Human Papillomaviruses and Cervical Cancer

During much of the 20th century, cervical cancer was a scourge. In large parts of the world, this remains the case, the disease often striking women younger than 40 years. In 1908, Friedrich Schauta in Vienna ended his monograph on radical vaginal hysterectomy for cervical cancer on the note that “the early detection of uterine cancer is the greatest challenge facing future generations of academic teachers and practicing physicians.” In the same year, Howard Kelly in Baltimore wrote that “the only avenue open with certainty to progress today lies in the direction of discovering our cases of cancer at an earlier stage in the disease.” Physicians battling this disease appreciated the importance of early detection, but did not know how to get there.

Papillomaviruses are a large and diverse group of small DNA viruses that infect epithelial tissues, and have evolved over millions of years. As parasites, they use species-specific animals and humans for replication. About 120 types of cutaneous or mucosal human papillomavirus (HPV) have been described in humans.

HPVs have a simple structure and are built of only a few proteins. The small circular genomes are organized into a set of six early genes (E6, E7, E1, E2, E4, and E5), which are involved in viral gene expression and replication control, and two late genes (L1 and L2), which encode the major capsid proteins. In cervical carcinogenesis, two of the early genes (E6 and E7) can transform cervical epithelium.

In 1976, Harald zur Hausen found the DNA of HPVs in cervical cancers and genital warts. In 1983, investigators in zur Hausen’s laboratory established HPV 16 as the leading candidate in the etiology of preinvasive and invasive cervical neoplasia. HPV types are widely classified into low-risk and high-risk groups according to their ability to promote malignant transformation. HPV types 16, 18, 31, 33, and others are now classified as high-risk types. In contrast, HPV 6, 11, 40, 42, and others are rarely found in cervical cancer and are considered low-risk types.

All cervical epithelia are vulnerable to HPV infection. The development of cervical cancer and its precursor lesions requires persisting infection with high-risk HPV (HR-HPV). HPV 16 infection results in predominantly squamous neoplasia, whereas HPV 18 and 45 have a greater tendency to induce glandular neoplasia. HPV 16 and 18 cause about 70% of cervical cancers. Together with HPV 31 and 45, and cofactors (e.g., smoking, immunodeficiency, number of sexual partners), they are the prime risk factors for cervical cancer.

Worldwide, about 300 million women are infected with HPVs. The majority of genital HPV infections remain asymptomatic, and the majority of infections resolve spontaneously. Genital HPV infection is transmitted almost exclusively through sexual and genital skin-to-skin contact. Most women acquire cervical HPV infection within a few years of initiating sexual intercourse. Coinfection with more than one HPV genotype is common, especially in young women. Most HPV infections clear as a result of cell-mediated immune response. About 90% of women with HPV infection become HPV-negative within 2 years. The peak rate of HPV infection is seen in women younger than 25 years, with a decline that plateaus around 30 to 35 years. In some countries, there is a slight increase in women over 50 years.

Cervical cancer is an occasional and late manifestation of infection with HR-HPV. The latency from initial HPV infection to invasive cancer is in the range of 8 years and more. HSIL correlates with a greater risk of progression to invasion than low-grade squamous intraepithelial lesions (LSIL). Spontaneous regression can occur in about 57, 43, and 32% of cases of CIN 1, CIN 2, and CIN 3 lesions, respectively, and persistence in 32, 35, and 56%. Only about 1% of CIN 1 lesions and 5% of CIN 2 lesions but more than 12% of CIN 3 lesions progress to invasive cervical cancer. In one study, untreated CIN 3 had a 30% probability of becoming invasive over a 30-year period.