The Processes and Challenges of the WHO Blue Books

October 26, 2021

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October 21, 2021

Yale Pathology Grand Rounds

Ian Alexander Cree, BMSc (Hons), MB, ChB, PhD, FRCPath, ALS

ID7075

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00:04Get started then.
00:40Hi everyone, welcome to today's grand round.
00:44Our speaker today is Dr. Ian Cray.
00:50Ian is a pathologist and an
00:54international civil servant.
00:56Is based at the International Agency
00:59for Research on Cancer in Lyon,
01:03where Ian is the head of humor
01:07classification responsible for all
01:09the blue books that we keep buying.
01:13And he is also head of evidence,
01:15synthesis and classification.
01:20He ended his undergraduate education at the
01:25University of Dundee and then his MBCHB,
01:30followed by a PhD in Immunology
01:33at the same place, and even then
01:38finished his pathology training.
01:40He was trained as a general
01:43pathologist at the same place,
01:45becoming a consultant
01:47pathologist in his alma mater.
01:51But since then,
01:52Ian has moved several times his
01:55previous positions held were senior
01:58lecturer and at the Institute of
02:03Ophthalmology and Ian mentioned that
02:06his major work was in ophthalmologic
02:09pathology and he got so excited
02:12with it that he was instrumentally
02:15involved with the first blue book
02:19on my pathology and his working.
02:22To bring out the second edition,
02:26or rather the 5th edition,
02:27what would be equivalent to the 5th edition?
02:31He went on to become consultant
02:34pathologist and a professor of
02:37histopathology at Queen Alexandra
02:39Hospital in Portsmouth and then
02:42Southampton in England and then
02:44became a professor of pathology at
02:47University of Warwick and a consultant
02:51pathologist at University Hospitals.
02:54In Coventry and Warwickshire,
02:56and just when he was getting ready
02:59to retire as the British system.
03:02And courageous their sin apologist to retire.
03:06He got an offer from Dublin to help
03:09them publish the new series of Blue
03:13books and become an international civil
03:17servant and of course moved to France.
03:22So just to give an idea that
03:25the series Blue Book,
03:27this is what they look like for those of
03:30us who are not in diagnostic pathology,
03:34and Ian has been involved with the 4th
03:37edition of the skin tumor Blue Book,
03:40the eye tumors and he is on the
03:44editorial board of the 5th editions
03:47of tumors of the digestive system.
03:50Breast humors soft tissue.
03:52In bone,
03:53female genital tract tumors
03:56and thoracic tumors,
03:58Ian's career has been built on
04:01translational path ologist,
04:03and on translational pathology,
04:05and he was involved in developing a
04:09number of molecular diagnostic methods,
04:13and he let you kiss early
04:16Cancer detection consortium.
04:18He has published more than 270.
04:22Papers and more than 150 of them
04:26were as first and last authors,
04:29and has been a coauthor in
04:32more than in about 8 books.
04:35So with that proof.
04:38Brief introduction.
04:40They will let Ian take the floor.
04:43Thank
04:44you very much. I'll start by saying
04:46thank you to to you for inviting me.
04:48It's a great pleasure to be here,
04:50at least virtually.
04:51I'm sorry I can't see the autumn
04:54colors around you and get to see
04:56and meet some of you properly,
04:58but maybe in the future. Who knows.
05:00I'm going to start by sharing my
05:02screen if I may, because I think
05:04that's the first order of business.
05:06Uhm, hopefully you can all see that.
05:09Uh, the.
05:12So this is the point where you have to
05:15shout if you can't because once I put
05:18the presentation on I can't see you.
05:20So I think
05:22we can see it
05:23good. Alright, let's go so.
05:27I was asked to talk about the.
05:30Processes and challenges.
05:31And this is not yet coming.
05:33Sorry though,
05:34it is of The Who blue books and.
05:40It's it's certainly had its challenges,
05:42and one of the challenges
05:44has been the process,
05:45so I think it's a fairly good title,
05:47actually. First of all,
05:48the declaration of interests.
05:50I am a pathologist has been said
05:51and based at the International
05:53Agency for Research on Cancer,
05:55which is a part of the
05:57World Health Organization.
05:58But the opinions I'm expressing
06:00our of course personal.
06:02I'm going to start with this.
06:03This is one of my favorite slides.
06:05Now I have to say it's a picture of Carl,
06:08Aeneas and Linnaeus described the
06:11natural world around us and we still
06:14use the classification that he put
06:16together and published in 1758.
06:19And if any of the blue books are still
06:21knocking around in 300 years time,
06:23I should be extremely pleased.
06:25But I'm afraid I won't be here to see it.
06:28The natural progression,
06:30though of all taxonomies,
06:32is that they evolved.
06:34And the natural our taxonomy of the
06:38natural world is also still evolving.
06:41This was a story from last Christmas.
06:44Nice Christmas story.
06:46Gentoo Penguins,
06:47which all look rather similar.
06:49There were actually two species,
06:52but now there are four,
06:53and that's on the basis of genetics.
06:55And that's exactly the same thing
06:56that's happening to a lot of tumors.
06:58Of course,
06:59where genetic investigation
07:01is proving very helpful.
07:03So taxonomy is the science of
07:05defining and naming groups of
07:08biological organisms on the
07:10basis of shared characteristics.
07:11And cancer classification is also based
07:15on the shared characteristics of cancers.
07:17That's currently mainly
07:19Histology and genetics,
07:20but it also includes things like radiology,
07:23cytology and a host of others.
07:27We take our remit for doing this
07:29from the 10th World Health Assembly,
07:32which in 1957 resolved to continue
07:35work on formulating international
07:37definitions of normal stature
07:39and statistical classification.
07:41The World Health Assembly is the governing
07:44body of the World Health Organization.
07:46It comprises 194 countries at the moment.
07:52I should say that I arc is a
07:55specialized agency of the World Health
07:57Organization and therefore it doesn't
07:59have the whole 194 to deal with.
08:02We've only got 28 and I think some of
08:04us feel that it's probably quite enough,
08:06but we would always like more.
08:09In the 4th edition, the WTO Bluebooks,
08:12which started in the 1960s, UM,
08:15became a synthesis of scientific evidence of
08:19illustrative cases and diagnostic criteria.
08:23They became indispensable to many
08:27pathologists because they gave you
08:30the international standards that
08:32were required to diagnose tumors.
