ISSUES IN CERVICAL CANCER SCREENING
| AFTER COLPOSCOPY: WHAT NEXT?— Carol E. Ball, MD, Assistant Professor of Obstetrics and Gynecology, University
of Minnesota and Medical Director, Planned Parenthood of Minnesota, South and North Dakota, St. Paul, MN
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| Cervical cytologic screening
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 | Age to start screening: begin cervical cancer screening 3 yr after onset of sexual activity, but no later than 21 yr of age;
human papillomavirus (HPV) infection common in sexually active people; can cause transient abnormalities on cytology
screen that will clear on their own
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| Interval: annually in woman ≤30 yr of age (biannually if using liquid-based cytology); >30 yr of age, every 2 to 3 yr after
3 consecutive negative cytologic tests; HIV, immunosuppression, or diethylstilbestrol (DES) exposure may require
more frequent screenings; not indicated posthysterectomy for benign disease (if cervix no longer present)
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| Age to stop screening: American Cancer Society (ACS) recommends 70 yr of age with 3 consecutive normal cytologic
tests, no history of cervical intraepithelial neoplasia (CIN) in past 10 yr, and no history of DES exposure or immunosuppression;
American College of Obstetricians and Gynecologists (ACOG) states it should be determined on individual basis,
based on medical history and risk factors for CIN
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| Data from Atypical Squamous Cells of Undetermined Significance (ASCUS)/Low-Grade Squamous
Intraepithelial Lesions (LSIL) Triage Study (ALTS)—risk of subsequently developing high-grade disease
(CIN 2 or greater) in women with abnormal cytology and negative colposcopy ≈13%; 11.7% in women diagnosed with CIN
1 in group not biopsied at colposcopy, and 11.3% in group with normal biopsy; positive HPV test with negative
colposcopy— not false-positive test; identifies woman at continued risk for CIN 2 or 3; conclusion of studies about follow-up
strategies for CIN 1—single positive HPV DNA test at 12 mo efficient method to detect CIN 3 and greater with
least referral to colposcopy (95% sensitive; referred only 55% of women for colposcopy); 2 repeat cytologic screens also acceptable
method of following women (less sensitivity and specificity, but still in acceptable range); 2 repeat cytologic tests at
threshold of LSIL provide inadequate sensitivity and not considered adequate follow-up
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| Management of CIN 1 with satisfactory colposcopy: follow-up preferred approach; treatment acceptable, but
should be used only in certain circumstances, eg, patient insists on treatment or patient might be lost to follow-up; follow-up
—repeat cytology at 6 and 12 mo or HPV testing at 1 yr (HPV DNA testing preferred approach); cytologic screen
and colposcopy at 1 yr also acceptable if HPV DNA testing unavailable; if cytology or HPV DNA test negative—
resume annual cytologic testing; with ASCUS—repeat colposcopy; if negative for CIN 1—resume annual cytology;
persistent CIN 1—follow-up or treatment acceptable; CIN 2 or greater—manage by American Society for Colposcopy
and Cervical Pathology (ASCCP) guidelines; cytology and colposcopy at 12 mo—if positive for CIN 1, follow or
treat; CIN 2 or greater— manage by ASCCP guidelines; cytologic and colposcopic regression—resume annual cytologic
screening
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| Management of CIN 1 with unsatisfactory colposcopy: diagnostic excisional procedure; cryotherapy or laser
ablation not acceptable; exceptions—adolescent patient (more likely to have regression of changes, and underlying
squamous cell carcinoma rare), pregnant patient (follow-up without treatment acceptable), and immunosuppressed patient
(falls into different follow-up category)
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| Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions (ASC-H): higher
risk of having high-grade lesion; review cytology results with pathologist; if confirmed or downgraded, follow guidelines
for ASCUS; if reading changed, observe by appropriate guidelines; patient with high-grade cytology and negative colposcopic
examination—endocervical sampling and careful assessment of vagina and vulva for lesions; younger woman
with unexplained high-grade cytology—diagnostic excisional procedure
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| Management of CIN 2 or 3: satisfactory colposcopy—diagnostic excisional procedure or ablation of transformation
zone acceptable; unsatisfactory colposcopy—diagnostic excisional procedure necessary, ablative procedure not acceptable;
follow-up—cytology screen at 4 to 6 mo or cytology and colposcopy at 4 to 6 mo; HPV DNA testing can be performed
at least 6 mo after treatment (8 mo average time in which HPV cleared from system posttreatment for CIN);
annual cytologic screening can be resumed with 3 consecutive negative screens or cytology and colposcopy; further colposcopic
examination required with ASCUS or greater; persistent positive HPV DNA test requires return to colposcopy;
if negative for HPV, small chance of residual disease (return to annual cytology)
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| Treatment modalities: randomized trial comparing cryotherapy, loop electrosurgical excision (LEEP), and laser
for CIN—only difference in failure rate noted with lesion size; high rate of persistent or recurrent disease, regardless of
treatment modality, with lesion covering more than two thirds of surface of cervix; cryotherapy—entire squamocolumnar
junction must be visualized; woman with unsatisfactory colposcopy should not be treated with ablative technique; entire
lesion should be visualized and should not go into canal >5 mm; colposcopy, cytology, and histology results must correlate
