Delese LaCour M.D.
Pediatric and Adolescent Gynecology
Johns Hopkins Community Physicians
January 29, 2010
Cervical Cancer Screening
 1943 Papanicolaou and Trout published their
monograph on the use of vaginal and cervical cytology
as a screening tool for cervical neoplasm
 The incidence of cervical cancer has been reduced by
50%
 Cervical cancer has dropped from the #2 female
cancer deaths to the 13th
Types of Cervical Cancer
 Squamous cell Approximately 80-90% of cervical cancers
 Adenocarcinoma 10%
 Clear cell cervical cancer
 Mucinous adenocarcinoma
 Adenosquamous
 Glassy cell carcinoma
 Stromal sarcoma
 Sarcoma botryoides
 Leiomyosarcoma
 Lymphoma
 Small cell cervical cancer
 Adenoid cystic carcinoma of the cervix
Technique for cervical cancer
screening
Collection Methods for Pap Smear
Collection Methods for Pap Smear
Bethesda System 2001

SPECIMEN ADEQUACY
Satisfactory for evaluation (note presence/absence of endocervical/ transformation zone component)
Unsatisfactory for evaluation . . .
Specimen rejected/not processed
Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because

GENERAL CATEGORIZATION (Optional)
Negative for intraepithelial lesion or malignancy
Epithelial cell abnormality

INTERPRETATION/RESULT
Negative for Intraepithelial Lesion or Malignancy
Organisms
Trichomonas vaginalis , Fungal oganisms consistent with Candida species
Shift in flora suggestive of bacterial vaginosis
Bacteria consistent with Actinomyces species
Cellular changes consistent with herpes simplex virus

Other non-neoplastic findings
Reactive cellular changes associated with
inflammation
radiation
intrauterine contraceptive device
Glandular cells status posthysterectomy
Atrophy
Bethesda System 2001
Epithelial Cell Abnormalities
Squamous cell
Atypical squamous cells (ASC)
of undetermined significance (ASC-US)
cannot exclude HSIL (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
encompassing: human papillomavirus/mild dysplasia/cervical intraepithelial neoplasia
(CIN) 1
High-grade squamous intraepithelial lesion (HSIL)
moderate and severe dysplasia, carcinoma in situ; CIN 2 and CIN 3
Squamous cell carcinoma
Glandular cell
Atypical glandular cells (AGC)
Atypical glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
Classification Terminology for Cervical
Cytology: The 2001 Bethesda System
Normal1
ASCUS2
LSIL3
HSIL3
 Two types of atypical squamous cells (ASC)4


Atypical squamous cells of undetermined significance (ASCUS)
Atypical squamous cells, cannot exclude high-grade squamous
intraepithelial lesions (ASC-H)
 Squamous intraepithelial lesions (SIL)4


Low-grade SIL (LSIL): Mild dysplasia, cervical intraepithelial
neoplasia 1 (CIN 1)
High-grade SIL (HSIL): Moderate and severe dysplasia, CIN 2/3,
carcinoma in situ (CIS)
1. Spitzer M, Johnson C. Philadelphia, Pa: WB Saunders Co; 2002:41–72. Copyright © 2000 by WB Saunders Company.
Reprinted with the permission of Elsevier. 2. Apgar BS, Zoschnick L. Am Fam Physician. 2003;68:1992–1998. Reprinted
with the permission of the American Academy of Family Physicians. 3. Cannistra SA, Niloff JM. N Engl J Med.
1996;334:1030–1038. Images reproduced courtesy of Dr. Graziella Abu-Jawdeh. 4. Solomon D, Davey D, Kurman R, et
al, for the Forum Group Members and the Bethesda 2001 Workshop. JAMA. 2002;287:2114–2119.
Classification of Histological Findings:
Cervical Intraepithelial Neoplasia
 Cervical intraepithelial neoplasia (CIN)1



CIN 1: Mild dysplasia; includes condyloma (anogenital warts)
CIN 2: Moderate dysplasia
CIN 3: Severe dysplasia; includes CIS
CIN1
Normal
CIN 1
(condyloma)
CIN 1
(mild
dysplasia)
CIN 2
(moderate
dysplasia)
CIN 3
(severe dysplasia/CIS)
Invasive
Cancer
Histology of
squamous
cervical
epithelium1
Basal cell
Basal membrane
 CIN caused by HPV can clear without treatment;
however, rates of regression are dependent on grade of
CIN.2
1. Bonnez W. In: Richman DD, Whitley RJ, Hayden FJ, eds. Washington, DC: American Society for Microbiology Press;
2002:557–596. Reprinted with the permission of the American Society for Microbiology Press. 2. Ostor AG. Int J Gynecol
Pathol. 1993;12:186–192.
Cervical cancer screening
Cervical cancer screening should begin at age 21
A) High prevalence of HPV infection in teenagers
B) Most dysplasia regresses spontaneously in
adolescents
C) Invasive cervical cancer is rare in those younger than
21
D) Potential for adverse effects of side effects


