Approach to The Patient With an Abnormal Pap Smear Part 1

Cervical cancer is the third most common gynecologic cancer in the United States. An estimated 10,370 new cases of invasive cervical cancer and 3,710 deaths occur annually, representing 1.4% of cancer deaths in women.1 In the United States, the incidence of cervical cancer decreased by more than 70% between 1950 and 2000, largely as a result of screening2; more than half of the incident cases of invasive cancer are diagnosed in women who have not been adequately screened. Screening cytology methods, such as the Papanicolaou (Pap) smear, are excellent means of identifying preinvasive disease; however, false positive rates are relatively high. Each year, approximately 3.5 million cervical cytologic tests are interpreted as indicating an abnormality requiring additional follow-up or evaluation.3

Epidemiology and Risk Factors for Cervical Cancer

The occurrence of invasive cervical cancer is related to age. Premalignant cervical lesions are usually diagnosed in women younger than 40 years, which is 10 to 15 years earlier than in women diagnosed with invasive cervical cancer. This age gap suggests a long latency period for malignant transformation. For example, the diagnosis of cervical intraepithelial neoplasia (CIN) is usually made in women in their twenties, whereas the diagnosis of carcinoma in situ (CIS) is made in women 25 to 35 years of age, and invasive cancer is diagnosed in women older than 40 years.

Infection with high-risk strains of human papillomavirus (HPV) is the most important risk factor for cervical cancer.4,5 HPV infection is usually transient6,7; however, persistent infection by high-risk HPV virus—most commonly, subtypes 16, 18, 31, and 45—is a prerequisite for the development of grade 1 and 2 CIN and invasive cervical cancer.8

HPV is usually acquired sexually; high-risk sexual behavior (e.g., having multiple sexual partners and promiscuous sexual partners) increases the risk for exposure to the virus.9 HPV is a necessary precursor of CIN, but it does not act alone; host factors such as age, immune function,10 a history of sexually transmitted disease (e.g., Chlamydia trachomatis),11 and smoking12 are surrogate markers for oncogenesis.

Natural History of Cervical Cancer

Early invasive cervical cancer is frequently asymptomatic, a fact that underscores the importance of routine screening. An abnormal Pap smear is frequently the first indication of a precan-cerous condition. The abnormalities observed on a cytologic smear or tissue biopsy of the cervix represent alterations in the degree of differentiation of cervical epithelial cells. An understanding of the natural history of low-grade and high-grade CIN lesions is central to the clinical management of patients who have abnormal cervical cytology.

CIN is a preinvasive pathologic intermediate of cervical cancer; it is slow to progress and can be easily detected and treated.

The severity of CIN is designated by the extent to which the lesion involves the epithelial thickness. CIN 1 refers to intraepithe-lial neoplasia in which cellular changes are confined to the basal third of the epithelium; CIN 2 refers to intraepithelial neoplasia in which cellular changes are confined to the basal two thirds of the epithelium; and CIN 3 refers to cellular dysplasia encompassing more than two thirds of the epithelial thickness, including full-thickness lesions. CIS demonstrates full-thickness evidence of neoplasia without invasion of the basement membrane; CIN 3 and CIS may persist unchanged for 10 to 15 years, but eventually the lesion progresses to invasive carcinoma.

Low-grade lesions do not necessarily progress to high-grade lesions. A large cohort study indicated that CIN 1 lesions regressed to normal within 2 years in 44% of patients; they regressed to normal within 5 years in 74% of patients.13 This series noted that the rates of progression of CIN 1 at 2 and 5 years were 2% and 6%, respectively; rates of progression of CIN 2 were 16% and 25%, respectively.

A primary goal of cervical cytologic screening is to identify women at risk for high-grade lesions; however, cytologic results are often equivocal. To improve the accuracy of cytologic interpretation, a standard system of terminology was adopted to distinguish findings most likely to be precancerous [see Test Interpretation—the Bethesda Reporting System, below]. Essentially, this reporting system classified a broad range of atypical findings into two categories: those findings that were more likely to represent high-risk lesions and those whose significance was undetermined.

Screening for Cervical Cancer

Who should be screened?

Abundant evidence indicates that regular gynecologic examinations and cervical cytology decrease cervical cancer incidence and mortality. However, among policy-making organizations, there is some variation in the recommendations concerning the age at which screening should start, the interval of screening, and the age at which routine screening should stop.

Commencement of Screening

The United States Preventive Services Task Force (USPSTF) recommends beginning cytologic screening within 3 years of onset of sexual activity or by age 21, whichever comes first.14 The recommendations of the American College of Obstetricians and Gynecologists (ACOG)15 and the American Cancer Society (ACS)16 are consistent with these guidelines. Other North American organizations, such as the Canadian Task Force on Preventive Health Care (CTFPHC), recommend that screening begin at onset of sexual activity or at 18 years of age.17

There is little value in screening women who have never been sexually active; however, many North American organizations recommend routine screening by age 18 or 21 on the basis of the generally high prevalence of sexual activity by that age and concerns that clinicans may not always obtain accurate sexual histories.

