Transcript Management of the Abnormal Pap Smear

Management of the Abnormal Pap
Smear, Cervical Dysplasia, and
Cervical Cancer
Todd D. Tillmanns MD
Assistant Professor
Department of Obstetrics & Gynecology
Division of Gynecologic Oncology
University of Tennessee and West Clinic
E-mail: [email protected]
CREOG OBJECTIVES
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Pre-invasive cervical disease:
1. describe the epidemiology of cervical dysplasia
2. elicit a pertinent history in a woman with an abnl pap
3. interpret pap test reports using bethesda classification system and
determine appropriate follow-up.
4.perform and interpret the results of diagnostic procedures for cerivical
dysplasia
5. treat cervical dysplasia with modalities, such as: cryosurgery, laser
ablation, leep, ckc
6. manage the complications resulting in the treatment of cervical dysplasia 7. establish an appropriate follow-up plan for a woman who has been treated
for cervical dysplasia
8. describe the structural changes in the cervix that are characteristic of
in-utero des exposure
Invasive cervical cancer:
1. describe the epidemiology of cervical ca
2. describe the typical clinical manifestations of cervical ca 3. describe the differential diagnosis of cervical ca 4. perform appropriate biopsies to diagnose
invasive cervical ca 5. describe the figo staging of cervical ca--maybe throw in your bulls-eye
here.
6. in consultation with a gyn onc, counsel the patient about the evaluation
and treatment (indications, complications) of cervical ca
7. describe the prognosis
8. describe the impact of treatment of cervical ca on sexual function and
manage/refer the patient appropriately
9. provide psychosocial support and long-term follow up for patients with
cervical ca.
Natural History of Dysplasia
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Human Papilloma Virus is etiologic in the
development of invasive cervical cancer.
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99% of cervical cancers worldwide are HPV positive1
96% of HSIL is HPV positive2
30% of HPV 16 CIN III will progress to cancer
Infection with a high-risk or carcinogenic HPV type is
associated w/ 100-fold or greater risk of developing
cervical cancer compared to someone who is not infected
1Bosch
FX, et al. J Natl Cancer Inst 1995; 87:796-802
2Matsukura M, et al. Int J Cancer 1995; 61:13-22
Relative Risk of Cervical Cancer
by HPV Type
Electron Micrograph of HPV
Cervical Histology Showing
HPV & Koilocytes
Cervical Cytology Showing
HPV & Koilocytes
Risk of Progression to
Cancer
Author
Ostor AG.
CIN I
CIN II
1%
5%
CIN III
>12%
Conventional Cervical Cytology
(Papanicolaou Smear)
Introduced in 1939
 Substantially unchanged in 50 years
 Responsible for a 76.6% reduction in the incidence of
invasive cervical cancer & 74.5% reduction in
mortality in the United States since 19501
 No randomized controlled trials have evaluated
efficacy
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Herrero R. Monogr Natl Cancer Inst 1996; 21:1-6
Conventional Cervical Cytology
(Papanicolaou Smear)
Good screening test
 Inexpensive
 High sensitivity & specificity
 Easy to perform, noninvasive, nonmorbid
 Reproducible
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Screening Guidelines
Early Detection of Cervical Cancer
American Cancer Society 2003
Screening
should begin approximately three years after a woman begins having vaginal
intercourse, but no later than 21 years of age
Screening
should be done every year with regular Pap tests or every two years using
liquid-based tests
At
or after age 30, women who have had three normal test results in a row may get
screened every 2-3 years. However, doctors may suggest a woman get screened more if
she has certain risk factors, such as HIV infection or a weakened immune system
Women
70 and older who have had three or more consecutive Pap tests in the last ten
years may choose to stop cervical cancer screening
Screening
after a total hysterectomy (with removal of the cervix) is not necessary unless
the surgery was done as a treatment for cervical cancer
Wright et al: ASCCP Cytol
Atypical Squamous Cells
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ASC:
– Atypical Squamous Cells of Undetermined Significance (ASC-US)
– Atypical Squamous Cells cannot exclude HSIL (ASC-
ASC is poorly reproducible
 ASC has a 5-17% chance of having CIN II-III
 CIN III is diagnosed in 24-94% of those with
ASC-H
 Risk of invasive caner
with ASC is low (0.1-0.2 %)
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Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing ASC
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Sensitivity of a single repeat test for detecting CIN II-III after ASC
is low (0.67-0.85)
Colposcopy; mean sensitivity for distinguishing normal from
abnormal was 0.96 and weighted specificity was 0.48
Sensitivity of HPV testing to detect CIN II-III in women with ASC
is (0.83-1.0) better than a single Pap. The (-) predictive value for
high risk HPV is 0.98
Between 31% and 60% of all women with ASC will have high risk
HPV, but this decreases with age
Reflex HPV: 40-60% of women will be spared colposcopy and (-)
testing assures women that they do not have a lesion
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
ASCCP Management Guidelines ASC-US: HPV
Testing
HPV DNA Testing
Repeat Cytology
@ 4 - 6 mos
Preferred if
liquid-based cytology
or co-collection available
Colposcopy
“When liquid-based cytology is used, or when co-collection for
HPV DNA testing can be done, "reflex" HPV DNA testing is the
preferred approach”
Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for 2001 ASCCP-Sponsored Consensus Conference. 2001
Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.
