1. 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

2. 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.
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.

3. 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; 87:
2Matsukura M, et al. Int J Cancer 1995; 61:13-22

4. Relative Risk of Cervical Cancer by 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
Author
CIN I
CIN II
CIN III
Ostor AG. 1% 5%
>12%

9. 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; 21:1-6

10. Conventional Cervical Cytology (Papanicolaou Smear)
Good screening test
Inexpensive
High sensitivity & specificity
Easy to perform, noninvasive, nonmorbid
Reproducible

11. Wright et al: ASCCP Cytol
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

12. 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 ( %)
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:

13. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing ASC
Sensitivity of a single repeat test for detecting CIN II-III after ASC is low ( )
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 ( ) 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:

14. ASCCP Management Guidelines ASC-US: HPV Testing
HPV DNA Testing
Repeat Cytology
@ mos
Preferred if
liquid-based cytology
or co-collection available
Colposcopy
The other common STD, HPV which can lead to pap smear abnormalities.
ASCCP recommends HC2 testing for the management of ASC-US results when liquid based cytology is used. Approximately 60% of all Pap smears performed in the US are ThinPrep Pap Tests. Approximately 25-30% of all ASC-US pap result are triaged to HC2 testing.
“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 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:

15. Patient Management Using HPV Triage
ASCUS
HPV TEST
Low Risk + or HPV–
HPV +
Our next step is to incorporate HPV Testing into everyday protocols. As we’ve discussed, only a small percentage of women with initial ASCUS Pap results have persistent or high-grade lesions that will progress to cervical cancer. The key is to identify which of these women have HSIL or that have the potential to develop a significant lesion. Using HPV testing as an adjunct to cytology can effectively identify the women who need to go on to colposcopy and direct the HPV negative/HPV low-risk positive women back into more normal screening intervals.
Repeat Pap and/or HPV Test in 12 mo. or return to routine screening at discretion of clinician
COLPOSCOPY
BIOPSY/ABLATION

16. 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 2002;287:

17. 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 2002;287:

18. 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”
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:

19. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
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 2002;287:

20. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
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 2002;287:

21. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
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 2002;287:

22. 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
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:

23. 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.
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:

24. 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.
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:

25. Managing LSIL with Satisfactory and Unsatisfactory 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 2002;287:

26. Transformation Zone

27. 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; 151:201-6)

28. 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%

29. 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

30. 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

31. Cervical Conization

33. 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. Blaustein’s Pathology of the Female Genital Tract 5th edition Springer-Verlag. New York. pp.216

34. 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
Tennessee ranked 7th in mortality from Cervical Cancer
Overall 5-year survival is approximately 70%2
1Int J Cancer 1993; 54:
2Cancer Facts and Figures -2005, ACS 2005

35. Age-adjusted* Death Rates and Rank from Cervical Cancer
United States 49 44 30 31 29 40 51 19 42 41 39 43 47 16 32 26 37 35 36 25 45 21 20 2
Age-adjusted
Death Rate (Rank) 50 12 17 23 3 24 48 1 38 22 27 28 5
(41-51) 15 34 7 11 33 9 8
(31-40) 14 18
(22-30) 4 46 10
(11-21) 6
(1-10) 13
*Age-adjusted to 2000 population
-Rank 1 is worst; 51 is best.
-Rates are per 100,000

36. Lifetime Probability of Developing Cancer, by Site, Women, US, 1997-1999
Risk
All sites in 3
Breast in 8
Lung & bronchus 1 in 17
Colon & rectum in 18
Uterine corpus in 37
Non-Hodgkin lymphoma 1 in 56
Ovary in 58
Pancreas in 80
Melanoma in 81
Urinary bladder in 88
Uterine cervix 1 in 123
Source: Surveillance, Epidemiology, and End Results Program, , Division of Cancer Control and
Population Sciences, National Cancer Institute, 2002.

37. Test Trends in Recent* Pap Prevalence (%), by Educational Attainment, Women 25 and Older, US,
Some college or greater
High School graduate
All women 18 and older
Prevalence (%)
Less than High School
* A Pap test within the past three years. **Includes fewer than 50 states and District of Columbia
Source: Behavior Risk Factor Surveillance System, , , 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
White
African American
Asian
American Indian
Latina
2.6
5.6
2.8
3.6
Mortality rates per 100,000 based on 2000 US standard population
American Cancer Society 2005

39. Cancer Survival*(%) by Site and Race,1992-1998
African
Site
White
% Difference
American
All Sites
Breast (female)
Colon & rectum
Esophagus
Leukemia
Non-Hodgkin lymphoma
Oral cavity
Prostate
Urinary bladder
Uterine cervix
Uterine corpus
*5-year relative survival rates based on follow up of patients through 1999.
Source: Surveillance, Epidemiology, and End Results Program, , Division of Cancer Control and
Population Sciences, National Cancer Institute, 2002.

