Burghardt's Primary Care Colposcopy

Chapter 1

Human Papillomaviruses and Cervical Cancer

1.1 Etiology of Cervical Cancer

1.2 Natural History of Cervical Cancer

1.3 Morphogenesis of Cervical Cancer

1.4 HPV Vaccines

1 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.

1.1 Etiology of Cervical Cancer

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.

1.2 Natural History of Cervical Cancer

HPVs infect epithelial basal cells (reserve cells), which are responsible for regeneration of the epithelium (Fig. 1.1). Subcolumnar reserve cells enable metaplasia from columnar to squamous epithelium.

HPV infection probably occurs when minor trauma (e.g., sexual intercourse) exposes the basal cells (reserve cells) of the cervical mucosa to the virus. Expression of viral genes in individual infected basal cells leads to lateral extension of the initially HPV-infected cell clone (Fig. 1.2a,b).

The time from HPV infection to the development of high-grade squamous intraepithelial lesions (HSIL) varies widely. Generally, persisting infection with HPV 16, 18, or 45 entails a 20 to 30% risk for cervical intraepithelial neoplasia grade III (CIN 3, HSIL) over the next 5 years. However, some high-grade lesions, particularly with HPV 16 infection, develop quickly (i.e., 1 or 2 years after infection). Women with multiple HR-HPV infections are at increased risk.

Fig. 1.1 Individual reserve cells in the basal layer of the columnar epithelium. The nuclei stain darkly for p63.

Fig.1.2 (a) HPV entry model: uptake of HPV into the basal cells is mediated by endocytosis. Upon release from the particle, the circular viral genome is transported to the nucleus, where it resides as an extrachromosomal molecule. (b) Schematic description of the three distinct phases of HPV infection at the cervix. Minor lacerations of the epithelium permits contact of HPV with the cervical reserve (basal) cells. In the latent phase, the HPV genome releases viral copies in low numbers and without significant viral gene expression. In some instances, low levels of viral gene expression occur and result in viral replication (permissive phase). The late gene products permit packaging of the replicated viral genomes, and newly produced HPVs are released at the surface of the cervix. Morphologic effects include low-grade squamous intraepithelial lesions (LSIL). Transforming infections cause HSIL and adenocarcinoma in situ (AIS).

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.

1.2.1 Phases of HPV Infection

HPV infections go through three phases of viral gene expression: the latent phase, the permissive (productive) phase, and the transforming phase. After intraepithelial neoplastic transformation, some HSIL and adenocarcinoma in situ (AIS) will progress to invasive cervical cancer (Fig. 1.2).

Latent Phase

Latent infection does not produce infectious particles, remains clinically inapparent, and triggers no histopathologic changes. Most HPV infections probably end this way, without initiation of major viral gene expression.

Permissive (Productive) Phase

Permissive (productive) infection shows no signs of cellular transformation and can be caused by either low-risk or high-risk HPV types. It frequently results in characteristic morphologic changes of the infected cervical squamous epithelium (koilocytosis) (Fig. 1.3). This corresponds to condylomas or CIN 1 in histologic specimens or LSIL in cytologic specimens. Probably about 90% of productive infections become undetectable within 1 to 2 years, corresponding to spontaneous resolution of LSIL.

Fig. 1.3 (a, b) Permissive (productive) HPV infection with viral replication. (a) Staining for L1 shows HPV capsid protein (red) in superficial layers of the infected epithelium. (b) In situ hybridization shows newly produced HPVs (blue). (This image is provided courtesy of S. Syrjänen.)

Transforming Phase

Transforming infections are almost always associated with HR-HPV types. Transforming infections cause high-grade lesions. These lesions are referred to as CIN 2/3 in histology and HSIL in cytologic specimens (Fig. 1.4). For cancer to develop, HPV has to evade immune detection over a prolonged period for genetic abnormalities to accumulate. Not all HSIL or AIS will progress to invasive cancer.

1.3 Morphogenesis of Cervical Cancer

Squamous cell cervical cancer can develop in metaplastic squamous epithelium (inside the transformation zone) or in the original squamous epithelium.

1.3.1 Morphogenesis of Squamous Cell Carcinoma in Metaplastic Epithelium

Squamous cell carcinoma inside the transformation zone develops via SIL in fields of squamous epithelium of metaplastic origin. Metaplasia begins with the appearance of a row of subcolumnar reserve cells in a well-defined field (Figs. 1.5a-c and 1.6a-d). Later, immature metaplastic squamous epithelium can become mature (Fig. 1.7). Different fields of (immature and mature) metaplastic squamous epithelium can arise on the same cervix, simultaneously or at different times. If present, HPV infection usually does not affect the entire metaplastic epithelium. In permissive (productive) infections, virus replication is also limited to sharply defined fields (Fig. 1.8).

HSIL can appear at the very beginning of...