Grading Systems for CTA Rejection Proposals and Prospects

1. Grading Systems for CTA RejectionProposals and Prospects David E. Kleiner, M.D., Ph.D. National Cancer Institute

2. Setting the Stage • Grading system philosophy and choices of grading systems • Review of published grading system criteria for CTA acute rejection • Comparison of existing systems looking for common themes • Where do we go from here?

3. What Are the Goals in Creating a Grading System? • Stratification for treatment/protocol entry • Minimum hepatic fibrosis for HCV therapy • Prognostication • Cancer Staging and Grading • Structured pathology data collection • NASH-CRN Feature Scoring System

4. Some Definitions • Stage – Stratification of the level of progress of a disease to its final end-point (Clinical Tool) • Grade – Stratification of the severity of a disease or disease feature at a particular point in time (Clinical Tool) • Scoring – the assignment of quantitative or semi-quantitative values to individual disease features (Research Tool) It is usually possible for therapeutic intervention to improve the Grade of a disease but it is usually difficult or impossible to improve the Stage of a disease

5. Organ Failure Cirrhosis Loss of Function (Stage) Rate (Grade) The apparent rate may or may not be a good predictor of progression Onset of Disease Death Time

6. Types of Grading Systems • Tiered Systems • Each grade is differentiated by the addition of a new lesion • Banff Renal Acute Cellular Rejection Grade I vs II • Progressive Severity Systems • Gradual worsening of one or more features with (arbitrary) thresholds • Banff Renal Acute Cellular Rejection Borderline vs Ia vs Ib • Composite Score Systems • Grade is a summation of scores of individual features • Hepatitis inflammation grading

7. Tiered Grading Systems • Advantages: Easy to use, Probably better reproducibility • Disadvantages: Doesn’t account well for variation in severity of features, especially when features seem inappropriately mild or negative

8. Progressive Severity System • Advantages: Better system when features generally vary in parallel. Natural relationship to scoring individual features • Disadvantages: Need to define thresholds for each feature -> decreases reproducibility. Difficulties assigning grade if features are out of sync with one another.

9. Composite Score System Sum the individual scores:0: Grade 0; 1-3: Grade 1; 4-6: Grade 2; 7-9: Grade 3 • Advantages: Most sophisticated system. Accounts well for individual variation between features. Relates well to scoring systems. Better for clinical trials • Disadvantages: Threshold problems. Implied weighting of features, therefore requires advanced knowledge of relative importance of features

10. Published Systems for Grading CTA Rejection • The Pathology of Full Thickness Cadaver Skin Transplant for Large Abdominal Defects • Bejarano et al., Am. J. Surg. Pathol. 28: 670-675; 2004 • Steroid- and ATG-Resistant Rejection After Double Forearm Transplantation Responds to Campath-1H • Schneeberger et al., Am. J. Transplant 4: 1372-1374; 2004 • Pathological Score for the Evaluation of Allograft Rejection in Human Hand (Composite Tissue) Allotransplantation • Kanitakis et al., Eur J. Dermatol. 15: 235-8; 2005 • Composite Tissue Allotransplantation: Classification of Clinical Acute Skin Rejection • Cendales et al., Transplantation 81:418-22; 2006

11. Abdominal wall transplantation • 9 patients (5 adults, 4 children), 10 transplants • 22 specimens (17 punch biopsies, 3 graft excisions, 2 post-mortem) • Blind categorization (3 pathologists) of multiple histologic features related to inflammation, epidermal changes and stromal changes • Features were analyzed with respect to an overall clinico-pathologic determination of the presence of rejection

12. Histologic Associations with Rejection

14. Case report of 41 M with double forearm transplantation • Grading system presented based on clinical experience with prior rejection episodes and on published literature of CTA rejection • Reported 2 Grade I rejections that were steroid-responsive and one Grade IVa rejection that was steroid-resistant and ATG-resistant but responded to Campath-1H • Follow-up biopsies confirmed resolution of infiltrates

16. Hand/Forearm Transplants • 6 patients (all M), 33.8 yrs (22-48) • 89 skin biopsies (punch or scalpel) • Biopsies reviewed for a variety of epidermal, adnexal, inflammatory and vascular changes • Immunoperoxidase staining for lymphocyte phenotype, HLA, mast cells • Grading based on biopsy review, grouping similar biopsies together into 5 grades

18. Forearm transplantation • 2 patients, 11 biopsies • Biopsies were ranked by overall severity of changes and grouped into categories to set definitions • Interobserver agreement tested on grading 18 additional biopsies from abdominal wall transplants

20. Common Themes • Perivascular lymphocytic infiltrates become progressively more intense and involve more vessels with increasing grades • Inflammation extends to involve dermal stroma, epidermis (including DEJ), adnexa at moderate to marked grades • Epidermal apoptosis/necrosis only at higher grades • All tiered grading systems with implied worsening inflammation with increasing grade

21. Grades from None/Non-specific to Mild/Moderate Proposal 1st author: 1. Bejarano, 2. Schneeberger, 3. Kanitakis, 4. Cendales

22. Grades from Moderate to Very Severe Proposal 1st author: 1. Bejarano, 2. Schneeberger, 3. Kanitakis, 4. Cendales

23. Approximate Grade Equivalences

24. Conclusions and Challenges • There is already substantial agreement on basic grade stratification for acute rejection • Histologic features of rejection (especially at mild grades) are also seen in a large variety of non-rejection pathologies • Published experience using pathology grading in prospective studies is very limited • Future refinements may require prospective systematic evaluation of biopsy features, similar to other developed rejection classification systems • We should consider defining scoring thresholds for scaling individual features (inflammation, epidermal injury etc.)