40. Cervical Cancer: Improved Mortality & Morbidity with Early Identification
FIGO Stage % Cases Year Survival
I % %
II % %
III % %
IV % %
FIGO Annual Report. J Epi & Biostat 1998; 3(1)

41. 3. Janicek et al. CA Cancer J 2001;51:92-114.
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, 2001; ACS. Cancer Facts & Figures 2004.
3. Janicek et al. CA Cancer J 2001;51:

42. Presenting Symptoms Pre-invasive disease Invasive cervical cancer
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, 2001;

43. Cervical Cancer Differential Diagnosis
Cervical condyloma or dysplasia
Uterine cancer extending to cervix
Metastatic disease to cervix
Cervical or endometrial polyp

44. 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, 2001;

46. Cervical Cancer: Improved Mortality & Morbidity with Early Identification
FIGO Stage % Cases Year Survival
I % %
II % %
III % %
IV % %
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

48. 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

49. Chemotherapy Advanced/recurrent disease
Agents with > 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, 2001;
PDQ®. Cervical Cancer Treatment. Lastmodified 6/03. Rein DT, et al. Anti-Cancer Drugs 2001;12:

50. Advanced Cervical Cancer
Author
Stage n
Treatment
3 yr Med Surv (%)
PFS
P-val (RR)
Whitney et al. 1999
IIb-IVa
177
191
EB + ICRT + PF
EB + ICRT + HU 67 57
0.03 (0.79)
Morris et al. 1999
195
193
EB + ICRT 76 63
Rose et al. 1999
176
173
EB + ICRT + P
EB + ICRT + PFHU 65 47
0.001 (0.57)
0.001 (0.55)
EB=external beam, ICRT=intracavitary radiation therapy, P=platinum, F=5-FU, HU=hydroxyurea

51. 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
Increase platinum dose
Add ifosfamide to cisplatin
Add paclitaxel to cisplatin
Thus, single agent cisplatin at 50 mg/m2 became the best choice

52. 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
Phase 3 Randomized Trial of 12 vs. 3 Months of Single Agent Paclitaxel in Patients with Advanced Ovarian Cancer Who Attained a Clinically-Defined Complete Response to Platinum/Paclitaxel-Based Chemotherapy: A Southwest Oncology Group and Gynecologic Oncol Maurie Markman*, P Y Liu, Sharon Wilczynski, Bradley J Monk, Larry Copeland, David Alberts. Cleveland Clinic Foundation, Cleveland, OH, Southwest Oncology Group Statistical Center, Seattle, WA, City of Hope National Medical Center, Duarte, CA, Univ of California Irvine Medical Center, Orange, CA, Ohio State Univ Health Center, Columbus, OH, University of Arizona Cancer Center, Tucson, AZ.
Objectives: We wished to determine if continuing the cycle-specific cytotoxic agent, paclitaxel, for an extended period of time in women with advanced ovarian cancer who had achieved a clinically-defined complete response to a platinum/paclitaxel- based chemotherapy regimen could prolong the time of subsequent progression-free survival and possibly favorably impact ultimate survival.
Methods: Patients entered into this phase 3 trial were randomized to receive either 3 or 12 cycles of single agent paclitaxel (initially 175mg/m2 over 3 hours) administered every 28 days. Patients were then followed without further therapy and observed for progression-free survival (PFS, primary study endpoint) and overall survival. Due to a higher rate of early withdrawal in the 12-cycle arm, secondary to the development of peripheral neuropathy, the dose of paclitaxel in both arms was decreased to 135mg/m2.
Results: As of 9/6/01, a total of 277 patients (262 evaluable), well-balanced for prognostic factors, had entered the trial, with a total of 54 PFS events having developed among 222 patients with follow-up data. With the exception of peripheral neuropathy there were no major differences in toxicity between the study regimens. The median PFS was 21 and 28 months in the 3-cycle and 12-cycle paclitaxel arms, respectively. One-sided p values from an unadjusted log rank test and an adjusted Cox model analysis (for stratification factors) were and , respectively, both in favor of the 12-cycle arm. The Cox model adjusted 3-cycle vs. the 12-cycle paclitaxel progression hazard ratio was estimated to be 2.31 (99% confidence interval of ). With a protocol-specified early termination boundary of p=0.005, these findings led the SWOG Data and Safety Monitoring Committee to discontinue the trial. As of the date of study closure there was no difference in overall survival between the treatment arms.
Conclusions: 12 cycles of single agent paclitaxel administered to women with advanced ovarian cancer who attain a clinically-defined complete response to initial platinum/paclitaxel-based chemotherapy significantly prolongs the duration of progression free survival. Whether ultimate survival of this patient population is improved remains to be determined.
1º endpoint : Survival
2º endpoints: PFS,ORR, QOL, toxicity
Long H, et al SGO 2004

53. Results GOG 179
Long III HJ. SGO 35th Annual Meeting 2004 [Abstract 9]

54. Progression-free survival

55. Overall survival

56. Chemotherapy for recurrent disease – 2004
GOG 179 – Predictor of response
Prior cisplatin therapy with RT
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

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

58. 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]

59. Future Directions
GOG Cervical cancer stage IVB, recurrent, persistent

60. 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; 82:2241

61. 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

62. THANK YOU !
Questions / Comments ?