American College of Obstetrics and Gynecology
Practice Bulletin No 109, Dec 2009
High prevalence of HPV infection
in teenagers
Risk of Acquiring HPV After First
Intercourse in Female Adolescents
70
Cumulative risk of cervical HPV infection
in female adolescents with only 1 sexual partner
Cumulative Risk
of HPV (%)
60
50
40
30
20
10
0
0
12
24
36
48
60
Time Since First Intercourse (Months)
From Collins S, Mazloomzadeh S, Winter H, et al. High incidence of cervical human papillomavirus infection in women during
their first sexual relationship. Br J Obstet Gynaecol. 2002;109:96–98. Reprinted with the permission of the Royal College of
Obstetricians and Gynaecologists.
Projected Age-Specific Prevalence of HPV
(Based on a Mathematical Model)
0.3
HPV
LSIL
HSIL
Prevalence
0.25
0.2
0.15
0.1
0.05
0
15
25
35
45
55
65
75
Age
From Myers ER, McCrory DC, Nanda K, Bastian L, Matchar DB. Mathematical model for the natural history of human
papillomavirus infection and cervical carcinogenesis. Am J Epidemiol. 2000;151:1158–1171. Reprinted with the permission of
Oxford University Press.
HPV Infection in Female Adolescents1

81.6% infected with multiple
types
 Mean number of HPV types
per HPV-positive subject = 4.9
 Of the 60 subjects, Pap smear
results were available for 54.

