What Makes the Lymphoid Proliferation Associated with Infectious Agents Unique?

Name: What Makes the Lymphoid Proliferation Associated with Infectious Agents Unique?
Uploaded: 2022-01-14T17:17:25.493Z
Duration: 1 h 5 min 4 s
Description: January 13, 2022 Yale Pathology Grand Rounds Kikkeri N. Naresh, MD

January 14, 2022

January 13, 2022

Yale Pathology Grand Rounds

Kikkeri N. Naresh, MD

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00:00It's my great pleasure to introduce
00:02Doctor Naresh, Carrie to Yale Yale grants.
00:06Naresh completed his Bachelor of
00:08Medicine and Bachelor of Surgery
00:11at Government Government Medical
00:12College where he also received.
00:15Also received my in clinical pathology
00:17he he then did his training in pathology
00:21theology at the prestigious Jipmer Institute.
00:24Nourish began his his anger at Tata
00:27Memorial Hospital where he quickly
00:29rose and banged to become.
00:31Full professor in in pathology,
00:33he moved in 2004 to London,
00:35where he was a professor and a
00:37professor in the cellular and
00:39molecular pathology Imperial Condon.
00:43In 2020 actually move the middle
00:47to pandemic pandemic.
00:48He professor and section head of
00:50pathology in the Clinical Research
00:52Division Vision Hutchinson Cancer Center
00:54with appointment at the University
00:56of Washington Department of Labor.
01:01Now Russia has authored over 250
01:03original manuscripts and use scripts
01:05with on the biology of lymphoma.
01:07Developing new items to improve lymphoma,
01:09lymphoma and the study of the
01:12lymphoma lymphoma microenvironment.
01:14His other research in research
01:15interest in a focus in lymphoma
01:17causing infectious agents which is
01:19the topic of his talk to talk today.
01:21In addition to his extensive scholarship,
01:24nourish has taken on leadership roles
01:25in several roles in several large
01:27internationals including our next edition
01:29of The Who in Hematopathology mythology.
01:32Atlas of Blood Cancer
01:34Genomics which has met him.
01:36Please join please join me in a rush to yell.
01:38Thank you,
01:40thank you Mina.
01:41It's been a pleasure and thanks for
01:43inviting me and it gives me great
01:46pleasure to give this presentation.
01:47Obviously I would have loved to
01:50be there in person but under the
01:52current prevailing circumstances I
01:54think this is the best we can do.
01:57And I chose this topic of lymphoid
02:01proliferations in infectious agents.
02:03Because over a period of time though,
02:05my lymphoma research across many different
02:08types of lymphomas has gone ahead.
02:10This is something which I started with.
02:12My research started with a particular
02:14aspect of Epstein Barr virus in
02:17Hodgkin lymphoma and later on I've
02:19had opportunity to work on post
02:21transplant lymphoproliferative and
02:24then the HIV associated lymphomas
02:26and my interest in infectious agents
02:29and informers has been kept alive
02:31through these research opportunities.
02:34So.
02:41So this was the first work of mine,
02:44which really caught a lot of
02:46attention but also gave me a
02:48very good platform to continue my
02:50research in the field of lymphomas.
02:52And this was when we were looking
02:56at Hodgkin lymphoma and that was
02:57the early time when Eber in situ
02:59hybridization had come into place and
03:01then we were looking at proliferation.
03:02At that time we didn't use Key 67,
03:04we were using something called
03:06proliferation cell nuclear antigen
03:08and thing that struck me was.
03:10That Hodgkin's which worry baby
03:14positive those had a higher P CNA
03:17expression in the Reed Sternberg cells.
03:20And if you can see that those cases
03:23those which were PC and a low had
03:25nearly 50% cases for EBV negative
03:28but those which were PC and a high
03:31most of them worry be positive.
03:33So then we let on to the hypothesis
03:36thinking that expression of PC keeps
03:39maintains the Reed Sternberg cells.
03:41In cell cycle,
03:42although it goes through a cell cycle
03:44called endocytosis or endo reduplication,
03:47but that makes the cells more
03:50susceptible to chemotherapy.
