1. Introduction to INDONESIA Ring QUALITY ASSESSMENT (RQA)
Dr. Diah Rini Handjari, SpPA(K)

2. OUTLINE Why QA is important? What is Ring Study?
Indonesia Ring Quality Assessment
Lessons Learned

3. Promoting HER2 testing through Centers of Excellence (COE)
Phase 1
Phase 2
Try to achieve CoE status
Achieve CoE status:
Provide leadership, best practice guidance and training to local centres
Ongoing assessment and improvement
Participate in EQA
Institutional mapping tool
Lead local activities for peer education
Ring studies
Preceptorships
Become Center of Reference:
Implement national-level initiatives to reduce testing variations between centres
Lead national-level quality initiatives
HER2 testing guidelines
Conduct External QA programme
Phase 3
CoE, Centre of Excellence; HER2, human epidermal growth receptor 2.
For healthcare professionals only

4. Three key elements of a QA system
Internal QA plan
External QA schemes
Participation in ring studies
Ideally, there should be three key elements of an optimal quality system:
Internal quality assurance plan
External quality assurance plan
Participation in ring studies.
Internal and external quality assurance plans should be mandatory in every laboratory.
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

5. Internal QA – optimal protocol
Ongoing QC and equipment maintenance
Ongoing laboratory training and competency checks
Protocols - adhere to defined standards
Routine controls (positive, negative, and internal)
Repeat test if not as expected with each batch
Monitoring the rates of positivity and negativity for comparison with published rates
Ongoing education and competency assessment of pathologists
e.g. peer comparisons
Ongoing regular reassessment and review, analysis of deficiencies, remedial action
An ideal internal QA plan includes:
ongoing QC measures and equipment maintenance with the necessary supporting documentation
ongoing laboratory training and competency checks
adherence to protocols, which should detail every step of the testing process
use of routine controls (positive, negative, and internal) and adhering to principles of repeating assays when controls are not as expected
monitoring the rates of HER2 positivity and negativity for comparison with published rates – these comparisons are able to detect and highlight discrepancies in reporting trends
ongoing and regular education and competency assessment of pathologists (e.g. peer comparisons), possibly on an annual basis. this will prevent complacency and promote constant reassessment of scoring and interpretation procedures
ongoing regular reassessment and review of protocols, manuals and work processes in laboratories. it will provide an analysis of deficiencies and the necessary remedial action.
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

6. What do external QA plans look for?
CAP accreditation elements requiring documentation at inspection
Validation of test method
Use of protocols
Training of personnel involved in testing
Proper labelling of samples and reagents
Proper storage of samples and reagents
Equipment calibration and QC
Internal QA plan and evidence that it is followed
Quality of tests for interpretation
Ongoing competency assessment of technicians and pathologists
Report adequacy and quality
Accurate submission of results
One key example of an external validation is the accreditation process by CAP, which assesses a number of criteria in laboratories performing HER2 testing.
Validation of test method
Use of protocols
Training of personnel involved in testing
Proper labelling of samples and reagents
Proper storage of samples and reagents
Equipment calibration and QC
Internal QA plan and evidence that it is followed
Quality of tests for interpretation
Ongoing competency assessment of technicians and pathologists
Report adequacy and quality
Accurate submission of results.
Wolff AC, et al. J Clin Oncol 2007;25:118–145.
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

7. Benefits of participating in external QA
Acquires or demonstrates accuracy of HER2 testing in your laboratory
Validates the testing methodology of your laboratory
Many programmes offer advice and assistance if performance is poor
Insight into technical and interpretative difficulties unique to your laboratory, allowing remedial/corrective action to be taken
Active participation in external QA provides many benefits, including:
demonstration of or acquirement of accurate HER2 testing in a laboratory
validation of the testing methodologies used in a laboratory, as assessed by an external party
provision of advice and assistance to a poorly performing laboratory by the evaluating party, particularly with technical evaluation programmes
provision of insight into technical and interpretative difficulties unique the laboratory, thereby leaving remedial/corrective action to be taken.
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