37% had ≥1 abnormal result.
Most severe Pap smear result for
each individual subject (n=54)
70
63.0
60
Patients (%)
 Single-center study in 60
female adolescents (14–17
years of age) monitored over
2.2 years
 81.7% cumulative prevalence
(49/60)
50
40
30
16.7
20
18.5
10
1.9
0
Normal ASCUS
1. Brown DR, Shew ML, Qadadri B, et al. J Infect Dis. 2005;191:182–192.
LSIL
HSIL
Prevalence of HPV Infection in Young Men
Study Author, Year
Baldwin, 2004*,1
N
393†
Selected
Age Range
(Years)
18–24
HPV
Prevalence
(%)
34%
Weaver, 20042
317
18–25
33%
Svare, 2002*,3
44
18–24
48%
Kataoka, 19914
108
18–23
29%
*Conducted at a sexually transmitted disease clinic
† Number includes all patients included in the study (18–70 years of age).
1. Baldwin SB, Wallace DR, Papenfuss MR, Abrahamsen M, Vaught LC, Giuliano AR. Sex Transm Dis. 2004;31:60:601–607.
2. Weaver BA, Feng Q, Holmes KK, et al. J Infect Dis. 2004;189:677–685. 3. Svare EI, Kjaer SK, Worm AM, Østerlind A,
Meijer CJLM, van den Brule AJC. Sex Transm Infect. 2002;78:215–218. 4. Kataoka A, Claesson U, Hansson BG, Eriksson M,
Lindh E. J Med Virol. 1991;33:159–164.
Most dysplasia regresses
spontaneously in adolescents
 A prospective study of 187 women aged 18-22 years old
found that LSIL had reverted to negative in 61% after 1
year and 91% after 3 years
 Only 3% progressed to CIN 3
 Two smaller studies of adolescent females with biopsy
confirmed CIN 2 showed 65-75% regression after 18
months and 36 months
 ACOG practice bulletin 2009
Estimated Likelihood of Time to LSIL
Regression in Adolescents
 In a study of women 13–22 years of age, there was a 91%
probability of regression of LSIL cases within 36 months.
 The probability of progression to HSIL within this same time
frame was 3%.
12-month
regression
rate = 61%
Estimated Proportion
With LSIL*
1.0
0.8
36-month
regression
rate = 91%
0.6
0.4
0.2
0
0
10
20
30
40
Months After Diagnosis
50
60
*The shaded area indicates point wise 95% CIs.
From Moscicki A-B, Shiboski S, Hills NK, et al. Regression of low-grade squamous intra-epithelial lesions in young women.
Lancet. 2004;364:1678–1683. Reprinted with the permission of Elsevier Ltd.
Incidence and Progression of SIL and
CIN 2/3 in Female Adolescents
1
N=602
18–20 years of age
0.9
Cumulative Incidence
Cervical SIL
Vaginal SIL
CIN 2/3
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
4
8
12
16
20 24 28
Months
32
36
40
44
48
Time from detection of first incident HPV infection to progression of lesions
From Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial
infection. J Infect Dis. 2005;191:731–738. Reprinted with the permission of the University of Chicago Press.
Risk of Cervical Lesions and Cancer in
Women Exposed to HPV at a Young Age1
Relative risks for CIN and invasive cancer increase
with decreasing age of first sexual intercourse
Relative Risk Estimates*
7
6
5
Age at First Intercourse (Years)
≥23 or Never
18–22
≤17
4
3
2
1
0
CIN
(n=206)
Invasive Cervical Cancer
(n=327)
*Mantle-Haenszel estimates adjusted for age only
1. La Vecchia C, Franceschi S, DeCarli A, et al. Cancer. 1986;58:935–941.
Invasive cervical cancer is rare in
those younger than 21
Only 0.1 % of cervical cancers occur before
age 21
National data from 1998 through 2003
identified 14 cases of invasive cancer /year in
those ages 15-19
SEER 2002-2006 incidence rate of 1-2 cases
per 1,000,000 females aged 15-19 (Surveillance
Epidemiology and End Results)
Pap Smear Abnormality Rates in
Adolescent Versus Adult Women
Simsir1
Edelman2
Pap Smear Abnormality Rates (%)
35
30
25
29
Adolescents (n=528)
Adolescents (n=271)
Adults (n=10,312)
Total Population (n=29,295)
P<0.0002
20.7
23
20
16
15
15
P=0.04
13
13.2
12.2
9.9
10
7
P=0.001
5
0.2
1.2
P=NR*
0
P<0.00001
7.7
2.5
0.1
0.7 0.6
P=NR*
0 0.2
HSIL
Carcinoma
0
All
Abnormal
Results
ASCUS
LSIL
HSIL
SCC †
All
Abnormal
Results
ASCUS
LSIL
*NR = statistically significant but P value not reported
†SCC = squamous cell carcinoma
1. Simsir A, Brooks S, Cochran L, Bourquin P, Ioffe OB. Acta Cytol. 2002;46:272–276. 2. Edelman M, Fox AS, Alderman EM,
et al. Cancer. 1999;87:184–189.
Comparative Incidence of CIN in Adolescent
and Adult Women1
Annual Incidence per 1000 Women
6
15–19 years of age (n=6261)
5
20–24 years of age (n=1570)
25–29 years of age (n=2919)
4
3
2
1
0
CIN 1
CIN 2
1. Insinga RP, Glass AG, Rush BB. Am J Obstet Gynecol. 2004;191:105–113.
CIN 3
Incidence of HPV Infection and LSIL in
Female Adolescents and Young Women1


105 HPV-negative at
baseline
496 with prevalent HPV
infection
 54 incident HPV infections
 109 incident LSIL cases in
HPV-positive subjects
70
HPV-Negative at Baseline
60
51
(54/105)
HPV-Positive at Baseline
50
Incidence (%)
 Prospective cohort study
of female adolescents and
young women (13–21
years of age) with median
follow-up of 50 months
40
30
19
(10/54)
20
22
(109/496)
10
0
HPV Infection
1. Moscicki A-B, Hills N, Shiboski S, et al. JAMA. 2001;285:2995–2002.
LSIL
LSIL
Potential for adverse effects of
side effects
 Significantly increased risk of :
 Preterm birth
 Low birth weight
 Neonatal intensive care admissions
 For every 18 LEEPs preformed there will be an additional
preterm birth

Suh-Burgmann B and Kinney W 2006 ASCCP Vol 10 , Issue
2,2006
Management of LGSIL
Abnormal Pap ASCUS-H
Management of HGSIL
Abnormal Pap CIN1
Abnormal Pap CIN 2-3
How often to screen
 Frequency of cervical cytology screening
 Every 2 years for women aged 21-29
 Women aged 30 or older with three consecutive negative
pap smears can be followed every three years
More frequent screening for