03:51And then we looked at the outcomes
03:53in these patients and patients.
03:55With EBV,
03:56positive Hodgkin lymphoma did
03:58exclude mean much better than
04:01those which worry be negative.
04:03Again.
04:04If you look at subsequent to our publication,
04:07there have been many other studies
04:09which have come from different
04:10parts of the world and different
04:12people have had different reasons.
04:14Some people have in many parts the Western.
04:17You know Western Europe and in the US
04:19people have shown that EBV positive disease.
04:21How about Porter survival?
04:22But in the setting of the developing
04:24country with these patients are all
04:26from India eBay be positive disease
04:28had a superior survival to EBV,
04:30negative disease and also.
04:32And this was independent of patients
04:35age and stage of Hodgkin lymphoma.
04:38We also showed at the same time
04:40that almost 98% I think only there
04:44was only one case out of the 50
04:46cases of pediatric Hodgkin lymphoma
04:48which was even with negative the
04:49rest of the 49 or 50 cases.
04:51Bloody may be positive,
04:53so you may be positive ITI was is
04:55very high in the pediatric setting,
04:57especially in a developing
05:00country like India.
05:01So this was the first one which really
05:04led on to this part of my research and
05:07then I will take you through other areas,
05:10partly from translational research and and
05:13most and quite a lot of clinical aspects.
05:16So if you look at infectious
05:18agents in lymphoid proliferations,
05:20we have a list of viruses.
05:21EBV was the first to be recognized then.
05:23Of course we have the Kaposi sarcoma virus,
05:26or the human herpes type age.
05:28Then hepatitis C and hepatitis
05:30B virus human T cell leukemia.
05:33Wireless one HTLV one and human
05:36immunodeficiency virus or HIV,
05:37but we can't forget the bacteria
05:40which can associated with them for
05:42proliferations like the Helicobacter
05:44campylobacter gorilla and chlamydia.
05:46I'm not going to be discussing these.
05:48I'll primarily restrict my
05:50discussion to ebb and HP,
05:52and partly I will touch on STL.
05:56So if you look at infectious
05:57agents in these disorders,
05:59we have a set of diseases where
06:01the infectious agent is present
06:03within the neoplastic cells.
06:05Classic examples that are EBV
06:07HHV 8 and HTLV one and there are
06:11others where infectious agents are
06:13present outside of the neoplastic
06:15cells like HIV like Helicobacter
06:17hepatitis virus C so on and so
06:20forth where the the tumor cell
06:23itself is not infected by the virus.
06:26And if you look at again,
06:28this is a mix of different types
06:30of lymphoid proliferations.
06:32You have some acute and
06:33non malignant conditions,
06:34like the infectious mononucleosis
06:36we have heard about this and
06:38learned about this for many years.
06:40I'm not going to develop much time on
06:42this and then we have other chronic
06:44and non malignant or polyclonal
06:46diseases like chronic active infection,
06:48multicentric Castleman disease in the
06:50HIV studying and with HV-8 HTLV 1 carriers,
06:54States and associated gastritis.
06:56These are all polyclonal,
06:58non malignant proliferations.
07:00Again,
07:00the question about malignancy and being
07:04non malignant it it gets into a grey
07:07area with with chronic active infection.
07:10We will discuss that and then we
07:12have what we currently call as
07:15polymorphic lymphoproliferative
07:16disorders and these these came to
07:19light and was best exemplified in the
07:21post transplant setting but now more
07:24and more we recognize this across other.
07:26Immune deficiency areas.
07:28Then we also have lymphomas allow quite a
07:32few are full blown lymphomas which many
07:35of these lymphomas look like what one
07:37would see in an immune competent setting.
07:40So if you put them as those
07:43where the informatics agent is.
07:47Is always associated with the
07:49disease is likely be positive.
07:51Diffuse large B cell lymphoma
07:54lymphomatoid granulomatosis fibron
07:55associated DLBCL primary effusion.
07:58Lymphoma so on and so forth.
08:00All these diseases are always
08:03associated with the infectious agent.
08:06Then we have a set of diseases where.
