Management of abnormal Papanicolaou smears: A review

HONORABLE MENTfON PAPER

MANAGEMENT OF ABNORMAL PAPANICOLAOU SMEARS: A REVIEW

Sheetal G. Kanar, MD

ELSEVIER

Cytologic cervical screening has led to a dramatic reduction in the incidence of and death rates from cervical cancer. The new system of classification of Papanicolaou smears was introduced in 1991. The revised version of the Bethesda System combines human papiilomavirus (HPV) and cervical intraepithelial neoplasia Ilmild atypia into low-grade squamous intraepithelial lesion (LGSIL); and moderate dysplasia, severe dysplasia, and carcinoma in situ into high-grade squamous intraepithelial lesion. An additional classifcation, Atypical Squamous Cells of Undetermined Significance (ASCUS) has also been created. Controversy still persists regarding the evaluation and management of patients with atypical squamous cells of undetermined significance (ASCUS) and LGSIL. The majority of women with mild atypia on one Papanicolaou smear will have complete cytologic and colposcopic regression over a short interval. However, studies show that up to 16% of these lesions progress, and therefore diligent follow up is essential. The rate of colposcopically detected lesions that are more advanced than mild atypia is 10-30‘S in women with mild dysplasia on Papanicolaou smear. In the United Kingdom, a decision analysis model was used to determine whether mild dysplasia is best managed by colposcopy versus folFrom the Department of Obstetrics/Gynecology. George Washington Ilniversity Hospital, Washington, DC.

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low-up cytology. It was determined that the cost and mortality for the two methods are similar. Such analyses need to be carried out in the United States where the frequency of screening and of follow-up smears is higher. Current recommendations for the follow-up of ASCUS is by repeat cytology every 4-6 months for 2 Colposcopy is recomyears. mendedforpersistentASCUS. According to current guidelines, LGSIL can be managed by immediate colposcopy or follow-up cytology, More studies are needed using the Bethesda system. Studies diflerentiating between ASCUS and LGSIL are needed to evaluate di$erences in malignant potential and management between these two cytologic abnormalities. Newer techniques, including HPV typing, cervicography, and computerized colposcopy, may help identify patients at risk for the development of cervical neoplasia. (Prim Care Update OblGyns 1998;5:95-100. 0 1998 Elsevier Science Inc. All rights reserved.)

This article reviews the history of cervical cancer screening, classification of Papanicolaou smears, management of abnormal Papanicolaou smears, deficiencies in current literature, and recent advances. The focus of the article is management of abnormal Papanicolaou smears. The more controversial management of mildly atypical Papanicolaou smears is discussed in detail, and literature will be presented to support “conservative” Inc., all rights

reserved.

1068-607X/98/$19.00

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(repeat Papanicolaou smears) ver(immediate colsus “aggressive” poscopy) management of mildly atypical smears.

History of Cervical Cancer Screening The cytologic evaluation of cells from the vagina and the cervix was first proposed by Dr. George Papanicolaou in the 1940s. Since then various studies have proven cervical cytology to be the most efficacious and cost-effective method for cancer screening. Community-wide Papanicolaou smear screening was followed by a dramatic reduction in both the incidence of and death rates from cervical cancer. This was perhaps best demonstrated in British Columbia, Canada, where the incidence of cervical cancer dropped from 25 cases per 100,000 women years in 1954 to 8 cases per 100,000 in 1984. Death rates from cervical cancer fell from a high of 13 cases per 100,000 in 1962 to 3 cases per 100,000 in 1983.l Worldwide variations in the incidence of cervical cancer also reflect differences in the use of screening programs. Cervical cancer is the second most common female malignancy in the world and the most common female malignancy in developing countries where cytologic screening is infrequent. In contrast, in the United States, where cytologic screening is widespread, cervical cancer is the seventh most common female malignancy.’ It is recommended that all women

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who are or who have been sexually active or who have reached 18 years of age should have an annual cervical smear and pelvic examination. It is further recommended that after a low-risk woman has had three or more consecutive satisfactory, normal annual examinations, the cervical smear could be performed less frequently at the discretion of her physician.3 In 1989, the U.S. Preventive Services Task Force recommended that the time interval between smears should be 1-3 years, depending on the presence of risk factors for cervical cancer.4