Patient Management Using HPV Triage
ASCUS
HPV TEST
Low Risk + or HPV–
Repeat Pap and/or HPV Test
in 12 mo. or return to routine
screening at discretion of
clinician
HPV +
COLPOSCOPY
BIOPSY/ABLATION
ASC Special Circumstances
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Postmenopausal Women
– Using intravaginal estrogen followed one week later
with Pap If (-) then repeat 6 months later
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Immunosuppressed Women
– Referral colposcopy is recommended
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Pregnant Women
– Same as non-pregnant
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Atypical Glandular Cells and AIS
AGC : Atypical Glandular Cells (endocervical,
endometrial, or glandular cells not otherwise
specified)
 AGC: Favor Neoplasia
 AIS: Adenocarcinoma in situ
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Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AGC Category
9-54% of women with AGC have biopsy
confirmed CIN
 0-8% have AIS
 1-9% have invasive cancer
 Biopsy confirmed CIN II-III, AIS, or invasive
cancer have been found in 9-41% of women with
AGC NOS compared to 27-96% of women with
AGC “favor neoplasia”
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Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AIS Category
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The cytologic interpretation of AIS is associated
with a very high risk of women having either AIS
(48-69%) or invasive cervical adenocarcinoma
(38%).
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing AGC and AIS
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Screening cervical cytology has a sensitivity of only
50%-72% for identifying glandular neoplasia
CIN is the most common neoplasia identified in women
with the cytologic result of AGC
Repeat cervical cytology is less sensitive than colposcopy
for identifying CIN II-III
This supports using colposcopy
There is a higher risk of CIN II-III, and AIS in
premenopausal women compared to menopausal women
½ of the women with AIS have a coexisting squamous
lesion
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AGC and AIS Management
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Colposcopy and ECC is recommended for women with
all subcategories of AGC with the caveat that women
with atypical endometrial cells should have an EMBX
EMBX should be performed in conjunction with
colposcopy in women older than 35 with AGC and in
younger women with AGC with unexplained bleeding or
AIS
There is insufficient data to allow an assessment of HPV
DNA testing in the management of women with AGC or
AIS
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AGC favor dysplasia
AGC favor dysplasia or AIS with (-) colpo should
receive a diagnostic excisional procedure CKC
 If no neoplasia identified at initial workup, then
repeat cytology q 4-6 months until normal x 4
 Acceptable options include referral
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Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
LSIL
Median rate of LSIL in the USA is 1.6%, but high
risk populations have reported LSIL rates as high
as 7.7%.
 15-30% of women with LSIL on cervical cytology
will have CIN II-III identified on subsequent
cervical biopsy.
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Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing LSIL
53-76% likelihood of abnormal Pap on follow up
cytology
 83% of women referred for the evaluation of an
LSIL cytology result tested positive for high risk
HPV types.
 HPV DNA and LEEP do not appear to be useful
for the initial management of women with LSIL
 Colposcopy with directed biopsies is the initial
best option.