08:09Some of them are proportion of them
08:11are associated with infectious agent,
08:13and the rest are not,
08:14and you have the marginal zone
08:16lymphoma diffuse large B cell lymphoma,
08:18plasmablastic lymphoma, Burkitt lymphoma,
08:20plastic Hodgkin lymphoma,
08:22so on and so forth.
08:23There only a proportion of cases are
08:25in positive for the infectious agent
08:27then you have some cases where very
08:30rarely an association has been found
08:32like you as a follicular lymphoma.
08:34Rare follicular lymphoma sorry
08:36be associated in SL where you
08:38can have a hot skin like.
08:41Richter transformation,
08:42which can be be positive.
08:44Then you also have very rarely.
08:45You can have another dominant optical
08:48lymphoma which is EBV associated.
08:51So I'm going to discuss these
08:53entities and these situations
08:56from different perspectives,
08:57partly and videology and pathogenesis.
09:00Then a few of the aspects of
09:02genomics and and immune aspects.
09:04Then we will spend a bit of time
09:06about apology and immunophenotype
09:08diagnosis or the criteria for
09:10diagnosis how these impact on
09:12classification and how these impact
09:14on outcomes and follow up.
09:17So first,
09:18if we take Epstein Barr virus and Burkitt
09:21lymphoma. This was Burkitt when he,
09:24in his initial descriptions and subsequent
09:26to that we appreciated the Burkitt lymphoma,
09:29the endemic form of Burkitt lymphoma
09:31is seen in a specific Equatorial band
09:35across the world which includes parts of
09:38South America and parts of Equatorial
09:41Africa and most of these are difficult.
09:44Look at the incidents even within Africa.
09:47You will see like places like Nigeria
09:50and Uganda which are within the band.
09:52Just be across the equator between the Tropic
09:56of Cancer and the Tropic of Capricorn.
09:58Those have a very high incidence,
10:00whereas outside of those areas,
10:02like if you look at Namibia,
10:04if you look at Zimbabwe you have a lower
10:07incidence and again this is data from 1988.
10:10If you look at the current data it is
10:14slightly diluted and partly diluted
10:16and partly changed because of the HIV.
10:18Epidemic now in South Africa and Bob
10:21with the incidence might have gone
10:23higher because of the HIV association,
10:25but before the HIV epidemic one could
10:29see that Uganda and Nigeria had a much
10:33higher incidence compared to the rest
10:35of African countries and rest of the
10:37world and in endemic Burkitt lymphoma.
10:41Almost all cases are EBV positive,
10:43whereas outside the endemic areas
10:45only about 25 to 30% REB positive.
10:48So if you look at it association
10:51within Berkman Firma,
10:52it's gotta a differential geographic
10:55distribution like an African,
10:57nearly hundred.
10:57When I say Africa here in Equatorial Africa,
11:00nearly 100% of them are EBV positive,
11:02but as when you come outside of Africa,
11:04it varies from 25% to some areas,
11:07like in South America,
11:08where it can be nearly 50% in like
11:11in Mexico is around 50%,
11:12but in the he could in the belt
11:14that I showed you it can be higher
11:17than 50% and the same thing is true
11:18if you look at Hodgkin lymphoma.
11:20And not all Hodgkin's are associated
11:22with EBV, and if in Africa,
11:24again in the same regions,
11:26you will see most of them on
11:27eBay be positive,
11:28but outside of Africa and some parts
11:31of South America you have variable
11:34incidence of EB within the Hodgkin
11:37lymphoma in the classic Hodgkin lymphoma.
11:40So what all these things do tell us is easy.
11:43Be really relevant for neoplastic,
11:46for lymphoma Genesis.
11:48In any of these slim firms,
11:50so that has always been questioned,
11:51because not every single case of
11:54an EBV associated lymphoma is
11:57associated with Debbie.
11:59And again this has got an impact
12:01on the distribution of patients.
12:03Like if you look at EBV positive diseases
12:06from from England and here you can see.
12:09But even the positive disease,
12:11you get a very early peak in the in the very
12:14early on in the in the 1st and 2nd decades.
12:17You can have EBV positive disease.
12:19Then you have a a second peak around
12:2140 or 50 years and then a third
12:24peak in the 6th and 7th decade.
