The Rapidly Changing Landscape of Cervical Screening, Management and Terminology Mohi Ghofrani, MD, MBA PeaceHealth Laboratories Vancouver mghofran@swmedicalcenter.org
2012 Was a Big Year for Cervical Cancer Screening March: New cancer screening guidelines published June: Unified terminology for HPV- related squamous lesions published September: Consensus conference to update management of abnormal screening results
The LAST* Project * Lower Anogenital Squamous Terminology
RecogniSon of Pre- cancers Normal cervical transformason zone Surface or intraepithelial carcinoma Squamous cell carcinoma invading into underlying stroma
EvoluSon (& ProliferaSon) of Terminologies PIN Surface or intraepithelial carcinoma PaIN Erythroplasia of Queyrat Condyloma CIS Not CIS Low- grade dysplasia CIS Severe dysplasia Moderate dysplasia Mild dysplasia CIS CIN 3 CIN 2 CIN 1 High- grade dysplasia VIN CIN 3 CIN 2 CIN 1 VaIN Bowen s disease AIN HSIL LSIL Bowenoid papulosis
What You See in the Pathology Report Vulvar squamous cell carcinoma in situ Cervical intraepithelial neoplasia 3 Anal condyloma with severe dysplasia Bowen s disease High- grade squamous intraepithelial lesion Erythroplasia of Queyrat High- grade squamous dysplasia
What We See Under the Microscope Vulvar squamous cell carcinoma in situ Cervical intraepithelial neoplasia 3 Anal condyloma with severe dysplasia CIN d 3 isease AIN 3 (female) Bowen s A unified terminology is needed High- grade squamous intraepithelial to represent this unified biology lesion Erythroplasia of Queyrat High- grade squamous dysplasia AIN 3 (male) PeIN 3
3- Tiered Terminologies Imply Progression CIN 1 Mild dysplasia CIN 2 Moderate dysplasia CIN 3 Severe dysplasia
CIN 2 is NOT a Precursor of CIN 3 If it was, it would be seen in younger pasents In ALTS, the median age of both was 24 years If it was, it would be more common (unless transit Sme is very short) In ALTS, of 650 HSIL cytology interpretasons, 14.9% were CIN 2, 30.3% were CIN 3 on follow- up
Terminology Should Mirror Biology LSIL (CIN 1) HPV infecson producsve phase??? (CIN 2) HSIL (CIN 3) HPV persistence pre- cancer
CIN 2 is NOT a DisSnct Biologic EnSty It is poorly reproducible (similar to ASC- US) In ALTS, only 46% of CIN 2 confirmed on review 27% downgraded: it was an ugly CIN 1 27% upgraded: it was a not so ugly CIN 3
How Can We Improve Reproducibility? Reduce the number of Sers LSIL HSIL Use biomarkers p16 Ki- 67 ProEx C
Superficially Invasive Squamous Cell Ca LAST literature review highlighted inconsistent use of microinvasive terminology for different sites Early perianal cancers staged as skin cancers The term SISCCA recommended for completely excised, minimally invasive SCC that is amenable to conservasve surgery (similar to HSIL) State LVI, number of foci, and margin status in report For cervix, follows the AJCC 7 definison of pt1a1, FIGO stage IA1: 3 mm deep, 7 mm horizontal spread
The New Screening Guidelines ACS- ASCCP- ASCP (March 2012) USPSTF (March 2012) NCCN (May 2012) ACOG (November 2012)
LSIL HSIL
When Papanicolaou published his work in 1941, cervical cancer killed >13,000 women a year in the US alone, and was the #1 cause of cancer death in women That number is now ~4,000 (~70% reducson), and it ranks #13
But Cytology Is Not Perfect ASC- H or atrophy? ASC- US or reacsve?
The Role of HR- HPV Harald zur Hausen, 2008
TesSng for HR- HPV Enhances Cytology ASC- H or atrophy? ASC- US or reacsve?