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Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing LSIL with Satisfactory
and Unsatisfactory Colposcopy
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Satisfactory Colposcopy
– ECC is an acceptable option with follow up in 6 months if
normal
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Unsatisfactory Colposcopy:
– ECC in non pregnant with follow up in 6 months if normal –vsLEEP Cone
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Pregnancy
– Colposcopy with biopsy only if high grade lesion or cancer is
suspected
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Adolescents
– Acceptable option is follow up in 6 months without colposcopy
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Transformation Zone
Cryotherapy
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Nitrous oxide or CO2 refrigerant
Lesion covered by probe, lubricant
Freeze 4-6 mm beyond probe
Freeze - Thaw - Freeze Technique
Failure in 7% of 422 CIN III patients1
1(Bryson. Am J Ob Gyn 1985; 151:201-6)
LEEP
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Transformation zone excised to depth of 7-8 mm
Provides tissue diagnosis
Easy to perform
Well tolerated by patients
Can be performed in outpatient setting
Success rates 90-96%
Cone Biopsy
Indications
(+) ECC
 Cytologic abnormality not consistent w/ tissue
diagnosis
 Unsatisfactory colposcopy
 Microinvasion on biopsy, r/o invasive cancer
 Adenocarcinoma in situ or invasive adenocarcinoma
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Cone Biopsy
2 Methods:
Cold Knife Cone Biopsy
 LEEP Cone Biopsy or Laser Cone Biopsy
 Equivalent results for most indications
 Exceptions include:
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Microinvasion on biopsy, r/o invasive cancer
 Adenocarcinoma in situ or invasive adenocarcinoma
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Cervical Conization
Top-Hat Pathology
Risk Factor
Normal
Abnormal
p-value
p-value
(Univariate) (Multivariate)
0.104
Endocervical
Curettage
Unsatisfactory
Colposcopy
Two-Step
Discrepancy
Ablation
Age < 21
Age 22-34
Age > 35
113 (78.5)
31(21.5)
16 (80.0)
4 (20.0)
0.767
47 (94.0)
3 (6.0)
0.013
25 (78.1)
43 (91.5)
113 (81.3)
47 (75.8)
7 (21.9)
4 (8.5)
26 (18.7)
15 (24.2)
0.558
0.057
0.796
0.154
0.051
In Utero Exposure to DES
In women exposed to DES in utero, the normal
migration of the squamous epithelium is
prematurely halted.
 The original SCJ is often located in the vagina
rather than on the exocervix.
 In these women the entire cervical portio can be
covered with endocervical columnar epithelium.
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Kurman, RJ. Blaustein’s Pathology of the Female Genital Tract
5th edition. 2002 Springer-Verlag. New York. pp.216
Cervical Cancer
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2nd most important cancer in women worldwide
Most important cancer in developing countries1
Approximately 10,370 new cases/yr in U.S.2
Approximately 3,710 deaths/yr in U.S.2
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1991-1995 Tennessee ranked 7th in mortality from Cervical
Cancer
Overall 5-year survival is approximately 70%2
1Int
J Cancer 1993; 54:594-606
2Cancer Facts and Figures -2005, ACS 2005
Age-adjusted* Death Rates and Rank from Cervical Cancer
United States 1996-2000
49
44
30
40
31
29
41
1942
51
39
47
37
36
21
Age-adjusted
Death Rate (Rank)
24
34
2.3-1.8 (41-51)
2.6-2.3 (31-40)
3.1-2.6 (22-30)
3.4-3.1 (11-21)
3.8-4.8 (1-10)
50
46
48
25
35
12
38
11
33
10
16
32
23
17
22
2
3
27
5
15
7
9
8
4
14
18
6
13
*Age-adjusted to 2000 population
-Rank 1 is worst; 51 is best.
-Rates are per 100,000
43
26
45
20
28 1
Lifetime Probability of Developing Cancer, by
Site, Women, US, 1997-1999
Site
Risk
All sites
1 in 3
Breast
1 in 8
Lung & bronchus
1 in 17
Colon & rectum
1 in 18
Uterine corpus
1 in 37
Non-Hodgkin lymphoma
1 in 56
Ovary
1 in 58
Pancreas
1 in 80
Melanoma
1 in 81
Urinary bladder
1 in 88
Uterine cervix
1 in 123
Source: Surveillance, Epidemiology, and End Results Program, 1973-1999, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2002.
