Lessons From Cases of Screened Women Who Developed Cervical Carcinoma

Size: px

Start display at page:

Download "Lessons From Cases of Screened Women Who Developed Cervical Carcinoma"

Norah Matthews
5 years ago
Views:

Lessons From Cases of Screened Women Who Developed Cervical Carcinoma R.

The primary clinical goals of cervical screening are to reduce the incidence, morbidity,

Opportunity to study specific clinically consequential cervical screening system

development of lesional morphology preceding proven cases of cervical cancer (true

Clinical Ablation Early Stage (Asymptomatic) Cervical Cancer Pap detection & Clinical

Cancer + Lymph Nodes Outcome: Incidence of Cervical Cancer Outcome: Morbidity and

100,000 97,144 111,019 113,197 108,554 105,248 80,000 60,000 40,000 20,000 9,120 11,009

1 Lessons From Cases of Screened Women Who Developed Cervical Carcinoma R. Marshall Austin MD,PhD Magee-Womens Hospital of University of Pittsburgh Medical Center Why Focus Study On Cases of Invasive Cervical Carcinoma in Screened Women? The primary clinical goals of cervical screening are to reduce the incidence, morbidity, and mortality associated with cervical carcinoma in the screened population. Opportunity to study specific clinically consequential cervical screening system failures and assess risk management strategies Opportunity to study the spectrum and development of lesional morphology preceding proven cases of cervical cancer (true cervical precancers as well as cervical malignancies) Progressive CIN3 Pap detection & Clinical Ablation Early Stage (Asymptomatic) Cervical Cancer Pap detection & Clinical Ablation Early Stage (Asymptomatic) Cervical Cancer Late Stage (Symptomatic) Cervical Cancer + Lymph Nodes Outcome: Incidence of Cervical Cancer Outcome: Morbidity and Mortality due to Cervical Cancer MWH Data MWH Cytotechnologist Management Staff 120, ,000 97, , , , ,248 80,000 60,000 40,000 20,000 9,120 11,009 18,652 10,590 30,150 11,798 25,771 12,268 27,981 11, Pap tests HPV tests Histological data 535,162 Pap test results 111,674 hrhpv DNA test results 56,952 data entries: biopsies and surgical procedures 1

Decisive Scientific Factors In Success of Pap test Immediate wet fixation to preserve fine structural detail Skill of the cytologist Carmichael, DA 1973. The Pap Smear Life of George N.

questionable cells 3) Insertion of slides into blinded multiple slide challenge sets First, the Good News Agency for Healthcare Policy and Research Evidence Report/Technology Assessment Number 5

2 Decisive Scientific Factors In Success of Pap test Immediate wet fixation to preserve fine structural detail Skill of the cytologist Carmichael, DA The Pap Smear Life of George N. Papariolaou Targeted Educational Rescreening 1) Surgical Pathology Diagnoses of Cervical Cancer, CIN3, or AIS 2) Retrospective reviews of negative or atypical Paps to identify lesional or questionable cells 3) Insertion of slides into blinded multiple slide challenge sets First, the Good News Agency for Healthcare Policy and Research Evidence Report/Technology Assessment Number 5 Evaluation of Cervical Cytology (1999) Most cervical cancer is slow-growing and can be prevented by relatively infrequent screening (Q3 yrs) with the relatively insensitive (50%) conventional Pap smear. Agency for Healthcare Policy and Research Evidence Report/Technology Assessment Number 5 Evaluation of Cervical Cytology (1999) Conclusions: Estimates of the sensitivity of the conventional Pap test are biased in most studies; based on the least biased studies, sensitivity is near 50 per cent, much lower than generally believed. Cervical Cancer Cases per 100,000 women screened ages ( Evaluation of Cervical Cytology 1999 ) Pap Smear 40% FN 60% FN 90% FN No Pap Q3 yr screens Q2 yr screens Q1 yr screens

From Human Papillomavirus to Cervical Cancer Obstet Gynecol 116: 177-185, 2010 Progressive Vs.

425-34, 2008 Now, the Bad News At least 15% of cervical cancer is not as slow-growing as the majority of cervical cancers and cannot be prevented with relatively infrequent (Q3 yrs) screening with

3 From Human Papillomavirus to Cervical Cancer Obstet Gynecol 116: , 2010 Progressive Vs. Non-progressive CIN3 Non-progressive CIN3 Progressive CIN3 Early Stage (Asymptomatic) Cervical Cancer Late Stage (Symptomatic) Cervical Cancer + Lymph Nodes New Zealand Experiment Lancet Oncol 9: , 2008 Now, the Bad News At least 15% of cervical cancer is not as slow-growing as the majority of cervical cancers and cannot be prevented with relatively infrequent (Q3 yrs) screening with the relatively insensitive (50%) conventional Pap smear Limited Impact of Cervical Smear Screening on Cancer Rates in Younger Women Cancer Causes and Control 1997; 8: Squamous Versus Glandular Cervical Cancer Incidence Rate Trends Joinpoint regression used to calculate trends (Squamous Cervical Cancer) The rate of decline has accelerated for squamous cell lesions since 1997 coincident with more widespread use of liquidbased cytology. Adenocarcinoma rates continue to increase, and the greatest rate of increase is in younger white women (Smith H.O., SGO Annual Meeting, March Source: SEER) 3

Impact of Pap Screening on Incidence of Endocervical Adenocarcinoma- Australia Cancer Cytopathology 2003; 99: 336-341 Two Types of Cervical Carcinoma Type I Cervical Cancer (Slow-Growing) EXTENSIVE

4 Impact of Pap Screening on Incidence of Endocervical Adenocarcinoma- Australia Cancer Cytopathology 2003; 99: Two Types of Cervical Carcinoma Type I Cervical Cancer (Slow-Growing) EXTENSIVE CIN3 Limited Superficial Invasive Cancer Type II Cervical Cancer (Rapidly Progressive) LIMITED EXTENT CIN3/AIS Invasive Cancer LSIL Not seen in Paps preceding cervical cancer LSIL It now seems unlikely that cervical cancer develops according to a former morphology-based model of stepwise progression from CIN1 to CIN2 to CIN3 to cancer. Am J Clin Pathol 127: , 2007 An ALTS Report Pathway to Cervical Cancer Exposure HPV Infection CIN1/2 Latent Infection Persistent Infection CIN2 CIN3 ~ Carcinoma in situ CANCER What Is Often Observed in Paps of Screened Women Who Develop Cervical Cancer? Overlooked or difficult to interpret manifestations of high grade intraepithelial lesions (Squamous or Glandular) 4

5 Cytologic Manifestations of High Grade Squamous Intraepithelial Lesions in Patients Later Developing Cervical Cancer Abnormalities in large cell groups, smaller cell clusters, and isolated mature and immature metaplastic squamous cells Sometimes interpretable as HSIL Not infrequently interpretable only as ASC-H or ASC-US Adjunctive high risk HPV testing is useful in risk stratification assessments 5

6 6

7 7

8 8

Two Types of Cervical Carcinoma Type I Cervical Cancer

Type II Cervical Cancer (Rapidly Progressive) LIMITED EXTENT

of LBC and HPV Co-testing (All 2000 women had colposcopy and cx

94% 98% 100% TPPT LSIL+ 87% 93% 100% TPPT HSIL+ 77% 91% 100%

9 Two Types of Cervical Carcinoma Type I Cervical Cancer (Slow-Growing) EXTENSIVE CIN3 Limited Superficial Invasive Cancer Type II Cervical Cancer (Rapidly Progressive) LIMITED EXTENT CIN3/AIS Shanxi Province Cervical Cancer Screening Study Impact of LBC and HPV Co-testing (All 2000 women had colposcopy and cx biopsies) CIN2+ CIN3+ Cancer HPV DHC2+ 95% 98% 100% TPPT ASCUS+ 94% 98% 100% TPPT LSIL+ 87% 93% 100% TPPT HSIL+ 77% 91% 100% Colposcopy+ 81% 91% 100% Invasive Cancer Belinson et al, Gyn Oncol 83: ,

Cytologic Manifestations of High Grade Glandular Intraepithelial Lesions in Patients Later

honeycomb pattern Nuclear overlap and crowding Variation in nuclear size Hyperchromatism,

characteristic of reactive endocervical cells Increased numbers of glandular cell groups

specified Classic AIS very rarely seen Age 23 About 21/2 yrs before Diagnosis of (Fatal)

10 Cytologic Manifestations of High Grade Glandular Intraepithelial Lesions in Patients Later Developing Cervical Cancer Abnormalities in glandular cell groups Loss of an orderly honeycomb pattern Nuclear overlap and crowding Variation in nuclear size Hyperchromatism, irregular or granular chromatin, parachromatin clearing Absence of small uniform nucleoli characteristic of reactive endocervical cells Increased numbers of glandular cell groups Difficult cases often interpretable only as atypical glandular cells, not otherwise specified Classic AIS very rarely seen Age 23 About 21/2 yrs before Diagnosis of (Fatal) Adenocarcinoma of Cervix Oral Contraceptive Use History Liquid-Based Cytology Original Interpretation: Negative 10

11 11

12 Age 24 About 11/2 yrs before Diagnosis of (Fatal) Adenocarcinoma of Cervix Oral Contraceptive Use History Liquid-Based Cytology Original Interpretation: Negative 12

13 13

14 Age 32 About 2 1/2 yrs before Diagnosis of (Fatal) Adenocarcinoma of Cervix Oral Contraceptive Use History Liquid-Based Cytology Original Interpretation: Negative 14

15 Age 62 About 3 yrs before Diagnosis of (Fatal) Clear Cell Adenocarcinoma of Cervix Liquid-Based Cytology Original Interpretation: Negative 15

16 What Is Often Observed in Paps of Screened Women Who Develop Cervical Cancer? Difficult to interpret or overlooked manifestations of carcinoma 16

Age 25 About 4 months before Diagnosis of (Fatal)

Liquid-Based Cytology Original Interpretation: AGC

Glandular Lesions in Patients Later Diagnosed with

abnormalities- sometimes more marked Macronucleoli

17 Age 25 About 4 months before Diagnosis of (Fatal) Adenocarcinoma of Cervix Oral Contraceptive Use History Liquid-Based Cytology Original Interpretation: AGC Cytologic Clues to Presence of Invasive Malignant Glandular Lesions in Patients Later Diagnosed with Cervical Cancer Previously described glandular cell abnormalities- sometimes more marked Macronucleoli Multiple irregular nucleoli Clinging tumor diathesis surrounding abnormal glandular cell groups 17

18 18

19 (25yo) 2 months before Diagnosis of (Fatal) Adenocarcinoma of Cervix Liquid-based Cytology Original Interpretation: Atypical Glandular cells Squamous Intraepithelial Lesion 19

20 20

21 Age 33 About 1 1/2 yrs before Diagnosis of (Fatal) Adenocarcinoma of Cervix Oral Contraceptive Use History Liquid-Based Cytology Original Interpretation: Negative 21

22 Age 34 Less than 1/2 yr before Diagnosis of (Fatal) Adenocarcinoma of Cervix Oral Contraceptive Use History Liquid-Based Cytology Original Interpretation: AGC 22

23 23

24 Age 66 Less than 6 months before Diagnosis of (Fatal) Clear Cell Adenocarcinoma of Cervix Liquid-Based Cytology Original Interpretation: AGC (but downgraded to negative) 24

Resection Progression Rates for Development of Stage III Cervical Cancer Agency for Healthcare Policy and Research (AHCPR) Evidence Report/Technology Assessment Number 5 Distribution of cases by

25 Resection Progression Rates for Development of Stage III Cervical Cancer Agency for Healthcare Policy and Research (AHCPR) Evidence Report/Technology Assessment Number 5 Distribution of cases by stage in an unscreened population should be a function of the progression rate and the likelihood of symptoms (since cases would only be detected with symptoms) Stage I to Stage II progressionslow- 4 years fast- 11 months average- 2 ½ yrs Stage II to Stage III progressionslow- 3 years fast- 11 mos average- 2 yrs Take Home Lessons Continuing education emphasizing targeted blinded educational rescreening of challenging Paps preceding cancer, CIN3, and AIS histopathology diagnoses Special emphasis on identification of glandular neoplasia and abnormal squamous metaplasia Cautious workload to enable cautious examination of cell groups and vigilant identification of abnormal single cells Liquid-based cytology for immediate wet fixation and enhanced cellular sub-sampling Computer-assisted screening to help standardize screening process Take Home Lessons Liberal rescreening utilizing broad criteria for high risk case selection and highly selected quality control cytotechnologists Encouragement of routine HPV co-testing in women 30 and older. Liberal default to reflex HPV testing in women with atypical glandular cell changes and/or atypical squamous metaplasia. Monitor HPV detection rates for all women 30 and older with negative Pap co-test results- +hrhpv in 49 of 25,259 (1.9%) MWH negative Paps in women 30 and older- Gyn Oncol 2009; 115: HPV tests can be negative in cervical cancer cases (Kaiser Permanente) Pap Result #CxCa HC2+ HC2-neg HSIL AGC ASC-H ASC-US LSIL Negative Negative 9 9 Total (11%) Obstet Gynecol 2010; 116:76-84; J Lower Genital Tract Disease 2010; 14: 247A, 255A. RELATIVE SCREENING TEST SENSITIVITY (MWH-UPMC ) ONE YEAR PRIOR TO CIN2/3/AIS/CxCA TISSUE DIAGNOSES Diagnostic Cytopathology 2010; 11: TIME SCREENING TESTS SENSITIVITY 6 MONTHS PAP (ASCUS+) 98.2% (2406/2449) 6 MONTHS HPV 96.9% ( 807 / 833 ) 6 MONTHS PAP & HPV 99.9% (2413/2415) 1 YEAR PAP (ASCUS+) 96.2% (2945/3061) 1 YEAR HPV 96.1% (1010/1051) 1 YEAR PAP & HPV 99.9% (2957/2961) 25

HPV-Negative Results in Women Developing Cervical Cancer: Implications for Cervical Screening Options

HPV-Negative Results in Women Developing Cervical Cancer: Implications for Cervical Screening Options R. Marshall Austin MD,PhD Magee-Womens Hospital of University of Pittsburgh Medical Center (UPMC) (raustin@magee.edu)