CE2. 5 HOURS Continuing Education By Kim K. Choma, MSN, APN,C & ASC-US HPV Testing When the Pap result is atypical squamous cells of undetermined significance, testing for the human papillomavirus may be the best approach to determining treatment. Jodie Zeke, a nurse practitioner, received initial Papanicolaou (Pap) test results of 27-year-old Laura Richardson that showed atypical squamous cells of undetermined significance (ASC-US). This was Ms. Richardson s first abnormal Pap test result; she had no history of sexually transmitted diseases and had had few sexual partners. Ms. Richardson had the option of repeating the Pap test in four months, but she didn t want to wait that long for results. She also could have had an immediate but was uncomfortable with the prospect of an invasive test. Instead of ordering immediate and possible biopsy, Ms. Zeke decided instead to order a test for the human papillomavirus (HPV), explaining to Ms. Richardson that because her initial Pap test was a liquid-based cytologic smear (known as liquid cytology, in which the cells swabbed from the cervix are rinsed in a vial of liquid preservative), another sample from the vial could be used to perform an HPV test. She wouldn t have to return for another pelvic examination. The HPV test results showed that Ms. Richardson did indeed have a cancer-associated (high-risk) form of HPV, and Ms. Zeke referred Ms. Richardson for immediate. Ms. Richardson was Kim K. Choma is a women s health nurse practitioner in private practice in Hillside, NJ. The author gratefully acknowledges Joseph A. Cerro, MPh, MA, senior scientist at the Bayer Corporation, Pharmaceutical Division, in West Haven, CT, for his assistance. Contact author: kimchoma@excite.com. terribly upset, saying that she had no idea she had a sexually transmitted disease. How could it have happened, she asked, when she d had only a few sexual partners and had never had any indication of a viral infection? About 75% of people of reproductive age have been infected with the sexually transmitted virus, yet many women, who are at increased risk for cervical cancer as a result of HPV infection, are unaware of the dangers associated with it. 1 Cervical cancer claimed an estimated 4,100 lives in the United States in 2002. 2 It therefore behooves nurses to know how to respond to patients who may not know of their risks. The best defense against invasive cervical cancer is early detection of abnormal cell growth. The National Cancer Institute (NCI) estimates that 50 million Pap tests are performed each year in the United States, and that more than 2 million women a year are diagnosed with ASC-US. 3 Many clinicians manage ASC-US aggressively, with immediate involving a pelvic examination, cervical exposure to acetic acid, cervical inspection under magnification, and cervical biopsy if indicated. Five percent to 10% of these 2 million women have high-grade cervical intraepithelial neoplasia (CIN) abnormal cervical cell growth. Cervical lesions are usually detectable with the Pap test, and treatment is generally not associated with complications. 4, 5 Widespread use of the Pap test in the United States during the past 50 years 42 AJN February 2003 Vol. 103, No. 2 http://www.nursingcenter.com
Findings on Papanicolaou smear Normal Large, surfacetype squamous cells Small, pyknotic nuclei Severe dysplasia (HSIL) Basal type cells Very high nucleus:cytoplasm ratio Marked hyperchromasia Abnormal chromatin Mild dysplasia (LSIL) Mild increase in nucleus:cytoplasm ratio Hyperchromasia Abnormal chromatin pattern Squamous cell carcinoma Marked pleomorphism Irregular nuclei Clumped chromatin Prominent nucleoli Normal cells Precancerous cells Cancerous cells Ectocervical lesion The National Cancer Institute s Bethesda System is a revision of the terminology used to describe cervical epithelial abnormalities. LSIL (low-grade squamous intraepithelial lesion) encompasses, among other classifications, mild dysplasia. HSIL (high-grade squamous intraepithelial lesion) encompasses, among other classifications, severe dysplasia. has resulted in a substantial decrease in the incidence of and deaths from cervical cancer, 2 although the test has limitations, including false-negative and false-positive results. False-negative results, the failure to detect lesions when they are present, occur at a rate (for a single Pap test) of about 20% 6 ; rates as high as 73% have been reported. 7 Hence, the Pap test can fail to identify a substantial proportion of patients who have cervical lesions. About two-thirds of false-negative results are caused by errors in sample collection or preparation by clinicians, while the remaining third are the result of a cytologist or technician mistaking abnormal cells for normal ones. 8, 9 False-positive results, the judging of normal cells to be abnormal, occur at a rate of about 5%, 10 and ajn@lww.com AJN February 2003 Vol. 103, No. 2 43
Risk Factors Certain factors may lead to the development of cervical intraepithelial neoplasia and cervical carcinoma, including the following: multiple sex partners or male partners who themselves have had multiple sex partners male sex partners who have had other sex partners with cervical cancer current or prior infection with the human papillomavirus, herpes simplex virus, or HIV; condylomata history of other sexually transmitted diseases immunosuppression smoking or use of other drugs, including alcohol history of cervical dysplasia or cervical cancer or endometrial, vaginal, or vulvar cancer low socioeconomic status Sources: Bristow RE, Montz FJ. Workup of the abnormal Pap test. Clin Cornerstone 2000;3(1):12-24; Recommendations on frequency of Pap test screening. Washington, DC: American College of Obstetricians and Gynecologists (ACOG): 1997. they may occur at an even higher rate. In reviewing all smears of women enrolled who d received ASC- US diagnoses, researchers in the Atypical Squamous Cells of Undetermined Significance Low-grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study (ALTS) downgraded the diagnosis to negative in 31% of cases. 11 The financial and psychological burdens associated with provide incentive to better determine who requires and who would benefit from alternative approaches. In the ALTS, three approaches to managing ASC-US were compared: immediate with cervical biopsy, testing for cancer-associated (high-risk) HPV infection, and follow-up cytologic testing. The ALTS researchers concluded that HPV assays are sensitive detectors of precancerous lesions. Hence, HPV testing may be a convenient tool for identifying the relatively small number of patients who are at highest risk for cervical cancer, while making and biopsy unnecessary for those whose ASC-US condition is likely to regress. Because of advances in the understanding of cervical cancer prevention and recent findings from research trials, the NCI held a workshop for 400 professionals in May 2001 to review the terminology used in the Bethesda Classification System (the group s recommendations are online at http:// bethesda2001.cancer.gov/terminology.html). 12 In September 2001 the American Society for Colposcopy and Cervical Pathology devised guidelines, using the revised terminology, for the management of cytologic abnormalities and cervical cancer precursors. These guidelines were designed to help clinicians treat women who have cytologic abnormalities and who may also have high-risk HPV. 13 (See The Consensus Guidelines ASC-US Algorithm, page 45.) No recommendations were made for treatment of women with low-risk HPV types. Most cervical squamous cell abnormalities are categorized (in the 2001 Bethesda system) as follows: atypical squamous cells (ASC), which can be subcategorized in two ways: atypical squamous cells of undetermined significance (ASC-US) atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesion (ASC-H) low-grade squamous intraepithelial lesion (LSIL), which encompasses HPV, dysplasia, and CIN 1 (mild dysplasia) high-grade squamous intraepithelial lesion (HSIL), which encompasses moderate dysplasia, severe dysplasia (CIN 2 and CIN 3, respectively), and carcinoma in situ squamous cell carcinoma, an invasive form of cervical cancer THE LIMITS OF CYTOLOGIC SCREENING Pap test results of HSIL are associated with persistent or progressing lesions, or in the worst case, with undetected invasive carcinoma. Consequently, immediate with cervical biopsy is indicated; this practice is generally accepted without argument. 14 In contrast, the management of ASC-US and LSILs varies and is controversial because these two diagnoses do not always indicate a precancerous condition. The most common abnormality found in Pap tests is ASC-US; about 5% of all Pap test diagnoses delivered each year are ASC-US. 15 Roughly two-thirds of patients with ASC-US and half of patients with LSILs experience spontaneous regression of symptoms. 16 Providers have not had effective means of predicting whether atypical cells will become a significant preinvasive lesion or malignancy. As a result, consensus on the best way 14, 17 to manage ASC-US has been difficult to reach, leaving providers to decide whether to pursue conservative or aggressive options. Conservative management of ASC-US or LSILs consists of follow-up Pap tests at four-to-six-month intervals (for a total of three tests). The effectiveness of the conservative approach can be seriously undermined if patients don t comply with follow-up screening. Also, the impact of ambiguous test results 44 AJN February 2003 Vol. 103, No. 2 http://www.nursingcenter.com
