ISSUES IN CERVICAL CANCER PREVENTION
| HPV: EPIDEMIOLOGY, CLINICAL BURDEN, AND PREVENTION OF DISEASE —Levi S. Downs, Jr, MD,
Assistant Professor, Department of Obstetrics, Gynecology, and Women’s Health, University of Minnesota Medical
School, Minneapolis
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| Prevalence of human papillomavirus (HPV): United States—estimated 20 million people infected with HPV; annual
incidence estimated at 6 to 9 million people; study at McGill University (2001) shows incidence in college-age
sexually active women 80% (lifetime risk 50%); investigators believe real prevalence of HPV unknown; 1.4 million
annual cases of low-grade cervical dysplasia (significantly lower number of cases of high-grade dysplasia) contrasted
with only 9000 annual cases of cervical cancer (multifactorial reasons, eg, some women have ability to clear
viral infection repeatedly); cervical cancer—leading cause of cancer death in sub-Saharan Africa; second most
common cause of overall female cancer-related mortality worldwide; in United States, cervical cancer second to
breast cancer as leading type of cancer in women <40 yr of age
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| HPV types: several species infected with HPV (eg, oral HPV in canines); >100 types identified; types categorized
based on DNA sequence of specific viral type; 30 to 40 types infect anogenital region; currently 21 classified as
high-risk types (HPV types 16 [HPV-16] and 18 [HPV-18] account for majority of cervical cancers); low-risk types
(HPV types 6 [HPV-6] and 11 [HPV-11]) associated with low-grade dysplasia (cervical intraepithelial neoplasia
grade I [CIN I and genital warts])
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| Risk factors: young age—data show 75% of patients infected over 5-yr period were 15 to 24 yr of age; lifetime
number of sexual partners—more people exposed to, higher likelihood of infection; early age of first sexual
intercourse—increases likelihood of exposure to high number of sexual partners; cells of cervical transformation
zone highly active in pubescent girls and more sensitive to impact of HPV infection; high-risk male partner; tobacco
use—potential concentration of carcinogens in mucus of cervix; suspected more likely due to decreased secretion
of antibodies (IgG and IgA) involved in protection against HPV infection; oral contraceptives—believed
related to change in sexual practices (eg, decreased use of barrier methods); animal models show direct molecular
link between exposure to estrogen and progesterone and progression of HPV-related disease; age at first intercourse
independent risk factor for development of cervical cancer and persistent HPV infection—lifetime risk increased
2-fold for women beginning sexual intercourse (regardless of number of partners) at 18 yr of age; risk
increased 6-fold for women <17 yr of age
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| Biology of HPV infection: break in epithelium necessary for viral particles to migrate to basal cell layer of cervix,
where replication and production of proteins occurs; in setting of high-risk HPV infection, viral DNA (circular) integrated
into host’s DNA (linear); where DNA inserts (still circular) into host genome variable, but where it breaks
(becomes linear for insertion to occur) always occurs in region of gene that codes for protein E2 (regulatory protein);
when E2 nonfunctioning, overexpression of E6 and E7 occurs; interferes with p53 and retinoblastoma protein
(pRB; tumor suppressor proteins) function, eventually leading to cervical cancer; natural history of HPV infection
and potential progression to cervical cancer—generally takes between 10 to 20 yr (weakened immune system or
more virulent viral strain can shorten time span); repeated use of Papanicolaou (Pap) test and increasing sensitivity
helps in identifying lesions likely to progress to cervical cancer; CIN II and III markers for cervical cancer; cervical
cancer—in United States, primarily disease of minority (underserved) population (eg, incidence and mortality in
black women twice that of white women); significant decrease in incidence over past 30 yr, but plateauing; in
2000, number of cases in United States estimated to be 15,000; in 2006, <10,000 estimated cases (30% decrease,
without implementation of vaccine program); other HPV-associated cancers—≈50% of vulvovaginal cancers,
50% of penile cancers, >70% of anal cancers, and 20% of oropharyngeal cancers (but ≥50% when cancers directly
related to cigarette smoking subtracted)
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| HPV vaccine: quadrivalent vaccine currently available; bivalent vaccine in development that specifically targets