to within 1° of discrepancy; if performed, endocervical sampling must be negative and invasion must be ruled out;
LEEP—can be used in almost any situation where treatment of CIN necessary; not always best choice (eg, pregnancy,
where thermal artifact could preclude accurate diagnosis, and suggestion on cytology of invasion or marked glandular abnormality);
cold-knife conization—preferred approach for adenocarcinoma in situ and adenocarcinoma; cold-knife cone
preferred approach when CIN beyond limits of visualization; essentially “fishing expedition”; potential for cervical distortion
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| Choice of procedure for CIN 2 or 3: satisfactory colposcopy—ablative or excisional methods equally successful;
unsatisfactory colposcopy—must be treated with excisional method; risk for missed occult cancer greater when lesion
high-grade, and risk increases with large CIN 3 lesion; consider excisional procedure in patient with CIN 3, particularly
those with large lesion covering more than two thirds of cervix; ablative procedures—contraindicated in treatment of
women with CIN 2 and 3 and unsatisfactory colposcopy, except when used peripheral to central cervical excision procedure;
occult invasive carcinomas in certain percentage of women with CIN 2 and 3 and unsatisfactory colposcopy; cold-
knife conization, laser cone, or LEEP acceptable treatment options, and all produce comparable success rates
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| Management of CIN 2 and 3: expectant management with repeat cytology and colposcopy not acceptable for most
women with CIN 2 and 3 (exceptions pregnancy and noncompliant adolescent); hysterectomy—inappropriate treatment
for CIN, unless other compelling reasons present; CIN 2 and 3 in pregnancy—unless invasive cancer cannot be ruled
out, high-grade disease detected during pregnancy generally followed until postpartum; adolescents—often transient
disease, even though CIN 2 considered high-grade; immunosuppressed woman—different management protocol for
follow-up care; should be treated by clinician with expertise; high risk for recurrent disease, even with treatment
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| Conclusions about follow-up of women treated for CIN 2 and 3: cervical cytology or combination of cytology
and colposcopy appropriate; HPV DNA testing good method for follow-up after treatment; repeat cytology every 4
to 6 mo in first year, every 6 mo in second yr; threshold for return to colposcopy quite variable, use ASCUS as threshold;
after 3 negative Papanicolaou (Pap) tests, resume annual testing; studies show clearance of HPV DNA in majority of
women successfully treated, and women remaining HPV–positive at increased risk for recurrence; 100% of women with
persistent disease HPV-positive; positive HPV test presents significantly high odds ratio for treatment failure independent
of cytology and margin status; ASCCP recommendations for HPV testing—perform every 6 mo after treatment,
and if positive, return to colposcopy; if negative, return to annual follow-up; repeat conization based on single positive
HPV test not corroborated by other findings unacceptable; ASCCP recommendations for margins—if CIN identified at
margins at time of diagnostic excisional procedure or if postprocedure endocervical assessment contains CIN, addition of
colposcopy and endocervical sampling should be included in follow-up; repeat diagnostic excisional procedure acceptable
when CIN 2 or 3 identified; hysterectomy acceptable when endocervical margin or postprocedure endocervical sampling
positive and when repeat diagnostic excision not feasible; hysterectomy also acceptable for treatment of recurrent
and persistent biopsy-confirmed CIN 2 and 3
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| DIETHYLSTILBESTROL EXPOSURE —Rise C. Hatten, MD, Adjunct Professor, University of Minnesota Medical
School; Department of Obstetrics and Gynecology, Regions Hopsital; HealthPartners Medical Group and Clinics, St. Paul,
MN
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| History of DES: first potent nonsteroidal estrogen synthesized in 1938; in 1942, first published report of decrease in urinary
estradiol and progesterone in women with adverse pregnancy outcomes; in 1944, used as “pregnancy booster”; in
1949, endorsed as antimiscarriage drug, dispensed with prenatal vitamins; initially used in early pregnancy to prevent
miscarriage; eventually used in high-risk pregnancies; in 1953, Diekmann published study showing DES not effective
and in some patients, appeared to cause miscarriage; in 1964, peak sales of DES; in 1959, banned from poultry feed; documented
>4 million women in United States exposed; estimated 10 million American women exposed; used in Northern
Europe, Australia, India, and Russia; possible that 1 in 20 women exposed; in 1971, Herbst reported 7 cases of young
women with clear cell adenocarcinoma of vagina and cervix (only 3 cases in previous 100 yr); in 1971, Food and Drug
Administration (FDA) published warning about DES; in 1973, DES pulled from American market (early 1980s in other
parts of world); DES mothers range from 50 to 80 yr of age, daughters 33 to 60 yr of age; after association with vaginal
clear cell adenocarcinoma established, other abnormalities documented (dysplasia, anatomic abnormalities, infertility
and reproductive concerns, and other malignancies)
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| Embryology: first 8 wk of intrauterine life—development of uterus, fallopian tubes, external genitalia, and lower vagina;
9 to 10 wk—mullerian ducts fuse across midline; 10 to 12 wk—lower vagina starts to grow (vagina solid); 15
wk—uterus and vagina meet; 16 wk—vaginal plate complete; 17 wk—vagina canalizes; 18 wk—cervix defined;