The Consensus Guidelines ASC-US Algorithm Management of Women with Atypical Squamous Cells of Undetermined Significance (ASC-US) Repeat Cytology @ 4-6 mos HPV DNA Testing Preferred if liquid-based cytology or co-collection available Negative ASC HPV Positive (for high-risk types) HPV Negative (for high-risk types) Repeat Cytology @4-6 mos Negative ASC Colposcopy Repeat Cytology @12 mos Routine Screening No CIN / Cancer CIN / Cancer HPV Negative or unknown HPV Positive (for high-risk types) Manage per ASCCP Guideline Repeat Cytology @12 mos Cytology @6 & 12 mos OR HPV DNA testing @ 12 mos ASC or HPV (+) Negative Repeat Colposcopy Routine Screening HPV = human papillomavirus; ASC = atypical squamous cells; CIN = cervical intraepithelial neoplasia; ASCCP = American Society for Colposcopy and Cervical Pathology; (+) = positive. The Consensus Guidelines ASC-US Algorithm originally appeared in and is reprinted from the Journal of Lower Genital Tract Disease, Volume 6, Issue 2, and is reprinted with the permission of the ASCCP. American Society for Colposcopy and Cervical Pathology 2002. No copy of the algorithm may be made without the prior consent of the ASCCP. on patients shouldn t be discounted, especially when follow-up screening takes place months after an initial inconclusive finding. The conservative approach is preferred unless the patient 14 had suspicious findings, such as visible lesions, on previous gynecologic examinations. had previous abnormal Pap tests results. is unlikely to return for follow-up. has a history of sexually transmitted diseases. is involved in high-risk sexual behaviors (such as having a number of partners). is a long-term or heavy smoker. is immunocompromised. Any of these points can indicate the need for immediate with cervical biopsy. Aggressive management involves immediate referral for with cervical biopsy. Endocervical curettage, the scraping of the cervical canal with a curette to obtain epithelial cell samples, is typically performed in conjunction with if abnormal cells aren t immediately apparent through magnification. Colposcopically directed biopsy is regarded as the gold standard for identifying dysplasia, but even with this method cases of advanced dysplasia can be missed because of imperfect sampling or regression of lesions from the time 10, 18 of the initial Pap test. ajn@lww.com AJN February 2003 Vol. 103, No. 2 45
These results indicate that HPV testing is a viable option for women and their [clinicians] to consider when deciding what to do about ASC-US. Diane Solomon, principal investigator There are several disadvantages to the use of for frontline management of ASC-US, including the following. Emotional distress. The discomfort associated with biopsy may produce anxiety, sometimes extending well beyond completion of the procedure. Cost. Even though without cervical biopsy is somewhat less costly than conservative management (with its three Pap tests) (roughly $115 versus $159, respectively), with cervical biopsy can be nearly three times as expensive (approximately $454) 19 and may discourage those without health insurance. Hence, is recommended only for those women who are most likely to develop invasive carcinomas. 11 The ASCUS LSIL Triage Study (ALTS) A comparision of three approaches to management of ASC-US. From November 1996 to December 1998, 3,488 women from four clinics in the United States who had just received a diagnosis of atypical squamous cells of undetermined significance (ASC-US) as a result of a Papanicolaou (Pap) test participated in the study. Study participants were randomly assigned to one of three management groups, referred to as study arms: the immediate- arm the human papillomavirus (HPV) arm, which involved rescreening with a liquid-based cytologic Pap test and an HPV test; findings of any high-grade squamous intraepithelial lesion (HSIL) or high-risk HPV types (those carrying a high risk of subsequent cervical cancer) indicated the conservative management arm, which entailed rescreening with a Pap test only; only women with a diagnosis of HSIL or worse (HSIL+) were referred for (otherwise the women were referred for a repeat Pap test six months later) Nurse