Vascularized Composite AllotransplantationBanff VCA

Linda C. Cendales, M.D.Associate Professor of Surgery

Duke University Medical Center on behalf of

The Banff VCA Working Group

< 250 VCA recipients worldwide

Congratulations to the field of

Vascularized Composite Allotransplantation

for organizing themselves under the Banff Structure

Coming together and agreeing to systematically study VCA pathology is

a significant step

But the hard work starts now

We started talking together in a common language

We can now argue

The Towel of Babel

Painting by Peter Bruegel the Elder, 1583

We cannot have arguments and organize ourselves until we have a

common language.

A common language facilitates disagreement in a good way

A common language allows for collaboration

Diagnosis of Transplant Rejection in the 1980’s

Transplantation 1984 Dec;38(6):709-13.Relationships among the histologic pattern, intensity, and phenotypes of T cells infiltrating renal allografts.Kolbeck PC, Tatum AH, Sanfilippo F.

Histopathology. 1980 Sep;4(5):517-32.The relation of different inflammatory cell types to the various parenchymal components of rejecting kidney allografts.Reitamo S, Konttinen YT, Ranki A, Häyry P.

Common Language

Vascularized Composite Allotransplantation

Before 2007

Nothing

VCA Banff

Now

Keeping this group together under this framework is how this is going to go

forward

We can now answer the questions

Unanswered Questions

Histologic Features of Antibody Mediated Rejection after Face Transplantation

Anil Chandraker MD FASN FAST FRCP

Medical Director of Kidney and Pancreas TransplantationBrigham and Women’s Hospital

Director, Schuster Family Transplantation Research CenterBrigham and Women's Hospital

Associate Professor of Medicine, Harvard Medical School

Pre-Sensitized Recipient of a Full-Face Allotransplant

Acute Cellular Rejection

Complement Deposition (C4d)Pre- cellular rejection Cellular rejection Post-

treatment

Pre-sensitized patient

Not pre-sensitized patient

Graft vasculopathy in the skin in vascularized composite allografts

J. KanitakisDepts. of Dermatology/Pathology Ed. Herriot Hospital, Lyon, France

BANFF‐CST Joint Scientific Meeting

October 8, 2015 Vancouver, British Columbia

Sudden necrotic ulceration

Progression to scaly erythematous maculopapules

SSG

initial aspect

SSGNovember 2014

ID Nov 2014 – 9 years postTx

(face)

CD20

CD4

C4d

Banff grade III

thickening/luminal obstruction of the nutrient SSG artery ≈ graft vasculopathy

SSG ulceration ID Nov 2014 – 9 years postTx - SSG

C4d-

AR rejection on the face (Banff III)Graft vasculopathy of the SSG

Cutaneous Changes among Transplant Patients

Adela Rambi G. Cardones, M.D.Immunodermatology, Chronic GVHD Clinic

Director, Inpatient Consult ServiceAssistant Professor

Duke University Department of Dermatology

Atypical Acute Rejection After Hand Transplantation

Schneeberger S, et al. American Journal of TransplantationVolume 8, Issue 3, pages 688-696, 5 FEB 2008 DOI: 10.1111/j.1600-6143.2007.02105.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2007.02105.x/full#f3

Nails (Distinctive Signs)

Dystrophy, pterygium, longitudinal ridging.

VCA Research Laboratory - Mission

Expanding the Banff VCA Criteria

Gerald Brandacher, MD, FASTAssociate Professor or Surgery

Scientific DirectorReconstructive Transplantation Program

Johns Hopkins University School of MedicineBaltimore, MD, USA

on behalf of the AST VCA Advisory Council Working Group

Question from the AST Working Group

Does biopsy site matter? The skin anatomy and characteristics differ significantly depending where on the hand or face the biopsy is taken. Should this be reflected in the Banff Criteria?

While 4 mm biopsies provide a great deal of information, many centers do not feel a biopsy of this size is practical. Should this criteria be revisited? Additionally would more information be gained from two smaller biopsies, one taken from an area of involvement and one from a “normal” area?