Classification of Papanicolaou Smears The classification of the Papanicolaou smear results was originally based on the numerical Papanicolaou class designations. In the past two decades, the inadequacy of that system has been realized and extensive revision has taken place. In December 1988, a workshop sponsored by the National Cancer Institute addressed the issue of lack of standardization of cervical smears, and a new system, the Bethesda system was developed.5 In April 1991, a second workshop was held to improve on the existing system and the revised Bethesda system was developed (Table 1).6 The Bethesda system incorporates human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN) I/mild dysplasia within the common category of low-grade squamous intraepithelial lesion (LGSIL) for the following reasons: Long-term follow-up studies have shown that lesions classified askoilocytosis and mild dysplasia progress to high-grade squamous intraepithelial lesion (HGSIL) at similar rates.7-g A recent analysis has demonstrated a similar distribution of 96

Table 1. The Bethesda

System: Revised

Version

Adequacy of the specimen Satisfactory for evaluation Satisfactory for evaluation but limited by . . . Unsatisfactory for evaluation General categorization Within normal limits Benign cellular changes (see: Descriptive diagnoses] Epithelial cell abnormalities (see: Descriptive diagnoses) Descriptive diagnoses

Benign cellular changes Infection Trichomonas vaginalis Candida species Predominance of coccobacilli; shift in vaginal flora Actinomycosis species Cellular changes consistent with herpes simplex virus Other Reactive changes Inflammation Atrophy Radiation Intrauterine device Other Epithelial cell abnormalities Squamous cell ASCUS: qualify (favor reactive/favor neoplasia) LGSIL encompassing human papillomavirus/mild dysplasiaKIN HGSIL encompassing moderate and severe dysplasia, carcinoma CIN II, CIN III Squamous cell carcinoma Glandular cell Normal endometrial cells Atypical glandular cells of undetermined significance Endocervical adenocarcinoma Endometrial adenocarcinoma Extrauterine adenocarcinoma Adenocarcinoma N.O.S. Other malignant neoplasms (specify) Hormonal evaluation (applies to vaginal smears only) Compatible with age and history Incompatible with age and history: specify Hormonal evaluation not possible: specify ASCUS, atypical squamous cells lesion; CIN, cervical intraepithelial

ofundetermined neoplasia;

significance; HGSIL, high-grade

low- and high-risk HPV types in koilocytosis and CIN I.l”,ll a 3. Studies have demonstrated lack of inter- and intraobserver reproducibility between CIN I and koi1ocytosis.l’ The Bethesda system incorporated moderate and severe dysplasia and carcinoma in situ (CIS) together because the distinction between moderate and severe dysplasia and between severe dysplasia and CIS has been shown to be irreproducible, and management of

LGSIL, low-grade squamous squamous intraepithelial

I in situ,

intraepithelial lesion.

both is essentially the same.l’ Additionally, cytologic abnormalities classified as HGSIL tend to be associated with high-risk and intermediate-risk HPV types5

Management of Abnormal Papanicolaou

Smears

Generally, it is accepted that patients with HGSIL including CIS should be managed by immediate Prim

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colposcopic evaluation, directed biopsy, therapy based on the histology and colposcopic findings, and follow-up at regular intervals. However, controversy still persists regarding the evaluation and management of patients with atypical squamous cell of undetermined significance (ASCUS) and LGSIL. The controversy mainly centers around whether patients with mild atypia should be followed conservatively or referred for immediate colposcopy. To fully understand this issue, the following questions need to be considered: What happens to mildly atypical cells seen on Papanicolaou smear over the course of time? What percentage of these lesions regress, persist, and progress? What is the accuracy of cytology compared with colposcopy and biopsy? What percentage of women with cytologically normal smears will have colposcopic and/or histologic abnormalities? How does management with follow-up Papanicolaou smears versus colposcopy affect the number of missed cancers and how do these two options compare in relative cost? What are the current guidelines for the management of ASCUS and LGSIL?