08:35And I think that's where we owe
08:38them a great debt of gratitude.
08:40However, it must be said that
08:42not everybody was pleased.
08:44And those of you that have seen this slide
08:46before, and it has been around a bit.
08:48I got mine from that at Jabot and I'm very
08:51pleased to give her the credit for that.
08:55But here you can see a dinosaur.
08:57It's obviously a gynecological dinosaur,
08:59and it's eating a CNS blue book.
09:02I'm not sure they're actually suggesting
09:04that that guy, any pathologist,
09:05start reporting all the CNS pathologies.
09:07So don't worry too much.
09:09But certainly there were suggesting that
09:11these books were somewhat out of date.
09:14By the time they were published and they
09:16took about three years to publish each book.
09:19So that was one of the challenges the entire
09:224th edition took over 12 years to publish,
09:25so it was a mammoth task,
09:27and one that a smartly small
09:29number of people took on and did,
09:31and we owe them a great debt of gratitude,
09:34of course.
09:36However, we needed to innovate.
09:38We needed to change things,
09:39so there are a number of
09:41innovations for the 5th edition.
09:43And these really fall into three categories.
09:46The first was better governance.
09:48The entire 4th edition was actually
09:50led by just three pathologists,
09:53and that's probably nothing like enough.
09:57I certainly when I was appointed,
09:59didn't wish to try and lead it myself,
10:02and therefore I decided it would be a
10:04good idea to have an editorial board.
10:06And I borrowed from the National Institute
10:09for Clinical Excellence in the UK,
10:11which in its committees has both standing
10:14and expert members and the standing
10:16members are there to provide the
10:18continuity and the overall expertise,
10:20and they're usually
10:21fairly senior individuals.
10:22The experts are there to provide
10:25the hard experts opinion that's
10:28required to make decisions within
10:31health technology assessment.
10:33In the case of Nice or classification
10:36in this instance.
10:37And we try to do what we
10:39do based on evidence,
10:41and that now includes things
10:43like systematic reviews,
10:44which historically pathologists have
10:45not really been involved in very much.
10:49We are about evidence and not eminence.
10:53Expert opinion is still is still
10:57very relevant, but it's not.
11:00It's not of great significance.
11:03It's really important that we.
11:06Have also selection by informed
11:09Bibliometrics and we we we.
11:14We use both author and editor
11:17selection using this process,
11:19which allows us to look at what people
11:22have published and decide what is.
11:25What is is is most fair in
11:27in terms of who to appoint.
11:30It's not a simple process,
11:32it's something we have to do quite carefully,
11:34because clearly we don't want everybody
11:36to come from one country or another.
11:38We want to have a geographical spread as
11:40well as a spread of expertise and experience,
11:43and we try and do that using a system
11:45which we've actually developed called
11:47the Blue Book Expert Selection Tool,
11:50which is a form of cross.
11:54It uses cross referencing to identify
11:57papers published by authors and
12:00who they have Co published with,
12:02so it's a Co citation system.
12:05I'm not going to talk about that much more,
12:07actually,
12:07'cause it's it's quite complex.
12:10In terms of quality.
12:13Uhm?
12:14We've got a hierarchical classification
12:16using Linnane principles,
12:18and that gives us some tremendous scope
12:22to collapse and expand particular
12:26diagnostic categories quite easily.
12:29In terms of quality,
12:30I'll talk about that a little bit more later,
12:32and we've certainly upped the quality
12:34of images we tried to ensure that
12:37references are up to date and relevant,
12:40and there's quite a bit more.
12:43We get our epidemiology from epidemiologists,
12:46which is a bit of a novel turn,
12:48but the epidemiologists in arc and
12:50there are a lot of them were fairly
12:53scathing about the pathologist's
12:54ability to do this, so we said,
12:56well, why don't you do it?
12:58And luckily, they said yes.
13:00We try to incorporate new
13:02information whenever we can,
13:04and we harmonize topics across series,
13:06particularly neuroendocrine neoplasms,
13:09humita,
13:09lymphoid disease and soft tissue tumors.
13:16We've improved the speed with which
13:18we can produce the books by just
13:21taking a process management approach.
13:23It's lean management, really.
13:26So we've tried to improve things
13:29at every stage by setting deadlines
13:31and trying to meet them and also by
13:35improving the way in which we handle
13:38matters in an automated fashion as far
13:41as possible within the software that
13:44we used to produce the whole thing.
13:46We have a website that allows easier
13:49access to references to whole slide
13:51images and it now allows notes and
13:53it also allows feedback so that
13:56then allows those that are part
13:58of the community that use and buy
14:00the books and the website too.
14:05Come back to us in a much easier way
14:07and a much more organized way too,
14:09which is probably better.
14:11So the 5th edition books look
14:13a little bit different.
14:13The 4th edition,
14:15they've got a slightly modernized cover.
14:17There are slightly lighter blue,
14:18so you can tell which is which on the shelf,
14:21and there's quite a lot of thought
14:23gone into the design of both
14:24the cover and the spine.
14:26We've kept the nine photographs in the
14:28front 'cause that makes them instantly
14:30recognizable as a WHO blue book.
14:33And we've gone for a two column
14:35format inside.
14:36So the photographs,
14:37which were rather small in the previous
14:40edition in a three column format
14:41and now on the whole much larger,
14:44and that certainly helped.
14:46We've incorporated clinical photographs.
14:48We've incorporated epidemiological
14:50graphs as well. Uh, diagrams.
14:53So there's a wealth of information in these.
14:56Volumes,
14:57but I should say at the outset
14:59they are not textbooks.
15:01This is a taxonomy would be describing
15:04the criteria for each tumor type,
15:06which results in that classification.
15:08We're not trying to tell you
15:10how to diagnose them,
15:11that's something that a textbook would do.
15:14In terms of who?
15:16Therefore,
15:17the other thing is that they're
15:19not just for pathologists,
15:20this is the taxonomy of cancer,
15:22and just as a gardener or a.
15:27A farmer will be interested
15:29in the plants on their land.
15:31People with different ideas of of
15:33what they want are quite capable
15:36of looking at the same taxonomy
15:38and getting something from it.
15:40The doublet show blue books then
15:42provide a definitive evidence based
15:44classification of all cancer types to
15:46enable diagnosis and research worldwide.
