6 Pap Smear and Human Papilloma Virus Testing Benjamin Piura and Ruthy Shaco-Levy After breast cancer, cervical cancer is the second most common malignancy diagnosed in women worldwide. Approximately 500 000 new cases of cervical cancer are diagnosed each year, and nearly 250 000 women die of this disease each year worldwide. Cervical cancer is the most common malignancy encountered in women in developing countries. The majority of these cases occur in countries with limited or no effective screening programs using the Papanicolaou (Pap) smear test1 for detecting cervical cellular abnormalities, which places women at a greater risk for developing cervical cancer. In the United States, Finland, Sweden, Iceland, and other developed countries where Pap smear screening is widely used, rates of cervical cancer have noticeably dropped up to 50% over the past 20–30 years (see Evidence Box 6.1). However, health disparities prevent more lives from being saved with Pap smear screening, even in developed countries. Indeed, despite the test’s widespread availability in the United States, for example, more than 10 000 new cases of cervical cancer are diagnosed each year, and almost 4000 women die each year unnecessarily from this preventable disease. About 50% of women with cervical cancer in the United States did not have a Pap smear test in the preceding 3 years, and an additional 10% had not been screened in the past 5 years. Nevertheless, more than 50 million Pap smears are performed each year in the United States alone, and 7% (3.5 million) of these give abnormal test results. It has been estimated that women who never had a Pap smear have a 3.5% risk of developing cervical cancer, whereas the risk is reduced to 0.8% with Pap smear screening. Since infection with human papilloma virus (HPV) has been found in almost all cervical cancers, testing for the presence of high-risk HPV types in cervical samples has now become a part of routine clinical work-up in women with equivocal Pap smear test results. There are a number of outdated terminologies regarding Pap smear results (Table 6.1). The lack of a common terminology initially resulted in widespread confusion about what really constitutes an abnormal test result. This confusion necessitated further action. In December 1988, a National Cancer Institute workshop held in Bethesda, Maryland, provided for the first time a consensus, now known as the Bethesda System, on how to properly read Pap smears. The result was initial guidelines designed to decrease the variability among laboratories reporting the results. The three most important contributions of this Bethesda System were:
Pap Smear Terminology
| Papanicolaou | United States | United Kingdom |
| Normal | Normal | Normal |
| Inflammatory | Inflammatory | Inflammatory |
| Atypical cells | Mild atypia Moderate atypia | Mild dyskariosis Moderate dyskariosis |
| Carcinoma in situ | Severe atypia | Severe dyskariosis |
| Carcinoma | Carcinoma | Carcinoma |
Key Terminology Changes in the 2001 Bethesda System
The Bethesda System was revised in 1991 and 2001. The 2001 Bethesda System (Table 6.2) reflects the most current knowledge about the biology of Pap test abnormalities and addresses new screening technologies such as the liquid-based, thin-layer Pap smear and HPV testing. It recommends dividing the category of atypical squamous cells (ASCs) into two subcategories: a) atypical squamous cells of undetermined significance (ASCUS), and b) atypical squamous cells that cannot exclude high-grade intraepithelial lesion (ASC-H).
Overall, among all women with ASC, the risk of developing invasive cancer is low (0.1–0.2%). Nevertheless, the prevalence of CIN 2, 3 confirmed by biopsy among women with ASC is 7–12%, whereas the prevalence of CIN 2, 3 confirmed by biopsy among women with ASC-H ranges from 26% to 68%. Rates of high-risk HPV DNA positivity are 40–51% among women with ASCUS, whereas they are 74–88% among women with ASC-H. Consequently, ASC-H should be considered to represent equivocal HSIL and a productive HPV infection. Thus, the performance of HPV testing allows for clear statements regarding the meaning of an ASC interpretation.
The 2001 revisions to the Bethesda System also eliminated the category of AGCUS (atypical glandular cells of undetermined significance) and identified three subcategories of atypical glandular cells (AGCs):
- AGC not otherwise specified
- AGC favoring neoplasia
- adenocarcinoma in situ (AIS)
| Specimen adequacy |
| Satisfactory for evaluation (8000–12 000 well-visualized squamous cells for conventional smears and 5000 squamous cells for liquid-based preparations (note presence/absence of endo-cervical/transformation zone component-there should be at least 10 well-preserved endocervical or squamous metaplastic cells) |
| Unsatisfactory for evaluation (specimens with >75% of epithelial cells obscured) |
| General categorization |
| Negative for intra-epithelial lesion or malignancy |
| Epithelial cell abnormality |
| Other |
| Interpretation/result |
| Negative for intra-epithelial lesion or malignancy |
• Organisms
|
| • Other non-neoplastic findings Reactive cellular changes associated with:
Glandular cells status posthysterectomy Atrophy |
| Epithelial cell abnormalities |
• Squamous cell
|
| • Low-grade squamous intra-epithelial lesion (LSIL) (generally a transient infection with HPV) encompassing: human papilloma virus/mild dysplasia/cervical intra-epithelial neoplasia (CIN) 1 |
| • High-grade squamous intra-epithelial lesion (HSIL) (more often associated with HPV persistence and higher risk of progression) encompassing: moderate and severe dysplasia, carcinoma in situ; CIN 2 and CIN 3 |
| • Invasive squamous cell carcinoma |
| • Glandular cell |
• Atypical glandular cells (AGC)
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