when vagina canalized, epithelium from urogenital sinus grows upward to cover vagina, and smooth muscle develops;
DES prevents vaginal plate from growing upward and developing; fallopian tubes and cervical tissue lower in vagina
than in nonexposed woman; mullerian or glandular tissue may cover entire vagina; decreased epithelium in vagina; increased
glandular tissue in vagina (adenosis); ovaries and vulva not affected
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| Adenosis: sheaths of glandular tissue; found in 34% of DES daughters; found in 5% of nonexposed daughters; majority in
upper and anterior vagina, but can be anywhere; over time, regresses by squamous metaplasia; clear cell adenocarcinoma
of vagina always associated with adenosis; adenosis common, clear cell adenocarcinoma rare
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| DES cervix: abnormal stromal support; unusual structures (present in ≈1 of 5 women); often shortened weak cervix; increased
risk for high-grade squamous intraepithelial lesion (HSIL) because of enlarged transformation zone; consider colposcopy
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| Reproductive issues: higher risk of never achieving pregnancy and lower chance of having successful pregnancy than
nonexposed woman; earlier the exposure, worse the prognosis; high risk for ectopic (cornual) pregnancy; higher risk for
second trimester loss because of incompetent cervix; higher risk for preterm labor because of abnormally small uterine
cavity; abnormal hysterosalpingography (HSG)—86% of women with abnormal cervix have abnormal HSG; >50%
of women with normal cervix have abnormal HSG; 82% of women with adenosis have abnormal HSG; overall outcome
still good for most women; cerclage not recommended; surgical correction for abnormalities attempted with disappointing
results
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| Vaginal clear cell adenocarcinoma: 750 cases reported; estimated risk 1 in 1000; 40 times risk of nonexposed
woman; most common age group 20 yr of age, followed by 40 to 48 yr of age, and women in 30s; no clear evidence of
link with hormonal agents; presents with abnormal bleeding or discharge; not detected on cytology screen, diagnosed by
biopsy; thorough pelvic examination critical; mass described as rough, indurated, sandy, granular, and nodular; survival
excellent with early detection; majority detected in stage 1; 5-yr survival rate 75%, regardless of stage; annual
examination—consists of thorough vaginal examination (all 4 quadrants); colposcopy not recommended; thin preparation
of cervix recommended with 4-quadrant sweep of vagina and separate specimen from large area of adenosis
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| DES population issues: DES mothers—slight increase in breast cancer (relative risk 1.3); no evidence of association
with birth control pills (BCPs) or hormone replacement therapy (HRT); no evidence of increase in other gynecologic
cancers; DES daughters—slight increase in breast cancer in women >43 yr of age; BCPs not contraindicated; DES
sons—literature suggests connection with epididymal cysts, hypoplastic testicles, undescended testicles, low sperm
count, and low sperm mobility; third-generation daughters—Kaufman (2002) showed no increase in structural abnormalities
in DES granddaughters to date, suggesting third-generation carryover effects of in utero DES exposure unlikely;
Klip (2002) findings suggest increased risk for hypospadias in sons of women exposed to DES in utero; one
reported case of clear cell adenocarcinoma of vagina in granddaughter 8 yr of age, suggesting DES possibly can cause
genetic changes at molecular level
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Educational Objectives
| The goal of this program is to educate the listener about the management of women with cervical intraepithelial neoplasia
(CIN) and the identification of women exposed to diethylstilbestrol (DES) in utero. After hearing and assimilating this program,
the clinician will be better able to:
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| 1. Determine the age to start cervical cancer screening, the interval between screening, and the age to stop screening.
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| 2. Follow the guidelines for the management of women with CIN.
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| 3. Determine the most appropriate treatment modality for women diagnosed with CIN.
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| 4. Identify women exposed to DES in utero.
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| 5. Discuss the risks associated with DES in utero exposure.
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Suggested Reading
American College of Obstetricians-Gynceologists. ACOG Committee Opinion. Evaluation and management of
abnormal cervical cytology and histology in the adolescent. Obstet Gynecol 107(4):963, 2006; American College of
Obstetricians-Gynceologists. ACOG Practice Bulletin number 66, September 2005. Management of abnormal cervical
cytology and histology. Obstet Gynecol 106(3):645, 2005; Kaufman RH et al: Findings in female offspring of
women exposed in utero to diethylstilbestrol. Obstet Gynecol 99(2):197, 2002; Palmer JR et al: Risk of breast cancer
in women exposed to diethylstilbestrol in utero: preliminary results (United States). Cancer Causes Control 13(8):753,
2002; Wright TC et al: 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia.
Am J Obstet Gynecol 189(1):295, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Drs. Ball and Hatten were recorded at the 24th Annual OB/GYN Update, sponsored by HealthPartners Institute for
Medical Education, held on April 20-21, 2006 in Minneapolis, MN. The Audio-Digest Foundation thanks the speakers
and the sponsor for their cooperation in the production of this program.
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