15:51And our diagnosis of cancers
15:54and other tumors underpin
15:56individual patient treatments.
15:58Of course, that's why we do it,
16:00but they also underpin research
16:02into all aspects of cancer,
16:04causation, prevention and therapy.
16:06And then they also underpin education.
16:09So it really is the basis of
16:10an awful lot of what we do.
16:14In terms of the classification turns,
16:16we use usually A5 level
16:20classification with subtypes.
16:22As a further level.
16:24So we start off, usually with sites,
16:27for instance stomach.
16:29We then have a category which is
16:32often lineages based epithelial plasm,
16:34something like that and then a
16:37family or class which in this
16:39example I've given as abnormal other
16:42pre malignant neoplastic lesions.
16:44We might separate those and some other
16:46volumes and then a type would be adenoma.
16:49So you'd expect to see gastric
16:52adenoma in the diagnosis perhaps.
16:55And then the subtype, UM,
16:58would be public land in this example.
17:01Variant is not a word.
17:03We try to use anymore within the blue books.
17:07In terms of the Histology or
17:09what is now called the subtype.
17:12The reason for that is partly because
17:14it's been somewhat hijacked by others.
17:16It's used variably by geneticists and
17:19by others to describe variations that
17:21may or may not be part of the classification.
17:24So we've tried to avoid it where possible
17:28and deal with it when we absolutely have to.
17:32We haven't, though I should say,
17:34switched from calling mutations as you
17:36may very well know them sequence variants,
17:40which is what most geneticists would do now.
17:43In terms of staging grade,
17:45those are dealt with separately
17:48within the books.
17:49Honestly, the early sort of
17:51points that we realized was that.
17:53Your view of the classification really
17:55depended on what you were doing.
17:58So if you were a geneticist or a histo,
18:00pathologist or radiologist,
18:04you looked at things very differently.
18:06And that's a multidimensional problem
18:09and it's very hard to put multiple
18:11dimensions into a two dimensional book.
18:14So we decided to make it slightly easier
18:17on ourselves by having a database.
18:19So the classification is now a database.
18:22It's a relational database and it means
18:24that we can now use the headings for
18:28each of the tables to develop the two
18:31dimensional layout you see in the books,
18:34and that's why you will see
18:37things like etiology unknown.
18:40It's not because we didn't.
18:43Yeah,
18:44we didn't leave etiology Alex because
18:46there was nothing to put in there.
18:48We actually have to say something for
18:51each of these headings in the book.
18:53We don't, uh.
18:57Make any distinction underneath these
18:59headings so that the open bullet points are.
19:03You can be used or not used as as
19:05people wish and you'll see them
19:07in some of the larger sections,
19:09particularly where it breaks up the text,
19:11but you won't otherwise see them at all.
19:16So we start off with the definition.
19:17The definition now has to be less than
19:20100 words and it has to define what
19:23something is and not what it's not.
19:25And it has to be usable by
19:28people outside pathology.
19:30Uhm, because it is used on its own,
19:32it's used for instance,
19:34with the ICD 11 codes.
19:36I won't go into coding 'cause
19:37that is pretty specialist,
19:39but suffice it to say that
19:41that we have the International
19:43Classification of Diseases on koleji.
19:46Uhm, which is used largely
19:48by cancer registries,
19:49and we have the International
19:51Classification of Diseases Version 11,
19:53which is the new one that's taking
19:56over from ICD 10 at the moment.
19:58And it's still really under development.
20:02We give related terminology and
20:04we divide that into two types,
20:07acceptable and not recommended.
20:09And that's because we don't want
20:12to stop people doing things.
20:14It's not our role,
20:15but it's certainly necessary to
20:17say what is a good idea and what
20:20perhaps isn't such a good idea.
20:22We list subtypes and we described
20:24them under whichever category they
20:26all categorization they come into.
20:29So if it's a histological
20:30subtype comes under Histology.
20:31If not,
20:32it might be a genetic one described
20:34under the molecular pathology.
20:38The clinical features and radiology come
20:40next and we put them together because
20:42they seem to fit fairly well that way,
20:44at least in in the first book we did,
20:47which was in digester.
20:49Uhm, epidemiology.
20:50I've talked about already and etiology.
20:53We covered the causes and this
20:56predisposing factors going here so
20:58that the predispositions genetic
21:00predisposition would go in there.
21:03In terms of pathogenesis,
21:05that is largely these days molecular,
21:08but we do try to make sure that we cover
21:11other other parts of that as well.
21:13A macroscopic appearance in
21:15histopathology probably needs no
21:17introduction to this audience,
21:19but it has all the usual things
21:21you'd expect under there.
21:22We try to have differential
21:24diagnosis at the end,
21:25which is very helpful to to
21:28many pathologists I know.
21:30In terms of cytology,
21:32that is now being dealt with,
21:34in addition to the blue books as
21:36a series of reporting systems,
21:38foresighted pathologists and we've
21:40teamed up with the International
21:42Academy of Cytology to produce those,
21:44and I'll show you a mock up of the
21:47cover later in terms of diagnostic
21:50molecular pathology that is restricted
21:52to what you would do in a patient.
21:54So if you wouldn't do another patient,
21:56it won't appear there.
21:57It'll appear on the pathogenesis.
21:59One of the innovations that we have
22:03introduced is the addition of essential
22:06and desirable diagnostic criteria.
22:09And the reason we've done that is
22:12because in the previous 4th edition
22:14it was sometimes quite hard to
22:16find out which were the essential
22:19features that you needed to see in
22:21order to make a diagnosis or to
22:23classify tumor within a certain range.
22:26And that's something that we felt was.
22:29It was a good idea to actually write down,
22:31so that's what we've tried to do.
22:32It's quite a challenging experience,
22:34and some of you I know in this
22:36room have had it.
22:38We use the UICC staging system
22:41because we are international.
22:42This is the international staging system.
22:45But UICC and AJ CC work
22:47very closely together,
22:49so if you're using the AJC,
22:51it's the same thing.
22:53In terms of prognosis and prediction.
22:57We talk about prognostic factors
22:59and predictive biomarkers in some
23:01detail in certain tumor types,
23:03where that's really important,
23:04and that's an increasing number.
23:05Of course,
23:06and then we're developing links
23:08to other resources which will
23:10mainly go on the website,
23:11and that's particularly to the international
23:14collaboration for cancer reporting.