clinicians performed pelvic examinations on all patients. Pap tests and HPV testing were performed using the ThinPrep (Cytyc, Boxborough, Massachusetts) liquid-based Pap test and the hybrid capture 2 (HC2) assay (Digene, Gaithersburg, Maryland), respectively. A photographic image of the cervix was also obtained. All women in the immediate arm received colposcopic examinations. If any cervical intraepithelial neoplasia (CIN) was detected, a directed biopsy was performed. If the biopsy showed CIN of grade 2 (moderate) or above (CIN 2+), a loop electrosurgical excision was performed, in which a thin loop of wire is used to excise abnormal tissue from the cervix; the tissue is then sent for histological analysis. Patients assigned to the HPV and conservative management arms were referred for if their Pap tests at enrollment revealed HSIL+ (HSIL, glandular abnormalities, or cancer). From that point on for women in these two arms, management was the same as that for women in the arm. Also, patients in the HPV arm were referred for if the HC2 test was either positive for a high-risk HPV type or if the HC2 test was missing (the test wasn t performed or the specimen of cervical cells was inadequate for DNA analysis). Sensitivity. The accuracy of a test its ability to determine whether a disease state exists is referred to as its sensitivity. Biopsy taken during is the gold standard (the most sensitive method) for assessing cervical epithelial tissue, but it s also expensive. One of the aims of the ALTS was to determine whether HPV testing enhanced clinicians ability to establish which women of those who had Pap test results of ASC-US required immediate treatment. Researchers found that the HC2 test was an extremely sensitive method of detecting precancerous lesions (96% of women who were confirmed to have CIN 3+ or CIN 2+ had an HC2 test result showing high-risk HPV). These results indicate that HPV testing is a viable option for women and their [clinicians] to consider when deciding what to do about ASC-US, said Diane Solomon, ALTS principal investigator. 46 AJN February 2003 Vol. 103, No. 2 http://www.nursingcenter.com
Design of the ALTS 3,488 women with ASC-US (as determined by Pap test) were randomly assigned to 1 of 3 groups (arms). Immediate (n = 1,163) HPV (n = 1,161) Conservative management (n = 1,164) Seen by nurse clinicians for enrollment examination 1,149 underwent (1.2% lost to follow-up) 651 (56.1%) referred for 510 (43.9%) not referred for 101 (8.7%) referred for 1,063 (91.3%) not referred for 611 underwent (6.9% lost to follow-up) 94 underwent (6.1% lost to follow-up) 114 underwent loop electrosurgical excision 130 underwent loop electrosurgical excision 65 underwent loop electrosurgical excision Findings among the 1,149 women in the immediate arm of the ALTS who underwent CIN 2 6% CIN 3+ 5% ASC-US 2% CIN 1 15% No pathological lesion on biopsy 47% No lesion found on 25% Biopsy taken during is considered the gold standard for identifying cervical cancer and precancerous lesions. The proportion of histologically confirmed lesions in the immediate arm reflects the prevalence of the disease in the total study population. ajn@lww.com AJN February 2003 Vol. 103, No. 2 47
HPV in Men Who Have Sex with Men Screening may help prevent development of anal cancer. O f the approximately 120 HPV types, about 30 infect the squamous epithelium of the lower anogenital tracts of both men and women. In fact, anal cancer and cervical cancer are screened similarly. Because HPV is a precursor to anal cancer, men who have sex with men, particularly those who are HIV positive, are susceptible to anal cancer. Some clinicians argue that HPV testing in these men could help in preventing anal cancer. (For more information, see http://mednews.stanford.edu/news_releases_html/2002/ junreleases/anal_cancer.html.) ADVANCES IN DIAGNOSIS Virtually all cervical carcinomas harbor at least one of several specific strains of HPV.20, 21 Indeed, about half of all cervical cancers worldwide are characterized by the presence of HPV type 16 DNA. 22 This is important because proteins produced by some HPVs play a major part in the progression of lesions to malignancy by interfering with the normal activity of tumor-suppressor genes. Early detection of HPV type 16 and other cancer-associated HPV types in cervical cell samples may predict patient susceptibility to dysplasia. 