Table 1 The 2001 Bethesda System (Abridged)29

Specimen adequacy

Satisfactory for evaluation (note presence or absence of endo-cervical/transformation zone component)

Unsatisfactory for evaluation (specify reason)

Specimen rejected/not processed (specify reason)

Specimen processed and examined but unsatisfactory for evaluation of epithelial abnormality because of (specify reason)

General categorization (optional)

Negative for intraepithelial lesion or malignancy

Epithelial cell abnormality



Negative for intraepithelial lesion or malignancy


Trichomonas vaginalis

Fungal organisms morphologically consistent with Candida species

Shift in flora suggestive of bacterial vaginosis

Bacteria morphologically consistent with Actinomyces species

Cellular changes consistent with herpes simplex virus

Other non-neoplastic findings (optional to report; list not comprehensive)

Reactive cellular changes associated with the following:

Inflammation (includes typical repair)


Intrauterine contraceptive device

Glandular cells status post hysterectomy


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) (cellular changes consistent with HPV, mild dys-plasia, CIN 1)

High-grade squamous intraepithelial lesion (HSIL) (moderate to severe dysplasia, CIN 2, CIN 3, CIS)

(indicate if there are features suspicious of invasion)

Squamous cell carcinoma

Glandular cell

Atypical glandular cells (specify endocervical, endome-trial, or not otherwise specified)

Atypical glandular cells, favor neoplastic (specify endocervicalor or not otherwise specified)

Endocervical adenocarcinoma in situ (AIS)


Other (list not comprehensive)

Endometrial cells in a women > 40 years

CIN—cervical intraepithelial neoplasia

CIS—carcinoma in situ

Screening Interval

Because cervical cancer is slow growing, considerable uncertainty surrounds the issue of the screening interval. The USPSTF found no direct evidence that annual screening achieves better outcomes than screening every 3 years. The most direct evidence on which to base a recommendation of a screening interval comes from a prospective cohort analysis of a randomized controlled trial.18 Among 2,561 women (mean age, 66.7 years) with normal Pap tests at baseline, 110 had an abnormal Pap test within the next 2 years. No woman was found to have CIN 2, CIN 3, or invasive cancer; only one woman had CIN 1 or CIN 2. Thus, the positive predictive value of screening 1 year after a negative Pap test was 0%; after 2 years, the positive predictive value was 0.9%. The authors concluded that Pap tests should not be repeated within 2 years after a negative test. A large study of women younger than 65 years, which included data from the National Breast and Cervical Cancer Early Detection Program and which used a model to estimate the rate at which intraepithelial neopla-sia progresses to cancer, found that little further mortality reduction from cervical cancer was achieved by screening every year as compared with every 3 years.19

On the basis of the limited evidence, the USPSTF recommends screening at least every 3 years. The ACS guidelines recommend waiting until age 30 before lengthening the screening interval from 1 to 3 years. The ACOG recommends initiating screening with annual smears for 2 or 3 years; if these are negative, intervals of up to 3 years may be appropriate.20 The ACOG identifies additional risk factors that might justify annual screening, including a history of cervical neoplasia, infection with HPV or other sexually transmitted diseases, or high-risk sexual behavior; however, data by which to determine the benefits of these strategies are limited.20

Cessation of Screening

The USPSTF recommendations state that screening can be discontinued in women who have had a total hysterectomy for benign disease (i.e., disease in which there is no evidence of cervical neoplasia or cancer), given the low yield of screening and the potential harms from false positive results in this popula-tion.18 In women with a cervix, the optimal age to discontinue screening is not clear, but the risk of cervical cancer and the yield of screening decline steadily through middle age. However, screening is recommended in older women who have not been previously screened or when information about previous screening is unavailable.14

The USPSTF recommends discontinuing routine screening for women older than 65 years who have had adequate recent screening with normal Pap smears and are not otherwise at high risk for cervical cancer.18 The ACS guidelines recommend that screening can be safely stopped in older women who have had three or more documented, consecutive, technically satisfactory, normal cervical cytologic tests and who have had no abnormal cytologic tests within the past 10 years; routine screening may be discontinued at age 70.16

Available tests

There are several methods for cervical cancer screening: the conventional cytologic Pap smear, the liquid-based Pap smear, and HPV DNA testing in combination with cervical cytology. The purpose of these tests is to screen for cellular abnormalities that are associated with an increased risk of the development of cervical cancer.

Conventional Cytology (Pap Smear)

The Pap smear is the standard screening test for genital tract neoplasia. The reported sensitivity of a single Pap smear varies widely, ranging from 32% to 92%.21 This low sensitivity prompted the recommendation found in early guidelines that cytologic screening be made annually.22 False negative rates have been attributed to poor sample preparation, in which precursor cells were obscured by blood, pus, air-drying artifacts, and other cells.23 A conventional Pap smear costs $25 to $40.

