Management of the Abnormal Pap Smear, Cervical Dysplasia, and Cervical Cancer

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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 ttillmanns_at_westclinic.com

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CREOG OBJECTIVES

• 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.

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Natural History of Dysplasia

• Human Papilloma Virus is etiologic in the
  development of invasive cervical cancer.
• 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 87796-802
• 2Matsukura M, et al. Int J Cancer
  1995 6113-22

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Relative Risk of Cervical Cancerby HPV Type
5
Electron Micrograph of HPV
6
Cervical Histology Showing HPV Koilocytes
7
Cervical Cytology Showing HPV Koilocytes
8
Risk of Progression to Cancer
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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
• Herrero R. Monogr Natl Cancer Inst
  1996 211-6

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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
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Atypical Squamous Cells

• 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 )

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
13
Managing ASC

• 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
20022872120-2129
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ASCCP Management Guidelines ASC-US HPV Testing
HPV DNA Testing
Repeat Cytology _at_ 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. 20022872120-2129.
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Patient Management Using HPV Triage
ASCUS
HPV TEST
Low Risk or HPV
HPV
COLPOSCOPY BIOPSY/ABLATION
Repeat Pap and/or HPV Test in 12 mo. or return to
routine screening at discretion of clinician
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ASC Special Circumstances

• Postmenopausal Women
• Using intravaginal estrogen followed one week
  later with Pap? If (-) then repeat 6 months later
• Immunosuppressed Women
• Referral colposcopy is recommended
• Pregnant Women
• Same as non-pregnant

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
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Atypical Glandular Cells and AIS

• AGC Atypical Glandular Cells (endocervical,
  endometrial, or glandular cells not otherwise
  specified)
• AGC Favor Neoplasia
• AIS Adenocarcinoma in situ

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
18
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

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
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AIS Category

• 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
20022872120-2129
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Managing AGC and AIS

• 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
20022872120-2129
21
AGC and AIS Management

• 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
20022872120-2129
22
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

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
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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.

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
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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.

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
25
Managing LSIL with Satisfactory and
Unsatisfactory Colposcopy

• Satisfactory Colposcopy
• ECC is an acceptable option with follow up in 6
  months if normal
• Unsatisfactory Colposcopy
• ECC in non pregnant with follow up in 6 months if
  normal vs- LEEP Cone
• Pregnancy
• Colposcopy with biopsy only if high grade lesion
  or cancer is suspected
• Adolescents
• Acceptable option is follow up in 6 months
  without colposcopy

Wright et al ASCCP Cytol Guidelines JAMA
20022872120-2129
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Transformation Zone
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Cryotherapy

• 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 151201-6)
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LEEP

• 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

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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
• Microinvasion on biopsy, r/o invasive cancer
• Adenocarcinoma in situ or invasive adenocarcinoma

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Cervical Conization
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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.

Kurman, RJ. Blausteins Pathology of the Female
Genital Tract 5th edition. 2002 Springer-Verlag.
New York. pp.216
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Cervical Cancer

• 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
• 1991-1995 Tennessee ranked 7th in mortality from
  Cervical Cancer
• Overall 5-year survival is approximately 702
• 1Int J Cancer 1993
  54594-606
• 2Cancer Facts
  and Figures -2005, ACS 2005

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Age-adjusted Death Rates and Rank from Cervical
Cancer United States 1996-2000
49
44
31
30
29
19
40
51
42
41
43
39
47
16
32
26
37
45
35
25
36
20
21
2
23
17
50
Age-adjusted Death Rate (Rank)
12
3
48
1
24
27
28
38
22
5
15
2.3-1.8 (41-51)
34
7
11
9
33
8
2.6-2.3 (31-40)
18
14
4
3.1-2.6 (22-30)
46
10
6
3.4-3.1 (11-21)
3.8-4.8 (1-10)
13
Age-adjusted to 2000 population -Rank 1 is
worst 51 is best. -Rates are per 100,000
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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.
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Test Trends in Recent Pap Prevalence (), by
Educational Attainment, Women 25 and Older, US,
1992-2000
Some college or greater
All women 18 and older
High School graduate
Less than High School
Prevalence ()
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
38
Incidence and Mortality Rates 1997-2001 by
Race/Ethnicity
Mortality rates per 100,000 based on 2000 US
standard population
American Cancer Society 2005
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Cancer Survival() by Site and Race,1992-1998
African
Site
White
Difference
American
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 Prosta
te 98 93 5 Urinary bladder 82 65 17 Uterin
e 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.
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Cervical Cancer Improved Mortality Morbidity
with Early Identification

