KEY POINTS■ Approximately 80% of women will be infected with human papillomavirus (HPV) at some point during their lifetime; however, a premalignant cervical lesion will actually develop in very few. Most infections will be transient.
■ Dysplasia seen on histology specimens is referred to as cervical intraepithelial neoplasia (CIN). Dysplasia seen on cytology is referred to as a squamous intraepithelial lesion (SIL). High-grade dysplasia as a manifestation of HPV infection will progress to carcinoma if left untreated.
■ The American Society for Colposcopy and Cervical Pathology and the American College of Obstetricians and Gynecologists recommend that every woman should be screened for cervical cancer by Pap smear starting at age 21 years or within 3 years of initial sexual activity—whichever comes first. Women younger than 30 years should be screened annually. Screening frequency can be lowered to every 2 to 3 years in women older than 30 years provided that three consecutive cytology findings are negative.
■ “Reflex” HPV testing is beneficial in triaging women with atypical squamous cells of undetermined significance seen on cervical cytology. Primary HPV testing as an adjunct to cervical cytology in women older than 30 years has increased sensitivity for detecting CIN II or CIN III.
Human papillomavirus (HPV) that infects the GU tract is the most common sexually transmitted infection in both men and women in the United States. Currently, an estimated 20 million Americans are infected with HPV; and each year, approximately 6.2 million people become newly infected.
1 HPV infection manifests as genital warts and is known to cause cervical cancer in women.2 Cervical cytology screening programs are among the most remarkable successes achieved in the prevention of cancer and cancer-related deaths. The introduction of HPV testing has further improved screening protocols. HPV DNA can now be readily identified through commercially available clinical tests.3 However, an understanding of the current recommendations for ordering an HPV test as well as an awareness of its limitations and risks are essential.
Approximately 80% of women will be infected with HPV at some point during their lifetime;4 however, a premalignant cervical lesion will actually develop in very few. Most cases will be transient viral infections, but a major limitation of the HPV test is that it does not distinguish a benign viral infection from a true precancerous lesion. Although clinical trials have shown that HPV testing has a role in cervical cancer screening protocols, inappropriate use of this test can lead to unnecessary follow-ups or invasive diagnostic procedures performed on a patient with a transient infection. This article reviews the current cervical cancer screening guidelines, with a focus on the role of HPV testing.
Human papillomavirus infection More than 100 types of HPV have been identified.5,6 These viruses are grouped as low- or high-risk based on their association with cervical cancer. Low-risk virus types (nononcogenic viruses) cause a spectrum of benign abnormalities. These viruses do not undergo a malignant transformation; instead the viruses cause koilocytes, cytologic changes consistent with HPV infection, or lead to condyloma acuminatum, a verrucous growth readily seen on physical examination of the cervix, vagina, perineum, or anus.3 The genital warts are usually caused by HPV types 6 and 11, the most commonly occurring low-risk HPV viruses. The high-risk virus types (oncogenic viruses) can also cause cytopathic changes seen on cytology as koilocytes; but unlike low-risk viruses, oncogenic viruses can cause changes that can be precursors to abnormal cellular development (dysplasia) that ultimately lead to malignant transformation and cervical cancer in susceptible patients.2
The most commonly occurring high-risk HPV types in the United States, HPV-16 and HPV-18, account for most cervical cancers. Other high-risk types that can be identified with FDA-approved assays are 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Both low- and high-risk viruses can cause condyloma. However, infections that progress to moderate or severe dysplasia are caused by the high-risk types.4 Although 80% of HPV infections are caused by high-risk types,4 most HPV infections do not require treatment. Approximately 70% of new HPV infections resolve within 1 year, and 90% of lesions regress spontaneously within 2 years.7 Persistent HPV infections can lead to cervical cancer 5 to 10 years after the onset of infection. Studies show that 10% of HPV infections progress to moderate or severe dysplasia within 2 years.8
CLASSIFICATION OF PRECANCEROUS LESIONS
Understanding the pathogenesis of precancerous lesions is essential to understanding the current cervical screening guidelines. Figure 1 illustrates the continuum of HPV infection as it develops into carcinoma in the cervical epithelium. The development of cervical cancer is a continuous disease process that progresses gradually through stages.2,4 HPV infects the cervical epithelium and causes pathognomonic changes, including cytoplasmic vacuolization, nuclear atypia (koilocytosis), and multinucleation. These changes can be seen on histology and cytology and are characteristic of condyloma acuminatum. As HPV infection progresses, dysplasia develops in the squamous epithelium. The Bethesda System is used for reporting cytology findings. Its terminology correlates with the progression of lesions in the cervix.
Dysplasia seen on histology specimens is referred to as cervical intraepithelial neoplasia (CIN), and the lesions are classified as grades I (mild), II (moderate), or III (severe). CIN I represents a benign viral infection similar to condyloma acuminata; therefore, these two diagnoses are simply referred to as low-grade lesions. Dysplasia seen on cytology is referred to as a squamous intraepithelial lesion (SIL). Cells taken from low-grade lesions are called low-grade SIL (LSIL), and cells taken from high-grade dysplasia are referred to as high-grade SIL (HSIL). HSIL corresponds to CIN II or CIN III. Highgrade dysplasia as a manifestation of HPV infection is a premalignant lesion and, if left untreated, will progress to carcinoma. HPV DNA in these high-grade lesions is incorporated into the host genome leading to cancer.2
Squamous cells that do not meet the diagnostic criteria for one of the Bethesda System categories are termed atypical squamous cells (ASC). Cytologists further classify these cells as atypical squamous cells cannot exclude high grade (ASC-H) if a high-grade lesion is suspected or as atypical squamous cells of undetermined significance (ASC-US) if a benign process is suspected. In the United States, ASC-US lesions are diagnosed in more than 2 million women and LSIL is diagnosed in more than 1 million women each year.9 The American Society for Colposcopy and Cervical Pathology (ASCCP) established guidelines for when to refer a patient for colposcopy and when only repeat cytology is appropriate. According to ASCCP guidelines, cytology that reveals LSIL, HSIL, or ASC-H should be followed-up with colposcopy to look for CIN.10