cells, but no squamous epithelium was present for evaluation. Since the biopsy showed no evidence of dysplasia or HPV cytopathic effect, the patient was asked to follow up in 6 to 12 months.
At 6 months, her physical exam was normal with the exception of presumed bacterial vaginosis. A Pap smear was repeated and showed ASC-US, which was HPV positive. A colposcopy was performed, and lesions were biopsied. Pathologic examination of two biopsies showed squamous and endocervical mucosa present with reactive epithelium changes, but no dysplasia or HPV cytopathic effect was identified. Six months later a repeat Pap was normal and HPV testing was negative, so she was told to return in 1 year.
At her next annual exam, a Pap examination showed atypical squamous cells including both low-grade and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively). She was again HPV positive. Three biopsies were obtained which showed high-grade dysplasia that could not be further characterized due to scant sampling, but was likely CIN 2 or CIN 3 (cervical intraepithelial neoplasia, a cervical cancer precursor). Subsequently, she underwent a loop electrosurgical excision procedure (LEEP) which did not show any remaining dysplasia at the margins.
1 1. What is the most common outcome of HPV infection? In what patient population is HPV most prevalent?
2 2. Describe the range of infectious complications associated with HPV.
3 3. What are the pathologic changes associated with persistent HPV infection of the female genital tract?
4 4. Several molecular tests are available for the detection of HPV DNA. What are the challenges associated with these tests? What are the advantages of molecular tests for HPV?
5 5. What guidelines exist for the monitoring of HPV infection and atypical Pap results? At what intervals should testing take place?
6 6. How can HPV infections be prevented?
CASE 6 CASE DISCUSSION
1. HPV is the most common sexually transmitted infection, resulting in ~14 million new infections annually in the U.S. Although there are an estimated 79 million HPV infections currently in the U.S., about 90% are asymptomatic and resolve within 2 to 3 years with no associated morbidity. The peak prevalence for HPV infections is seen in sexually active individuals 15 to 24 years old; this group represents 50% of all new HPV and other sexually transmitted infections. For this reason, it is not recommended that women under 30 years of age be routinely tested for HPV. In this patient population, HPV infection is most commonly transient and poses no risk for the development of cancer.
2. There are over 150 types of HPV, 40 of which can be sexually transmitted. HPV can cause either a cutaneous or mucosal infection depending on the tropism of the specific virus. Cutaneous infections present as non-genital warts, which include common warts, plantar warts, and flat warts. HPV types 1, 2, 3, 7, and 10 are most commonly associated with cutaneous warts. Although relatively common in all age groups, warts occur with a peak incidence in children aged 12 to 16. Mucosal infections include genital warts; cancers of the cervix, anus, external genitalia, and oropharnyx; and recurrent respiratory papillomatosis. Among sexually active individuals, genital warts range in prevalence from 1 to 10% with a peak incidence in 20- to 24-year-old persons. Risk factors associated with genital warts include infection with HPV types 6 and 11, introduction of new sexual partners, and an increased number of sexual partners. Cervical cancer is most commonly caused by persistent infection with types 16 and 18, which, combined, cause ~70% of cervical cancers. The remainder is caused by other high-risk HPV types. (See question 3 for further discussion of HPV and cervical cancer.) The incidence of HPV-associated anal cancer has been on the rise during the past 30 years and is primarily due to type 16. Risk factors for this uncommon cancer include female gender, HPV infection, increased number of partners, genital warts, cigarette smoking, receptive anal intercourse, and HIV infection. Some cancers of the external genitalia (penile, vulvar, and vaginal cancers) are associated with HPV infections and tend to occur in younger patients than HPV-negative cancers. Squamous cell carcinomas of the head and neck may also be due to HPV, but like cancers of the external genitalia, not all are associated with HPV. HPV-associated head and neck cancers are primarily found in the oropharynx and the base of the tongue and tonsil. Oral cancers due to HPV infection occur in younger individuals with increased sexual risk factors and are more common in men. Lastly, recurrent respiratory papillomatosis (RRP) is thought to be due to HPV acquisition during birth and presents as laryngeal warts in childhood, although adult cases have also been reported. RRP is associated with HPV types 6 and 11 and is generally benign. However, if not removed, laryngeal warts can lead to obstruction and can occasionally be aggressive and malignant.
3. The development of cervical cancer usually takes several years of persistent HPV infection. Thus, the patient’s recent change in sexual partners is likely not the initial source of the HPV infection causing her cervical changes. Disease progression is linked to high-risk oncogenic HPV types (e.g., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 69, 82), whereas low-risk types are only rarely associated with the development of cervical cancer and, therefore, are not routinely detected by HPV tests (e.g., 6, 11, 40, 42, 43, 44, 54, 61, 72, 81). Two main classification systems exist to describe HPV-associated changes in the cervical epithelium. The Bethesda system is primarily used to described changes seen by cytology (i.e., liquid-based Pap testing), whereas the CIN system is primarily used to describe the neoplasia seen by histology (i.e., biopsies obtained during colposcopy). Table 6.1 summarizes dysplasia classification and the associated interpretations. It should be noted that persistent HPV infection with a high-risk type most often does not progress through all of these stages. All precancerous stages have a significant likelihood of regression, with a greater percentage of the low-grade abnormalities regressing compared to high-grade dysplasia. It has been reported that up to 43% of CIN 2 and 32% of CIN 3 may regress without intervention. Invasive cancer is more commonly diagnosed in women over 40 years old, typically 8 to 13 years after identification of a high-grade lesion.
4. There are currently four FDA-approved tests for the detection of HPV DNA from liquid cytology specimens. The detection chemistries range from hybrid capture and Invader chemistry (signal amplification) to PCR and transcription-mediated amplification (target amplification of DNA and RNA, respectively). The initial clinical trials were performed with the hybrid capture system. Using CIN 2 or greater as an endpoint, hybrid capture had a 96% sensitivity (compared to 55% sensitivity of Pap smear). The development of amplification-based tests has led to an increase in analytic sensitivity, but no apparent increase in clinical sensitivity. The detection of HPV DNA by molecular screening has reduced cervical cancer rates by providing detection often prior to traditional cytology. Further, a negative HPV test in the setting of ASC-US prevents many unnecessary colposcopies. An additional advantage is the ability to detect only high-risk HPV types, which increases the clinical specificity of HPV detection. The more recently approved tests also have the ability to provide type-level results for types 16 and 18 such that positive women (even with normal Pap smear) will be followed by colposcopy due to the increased oncogenic potential of these types. One concern with the molecular methods is sample contamination, particularly if liquid cytology specimens are processed via automation. Some versions of automated processors have been shown to cross-contaminate specimens, but more recent automation appears not to have that problem. Nonetheless, to minimize the possibility of laboratory contamination, it is prudent to aliquot from the liquid cytology vial for HPV testing prior to placing the vial on an automated processor. Another concern is that a negative HPV test in a low-risk patient increases the time until the next Pap/HPV test to 5 years. Many physicians are concerned that patients will cease to present for annual health maintenance, which includes screens for many other important women’s health issues, such as breast cancer.
5. Three guidelines exist for cervical cancer screening. Guidelines updated in 2012 are available from the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP); from the American College of Obstetricians and Gynecologists (ACOG); and from the U.S. Preventative Services Task Force (USPSTF). All three guidelines agree that women