How invasive cervical cancer audit affects clinical practice

How invasive cervical cancer audit affects clinical practice Referring to NHSCSP and EU guidelines and audits in Southampton and London Amanda Herbert Guy s & St Thomas Foundation NHS Trust

What is the importance of invasive cervical cancer audit? Identifies areas where screening procedures could be improved Provides information to women about why their cancers were not prevented Provides information about the effectiveness and limitations of screening Demonstrates the importance of quality assurance guidelines (EU and NHSCSP)

NHSCSP guidelines for cervical cancer audit http://www.cancerscreening.nhs.uk/cervical/publications/nhsc sp28.html (first document and changes for 2012-13) http://www.cancerscreening.nhs.uk/publications/cs3.pdf

Aims and objectives of NHSCSP invasive cervical cancer audit

Co-ordinated by hospital-based programme co-ordinator (HBPC) who may be a cytopathologist gynaecologist or senior cytotechnologist HBPC works with lead consultants in cytopathology, gynaecological histopathology and colposcopy (and GPs) Overseen by Quality Assurance Reference Centre (QARC) and Screening Commissioner

NHSCSP 2012-13 update (mainly concerns slide reviews) Conventional smears need not be reviewed (conversion to LBC completed in 2008) Cytology slides within 5 years should be reviewed internally (previously within 10 years); excluding positive tests leading to diagnosis (with report provided to QARC) External (QARC) review of all negative and inadequate smears reported within 2 years; and any that were upgraded on internal review to high-grade All histology biopsies taken within 10 years before the diagnostic biopsy should be reviewed by a pathologist who did not report the slide; external review for discrepancies that would have altered management

European Guidelines for Quality Assurance in Cervical Cancer Screening 2008 PDFs can be downloaded FREE Wiener H et al. European guidelines for quality assurance in cervical cancer screening: cytology laboratories. Cytopathology 2007;18:67-78. Arbyn M et al. European guidelines for quality assurance in cervical cancer screening: recommendations for collecting samples for conventional and liquid-based cytology. Cytopathology 2007;18:133-9. Herbert A et al. European guidelines for quality assurance in cervical cancer screening: recommendations for cervical cytology terminology. Cytopathology 2007;18:213-9.

Can invasive cancer audit show where and why these guidelines matter? Rescreening of smears from patients with negative or low-grade test results less than 3-5 years before the diagnosis of invasive cancer forms an important part of quality control but should be taken in the context of all components of the screening history including cytological screening errors, sampling errors, noncompliance with follow-up recommendations, incomplete treatment and whether or not the cancer was screen-detected EU guidelines, 2nd edition 2008

Can invasive cancer audit show where and why these guidelines matter? References National audits (UK, NZ, Sweden [Andrae et al. J Natl Cancer Inst 2008; BMJ 2012; Silfverdal et al. Am J Obstet Gynecol 2009], Finland, Norway, Slovenia) Southampton & south west Hampshire (382 cancers 1985-1996 - BJOG 2009;116:845 853 & 854 859) Guy s & St Thomas (133 cancers 1999-2007 - BJOG 2010; 117(6):736-45. Many women (up to 50%) with cancer have previously been screened. Why? Could these cancers have been avoided? If not, why not?

Results of Southampton audit (before during and after the introduction of organised screening and improved QA 1988-90) Significant trend towards screen-detected cancers in previously screened women (cytology within 5 years of diagnosis) as organised screening and improved QC became established (1985-87; 1988-90; 1991-93; 1994-96) Incidence fell from 16.8 to 10.4/100,000 women (in line with England as a whole) Strong association between screen-detected cancers, early FIGO stage, younger age groups and interval cancers

Trends in cancers according to screening history Southampton and south west Hampshire

Incidence per 100,000 eligible women aged 25-64 screened and not screened within five years Screened within 5yrs Not screened within 5yrs

Effect of organised cervical screening in England 1971, 1986, 2001 - and 2010 (40 years) Office for National Statistics data (n) = incidence in Cancer incidence per 100,000 women in each age band year per total 100,000 Screening women aged 35-64 years started in 1967 2000 ca in situ 4000 cancers 5-year age bands

Effect of organised cervical screening in England 1971, 1986, 2001 - and 2010 (40 years) Office for National Statistics data Cancer incidence per 100,000 women in each age band (n) = incidence in year per total 100,000 Cancers, deaths and CIS/CIN3 increased x2, x2 and x3 in young women Increased screening coverage and risk (Peto 2004) 5-year age bands

Effect of organised cervical screening in England 1971, 1986, 2001 - and 2010 (40 years) Office for National Statistics data Cancer incidence per 100,000 women in each age band (n) = incidence in year per total 100,000 NHSCSP launched in 1988 All women aged 20-64 screened every 3-5 years 5-year age bands

