Papanicolaou Smear

Etiology and Epidemiology

In the United States, death due to cervical cancer has declined by more than 60% since the 1950s. Once one of the most frequent cancers affecting women of childbearing age, it now ranks 14th. In 2010, approximately 12,000 women were diagnosed with cervical cancer, with about 4000 resulting in death. From 2002 through 2012, the rate of cervical cancer decreased by 1.3%, and deaths from cervical cancer decreased by 0.9%. In 2014, Hispanic women were reported to have the highest rate of getting cervical cancer, while African-American women had the highest death rate from the disease.[5][6][7]

Cervical cancer is much more common in countries without widespread screening programs. More than 80% of cervical cancer cases are found in developing countries. Cervical cancer is still the third most common cause of cancer in women worldwide. Annually, there are approximately 528,000 new cases of cervical cancer, with 266,000 deaths. These statistics make it the second most common cause of cancer-related death in women.

Pathophysiology

In the 1980s, researchers discovered that virtually all cervical cancer cases were caused by human papillomavirus (HPV). There are more than 100 types of HPV, and 40 can be transmitted sexually, while 15 are considered "high-risk HPV" or cancer-causing. There are 2 subtypes of HPV, 16 and 18, which cause about 70% of cervical cancers worldwide.

Cervical infection with high-risk HPV is usually required for the development of cervical cancer. However, HPV infection alone is not sufficient for progression to neoplasia. Most infections with high-risk HPV are transient and do not progress to cervical intraepithelial neoplasia (CIN). A small portion of women infected with high-risk HPV develop cervical cancer. Cigarette smoking, a compromised immune system, and HIV infection are all cofactors in HPV persistence.[8][9][10][11]

Specimen Requirements and Procedure

In 2009, the American College of Obstetricians and Gynecologists (ACOG) recommended that women begin having pap smears at 21. ACOG also recommends that women aged 21 to 29 have Pap smear testing every 3 years. The organization noted that women ages 30 to 65 should have pap smears with HPV testing every 5 years, and screening should stop after age 65. There are special populations of women who should be screened more frequently for cervical cancer than the general population. They include women infected with HIV, immunocompromised women (such as organ transplant patients), women exposed to diethylstilbestrol while in utero, and women previously treated for CIN 2, CIN 3, or cervical cancer.

In 2018, the United States Preventive Services Task Force (USPSTF) revised its recommendations as follows:

• Grade A recommendation: Screening for cervical cancer every 3 years with cervical cytology alone in women aged 21 to 29 years
• Grade A recommendation: Screening every 3 years with cervical cytology alone, every 5 years with hrHPV testing alone, or every 5 years with hrHPV testing combined with cytology (co-testing) in women aged 30 to 65.
• Grade D recommendation: No screening for cervical cancer in women younger than 21 years.
• Grade D recommendation: No screening for cervical cancer in women older than 65 years who have had adequate prior screening and are not otherwise at high risk of cervical cancer.
• Grade D recommendation: Screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and do not have a history of a high-grade precancerous lesion or cervical cancer.

Diagnostic Tests

Women with epithelial cell abnormality on pap smear should be further tested with colposcopy and biopsy (see Image. Squamous Cells, Acute Inflammation). A colposcope is a binocular microscope that allows visual inspection of the cervix. Gross abnormalities visualized on colposcopy can then be biopsied for further classification.

Testing Procedures

There are 2 acceptable techniques for collecting the Pap Smear: liquid-based and conventional. A clinician places a speculum into the woman's vagina and identifies the cervix. The liquid-based method involves collecting cells from the transformation zone of the cervix by using a brush and transferring the cells to a vial of liquid preservative. The conventional technique involves collecting cells from the transformation zone of the cervix by using a brush and spatula, transferring the cells to a slide, and fixing the slide with a preservative. The liquid-based technique allows testing for HPV, gonorrhea, and chlamydia from a single collection. Theoretically, the liquid-based technique has the advantages of easier interpretation, fewer unsatisfactory results, and the filtering of blood and debris.

Interfering Factors

Vaginal discharge, blood, and lubricants can interfere with the interpretation of Pap smears. When performing Pap smears, many providers use water or a small amount of water-based lubricant to minimize patient discomfort.

Results, Reporting, and Critical Findings

Bethesda System for Reporting Cervical Cytology

The Bethesda System for Reporting Cervical Cytology has been the accepted reporting system in the United States since 1988. The 2014 revision is the most recent.

• Specimen type: Indicates whether it is conventional or liquid-based
• Specimen adequacy: Indicates if it is satisfactory for evaluation or unsatisfactory for evaluation
• General categorization
  • Negative for intraepithelial lesion or malignancy
  • Other
  • Epithelial cell abnormality
• Interpretation/results
  • Negative intraepithelial lesion (ie, there is no cellular evidence of neoplasia)
  • Nonneoplastic findings (nonneoplastic cellular variations, reactive cellular changes, glandular cells posthysterectomy)
  • Organisms (Trichomonas vaginalis, bacterial vaginosis, Candida species, Actinomyces species, cellular changes consistent with herpes virus, cellular changes consistent with cytomegalovirus)
  • Other
  • Endometrial cells in a woman older than 45 years old

Epithelial cell abnormalities

• Squamous cell
  • Atypical squamous cells (ASC)
  • Of undetermined significance (ASC-US)             
  • Cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H)
  • Low-grade squamous intraepithelial lesion (LSIL):  mild dysplasia or cervical intraepithelial neoplasia (CIN) 1
  • High-grade squamous intraepithelial lesion (HSIL):  moderate and severe dysplasia, CIN 2 and CIN 3
• With features suspicious for invasion (if invasion suspected)
• Squamous cell carcinoma 
  • Endocervical cells (not otherwise specified)
  • Endometrial cells (not otherwise specified)
  • Glandular cells (not otherwise specified)
  • Endocervical cells favor neoplastic
  • Glandular cells favor neoplastic
  • Endocervical adenocarcinoma in situ
• Adenocarcinoma Endocervical
  • Endometrial
  • Extrauterine
  • Not otherwise specified
• Other malignant neoplasms

Clinical Significance

Since the discovery of HPV subtypes causing most cervical cancer cases, 2 vaccines have been created to decrease the number of new cervical cancer cases in the future. A bivalent vaccine offers protection from HPV subtypes 16 and 18. The quadrivalent vaccine also protects users not only from HPV 16 and 18 but also subtypes 6 and 11, which cause 90% of genital warts. There is continuing research on vaccines for cervical cancer prevention.

Quality Control and Lab Safety

A computer-aided automated device can interpret Pap smear specimens. If using a computer-aided system, the Bethesda System for Reporting Cervical Cytology requires documentation of the device and its result.