grading systems for cta rejection proposals and prospects david e. kleiner, m.d., ph.d. national...
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Grading Systems for CTA RejectionProposals and Prospects
David E. Kleiner, M.D., Ph.D.
National Cancer Institute
• 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?
Setting the Stage
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
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
Time
Lossof
Function(Stage)
Cirrhosis
OrganFailure
Onset ofDisease
Death
The apparent ratemay or may not bea good predictor of progression
Rate (Grade)
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
Tiered Grading SystemsInflammation Epithelial Injury Vascular Injury
Grade 1 + - -Grade 2 + (any) + -Grade 3 + (any) + (any) +
• 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
Progressive Severity System
Inflammation Epithelial Injury Vascular Injury
Grade 1 + + +Grade 2 ++ ++ ++Grade 3 +++ +++ +++
• 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.
Composite Score System
Inflammation Epithelial Injury Vascular Injury
Score Range 0-3 0-3 0-3
• 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
Sum the individual scores: 0: Grade 0; 1-3: Grade 1; 4-6: Grade 2; 7-9: Grade 3
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
• 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
Histologic Associations with Rejection
Non-Rejection
(mean/mode)
N = 9
Rejection
(mean/mode)
N = 13
p
No. infiltrated vessels 0.1 (0.2%) 12.7 (35%) 0.017
Intensity of Perivascular Infiltrates 0.0 2.0 0.00007
Location of perivascular infiltrates None Upper dermis 0.00011
Small Lymphocytes 0.0 1.7 0.00007
Large Lymphocytes 0.0 1.0 0.014
Eosinophils 0.0 0.6 0.04
Endothelial Plumping 0.4 1.1 0.011
Spongiosis 0.0 1.1 0.03
No Rejection
Grade 0
No perivascular infitrates.
Indeterminate for Rejection
Grade 1
< 10% of vessels with perivascular infiltrates, no spongiosis, eosinophils, large lymphocytes, epidermal infiltrates or stromal inflammation.
Mild Rejection
Grade 2
11-50% of vessels with perivascular infiltrates, +/- mild spongiosis, eosinophils. No epidermal infiltrates, stromal infiltrates or large lymphocytes.
Moderate Rejection
Grade 3
>50% of vessels with perivascular infiltrates +/- epidermal/stromal inflammation, eosinophils, endothelial plumping, large lymphocytes. No dyskeratosis.
Severe Rejection
Grade 4
>50% of vessels with perivascular infiltrates with dyskeratosis, heavier lymphocytic infiltrates in the epidermis, moderate to severe spongiosis, stomal inflammation extending to basal layer
• 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
Minimal Rejection
Grade I
Perivascular lymphocytic and eosinophilic infiltrates
Mild Rejection
Grade II
Additional interface reaction in epidermis and/or adnexal structures
Moderate Rejection
Grade III
Diffuse lymphocytic infiltration of epidermis and dermis
Marked Rejection
Grade IVa
Necrosis of single keratinocytes and focal dermal-epidermal separation
Marked Rejection
Grade IVb
Necrosis and loss of the epidermis
• 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
No Rejection
Grade 0
Normal or very low density infiltrates around a few vessels
Mild Rejection
Grade I
Mild dermal lymphocytic infiltrate forming perivascular cuffs in upper and occasionally mid-dermis. The epidermis is unaffected.
Moderate Rejection
Grade II
Moderately dense dermal infiltrate, perivascular and interstitially between collagen bundles, +/- mild degree of epidermal exocytosis, spongiosis. No necrotic keratinocytes
Severe Rejection
Grade III
Dense lymphocytic infiltrate around blood vessels in upper, mid, lower dermis and eccrine sweat glands. Band-like infiltrate in papillary dermis with lichenoid epidermal changes, spongiosis, exocytosis, variable epidermal apoptosis
Very Severe Rejection
Grade IV
Pandermal inflammation with large cuffs of lymphocytes, variable epidermal thickness with areas of necrosis, thinning, hyperplasia, basal cell vacuolization, epidermal apoptosis
• 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
Nonspecific Changes
Grade 0
No or only mild lymphocytic infiltration, no involvement of adnexa or epidermis
Mild Rejection
Grade 1
Superficial perivascular inflammation in upper dermis, no involvement of epidermis
Moderate Rejection
Grade 2
Features of Grade 1 plus inflammatory infiltration of adnexal structures
Severe Rejection
Grade 3
Bandlike superficial dermal infiltrate with more continuous involvement of the epidermis, mid and deep dermal perivascular infiltrate
Necrotizing Rejection
Grade 4
Grade 3 with necrosis of epidermis or other tissues
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
Nominal
GradeProposal Perivascular Dermal Inf
Epidermal/
Adnexal
Apoptosis/
Dysker.Necrosis
0 1 - - - -
2
3 -/+ - - - -
4 -/+ - - -
1 1 + - - -
2 + - - - -
3 + - - - -
4 + - - -
2 1 ++ - - -
2 + - +/- - -
3 + + +/- - -
4 + - + - -Proposal 1st author: 1. Bejarano, 2. Schneeberger, 3. Kanitakis, 4. Cendales
Grades from None/Non-specific to Mild/Moderate
Nominal
GradeProposal Perivascular Dermal Inf
Epidermal/
Adnexal
Apoptosis/
Dysker.Necrosis
3 1 +++ +/- +/- -
2 + + + - -
3 + + + +/- -
4 + + + -
4 1 +++ + + +
2 + + + + -
3 + + + + +
4 + + + +
5 2 + + + + +
Proposal 1st author: 1. Bejarano, 2. Schneeberger, 3. Kanitakis, 4. Cendales
Grades from Moderate to Very Severe
Approximate Grade EquivalencesFirst Author
Bejarano Schneeberger Kanitakis Cendales
00 0
11
2 1 1
3 2 2 2
43
3 34a
4b 4 4
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.)