Banff 2024 Pancreas Transplantation Report: Diagnosis and Impact of Chronic Active T-Cell Mediated Allograft Rejection, Re-Evaluation of the Indeterminate Category and Utilization of CD3/CD68 Immunostains in Biopsies with Ambiguous Findings
Maike Buettner et al
Read the full manuscript on the SSRN site
Abstract
The 2022 meeting report, provided more specific criteria for T-cell mediated (TCMR) and antibody mediated rejection (AbMR). Criteria for chronic active (ca) rejection and discussions on the potential value of lymphoid immunostains, were also introduced. The latter topics were central in the pancreas session in the 2024 Banff conference held in Paris (France), and in subsequent consensus discussions.
In this report, criteria for caTCMR where confirmed, but the requirement of underlying stage 1 fibrosis (≥30% of core) was removed to allow for earlier diagnosis. The criteria initially proposed for caAbMR remain unchanged. Ca rejection is associated with increased risk of graft loss and often occurs in patients with repeated or untreated rejection.
Criteria defining the indeterminate (IND) category were expanded to include lobular changes below rejection thresholds. Understanding common clinical scenarios coinciding with IND biopsies, allows for more refined etiological diagnosis and better therapeutic options.
Systematic evaluation of CD3 and CD68 immunostains contributed to more accurate diagnoses and was essential in 9.5% of cases, facilitated the diagnosis in 49% of cases and helped rule out TCMR in 80% IND biopsies.
The working group expects that the current recommendations and refinements can enhance the applicability and reproducibility of the pancreas schema.
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Clinical feasibility and utility of the classification
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Thank you all very much for your interisting and helpful thoughts!
Below you will find replies to hopefully most of the comments:
- „In the footnotes to the Rejection Grading Schema, lymphocytes without ductal epithelium damage is listed as insufficient for the diagnosis of ACMR. Should it be mentioned that this is acceptable in the Indeterminate category?“
o Single intraepithelial lymphocytes without reactive epithelial changes would not be sufficient for an indeterminate diagnosis and accepted as a normal finding
- The “Indeterminate” category: what is “subtle focal or multifocal or mixed interstitial inflammation”? This will be difficult to use as a guidance.
o The most important part here is that it is „subtle focal or multifocal mononuclear or mixed interstitial inflammation not sufficient for a diagnosis of active TCMR“. So anything that is more than normal and does not fulfill the criteria of TCMR or AMR. Clear cutoffs have so far not been defined or validated. Further research is needed.
- I find the definition of Chronic Active Rejection to be unclear. I see that the concepts overlap in some areas, making it complex to establish a definitive diagnosis in certain cases
o The chronic active issue is surely difficult, but it reflects the progressive deterioration with increasing fibrosis in some tranplants that can be seen over time. In the update of the report we tried to clarify some of the points and give some examples. Surely borders between active and chronic active rejection are fluent and sometimes it is difficult to assign a clear diagnosis. A good description of the morphology including the stage of fibrosis and degree and activity of inflammation will help to guide clinical decision making in ambiguous cases.
- I agree with the fact that the classification for CA is ambiguous and from the clinical point of view I wonder how useful it is. Wouldn’t it be more appropriate, like it as been proposed in kidney, to move into an activity and chronicity index within in the spectrum of TCMR, AMR or mixed rejection. That would be more helpful to decide treatment for example.
o Activity and chronicity indices are surely worth thinking about, but cannot be generated without further validation at the moment. As in the kidney it would probably make sense to develop such tools to accompany but not replace the diagnosis according tot he Banff classification.
- In the manuscript it is written “Early biopsies (>90 days post-transplant)” where it should be ≤ 90 days like in figure 4 , shouldn’t it?
o Absolutely! Thank you!
- Given the heterogenicity of the diagnosis, and the good results of C3d and CD68 staining, shouldn’t it be emphasized the need for these stainings to rule out active rejection?
o The use of CD3 and CD68 is very helpful indeed and we would encourage to perform the staining in all ambiguous cases. We hope that including a whole section on the topic in the report helps to encourage pathologists to apply the stainings more frequently.
- Is there a difference in response to treatment in IND for cause or protocol biopsies?
o We don´t know for sure, however, based on the few studies available and referenced in the manuscript, it appears that in contrast to active TCMR biopsies that uniformly respond if treated in a timely manner, IND biopsies do not have a predictable response to treatment independently of the clinical setting. This is likely due to the heterogeneous causes of IND biopsies.