21 Also, a recent study has shown a vaccine to have some efficacy against HPV type 16, which could have a profound effect on the incidence of cervical cancer. (See News, page 20, for more information.) HPV types 6, 11, 42, 43, and 44 are often associated with genital warts or flat lesions that may not always be visible; these types are rarely found in cervical cancer and are termed low-risk HPV types. 23 The NCI deems a number of HPV types high risk because they are found primarily in cervical and other anogenital cancers. HPV types 16, 18, 31, and 45 account for roughly 80% of cervical cancers. 23 Both low- and high-risk HPV types may resolve spontaneously without treatment, but clinicians can t at present determine which will regress or 21, 23 progress. DETECTING HPV The Hybrid Capture 2 (HC2 or HC-II) assay (Digene, Gaithersburg, Maryland), is currently the only assay approved by the Food and Drug Administration for the detection of HPV. HPV DNA specimens collected during a liquid-based cytologic Pap test are obtained with a separate cervical brush and placed in a transport medium. (If providers use the conventional, nonliquid smear method, patients will have to return to have DNA probe cultures taken.) With the HC2 assay, samples are incubated with probes that detect high-risk HPV types. If a Pap test shows ASC-US, the practitioner can order the laboratory to obtain another sample of cells from the Pap vial for the HC2 test. This is called reflexive HPV testing, and it s relatively inexpensive when compared with and biopsy 19, 24, 25 ; the assay costs about $50 when cell samples are taken from the same vial used for the Pap test. HPV test results using HC2 are categorized as either high-risk positive or negative. Testing for specific HPV types is usually done in research settings. THE ALTS It appears that adjunctive HPV testing with Pap screening might provide sensitivity comparable to that of with cervical biopsy. The ALTS was designed to help resolve the controversy surrounding the management of ASC-US and to determine whether HPV testing is a cost effective and accurate way to triage women who 8, 11, 26 have ASC-US. Findings of the ALTS support the use of HPV testing as a component of cervical cancer screening. With respect to the detection of CIN 2 and CIN 3 (the plus signs indicate that grade or higher), the HC2 method is more sensitive than a single follow-up Pap test for triaging patients with an initial ASC-US 8, 11, 26 diagnosis. Also, a negative HC2 test result strongly indicates that the patient is free of dysplasia, which should minimize a patient s anxiety. (See The ASCUS LSIL Triage Study (ALTS), page 46.) Some interpretive caution is merited. 27, 28 The first report from the ALTS included data from only one follow-up Pap test from study subjects (final data have not been reported). 11 Conservative management is based upon a program of periodic Pap testing, not a single follow-up. The cumulative 14, 17 sensitivity of several cytologic tests may be greater than that of a single Pap test, perhaps even approaching the sensitivity of HC2 testing. Hence, conservative management may be as effective as a single HPV test for detecting neoplastic conditions. It s unclear, however, whether the stress and cost of extended follow-up visits would outweigh the benefits of a single Pap test with adjunctive HPV testing. Forthcoming studies will investigate cost effectiveness, utility, and patient compliance under various management approaches. 29 Similarly, the effect of patient age on HPV test sensitivity was not analyzed in the ALTS (study par- 48 AJN February 2003 Vol. 103, No. 2 http://www.nursingcenter.com
ticipants were at least 18 years old). For example, cervical cancer rarely occurs in women in their teens and early 20s, yet the incidence of HPV infection is significantly higher in this age group than in women older than 40. 30 Hence, it s unknown whether HPV testing is useful for determining the course of treatment ( or conservative methods) in young women with ASC-US. IMPLICATIONS FOR NURSING PRACTICE Be sure to know the risk factors for cervical abnormalities so that you can teach patients about them. Remind your patients of proper preparations for a Pap test, such as abstaining from intercourse for 24 hours prior to testing, avoiding placing any substances in the vagina (such as douches, contraceptive gels, and lubricating preparations) for 48 hours prior to testing, and waiting until midcycle to be tested. 