HPV Biology in Cervical Pre- cancers It isn t the mere presence of HR- HPV, that is important Viral load isn t important either It s the persistence of HPV that is important True HPV persistence is uncommon
Women who develop cervical cancer typically aren t the ones who were screened in 3-5 year intervals, but rather those who were never screened in the first place (JNCI 2011;103:368).
2012 Age- Specific Screening Guidelines summary Age Screening Guideline < 21 No Pap or HPV screening 21-29 Pap only q 3y; no HPV cotessng (only reflex if ASC- US) 30-65 Preferred: Pap + HPV cotessng q 5y Acceptable: Pap q 3y > 65 No Pap or HPV screening (if no history)
Updates to the 2006 ASCCP Management Guidelines September 14-15, 2012 Bethesda, Maryland
Why Update the 2006 Guidelines? Management guidelines needed to conform to updated screening guidelines New definison of rousne screening Co- tessng is preferred screening in women 30-65 How to manage discordant Pap/HPV results Adjust adolescent guidelines now that women <21 are no longer screened
The Pre- meesng Process Working groups reviewed evidence New published evidence since 2005 Data from large databases (especially KPNC) Dray guidelines developed by 7/15/12 Posted on web for public comment in August Revised prior to meesng
Types of RecommendaSons Recommended: Good data to support use when only one opson is available Preferred: OpSon is the best (or one of the best) when there are mulsple other opsons Acceptable: One of mulsple opsons when there are either data indicasng that another approach is superior or when there are no data to favor any single opson Not recommended: Weak evidence against an opson that carries minimal risk Unacceptable: Good data against use
Consensus Conference Ground Rules We are sezng nasonal public health guidelines that will impact millions of women Comments should recognize this Avoid advocasng guidelines that aim to prevent rare outcomes by imposing substansal burdens on large populasons Example: Cervical cancer risk ages 15-19 = 1/1,000,000. StarSng screening at 21 yo means these young women will not present unsl symptomasc and may have worse outcomes than if screened and detected earlier
Consensus Conference Ground Rules Avoid requiring acsons clinicians shun e.g., 2006: We dropped requirement that Pap and biopsy slides be read when discordant wasn t happening Avoid criscizing evidence that doesn t capture rare events e.g., HPV- /LSIL requires colposcopy because she might have vaginal melanoma. Avoid scoring debasng points by asking opponents to prove a negasve e.g., More intensive follow- up might have found more cancers you never know. Unless you can prove that s wrong, we should recommend it.
Consensus Conference Ground Rules Base comments on evidence; avoid statements like: I m just not comfortable with I know what the evidence says but I had a pasent once whose history shows I heard about a lawsuit over just this issue I know differences in that paper didn t reach significance but
New Technology Requires New Guidelines Now that new screening guidelines recommend HPV cotessng, the number of combined cytologic, histologic, and now virologic permutasons increases several- fold Risk of concurrent or future (5- year risk) of (pre- )cancer used as the common currency Regardless of specific combinason of tests done
Equal Management of Equal Risks Ensures simplified and consistent management of different combinasons of tests implying equal risk of precancer or cancer Basing recommendasons on risk ensures that new guidelines promote management that is comparable to exissng and accepted pracsce We are not proposing changing risk thresholds for acson
Defining Risk Risk of CIN3 or worse (CIN3+) is best available metric of cervical precancer or cancer risk CIN3 is widely regarded the definison of a true precancer We will use CIN2 or worse (CIN2+) if too few CIN3+ Two types of risk: Immediate risk: Dictates referral for immediate colposcopy Future risk: Determines intensity of subsequent follow- up
CalculaSng Risk Total (or cumulakve) risk is the sum of two data points: Immediate risk if pasent referred for immediate colposcopy Future risk over the next 5- years of follow- up Example: 1,000 women aged 30+ with LSIL 24 are diagnosed with CIN3+ at their immediate colposcopy: 2.4% immediate risk 29 more are diagnosed with CIN3+ over the next 5 years: 2.9% future risk CumulaSve risk: 2.4% + 2.9% = 5.3% CIN3+ risk over 5 years
Data Source: KPNC By far the longest/largest real clinical experience with HPV tessng and cotessng with high follow- up rates Longitudinal data from 2003-2010 available with nearly every combinason of cytology, HPV, biopsy and treatment: Over 1 million women age 30+ undergoing cotessng 440 cancers, 3,231 CIN3+, 7,581 CIN2+ Nearly 400K women age < 30 with cytology and HPV triage of ASC- US 26 cancers, 1,231 CIN3+, 4,193 CIN2+ KPNC management guidelines similar to 2006 ASCCP guidelines The data is from rousne clinical pracsce, not a clinical trial
SPEAKER S DISCLAIMER The following predicsons are based on preliminary discussions and dray guidelines. There is no guarantee that they will appear in the final version of the ASCCP guidelines which are set to be published in March 2013. They are not to be used as a basis for clinical decision- making.
PredicSon: HPV- NegaSve LSIL HPV- negasve LSIL has a 5- year risk of CIN3+ comparable to (lower than) ASC- US cytology Currently, acceptable management for ASC- US cytology (if not doing preferred HPV tessng) is: Repeat Pap, or Immediate colposcopy So for HPV- negasve LSIL: Repeat cotessng at 1 year will be preferred Immediate colposcopy will be acceptable
PredicSon: Pap- NegaSve/HPV- PosiSve Pap- negasve/hpv- posisve cotest has a 5- year risk of CIN3+ comparable to (higher than) ASC- US Currently, acceptable management for ASC- US cytology (if not doing preferred HPV tessng) is: Repeat Pap, or Immediate colposcopy So for Pap- negasve/hpv- posisve cotest: Repeat cotessng at 1 year will be acceptable Immediate colposcopy acceptable if HPV genotype is 16/18
PredicSon: ASC- US Triage by Genotyping KPNC data showed among women with HPV+ ASC- US, the risk of CIN3+ was double if HPV genotyping detected HPV 16 or HPV 18 Nonetheless, the risk in women with ASC- US who were HPV 16 and HPV 18 negasve ssll exceeded the threshold for colposcopy Therefore, genotyping will not be recommended for triage of ASC- US JNCI (2011) 103:368
PredicSon: Guidelines for Adolescents The 2006 guidelines for management of adolescents (women < 21) will apply to women age 21-25
PredicSon: LAST in the New Guidelines UnSl a comprehensive evidence review and consensus guidelines development process can be conducted, histopathology results reported as LSIL should be managed as CIN1 and those reported as HSIL should be managed as CIN2-3. This will mean individualized (favor conservasve) management in young women Waxman AG et al. Ob Gyn 120:1465, Dec. 2012
PredicSon: HPV- negasve ASC- H & AGC The risk of CIN3+ with HPV- negasve ASC- H and HPV- negasve AGC was in the range of ASC- US cytology (1 year return) This has been confirmed in other studies However, the number of such cases in the KPNC dataset was very low Therefore, HPV status will not be recommended for the triage of ASC- H and AGC 100% 80% 60% 40% 20% 0% All <= 50 > 50 All <= 50 > 50 HPV- posisve HPV- negasve HSIL No HSIL Ghofrani M (2012) JASC 1:S39
Risk Management vs. Guideline Complexity Personalized risk management is necessarily complex The more special cases there are and the more intricate the guideline is: Harder to write and defend the guideline Harder to remember and implement When could complexity outweigh personalized risk management for a specific condison? Small risk difference from another condison CondiSon is a rare outcome A}aining opsmal risk management not as crucial
Disclaimer (From 2006 Document) Guidelines are based on best available evidence Quality evidence not available for all quessons Some guidelines based solely on expert opinion Guidelines should never subsstute clinical judgment Guidelines cannot apply to all clinical situasons Judgment should be used in applying guidelines to individual clinical situasons
Summary 2012 was a big year for cervical cancer screening Widely- agreed screening intervals were published that balance sensisvity and specificity Guidelines for management of abnormal screening results were updated accordingly A uniform terminology for HPV- related disease of the LAT was adopted that be}er reflects its biology Guidelines will never subsstute clinical judgment