Why do invasive cancers occur in populations with organised screening? Failure to screen the population at risk Irregular uptake and compliance False-negative cytology High-grade cytology reported as low-grade Failure to follow up low-grade cytology Delays or failures in referral of women recommended for colposcopy Treatment failures Some cancers are detected by cytology

Guy s & St Thomas Audit 1999-2007 (133 cases) Screen-detected cancers were relatively more frequent in younger women (98.5% were either stage IA or IB1) Number of cancers in each age band Age band (years)

Incidence of in-situ cervical carcinoma England 1980, 1990, 2000, 2010 (ONS data) Rates per 100,000 women in each age band (n) = rate in year per total 100,000 5-year age bands

Incidence of invasive cervical carcinoma England 1980, 1990, 2000, 2010 (ONS data) Rates per 100,000 women in each age band (n) = rate in year per total 100,000 Cancers = 3% of CIN3 + cancer at age 25-29 5-year age bands

Reasons why cancers were not prevented Southampton (SSWH) and Guy s & St Thomas (GSTT)

No previous cytology Southampton: 38.%; GSTT: 30.8% As screening becomes organised the percentage of cancers in women with no previous cytology declines (e.g. London vs. Southampton; Southampton over time) If every woman has been screened all cancers will be interval cancers 10% of women in England have no cytology test recorded on the central computer Many of these (in London at least) have been previously screened outside the UK Some are too young to have been offered screening within 3 years (<25) others too old (70+)

Case histories No cytology record in UK (excluding tests within 6 months of diagnosis) Woman aged 30 Symptomatic adenocarcinoma (stage IB1) presented with postcoital and intermenstrual bleeding TP cytology typical of AIS: reported?glandular neoplasia Trachelectomy: grade 2 adenocarcinoma, lymphovascular invasion but lymph nodes clear Screening history: No record in UK Previous negative smear in Sweden!

Case histories No cytology record in UK (excluding tests within 6 months of diagnosis) Woman aged 25 Symptomatic adenocarcinoma (stage IB1) presented with post-coital bleeding TP reported as?glandular neoplasia Died with lung metastases aged 28 Screening history: Was refused cytology test aged 19 and 21 (elsewhere in UK) because she was too young

Cytology >5 years before diagnosis: 21 of 133 (15.8%) 1 had previous low-grade cytology, not followed up 2 had previous CIN treatment, inadequate follow-up

Case histories Negative cytology >5 years before diagnosis) Woman aged 28 (medico-legal case) Routine cytology: severe dyskaryosis (HSIL favor CIN3) Screen-detected adenocarcinoma (stage IB1) treated by trachelectomy: completely excised, lymph nodes clear Screening history: Routine conventional smear aged 22, reported negative Moderate dyskaryosis on review (HSIL, favor CIN2) Defaulted from three reminders for screening aged 25

Reasons why cancers were not prevented Southampton (SSWH) and Guy s & St Thomas (GSTT)

Previous negative cytology 49/133 (37%) 27 negative only, 22 other factors Most frequent finding in interval cancers 11 (8%) had been screened as negative within 3.5 years with at least two tests within 10 years 16 had been screened as negative but less frequently than recommended (3.5-5.0 years, only one previous test, long gaps before a recent test) 22 had other factors: also had low-grade repeats, delayed referral and/or CIN treatment) >50% confirmed as negative on review Others showed known pitfalls for false negatives

Some cancers are more difficult to prevent Austin and Zhao. Cytopathology 2012;23:6-12 Rapidly progressive cancers Cancers in young women Adenocarcinomas Cancers in older women (TZ in canal) (b) 26-year-old woman with small focus of CIN3 adjacent to poorly differentiated SqCC

Case histories Negative cytology 0.5-5 years before diagnosis (interval cancer) Woman aged 57 Severe dyskaryosis on routine smear Screen-detected stage IA1 squamous cell carcinoma in background of CIN3 involving crypts on LLETZ; incompletely excised No residual CIN or cancer on hysterectomy Screening history: Five routine cytology tests every 3 years between age 42 and 54, all reported as negative; confirmed on review

Case histories Negative cytology 0.5-5 years before diagnosis (interval cancer) Woman aged 35 Presented with intermenstrual bleeding; polypectomy Poorly differentiated adenosquamous carcinoma involving all margins lf the biopsy No residual carcinoma on hysterectomy; later recurrence and distant metastases; died Screening history: Four 3-yearly cytology tests every between age 22 and 31, all negative?glandular neoplasia (occasional cells) found on review of latest test 5 years before diagnosis

HSIL as small, pale or sparse cells (or all three) Hyperchromatic crowded groups (microbiopsies) overlooked Inadequate smears/lbc slides reported as negative HSIL misinterpreted as inflammatory HSIL favour CIN2 thought to be reactive metaplasia Known pitfalls at risk for being false negative

CGIN/AGC not recognised HSIL interpreted as reactive endocervical cells Known pitfalls at risk for being false negative

Previous repeats for LSIL/ASC/AGC HSIL misinterpreted as LSIL or ASC-US ASC-H or AGC not identified as such Follow-up sometimes not regarded as important Cancers rare in women followed up as recommended Referral of all LSIL and HPV triage for ASC-US should help

Case histories Repeat for low-grade 0.5-5 years before diagnosis (interval cancer) Woman aged 28 Referred for mild dyskaryosis; previous borderline (ASC-US) LLETZ: screen-detected stage IA1 adenocarcinoma in a background of CIN1-2 Screening history: Referral smear reviewed: atypical glandular cells also seen

Slide review GSTT 1999-2007 Neg. Inad. LSIL ASC-US ASC-H AGC HSIL+ Negative (n = 33) 20 2 0 1 2 1 7 Inadequate (n = 4) 1 1 0 0 0 0 2 LSIL/ASC (n = 9) 0 0 1 1 2 2 3 Total (n = 46) 21 3 1 1 4 3 12

Cytology errors - How do EU guidelines help? Regular screening recommended (3-5 yearly) Rapid review of all negative or inadequate smears/slides recommended: internal QC Automated screening could be a powerful IQC tool as a method of rapid review (TP imager) Comparison of laboratory reporting rates may identify laboratories where HSIL might be missed or misinterpreted (EQA) Terminology - importance of ASC-H and AGC Training, update, continuing professional development, accreditation, proficiency testing (EQA), audit recommended for all laboratory staff

Reasons why cancers were not prevented Southampton and Guy s & St Thomas audits

Reasons for delay diagnosis/referral Referral advised >6 months before diagnosis Long colposcopy waiting lists (relatively short period of time in Southampton 1988-1990) Interval of several months between referral, first biopsy and LLETZ (short period of time at GSTT) Women did not attend appointments (DNA) Women moved / travelled abroad / address not known (especially in London) Investigation / diagnosis delayed by pregnancy Referral for low-grade abnormalities not regarded as urgent or lesion not found at colposcopy Refused treatment (one for 7 years)

Previous treatment of CIN About 10% of cancers (both audits) were in women previously treated for CIN (usually CIN3, sometimes CIN2, occasionally CIN1) Most had incomplete excision, persistent abnormal cytology or biopsies after initial treatment or had defaulted from follow-up Rare in women treated for CGIN Small proportion of women treated for high-grade CIN (16 of 3,027 cases in nine years: 0.5%) More likely to have had initial treatment when aged over 35 years Low awareness of risk of recurrence: higher after incompletely excised or unconfirmed CIN3

Age of women at time of CIN treatment 100% 80% 60% 40% 65+ years 50-64 years 35-49 years 20-34 years 20% 0% CIN2+ (n = 3,027) Cancer, previous CIN Rx (n = 16)

Case histories Previous treatment of CIN (interval cancer) Woman aged 40 (medico-legal case) Stage IIA invasive squamous cell carcinoma diagnosed on investigation of pelvic pain Mass in fornix thought to be endometriosis Biopsy: squamous cell carcinoma Screening history Three conventional follow-up smears reported as negative; disagreement about LUS vs. ASC-H on cytology of one Previous history not known by gynaecologist or cytopathologist: incompletely excised CIN3 (in crypts) Histology review of deeper levels showed focal invasion

Case histories Previous treatment of CIN (interval cancer) Woman aged 42 Severe dyskaryosis Colposcopy LBC: ASC-H Biopsy: high-grade CIN,?invasion LLETZ: focal koilocytosis ASC-US and ASC-H at colposcopy HC2-negative (x2) Hysterectomy for IMB: focal CIN3 IA1 squamous cell carcinoma and Screening history: Previous negative cytology since age 27

Invasive cancer audit shows where and why these guidelines matter Consistent terminology allows comparison of reporting rates and identification of ASC-H / AGC Rapid review, preview (or automated QC) allows potential false negatives to be avoided Recommendations for follow-up, investigation and counseling of women avoid default Accreditation supports monitoring outcome, audit, IQC and EQA of all aspects of screening Cancer audit identifies areas where procedures could be improved Screen-detected cancers should be put in context of CIN2+ detected during the same period of time

Cancers should be placed in the context of CIN2, CIN3 & CGIN (AIS) detected during the same period of time Number of cancers in each age band (GSTT 1999-2007) 800 600 Screen-detected (n = 65) Symptomatic (n = 68) CIN2 (1472) CIN3/CGIN (1555) 400 200 0 20-29 30-39 40-49 50-59 60-69 70+ Age band (years)

Thank you for listening!