Pancreas Transplant Pathology: Controversial

Lesions

Lois J. Arend PhD, MD

University of Cincinnati Department of Pathology

American Journal of Transplantation 2008; 8: 1237–1249Banff Schema for Grading Pancreas Allograft Rejection: Working Proposal by a Multi-Disciplinary International Consensus PanelC. B. Drachenberg, J. Odorico, A.J. Demetris, L. Arend, I. M. Bajema,J. A. Bruijn, D. Cantarovich, H. P. Cathro, J. Chapman, K. Dimosthenous,B. Fyfe-Kirschner, L. Gaber, O. Gaber, J. Goldberg, E. Honsova, S. S. Iskandar, D. K. Klassen, B. Nankivell, J. C. Papadimitriou, L. C. Racusen, P. Randhawa, F. P. Reinholt, K. Renaudin, P. P. Revelo, P. Ruiz, J. R. Torrealba, E. Vazquez-Martul, L. Voska, R. Stratta, S. T. Bartlett and D. E. R. Sutherland

1. Normal2. Indeterminate 3. Cell-mediated rejection

Acute cell-mediated rejection- Grade I/Mild acute cell-mediated rejection- Grade II/Moderate acute cell-mediated rejection- Grade III/Severe acute cell-mediated rejection

Chronic active cell-mediated rejection4. Antibody-mediated rejection = C4d + donor specific antibodies + graft

dysfunctionHyperacute rejectionAccelerated antibody-mediated rejectionAcute antibody-mediated rejectionChronic active antibody-mediated rejection

5. Chronic allograft rejection/graft sclerosis- Stage I (mild graft sclerosis)- Stage II (moderate graft sclerosis)- Stage III (severe graft sclerosis)

6. Other histological diagnosis. e.g. CMV pancreatitis, PTLD, etc.

Allograft Pancreas Grading

American Journal of Transplantation 2008; 8: 1237–1249

Outline

• Drug Toxicity• Significance of C4d Labeling• Significance of Acinar Inflammation• Chronic Rejection/Sclerosis

Drug Toxicity

• Exocrine pancreas– Acute pancreatitis

• Anti-neoplastics, sulfonamides, diuretics, alcohol, azathioprine, oral contraceptives

• Acinar cell necrosis or apoptosis, inflammation, necrosis

• Endocrine pancreas– Diabetes

• Calcineurin inhibitors, thiazide diuretics• Vacuolation, swelling, apoptosis of islet cells• Reduced insulin staining of beta cells

Exocrine Pancreas

• Acute pancreatitis– Drugs, duct obstruction, viruses, toxic

chemicals, trauma• Some features of acute pancreatitis can

overlap with acute rejection• Distinguishing between the two can be difficult• Venulitis and more mononuclear dominant

infiltrate favors rejection• Many centers will treat for rejection if no clinical

reason for pancreatitis is evident

Endocrine Pancreas• Diabetes

– Caused by immunosuppressive agents• No inflammation – vacuolation or drop-out

– Caused by recurrent autoimmune disease• Mononuclear cell infiltrate, similar to rejection

– Should routine immunostaining be included as part of the grading scheme?

• Immunostaining for insulin and glucagon may not be routine at some centers

Significance of C4d Staining

• Antibody-mediated rejection, complement activation, deposition on endothelial cells– Indication of AMR

• Acute

• Chronic?

• Accessibility of staining by IHC on paraffin• Non-specificity of paraffin section staining• Frozen sections for IF?

Significance of C4d Staining• Correlation between C4d+ IAC and:

– Development of DSA

– Allograft dysfunction

• C4d staining of artery intima or media, and interstitial collagen– No correlation with DSA or dysfunction

• Islet capillaries– No correlation with DSA or blood glucose

• C4d+ IAC correlated with DSA and graft dysfunction

Torrealba, et al Transplantation 2008; 86: 1849

Retrospective Review of C4d Staining

• 2003 – 2009

• 22 biopsies with C4d immunostaining performed

• 2 cases with C4d+ IAC labeling

• No correlation with rejection grade– Sclerosing grade III; ACR III (old grade V)

• DSA not available

Significance of Acinar Inflammation –

• Mild acinar inflammation and injury to acinar cells (Grade I)

• Acinar injury easily leads to fibrosis

• Fibrosis -> poor prognosis

Significance of Acinar Inflammation –

• Mayo clinic study

• 2 year period – 18 biopsies for grade II

• 25 follow-up biopsies

• 10 were unchanged, 1 grade III, 1 grade IV

• Conclusion: Grade II may not have unfavorable prognosis

Casey, et al., Transpl, 2005

Significance of Acinar Inflammation –

• Minnesota study

• 8 year period – 914 pancreas grafts

• 80 grafts lost to chronic rejection

• 91% of these had prior rejection episode

• 70% with late functioning grafts had never had acute rejection

Humar, et al., Transpl, 2003

Cincinnati Experience –

• Small sample

• Two cases with Grade II rejection

• One graft progressed to Stage III sclerosis in one year

• One graft progressed to Stage III sclerosis in nine months

1 month post-txp

4 months post-txp

7 months post-txp

10 months post-txp

12 months post-txp

Proposal –

• Should acinar inflammation of any degree be considered severe and treated aggressively?

– Septal category of rejection

– Acinar category– Arteritis category

Treatment of rejection

• Treat any form of pancreatic rejection aggressively– All but mildest cases treated with anti-

thymocyte therapy

• Low threshold for treatment of pancreas rejection

Chronic Rejection/Sclerosis

• Is graft sclerosis always due to rejection?

• Drug toxicity, infections, vascular complications

• Avoid CAN analog ?CAP

• Distinguish cause of sclerosis if possible

Summary

• Distinguishing rejection from many other insults can be difficult

• Significance of C4d+ unclear

• Any degree of acinar inflammation may benefit from early aggressive treatment

• Defining causes of chronic injury

• Rejection grade correlation with outcome

Acknowledgements

SurgerySteve Woodle, MD

Transplant PharmacyJason Everly, PharmDRita Alloway, PharmD

NephrologyPrabir Roy-Chaudhury, MDGautham Mogilishetty, MDAmit Govil, MD

PathologyPravina Desai

NEJM 356; 2007