There appears to be distinct differences between infiltrates and histology of skin from hand vs. face transplants. Should these differences be reflected in the histological grade of rejection?

Question from the AST Working Group

Specific criteria to be reconsidereda.Is the PAS stain still relevant and routinely performed?b.CD163 may be a preferable marker to CD68 for macrophages.c.What is the rationale to include both CD19 and CD20?d.Why is CMV proposed as a recommended immunohistological stain (would be unusual in the differential of rejection).e.Inclusion of additional immunohistochemistry markers e.g. FoxP3.

Question from the AST Working Group

Many centers continue to report histological grades of 0-I, I-II and II-III from review of VCA skin biopsies. As it is still unclear what histology that is less severe than a grade I means, should we expand the criteria?

Is the granularity of the current criteria sufficient?

Discussion

• Unanswered questions collected over the years by the Banff VCA group

• Reviewed results of Banff VCA survey• Reviewed Proposal for collection data

form• Reviewed AST VCA advisory council

questions• VCA Working Group Workshop, May 21,

2016, Durham, NC

• Challenges grading Banff VCA 0-I-II• Specificity of isolated dyskeratotic/apoptotic

keratinocytes • Does location alter the specificity of isolated

dyskeratotic/apoptotic cells?– Epidermis– Follicular epithelium– Sweat gland epithelium– Basal vs. suprabasal/at all levels

• Analogy to GVHD • Value of a numeric threshold• Role of mast cells in chronic immune injury• Role of C4d staining and/or DIF staining for C4d in the

management of rejection

Banff VCA – Unanswered Questions

Banff VCA – Unanswered Questions

• Significance of focal epidermal changes (i.e. spongiosis and/or lymphocyte exocytosis) in Banff VCA grades

• Study of effector functions of antibody and its manifestations in tissues (acute and chronic)

• Detection of antibody functions – Biopsy: histology, genomics– Blood: serological, cellular

• Chronic changes• Relationship of graft function and rejection

– Acute and Chronic

Banff VCA – Unanswered Questions

•Interpretation of long-term changes and related biomarkers•Differential diagnosis of inflammation vs. rejection•Scope of Disease - Antibody Mediated Rejection•Significance of myointimal proliferation•Vasculopathy, role of antibody

Banff VCA Survey

We translated these results into a one-page form to standardize

the collection of data

Banff VCA Resource

Human and Animal Histology/Immunohistochemistry Core

• VCA clinical samples (>2000)– Tissue samples: muscle, skin, tendon, nerve, artery, vein

• Histopathology Core• Digital Library

– Digital slide scanning – Aperio AT [400 slide scan capability]

• Dedicated Lab Space• Histology Staff

Digital Library

AST VCA advisory council questions

• Many centers continue to report histological grades of 0-I, I-II and II-III from review of VCA skin biopsies.  As it is still unclear what histology that is less severe than a grade I means, should we expand the criteria?

• New information is accumulating regarding the importance of loss of capillaries and importance of evaluating small vessel vasculopathy.  Should a grading scale for early signs of “chronic” rejection be proposed?

• There appears to be distinct differences between infiltrates and histology of skin from hand vs. face transplants.  Should these differences be reflected in the histological grade of rejection?

• While 4 mm biopsies provide a great deal of information, many centers do not feel a biopsy of this size is practical.  Should this criteria be revisited?  Additionally would more information be gained from two smaller biopsies, one taken from an area of involvement and one from a “normal” area?

• While the current criteria do note that the level of involvement in the graft should be reported, this is not reflected in the histological score.  Practically, this histologic score is used interchangeable as “Grade of Rejection”.  Should the working group propose an actual “Grade of Rejection” vs. “grade of histology” that would reflect clinical parameters such as a.    level of involvement, b. Edema, c. Induration

• Does biopsy site matter?  The skin anatomy and characteristics differ significantly depending where on the hand or face the biopsy is taken.  Should this be reflected in the Banff Criteria?

AST VCA advisory council questions

Workshop on VCA Pathology

May 21, 2016 Durham, NC

Thank you