1. Advances in the Screening, Diagnosis, and Treatment
of Cervical Disease

2. Cervical Cancer Second most common cancer among women worldwide1
The American Cancer Society estimates that in 2002, ~13,000 new cases of invasive cervical cancer will be diagnosed in the United States, with about 4,100 deaths2 . In 2001, the estimates were ~ 12,900 cases and 4,500 deaths.
75% decreased incidence and 73% decreased mortality since Pap screening began in 1949
However, cervical cancer mortality has not declined in the US since the 1980s 3
1. Walboomers et al. J Pathol. 1999;189:12-19.
2. American Cancer Society, Cancer Facts & Figures 2002.
3. Chu KC et al. Cancer. 1999;86:

3. Cervical Cancer Statistics
Years
Description
U.S. Statistic
1998
Death rate from cervical cancer2
3.0 per 100,000 women
2000
Cervical cancer deaths2
~ 4,600
2001
Cervical cancer deaths1
~ 4,400
Change in the number of cervical cancer deaths1
 74%
Annual change in invasive cervical cancer mortality3
 4.6%
 1.6%
Incidence of invasive cervical cancer (overall) 3
8.7 per 100,000 women
Incidence of invasive cervical cancer by race: 3
White
Black
Asian/Pacific Islander
American Indian/Alaskan National
Hispanic
8.1 per 100,000 women
11.0 per 100,000 women
10.3 per 100,000 women
6.4 per 100,000 women
14.4 per 100,000 women
Annual change in invasive cervical cancer incidence3
 4.8%
 1.1%
New diagnoses of cervical cancer2
~ 12,800
New diagnoses of cervical cancer1
~ 12,900
Approximately 13,000 new cases of cervical cancer and 4,500 deaths occur annually in the U.S., making this the seventh ranked cancer and accounting for about 1.7% of cancer deaths in women.
However, it should be kept in mind that cervical cancer has been considered the second leading cause of death from cancer in women worldwide and the leading cause in many developing countries.
It is only because Pap screening has been so successful in identifying cervical cancer precursors—leading to their eradication and the prevention of their progression to cancer—that women in North America and Europe have largely been spared from developing invasive carcinoma of the cervix.
American Cancer Society Inc., Available at:
U.S. Department of Health and Human Services. Healthy People 2010: Understanding and Improving Health, 2nd ed. Washington, D.C.: U.S. Government Printing Office, November Available at:
National Cancer Institute. SEER Cancer Statistics Review Available at:

4. U.S. Trends in Cervical Cancer Morbidity and Mortality
20,000
1970
1975
1980
1985
1995
1990
15,000
10,000
5,000
Number of Cases
This chart, based on figures from the National Cancer Institute, illustrates how the
incidence and mortality of cervical cancer has stopped decreasing in women under 50.
In fact, as the graph demonstrates, incidence may be rising. A discussion in the December
1996 issue of OBG Management entitled “Improving the Detection of Cervical Disease”
cited early exposure to human papillomavirus (HPV) as potentially responsible for this
increase.
The two graphs cannot be considered in tandem, as there may be many years between the identification of cervical cancer and/or its precursors and a woman’s resultant death from the disease.
Year
Source: National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) data,
American Cancer Society 2001.

5. SEER Trends in North American Incidence of Cervical Adenocarcinoma
Cumulative Rate per 1000 Women
Year of Birth
0.05
0.10
0.15
0.20
0.25
0.30
1930
1940
1950
1960
Black, USA
White, USA
Canada
Hispanic, USA
The SEER (Surveillance, Epidemiology, and End-Results) program of the National Cancer
Institute is the most authoritative source of information concerning cancer incidence and
survival in the United States. Using population-based cancer registries, 3 aspects of the
cancer incidence trend have been studied (age, calendar period of diagnosis, and birth
cohort). There was a significant increase in the cumulative incidence of cervical
adenocarcinomas in women born in the 1930s and in successive cohorts thereafter in white
and Hispanic US women. A similar increase was observed in Canadian women. This increase
in the incidence of cervical adenocarcinoma may also, in part, be the result of an increasing
prevalence of human papillomavirus infection. Interestingly, there were no changes in
incidence within black populations in the United States.
Source: Vizcaino AP et al. Int J Cancer. 1998;75:

6. Risk Factors Associated With Precancerous Changes and Cancer of the Cervix
Human papillomavirus (HPV) infection
Sexual activity: multiple partners; begun at an early age
Parity
Human immunodeficiency virus (HIV)
Immunosuppressed status
Smoking
History of other sexually transmitted diseases –e.g., Herpes simplex, Chlamydia, bacterial vaginosis
Oral contraceptive use
Low socioeconomic status
Poor diet–e.g., vitamin deficiency
Alcoholism
A number of general risk factors, shown on this slide, have been identified as
being associated with cervical cancer. Individually, these factors may be dependent or
independent variables. The first few are related to sexual activity (the risk of acquiring HPV
infection), whereas the remainder are generally indicative of immune status (the difficulty of
clearing the infection).
It is now established that HPV is the cause of most of the common cervical neoplasms.

7. Cervical Epithelium Showing Progressive Degrees of Dysplasia and Neoplasia
LSIL
HSIL
Koilocytosis CIN CIN CIN3
This slide is a diagram of cervical epithelium showing progressive degrees of dysplasia and neoplasia, and the correlating terminology.
Basement membrane
Normal Mild Moderate Severe Carcinoma
squamous in situ
epithelium Dysplasia

8. Natural History of Cervical Lesions
Biopsy Regress Persist Progress Progress
Result to CIS to Invasion
CIN % % % %
CIN % % % %
CIN % <56% >12%
This table shows the natural history of cervical lesions, as reported by ÖstÖr’s group from data in papers published from 1951 to 1990.
Source: ÖstÖr AG. Int J Gynecol Pathol. 1993;12(2):

9. Natural History of Cervical Lesions
ASCUS % (57.51, 78.86) % (0.8, 13.5) % (0, 2.25)
LSIL % (35.92, 58.86) % (6.08, 35.55) % (0, 0.71)
HSIL % (16.57, 53.49) % (12.82, 32.92) % (0, 3.95)
Pap Regress Progress to/ Progress to
Diagnosis to Normal Persist as HSIL Invasive Cancer
(95% CI) in 24 months in 24 months
(95% CI) (95% CI)
This table shows the natural history of cervical lesions, as reported by Melnikow and colleagues, who applied meta-analytical techniques to their review--excluding studies with inconsistencies in design and reporting, and those published before They also set a time of observation of at least 2 years.
Source: Melnikow J et al. Obstet Gynecol. 1998;92(4Pt2):

10. Progression and Regression of Cervical Lesions
Mild to moderate or worse % % %
Mild to severe or worse % % %
Moderate to severe or worse % % %
Regression
Mild to first normal Pap % % %
Moderate to first normal Pap % % %
Mild to second normal Pap % % %
Moderate to second normal Pap 6.9% % %
Grade of Dysplasia Within 2 years Within 5 years Within 10 years
Holowaty and colleagues calculated progression through stages of dysplasia, as well as for regression to normal, from over 70,000 historical records. Their data are shown on this slide.
Source: Holowaty P et al. J Natl Cancer Inst. 1999;91(3):

11. Mean Age at Diagnosis of Cervical Lesions
Carcinoma Postmenopausal Premenopausal
(61.9%) (32.4%)
HSIL Premenopausal Postmenopausal
(72.2%) (10.7%)
LSIL Premenopausal Pregnant
(74.4%) (10.2%)
Glandular Premenopausal Postmenopausal
Intraepithelial (50.3%) (38.5%)
Lesion
Diagnosis Mean Patient Predominant Second Most
Age (Years) Patient Status Prevalent Patient
Status
Jones and colleagues assessed age distribution at time of diagnosis, shown on this slide. Despite general indications for predominant patient ages at diagnosis, some countries have identified that there has recently been a higher incidence of cervical carcinoma diagnosed in younger women.
Source: Jones BA et al. Arch Pathol Lab Med. 2000;124:

12. Cervical Cancer Screening Guidelines: American Cancer Society
All women should have yearly Pap smears starting at age 18 or when they begin having sex, whichever occurs first
The doctor may decide to do the test less often if a woman has had 3 normal tests in a row
If a hysterectomy was done for cancer, more frequent Pap tests may be recommended
Women who have had their uterus removed and those past menopause still need to have regular Pap tests
The Pap test has been in use for over 50 years as the primary screening for cervical disease. This slide lists the American Cancer Society’s recommendations for pap testing.
The American Cancer Society (ACS) does not specify an upper age limit for monitoring. Furthermore, women who have had their uterus, with or without the cervix, removed may still require routine testing for cervical or vaginal epithelial changes. If screening is normal, then it may be decided to be done less frequently.
New ACS guidelines for cervical cancer screening are expected at the end of Those guidelines should appear on the ACS website after that time.

13. Bethesda System 2001
Specimen Type: Indicate conventional Pap smear vs. liquid-based vs. other
Specimen Adequacy
Satisfactory for evaluation (describe presence or absence of endocervical/transformation zone component and any other quality indicators--e.g., partially obscuring blood, inflammation, etc.)
Unsatisfactory for evaluation (specify reason)
Specimen rejected/not processed (specify reason)
Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because of (specify reason)
The primary system of nomenclature used in the United States for cervical cytology found on Pap testing is the Bethesda System. This system was originally developed from a National Cancer Institute (NCI) workshop in 1988 in Bethesda, MD. In 1991, a second workshop was sponsored by the NCI, resulting in further refinement.
The Bethesda 2001 workshop took place April 30 to May 2, 2001, resulting in further clarification of terminology and reporting of cervical cytology.
Bethesda 2001 includes the need for the cytologist to note whether endocervical transformation zone (TZ) cells are in the sample when the specimen is satisfactory for evaluation.

14. Bethesda System 2001 (continued)
General Categorization (optional)
Negative for intraepithelial lesion or malignancy
Epithelial cell abnormality: See interpretation/result (specify “squamous” or “glandular” as appropriate)
Other: See interpretation/result (e.g., endometrial cells in a woman  40 years of age)
Automated Review: If case examined by automated device, specify device and result
Ancillary Testing: Provide a brief description of the test methods and report the result so that it is easily understood by the clinician

15. Bethesda System 2001 (continued)
Interpretation/Result
Negative for Intraepithelial Lesion or Malignancy (when there is no cellular evidence of neoplasia, state this in the General Categorization above and/or in the Interpretation/Result section of the report, whether or not there are organisms or other non-neoplastic findings)
Organisms
Trichomonas vaginalis
Fungal organisms morphologically consistent with Candida spp
Shift in flora suggestive of bacterial vaginosis
Bacteria morphologically consistent with Actinomyces spp.
Cellular changes consistent with Herpes simplex virus
Other Non-Neoplastic Findings (optional to report; list not inclusive):
Reactive cellular changes associated with
Inflammation (includes typical repair)
Radiation
Intrauterine contraceptive device (IUD)
Glandular cells status post hysterectomy
Atrophy

16. Bethesda System 2001 (continued)
Other (list not inclusive)
Endometrial cells (in a woman  40 years of age)
(specify if ‘negative for squamous epithelial lesion’)
Epithelial Cell Abnormalities
Squamous Cell
Atypical squamous cells
Of undetermined significance (ASC-US)
Cannot exclude HSIL (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
Encompassing: HPV/mild dysplasia/CIN1
High-grade squamous intraepithelial lesion (HSIL)
Encompassing: moderate and severe dysplasia, CIS/CIN2 and CIN3
With features suspicious for invasion (if invasion suspected)
Squamous cell carcinoma

17. Bethesda System 2001 (continued)
Glandular Cell
Atypical
Endocervical cells (NOS* or specify in comments)
Endometrial cells (NOS or specify in comments)
Glandular cells (NOS or specify in comments)
Endocervical cells, favor neoplastic
Glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
Endocervical
Endometrial
Extra uterine
NOS
Other Malignant Neoplasms: (specify)
* NOS = Not otherwise specified

18. Bethesda System 2001 (continued)
Educational Notes and Suggestions: (optional)
Suggestions should be concise and consistent with clinical follow-up guidelines published by professional organizations (references to relevant publications may be included)

19. Bethesda 2001 Changes
Satisfactory: Liquid-based—minimum 5,000 epithelial cells; presence of epithelial cell abnormality
“SBLB” eliminated
Unsatisfactory: specimen rejected/not processed; or specimen processed/examined, but unsatisfactory because of (specify reason)
WNL and BCC are now Negative for Intraepithelial Lesions or Malignancy; includes BCC (e.g., organisms and reactive changes) as descriptor only
The multiple subcategories of ASCUS have been reduced to ASC-US or ASC-H, with no other modifiers
The subcategories of AGUS (now AGC) have been expanded to allow for a more descriptive diagnosis of glandular abnormalities; AIS is now a distinct subcategory
This slide highlights the major changes that Bethesda 2001 includes.
Regarding specimen adequacy, the previous Bethesda System included the term “satisfactory but limited by (SBLB),” which clinicians found confusing. As a result, the SBLB terminology was eliminated in Bethesda 2001, while maintaining provisions for describing specimen adequacy. Additionally, Bethesda 2001 has streamlined the designation of unsatisfactory specimens—either the specimen is unsatisfactory because it was rejected/not processed, or the specimen was processed and examined, but was unsatisfactory for evaluation of epithelial abnormalities because of a specific reason (as cited by the laboratory).
The Within Normal Limits (WNL) category of the previous system is replaced by Negative for Intraepithelial Lesions or Malignancy in Bethesda Benign Cellular Changes (BCC) is included as a descriptor only.
The multiple categories of ASCUS have been reduced to two categories: ASC-US or ASC-H. The subcategories of AGC, formerly AGUS, have been expanded to allow for a more descriptive diagnosis of glandular abnormalities. In addition, the previous system included a subcategory for adenocarcinoma under glandular cell abnormalities, while Bethesda 2001 includes a subcategory for adenocarcinoma and a subcategory for endocervical adenocarcinoma in situ (AIS) as distinct entities.

20. The Bethesda System 2001 LSIL = HPV / mild dysplasia / CIN1
HSIL = moderate and severe dysplasia / CIS / CIN2 and CIN3
ASCUS = ASC-US (undetermined significance) or
ASC-H (cannot exclude HSIL)
The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses standardizes the reporting of cytologic findings on Pap smear.
The continuum of precancerous squamous abnormalities is divided into low-grade SIL (LSIL) or high-grade SIL (HSIL) under the Bethesda System.
The cytologic terms LSIL and HSIL correlate with the old histopathologic nomenclature CIN 1 and CIN 2-3.
LSIL includes changes consistent with HPV infection, mild dysplasia, and CIN 1.
HSIL includes changes consistent with moderate and severe dysplasia, CIN 2, CIN 3, and CIS.
Squamous abnormalities that do not fulfill criteria for SIL are termed ASCUS .
Under The Bethesda System 2001, atypical squamous cell (ASC) abnormalities have been subdivided into two further categories: ASC-US (atypical squamous cells of undetermined significance) and ASC-H (atypical squamous cells, cannot exclude HSIL).
Monitoring recommendations and follow-up management vary according to the type of abnormality found on Pap smear, and on results of histology from colposcopy and directed biopsy.

21. Annual Number of Women with Abnormal Pap Results in the US
LSIL
Cancers
HSIL
2 - 3 million
1.25 million
300,000
12,800
ASC
AGC
180, ,000
The abnormal morphologic changes described by TBS include atypical cells (ASC), atypical glandular cells (AGC), low- and high-grade intraepithelial lesion (LSIL and HSIL), and squamous and adenocarcinoma.
Source: J. Thomas Cox, with permission.

22. Sensitivity of the Pap Smear
The limitations of the conventional Pap smear result in a test that is less sensitive than generally believed. False-negative results in cervical cytology are a major concern to the clinician and patient, as the disease is present clinically on the cervix but is undetected on the slide.
Although the exact rates of false-negatives are not known, an estimated figure of 49% has been reported. Between 5% and 10% of results are false positive, where a perceived abnormality is identified on the slide but is not actually clinically present. Likewise, inconclusive results, such as atypical squamous cells of undetermined significance (ASCUS) may create concern among patients and providers.
Overall, it is estimated that about two-thirds of the false negative Pap tests are related to sampling errors, and the remaining one-third due to detection error.
This slide summarizes a meta-analysis of conventional Pap smear accuracy, and a study by Fahey. The Agency for Health Care Policy and Research (AHCPR) analysis identified 57 studies published before 1992 that compared Pap smear results with histology. The report concluded the mean sensitivity of the conventional Pap is 51%.
Prevalence of disease is a strong and consistent factor associated with between-study variation. Higher disease prevalence is associated with higher estimates of sensitivity and lower estimates of specificity.
The Fahey analysis demonstrated that the mean sensitivity of the conventional Pap is 58% (95% CI, 49–67) in a screening population, and 66% (95% CI, 58–73) in a follow-up population in which there is a higher prevalence of disease.
1. Agency for Health Care Policy and Research (AHCPR). Evaluation of Cervical Cytology
2. Fahey MT, et al. Am J Epidemiol. 1995;141:
Mean Sensitivity of Conventional Pap Smear (%), 95% CI
1. Agency for Health Care Policy and Research (AHCPR). Evaluation of Cervical Cytology
2. Fahey MT et al. Am J Epidemiol. 1995;141:

23. Two Types of Screening Conventional Pap Smear Liquid-Based
Cervical cell sample manually “smeared” onto slide for screening
Liquid-Based
Cervical cell sample put into liquid medium for suspension before automated thin layer/monolayer slide preparation
ThinPrep® 2000 System
SurePathTM (formerly AutoCyte® PREP)
As with any screening test, false negative Pap smears may occur. These can be due to one or more of three general types of errors: sampling, laboratory screening, or interpretation.
New Pap smear technologies have been shown to increase the accuracy of the test, i.e., increasing true positive results (sensitivity) and decreasing false negatives. Thin layer or liquid-based technologies improve the sample quality, resulting in decreased false-negative sampling and screening errors.
The ThinPrep® 2000 System has been approved by the FDA as significantly more effective than conventional Pap testing for the detection of LSIL and more severe lesions.
AutoCyte® PREP was approved by the FDA as a replacement for conventional Pap testing, with similar results but with significantly fewer unsatisfactory cases.
Both the ThinPrep® 2000 System and SurePathTM are liquid-based, thin layer cytologic screening techniques. The major difference between these methods is that the SurePathTM has been shown to be statistically equivalent to conventional Pap for its intended use while the ThinPrep® 2000 System has proven to be statistically significantly superior to conventional Pap for its intended use. Product labels approved by the FDA reflect this difference in sensitivity.