Liquid-Based Cervical Cytology

Liquid-based cytology offers higher sensitivity and comparable specificity to that of the conventional Pap smear.24 The liquid-based test costs $45 to $60. If used at 3-year intervals, the liquid-based test is cost-effective.25 Evidence-based reports show that both liquid-based and conventional cytology are acceptable screening tests.26 One advantage of liquid-based cytology is that HPV testing can be performed on the same preparation (see below).

Cytology and HPV DNA Testing

HPV DNA testing in combination with conventional or liquid-based cytology has been approved by the Food and Drug Administration for primary screening for cervical cancer in women older than 30 years.27 In this age group, the combination of cytology and HPV DNA testing has been reported to have a sensitivity approximately 10% to 20% greater than that of a single conventional cytologic smear; however, specificity is lower.28 Because of the high negative predictive value of these combined tests, women who test negative on both the cytologic and HPV DNA testing can increase their screening interval to 3 years.27

Test interpretation—the bethesda reporting system

The most common abnormal cervical cytologic result is one of uncertainty. Interpretation of equivocal cytologic findings is complicated by confusion among laboratories and clinicians concerning the use of multiple classification systems and inconsistently defined numerical grading conventions. The Bethesda System, which was introduced in 1988 and is periodically updated (most recently in 2001), was devised as a uniform system of terminology to guide the interpretation of cytologic findings. A significant contribution of the Bethesda System was the standardized laboratory report that includes a description of specimen adequacy (to improve the consistency and quality of reporting) and that uses simplified terminology for the interpretation of equivocal cytologic findings [see Table 1].

Specimen Adequacy

The 2001 update of the Bethesda System qualifies specimens as being either satisfactory or unsatisfactory for evaluation.29 Minimal squamous cellularity varies with the specimen type: an estimated 8,000 to 12,000 well-visualized squamous cells are acceptable for conventional smears, and 5,000 squamous cells are acceptable for liquid-based preparations. Epithelial cells may be obscured by blood or inflammation and still be considered satisfactory; however, if more than 75% of epithelial cells are obscured, the specimen is unsatisfactory. For specimens containing adequate squamous cellularity, the cytologic report notes the presence or absence of an endocervical/transformation zone component. Adequate endocervical cellularity consists of at least 10 well-preserved endocervical or squamous metaplastic cells.

Interpretaton of Specimen

The Bethesda System stipulates that cervical cytology is primarily a screening test, and the interpretation of morphologic findings described by the cytologic report must be integrated into a clinical context to establish a diagnosis.

Specimens are broadly defined as negative for intraepithelial lesion or malignancy or positive for epithelial cell abnormality.

Epithelial abnormalities include atypical squamous cells, low-and high-grade squamous intraepithelial lesions (LSIL and HSIL), and atypical glandular cells (AGC). A finding of atypical squamous cells that cannot be determined as precancerous is the most common result, and its correct interpretation poses a clinical challenge.

Atypical squamous cells The 2001 Bethesda System qualified a finding of atypical squamous cells (ASC) in two ways: (1) ASC of undetermined significance (ASC-US) and (2) ASC for which HSIL cannot be excluded (ASC-H) [see Table 1]. A finding of undetermined significance emphasizes that some cases of ASC-US are associated with underlying CIN 2,3. ASC-H is used when there are cytologic features suggestive of HSIL but definite evidence is lacking. The ASC-H category constitutes approximately 5% to 10% of all ASC, but it includes women at greatest risk for CIN 2,3.30,31 HSIL is more often associated with viral persistence and higher risk of progression, whereas LSIL is generally the result of a transient infection of HPV.32,33

Squamous epithelial lesions The Bethesda System classifies squamous intraepithelial lesions as low-grade (LSIL) or high-grade (HSIL). Cellular changes consistent with HPV, mild dysplasia, and CIN 1 are combined within the category of LSIL. Moderate to severe dysplasia, CIN 2, CIN 3, and CIS are combined within the category of HSIL. In the Bethesda System, CIN and dysplasia terminology can be used either as substitute terms for squamous intraepithelial lesions or as additional descriptors of intraepithelial lesions.

Atypical glandular cells The Bethesda System classifies glandular cell abnormalities into three types: atypical endocervi-cal cells, endometrial cells, and glandular cells. In the majority of cases, morphologic features permit differentiation between atypical endometrial and endocervical cells. The management of patients with glandular abnormalities may vary significantly, depending on cell type, and distinguishing between these cell types is justified, when possible. The Bethesda System distinguishes AGC (either endocervical, endometrial, or AGC that are not otherwise specified [AGC-NOS]) from AGC (either endocer-vical or AGC-NOS) that favor neoplasia, because these two categories are associated with different degrees of risk of significant disease. Biopsy-confirmed high-grade lesions, including CIN 2,3, adenocarcinoma in situ, and invasive cancer, have been found in 9% to 41% of women who have AGC-NOS, as compared with 27% to 96% of those who have AGC that favors neoplasia.

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