief vaginal packing.
Tools used for cervical evaluation and biopsy. From top to bottom: endocervical curette, endocervical speculum, and cervical biopsy forceps.
Traditionally, biopsies have been limited to the most severe-appearing lesions. However, two studies have shown that colposcopically directed biopsy detects only 60 to 70 percent of high-grade disease. Disease detection rates increase with the addition of random biopsies of normal-appearing epithelium and with the total number of biopsies taken (Gage, 2006; Pretorius, 2004; Zuchna, 2010)). The American College of Obstetricians and Gynecologists (2013) recommends biopsy of all acetowhite lesions regardless of colposcopic impression, and repeat colposcopic evaluation is suggested for persistent low-grade cytologic abnormalities or HPV-positive results to counter the imperfect detection of HSIL by colposcopy.
For nonpregnant patients, endocervical sampling by curettage or brushing evaluates the endocervical canal epithelium that lies beyond the colposcope’s view. Endocervical sampling is currently recommended during colposcopy in the following situations (American College of Obstetricians and Gynecologists, 2013; Massad, 2013):
Colposcopy is inadequate, or colposcopy is adequate but no lesion is identified. Endocervical sampling is acceptable in other cases at provider discretion.
Initial evaluation of ASC-H, HSIL, AGC, or AIS cytology test results.
Surveillance 4 to 6 months after excisional therapy if specimen margins are positive for HSIL.
Surveillance after conization for AIS has been performed in women wishing fertility preservation. Negative endocervical curettage results add reassurance to this management (Schorge, 2003).
Endocervical sampling can be performed by either curettage or brushing. Endocervical curettage is performed by introducing an endocervical curette 1 to 2 cm into the cervical canal (see Fig. 29-16). The length and circumference of the canal is firmly curetted, carefully avoiding sampling of the ectocervix or the lower uterine segment. Endocervical scrapings admixed with cervical mucus are then removed using a ring forceps or cytobrush and included with the curettage specimen. Alternatively, vigorous brushing with a cytobrush may be used to obtain an endocervical tissue specimen. Endocervical brushing is more sensitive than curettage, but grading of any dysplasia present is more difficult. Endocervical sampling is often the most uncomfortable part of a colposcopic evaluation, and cramping is common.
Vaginoscopy showing multifocal acetowhite human papillomavirus (HPV) lesions after application of 5-percent acetic acid.