8. CAP (breast and gastric cancer)
CAP provides accreditation for HER2 testing in breast and gastric cancer
Proficiency testing in breast cancer (based on the ASCO/CAP HER2 Testing Guidelines and accreditation checklists)
Quality management/QC
Results reporting
CAP-accredited laboratories performing HER2 testing by IHC or ISH are required to enrol and participate in CAP-accepted proficiency testing
Performance is monitored; laboratories must receive a passing score of 90% or better on each mailing to be considered successful
Laboratories that send HER2 slides to another facility for processing/staining and have them returned for interpretation will be required to participate in proficiency testing
In breast cancer, CAP provides accreditation for laboratories carrying out HER2 testing in breast and gastric cancer. It specifically offers:
proficiency testing in breast cancer(based on the ASCO/CAP HER2 Testing Guidelines and accreditation checklists)
quality management/quality control
results reporting.
CAP-accredited laboratories performing HER2 testing by IHC or ISH are required to enrol and participate in CAP-accepted proficiency testing.
Performance is monitored and laboratories must receive a passing score of 90% or better on each mailing to be considered successful.
Laboratories that send HER2 slides to another facility for processing/staining and have them returned for interpretation will also be required to participate in proficiency testing.
CAP website. Available at: (Accessed March 2012)
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

9. Australian HER2 testing laboratory certification (breast cancer)
All laboratories must take part in the RCPA QAP for HER2 testing and have satisfactory results
All HER2 results are evaluated, with feedback provided to the participating laboratories
Minimum case reports per year
50 cases per pathologist
150 cases per laboratory
The pathologist must:
Have an established interest in breast pathology
Report on breast cancer cases on a routine basis
HER2 results must be provided ≤7 working days from the date of request
In another example of external quality assurance for breast cancer, the Royal College of Pathologists of Australasia requires all Australian laboratories performing HER2 testing in breast cancer to participate in its quality assurance programme, with the following acceptance criteria:
All HER2 results will be evaluated and must be shown to achieve satisfactory results
Each pathologist must handle a minimum of 50 case reports per year, have an established interest in breast pathology and report on breast cancer cases on a routine basis
Each laboratory must handle a minimum of 150 cases per year. This would promote the creating of central laboratories that would specialise in testing as opposed to the distribution of cases to small, potentially under resourced laboratories
Test results must also be provided within 7 working days from the date of request.
RCPA QAP, Royal College of Pathologists of Australasia Quality-Assurance Programme
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

10. RCPA QAP
Provides laboratories with tissue microarray slides with multiple cases
Twice yearly for breast and gastric carcinomas
Technical modules
Virtual microscopy available
The RCPA quality assurance programme provides laboratories with TMA slides that contain multiple cases (up to 50 cases).
These cases are provided twice a year covering breast and gastric carcinomas.
It provides technical modules and also allows users to participate online through a virtual microscopy programme that can be downloaded from the website.
Available at: (accessed March 2012)
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

11. United Kingdom NEQAS Open to laboratories worldwide
Schemes for IHC and ISH
For IHC, participating laboratories test UK NEQAS-ICC cell-line sections on a quarterly basis and return them to the organising centre
Sections are evaluated by a panel of four expert assessors with the median taken as the final score
Systems are in place to identify and rectify suboptimal performance, providing advice for improvement and technical advice and training
External accreditors like the United Kingdom National External Quality Assessment Scheme (UK NEQAS) and NordiQ are available to other laboratories worldwide.
These schemes, which cover IHC and ISH, provide participating laboratories cell-line sections for testing and scoring on a quarterly basis.
The sections are then returned and assessed by a panel of experts.
These evaluation systems identifies and rectifies suboptimal performance, and provides valuable advice on improvements, and technical advice and training.
UK NEQAS website. Available at: (accessed March 2012).
NEQAS, National External Quality Assessment Scheme
For healthcare professionals only .
SPHERE
Scientific Partnership for HER2 Testing Excellence

12. NordiQC (breast cancer)
An independent scientific organisation, promoting the quality of IHC by:
Arranging schemes for pathology laboratories
Assessing tissue stains
Giving recommendations for improvement
Providing good protocols
NordiQC is a Danish-based organisation that works along a similar premise and provides recommendation for improvements.
The organisation also provides participating laboratories with good protocols.
NordiQC website. Available at: (accessed March 2012).
NordiQC, Nordic immunohistochemistry Quality Control
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

13. WHAT IS Ring study or RING QUALITY ASSESSMENT?
Form of external quality assessment (EQA)
Coordinated slide exchange programs led by a reference or central testing laboratory
Specimens are circulated to participating laboratories for assessment by IHC, ISH, or both
Specimens are pre-scored by the originating centre
Interpretation by other laboratories remains blinded
Participating laboratories stain and interpret samples based on the laboratories’ validated HER2 testing protocols
Results are collated by the coordinating laboratory and communicated to participants
IHC, immunohistochemistry; ISH, in situ hybridisation; HER2, human epidermal growth factor receptor 2.