• FIGO Stage Cases 5-Year Survival
• I 46 83
• II 28 64
• III 21 38
• IV 4 14
• FIGO Annual Report. J Epi Biostat
  1998 3(1)

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Risk Factors

• HPV infection (plus cofactors)1
• Subtypes 16, 18, 31, 35, 39
• Sexual behavior1-3
• Sex at young age multiple partners
• High parity race low socioeconomic status
• 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, 20011526-1550. 2. ACS. Cancer Facts
Figures 2004. 3. Janicek et al. CA Cancer J
20015192-114.
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Presenting Symptoms

• Pre-invasive disease
• no symptoms
• Invasive cervical cancer
• 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,
20011526-1550.
43
Cervical Cancer Differential Diagnosis

• Cervical condyloma or dysplasia
• Uterine cancer extending to cervix
• Metastatic disease to cervix
• Cervical or endometrial polyp

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Diagnostic Modalities

• Clinical staging (FIGO)
• EUA, Cystoscopy, Proctoscopy, appropriate
  biopsies
• CKC only for microscopic disease
• Review Bulls Eye and treatment based on stage

45
FIGO Staging

Eifel et al. Carcinoma of the Cervix. In Devita
et al (eds). CA Principles Practice of Oncol,
6th ed. Lippincott Williams Wilkins, Phila, PA,
20011526-1550.
46
Cervical Cancer Improved Mortality Morbidity
with Early Identification

• FIGO Stage Cases 5-Year Survival
• I 46 83
• II 28 64
• III 21 38
• IV 4 14

FIGO Annual Report. J Epi Biostat 1998 3(1)
47
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
• Vaginal shortening
• Vaginal coaptation with radiation therapy
• Radiation necrosis
• Loss of ovarian function
• Decreased lubrication

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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

• Advanced/recurrent disease
• Agents with gt 15 response
• cyclophosphamide ifosfamide melphalan
• cisplatin carboplatin doxorubicin
• topotecan irinotecan methotrexate
• vincristine vindesine vinorelbine
• paclitaxel/docetaxel 5-FU
• 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,
20011526-1550. PDQ. Cervical Cancer Treatment.
http//cancer.gov/cancer_information/PDQ.
Lastmodified 6/03. Rein DT, et al. Anti-Cancer
Drugs 200112787-795.
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Advanced Cervical Cancer
EBexternal beam, ICRTintracavitary radiation
therapy, Pplatinum, F5-FU, HUhydroxyurea
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Recurrent DiseaseTreatment in the 80s and 90s

• Platinum-based therapies most effective
• Cisplatin more active than carboplatin
• 3 ways to increase response without prolonging
  survival
• Increase platinum dose
• Add ifosfamide to cisplatin
• Add paclitaxel to cisplatin
• Thus, single agent cisplatin at 50 mg/m2 became
  the best choice

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Treatment of recurrent disease - 2004

• Cisplatin 50 mg/m2
• Topotecan 0.75 mg/m2/d1-3
• Cisplatin 50 mg/m2 d1

GOG 179 Schema
R A N D O M I Z E
293 patients Cervical cancer Stage
IV Recurrent Persistent

• 1º endpoint Survival
• 2º endpoints PFS,ORR, QOL, toxicity

Long H, et al SGO 2004
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Results GOG 179
Long III HJ. SGO 35th Annual Meeting 2004
Abstract 9
54
Progression-free survival
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Overall survival
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Chemotherapy for recurrent disease 2004

• GOG 179 Predictor of response
• Prior cisplatin therapy with RT

• Platinum-free interval
• Performance status
• Site of recurrence higher in non-irradiated
  sites

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Adverse Events GOG 179
Long III HJ. SGO 35th Annual Meeting 2004
Abstract 9
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Summary GOG 179

• 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
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Future Directions

• GOG 204 - Cervical cancer stage IVB, recurrent,
  persistent

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Potential benefit in resecting grossly involved
nodes

• 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 822241
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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 ?