12:26Whereas when you look at EB
12:28negative diseases,
12:29you have a single pick somewhere
12:31in the early adulthood
12:33between the 20s and 30s and then the
12:36incidence decreases and if you put them.
12:40Across the world, if you see you have
12:42so you got even the positive disease
12:44comes with three peaks and even with
12:46negative disease is a single peak.
12:48So many people have actually questioned.
12:50Purely based on epidemiology.
12:52Whether you have EBV positive,
12:54Hodgkin lymphoma ribbon,
12:56negative Hodgkin lymphoma similarly
12:59positive Burkitt lymphoma,
13:00EBV negative Burkitt lymphoma would be
13:03the right way to classify these diseases.
13:06And again, now this kind of
13:08classification is getting some
13:10more traction because of genomics.
13:13And the same thing is true if you
13:15look at the HTLV 1 HTLV 1 positive
13:18aitl is again seen in specific
13:20areas across the world,
13:21but in today's migration and and with
13:25the immigration that happens one should
13:27not be surprised if one sees an HTLV
13:31positive ATL outside these endemic
13:33areas like where I used to work in the UK.
13:37It was we used to
13:38frequently see cases of ATL.
13:40Most of the patients were
13:42of Caribbean origin.
13:43And somewhere off of African origin,
13:45but most were of Caribbean knowledge.
13:47So similarly in the US there is.
13:51There are many cases of ATL
13:54which go underdiagnosed because
13:56it shall be one is not tested.
13:59If you look at when we come to pathogenesis
14:02of how does EBV contribute to the
14:04classic example is Burkitt lymphoma.
14:07Often we think that EBV doesn't
14:09act on its own, along with EBV.
14:11You have cofactors like malaria and
14:13HIV which results in enhanced B
14:16cell activation and proliferation,
14:18and when these activities going
14:20on in the general center,
14:21you have these translate translocation
14:24of immuno globulin and C.
14:26MYC occurs.
14:27Usually most of these cells are expected.
14:30Don't die,
14:30but some of these cells because of
14:34Debbie Gene products can can survive
14:36and these gene products will suppress
14:39the appetite ossis program and these
14:41cells go on to become Burkitt lymphoma.
14:44Of course,
14:44this is a very simplistic view,
14:46but if you again look at the within,
14:49if you look at the the breakpoints in
14:51the C MYC and in the immuno global
14:54engine you do see differences between
14:56African Burkitt lymphoma and the non
14:58endemic sporadic Burkitt lymphoma.
15:00In the African Burkitt lymphoma,
15:03the endemic Burkitt lymphoma
15:05within the immunoglobulin gene the
15:08the break is in the J region,
15:10whereas in the non endemic Burkitt
15:12lymphoma most of them have a break.
15:13In this which region.
15:15So when you put this on to
15:17the what could happen,
15:18where does the J region more
15:21susceptible for a translocation
15:22it would appear that most of
15:25the African Burkitt lymphoma,
15:26the translocation is likely to
15:28happen in the bone marrow,
15:29whereas in most of the non endemic Burkitt.
15:31Comma,
15:32it should be happening in the
15:34germinal center when the class
15:35switch recombination occurs.
15:37So there are these kind of differences
15:39even at A at a genetic level.
15:42This was a recognized way back in
15:44the early late 90s and early 2000s.
15:49So with all these things in mind,
15:50so does how does EBV really contribute
15:53to the pathogenesis of lymphomas?
15:55So I'm going to present to you
15:57three pieces of information of
15:59evidence which would support that.
16:02EB is crucial for lymphoma Genesis.
16:06We and others have shown that
16:08the association reduces the need
16:10for additional somatic mutations
16:11in the host genome for lymphoma,
16:14GENESIS 2 AKA,
16:15and we have also shown that that
16:17altered the genome is far more potent,
16:20and Informa Genesis than EB0
16:24which is not altered.
16:25Then we have also shown that type
16:28EB is far more oncogenic than
16:31type BEPB and I will take you
16:33through these pieces of evidence.
16:34So currently what we?
16:35I believe is that when EBV
16:37infection occurs on a beat cell,
16:40most of these cells are under the
16:42control of teasel both CD four
16:44and CD 8 positive T cells and it
16:46goes into a steady state where
16:48you have a latent infection,
16:50very low level infection of memory
16:52B cells are persistent infection,
16:55but some change within the IBD
16:57is likely to happen,
16:59and this is important for making the cell
17:02not susceptible to the T cell control.
17:05And giving rise to EBV positive lymphoma.
17:12So this is 1.
17:13This is a work which we did on
17:16posttransplant lymphoproliferative disorders,
17:18primarily.
17:18Here you can see these are EBP negative.
17:21This is a mutational landscape
17:23of EBV negative, diffuse,
17:24large B cell lymphoma and here is
17:26the mutational landscape of EBV.
17:28Positive, diffuse,
17:29large B cell lymphoma and you can
17:31easily recognize that the number
17:33of mutations seen in EBV positive
17:36DLBCL is far fewer than EB negative.
17:38If you flash piece or lymphoma,
17:40thereby suggesting that if we can.
17:43Substitute the role of many driver gene
17:46mutations in the development of lymphoma.
17:50The same thing is true what we see
17:53what we saw in post transplant
17:54studying is also true outside
17:56of the post transplant study.
17:57When you look at me positive,
17:59diffuse large B cell lymphoma,
18:00there's a lower mutational
18:01burden as compared to EBV.
18:03Negative issues,
18:04large piece of lymphoma and again EBV.
18:06Positivity is almost mutually exclusive
18:09with mediate mutations or CD 79 eight
18:11mutations and often it involves the
18:14alterations in Africa be wind and
18:16L6 taxed at both way and there are
18:19some specific mutations that occur.
18:21Positive ITI fueled large pizza
18:23lymphoma which makes it quite unique.
18:26When you look at EBV positive
18:30Burkitt lymphoma similar.
18:32A similar trend occurs.
18:33The driver gene mutations
18:34may be positive bucketing for
18:36mice far fewer than he may be.
18:38Negative Burkitt lymphoma.
18:40Of course,
18:41other mutations within the which
18:43are non driver mutations occurring
18:45as a result of activation induced
18:47cited in that is far more frequent
18:50in positive Burkitt lymphoma,
18:52again bringing to question that
18:53this may be because EBV gives a
18:56proliferative advantage within
18:57the germinal center and are those
19:00cells to survive,
19:01but the driver gene mutations are far fewer.
19:03Any positive bucket info?
19:06Another piece of evidence which we looked
19:09at was to look at the EBD subtypes in
19:12post transplant EBV positive PTLD Sandy.
19:15Be positive HIV influence
19:17within the PTLD setting.
19:20Most of the positive Pete Liz harbored
19:24Taipei EBV virus whereas in HIV, HIV.
19:29Already infamous,
19:30there was an even distribution
19:33between Taipei and Taipei,
19:35but more importantly what we saw was
19:37those cases which are associated with
19:40type B had a very long period of HIV
19:43positive ITI before they developed lymphoma,
19:45so we tend to we from this we
19:49hypothesize that Taipei is far
19:51more on Pjanic than type P.
19:53Then we let down to look at mutations
19:57within the IBD and we identified.
20:00And we showed that in a in
20:02a mouse model having EBV.
20:063B Knockout would make the
20:10mouse susceptible for lymphoma.
20:13For the development of a lymphoma,
20:14here are mice.
20:15The three types of my swan which
20:17are infected with the wild type web
20:20and then when it was infected with
20:22Aetna Trib Knockout virus and then
20:25in another step we reintroduced Abner
20:273B from into the stock out and you
20:30can see that 50% of the mice were
20:33infected with ethnicity knockout
20:35developed lymphomas whereas those which were.
20:38Infected with the wild type virus or
20:40the revertant virus did not develop
20:42any lymphomas in spleen and then
20:44we also went on to look at human
20:47lymphomas to look at Abernathy B
20:49mutations and a large variety of
20:51AB positive human infamous showed
20:53mutations in their blood 3B.
20:56And here are the.