HPV types responsible for cervical cancer; therapeutic vaccines in development (in phase 3 trials) to treat women
with high-grade HPV-related lesions (eg, DNA vaccine); current vaccine—designed to prevent disease related to
HPV-6, -11, -16, and -18; injection combination of proteins (viral-like particles); protein in vaccine exact replication
of outer shell of viral types 6, 11, 16, and 18; proteins reassemble to exactly replicate outer capsid of HPV vaccine;
aluminum adjuvant added to enhance impact of protein’s response from immune system
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| Research data: lifetime follow-up of subjects in Norwegian study to provide data on side effects or new toxicities
associated with HPV vaccine and differences in rate of prevention; HPV-16– and HPV-18–related CIN II and
III as end point—vaccine showed 100% efficacy against HPV-16– and HPV-18–related cervical cancer precursors;
impact of vaccine on vulvar or vaginal dysplasia as end point—vaccine showed 100% efficacy in prevention
of high- or low-grade disease of vulva or vagina; CIN (any grade) and genital warts as end point—95%
efficacy; data looking at combined population (subjects exposed to HPV types 6, 11, 16, and/or 18 at enrollment or
those naive to virus)—>73% of patients negative for all 4 HPV types; 20% negative for at least 3 HPV types; reduced
likelihood of HPV-16 and HPV-18–related CIN II and III or adenocarcinoma in situ (AIS)—data show
39% fewer cases of HPV-related CIN II and CIN III in patients given vaccine, compared to patients given placebo;
reduced likelihood of HPV-6, -11, -16, and -18–related dysplasia or genital warts—70% difference in patients
given vaccine, compared to patients given placebo; demonstrates some benefit with prevention of disease
for women already infected with HPV; immunity—duration of protection with vaccine unknown beyond 48 mo;
bridging study comparing efficacy of vaccine in girls 10 to 15 yr of age to women 15 to 25 yr of age—younger age
group had greater antibody response than older group when quadrivalent and bivalent vaccines administered;
data looking at vaccinating boys and men— boys 10 to 15 yr of age consistently had higher antibody response
than other 3 groups compared (young girls, adult women, adult men); data currently being reviewed by Food and
Drug Administration (FDA); vaccination of boys likely to be recommended in 2008
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| Adverse events: at 4 to 6 yr of follow-up, no significant adverse events associated with quadrivalent vaccine; majority
of adverse events in clinical trials related to local site reaction (usually clears within 3-5 days); original trials
showed higher rate of fever among subjects receiving vaccine, but phase 3 trials showed no significant
difference between vaccine or placebo groups
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 | Pregnancy: counsel patients to avoid pregnancy while receiving series of injections; 1200 pregnancies among subjects
receiving vaccine in phase 3 clinical trials; number of subjects carrying pregnancy full term similar between
vaccine and placebo groups; congenital anomalies—data show 5 congenital anomalies on vaccine arm and none
on placebo arm; geneticists’ review showed anomalies likely related to multifactorial causes, not one specific
factor; independent groups and pharmaceutical companies presently tracking congenital anomalies and other
problems associated with vaccine in pregnancy
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| Advisory Committee on Immunization Practices (ACIP): recommends all girls 11 to 12 yr of age be vaccinated
for the prevention of disease related to HPV; also recommends vaccination of girls <11 yr of age if at risk for
sexual activity (at discretion of physician), as well as “catch-up” vaccination for girls and women 13 to 26 yr of age
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| Questions and answers: vaccinating women >26 yr of age—level of antibody necessary to produce protection in
woman >26 yr of age unknown; clinical end points of ongoing studies likely available in 2 yr; use of vaccine in patient
with CIN—patient with high-grade disease should be vaccinated; data involving bivalent and quadrivalent
vaccines showed decreased incidence of persistent low-grade dysplasia in patients receiving vaccination (question
whether natural regression occurred); gynecologic and oncology group of National Cancer Institute (NCI) investigating
whether low-grade infection clears faster in young women with low-grade dysplasia with preventive vaccination;
vaccinating boys—soon-to-be published data show vaccine equally as safe in men as in women; continuing
vaccine after pregnancy—patient should resume series 2 to 4 wk postpartum