23:16CAP is one of the founding
23:18members of that organization,
23:20as is the Royal College of
23:22Pathologists and many others,
23:25and.
23:26It produces the structured reports which
23:29depend very heavily on the blue books
23:33and the staging resource is produced by UIC.
23:37In terms of numbers,
23:38we have roughly 200 people
23:40on the editorial board,
23:43between the standing and the expert members,
23:45or will have by the end of the series.
23:48The authors are really need to
23:50update that figure because we've
23:51already hit two and a half thousand.
23:53Uhm, so it's a it's a very big project,
23:57this one and it has a lot of
23:59people involved in it and we're
24:00extremely grateful to all of them.
24:02It's a it's a mammoth task and it has
24:06enormous impact for patients particularly.
24:10In terms of subscribers,
24:13we think we have about 60,000.
24:15They are mainly pathologists,
24:17but not entirely probably
24:19around 8590% pathologists.
24:22And if you're anything like me
24:24when you reach for your blue book,
24:25it's not there because somebody borrowed it.
24:28And therefore we think we've got a lot more
24:31users than we have actual subscribers.
24:33Uh, the whole team is the whole thing,
24:37is run by a small team of people in
24:40Leon and and there are twelve of us
24:42and it's it's great to have them there.
24:45It is possible to join us.
24:47We have a number of fellows that joined us
24:49from time to time and visiting scientists.
24:52So if you've got the opportunity
24:54and you'd like to do it,
24:56we can fit a couple of people in,
24:57usually into the office space we have.
25:02And it would be lovely to welcome
25:04people from Yale if we could.
25:05In terms of what we've done already,
25:08well, we've published digestive breast,
25:10soft tissue and bone female
25:12genital and thoracic tumors.
25:14The central nervous system volume
25:16is about to be stitched together in
25:19from the individual chapter proofs
25:21and it will go to the printers
25:23on the 12th of November.
25:25So it will appear on the website,
25:27probably towards the end of
25:29this month as well.
25:31In terms of the pediatric tumors volume,
25:34that is massive.
25:36It's the equivalent of two books,
25:38and it needs to be coordinated
25:40with quite a lot of the others,
25:42so it's proving quite a tough one to do.
25:44And and we've got the draft,
25:46but we haven't met yet.
25:48Managed as yet to get it through technical
25:51editing, so it is a bit delayed,
25:52but it is on its way.
25:55The urogenital male genital
25:57tumors is also impressed.
25:59That is with the technical editor
26:01at the moment and it should come
26:03out relatively early next year.
26:05I hope within Q1 or possibly Q2.
26:09In terms of the head and neck and the
26:11endocrine near endocrine and endocrine,
26:13they are being edited at the moment's ready
26:17for technical editing early next year,
26:19so they should be out sometime
26:22over the summer.
26:23And then the humours of lymphoid
26:25tumors volume is being written.
26:26Uh,
26:27and then we're about to start
26:29the skin and the I.
26:30We set our timescale for doing things
26:33at the beginning of the process so
26:35that that we could get the whole
26:37thing done within the five to six
26:39years that we felt was optimal
26:41and and that was backed up by the
26:44findings of a large survey that I'm
26:46sure some of you participated in.
26:48And again, thank you for doing that.
26:50And we're going to finish the whole
26:52series of the 14th volume on genetic
26:54tumor syndromes because that's
26:56becoming increasingly important that
26:57we felt we could not ignore that.
27:01The website now has a new look,
27:05and if you haven't seen it,
27:06I'd recommend getting onto it.
27:08If you can, you can preview it before
27:10you have to pay a subscription for it.
27:13It is a subscription website and we
27:15do sell the books and the reason for
27:18that is that this is a not for profit
27:20exercise that is completely funded by
27:23sales of the books and and the website.
27:27Now, yes, we could apply for grants and
27:30we could try and find external funding.
27:33But then that external funding would
27:35have a say in how we did things,
27:37and that's not something we want
27:39at the moment.
27:40This is essentially in the
27:42hands of its subscribers,
27:44so that's 60,000 people and it's
27:48very hard to make it anything other
27:50than what it is as a definitive
27:52classification on that basis.
27:57The actual write up for each tumor
27:59looks very similar to the book.
28:00It's just a single column across a text,
28:02but it's the same text, the blue numbers
28:05there are actually pub Med ID's,
28:07so when you click on one of those,
28:09a hyper link takes you straight to pub
28:11Med to the reference and to the evidence
28:14we've quoted for that particular statement.
28:16We also have whole slide images
28:18and in the breast, but we have
28:21whole slide images for every tumor.
28:23And when you click on it,
28:25you get a legend just as you
28:27would for anything else,
28:28and then you get into the slide and then
28:31you can go to very high power view.
28:33So I was asked to talk about
28:36the challenges and.
28:38I expected some of them and the
28:41expected ones included the fact that
28:43we needed to produce these volumes
28:45faster without compromising quality.
28:47We knew that was going to be
28:49something that was important.
28:50We also knew that whole genome
28:52sequencing was coming into mainstream
28:54diagnostic practice for some things,
28:56and XM sequencing for others.
28:59We knew that there was a lot of
29:01genetics that we had to get in.
29:03We kind of thought artificial
29:04intelligence probably a little bit
29:06too early for the 5th edition,
29:07but it has actually come into
29:09one or two points already.
29:11And it's certainly set to do more.
29:14We did think that perhaps radiologists
29:16were trying to take over from
29:18pathology in terms of some diagnostic
29:20entities that hasn't really happened,
29:22but we're very pleased to say that we
29:24do have a radiology Advisory Board
29:26that gives us an enormous amount of
29:29support in making sure the radiology
29:31within the books is as good as it can be.
29:34The radiologists actually
29:35don't have anything like it,
29:36so they're really quite interested
29:37in what we're doing.
29:40There was some unexpected stuff too,
29:41of course. Look, the confusing terminology
29:45within pathology is something that
29:47most of us have lived with and dealt
29:49with for most of our working lives,
29:51but we did have some really.
29:54We do have some really good ones and
29:55we are trying to reduce the confusion
29:58wherever possible because it does
29:59impact on patients occasionally.
30:01The best one we came across was,
30:03I think, in the digestive volume
30:04and it was this one inflammatory
30:07pseudo tumor like follicular stroke
30:09fibroblastic dendritic cell tumor.