Test Trends in Recent* Pap Prevalence (%), by Educational
Attainment, Women 25 and Older, US,
1992-2000
100
Some college or greater
80
High School graduate
Prevalence
(%)
All women 18 and older
60
Less than High School
40
20
0
1992**
1993**
1994**
1995**
1996
Year
1997
1998
1999
2000
* A Pap test within the past three years. **Includes fewer than 50 states and District of Columbia
Source: Behavior Risk Factor Surveillance System, 1992-1995, 1996-1997, 1998, 1999, 2000, National Center for Chronic
Disease Prevention and Health Promotion, Center for Disease Control and Prevention,1997, 1999, 2000, 2000, 2001
Incidence and Mortality Rates 19972001 by Race/Ethnicity
White
African
American
Asian
American
Indian
Latina
2.6
5.6
2.8
2.8
3.6
Mortality rates per 100,000 based on 2000 US standard population
American Cancer Society 2005
Cancer Survival*(%) by Site and Race,1992-1998
Site
White
African
American
% Difference
All Sites
64
53
11
Breast (female)
88
73
15
Colon & rectum
63
53
10
Esophagus
15
8
7
Leukemia
47
38
9
Non-Hodgkin lymphoma
56
46
10
Oral cavity
59
35
24
Prostate
98
93
5
Urinary bladder
82
65
17
Uterine cervix
72
60
12
Uterine corpus
86
61
25
*5-year relative survival rates based on follow up of patients through 1999.
Source: Surveillance, Epidemiology, and End Results Program, 1973-1999, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2002.
Cervical Cancer:
Improved Mortality & Morbidity with Early
Identification
FIGO Stage
I
II
III
IV
% Cases
46%
28%
21%
4%
5-Year Survival
83%
64%
38%
14%
FIGO Annual Report. J Epi & Biostat 1998; 3(1)
Risk Factors
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HPV infection (plus cofactors)1
– Subtypes 16, 18, 31, 35, 39
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Sexual behavior1-3
– Sex at young age; multiple partners
– High parity; race; low socioeconomic status
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History of smoking1-3
Oral contraceptives (?)3
– controversial
1.
Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of
Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550.
2. ACS. Cancer Facts & Figures 2004.
3. Janicek et al. CA Cancer J 2001;51:92-114.
Presenting Symptoms
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Pre-invasive disease
– no symptoms
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Invasive cervical cancer
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abnormal vaginal bleeding
pelvic pain (locoregional disease)
flank pain (hydronephrosis)
triad (siatic pain, leg edema, hydronephrosis)
» Extensive pelvic wall involvement
– hematuria, incontinence (bladder involvement)
– constipation (external compression of rectum)
» not common at early diagnosis
Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of
Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550.
Cervical Cancer Differential
Diagnosis
 Cervical
condyloma or dysplasia
 Uterine cancer extending to cervix
 Metastatic disease to cervix
 Cervical or endometrial polyp
Diagnostic Modalities
Clinical staging (FIGO)
 EUA, Cystoscopy, Proctoscopy, appropriate
biopsies
 CKC only for microscopic disease
 Review Bulls Eye and treatment based on stage
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FIGO Staging
Stage 0
Stage I
Stage II
Stage III
Stage IV
 Carcinoma in situ, intraepithelial
carcinoma, no stromal invasion
 Carcinoma confined to cervix
 Extends beyond cervix but not pelvic
wall
 Involves vagina but not lower third
 Extends onto pelvic side wall, lower
third of vagina
 Hydronephrosis
 Extends beyond pelvis
 Involves bladder/rectum mucosa
Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of
Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550.
Cervical Cancer: Improved Mortality &
Morbidity with Early Identification
FIGO Stage
I
II
III
IV
% Cases
46%
28%
21%
4%
5-Year Survival
83%
64%
38%
14%
FIGO Annual Report. J Epi & Biostat 1998; 3(1)
Counseling Patient After Diagnosis
of Cervical Cancer
Treatment modalities based on stage
 Side effects and toxicities of whole pelvic
radiation and brachytherapy with chemotherapy
 Sexual side effects of different treatment
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–
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Vaginal shortening
Vaginal coaptation with radiation therapy
Radiation necrosis
Loss of ovarian function
Decreased lubrication
Follow Up After First Line
Therapy
Every 3 months for the first 2 years
 Every 6 months for the following 3 years
 Pap smear at each visit
 85% of patients that recur will recur in 2 years
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Chemotherapy
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Advanced/recurrent disease
– Agents with > 15% response
cyclophosphamide
cisplatin
ifosfamide
carboplatin
melphalan
doxorubicin
topotecan
vincristine
paclitaxel/docetaxel
irinotecan
vindesine
5-FU
methotrexate
vinorelbine
– Platinum regimens commonly used
– Combination regimens
» Previously
 Higher
ORR but no survival advantage vs single-agents
Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed.
Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550.
PDQ®. Cervical Cancer Treatment. http://cancer.gov/cancer_information/PDQ. Lastmodified 6/03.
Rein DT, et al. Anti-Cancer Drugs 2001;12:787-795.
Advanced Cervical Cancer
Author
Stage
n
Treatment
3 yr Med
Surv (%)
Whitney et al. 1999
IIb-IVa
177
191
EB + ICRT + PF
EB + ICRT + HU
67
57
Morris et al. 1999
IIb-IVa
195
193
EB + ICRT + PF
EB + ICRT
76
63
Rose et al. 1999
IIb-IVa
176
173
177
EB + ICRT + P
EB + ICRT + PFHU
EB + ICRT + HU
65
65
47
PFS
P-val (RR)
0.03 (0.79)
0.001 (0.57)
0.001 (0.55)
EB=external beam, ICRT=intracavitary radiation therapy, P=platinum, F=5-FU,
HU=hydroxyurea
Recurrent Disease
Treatment in the 80’s and 90’s
Platinum-based therapies most effective
 Cisplatin more active than carboplatin
 3 ways to increase response without prolonging
survival
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– Increase platinum dose
– Add ifosfamide to cisplatin
– Add paclitaxel to cisplatin
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Thus, single agent cisplatin at 50 mg/m2 became
the best choice
Treatment of recurrent disease 2004
GOG 179 Schema
293 patients
Cervical cancer
Stage IV
Recurrent
Persistent
R
A
N
D
O
M
I
Z
E
Cisplatin 50 mg/m2
Topotecan 0.75 mg/m2/d1-3
Cisplatin 50 mg/m2 d1
•1º endpoint : Survival
•2º endpoints: PFS,ORR, QOL, toxicity
Long H, et al SGO 2004
Results GOG 179
Overall Response
Rate
Median
PFS
(months)
Median Survival
(months)
Topotecan plus
Cisplatin
(N=148)
Cisplatin
27%*
13%
4.6†
2.9
9.4‡
6.5
*P = 0.004; †P = 0.014; ‡P = 0.017
PFS = progression-free survival
Long III HJ. SGO 35th Annual Meeting 2004 [Abstract 9]
(N=145)
Progression-free survival
Overall survival
Chemotherapy for recurrent
disease – 2004
GOG 179 – Predictor of response
 Prior cisplatin therapy with RT
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No prior platinum Prior platinum
CDDP arm
20%
8%
TOPO/CDDP arm
39%
15%
• Platinum-free interval
• Performance status
• Site of recurrence – higher in non-irradiated sites
Adverse Events GOG 179
Grade 3/4 Adverse
Events
(% patients)
Neutropenia
Topotecan +
Cisplatin
(N=148)
70%
Cisplatin
Anemia
37%
23%
Febrile neutropenia/
infection
Nausea/emesis
16%
8%
13%/14%
8%/8%
Metabolic
12%
10%
Long III HJ. SGO 35th Annual Meeting 2004 [Abstract 9]
(N=145)
1%
Summary GOG 179
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Statistically significant prolonged survival for patients treated
with topotecan plus cisplatin vs. cisplatin alone
QOL scores remained stable during treatment compared to
baseline
– No statistical differences between treatment groups
Adverse events more frequent in the combination arm
Long III HJ. SGO 35th Annual Meeting 2004 [Abstract 9]
Monk BJ. SGO 35th Annual Meeting 2004 [Abstract 125]
Future Directions
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GOG 204 - Cervical cancer stage IVB, recurrent,
persistent
Potential benefit in resecting
grossly involved nodes
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University of Minnesota experience
– 266 patients underwent extraperitoneal staging
prior to RT
– Extended field RT if PA nodes positive
– Similar survival to microscopic nodes and grossly
involved but resectable nodes suggesting a
therapeutic benefit from surgery
Cosin et al, Cancer 1998; 82:2241
SUMMARY
CDDP + WPR + ICRT for advanced stage
cervical cancer
 Recurrence: Protocol CDDP + Topotecan
 Role of EPLND?
 Close follow up every 3 months x 2 years then
every 6 months x 3 years with Paps at each visit
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THANK YOU !
Questions / Comments ?