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| MODERN MANAGEMENT OF THE ABNORMAL PAP TEST —Sharon Bond, CNM, APRN-BC, Assistant Professor
of Nursing, Nurse-Midwifery Program, Medical University of South Carolina, College of Nursing, Charleston
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| The Bethesda system: classification system developed in 1988 and updated in 2001; continues to evolve; developed
to standardize reporting and terminology and enhance communication between health care provider and laboratory;
explosion of knowledge and new technologies (eg, liquid-based screening, HPV/DNA testing, HPV
vaccine) brought about changes to classification system; shift in emphasis from find and treat all dysplasia to identify
and treat significant cancer precursors
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| Screening issues: when to start—changed from 18 yr of age to 21 yr of age, or 3 yr after onset of intercourse; if
tested earlier, likely to be abnormal (reflecting transient HPV infection); when to stop—up to provider and patient
based on risk; 65 to 70 yr of age with 3 normal Pap test results and no abnormal results in 10 yr; post-hysterectomy
for benign disease; options for women >30 yr of age—continue annual screening, or Pap test with adjunctive HPV
test every 3 yr; high prevalence of HPV infection <30 yr of age; prevalence of HPV decreases in women ≥30 yr of
age, but positive HPV result in woman >30 likely represents persistent infection; HPV screening approved for
women >30 yr of age; screen annually—immunosuppressed women (eg, organ transplantation, history of cancer
or CIN II or III, diethylstilbestrol [DES] exposure)
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| Women >30 yr with negative Pap test and negative HPV test: rescreen in 3 yr; guideline based on high negative-predictive
value for underlying CIN when both tests negative (risk for CIN II or III, 1 in 1000; risk for cancer
lower); does not preclude patient from returning every year for annual physical examination
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| Woman, 35 yr of age, with complete hysterectomy for benign disease and lifetime history of negative
Pap tests: annual screening no longer necessary; guideline based on fact that cancer risk low
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| Women >30 yr with ≥1 positive test: negative Pap test and positive HPV test—repeat Pap and HPV tests in 6 to
12 mo; positive Pap and HPV tests—perform colposcopy, including vagina and vulva; 60% of patients clear HPV
infection within 6 mo; if colposcopy negative, follow with Pap and HPV tests in 12 mo; if Pap and HPV tests negative,
rescreen in 3 yr; positive Pap test (atypical squamous cells of undetermined significance [ASC-US]) and negative
HPV test—repeat Pap test in 12 mo; sensitivity of combination screening, 83% to 100% for detection of CIN
II and III; specificity 70% to 96%; HPV testing—no indication to test for low-risk HPV types; test only for high-
risk types
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| Atypical squamous cells of undetermined significance (ASC-US): comprises 90% to 95% of ASC Pap tests; abnormal
cellular changes; not sufficient to call low-grade squamous intraepithelial lesion (LSIL); 50% will be HPV-
negative; 1 in 1000 risk for invasive cancer; 5% to 17% risk for CIN III; further evaluation recommended
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| ASC–cannot exclude high-grade squamous intraepithelial lesion (HSIL; ASC-H): comprises 5% to 10% of ASC-
US Pap tests; clear abnormalities; not sufficient to call HSIL; low risk for invasive cancer; CIN II or III found on
24% to 94% of biopsies; further evaluation recommended
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| Managing abnormal results: ASC-US—3 options 1) repeat Pap at 4 to 6 mo until 2 consecutive negative results,
then return to routine screening; 2) immediate colposcopy; 3) triage using HPV testing (if negative, return to annual
Pap screening; if positive, send patient for colposcopy); ASC-H—colposcopy; higher risk for CIN II or III
(found on 24% to 94% of biopsies); positive HPV test does not put patient in ASC-H category; pregnant
patient—manage ASC-US category same as nonpregnant patient; postmenopausal patient—colposcopy; or, if
evidence of atrophy, trial of vaginal estrogen cream with repeat Pap 1 wk after therapy (cellular changes mimicking
dysplasia often regress with estrogen vaginal cream); return to annual screening, with 2 negative Pap tests 4
to 6 mo apart
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| Management of atypical glandular cells (AGC) or endocervical AIS (formerly AGC-US): colposcopy
with endocervical curettage; endometrial biopsy for women >35 yr of age or abnormal bleeding; repeat Pap test not