30:11And all of us in the room kind of looked
30:13at one another and said, what is it?
30:15And and then looked at John Chan,
30:17'cause he's always got the answer.
30:18And and on very kindly turn around and say,
30:21well, it's an EBV positive
30:23inflammatory dendritic cell sarcoma.
30:25So we said, well, why did we call it that?
30:28And the answer was that we did,
30:30so it's one of the very few that we've
30:33actually taken essentially outside
30:36the system and made a change because
30:38we felt the name is just impossible.
30:41Uhm, we have a problem with Mitoses
30:45and the major problem there.
30:47I'll show you in a moment,
30:48but it's to do with standardized
30:51international units.
30:52We had committed very early on
30:55to use HGVs notation,
30:57so the huger notation for genes,
31:00mutations, fusions, rearrangements,
31:02alterations and sequence variants.
31:05And we said that we would do this.
31:08It proved to be quite a challenge,
31:10because although molecular pathology
31:12has become very common in some settings,
31:15in others, it is more challenging.
31:20It turns out that that we have some
31:22problems in terms of counting as well,
31:25particularly bases and histones,
31:27and we've had to publish a paper on
31:30that to produce a notation that works.
31:34Uhm,
31:34and then of course we have this
31:36problem of whether we call things
31:38variants or subtypes and what's
31:40histological pattern when it's at home.
31:42So there have been a few things and
31:45I'll go through a few of them just now.
31:48One of the first things though,
31:50was to think about evidence based pathology.
31:55When in the 4th edition, the books
31:58are essentially a consensus document,
32:00a consensus statement of experts and
32:04about 30 to 40 experts involved in the
32:08meeting that would produce the consensus
32:10based on what authors had written.
32:12And the question really in our minds was
32:14whether this was eminence or evidence.
32:16And the answer is it probably is evidence.
32:19It certainly is evidenced because
32:21those experts are expert for reason.
32:24Uhm, but here you've got someone
32:26who is extremely eminent.
32:28The future King of England.
32:30But I'm not convinced that you
32:31want him staring at a microscope
32:33looking at your biopsy.
32:34Or mine for that matter.
32:37In terms of of confusing terminology.
32:40I've already mentioned one.
32:42I'm going to just select one here
32:44and it's pseudo tumor.
32:45That's about halfway down.
32:46It's a term used to refer to
32:49any number of pathologists,
32:50both benign and malignant,
32:52that may produce a mass.
32:54It's imprecise,
32:55it's not a good term,
32:57and we've tried to extract it from
32:59the books and over nearly succeeded.
33:01There is one in one of the books.
33:03For those of you that want to
33:05go looking for it.
33:06But there are other things here
33:07that we've known for a long time.
33:09Things like carcinoid,
33:11which is potentially imprecise as well,
33:14but is still very much used clinically in
33:17the lung field and impossible to change.
33:20Certainly in this edition.
33:24In terms of assessment of mitoses,
33:26this was something that I first
33:28came across nearly 40 years ago.
33:30And I was really surprised to
33:31have to publish on it again.
33:33I have to say. Uhm?
33:37First of all, what do you call it?
33:39Well, it's a mitotic count.
33:40When you do it on a microscope,
33:42nearly always.
33:42And it's really a density measurement.
33:45So you are expressing the number term
33:48of mitoses per millimeter squared.
33:50Not pleased high power field
33:52as I'll show you in a moment.
33:55The mitotic index would be the
33:57number of mitosis is expressed
33:58as a percentage of the number
34:01of neoplastic cells present,
34:02and you'd have to count hundreds
34:04of cells in order to do it.
34:06It's definitely one for the artificial
34:08intelligence and and not for the human,
34:10I would suggest.
34:12Mitotic rate is actually the
34:14rate at which cells are entering
34:16mitotic phase of the cell cycle,
34:19expressed as a percentage
34:20of cells counted per hour.
34:22So it has a time in it.
34:24And that's not something you can
34:25really do in a form and fixed.
34:28Specimen.
34:28So in practice,
34:30pathologists use mitotic count but we
34:33often get the name and the numbers wrong.
34:36Why do we get the numbers wrong?
34:38Well,
34:39historically,
34:39we've tended to use high power fields,
34:42ignoring the fact that between microscopes,
34:45high power fields can differ by up to
34:48six times even at the same magnification.
34:51And the switch to digital
34:52pathology is actually not helped.
34:53It's paint things worse because
34:55the 400 times fields in digital
34:58systems are rectangular and
35:00they also vary in area and they
35:02can vary quite a lot in fact.
35:05So the potential for error is quite
35:07considerable and at times that could
35:09affect patient care or even diagnosis.
35:11It's solved really by the use of
35:15standardized international SI units,
35:16so size does matter and it's millimeters.
35:20So we recommend counting features
35:22like mitoses per millimeter
35:24squared with an indication of the
35:26area to be counted and the method
35:28used which can be hot spot or
35:30average to obtain the results.
35:33These kind of graticule's on slides
35:35are actually available very freely.
35:37You can get them from Amazon
35:39for about $13.00 each.
35:39If you haven't got one and like one
35:42there should be one knocking around
35:43the department somewhere I'm sure,
35:45or possibly several and.
35:48The Convention is to use a 40 times
35:52objective, but if you use a 10
35:54times IPS or a 12 1/2 times IPS,
35:56of course you'll get something
35:58different and it's pile squared.
36:00Calculate the area.
36:01You only have to do it once
36:03for your microscope.
36:04I always had it on a sticky label on
36:05my microscope when I was reporting
36:07and it was something that I
36:10referred to virtually all the time.
36:13In terms of counting mitoses as well,
36:16it's important to know whether you're
36:18doing an average or random count,
36:20which may not be all that random
36:22unless you use a random number
36:24generator to do it properly,
36:26or a hotspot method and the hotspot
36:29North method is what is generally used,
36:32so these are contiguous.
36:36If. Microscope fields around a hot
36:39spot where you found a lot of mitoses.
36:43It's a little bit hit and miss,
36:45but it's better than most other
36:47things and it's been shown to
36:49be in various publications.
36:53There are quite a few examples
36:55here of of tumors, and this is only
36:57looking at the first few books,
36:58so it's by no means comprehensive,
36:59but it's just a few examples of things
37:01where there is a problem and reassessment
37:04of mitoses is probably worth while.
37:07The other reason why it's worthwhile to
37:09reassess mitoses in in tumors is because
37:12it is very often used prognostically.
37:15And prognosis changes depending on what
37:17the treatment is and if the treatment
37:19of the tumor has changed overtime,
37:21then what was done previously in terms
37:25of prognosis is a bit of a problem.
37:28I used to teach a lot of ophthalmologists
37:31about retinoblastoma and I would
37:33start by telling them all the
37:34things that were bad prognostic
37:36factors for retinoblastoma patients,
37:38and then say at the end of the lecture right,
37:41you can ignore all that once
37:42you pass the exam,
37:43because actually all these
37:45patients get chemotherapy and
37:47they all virtually all get cured.
37:50In fact,
37:50we had one death in eight years
37:52when I was at Morefield,
37:53so it is something that has to be looked at.
37:58In terms of treatment as well as pathology.
38:03We have a little bit of a
38:05challenge with statistics as well,
38:06so most biological data is skewed
38:08and if you use a mean you've got an
38:11error there which you don't have.
38:13If you use a medium,
38:14so the median is preferred by
38:17statisticians with a range because
38:19it's not affected by skewed data.
38:21In terms of genomics and most of you,
38:24I'm sure we will know this, but.
38:28B RAF V 600 E UM is written
38:30in all sorts of ways.
38:32This is the correct way to write it,
38:34and it's really important that that's done.
38:37If it's done with sequencing and
38:39if it's done using an antibody,
38:40then it's still important to say
38:43B RAF P dot V600E if you can,
38:46simply because that then tells everyone
38:49that you're looking at the protein.
38:51And the beer after course of its
38:55approaching should not be in italics.
38:57We very often, though I don't know,
38:59and I'm sure some of you have you
39:01sit in the clinical meeting and
39:03someone asked the B raft positive or
39:05negative on the Melanoma completely
39:06missing the point about mutation.
39:10In terms of histones,
39:11the problem is that the methionine,
39:12the little green one here and gets chopped
39:16off during production of the protein.
39:19And what that means is that the
39:22antibodies are all named according
39:24to the numbering of the protein.
39:26Once the methionine has been taken out
39:29and not what you get on a sequencer,
39:32which will give you a 28,
39:34not a 27 or 35, not a 34.
39:37So we've suggested that instead,
39:39what one should do is put the
39:43histological number if you like in
39:46brackets and the genetics number in
39:48genetics derived number in as you
39:52would normally in a in the system,
39:55and for some reason I've got a
39:57little hyphen appeared there,
39:58which wasn't supposed to be there.
39:59Apologies for that. Uhm?
40:02The fusion genes.
40:03This is literally hot off the press.
40:06This hasn't even got a payment yet,
40:08but it's just come out in leukemia
40:10and it suggests that rather
40:12than the previous notation,
40:13which was very confusing for fusion genes,
40:17we should use a double colon instead
40:20as the current system of using a hyphen
40:25or a forward slash is actually used
40:29in lots of other settings as well, so.
40:33The clever people Hugo came up with,
40:35and Elizabeth Bruford is is one of them.
40:39Came up with this idea of using two colons,
40:41and I think it's going to take.
40:43We are implementing that within the blue box.
40:47If you're interested in genetics are awful,
40:49lot of resource is available.
40:51I would point out variant
40:52validated down here,
40:53which is actually quite a
40:55useful one and we do as well.
40:58Obviously use some of the other things here.
41:01Gene names and gene cards I
41:04use quite a lot as well.
41:06I want to spend the last sort of 10
41:08minutes or so talking about research needs.
41:12Uhm, because we have lots of evidence gaps,
41:14we know they're there.
41:15If you look for the word unknown within
41:18virtually any of the blue books,
41:20you'll find 150.
41:22Also instances of it.
41:24And those are the things we
41:25know we don't know.
41:29In terms of of evidence gaps then.
41:33We have all sorts of things that
41:35have come out of the blue books,
41:36so we can actually say right?
41:38There's a need for more genetic
41:40studies of neuroendocrine tumors.
41:41There's a need for
41:43computational studies of Chi,
41:4467 perhaps of mitotic count.
41:47And we need to know what there is.
41:50So this was a this.
41:52This little list came out of a
41:54meeting on neuroendocrine tumors,
41:55which led to the current classification
41:58of new endocrine tumors,
42:00which has been applied across the series.
42:08I'm a Scotsman and I'm sorry I've got
42:09to give you a little bit of burns,
42:11but there is a translation at the bottom
42:12for those of you that are having a problem.
42:14UM, facts are chiels at winner
42:16Ding a downer be disputed. Uhm?
42:19It's essentially an older version of facts
42:23that are things that you can't dispute.
42:29And. As Donald Rumsfeld put it,
42:32we have known knowns.
42:33We have things that we know we know.
42:36They are straightforward.
42:38They're not under any.
42:41Control the C in pathology or anywhere else.
42:44And there are plenty of those
42:45in the blue books,
42:46and it's sometimes hard to
42:48find a reference for them,
42:49because actually we know that true.
42:52Then there were the known unknowns.
42:55There are things we know we don't know,
42:58and those are the unknowns that I've
43:01talked about in the books so far.
43:03But there are also undoubtedly a lot of
43:06unknown knowns things that we've forgotten,
43:08and a lot of that these days has
43:10come from things like electron
43:12microscopy and ultrastructure,
43:13which is not very fashionable and
43:15and it's quite surprising how little
43:17of it gets into the blue box,
43:19but I have pleased to say that in
43:22the endocrine volume you'll find
43:24that does happen because it's
43:26still there still important.
43:29And then we have the unknown unknowns.
43:30The things we don't know.
43:31We don't know,
43:33and that's something that
43:36really underpins research,
43:38so by looking at tumors carefully
43:41by looking at good well call
43:44it well put together series.
43:47And doing properly constructed
43:49cohort studies with.
43:51Protocols before you start the study,
43:54we can certainly get a lot further
43:56than we do. I think at the moment.
44:00And in terms of improving research quality.
44:03Why should it have lower standards
44:05when it affects gonna potentially
44:06affect huge numbers of patients than
44:09we would accept in clinical practice?
44:11So in clinical practice you would not
44:14accept a sample into your laboratory
44:16that didn't have 4 identifiers.
44:18But you would quite happily accept that into
44:21a research lab with just one in many cases.
44:25Drug approvals require two independent
44:28confirmatory phase three clinical studies.
44:30And what does pathology need?
44:32Well. I think it needs levels of
44:35evidence the same as anything else.
44:37We struggle with systematic reviews
44:39and pathology because they have to
44:42be systematic reviews of high level
44:44evidence and we struggle with getting
44:47hold of independent prospective studies.
44:49Of independent cohort studies
44:51of sufficient size.
44:52Sample size calculations are
44:54rarely stated in pathology papers.
44:56They need to be.
44:58Uhm and withdrawn often to case reports,
45:01small cohort studies or expert opinion.
45:05And that's still evidence.
45:06But it's not very high level evidence.
45:12So to try and answer this,
45:14having put together a process for
45:17production of the classification of tumors,
45:19we thought it was important to try and
45:22support the other side of the coin through
45:25setting up the international collaboration
45:28for cancer classification research.
45:30Uh, what that's about is,
45:32UM, evidence based.
45:34Science about best practice,
45:37guidance about standards and accreditation,
45:41and about information systems as
45:42well to try and reduce the vast
45:45amount of data produced every year
45:47to something that's manageable enough
45:49to pull through into a blue book.
45:52And at the same time we can feedback
45:55the priorities and gaps that we
45:58identify during the bluebooks process
46:00into the sound of that community.
46:03And this seems to have hit a bit
46:04of a chord with a lot of people,
46:06and it is a collaboration of institutions,
46:08not individuals I should add.
46:10So if you would like to join us,
46:13I'm sure that would be a great,
46:15gratefully received a lot.
46:17R and we're very grateful to those
46:20that have helped to set this up.
46:22I'm just going to show you one project from
46:24it and this is called the WCT evidence map.
46:29And it's so WTTW classification of tumors,
46:34obviously,
46:35and what this allows us to do is to
46:39have a tool which allows us to examine
46:42the blue books to identify what the
46:45evidence is and where it's lacking.
46:48This is a stylistic
46:50interpretations of maps you get,
46:52and that's what a real one looks like,
46:53and I don't expect you to read it,
46:55but you can see the blobs that are red,
46:57that I'm afraid is the low level
46:59evidence and the little green ones are
47:01the ones you really want to see Blues.
47:03OK, but green is high level evidence,
47:05and in epidemiology there's
47:07remarkably little for some tumors,
47:09but of course it does depend
47:11on how common the tumor is.
47:12It depends on how much funding
47:14has gone into researching it,
47:16and all sorts of other things,
47:17so it's not surprising.
47:18But we got this,
47:20but I think it's important information to
47:22know so that we know what we don't know.
47:28I'm nearly finished,
47:29but to just break come back to the
47:32site of pathology reporting system
47:34and talk about the mock up for The Who
47:37psychopathology reporting system volumes,
47:40which will be coming out next year.
47:42And as you can see on the front,
47:44we've got the World Health Organization IIRC,
47:47and we've also got the
47:50International Academy of Cytology.
47:52It will look a little bit different
47:54and it will have this. Uh.
47:56I think it's it's probably fuchsia,
47:59but we have a layout editor who
48:02is far better at color than I am.
48:05And she thought that was probably quite
48:07a good idea to have something that
48:09defined it meant that you didn't confuse
48:12it with a blue book on the bookshelf.
48:15We are still very much interested
48:17in working on AI,
48:19and one of the things that is fascinating
48:22to me and it's it's part of some
48:25work I started when I was in Warwick.
48:27Is that there is?
48:29Clearly,
48:30a relationship between the genetics
48:31of tumors and their histopathology.
48:33All there should be.
48:34Because there's a relationship,
48:36but doing the genetics of tumors
48:37and their behavior,
48:38so we should be able to see that
48:40reflected in this to pathology.
48:42It's actually been quite a hard
48:43thing to demonstrate,
48:44but here in colorectal cancer using TCGA
48:47data we've been able to do just that,
48:51and the rock the rock curves here.
48:53The receiver operator characteristic
48:55curves and not too bad the area
48:59under them is about .89 best,
49:02which is almost at the point
49:03where you start thinking about
49:05putting it into practice,
49:07so it may be possible to
49:09identify some of the genetics.
49:12That we need to treat patients
49:14with from artificial intelligence
49:17based assessment of histopathology.
49:20And the other thing it tells us is
49:22which are actually the important
49:24features that we talk about when we
49:27look down a microscope for defining the
49:29characteristics of the patients tumor.
49:34So I'll finish by talking
49:36about how how you can help.
49:38First of all, if you can provide
49:40the evidence by doing research,
49:42that's a big help.
49:44Uhm, and and don't think that when you
49:46published the paper that's the end of it.
49:48It's a question of taking that research and.
49:52Pushing it in the direction where it will
49:55get into practice if at all possible.
49:57And then evaluate the evidence.
49:59Systematic review learn how to
50:00do systematic review properly,
50:01and it's not simple.
50:03You have to learn how to write protocols
50:06for it and assess evidence for bias,
50:11particularly.
50:12And it is quite a challenge to look
50:14through large numbers of papers.
50:17And then if you buy the books or the website
50:20you are actually funding the evidence.
50:21So thank you very much indeed for doing that,
50:24because that keeps the whole thing going.
50:26And finally, let us know what you think.
50:29You can give us feedback on the website.
50:31You can certainly email us a lot of people.
50:34Do I get an awful lot of emails and
50:36we're always open to receiving cases
50:39which are better representative
50:40cases than those in the books.
50:43And if course, if you find any errors,
50:46do tell us because that's
50:48the way we get them fixed.
50:50So in conclusion,
50:51there is a need for all cancer
50:53diagnosticians to contribute to
50:55research to gather the evidence
50:57a patient needs and to evaluate
50:59that evidence for use in practice.
51:02Our diagnosis underpinned the
51:04management of individual patients
51:06Cancer Research and epidemiology.
51:08It's pretty important stuff.
51:11In terms of implementation
51:13of academic research,
51:14pathology is almost unique.
51:18In being able to do that itself
51:21through the WTO classification of
51:23tumors which provide the international
51:25standards for knowing motors,
51:26you can't do that with drugs and you
51:29can't do it with a lot of other things.
51:31Which gulf governments really
51:34are the arbiters of?
51:36So we have a joint responsibility
51:39to ensure the accuracy of the
51:41classification and to fill gaps
51:44and knowledge wherever possible.
