Chapter 4: Preinvasive Disease of the Lower Genital Tract

INTRODUCTION

Over the past 3 decades, the work of population scientists, laboratory-based researchers, and clinicians has together promoted the understanding of the pathogenesis of preinvasive disease of the lower genital tract and its associated cancers. Elucidating the progression from preinvasive disease to invasive cancer was the first step in implementing the Pap test as one of the most successful cancer screening program in developed nations and has dramatically lessened the impact of cervical cancer in the United States and other developed countries. Furthermore, with the identification of the human papillomavirus (HPV) as the principal and necessary cause of cervical cancer, the development and application of HPV vaccines will potentially further reduce the burden of cervical cancer and other HPV-induced malignancies.

EPIDEMIOLOGY

Key Points

1. The HPV is the most common sexually transmitted infection and is the necessary cause for cervical dysplasia and cancer. HPV16 and 18 are the most common high-risk types implicated in carcinogenesis.

2. Additional risk factors for genital dysplasia including tobacco smoking, immunosuppression, early age at first intercourse, and multiple sexual partners.

3. The HPV proteins E6 and E7 are critical for malignant transformation; E6 binds and inactives the tumor suppressor gene p53, whereas E7 binds and inactivates the tumor supressor gene pRb.

Incidence of Cervical Dysplasia

In the United States, 2 to 3 million women are diagnosed with cervical cytologic abnormalities annually. The most common abnormality found by liquid-based cytology is atypical squamous cells of undetermined significance (ASC-US), accounting for 2% to 5% of all Pap test results. In contrast, low-grade squamous intraepithelial lesions (LSIL) account for 2% of Pap test results, and approximately 0.5% of Pap test results are high-grade squamous intraepithelial lesions (HSIL); less than 0.5% are suggestive of invasive cancer. Atypical glandular cells of undetermined significance (AGC) account for an additional 0.2% to 0.8% of Pap test results.

Every year, between 250,000 and 1 million women in the United States are diagnosed with cervical dysplasia. Histologic diagnosis of cervical dysplasia is based on a tissue biopsy and uses the Bethesda nomenclature; this differs from the nomenclature used for cytologic abnormalities diagnosed on Pap testing. Cervical intraepithelial neoplasia (CIN) is the formal histologic diagnosis of cervical dysplasia and is graded as 1, 2, or 3 based on the proportion of atypical cells in the cervical epithelium. CIN can occur at any age; the peak incidence is in women between the ages of 25 to 35 years (Figure 4-1).