Grading Systems for CTA Rejection Proposals and Prospects

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Grading Systems for CTA RejectionProposals and
Prospects

• David E. Kleiner, M.D., Ph.D.
• National Cancer Institute

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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?

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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

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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
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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
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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

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Tiered Grading Systems

• Advantages Easy to use, Probably better
  reproducibility
• Disadvantages Doesnt account well for variation
  in severity of features, especially when features
  seem inappropriately mild or negative

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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 -gt decreases reproducibility.
  Difficulties assigning grade if features are out
  of sync with one another.

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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

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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 81418-22 2006

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• 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

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Histologic Associations with Rejection
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• 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

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• 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

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• 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

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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

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Grades from None/Non-specific to Mild/Moderate
Proposal 1st author 1. Bejarano, 2.
Schneeberger, 3. Kanitakis, 4. Cendales
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Grades from Moderate to Very Severe
Proposal 1st author 1. Bejarano, 2.
Schneeberger, 3. Kanitakis, 4. Cendales
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Approximate Grade Equivalences
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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.)