Pap smear

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Synonyms and keywords: Papanikolaou test; papanicolaou test; pap test; cervical smear; smear test

Overview

In gynecology, Pap smear is a medical screening method, invented by Georgios Papanikolaou, primarily designed to detect premalignant and malignant processes in the ectocervix. It may also detect infections and abnormalities in the endocervix and endometrium.

Procedure

The endocervix may be partially sampled with the device used to obtain the ectocervical sample, but due to the anatomy of this area, consistent and reliable sampling cannot be guaranteed. As abnormal endocervical cells may be sampled, those examining them are taught to recognize them.

The endometrium is not directly sampled with the device used to sample the ectocervix. Cells may exfoliate onto the cervix and be collected from there, so as with endocervical cells, abnormal cells can be recognised if present but the Pap Test should not be used as a screening tool for endometrial malignancy.

The pre-cancerous changes (called dysplasias or cervical or endocervical intraepithelial neoplasia) are usually caused by sexually transmitted human papillomaviruses (HPVs). The test aims to detect and prevent the progression of HPV-induced cervical cancer and other abnormalities in the female genital tract by sampling cells from the outer opening of the cervix (Latin for "neck") of the uterus and the endocervix. The sampling technique changed very little since its invention by Georgios Papanikolaou (1883–1962) to detect cyclic hormonal changes in vaginal cells in the early 20th century until the development of liquid based cell thinlayer technology. The test remains an effective, widely used method for early detection of cervical cancer and pre-cancer. The UK's call and recall system is among the best; estimates of its effectiveness vary widely but it may prevent about 700 deaths per year in the UK. It is not a perfect test. "A nurse performing 200 tests each year would prevent a death once in 38 years. During this time she or he would care for over 152 women with abnormal results, over 79 women would be referred for investigation, over 53 would have abnormal biopsy results, and over 17 would have persisting abnormalities for more than two years. At least one woman during the 38 years would die from cervical cancer despite being screened." HPV vaccine may offer better prospects in the long term.

It is generally recommended that sexually active females seek Pap smear testing annually, although guidelines may vary from country to country. If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in three to twelve months. If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The patient may also be referred for HPV DNA testing, which can serve as an adjunct (or even as an alternative) to Pap testing.

About 5% to 7% of pap smears produce abnormal results, such as dysplasia, possibly indicating a pre-cancerous condition. Although many low grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast and Trichomonas vaginalis. A small proportion of abnormalities are reported as of "uncertain significance".

Technical Aspects

Samples are collected from the outer opening or os of the cervix using an Aylesbury spatula or (more frequently with the advent of liquid-based cytology) a plastic-fronded broom. The cells are placed on a glass slide and checked for abnormalities in the laboratory.

The sample is stained using the Papanicolaou technique, in which tinctorial dyes and acids are selectively retained by cells. Unstained cells can not be visualized with light microscopy. The stains chosen by Papanicolau were selected to highlight cytoplasmic keratinization, which actually has almost nothing to do with the nuclear features used to make diagnoses now.

The sample is then screened by a specially trained and qualified cytotechnologist using a light microscope. The terminology for who screens the sample varies according the country; in the UK, the personnel are known as Cytoscreeners, Biomedical scientists (BMS), Advanced Practitioners and Pathologists. The latter two take responsibility for reporting the abnormal sample which may require further investigation.

Studies of the accuracy of conventional cytology report:

• Sensitivity 72%
• Specificity 94%

In the United States, physicians who fail to diagnose cervical cancer from a pap smear have been convicted of negligent homicide. In 1988 and 1989, Karen Smith had received pap smears which were argued to have "unequivocally" shown that she had cancer; yet the lab had not made the diagnosis. She died on March 8 1995. Later, a physician and a laboratory technician were convicted of negligent homicide. These events have led to even more rigorous quality assurance programs, and to emphasizing that this is a screening, not a diagnostic, test, associated with a small irreducible error rate.

Liquid Based Monolayer Cytology

Since the mid-1990s, techniques based around placing the sample into a vial containing a liquid medium which preserves the cells have been increasingly used. The media are primarily ethanol based. Two of the types are Sure-Path (TriPath Imaging) and Thin-Prep (Cytyc Corp). Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for low and high risk HPV testing and reduced unsatisfactory specimens from 4.1% to 2.6%. Proper sample acquisition is crucial to the accuracy of the test; clearly, a cell that is not in the sample cannot be evaluated.

Studies of the accuracy of liquid based monolayer cytology report:

• Sensitivity 61% to 66%
• Specificity 82% to 91%

Some, but not all studies, report increased sensitivity from the liquid based smears.

Results

Micrograph of a Pap test showing a low-grade intraepithelial lesion (LSIL) and benign endocervical mucosa. Pap stain.

Micrograph of a Pap test showing trichomoniasis. Trichomonas organism seen in the upper right. Pap stain.

Micrograph of a Pap test showing changes of herpes simplex virus. Pap stain.

In screening a general or low-risk population, most Pap results are normal.

In the United States, about 2–3 million abnormal Pap smear results are found each year. Most abnormal results are mildly abnormal (ASC-US (typically 2–5% of Pap results) or low-grade squamous intraepithelial lesion (LSIL) (about 2% of results)), indicating HPV infection. Although most low-grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed.

In a typical scenario, about 0.5% of Pap results are high-grade SIL (HSIL), and less than 0.5% of results indicate cancer; 0.2 to 0.8% of results indicate Atypical Glandular Cells of Undetermined Significance (AGC-NOS).

As liquid based preparations (LBPs) become a common medium for testing, atypical result rates have increased. The median rate for all preparations with low-grade squamous intraepithelial lesions using LBPs was 2.9% compared with a 2003 median rate of 2.1%. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little.

Abnormal results are reported according to the Bethesda system. They include:

• Squamous cell abnormalities (SIL)
  • Atypical squamous cells of undetermined significance (ASC-US)
  • Atypical squamous cells – cannot exclude HSIL (ASC-H)
  • Low-grade squamous intraepithelial lesion (LGSIL or LSIL)
  • High-grade squamous intraepithelial lesion (HGSIL or HSIL)
  • Squamous cell carcinoma
• Glandular epithelial cell abnormalities
  • Atypical Glandular Cells not otherwise specified (AGC or AGC-NOS)

Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast, herpes simplex virus and trichomoniasis. However it is not very sensitive at detecting these infections, so absence of detection on a Pap does not mean absence of the infection.

Effectiveness

The Pap test, when combined with a regular program of screening and appropriate follow-up, can reduce cervical cancer deaths by up to 80%. Failure of prevention of cancer by the Pap test can occur for many reasons, including not getting regular screening, lack of appropriate follow up of abnormal results, and sampling and interpretation errors. In the US, over half of all invasive cancers occur in women that have never had a Pap smear; an additional 10 to 20% of cancers occur in women that have not had a Pap smear in the preceding five years. About one-quarter of US cervical cancers were in women that had an abnormal Pap smear, but did not get appropriate follow-up (woman did not return for care, or clinician did not perform recommended tests or treatment).

Adenocarcinoma of the cervix has not been shown to be prevented by Pap tests. In the UK, which has a Pap smear screening program, Adenocarcinoma accounts for about 15% of all cervical cancers

Estimates of the effectiveness of the United Kingdom's call and recall system vary widely, but it may prevent about 700 deaths per year in the UK. A medical practitioner performing 200 tests each year would prevent a death once in 38 years, while seeing 152 women with abnormal results, referring 79 for investigation, obtaining 53 abnormal biopsy results, and seeing 17 persisting abnormalities lasting longer than two years. At least one woman during the 38 years would die from cervical cancer despite being screened.

Since the population of the UK is about 61 million, the maximum number of women who could be receiving Pap smears in the UK is around 15 million to 20 million (eliminating the percentage of the population under 20 and over 65). This would indicate that the use of Pap smear screening in the UK saves the life of 1 person for every approximately 20,000 people tested (assuming 15,000,000 are being tested yearly). If only 10,000,000 are actually tested each year, then it would save the life of 1 person for every approximately 15,000 people tested.

Human Papillomavirus Testing

The presence of HPV indicates that the person has been infected, the majority of women who get infected will successfully clear the infection within 18 months. It is those who have an infection of prolonged duration with high risk types (e.g. types 16,18,31,45) that are more likely to develop Cervical Intraepithelial Neoplasia due to the effects that HPV has on DNA.

Studies of the accuracy of HPV testing report:

• Sensitivity 88% to 91% (for detecting CIN 3 or higher) to 97% (for detecting CIN2+)
• Specificity 73% to 79% (for detecting CIN 3 or higher) to 93% (for detecting CIN 3 or higher)

By adding the more sensitive HPV Test, the specificity may decline. However, the drop in specificity is not definite. If the specificity does decline, this results in increased numbers of false positive tests and many women who did not have disease having colposcopy and treatment. A worthwhile screening test requires a balance between the sensitivity and specificity to ensure that those having a disease are correctly identified as having it and equally importantly those not identifying those without the disease as having it. Due to the liquid based pap smears having a false negative rate of 15-35%, the American College of Obstetricians and Gynecologists and American Society for Colposcopy and Cervical Pathology have recommended the use of HPV testing in addition to the pap smear in all women over the age of 30.

Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed. Randomized controlled trial have suggested that HPV testing could follow abnormal cytology or could precede cervical cytology examination.

A study published in April 2007 suggested the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."

Automated Analysis

In the last decade there have been successful attempts to develop automated, computer image analysis systems for screening. Automation may improve sensitivity and reduce unsatisfactory specimens. One of these has been FDA approved and functions in high volume reference laboratories, with human oversight.

Practical Aspects

The physician or operator collecting a sample for the test inserts a speculum into the patient's vagina, to obtain a cell sample from the cervix. A pap smear appointment is normally not scheduled during menstruation. The procedure is usually just slightly painful, because of the neuroanatomy of the cervix. However, this can depend on the patient's anatomy, the skill of the practitioner, psychological factors, and other conditions. Results usually take about 3 weeks. Slight bleeding, cramps, and other discomfort can occur afterwards.

Other tests, including the TruTest, an endometrial biopsy used for early detection of uterine cancer, can be performed during the same visit.

2012 ACS, ASCCP and ASCP Release New Screening Guidelines for Cervical Cancer (DO NOT EDIT)

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Women should not be screened before age 21 Women 21 to 29 should be screened with the Pap test alone (conventional or liquid-based) every three years. HPV testing should NOT be used for screening in this age group. For women 30 and over, the preferred approach is the Pap test plus HPV testing ("co-testing") every five years. Continued screening with the Pap test alone (without HPV testing) every three years is an acceptable alternative. While screening with HPV testing alone is promising, at this time it is not recommended for most clinical settings. Screening is not recommended for women over age 65 who have had at least three consecutive negative Pap tests or at least two negative HPV tests the last 10 years, with the most recent test in the last 5 years. Women in this age group who have a history of pre-cancer (CIN2 or a more severe diagnosis) should continue routine screening for at least 20 years. Women who have undergone a hysterectomy (with removal of the cervix) for reasons not related to cervical cancer or pre-cancer should not be screened. Women who have been vaccinated against HPV should follow the age-specific recommendations in these guidelines (for unvaccinated women).

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2012 U.S. Preventive Services Task Force Recommendation Statement for Screening for Cervical Cancer (DO NOT EDIT)

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The USPSTF recommends screening for cervical cancer in women age 21 to 65 years with cytology (Pap smear) every 3 years or, for women age 30 to 65 years who want to lengthen the screening interval, screening with a combination of cytology and human papillomavirus (HPV) testing every 5 years. See the Clinical Considerations for discussion of cytology method, HPV testing, and screening interval (A recommendation). The USPSTF recommends against screening for cervical cancer in women younger than age 21 years (D recommendation). The USPSTF recommends against screening for cervical cancer in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. See the Clinical Considerations for discussion of adequacy of prior screening and risk factors (D recommendation). The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer (D recommendation). The USPSTF recommends against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years (D recommendation).

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