51:46So thank you for your attention.
51:49This is the tower which I
51:51are currently inhabits.
51:52It isn't in great condition and the
51:55French government is very kindly building
51:58us a new Center for the International
52:01Agency for Research on cancer,
52:03which will really be a focus
52:05for international Cancer
52:06Research around the world.
52:08And a nice view of of of Lyon in the summer.
52:12And thanks to my team in Leon,
52:15which has worked so hard,
52:18particularly on the 5th edition.
52:20And I'm also grateful to two
52:22distinguished visitors, Valerie White,
52:24from Vancouver and Delani Luca Hattie,
52:28from Colombo, Sri Lanka.
52:31Thank you very much.
52:34Thank you so much Ian,
52:37that it was really a pleasure.
52:40To understand what goes behind the
52:43scenes in producing these beautiful,
52:46extremely affordable and
52:48extremely user-friendly books,
52:50I do have a question.
52:52Since you mentioned how difficult
52:55it is to gather evidence.
52:58So in pathology,
52:59most of the work we produce is
53:04retrospective and observational.
53:06And it's really getting harder to get.
53:11Follow up on many of these patients,
53:13so is there any future for
53:17retrospective and observational data?
53:20Yes, I think I think there is an I
53:24mean the the. The there's certainly,
53:26you know it's very easy when you
53:28look at levels of evidence and you
53:30say Oh dear opinions worth nothing.
53:32Therefore, the review I published last month,
53:33I might as well not have bothered.
53:35I did a case report last year
53:37with one of my juniors.
53:38I shouldn't bother doing that either.
53:39That's not the case.
53:41Actually, my sixth case report my
53:446th postmortem autopsy when I was
53:47training led to the withdrawal
53:49of a drug from the market.
53:50It was dangerous.
53:52So Uhm, case reports matter.
53:55That was a case report.
53:58And you can learn an awful lot
53:59from some case reports.
54:00We talk about the end of one
54:02trial in in oncology quite often,
54:04so there are things that we can do
54:07with case reports with small studies.
54:09Even better if we can band together
54:12internationally and actually get bigger
54:15studies put together on samples that
54:18we collect prospectively with a protocol.
54:21And then we've got a chance of getting
54:24some proper funding into it as well.
54:26And and we probably find we can
54:29go beyond pathology and pathology
54:31is simply the study of disease.
54:33So how we do it?
54:35Doesn't really matter whether
54:37it's with a microscope.
54:39Or an MRI.
54:41Or sequencing device doesn't actually matter.
54:46What we what we need to do is
54:48know what our questions are
54:50and what we were trying to do.
54:52Classification in its own right
54:54taxonomy is actually something that
54:56I think matters and which we can.
54:59We can almost certainly do better
55:02with than we are at the moment
55:05and get people to fund.
55:07So I think the future is
55:10pretty bright actually.
55:11That said,
55:11you can still do an awful lot of
55:13the microscope there, graticule.
55:16Uhm? Thank you, there is a
55:19question posted in the chat.
55:22Is there an electronic
55:24version of these books?
55:25For example, is the database
55:28behind it is available for download
55:31and use in electronic systems?
55:34Is there an API for querying the
55:38latest version of the database via
55:41a public or paid Internet access?
55:45Right, so that that that's a
55:48that's a multiple question.
55:49It's a good one too.
55:51The answer is that it's not easily available,
55:54it is a SQL database.
55:56So theoretically, yes, you can do it.
56:00We've got the, uh, electronic system
56:03going in terms of the website,
56:06so the website is is searchable,
56:08so you can do searches on
56:10the website and it's not.
56:12A sophisticated, not sophisticated,
56:13perhaps as it might be.
56:15But it could become more sophisticated,
56:18and I think we'd be very open
56:20to working with people on that.
56:23In terms of what we have to safeguard,
56:25clearly we have to safeguard the
56:26income of the of the program.
56:28'cause if we don't,
56:29we've got a problem.
56:31But there are.
56:34You know there are examples of where
56:36that's been done very successfully,
56:37for instance Genomics England have done
56:39it with their data so you can access that.
56:42It's just been done as well for a
56:45very large pathology set up in the
56:47middle of England called Path Lake,
56:49which has half a million annotated
56:52whole slide images. So there are.
56:57There are ways of doing it.
56:58The short, the short question.
57:00The short answer though.
57:01Sure.
57:03So I say no more questions and
57:06it's time to wrap up and come.
57:09I would just remind the audience that
57:13you are welcome to volunteer contact Dr,
57:17Cree and volunteer.
57:20In data analysis, or in any way you
57:24think your talents can be used.
57:28I hand over to Doctor Lu our chair.
57:32Yeah, thank you and I will
57:34share my screen now.
57:36Thanks talk to create for your
57:38coming and I I think unfortunately
57:40we couldn't do it in person and
57:43couldn't present you some token
57:45to you know on behalf of the
57:47department and our faculty.
57:48So I think you know we come up with this.
57:53Play, you know
57:55it will mail it will. So this is,
57:57uh, we're not just giving you a
57:59virtual plug, it's real well alright
58:01yeah it will be a real life this is a
58:03picture of that and I hope you know this
58:05we just you know really you
58:08know express our gratitude
58:09and if we are leadership for this,
58:11you know you know great book
58:13which is making such immense
58:15impact on pathology practice
58:18and I think it also this is
58:20just a reminder, you know
58:21we are ready to, you know to work with
58:23you to collaborate. And best wishes for
58:26the next. You know, the 5th
58:27edition of the Blue Book and
58:30thank you very much and saying,
58:31you know, hopefully we can
58:32see you in person sometime.
58:34You know either in your place
58:36or in our place in the future.
58:38Thank you, appreciate and I will say it.
58:40You thanks doctor.
58:41You know Manju Prasad,
58:43you know she this is her
58:45idea. So I'm just kind of presented
58:47her idea in this is great that
58:49you know you know idea to get. You
58:51know they will this you know present.
58:55Thank you very much indeed.
58:56It's been a great honor
58:57and a privilege to be here,
58:58and I've enjoyed talking to
59:00some of you over the afternoon
59:02and my afternoon anyway.
59:04And I hope the rest of the day for you
59:07goes well and I'm sure we will be in touch.
59:10Thank you.
59:11OK, thank you very much.
59:12Thank you.