Powerpoint Cells Template

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Advances in the Screening, Diagnosis, and
Treatment of Cervical Disease
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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. 199918912-19. 2.
American Cancer Society, Cancer Facts Figures
2002. 3. Chu KC et al. Cancer. 199986157-169.
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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
1955 - 1992 Change in the number of cervical cancer deaths1 ? 74
1973 - 1981 Annual change in invasive cervical cancer mortality3 ? 4.6
1981 - 1998 Annual change in invasive cervical cancer mortality3 ? 1.6
1992 - 1998 Incidence of invasive cervical cancer (overall) 3 8.7 per 100,000 women
1992 - 1998 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
1973 - 1981 Annual change in invasive cervical cancer incidence3 ? 4.8
1981 - 1998 Annual change in invasive cervical cancer incidence3 ? 1.1
2000 New diagnoses of cervical cancer2 12,800
2001 New diagnoses of cervical cancer1 12,900
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U.S. Trends in Cervical Cancer Morbidity and
Mortality
Number of Cases
Year
Source National Cancer Institutes Surveillance,
Epidemiology and End Results (SEER) data,
American Cancer Society 2001.
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SEER Trends in North American Incidence of
Cervical Adenocarcinoma
Cumulative Rate per 1000 Women
Black, USA
White, USA
Canada
Hispanic, USA
Source Vizcaino AP et al. Int J Cancer.
199875536-545.
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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 diete.g., vitamin deficiency
• Alcoholism

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Cervical Epithelium Showing Progressive Degrees
of Dysplasia and Neoplasia
HSIL
LSIL
Koilocytosis CIN1 CIN2 CIN3
Basement membrane
Normal Mild
Moderate Severe Carcinoma squamous
in situ epithelium
Dysplasia
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Natural History of Cervical Lesions
Source ÖstÖr AG. Int J Gynecol Pathol.
199312(2)186-192.
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Natural History of Cervical Lesions
Source Melnikow J et al. Obstet Gynecol.
199892(4Pt2)727-735.
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Progression and Regression of Cervical Lesions
Source Holowaty P et al. J Natl Cancer Inst.
199991(3)252-258.
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Mean Age at Diagnosis of Cervical Lesions
Source Jones BA et al. Arch Pathol Lab Med.
2000124665-671.
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Cervical Cancer Screening GuidelinesAmerican
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

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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)

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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

 
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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
•  

 
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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
•  

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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)
• Atypical
• 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
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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)

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Bethesda 2001 Changes

• Satisfactory Liquid-basedminimum 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

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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)

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Annual Number of Women with
Abnormal Pap Results in the US
Source J. Thomas Cox, with permission.
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Sensitivity of the Pap Smear
Mean Sensitivity of Conventional Pap Smear (),
95 CI
1. Agency for Health Care Policy and Research
(AHCPR). Evaluation of Cervical Cytology. 1999.
2. Fahey MT et al. Am J Epidemiol.
1995141680-689.
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Two Types of Screening

• Conventional Pap Smear
• 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)

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Overcoming the Inherent Limitations of the
Conventional Pap Smear

• 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

• From ThinPrep Sampling Study, Hutchinson 1994

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Overview of Liquid-Based CytologyFDA 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

ThinPrep Pap Test Package Insert, Cytyc
Corporation AutoCyte PREPTM SYSTEM package insert
(now SurePathTM), TriPath Imaging, Inc.
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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 lt 0.001)
  increase in detection of HSIL lesions for
  ThinPrep specimens

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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

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HPV Risk Types

• Hybrid Capture2 (HC II) HPV DNA Test uses two
  RNA Probe cocktails to differentiate between
  carcinogenic and low-risk HPV types
• Low-risk
• 6 11 42 43 44
• High-risk
• 16 18 31 33 35 39 45 51 52 56 58 59 68

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HPV Prevalence and Cervical Cancer - Incidence by
Age 1,2
Cancer incidence per 100,000
HPV Prevalence ()
Age (Years)
1. Sellors et al. CMAJ. 2000163503. 2. Ries et
al. Surveillance, Epidemiology and End Results
(SEER) Cancer Stats NCI, 1973-1997. 2000.
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Incidence of Atypical Findings
1. Manos MM, Kinney WK, Hurley LB, et al. J Am
Med Assoc 1999281(17)1605-1610. 2. Chhieng DC,
Elgert PA, Cangiarella JF, et al. Acta Cytol
200044(4)557-566. 3. Stoler MH. Mod Pathol
200013(3)275-284.
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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 39.5 89.2
15.1 Based on Repeat Pap Resultc
38.9 76.2 12.9

• 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

Source Manos et al, JAMA. 1999281(17)1605-1610.
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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

Source Solomon D et al. J Natl Cancer Inst.
200193293-299.
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Sensitivity for CIN2 by HC II Pap by Age
Clinical Center Pap 18-22 23-28
29 Cutpoint () / Sens
() / Sens () / Sens
HC II 71 / 98 65 / 96
31 / 94 ASCUS 66 / 83
63 / 88 50 / 87
Sherman M, Schiffman M, Cox JT. J Nat Cancer
Inst. 2001
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Risk of CIN 2/3 for ASC referral Based on HPV
status at enrollment
Cox JT, et al. Am J Obstet Gynecol. 1995
Mar172(3)946-54.Solomon D, et al. J Natl
Cancer Inst. 200193293-299. Manos et al, JAMA.
1999281(17)1605-1610.
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Primary Findings ALTS
Management Sensitivity Referral PPV
NPV Modality
Colposcopy 100 100 11
100 HPV 96 56
20 99 Cytology ASC-US 85
59 17 96 Cytology
LSIL 59 26 26
94 Cytology HSIL 35 8
58 92 PPV positive predictive
value NPV negative predictive value
For detection of (CIN2)
Adapted from table 5, Solomon D et al. J Natl
Cancer Inst. 200193293-299.
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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

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AGC Findings from 306 LaboratoriesParticipating
in CAP Survey 2000
AGC Rate SIL AIS CA
0.3 40 5.8
5.5
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.
2000124672-681. (1-C)
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Clinical Significance of an AGC Pap
Source Richart et al. Contemp Ob Gyn. 2001
4615-17,25-28,30-32,35-43.
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Management of AGC
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Management of LSIL Special Circumstances

• Mod Abnormal Pap-fig 6

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Management of HSIL

• Mod Abnormal Pap-fig 8

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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

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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
  (Lugols or Schillers 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
• May be complicated by burn artifacts
•  

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Ablative Techniques

• Cryotherapy
• 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

   
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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.

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Cervical Cancer Outcomes by FIGO Stage

1. Morrow CP et al. In Morrow CP, Curtin JP
   (eds). Synopsis of Gynecologic Oncology, 5th ed.
   1998.
2. Benedet JL. Int J Gynecol Obstet.
   200070(1)135-147.
3. Einhorn N. Acta Oncol. 199635(2Suppl7)75-80.

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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

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Additional Information

• For a complete review of terminology and
  guidelines, go to
• Bethesda 2001 www.bethesda2001.cancer.gov
• ASCCP Consensus Guidelines www.asccp.org

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.
20022872114-2119.