31 Educate your patients on HPV transmission. Total abstinence from sex is the only way to prevent HPV transmission. Condoms do afford some protection, but they will not protect a partner (male or female) if there are lesions on areas not covered by the condom (such as the vulva, the base of penis, or the scrotum). Because HPV can lie dormant in the body for long periods before those infected develop noticeable symptoms such as genital warts, it s difficult to determine when HPV exposure occurred or from whom it was transmitted. Educate your patients on having HPV. HPV is extremely common. Replacing fear with confidence and knowledge can help a patient better cope with having HPV and help the reluctant patient return for follow-up examinations. Genital warts. If a patient has genital warts, which are associated with low-risk HPV types, she may follow the current consensus guidelines, which stipulate regular annual Pap testing if the initial test is normal. If the patient has ASC-US, immediate is warranted. Patients usually have the warts removed, either mechanically (with a laser or by freezing) or chemically. Guidelines for follow-up examinations are flexible. Clinicians may choose to see patients three or six months after warts are removed. A healthy immune system helps to keep HPV inactive. General recommendations include adequate sleep, proper nutrition, and reduced stress. 23 High-risk HPV types. A test result that s positive for a high-risk HPV type doesn t represent a diagnosis of cervical cancer. There is actually very little risk of developing cervical cancer unless the HPV goes undetected and untreated, which is why regular Pap testing and treatment for precancerous lesions are 21, 23 essential. Like Ms. Richardson, patients diagnosed with high-risk HPV are referred for immediate and possible biopsy. HPV symptoms. Except for visible external warts, HPV rarely has any noticeable symptoms; there may be slight itching with recently formed warts. If burning or itching is present, vaginitis or chemical irritants should be considered a cause. 32 Intra- or postcoital bleeding, vaginal bleeding between periods, and continuous abnormal discharge without burning or itching may be associated with cervical cancer. 32 The majority of people with an effective immune response will become HPV negative six to 24 months from the initial Pap test, whether they have high-risk or low-risk HPV. 23 It s unclear whether the virus is actually eradicated or merely suppressed until it s at undetectable levels. REFERENCES Complete the CE test for this article by using the mail-in form available in this issue or by going to Online CE at www.ajnonline.com. 1. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997;102(5A):3-8. 2. Jemal A, et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52(1):23-47. 3. National Cancer Institute. Questions and answers about the Pap test. 2001. http://cis.nci.nih.gov/fact/5_16.htm. 4. Ferenczy A, Franco E. Cervical-cancer screening beyond the year 2000. Lancet Oncol 2001;2(1):27-32. 5. O Meara AT. Present standards for cervical cancer screening. Curr Opin Oncol 2002;14(5):505-11. 6. Stoler MH. Advances in cervical screening technology. Mod Pathol 2000;13(3):275-84. 7. Renshaw AA, et al. The human false-negative rate of rescreening Pap tests. Measured in a two-arm prospective clinical trial. Cancer 2001;93(2):106-10. 8. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001;285(11):1500-5. 9. Selvaggi SM. Implications of low diagnostic reproducibility of cervical cytologic and histologic diagnoses. JAMA 2001;285(11):1506-8. 10.Renshaw AA. Measuring sensitivity in gynecologic cytology: a review. Cancer 2002;96(4):210-7. 11.Solomon D, et al. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93(4):293-9. 12.Solomon D, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287(16):2114-9. 13.Wright TC, Jr., et al. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287(16):2120-9. 14.Bristow RE, Montz FJ. Workup of the abnormal Pap test. Clin Cornerstone 2000;3(1):12-24. ajn@lww.com AJN February 2003 Vol. 103, No. 2 49
15.Davey DD, et al. Atypical epithelial cells and specimen adequacy: current laboratory practices of participants in the college of American pathologists interlaboratory comparison program in cervicovaginal cytology. Arch Pathol Lab Med 2000;124(2):203-11. 16.Melnikow J, et al. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol 1998;92(4 Pt 2):727-35. 17.Mashburn J. Evolution of the evidence-based Papanicolaou smear. J Midwifery Womens Health 2001;46(3):181-9. 18.Nanda K, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000;132(10):810-9. 19.Patient information for ASCUS Pap tests. Washington, DC: American Medical Women s Association, Inc.; 2002. http://www.amwa-doc.org/education/amwaguidelines 1.07.02_v1.pdf. 20.Walboomers JM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189(1):12-9. 