HIV infected women
Immunosuppressed women
Women exposed to DES
Women with previously treated CIN2, CIN 3 , or cancer
How often to screen
 Frequency
 Women with HIV should be screened
every 6 months in the first year of
diagnosis, then every year
 Women treated in the past for CIN2, CIN3,
or cancer are at risk for 20 years for
recurrence or persistence, annual
screening
Special Notes
 The frequency of those with same sex partners
 Penetrative sex at an early age
 Same screening in those who have been vaccinated
against HPV ( ACOG press release 11/09)
Pelvic Inflammatory disease in
pregnancy
 A 23 year old P2032 at 8 weeks and 6 /7 days presents to ER
with complaint of nausea, vomiting, and abdominal pain
Past Medical history : NC
Past Surgical history : TAB x 3
Social history : positive marijuana use
Gyn/OB history: new partner, history of Chlamydia, Trich, PID in past, SVD times two
Vitals 37.0 , RR 20, P 65, BP 97/59
PE: moderate distress
Abdomen soft, no rebound or guarding,
Pelvic: Yellow vaginal discharge, cervical motion tenderness
Sonogram: 8 week fetus with fetal HMS
Pelvic Inflammatory disease in
pregnancy
 Labs: WBC 4.9, Hct 39.9, Positive culture for
chlamydia, Trich on wet prep
 Hospital course: pt was admitted with diagnosis of PID
in pregnancy, Treated 48 hours with IV Gentamycin
and Clindamycin , po Azithomycin
 Discharge Home with Clindamycin for ten days
Pelvic Inflammatory Disease
 Most of the times multi-organism
 Can range from endometritis to pelvic
abcesses
 300,000 cases per year
 16-20% in Adolescents
 Clinical diagnosis overestimated and
difficult
Pelvic Inflammatory Disease
•Empiric treatment warranted if suspected
because of long term effects if untreated
•Begin treatment if sexually active and
– Uterine tenderness
–Adnexal tenderness
– Cervical motion tenderness (CMT)
Pelvic Inflammatory Disease
 Additional Criteria:
 Temp > 101 F (38.3 C)
 Mucopurulent cervical discharge
 WBC on microscopy
 Increased erythrocyte sedimentation rate
 Increased C-reactive protein
 Positive culture for N. gonorrhea or Chlamydia
Pelvic Inflammatory Disease
 Treat in hospital if:
 Surgical emergency cannot be excluded
 Pregnancy (rare 1: 1000 to 1:25000)
 No initial clinical response
 Does not tolerate PO
 Severe illness
 Tubo-Ovarian abscess
Pelvic Inflammatory Disease
 Rx. Outpatient:
 A:



Ofloxacin 400 mg PO BID X 14 days OR
Levofloxacin 500 mg PO QD X 14 days
+/- Metronidazole 500 mg PO BID X 14 days
 B:






Ceftriaxone 250 mg IM X 1 dose OR
Cefoxitin 2 g IM X 1 dose + Probenecid 1 g PO OR
Other third generation cephalosporin
Plus Doxycycline 100 mg PO BID X 14 days
+/- Metronidazole 500 mg PO BID X 14 days
CDC STD treatment guidelines 2006 1-94
Pelvic Inflammatory Disease
 In House
 A:


Cefotetan 2 g IV Q 12 OR Cefoxitin 2 g IV Q 6H
Plus Doxycycline 100 mg IV or PO Q12 H
 B:


Clindamycin 900 mg IV q8h
Plus Gentamicin 2mg/kg loading f/u 1.5 mg/kg Q8H
 C:




Ofloxacin 400 mg IV Q6h or Levofloxacin 500 mg QD
+/- Metronidazole 500 mg IV Q8H or Unasyn 3 g IV Q6H
Plus Doxycycline 100 mg PO IV Q12H
CDC STD treatment guidelines 2006 1-94
Pelvic Inflammatory Disease
 Pregnancy:
 Multiple reports in the literature (1:1000-1:25000)
 Easily confused with ectopic pregnancy
 Associated with fetal wastage and poor outcomes
 Etiology confusing:

Sperm carrying bacteria?

Infection prior to 12 weeks and membrane apposition?

Reactivation of latent disease?

Hematogenous or Lymphatic spread?
Lara-Torre E et al JRM 2002;47:959-61
Pelvic Inflammatory Disease
 Pregnancy (cont):
 Aggressive antibiotic treatment warranted prior to
uterine evacuation
 Conservative treatment may maintain pregnancy to
term
 Delay in diagnosis because of pregnancy may worsen
outcomes
 Decrease immune response in pregnancy may worsen
presentation and progression