Transcript Powerpoint Cells Template - Saint Francis Hospital and

Advances in the Screening,
Diagnosis, and Treatment
of Cervical Disease
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;86:157-169.
Cervical Cancer Statistics
Years
Description
U.S. Statistic
1998
Death rate from cervical cancer2
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
3.0 per 100,000 women
U.S. Trends in Cervical Cancer
Morbidity and Mortality
20,000
15,000
10,000
5,000
1970
1975
1980
1985
1990
1995
Year
Source: National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) data,
American Cancer Society 2001.
SEER Trends in North American Incidence
of Cervical Adenocarcinoma
0.30
0.25
Black, USA
0.20
White, USA
0.15
Canada
0.10
Hispanic, USA
0.05
0
1930
1940
1950
Year of Birth
Source: Vizcaino AP et al. Int J Cancer.1998;75:536-545.
1960
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
Cervical Epithelium Showing
Progressive Degrees of Dysplasia and
Neoplasia
LSIL
Koilocytosis
Basement
membrane
Normal
squamous
epithelium
HSIL
CIN1
Mild
CIN2
CIN3
Moderate Severe Carcinoma
in situ
Dysplasia
Natural History of Cervical Lesions
Biopsy
Result
Regress
Persist
Progress
to CIS
Progress
to Invasion
CIN1
57%
32%
11%
1%
CIN2
43%
35%
22%
5%
CIN3
32%
<56%
Source: ÖstÖr AG. Int J Gynecol Pathol. 1993;12(2):186-192.
--
>12%
Natural History of Cervical Lesions
Pap
Diagnosis
Regress
to Normal
(95% CI)
Progress to/
Persist as HSIL
in 24 months
(95% CI)
Progress to
Invasive Cancer
in 24 months
(95% CI)
ASCUS
68.19% (57.51, 78.86)
7.13% (0.8, 13.5)
0.25% (0, 2.25)
LSIL
47.39% (35.92, 58.86)
20.81% (6.08, 35.55)
0.15% (0, 0.71)
HSIL
35.03% (16.57, 53.49)
23.37% (12.82, 32.92)
1.44% (0, 3.95)
Source: Melnikow J et al. Obstet Gynecol. 1998;92(4Pt2):727-735.
Progression and Regression
of Cervical Lesions
Grade of Dysplasia
Within 2 years
Within 5 years
Within 10 years
Progression
Mild to moderate or worse
Mild to severe or worse
Moderate to severe or worse
11.1%
2.1%
16.3%
20.4%
28.8%
5.5%
25.1%
9.9%
32.0%
74.0%
63.1%
39.1%
29.0%
87.7%
82.9%
62.2%
53.7%
Regression
Mild to first normal Pap
44.3%
Moderate to first normal Pap
33.0%
Mild to second normal Pap
8.7%
Moderate to second normal Pap 6.9%
Source: Holowaty P et al. J Natl Cancer Inst. 1999;91(3):252-258.
Mean Age at Diagnosis of Cervical Lesions
Diagnosis
Mean Patient
Age (Years)
Predominant
Patient Status
Second Most
Prevalent Patient
Status
Carcinoma
56.4
Postmenopausal
(61.9%)
Premenopausal
(32.4%)
HSIL
33.8
Premenopausal
(72.2%)
Postmenopausal
(10.7%)
LSIL
30.8
Premenopausal
(74.4%)
Pregnant
(10.2%)
Glandular
Intraepithelial
Lesion
48.2
Premenopausal
(50.3%)
Postmenopausal
(38.5%)
Source: Jones BA et al. Arch Pathol Lab Med. 2000;124:665-671.
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
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)
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
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 nonneoplastic 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
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
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
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)
Bethesda 2001 Changes
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•
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 ASCUS 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
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)
Annual Number of Women with
Abnormal Pap Results in the US
Cancers 12,800
HSIL
LSIL
AGC
ASC
Source: J. Thomas Cox, with permission.
300,000
1.25 million
180,000-300,000
2 - 3 million
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. 1995;141:680-689.
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)
Overcoming the Inherent Limitations
of the Conventional Pap Smear
Conventional Pap Smear




Majority of cells not captured
Non-representative transfer
of cells
Clumping and overlapping of
cells
Obscuring material
Liquid-based Cytology*




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
Overview of Liquid-Based Cytology:
FDA Labeling
SurePath™
ThinPrep® Pap Test
•
Used as a replacement for the
conventional Pap smear
•
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 fewer Unsatisfactory and
SBLB cases as compared to the
conventional Pap smear
•
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
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
•
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
ThinPrep® Pap Test Package Insert, Cytyc Corporation
AutoCyte PREPTM SYSTEM package insert (now SurePathTM), TriPath Imaging, Inc.
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
HPV Testing – Essential Facts
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•
•
•
•
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
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
6 11 42 43 44
High-risk
16 18 31 33 35 39 45 51 52 56 58 59 68
30
30
25
25
20
20
15
15
10
10
5
5
0
0
Cancer incidence per 100,000
HPV Prevalence (%)
HPV Prevalence and Cervical Cancer Incidence by Age 1,2
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54
Age (Years)
1. Sellors et al. CMAJ. 2000;163:503.
2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
Incidence of Atypical Findings
Pap Smear
Cytology
Incidence
(Manos et al)
Incidence
(Chhieng et al)
Incidence
(Stoler)
HSIL
0.3%
SIL+ 2.5%
0.51%
LSIL
0.9%
--
1.97%
ASCUS
3.5%
5.7%
2.8%
AGUS
0.5%
0.5%
--
1. Manos MM, Kinney WK, Hurley LB, et al. J Am Med Assoc 1999;281(17):1605-1610.
2. Chhieng DC, Elgert PA, Cangiarella JF, et al. Acta Cytol 2000;44(4):557-566.
3. Stoler MH. Mod Pathol 2000;13(3):275-284.
Comparison of HPV Testing and Repeat
Pap in the Management of ASCUS
Triage
Strategy
Referred to Sensitivity
Colposcopya for HSIL+
PPV for
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:
a.
Prevalence of positive test result in women with ASCUS
b.
Referral to colposcopy based on positive DNA test for high-risk HPV types, from specimen on initial visit
c.
Referral to colposcopy based on repeat Pap test result of ASCUS or more severe
Source: Manos et al, JAMA. 1999;281(17):1605-1610.
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. 2001;93:293-299.
Sensitivity for CIN2+ by HC II & Pap
by Age
Clinical Center Pap
Cutpoint
18-22
%(+) / Sens
23-28
%(+) / Sens
29+
%(+) / 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
Risk of CIN 2/3+ for ASC referral
Based on HPV status at enrollment
HPV
Positive
HPV
Negative
Cox
1995
17%
(14/81)
0.74%
(1/136)
6.9%
(15/217)
Manos
1999
15%
(45/300)
1.2%
(6/498)
6.4%
(51/801)
ALTS
2001
20.1%
(136/651)
1.1%
(6/541)
11.9%
(142/1192)
Total
17.9%
(195/1087)
1.1%
(13/1175)
Cox JT, et al. Am J Obstet Gynecol. 1995 Mar;172(3):946-54.
Solomon D, et al. J Natl Cancer Inst. 2001;93:293-299.
Manos et al, JAMA. 1999;281(17):1605-1610.
Total risk
ASCUS
9.4%
(208/2210)
Primary Findings: ALTS
Management
Modality
Colposcopy
Sensitivity %*
Referral %
PPV %
NPV %
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. 2001;93:293-299.
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%
AGC Findings from 306 Laboratories
Participating 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. 2000;124:672-681. (1-C)
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%
27 – 96%
10 – 93%
AGUS neoplastic
Source: Richart et al. Contemp Ob Gyn. 2001; 46:15-17,25-28,30-32,35-43.
Management of AGC
Management of LSIL: Special Circumstances
•
Mod: Abnormal Pap-fig 6
Management of HSIL
•
Mod: Abnormal Pap-fig 8
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
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
• May be complicated by burn artifacts
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
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 nonfunctioning 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.
Cervical Cancer: Outcomes by FIGO
Stage
FIGO Stage
1.
2.
3.
5-Year
5-Year
Recurrence
Treatment Survival
Treatment Survival
(Einhorn3)
(Morrow et al1) (FIGO reports – Benedet2)
Stage I
82%
85%
76 – 90%
Stage II
61%
66%
50 – 70%
Stage III
37%
39%
30 – 35%
Stage IV
12%
11%
10 – 15%
Morrow CP et al. In: Morrow CP, Curtin JP (eds). Synopsis of Gynecologic Oncology, 5th ed. 1998.
Benedet JL. Int J Gynecol Obstet. 2000;70(1):135-147.
Einhorn N. Acta Oncol. 1996;35(2Suppl7):75-80.
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
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. 2002;287:2114-2119.