14. Ring studies can help ensure reliable and reproducible HER2 testing: experience in GC
Ring studies have been published from Germany, France and other countries
Preliminary data suggest that:
HER2 testing is reproducible between different pathologists as long as guidelines are adhered to
Pathologists responsible for HER2 status determination in BC require specific training and guidelines
Ring studies are highly valuable for ensuring accurate and consistent HER2 testing.
Preliminary data from ring studies conducted in gastric cancer testing suggest that:
HER2 testing is reproducible between different pathologists as long as guidelines are adhered to
pathologists responsible for HER2 status determination in gastric cancer appeared to improve in scoring accuracy with specific training and the provision of guidelines.
Reference:
Rüschoff J, et al. Virchows Archiv 2010;457:299–307.
Rüschoff J, et al. Virchows Archiv 2010;457:299–307.
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

15. Ring studies should determine if pathologists can reproduce HER2 testing and scoring
Inter-laboratory variation
Pre-selected samples representative of all tumour types
Commercial assays performed according to manufacturer’s recommendations
Inter-observer variation
Pre-stained tumour samples of known HER2 expression levels
Samples evaluated independently by different pathologists
Variation of HER2 scoring is determined independent of inter-laboratory staining variation
Ring studies are able to detect inter-laboratory variation when pre-selected samples representative of all tumour types are sent for testing.
The results allow for comparisons between other participating laboratories i.e. trends in the rates of positivity and negativity can be a measure of laboratory's performance.
Ring studies also allow for inter-observer variation, whereby pathologists evaluate pre-stained tumour samples of known HER2 expression levels.
With appropriate training and guideline adherence, pathologists produce comparable scores.
The supply of pre-stained samples ensures that any variation is independent of inter-laboratory staining variation.
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

16. Objectives of ring studies
Ring studies can evaluate variations in:
fixation and specimen handling
inter-institutional specimen staining, IHC and/or ISH analyses
inter-observer HER2 scoring and interpretation
These proficiency testing studies:
confirm technical and diagnostic competency and proficiency
provide information on inter-laboratory HER2 testing consensus
focus on interpretation of results, as well as methodological issues
identify inter-laboratory discordance in interpretation of HER2 testing results.
IHC, immunohistochemistry; ISH, in situ hybridisation; HER2, human epidermal growth factor receptor 2.

17. Example ring study flow chart
Select core BC TMA samples
Perform HER2 assessment (IHC or ISH) at different sites using commercial assays according to manufacturer’s instructions
Issues relating to IHC HER2 scoring in BC identified
Inter-laboratory variation
Select IHC pre-stained TMA sample series
Different pathologists evaluate samples independently (intensity and area scores)
Inter-observer variation
This is an example of a ring study flow chart.
HER2 testing website. Available at: (accessed March 2012).
For healthcare professionals only
SPHERE
Scientific Partnership for HER2 Testing Excellence

18. The value of ring studies
Ring studies provide valuable insight into:
testing performance of participating laboratories, highlighting areas for improvement
the level of agreement between pathologists
testing improvement following participation in quality initiatives e.g. UK NEQAS
Creates opportunities for publication

19. Example OF RING STUDY FROM India and Hongkong

20. Indonesia Ring Quality Assessment
First meeting (December 2015)
Objective:
Collective decision on ring study design and centers
Establish timeline

21. Scoring system (1) Scored by 2 pathologists
Each pathologist can give maximum score of 10
The score can be reduced if:
- false positive/negative staining
- non specific/ inappropriate staining
- excessive cytoplasmic staining
- weak/diffuse staining
- too strong/weak haematoxylin counterstain
- morphological/nuclear damage
- poor tissue preservation

22. Scoring system (2) Individual scoring method:
0/10 = slide not returned for assessment
1-4/10 = unacceptable
5-7/10 = borderline acceptable
8-10/10 = acceptable
Combined assessors scoring:
˂= 9/20 = unacceptable
10-12/20 = borderline acceptable
13-15/20 = acceptable
16-20/20 = excellent

23. Indonesia Ring Quality Assessment Run 1 – February 2016

24. Indonesia Ring Quality Assessment Run 2 – August 2016

25. What have we learned?
There are many variation in IHC technique between centers  it’s a challenge to standardized the result
Tissue fixation and processing method have an important role in determining IHC result
Whether it is automation or using manual technique, could result in a good staining quality
Good in house control tissue is crucial in determining IHC validation  but sometimes rather difficult to obtain

26. summary
Coordination and collaboration between centers is needed to speed up the her2 testing improvement
Continuous quality assurance program is mandatory to ensured assay validity