24. Overcoming the Inherent Limitations of the Conventional Pap Smear
Liquid-based Cytology*
Majority of cells not captured
Non-representative transfer of cells
Clumping and overlapping of cells
Obscuring material
Virtually all cells of sample are collected
Randomized, representative transfer of cells
Even distribution of cells
Minimizes obscuring material
The conventional Pap smear is limited by a high rate of false-negative results, the consequence
of sampling and preparation errors. Because much of the sample is discarded,
the cells on the slide may not provide a representative sample. In addition, the Pap smear
is often difficult to read because of clumping and the presence of obscuring material.
The ThinPrep® Pap Test™ overcomes these limitations because the thin layer technology
ensures a randomized transfer of representative cells with little chance of obscuring
Material. This provides the laboratory an optimal specimen with which to make an
accurate diagnosis.
Hutchinson ML, et al. Am J Clin Pathol. 1994;101:
* From ThinPrep Sampling Study, Hutchinson 1994

25. Overview of Liquid-Based Cytology: FDA Labeling
ThinPrep® Pap Test SurePath™
Used as a replacement for the conventional Pap smear
Specimen quality is significantly improved over that of the conventional Pap smear in a variety of patient populations
Significantly more effective than the conventional Pap smear for the detection of low-grade and more severe lesions in a variety of patient populations
Specimens should be collected using a broom-type or endocervical brush/spatula combination collection device
Increased HSIL+ detection by 59.7% (data from a multi-site, historical control study)
Approved as a specimen medium for HPV DNA testing using Digene Hybrid Capture® 2, as well as for chlamydia and gonorrhea screening
Used as a replacement for the conventional Pap smear
Significantly fewer Unsatisfactory and SBLB cases as compared to the conventional Pap smear
Provides similar results to the conventional Pap smear (data from a prospective split-sample comparison in a variety of patient populations and laboratory settings)
Specimens should be collected using a broom-type sampling device
In November 1996, the FDA approved the ThinPrep Pap Test as a replacement for the conventional Pap smear and affirmed the claim that the ThinPrep Pap Test is significantly more effective than the conventional Pap smear for the detection of low-grade squamous intraepithelial (LSILs) and more severe lesions in a variety of patient populations.
Additionally, the FDA acknowledged a significant improvement in ThinPrep Pap Test specimen quality over that of the conventional Pap smear in a variety of patient populations.
In August of 2001, the FDA provided approval for a PMA supplement allowing the inclusion of the HSIL+ data.
ThinPrep® Pap Test Package Insert, Cytyc Corporation
AutoCyte PREPTM SYSTEM package insert (now SurePathTM), TriPath Imaging, Inc.

26. HSIL+ Clinical Outcomes Trial
Direct-to-vial study to evaluate ThinPrep 2000 vs. conventional Pap for the detection of high-grade squamous and more severe lesions (HSIL+)
10 metropolitan academic hospitals, two groups of subjects per site:
Routine screening population
Referred for colposcopy
ThinPrep specimens (n = 10,226) collected prospectively compared to historical control cohort (n = 20,917)
These sites demonstrated a 59.7% (p < 0.001) increase in detection of HSIL+ lesions for ThinPrep specimens
Following initial FDA approval in May 1996, Cytyc conducted a multisite direct-to-vial
clinical study to evaluate the ThinPrep 2000 System vs the conventional Pap for the detection
of high-grade squamous intraepithelial and more severe lesions (HSIL+). Two types
of patient groups were enrolled in the trial from 10 leading academic hospitals in major
metropolitan areas throughout the US. From each site, one group consisted of patients
representative of a routine screening population and the other group of patients were
representative of a referral population enrolled at the time of colposcopic examination.

27. HPV Testing – Essential Facts
HPV is the major etiologic agent for cervical cancer
HPV detection is associated with an increased risk of high-grade CIN
Essentially all women with CIN3 have detectable HPV DNA
Persistent infection with high-risk HPV is necessary for development and maintenance of CIN3
HPV testing helps to clarify ambiguous cytology results and identifies persistent infection in women over 30
The rationale for HPV testing is based on the logic of the five essential clinical facts on
this slide and three basic premises:
First, the definitive link between the virus and development of cervical cancer and its
high-grade precursors.
Second, the challenges of repeat cervical cytology screening.
Third, the lack of an efficient clinical management protocol to address the unwieldy
number of ASCUS Pap smears reported in the United States each year.
We need a more effective way of dealing with ASCUS Pap test results.
As I will discuss in the second half of the program, recent performance data clearly
support the use of reflex HPV testing for the management of an ASCUS Pap result.
1 Walboomers JMM, et al. J Pathol. 1999;189:12-19.
2 Liaw K-l et al. J Natl Cancer Inst. 1999;91:
3 Nobbenhuis MAE, et al. Lancet. 1999;354:20-25.
4 Manos M, et al. JAMA. 1999;281:

28. HPV Risk Types
Hybrid Capture®2 (HC II) HPV DNA Test uses two RNA Probe cocktails to differentiate between carcinogenic and low-risk HPV types:
Low-risk
High-risk
HPV is a DNA virus that has a high incidence rate, a high spontaneous remission rate, a lengthy natural history, and a relatively low rate of transformation to cancer. Genital HPV infection is extremely common.
Types 6 and 11 and other non-oncogenic risk types are found in about 20% of women with low-grade abnormal cervical Pap smears and not found in high-grade disease or invasive cancer.
HPV types 16 and 18 are the prototypical oncogenic risk types. These and other high-risk HPV types are found in about 80% of women with low-grade abnormal Pap smears and are the only ones found in high-grade precancers and cervical cancers. Type 16 is predominant in squamous cell lesions and type 18 is found in a higher proportion of adenocarcinomas.
There is a commercial test, Hybrid Capture®2, manufactured by Digene Corporation, which uses the listed low- and high-risk probe cocktails.

29. HPV Prevalence and Cervical Cancer - Incidence by Age 1,2
40-44
15-19
20-24
25-29
30-34
35-39
45-49
50-54 5 10 15 20 25 30
HPV Prevalence (%)
Cancer incidence per 100,000
This graph shows HPV prevalence and cervical cancer incidence are a function of a woman’s age. A number of key observations can be made. First, the slide shows that in younger women, there is a high prevalence of HPV infection. As women age, however, the prevalence declines and the incidence of cancer increases.
Women over 30 years of age have a greater risk for developing high-grade lesions and cancer. Furthermore, women with persistent high-risk HPV infections are the population most at-risk for having or developing cervical cancer.
Data from the CMAJ study was collected from women aged 15-49, whereas the SEER data reported cancer incidence in all age-segments of the population.
1. Sellors et al. CMAJ. 2000;163:503.
2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI,
Age (Years)
1. Sellors et al. CMAJ. 2000;163:503.
2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI,

30. Incidence of Atypical Findings
HSIL % SIL+ 2.5% 0.51%
LSIL % %
ASCUS % % 2.8%
AGUS % % --
Pap Smear Incidence Incidence Incidence
Cytology (Manos et al) (Chhieng et al) (Stoler)
This slide lists three studies that provide information on the frequency of occurrence of Pap smear abnormalities—HSIL, LSIL, ASCUS, and AGUS.
Manos et al reported on 46,009 women undergoing routine screening with conventional Pap smears at Kaiser Permanente in Northern California. Chhieng et al reported on 43,456 Pap tests, and the data reported by Stoler are based partly on a study of 1.7 million Pap smears and extrapolated to the U.S. population.
Manos MM, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia. Using human papillomavirus DNA testing for equivocal Papanicolaou results. J Am Med Assoc 1999;281(17):
Chhieng DC, Elgert PA, Cangiarella JF, et al. Clinical significance of atypical glandular cells of undetermined significance. A follow-up study from an academic medical center. Acta Cytol 2000;44(4):
3. Stoler MH. Advances in cervical screening technology. Mod Pathol 2000;13(3):
1. Manos MM, Kinney WK, Hurley LB, et al. J Am Med Assoc 1999;281(17):
2. Chhieng DC, Elgert PA, Cangiarella JF, et al. Acta Cytol 2000;44(4):
3. Stoler MH. Mod Pathol 2000;13(3):

31. Comparison of HPV Testing and Repeat Pap in the Management of ASCUS
Triage Referred to Sensitivity PPV for
Strategy Colposcopya for HSIL HSIL+
Based on HPV Test b % % %
Based on Repeat Pap
Resultc % % %
PPV = positive predictive value
Notes:
Prevalence of positive test result in women with ASCUS
Referral to colposcopy based on positive DNA test for high-risk HPV types, from specimen on initial visit
Referral to colposcopy based on repeat Pap test result of ASCUS or more severe
Bethesda 2001 decreased the number of ASC subcategories from three (ASC “favor reactive”, “unqualified”, and “favor dysplasia”) to two (ASC-US and ASC-H). The latter, “atypical squamous cells—cannot exclude HSIL”, imparts a higher risk for high-grade intraepithelial neoplasia than ASC-US, and is therefore managed differently.
A study by Manos and colleagues provides important information on the management options for ASC and predicted outcomes of triage strategies. Manos’ group evaluated 995 eligible women with ASCUS on conventional Pap smear derived from a screening population of about 46,000 women. The mean age of the women with ASCUS in this study was 40, and the age range was All women had colposcopy (with biopsy and/or cervical curettage), HPV testing, and repeat liquid-based Pap testing.
The slide shows the calculated/theoretical percentage of cases which would be referred to colposcopy after either HPV testing or repeat Pap. It shows that half the cases would be referred to colposcopy if HPV testing were performed at the initial visit. The sensitivities and positive predictive values are not significantly different.
Of the original ASCUS Pap smear cases in the study, about 20% were diagnosed as having abnormal histology. Thus, the majority had no abnormality on colposcopy and biopsy. One cancer was found from ASCUS referral, consistent with usual estimate of approximately one cancer per 1000 ASCUS Pap tests.
Source: Manos et al, JAMA. 1999;281(17):

32. ALTS Study Design Randomized trial sponsored by NCI, 1995-2001
Enrolled 3488 women with community-based ASCUS and 1572 with LSIL results, randomized to three management arms:
Immediate colposcopy
HPV triage
Repeat cytology
Clinical follow-up every 6 months for 2-year period
LSIL arm discontinued due to limited utility of positive test result
This slide provides an overview of the study design and lists the 3 treatment strategies
that were evaluated.
The goal was to determine which strategy most rapidly allowed physicians to identify
women who should be sent to colposcopy, and effectively find CIN3. CIN3 was chosen
as the clinical endpoint because CIN3 lesions are considered high-risk for progressing
to cervical cancer.
Due to the large percentage of HPV positive women in the LSIL arm (86%), HPV testing
was not found to be an effective triage strategy for predicting CIN3.
HPV testing was conducted using Hybrid Capture® 2 from the residual ThinPrep® Pap
Test™ specimen.
Repeat cytology was conducted using the ThinPrep Pap Test.
The ALTS trial was published in the February 21st issue of the Journal of the National
Cancer Institute.
Source: Solomon D et al. J Natl Cancer Inst. 2001;93:

33. Sensitivity for CIN2+ by HC II & Pap by Age
Clinical Center Pap
Cutpoint %(+) / Sens %(+) / Sens %(+) / Sens
HC II / / / 94
ASCUS / / / 87
As reported for the ALTS study, this slide shows performance by management modality. HPV triage of ASC-US Pap results, conducted from the ThinPrep Pap Test vial was determined to be 96% sensitive for the detection of CIN2/3+. The use of HPV triage, reduced the number of negative findings on biopsy by 50% compared to direct colposcopy.
Sherman M, Schiffman M, Cox JT. J Nat Cancer Inst. 2001

34. Risk of CIN 2/3+ for ASC referral Based on HPV status at enrollment
Positive Negative ASCUS
Cox % % %
(14/81) (1/136) (15/217)
Manos % % %
(45/300) (6/498) (51/801)
ALTS % % %
(136/651) (6/541) (142/1192)
Total % % %
(195/1087) (13/1175) (208/2210)
HPV HPV Total risk
Cox JT, et al. Am J Obstet Gynecol Mar;172(3): Solomon D, et al. J Natl Cancer Inst. 2001;93:
Manos et al, JAMA. 1999;281(17):

35. Primary Findings: ALTS
Management Sensitivity %* Referral % PPV % NPV %
Modality
Colposcopy
HPV
Cytology ASC-US
Cytology LSIL
Cytology HSIL
PPV = positive predictive value; NPV = negative predictive value
As reported for the ALTS study, this slide shows performance by management modality. HPV triage of ASC-US Pap results, conducted from the ThinPrep Pap Test vial was determined to be 96% sensitive for the detection of CIN2/3+. The use of HPV triage, reduced the number of negative findings on biopsy by 50% compared to direct colposcopy.
*For detection of (CIN2+)
Adapted from table 5, Solomon D et al. J Natl Cancer Inst. 2001;93:

36. ASCCP Consensus Guidelines for the Management of Abnormal Cervical Cytology and Cervical Cancer Precursors
Held in Sept. 2001, NCI campus, 29 national and international organizations including ACS, NCI, CDC, ACOG, all the major cytopathology organizations, etc.
The guidelines were all evidence-based (to the limits of the literature)
They were placed on the Consensus Guidelines Website twice during the 6 months prior to the conference for public comment and appropriate revisions were made
All of the guidelines were approved by a majority and most were approved by 70-90%

37. This slide shown an algorithm for management of women with ASC-H.
Women with ASC-H Pap tests are best managed by referral to colposcopy due to the high rate of CIN2-3 identified with this Pap diagnosis. Women not found to have a lesion that explains the Pap at colposcopy may benefit by a review of the cytology, colposcopy, and histology. If the cytologic interpretation of ASC-H is upheld, either repeat Pap at 6 or 12 months or HPV testing at 12 months is recommended. Any repeat abnormal Pap or positive HPV test would require repeat colposcopy.

38. This slide shows an algorithm for the management of ASC-US.
The preferred approach for management of ASC-US is by “reflex” HPV testing directly from the remaining liquid in the Pap collection bottle. Women with HPV-positive ASC-US should be managed by colposcopy, whereas women with HPV negative ASC-US may be returned to two annual Pap tests before returning to routine screening if such screening is normally at longer biennial or triennial intervals.
Repeat Pap and immediate colposcopy are considered acceptable alternatives but have several disadvantages. Colposcopy of all women with ASC-US subjects a majority of women with this Pap reading who are normal to an expensive and often anxiety-producing procedure that may also lead to overdiagnosis and overtreatment. Repeat cytology requires several repeats to provide adequate reassurance that no significant disease has been missed, since the sensitivity of a single repeat conventional smear for the detection of CIN2-3 is relatively low ( ).
Repeat liquid-based cytology has somewhat improved sensitivity over the conventional smear, but would still require two repeat office visits and two repeat Pap tests set at a threshold for referral to colposcopy of any repeat abnormal >ASC. Although managing ASC by repeat cytology has been the standard approach, such recommendations have been based primarily on clinical opinion, with many questions remaining about ideal interval for repeat and the number of repeats required before returning to routine screening.

39. ASC in post-menopausal women is often due to the effects of estrogen loss on the epithelium. Hence, intravaginal estrogen followed by repeat cervical cytology obtained approximately one week following the end of the treatment is an acceptable option for women with ASC-US who have evidence of cytologic or clinical atrophy. A repeat normal Pap test following estrogen therapy may be followed in months by a second repeat Pap, and if this is also normal, the woman may return to routine cytological screening. In contrast, any repeat abnormal Pap (> ASC) should be evaluated by colposcopy.
Pregnant women with ASC-US should be managed in the same manner as non-pregnant women.
Immunosuppressed women with ASC-US should be referred to colposcopy. Immunosuppression increases the risk for detection of CIN2 or 3, and the addition of HPV testing is less likely to substantially decrease the number of women referred to colposcopy due to an increased likelihood of testing positive for HPV. This recommendation includes all HIV-infected women, irrespective of CD4 count, HIV viral load, or antiretroviral therapy.

40. AGC Findings from 306 Laboratories Participating in CAP Survey 2000
AGC Rate SIL AIS CA
0.3% % % %
Bethesda 2001 decreased the number of ASC subcategories from three (ASC “favor reactive”, “unqualified”, and “favor dysplasia”) to two (ASC-US and ASC-H). The latter, “atypical squamous cells—cannot exclude HSIL”, imparts a higher risk for high-grade intraepithelial neoplasia than ASC-US, and is therefore managed differently.
A study by Manos and colleagues provides important information on the management options for ASC and predicted outcomes of triage strategies. Manos’ group evaluated 995 eligible women with ASCUS on conventional Pap smear derived from a screening population of about 46,000 women. The mean age of the women with ASCUS in this study was 40, and the age range was All women had colposcopy (with biopsy and/or cervical curettage), HPV testing, and repeat liquid-based Pap testing.
The slide shows the calculated/theoretical percentage of cases which would be referred to colposcopy after either HPV testing or repeat Pap. It shows that half the cases would be referred to colposcopy if HPV testing were performed at the initial visit. The sensitivities, positive predictive values and negative predictive values are not significantly different.
Of the original ASCUS Pap smear cases in the study, about 20% were diagnosed as having abnormal histology. Thus, the majority had no abnormality on colposcopy and biopsy. One cancer was found from ASCUS referral, consistent with usual estimate of approximately one cancer per 1000 ASCUS Pap tests.
Jones BA, Novis DA. Follow-up of abnormal cervical cytology: a College of American Pathologists Q Probes Study of 16,132 cases from 306 laboratories. Arch Pathol Lab Med. 2000;124: (1-C)

41. Clinical Significance of an AGC Pap
Qualifier Any High-grade Lesion High-grade Glandular Lesion Only
AGUS reactive 5 – 39% 1 – 8%
AGUS NOS 9 – 41% 0 – 15%
AGUS neoplastic – 96% – 93%
The clinical significance of an AGC Pap is summarized on this slide from the findings of 14 studies of high-grade disease on AGUS follow-up.
Source: Richart et al. Contemp Ob Gyn ; 46:15-17,25-28,30-32,35-43.

42. Management of AGC
This slide shows an algorithm for the management of women with AGC.
The management recommendation for all women with any AGC Pap interpretation is colposcopy and endocervical sampling. The one exception is women with atypical endometrial cells, who should initially be evaluated by endometrial sampling. Endometrial sampling should also be performed at colposcopy in women with any AGC who are over the age of 35, and in younger women with AGC who have unexplained vaginal bleeding. The presence of a coexisting squamous abnormality on the cytologic interpretation does not change the management. Initial management of women with AGC by repeat Pap testing is unacceptable.
Because of the increased risk at colposcopy of missed glandular abnormalities, women with a negative finding for AGC on colposcopy, endocervical sampling or, where appropriate, endometrial sampling, continue to be at increased risk; the degree of risk varies with the subclassification of AGC. The risk of missed significant disease for women with AGC “favor neoplasia”, or with AIS, found to be negative on evaluation is too great to rely upon repeat cervical cytology for follow-up. Therefore, these women should have a cervical excision procedure. Whenever possible the excision procedure used should be a cold-knife conization due to the potential for thermal damage from electrosurgical or laser procedures to obscure the margins.
Women with AGC NOS negative on evaluation are at relatively lower risk for missed significant disease and may be managed by repeat Pap at 4 to 6 month intervals until four repeat negative Paps have been obtained. Any repeat Pap abnormality requires further evaluation, which varies depending upon the degree of abnormality noted. Acceptable options for the management of women with repeat cytology read as ASC or LSIL include repeat colposcopy or referral to a clinician experienced in the management of complex cytological situations. Women with repeat cytology read as AGC or HSIL are at very high risk for missed significant disease, including endometrial carcinoma. Therefore, acceptable options for the management of women with repeat cytology read as AGC or HSIL include cervical excision procedure or referral to a clinician experienced in the management of complex cytological situations.
Because some AGC Paps result from non-cervical changes, such as in the endometrium, Fallopian tubes, ovaries, or even metastatic disease, completely negative evaluations for continued repeat abnormalities may warrant diagnostic procedures to rule out other sources for glandular cytologic abnormalities.

43. This slide shows an algorithm for the management of women with LSIL
Colposcopy is the preferred management for women with LSIL. Subsequent management options depend upon whether a lesion is identified at colposcopy, whether the colposcopic exam is satisfactory, and whether the patient is pregnant.
When the colposcopy is satisfactory, endocervical sampling is acceptable for non-pregnant women with a visible lesion to biopsy in the transformation zone. When no lesion is identified and the patient is non-pregnant, endocervical sampling is preferred. If biopsy-confirmed CIN is not identified and the colposcopy is satisfactory, acceptable management options include follow-up by repeat cytology at 6 and 12 months with referral to colposcopy of any repeat cytology of ASC-US or greater, or HPV DNA testing at 12 months with referral to colposcopy of any HPV positive woman. The use of HPV testing as an alternative to follow-up by repeat cytology is based upon demonstration that only women with persistently positive HPV tests progress to high-grade CIN, and women who have resolution of their lesion become HPV-negative.
Endocervical sampling is preferred for women with LSIL and an unsatisfactory colposcopy. If biopsy-confirmed CIN is not identified and the colposcopy is unsatisfactory, acceptable management options include follow-up with repeat cytology at 6 and 12 months, or HPV testing at 12 months. Several studies have shown a low risk for significant missed disease when the referral cytology is LSIL, the colposcopy is unsatisfactory, and the endocervical sampling and indicated biopsies are negative. Hence, a diagnostic cervical excisional procedure does not appear to be necessary in these circumstances.

44. Management of LSIL: Special Circumstances
Mod: Abnormal Pap-fig 6
This slide shows an algorithm for the management of LSIL in postmenopausal women.
Post-menopausal women with LSIL are less likely to test positive for HPV, indicating that the effects of declining estrogen may result in cellular changes that are misclassified as LSIL. For this reason, providing a course of intravaginal estrogen followed by repeat cytology, obtained approximately one week after completing the regimen, is an acceptable option for women with LSIL who have clinical or cytologic evidence of atrophy and no contraindications to vaginal estrogen use. If the repeat cytology is ”negative for squamous intraepithelial lesion or malignancy”, the patient can return to routine cytologic screening, whereas if the repeat cytology is reported as ASC or greater, the patient should be referred for colposcopy.

45. This slide shows an algorithm for the management of LSIL in adolescents.
Adolescents are at virtually no risk for having cervical cancer. Therefore, for selected adolescents, follow-up without immediate colposcopy using a protocol of either repeat Pap at 6 and 12 months, with referral to colposcopy of any repeat abnormal Pap of ASC or greater, or HPV testing at 12 months, are acceptable options.