20:58Photomicrographs that we saw in
20:59in this in the spleens of these
21:02mice and here is the the white,
21:04those which are infected wild
21:06type virus and those which are
21:08infected with the revertant viruses.
21:11And here is the one with the knockout
21:13in the knockout mouse we found that
21:15there is a proliferation of what would
21:17be very similar to an EB positive
21:19monomorphic diffuse large B cell lymphoma.
21:22And which were richly be positive,
21:24large B cells and very low in T cells.
21:28Then we did some experiments to see
21:30why are they so few T cells in the
21:33knockout mice and we could show that
21:36they they had very little chemokine.
21:38CXCL 10 and CXCL 10, which was
21:41required for attracting the T cells,
21:44was absent in the knockout mice.
21:46And if we supplemented with
21:49lten this could be reverted so.
21:52Not only was EBV responsible,
21:54but the microenvironment which it
21:55induced or which we which it suppressed
21:58while responsible for the development
22:00of diffuse large B cell lymphoma's.
22:02Then we went on to look at differences in
22:06microenvironment in HIV positive classic.
22:09Of course here it is difficult
22:11because almost all HIV positive,
22:13classic Hodgkin lymphoma or EBV positive,
22:16so we had a set of HIV positive EBV
22:19positive classic article Informa.
22:21We tried to compare that.
22:23With HIV negative EBV negative
22:25classic Hodgkin lymphoma,
22:27not only did we find differences in the
22:30numbers of the microenvironment cells,
22:33but there was a difference
22:34in the in the type of cells.
22:36We found a unique population of CD
22:388 foxp 3 positive cells in the HIV
22:41positive setting which we did not see
22:43in the HIV negative set and similarly
22:45we found that there were more CD 57.
22:49There were fewer CD 57 positive cells.
22:51There was fewer plasmacytoid dendritic cells.
22:54Facility 123 positive cells
22:56in the HIV positive setting,
22:58so the microenvironment of EBV
23:01positive disease is different.
23:03We also then went on to look in the
23:05post transplant setting comparing
23:07post transplant diffuse large B
23:09cell lymphoma with the immune
23:11competent diffuse large B cell
23:12lymphoma and there were more T cells,
23:15particularly CD 8 positive T cells
23:17in the post transplant EBV positive
23:19diffuse large B cell lymphoma
23:21this and if you look at these we
23:23wanted to make sure that these were
23:25not easy be infected T cells and
23:27these T cells look larger.
23:29They look more stimulated
23:30but and they are clearly EBV
23:32negative and when we looked at.
23:35Whether there was clonal expansion
23:37of these reactive T cell populations,
23:39we could demonstrate that in a
23:41good proportion of post transplant
23:43liver proliferative disorders,
23:45there was a monoclonal expansion of T cells,
23:48which possibly those which were
23:50reactive to the to the EBV present
23:53in the monoclonal B cell population.
23:57Similar stories are similar kind
24:00of of pathogenic involvement of
24:03hedge viatour or Kaposi sarcoma
24:07herpesvirus also been identified.
24:09Much of this work has come from other
24:13investigators for the major investigator
24:15in this area is Ethel Merman.
24:17Tough.
24:18Along with Amy Chapman,
24:20who have shown that the key uncle
24:23proteins of the HP 8 drives the
24:25lymphoma Genesis which includes the
24:27Lana Lana protein than the recycling
24:30and we flip and various other key
24:33uncle proteins are responsible
24:34for this kind of lymphoma genesis,
24:36which happens in the study.
24:40But when we look at the lymphoid
24:42lesions within the which are
24:43associated with infectious agents,
24:45we see a variety and and a whole
24:48range of aggressiveness and disease.
24:51Biology.
24:52At one end of the spectrum you
24:54have self limiting diseases like
24:57infectious mono nucleosis are very
24:59benign conditions like the EBV
25:02positive cutaneous ulcer of the
25:04positive German or Tropic LPD.
25:07Then you have something which
25:09falls in the Gray zone.
25:10Like the immediate positive polymorphous
25:13lymphoproliferative disorder,
25:14the Castleman disease inflammatory
25:16granulomatosis fibron associated
25:18diffuse large B cell lymphoma,
25:20chronic active EBV infection.
