2. On December 6, 2021, a
Halloran lightening bolt of
out the blue!
“Who identified tubulitis as a marker of
TCMR? I learned about it from you. It is
a fundamental discovery! It outperforms
many of the gene transcript sets as a
predictor!” Phil said.
I poured over many editions of
Heptinstall’s textbook. Kendrick Porter’s
chapter mentioned finding lymphocytes
in urine during rejection but tubulitis
3. The fundamental discoveries of the Banff
Classification were foreshadowed in the clinical
trials of cyclosporine between the mid 1970s
and early 1980s. In 1983 cyclosporine received
FDA approval. That year James Burdick and I
started a protocol biopsy study of cyclosporine
treated patients biopsied at 1 and 4 weeks. In
1985 we described tubulitis in those biopsies as
“Mononuclear cells lying between tubular
epithelial cells, or beneath them just inside the
tubular basement membrane.” This became the
crucial backdrop against which the Banff
Classification was created 6 years later.
4. In the original Banff Classification
article in KI in 1993 Editor Tom
Andreoli thought the specificity
of tubulitis for acute TCMR and
the nonspecificity of the
interstitial inflammatory infiltrate
was so important that everything
about that should be put on the
first page and that was done.
5. In the original Banff
Classification article in KI in
1993 Editor Tom Andreoli
thought the specificity of
tubulitis for acute TCMR and the
nonspecificity of the interstitial
inflammatory infiltrate was so
important that everything about
that should be put on the first
page and that was done. That
paragraph begins and ends with
tubulitis! We described the
nonspecificity of interstitial
infiltrates in 1984 and the
specificity of tubulitis in 1985
6. Today and into the future tubulitis
remains just as important as ever. It
figured prominently in the the three
articles in the March 2022 issue of
AJT with cover graphic “Acute T
Cell-Mediated Rejection: Still a
Worthy Opponent”. For decades
tubulitis has been the focus of
morphometry programs, and so
now the best machine detection
systems use a combination of
hand-crafted features, texture
analysis, and machine learning, see
recent March and May 2022 Banff
Digital Pathology Working Group
videos with Ulysses Balis
https://youtu.be/KkVS7Hucvh0
https://youtu.be/uwodKQIamkE
7. The success of the Banff Classification resulted
in the adoption of “biopsy proven rejection” as
an end point in clinical trails, and of identifying
a central pathologist for those trials. Thirty
years ago, in 1992, clinical trials began with
mycophenolic acid with me as the central
pathologist. For the next three decades I saw 3-
7 times more biopsies from clinical trials than I
did from local patients, with many different
clinical trails of different compounds. There
were informal educational uses of the digital
images for fellow training in 2010 and 2019
when the fellow and I were in the same room
but only this year have we included such
teaching into the formal contracts. It took 30
years to accomplish that! We cannot identify
the clinical trial involved. “A clinical trial.” If we
wanted to publish cases that publication would
have to be after the clinical trial itself is
completed and published. We are talking years,
but unrecorded rounds presentations like this in
the interim are OK.
8. For today I am going to do the presentation
with screen captures from the Aperio slides
to maintain confidentiality. This is only the
second time in 30 years presenting clinical
trails pathology in these rounds, and I want
to see how these early presentations go
before going the full Aperio route at some
point in the future. The frame around the
live Aperio image tends to give away the
origin of the case.
9. The potential similarity of this recent case to
case 7 in the original 1991 slide set is
intriguing and emphasizes again two pivotal
dates in the past. 1983 when the FDA
approval of cyclosporine ended the “wild
west period” of transplantation and ushered
in the current period of transplantation
success, and 1991 when the Banff
classification ushered in the modern era of
transplant pathology, where the biopsy as
gold standard is always an elusive goal,
never quite realized, but with acceptance of
biopsies as the “next best thing” to a gold
standard.