46. Management of HSIL Mod: Abnormal Pap-fig 8
This slide shows an algorithm for management of women with HSIL.
All women with HSIL cytology should have colposcopy and endocervical sampling. Subsequent management depends upon whether a lesion is identified that correlates with the Pap test, whether the colposcopic exam is satisfactory, whether the patient is pregnant, and whether immediate excision is appropriate.
When no lesion or only biopsy-confirmed CIN1 is identified at colposcopy in women with HSIL cytology and the colposcopy is satisfactory, it is recommended, when possible, to have the cytology, colposcopy and histology reviewed. If the review yields a revised interpretation, then management should follow guidelines for the revised interpretation. If a cytologic interpretation of HSIL is upheld or review is not possible, a diagnostic excisional procedure is preferred in non-pregnant patients. A colposcopic re-evaluation with endocervical assessment is acceptable in special situations discussed below.
When no lesion is identified at colposcopy in women with HSIL cytology and the colposcopy is unsatisfactory, the cytology, colposcopy and histology should be reviewed whenever possible. If the review yields a revised interpretation, then management should follow guidelines for the revised interpretation. If a cytologic interpretation of HSIL is upheld or review is not possible, or only a CIN1 lesion has been identified, then a diagnostic excisional procedure is recommended in non-pregnant patients. Ablation is unacceptable.
Omission of an endocervical sampling procedure is acceptable when a cervical excision procedure is planned. In women with HSIL and a colposcopic impression of a high-grade lesion, initial evaluation using a cervical excision procedure is also an acceptable option. Triage of HSIL cytology using either HPV testing or repeat cytology is unacceptable.

47. Candidates for Ablative or Excisional Therapy
Patients who are suitable for ablative therapy have:
The entire transformation zone visualized (satisfactory colposcopy)
   No suggestion of microinvasive or invasive disease
   No suspicion of glandular disease
   Corresponding cytology and histology
Patients in whom excisional treatment is mandatory have:
         Unsatisfactory colposcopy
         Suspicion of invasion or glandular abnormality
This slide outlines parameters for patients who are candidates for ablative or excisional therapy, as reported by Martin-Hirsch and colleagues.
If CIN has been diagnosed, the lesion can be removed using LEEP, conization, laser excision, laser vaporization, or cyrotherapy.

48. Excisional Techniques
Conization
A cone of tissue is excised for further examination and/or to remove a lesion
The tissue is usually stained with iodine (Lugol’s or Schiller’s solution) to demarcate the area of resection
Cold Knife Cone
The use of a scalpel or “cold knife cone” since no electrosurgical current is used
Laser Conization
The use of a laser for excision of a cone of tissue
May be complicated by burn artifacts
LEEP (Loop Electrosurgical Excision Procedure)
The use of a thin electric wire loop, which may have cutting and cautery currents
Different sizes of loop and cautery tip available
This slide describes excisional techniques.

49. Ablative Techniques Cryotherapy Laser Vaporization Therapy
The use of a probe containing carbon dioxide or nitrous oxide to freeze the entire transformation zone and area of the lesion
Different sizes of probe available
Laser Vaporization Therapy
The use of a laser to vaporize the transformation zone containing the lesion
Requires suction to remove smoke
Different power levels are available
This slide describes ablative techniques.

50. Cervical Cancer: FIGO Nomenclature
Stage 0: Carcinoma in situ, cervical intraepithelial neoplasia Grade III
Stage I: The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded).
Stage II: Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or lower third of the vagina.
Stage III: The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or non functioning kidney are included, unless they are known to be due to other causes.
Stage IV: The carcinoma has extended beyond the true pelvis, or has involved (biopsy-proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to Stage IV.
The standard clinical staging system for cervical carcinoma is from the International Federation of Gynecology and Obstetrics (FIGO), as shown on this slide.
This clinical staging system is used after careful examination of the patient, which may include a pelvic exam with bimanual and visualization of the cervix, colposcopy, endocervical curettage, hysteroscopy (not a routine procedure), cystoscopy, proctoscopy, intravenous urography, and x-ray examination of the lungs and skeleton.
The most common cervical malignancy is squamous cell carcinoma, comprising 80-85% of cases. The second most common is adenocarcinoma, comprising 15-20% of cases.

51. Cervical Cancer: Outcomes by FIGO Stage
Stage I % % – 90%
Stage II % % – 70%
Stage III % % – 35%
Stage IV % % – 15%
FIGO Stage Year Year Recurrence
Treatment Survival Treatment Survival (Einhorn3)
(Morrow et al1) (FIGO reports – Benedet2)
This slide outlines combined data regarding 5-year survival and disease recurrence according to FIGO stage.
As with all cancers, the prognosis for cervical cancer is dependent upon the stage. The various stages consider tumor size, depth and extent of invasion, and involvement of lymph nodes and other structures and organs. The stage of disease will also drive its treatment, as may the cell type. The use of CT, MRI, and PET scanning can assist in determining tumor volume and extent of disease, and in planning radiation targeting.
Morrow CP, Curtin JP. Tumors of the cervix. In: Morrow CP, Curtin JP (eds). Synopsis of Gynecologic Oncology, 5th ed. Churchill Livingstone, Philadelphia, PA Cited in: Nguyen HN, Averette HE. Biology of cervical carcinoma. Sem Surg Oncol 1999;16(3):
Benedet JL. Progress in gynecologic cancer detection and treatment. Int J Gynecol Obstet ;70(1):
3. Einhorn N. Cervical cancer (cervix uteri). Acta Oncol 1996;35(2Suppl7):75-80.
Morrow CP et al. In: Morrow CP, Curtin JP (eds). Synopsis of Gynecologic Oncology, 5th ed
Benedet JL. Int J Gynecol Obstet ;70(1):
Einhorn N. Acta Oncol. 1996;35(2Suppl7):75-80.

52. Cervical Screening Summary
HPV is common and present in almost all cervical cancers
New screening technologies, specifically ThinPrep, provide an increase in detection of LSIL, HSIL, an improved specimen, and reflex HPV testing
New Bethesda nomenclature plus the results of the ALTS trial spurred new guidelines which provide an evidence-based approach to managing the problematic ASC-US Pap result
Reflex HPV testing is an efficient way to manage the ASC-US Pap test result, specifying who is at risk and in need of immediate colposcopy

53. Additional Information
For a complete review of terminology and guidelines, go to:
Bethesda 2001:
ASCCP Consensus Guidelines:
Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287: