1. Evaluating the Utilization of Lower Anogenital Squamous Terminology (LAST) Two-tiered Classification for High-Grade Preinvasive Cervical Lesions and Its Impact on Reporting
Meichin Hsieh, PhD, MSPH, CTR
Louisiana Tumor Registry/Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA
NAACCR/IACR 2019 Conference, Vancouver, BC, Canada
June 13, 2019

2. Background
Abstracting in situ of cervical cancer was no longer required by the standard setters in the United States since 1996.
Worldwide, over 95% of cervical neoplasia are HPV-related
In 2006, HPV vaccination was approved by FDA for females aged 9-26 first.
In 2011, CDC funded 4 state registries to participate in the Pre-invasive Cervical Cancer Surveillance (PCCS) Pilot Project
Assess the association of HPV vaccine usage with precancerous cervical lesion incidence in statewide populations
Collect pre-invasive cervical cancer including CIN3 (3-tiered classification system), CIS, AIS, and severe dysplasia diagnosed in 2009 and 2010
High-grade neoplasm/lesion NOS was not reportable term
CDC continue to fund 4 state registries to collect cervical in situ cancer as routine since then
However, worldwide, over 95% of cervical neoplasia are HPV-related
Due to increased understanding of HPV biology and cervical oncogenesis and apparent subjectivity when differentiating CIN2 and CIN3, the LAST Standardization Project………
to assess the association of HPV vaccine usage with precancerous cervical lesion incidence in statewide populations.

3. Background cont’d
In 2012, LAST Standardization Project recommended the 2-tiered classification system, low-grade and high-grade squamous intraepithelial lesions (SIL), for documenting HPV-associated non-invasive cervical lesions in the pathology reports and using p16 IHC staining to verify high-grade as needed.
Cervical lesions classified exclusively as high-grade SIL using this system were not initially reportable as pre-invasive cervical cancer in the PCCS project.
In 2018, Louisiana Tumor Registry (LTR) conducted an audit to evaluate the use of this classification and p16 IHC test in pathology labs and reports.

4. Objectives
Investigate the use of the 2-tiered terminology and p16 IHC testing on cervical biopsy specimens by laboratories;
Assess the search criteria needed to identify advanced pre-invasive cervical lesions; and
Assess the impact of underreporting cervical lesions caused by terminology changes.
The objectives of this audit are to ….

5. Methods Survey on pathology labs
Selected 10 labs with a high volume of precancerous cervical cases in Louisiana
Survey was conducted via a phone interview
Survey questions
1. Are pathologists using the recommended LAST 2-tiered terminology (LSIL/HSIL) on biopsy reports?
1a. Do pathologists also document the CIN2 or CIN3 (3-tiered) classification in addition to the 2-tiered terminology in the pathology reports?
2. Are pathologists performing p16 IHC staining for CIN2 cases?
2a. If so, is this done in house?
2b. Is p16 available on pathology report?
3. Are pathologists performing Ki-67 (grading), ProEx C or other IHC staining either alone or in combination with p16 IHC staining for CIN2 cases?
3a. If so, what type?
3b. Is Ki-67 or ProEx C or other IHC available on pathology report?
The audit process included two components: survey on pathology labs, auto-screening on pathology reports and manual review to identify reportable terms for pre-invasive cervical lesion..

6. Audit Software and Sampling Pathology Reports
AIM E-Path Reporter and audit software
Natural language processing (NLP) to interpret the content of pathology reports based on the provided terminologies (search terms)
Artificial intelligence (AI) engines perform content coding and report selection
5 Laboratories that used both the 2-tiered and 3-tiered term and also used the AIM E-Path reporting system were chosen for the QC audit
Pathology reports received in 2015 with a cervical specimen from a biopsy were included in the sample selection
Randomly selected equal number of positive and negative pathology reports with maximum up to 500 reports from each lab
Artificial Intelligence In Medicine Inc. (AIM)

7. Screening Pathology Reports
Eligibility and search criteria
Pre-2019 Criteria
2019 Criteria
Search Criteria
ICD-O-3: C53.x
Cervical biopsy specimen
CIN3, CIS, AIS, grade 3, any in situ epithelial tumors, and/or severe dysplasia documented
Reportable Terms
CIN3
CIS
AIS
Severe dysplasia
Search Criteria
Pre-2019 criteria
high-grade, high-grade squamous intraepithelial lesions (HSIL or HGSIL), CIN2, CIN2-3 (or CIN2/3), p16 IHC test with cervix
Reportable Terms
Pre-2019 terms
HSIL/HGSIL
High-grade
CIN2-3 with p16+
CIN2 with p16+

8. Manual Review Processing
Positive and negative pathology reports flagged by AIM software were reviewed by a clinician and/or a certified tumor registrar (CTR)
Recoded positive (reportable) terms based on 2019 criteria for each reportable report
Collected and recorded the presence of p16 IHC testing and the subsequent results of p16 IHC staining.
Categorized into three terminology subgroups:
Terms based on pre-2019 reportable terms only (CIN3, CIS, AIS, and severe dysplasia);
Terms based on new reportable terms only (HSIL, High-grade, and CIN2 or CIN2-3 with positive p16 IHC staining); and
Combination.
Both positive and negative pathology reports flagged by AIM software were reviewed by a clinician and/or a certified tumor registrar (CTR) who had extensive experience in reading pathology reports.
Then we categorized those reportable terms into 3 groups: ……

9. Data Analysis
Proportion of positive terminologies for reportable precancerous cervical cases and percentages of pathology reports with the p16 test performed by pathology laboratory were generated.
Kappa statistic, positive predictive value (PPV) and negative predictive value (NPV) based on AIM auto-coding versus manual coding (as the gold standard) were computed to assess the agreement, predictability and degree of discrepancy for reportability.
Used chi-square test to assess the association between p16 IHC testing and terminology group.

10. Flowchart of audit processing
Phone Interview 9 labs
Select 5 labs for audit
Use pre-2019 search criteria in AIM filter
Randomly sample: 987 positive & 987 negative
Add new search criteria in AIM filter
AIM auto-coded:
Positive: 1,273; Negative: 701
Manual review
Non-reportable
End
Reportable
Pre-2019 terms
New terms
Combination

11. Results: Survey Survey Questions 6 3 5 1 7 2 Ki-67 NA Responses Yes No
1. Are pathologists using the recommended LAST 2-tiered terminology (LSIL/HSIL) on biopsy reports? 6 3
1a. Do pathologists also document the CIN2 or CIN3 (3-tiered) classification in addition to the 2-tiered terminology in the pathology reports? 5 1
2. Are pathologists performing p16 IHC staining for CIN2 cases? 7 2
2a. If so, is this done in house?
2b. Is p16 available on pathology report?
3. Are pathologists performing Ki-67 (grading), ProEx C or other IHC staining either alone or in combination with p16 IHC staining for CIN2 cases?
3a. If so, what type?
Ki-67 NA
4b. Is Ki-67 or ProEx C or other IHC available on pathology report?
Nine out of 10 laboratories responded to our survey. Six laboratories used the 2-tiered terminology on biopsy pathology reports and the remaining used it for cytology reports (Pap test) only (Table 1). Of the 6 laboratories that used the 2-tiered terminology, 5 of them used it in combination with CIN terminology. Seven laboratories performed p16 tests and 5 of them also performed Ki-67 tests. All laboratories that reported using p16 and Ki-67 testing included test results in their pathology reports even if this testing was not done in house.

12. Agreement between AIM auto-coded and manual-coded
Reportable CIN3
Reviewer: Yes
Reviewer: No
Total
Count %
AIM: Yes
822
64.6
451
35.4
1,273
AIM: No
0.0
701
100.0
41.6
1,152
58.4
1,974
Based on 2019 new search criteria (pre-2019 plus high-grade term)
AIM auto-coded: 1,273 reportable & 701 non-reportable cases
Manual review: 822 reportable & 1,152 non-reportable
822 reportable cases, 475 (57.8%) identified by pre-2019 terms and 347 (42.2%) solely by new terms
Percentage of agreement is 77.2% with Kappa statistic of (moderate agreement).
PPV 0.65 (95% CI: )
NPV 1.00 ((5% CI: )
The strength of agreement was based on the range of Kappa values categorizing into: almost perfect ( ), substantial ( ), moderate ( ), fair ( ), slight ( ), and poor agreement (<0.00) (Landis JR et al, 1977).
Positive predictive value (PPV):
PPV = 0.65 implies that if the path reports were coded to reportable CIN3 by AIM, 65% of them would be truly reportable.
Negative predictive value (NPV):
NPV = 1 implies that if the path reports were coded to non-reportable CIN3 by AIM, 100% (all of them) would be truly non-reportable. In this case we will not miss any reportable cases.

13. Contained pre-2019 terms (N=475) Based on new terms only (N=347)
Frequency distribution of positive (reportable) terminology by pathology laboratory (N=822)
Terminology
Lab 1 (N=201)
Lab 2 (N=184)
Lab 3 (N=57)
Lab 4 (N=176)
Lab 5 (N=204)
Total (N=822)
Contained pre-2019 terms (N=475)
Based on new terms only (N=347)
Count (%)
1. AIS
2 (1.0)
0 (0.0)
2 (3.5)
11 (5.4)
15 (1.8)
15 (3.2)
2. CIN3
81 (40.3)
93 (50.5)
43 (75.4)
83 (47.2)
107 (54.5)
407 (49.5)
407 (85.7)
3. CIS
9 (4.5)
11 (6.0)
4 (2.0)
24 (2.9)
24 (5.1)
4. Severe Dysplasia
18 (9.0)
1 (0.5)
1 (1.8)
15 (8.5)
37 (4.5)
37 (7.8)
5. HSIL
107 (53.2)
53 (28.8)
25 (43.9)
112 (63.6)
190 (93.1)
487 (59.3)
278 (58.5)
209 (60.2)
6. High Grade
104 (51.7)
101 (54.9)
13 (22.8)
126 (71.6)
40 (19.6)
384 (46.7)
170 (35.8)
214 (61.7)
7. CIN2-3 with p16+
29 (14.4)
21 (11.9)
53 (6.5)
5 (1.1)
51 (14.7)
8. CIN2 with p16+
14 (7.0)
20 (10.9)
8 (4.6)
6 (2.9)
48 (5.8)
7 (1.5)
41 (11.8)
Pre-2019
2019 terms
This Table presents the frequency distribution of usage of reportable terminology including the pre-2019 and new reportable terminologies by pathology laboratory. In general, the most frequently used terms were HSIL (or HGSIL) (59.3%) followed by CIN3 (49.5%) and high-grade (46.7%). The use of the 2-tiered terminology varied by laboratory. Lab #5 used the “HSIL” term in the majority (93%) of their reportable pathology reports and Lab #2 favored using “high-grade” (Table 2). About 6.5% of reportable cases had CIN2-3 with a positive p16 and 5.8% had CIN2 with a positive p16 result in pathology reports.
New terms

14. Percentage of reportable term by subgroup and pathology laboratories in Louisiana (n=822)
For all labs combined, 84% of reportable pathology reports contained new terminology
Half (42.2%) were solely based on new terms
Rang of reportable terms use
Pre-2019 terms only: 3.9% %
New terms only: 19.3% %
Combination: 27.7%-54.9%.
Labs 4&5 were less likely to use pre-2019 terms only.
Of 822 cases that met the reportable criteria, 130 (15.8%) contained pre-2019 reportable terms only, 347 (42.2%) were solely based on the new reportable terms, and 345 (42.0%) included both pre-2019 and new reportable terms (Figure 2). Including new terms for precancerous cervical lesions resulted in a 73% increase in reportable cases. Pathology laboratories varied in their use of the new terminology, ranging from 3.9% % based on the pre-2019 terms only, 19.3% % based on reportable new terms only, and 27.7% % based on both pre-2019 and new terms in pathology reports.
*Combination (2019 reportable terms) indicates that both pre-2019 and new terms documented in the pathology report.

15. Proportion of p16 IHC testing by terminology group
Use of p16 IHC staining by laboratories ranged from 0% to 26.6% (Table 3) and was significantly associated with type of terminology group (p <0.0001). Advanced precancerous cervical lesions identified solely through the new reportable terminology had a higher percentage of p16 tests performed (36.9%) than those identified through pre-2019 terminology (6.9%) or using combination terms (15.9%).
P<0.0001

16. Summary of Results
After adding the HSIL (HGSIL)/ high-grade term in search criteria, positive reports increased by 29% for manual review.
84% of reportable pathology reports received in 2015 contained the 2-tiered terms.
Percentage of cervical biopsy specimens that had a p16 IHC test performed was 13.6%
Almost all new cases based on new terminology can be identified either by HSIL/HGSIL or high-grade term.
By including new terminologies, we were able to add 347 new cases with 73% increase in reportable advanced precancerous cervical lesions.

17. Conclusions The Audits findings helped to
Define the new eligibility criteria for reportable precancerous cervical cases
Highlight that both the 2-tiered and 3-tiered nomenclature are needed to ensure complete identification of all advanced precancerous cervical cases
Although the term HSIL/high-grade lesion include CIN2 (CIN2-3) or moderate dysplasia, its association with HPV and likelihood to predict cervical cancer progression makes it important to collect.
In order to align with the current practice and be able to compare data collected before 2019 and after, the 2019 reportable terms include
Pre-2019 reportable terms (AIS, CIN3, CIS, severe dysplasia)
HSIL/high-grade
CIN2 or CIN2-3 with positive p16 IHC tests

18. Co-authors LTR CDC Elizabeth Van Dyne, MD, MPH Xiao-Cheng Wu, MD, MPH
Jean A. Shapiro, PhD
Paran Pordell, MPH
Mona Saraiya, MD, MPH
LTR
Xiao-Cheng Wu, MD, MPH
Christina Lefante, MPH
Mary Anne Lynch, MPH
Natalie Gomez, BSN, RN
Brent Mumphrey, BS
Lauren Maniscalco, MPH
Rachna Jetly-Shridhar, MD

19. Acknowledgments
Louisiana hospital reference and free-standing pathology laboratories and pathologists
Funding source:
Centers for Disease Control and Prevention under National Program of Cancer Registries Component #2 cooperative agreement number U58DP
I would like to thank the hospital reference and free-standing pathology laboratories in Louisiana for their participation and regional and state central registrars for their diligence in cancer data collection.

20. Contact Information: