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6. Van der Pol B. 2007. Trichomonas vaginalis infection: the most prevalent nonviral sexually transmitted infection receives the least public health attention. Clin Infect Dis 44:23–25.
CASE 6
A 40-year-old woman presented to her primary care physician for a routine annual health exam. She had no concerns beyond stress related to marital problems. She reported regular menstrual cycles every 4 weeks and a normal Pap history with no record of previous sexually transmitted infections. Her review of systems and pelvic examination were normal. Cervical sampling for a Papanicolaou-stained (Pap) smear was performed. Cytologic examination showed atypical squamous cells of uncertain significance (ASC-US), so the pathologist ordered a human papillomavirus (HPV) molecular detection test, which returned positive. Molecular testing for Chlamydia trachomatis and Neisseria gonorrhoeae was negative.
Due to her HPV-positive ASC-US result, the patient was referred to a gynecologist for evaluation. During this visit she stated she and her husband of 20 years had separated during the last year, and she had a new sexual partner. A colposcopy was performed in which cervical lesions were identified and biopsied. Pathologic examination of the biopsy showed benign endocervical epithelium with acute inflammatory 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