21.zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2(5):342-50. 22.Bosch FX, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87(11):796-802. 23.Cox T, et al. Clinical proceedings: human papillomavirus (HPV) and cervical cancer. Washington DC: Association of Reproductive Health Professionals; 2001. http://www.arhp. org/healthcareproviders/onlinepublications/ clinicalproceedings/cphpv/contents.cfm?id=92. 24.Apgar BS, Brotzman G. HPV testing in the evaluation of the minimally abnormal Papanicolaou smear. Am Fam Physician 1999;59(10):2794-801. 25.Kim JJ, et al. Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance. JAMA 2002;287(18):2382-90. 26.Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. J Natl Cancer Inst 2000;92(5):397-402. 27.Kaufman RH. Is there a role for human papillomavirus testing in clinical practice? Obstet Gynecol 2001;98 (5 Pt 1):724-5. 28.Herbst AL, et al. The management of ASCUS cervical cytologic abnormalities and HPV testing: a cautionary note. Obstet Gynecol 2001;98(5 Pt 1):849-51. 29. Solomon D, Schiffman M. Re: Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a random trial. J Natl Cancer Inst 2001;93(12):950-1; discussion 951-2. 30.Stoler MH. HPV for cervical cancer screening: is the era of the molecular pap smear upon us? J Histochem Cytochem 2001;49(9):1197-8. 31.Contraceptive technology. Hatcher R, et al., editor. New York: Ardent Media; 1998. 32.Association of Reproductive Health Professionals. Quick reference guide to patient questions about HPV [Website]. 2001. http://www.arhp.org/healthcareproviders/ onlinepublications/clinicalproceedings.cfm?id=163. CE2. 5 HOURS Continuing Education GENERAL PURPOSE: To present registered professional nurses with the latest information on atypical squamous cells of undetermined significance (ASC-US) and human papillomavirus (HPV) infection, including significance, detection, and treatment options. LEARNING OBJECTIVES: After reading this article and taking the test on the next page, you will be able to: Discuss the nomenclature used in identifying cytologic abnormalities found on Papanicolaou smear. Outline the incidence, risk factors, symptoms, and classification of ASC-US, HPV, and cervical cancer. Describe the interrelationships among ASC-US, HPV, and cervical cancer and the appropriate protocols following diagnosis of ASC-US or HPV. To earn continuing education (CE) credit, follow these instructions: 1. After reading this article, darken the appropriate boxes (numbers 21 37) on the answer card between pages 40 and 41 (or a photocopy). Each question has only one correct answer. 2. Complete the registration information (Box A) and help us evaluate this offering (Box C).* 3. Send the card with your registration fee to: Continuing Education Department, Lippincott Williams & Wilkins, 345 Hudson Street, New York, NY 10014. 4. Your registration fee for this offering is $16.95. If you take two or more tests in any nursing journal published by Lippincott Williams & Wilkins and send in your answers to all tests together, you may deduct $0.75 from the price of each test. Within six weeks after Lippincott Williams & Wilkins receives your answer card, you ll be notified of your test results. A passing score for this test is 13 correct answers (76%). If you pass, Lippincott Williams & Wilkins will send you a CE certificate indicating the number of contact hours you ve earned. If you fail, Lippincott Williams & Wilkins gives you the option of taking the test again at no additional cost. All answer cards for this test on ASC-US and HPV Testing must be received by February 28, 2005. This continuing education activity for 2.5 contact hours is provided by Lippincott Williams & Wilkins, which is accredited as a provider of continuing nursing education (CNE) by the American Nurses Credentialing Center s Commission on Accreditation and by the American Association of Critical-Care Nurses (AACN 9722, category O). This activity is also provider approved by the California Board of Registered Nursing, provider number CEP11749 for 2.5 contact hours. Lippincott Williams & Wilkins is also an approved provider of CNE in Alabama, Florida, and Iowa, and holds the following provider numbers: AL #ABNP0114, FL #FBN2454, IA #75. All of its home study activities are classified for Texas nursing continuing education requirements as Type 1. *In accordance with Iowa Board of Nursing administrative rules governing grievances, a copy of your evaluation of this CNE offering may be submitted to the Iowa Board of Nursing. 50 AJN February 2003 Vol. 103, No. 2 http://www.nursingcenter.com