25:22Then you have the classic lymphomas
25:24without associated with infectious agents,
25:27and then you have some very aggressive
25:28disease like the Burkitt lymphoma,
25:30plasmablastic lymphoma,
25:30so on and so forth.
25:33I also what is important with these diseases.
25:35There is a risk of overdiagnosis,
25:37we know for a long time that
25:39infectious mononucleosis can
25:40be misdiagnosed as a lymphoma.
25:41And so also is true about the
25:44positive cricket aneus ulcer or
25:47associate Germany Tropic disease.
25:49So understanding these diseases is
25:51important from the point of view
25:54of recognizing them properly and
25:56not overdosing them as them first.
25:58I, I think most of you know very
26:01well about infectious mononucleosis,
26:03and I will skip this slide.
26:07Even the positive continuous also is is
26:09a is an important entity to recognize,
26:12because this have a very indolent behavior.
26:14These are circumscribed,
26:16painful but shadow.
26:17Shallow ulcer ative lesions which
26:19frequently occur in the orphan genetic
26:22causes skin or gastrointestinal tract most.
26:24It's not only mean it can be
26:26associated with the variety of immune
26:29suppressive conditions like medication
26:31associated like with methotrexate.
26:33Sometimes it can be just age related,
26:35immune senescence.
26:35It can occur in the background of.
26:37Community post transplantation.
26:38Also, it can occur with various malignancies.
26:42You can see a patient with lymphoma
26:44developing, ambiguities also,
26:45and many of these regress spontaneously,
26:48and some of them respond to withdrawal of
26:52immune suppression or immune reconstitution.
26:54And classically,
26:55this has a polymorphous infiltrate,
26:58and it got a typical large B cells,
27:00and some of them can resemble
27:02Hodgkin Reed Sternberg cells.
27:04It shows strong CD 30 Andy Barr expression.
27:07Many of the things in the past
27:08which might have been called as
27:10extranodal are because of *******.
27:11Informa need to be revisited
27:13whether there's many of them could
27:16be EBV positive Catania's ulcers.
27:18They can also explicitly 15,
27:21and they often express opto,
27:23but most of them lack Bob.
27:24One city Trinity expression
27:26is usually reduced,
27:28and typically there's a band of CD 3
27:30positive T cells and the periphery,
27:32and if one does clonality,
27:33there can be plotted both
27:36immunoglobulin or diesel gene
27:38rearrangements and nearly one half
27:40of them progress spontaneously.
27:42These are some of the pictures from
27:44the publication by Stephen Dodge
27:46Channel and you can see here is a
27:49shallow ulcer and the periphery
27:51you have a diesel infiltrate but
27:53towards the ulcer you see large.
27:55EBV positive B cells,
27:56which can show an article clone,
27:59another monoclonal expansion of TRB cells.
28:02And here's another case which shows
28:04not only CD 30 positivity but
28:06also profound city 15 expression.
28:12This is an entity which we for a
28:15long time we appreciated polymorphic
28:17type of post, transplant liver,
28:19proliferative disorders,
28:19but now more and more.
28:21We are seeing this in outside
28:24of the post transplant setting.
28:26We can see that in in the setting
28:29of autoimmune diseases or therapy
28:31related immune deficiency,
28:33but rarely we can also see it
28:34in the setting of a child here
28:36architecture of the node of the
28:38extra node log lesion is a faced.
28:41There's a heterogeneous of polymorphous.
28:43Infiltrate of immune cells,
28:45which includes B cells which has got a
28:48full spectrum of B cell differentiation.
28:50You will see large immuno blasts.
28:52You will see plasma cells so the whole
28:55range of visual differentiation is seen
28:57within this polymorphous infiltrate.
28:59And many of these large beetles can have
29:01features of Hodgkin Reed Sternberg cells.
29:03And these are EBV positive.
29:05Most often some people debate whether there
29:08could be any be negative polymorphous LPD,
29:10but defining that can be difficult.
29:13And distinguishing them from other
29:17reactive conditions can be difficult
29:19even with positive disease is
29:21more easily identified,
29:22and they can.