- I also found the table description of caTCMR confusing. "Concurrent active T-cell mediated rejection should be separately diagnosed ..." - was this referring to concurrent ABMR as the footnote (b) seems to be alluding to mixed rejection.
o In fact all scenarios are thinkable: AMR and/or TCMR which can be both active and/or chronic active. All components of the rejection, for which diagnostic criteria are fullfilled should be separately reported. The section on reporting of chronic active rejection was modified in the update of the report and some examples added in the hope to improve clarity.
- I don't think cTCMR or caTCMR is 'inactive'. The features all indicate involvement of immune cells - it's a term to help define activity and chronicity. If there is scarring post-rejection (which has resolved) - it'll be captured in the fibrosis indices. The cause of fibrosis can be elaborated but need not be the focus of the biopsy report if there are no features of rejection or immune activity to be useful for the transplant physician.
o Here we absolutely agree. We would also not use the term cTCMR as a diagnostic category and the term „active“ in chronic active is meant to highlight the progressive nature of the reaction. We tried to clarify this in the updated section on chronic active rejection.
- also just a suggestion for alternative version of the table (ignore if you don't feel this is useful)
o Thank you very much. This table looks great, we will see whether we can include it.
Thanks again and also to Cinthia who also gave input in this discussion !
also just a suggestion for alternative version of the table (ignore if you don't feel this is useful)
I also found the table description of caTCMR confusing. "Concurrent active T-cell mediated rejection should be separately diagnosed ..." - was this referring to concurrent ABMR as the footnote (b) seems to be alluding to mixed rejection.
I don't think cTCMR or caTCMR is 'inactive'. The features all indicate involvement of immune cells - it's a term to help define activity and chronicity. If there is scarring post-rejection (which has resolved) - it'll be captured in the fibrosis indices. The cause of fibrosis can be elaborated but need not be the focus of the biopsy report if there are no features of rejection or immune activity to be useful for the transplant physician.
Yes, this topic is really difficult. We have advanced significantly with the process of defining with accuracy the histological features. We need to keep working on the clinical applicability and impact of this diagnosis.
Concerning IND biopsies
Given the heterogenicity of the diagnosis, and the good results of C3d and CD68 staining, shouldn’t it be emphasized the need for these stainings to rule out active rejection?
Is there a difference in response to treatment in IND for cause or protocol biopsies?
In the manuscript it is written “Early biopsies (>90 days post-transplant)” where it should be ≤ 90 days like in figure 4 , shouldn’t it?
I agree with the fact that the classification for CA is ambiguous and from the clinical point of view I wonder how useful it is. Wouldn’t it be more appropriate, like it as been proposed in kidney, to move into an activity and chronicity index within in the spectrum of TCMR, AMR or mixed rejection. That would be more helpful to decide treatment for example.
In addition to concerns about the difficulty with the diagnosis of chronic active rejection, we have received the following additional comments from A. Mikhailov that need to be addressed in the revised version.
:• In the footnotes to the Rejection Grading Schema, lymphocytes without ductal epithelium damage is listed as insufficient for the diagnosis of ACMR. Should it be mentioned that this is acceptable in the Indeterminate category?
• The “Indeterminate” category: what is “subtle focal or multifocal or mixed interstitial inflammation”? This will be difficult to use as a guidance.
• Do we know how much residual inflammation can we expect in follow-up biopsies done 2 weeks, 1 month etc. after the index biopsy? Knowing this would be very helpful
I find the definition of Chronic Active Rejection to be unclear. I see that the concepts overlap in some areas, making it complex to establish a definitive diagnosis in certain cases
Chronic active rejection diagnosis and interpretation of active versus chronic changes continues to be an issue with pathologists and some non-pathologists. This section of the manuscripot will need to be clarified significantly.
Comment from H. Mesa
Regarding the examples for reporting chronic active TCMR.
Example 1: No evidence of active TCMR. Ca TCMR (stage 1) consisting of chronic transplant arteriopathy and focal lobular changes; overall inactive inflammation
I still find this confusing and contradictory: Ca (chronic active) TCMR overall inactive? It’s hard to understand the concept of chronic active, overall inactive. Is this really what you’re trying to say?