Mildly Atypical Cells Seen on Papanicolaou Smear: What Happens Over the Course of Time? In 1986, Nasiell et al.” identified 555 patients with mild cervical dysplasia and followed them with Papanicolaou smears for a minimum of 39 months. None of these patients received any treatment. They found that 62% of the lesions regressed, Volume

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22% persisted, and 16% progressed. In 1986, Campion et alI3 studied 100 patients with mild atypia by using three consecutive smears. These patients were followed by Papanicolaou smears and colposcopy for a minimum of 19 months. The authors showed that only 7% of these lesions regressed, 67% persisted, and 26% progressed. In 1992, Montz et a1.8studied 203 patients with LGSIL and 91 patients with ASCUS and followed their progress with Papanicolaou smears and colposcopy every 3 months for 9 months. Patients underwent biopsy, endocervical curettage, and treatment if the lesions progressed. They demonstrated that of the patients who had ASCUS, 54% regressed, 46% persisted, and none progressed. In the group who had LGSIL, 78% regressed, 18% persisted, and 4% progressed.8 The above studies and others have shown that the majority of women with one mildly atypical Papanicolaou smear will have complete cytologic and colposcopic regression over a short interval. However, some percentage of these lesions do progress, which indicates the serious biologic potential of these lesions. Therefore, diligent follow-up is essential. Also, longterm follow-up is needed to colposcopically document the durability of these regressions. The majority of women with multiple mildly atypical smears have either persistent or progressive lesions and should undergo definitive diagnosis and treatment.

Mild Atypia on Cervical Cytologyz Colposcopic and Histologic Findings In 1994, Regi et al-l4 performed colposcopy and biopsy on 100 patients who had LGSIL on Pap smear.

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Colposcopic examination revealed 26 normal results, 59 patients with an impression of LGSIL (HPV, CIN I) and 15 with an impression of HGSIL (CIN II or CIN III). Histology showed sections that were 39% normal, 51% LGSIL, and 10% HGSIL.14 Other studies reproduced these results. Bolger et a1.15followed 91 patients with mild atypia or koilocytosis. Results on colposcopy, 15 % were normal. All others underwent histologic evaluation. On biopsy, 14% had koilocytosis, 31% had CIN I, 18% had CIN II, and 22% had CIN III. Therefore, in women with mildly atypical Papanicolaou smears who undergo colposcopy, the rate of more advanced lesions is lo-30%. Among asymptomatic women showing CIN on colposcopy (ll%), 58% of these are not picked up by cytology alone.16 Most of these lesions were found to be small and focal. The following are some possible explanations for the decreased sensitivity of Papanicolaou smears compared to colposcopy and biopsy. The spatula may not conform perfectly to the topography of the cervix and small lesions may be missed or be too small to exfoliate sufficient abnormal cells to enable accurate detection by cytology. Inflammatory exudates associated with these lesions may obscure the cytologic evidence of disease. Early HPV may not present the same degree of cytologic atypia as more advanced cases, so their presence may not be as easily detected. The focal nature of some lesions may cause them to be missed on cytology* After answering the first two questions, we have, on the one hand, literature suggesting that most mildly atypical lesions regress over the course of time, and therefore, it would probably be safe to follow mildly atypical Papanicolaou smears with repeat cytology. However, on the other hand, there 97

KANAR are studies suggesting that lo-30% of mildly atypical lesions on cytology are found to be more advanced on colposcopy and histology. This possibility makes immediate colposcopy seem more prudent. It would be important to determine the difference in cost between these two options. Also, the two management choices need to be compared to see if more cancers are missed by choosing either of the options.

How Does Management With Follow-Up Papanicolaou Smears Versus Colposcopy Affect the Number of Missed Cancers, and How Do These Two Options Compare in Relative Cost? In order to answer this question, Johnson N et a1.17 used a decision analysis model to compare the expected mortality from missed cervical cancer and the cost of follow-up by colposcopy versus repeat cytology. Data for each component of the question were obtained from published work worldwide. The analysis began with the following scenario: a cytologist has just diagnosed mild dyskaryosis on a routine smear. There are now two possible course of action: performing a colposcopy or repeating the smear in 6 months. Each arm (colposcopy and repeat smear arm) had several possible outcomes. The rates of these outcomes were calculated by using published data worldwide. It was found that 65% of women with mild dyskaryosis will have CIN on colposcopy. The majority of these patients will undergo treatment with cure or spontaneous regression. The total number of women that will 98

have progression to cancer despite this management is 1.6 per 1,000 women with mild atypia. The authors also reported that “in women that underwent repeat cytology, 65% would have at least one repeat abnormality and, therefore, undergo colposcopy.” Using published data, it was calculated that the total number of cancers in this group is 2 in 1,000 if 5 yearly surveillance (ie, test every 5 years) is used, and 1.6 in 1,000 if 3 yearly surveillance is used. Lives lost was determined to be 50% for cervical cancer using published data. The difference in lives lost between immediate colposcopic management of all women with CIN versus follow-up management with cervical cytology was calculated to be 2 in 10,000 for 5 yearly surveillance and 0 for 3 yearly surveillance (this surveillance frequency refers to the interval between Papanicolaou smears after two consecutive normal smears). The authors also performed a cost analysis. It was found that 65% of the women in the repeat cytology group eventually needed colposcopy. Cost analysis was done using the cost of colposcopy and of treatment if necessary, the cost of smears, and the cost of follow-up. Two negative smears were considered adequate follow-up before returning to routine screening, and it was found that six additional follow-up Papanicolaou smears needed to be performed on four women to spare one woman from colposcopy (in the follow-up versus colposcopy arms). The cost analysis indicated that it was not financially cheaper to manage mild atypia by follow-up Papanicolaou smears. Therefore, the meta-analysis in the United Kingdom indicated no difference in mortality from cancer or in cost between the two management options. Such a metaanalysis needs to be performed in the United States, where the frequency of cervical cancer screen-

ing is every year (rather than every 3 years). If the rate of missed cancers and the relative cost of the two management options is determined to be the same in the United States, then the proper management option would involve a process of patient education and patient preference.

Current Guidelines for the Management of Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous lntraepithelial lesions ATYPICAL SQUAMOUS CELLS OF UNDETERMINED SIGNIFICANCE Follow-up by Papanicolaou smears without colposcopy is acceptable. Repeat Papanicolaou smears every 4-6 months for 2 years is recommended until three consecutive negative smears are encountered. For any two ASCUS readings in a 2-year period, colposcopy is recommended. For ASCUS favoring inflammation, screen for infection, treat, and then repeat the smear. A cytologic diagnosis of ASCUS in postmenopausal women not receiving hormone replacement therapy has implications different from those in premenopausal women. Atrophic cells can have the appearance of parabasal cells with a high N/C ratio. A course of topical estrogen cream should be tried and the cytologic smear repeated. If ASCUS persists, perform colposcopy. Any patient with poor compliance issues or previous abnormal smears should be considered for colposcoPY3 LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESIONS One option for management of LGSIL is to follow-up with PapaniPrim

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colaou smears every 4-6 months until three consecutive, satisfactory negative smears are encountered. If any of the repeat smears during this Z-year period are abnormal, a colposcopy should be performed. Immediate colposcopy, ECC, and directed biopsy of any abnormal area is another appropriate option.”

Deficiencies in Current literature There are several deficiencies in the current literature. They are as follows: 1. Most of the current literature

is based on older systems of cytologic classification. 2. There is a need for meta-analysis on cost versus mortality based on screening and follow-up frequency in the United States. 3. There is a lack of comparative studies in women with ASCUS/ LGSIL with and without risk factors for cervical cancer. The two most important risk factors to consider are HPV and human immunodeficiency virus (HIV) infections. 4. Studies using newer techniques such as HPV typing and cervicography are needed to determine if these can be helpful in managing some patients with mild atypia conservatively.

Recent Advances HUMAN PAPILLOMAVIRKJS

TESTING

Human papillomavirus DNA can be detected in 90% of preinvasive and invasive cervical neoplasms and in 25-30% of women with normal cytology. Therefore, HPV DNA testing that is not type specific lacks the specificity necessary to be a useful screening test because the vast majority of women with HPV DNA will be cytologically normal.

The finding of HPV DNA of a high-risk type (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, or -58) with a positive Papanicolaou smear has been associated with a neoplastic rather than a reactive process.18 However, these studies are preliminary, and at the present time, HPV testing should only be used by physicians who understand its limitations.”

CERVICOGRAPHY Cervigrams are slide photographs of the cervix, taken at the time of a pelvic examination using special photographic equipment after acetic acid has been applied to highlight abnormalities. Analysis of the projected image is carried out by experts in colposcopy. Cervicography has been shown to have high sensitivity and specificity for the detection of high-grade lesions in young women. It can be used in conjunction with cytology for the conservative management of ASCUS and LGSIL because the combination should substantially decrease the chance of missing a high-grade lesion.

COMPUTERIZED

COLPOSCOPY

Computerized colposcopy has the capacity to store, process, magnify, and quantify colposcopic images. It also allows comparison between two colposcopic images performed at different times, thus enabling objective analysis of any change in size, shape, location, or grade of a lesion. Authors of one study demonstrated that lesions that showed an increase in size revealed a progression on biopsy. All patients whose lesions decreased in size had normalized cytology within a 12month period.lg Computerized colposcopy replaces subjective evaluation with objective assessment and may hold promise for conservative management of mild dysplasia.

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AUTOMATED CYTOLOGIC RESCREENING PapNet and AutoPap are computerassisted systems. PapNet uses neural network technology to recognize and select potentially abnormal cells on a conventionally prepared gynecology smear. This assists the cytotechnologist in finding the (sometimes few) abnormal cells in a smear. Preliminary data suggest that PapNet can, by rescreening previously reported “normal smears,” help detect abnormalities that are missed in routine cytologic screening.‘”

Atypical Squamous Cells of Undetermined Significance and LowGrade Squamous lntraepithelial lesions Trial Study The ASCUS/LGSIL trial is in progress at the National Institutes of Health, and it involves six centers and randomization of 3,600 subjects each with ASCUS and LGSIL into three arms. The three arms of the randomized trial include: l l l

Immediate colposcopy HPV testing plus cytology Repeat cytology alone

The goals of the ASCUS/LGSIL study are

trial

1. To determine whether HPV testing can effectively triage women with a cytologic diagnosis of ASCUS or LGSIL. 2. To develop clinical management guidelines and prognostic information for ASCUS and LGSIL. 3. To determine whether the cost of screening and treatment for the potential precursor lesions of cervical cancer can be reduced through improved triage.

KANAR

Conclusions The management of mildly atypical cytologic smears (ASCUS and LGSIL) remains controversial. Literature indicates that the majority of these lesions regress to normal over time. Some studies show, however, that 1040% of these lesions are found to be more advanced on colposcopy. More studies are needed to assess the relative number of missed cancers and the relative cost using the two management options. More studies are also needed to determine if newer techniques such as HPV typing can be used to screen for patients at higher risk for cervical cancer and to manage these patients with more aggressive methods of diagnosis and treatment. Patient preference and involvement is important in any decision in which the course of action is controversial. Some patients may prefer follow-up Papanicolaou smears and avoid more aggressive procedures. Others may lean toward immediate colposcopy, biopsy, and treatment, if indicated, to reduce the possibility of progression of disease. Most gynecologists in the United States recommend immediate colposcopy for LGSIL and follow-up Papanicolaou smears for a single ASCUS smear. Patients who have a repeat ASCUS smear at any time within the z-year follow-up should be referred for colposcopy. Only a very few clinicians recommend conservative management of LGSIL, even though studies show complete regression of the majority of these lesions. This number may increase as newer techniques such as HPV typing are studied and become more widely available. Pending the results of the NCI-ALTS

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trial, management of mildly dysplastic lesions should revolve around patient education, involvement, and preference.

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Address correspondenceand reprint requests to Sheetal G. Kanar, MD, 5111 South 8th Road, Apt. 407. Arlington, VA

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