acceptable; insufficient studies to recommend triage using HPV testing; high percentage of women when evaluated
have AIS, and ≈40% have invasive adenocarcinoma of cervix
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| Management of patient with LSIL: colposcopy; 83% to 85% HPV-positive; triage not effective; repeat Pap in
4 to 6 mo not recommended (delays diagnosis); adolescents—before considering colposcopy, consider HPV infection
in adolescent if transient and clears on own; additional options include repeat Pap test in 6 mo or HPV
test in 12 mo; remember guideline of postponing initial Pap test until age 21 yr or 3 yr after first sexual activity;
postmenopausal—trial of estrogen cream with evidence of vaginal atrophy; other options include repeat Pap
test in 4 to 6 mo, or HPV test in 12 mo; ablation or excision for initial management, without biopsy confirmation,
not recommended
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| Management of CIN I on biopsy and satisfactory colposcopy: preferred management follow-up without
treatment (treatment also acceptable); other options include repeating Pap test at 6 and 12 mo, HPV testing at 12
mo, or repeat Pap test and colposcopy at 12 mo; decision to treat persistent or recurrent CIN I at 12 to 24 mo based
on patient/provider preference; low rate of progression
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| Management of HSIL: colposcopy with endocervical curettage; “see and treat” approach acceptable if lesion has
colposcopic appearance of HSIL; pathology review if no CIN I seen; excisional procedure recommended if review
continues to show HSIL; pregnant women—colposcopy with biopsy; endocervical curettage not acceptable; repeat
unsatisfactory colposcopy in postpartum period; diagnostic excision only with suspicion of cancer; reevaluate
6 wk postpartum; regression of HSIL possible postpartum; adolescents—some literature recommends follow-up
rather than treatment, with informed consent and reasonable assurance patient will return; with CIN I on biopsy,
follow with colposcopy and annual Pap tests (with CIN II, every 4-6 mo); treat CIN III
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| HPV testing: primarily used for follow-up of women treated for significant disease (CIN II or III or cancer); appears
to have greater sensitivity (eg, one study showed 92% to 100% sensitivity in CIN II or III) in detecting recurrent
or persistent disease than Pap test alone
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Suggested Reading
American College of Obstetricians and Gynecologists: ACOG Practice Bulletin No. 66. Management of abnormal
cervical cytology and histology. Obstet Gynecol 106:645, 2005; Advisory Committee on Immunization
Practice: Quadrivalent human papillomavirus vaccine. MMWR Morb Mortal Wkly Report 56:1, 2007; Dunne EF
et al: Prevalence of HPV infection among females in the United States. JAMA 297:813, 2007; Saraiya M et al:
Cervical cancer incidence in a prevaccine era in the United States. Obstet Gynecol 209:360, 2007; Sawaya G et al:
Estimates of cervical cancer screening cost-effectiveness in middle-aged women with three or more normal Pap test
results. Obstet Gynecol 205(Suppl), 2005. Schnatz PF et al: Clinical significance of atypical glandular cells on cervical
cytology. Obstet Gynecol 107:701, 2005.
Educational Objectives
| The goal of this program is to improve prevention of cervical cancer. After hearing and assimilating this program, the
clinician will be better able to:
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| 1. Discuss the natural history of HPV infection.
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| 2. Determine the effectiveness of the currently licensed HPV vaccine.
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| 3. Identify appropriate patients for vaccination with the HPV vaccine.
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| 4. Determine when to begin and when to discontinue Pap testing.
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| 5. Manage patients with Pap test abnormalities.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Downs is a consultant
and on the Speaker’s Bureaus for GSK and Merck. He receives grant support and honoraria from GSK, Merck,
and MGI Pharma. Ms. Bond is on the Speaker’s Bureau for Merck.
Acknowledgements
Dr. Downs was recorded at HealthPartners Institute for Medical Education’s 25th Annual OB/GYN Update, held
April 12-13, 2007, in Oakdale, MN. Ms. Bond was recorded at the Medical University of South Carolina’s Fall Symposium
on Issues in Women’s Health, How to Treat a Lady, held October 20-22, 2006, in Charleston, SC.
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