29:23Also, it can have monoclonal article,
29:26clonal proliferation of B cells and
29:29both nodal and external deliberations
29:32are presentations are known and
29:34some of them may also present with.
29:37For history cytosis.
29:39I'll take you through a few examples and
29:42I think it brings out the issues well.
29:45Here is a woman in 60s who had been
29:48treated with pancreatic cancer two
29:50years prior to this presentation
29:52and patient presented with fever and
29:54weight loss of three months duration,
29:57and there was a large periodic
29:59mass sub in centimeter dimension
30:02and patient also had right axilla
30:05re lymph adenopathy and needle
30:07core biopsy was undertake.
30:09And here you can see on on the left
30:12you can see predominantly small
30:13to medium sized cells and on the
30:15right you see amidst these small
30:17to medium sized cells you see some
30:19cells which look like mononuclear.
30:21Hodgkin cells are lacunar cells.
30:23You also know fields were completely
30:26lacking in this infiltrate and
30:28plasma cells were also not too many.
30:30And you can see these cells are
30:32rich in T cells.
30:33And they are predominantly city
30:358 positive T cells and there were
30:38many evil positive cells.
30:40You have some larger Lieber positive cells.
30:43And many smaller evil positive cells.
30:45And then we did further and you also
30:48had large CD 20 positive cells which
30:50were also both positive and these
30:52cells for CD30 and CD15 and Oct 2000.
30:55So there were some areas,
30:57those things which looked like
30:58Hodgkin's cells had a phenotype not
31:01too different from Hodgkin apart
31:03from strong expression of CD 20.
31:05Oneba as you see here,
31:07many cells are even positive and this
31:10includes both large cells like Hodgkin.
31:12Look like large cells and many
31:14smaller cells and medium sized cells.
31:16And when we did double state you
31:19can see that.
31:20These large cells libre positive CD,
31:22three negative but many of the
31:25small and medium sized
31:26cells were CD three and Eva dual positive.
31:29And here you can see that many of
31:31the smaller and medium sized Eber
31:33positive cells are CD 8 positive.
31:36So here's a situation where you
31:38have both CD 8 positive either
31:40positive cells and other facts.
31:43Fire CD 20 positive either positive
31:45cells and this is a classic exam
31:48and we try to we also undertook.
31:50Immunoglobulin T cell receptor gene
31:52rearrangement studies and we could
31:54not identify any particular clone,
31:56and the patients EBV levels waxed and vein.
31:59Then it fell off on its own,
32:00so this is a classic case of a
32:02polymorphism for polar disorder,
32:04with some features overlapping with a
32:06chronic EBV infection of the T cell type.
32:09And then there are some features
32:11which raises the possibility of
32:13an evolving fortune like process.
32:15However,
32:15this patient was not treated
32:17for any Hodgkin lymphoma,
32:19but eventually within two months time
32:21patient developed a treatment related.
32:23I could buy leukemia,
32:25but so this gives you an impression in a
32:28patient with a post Trump a patient who
32:30had been treated for pancreatic cancer,
32:32had a reduced immune.
32:36Capacity and then develop an EBV positive
32:41polymorphous lymphoproliferative disorder.
32:42In contrast to that,
32:44here is another case where the
32:45fact is a is a man in 60s who
32:47presented with pancytopenia with
32:49a clinical diagnosis of HLH.
32:51I had lower hemoglobin at a low white
32:53cell count and a low platelets and
32:56bone marrow investigations were done
32:59which showed a hypercellular marrow
33:02with trilineage hematopoiesis flow on.
33:04The peripheral blood showed that
33:05there was an increase in the cur
33:07gamma delta T cells and the same
33:09thing was also there in bone marrow
33:11and these cells were a bit larger.
33:13Here are the flow plots focus
33:15on the red cells here.
33:16These were larger cells with a
33:19slightly higher side scatter and
33:21these were gamma delta T cells.
33:23Which were CD,
33:24four negative and CD eight was
33:27mostly negative of weak CD 8 and
33:29these were CD 56 positive cells and
33:33CD five was completely negative.
33:35And here's the border from the patient
33:37and you can see there were an atypical,
33:39slightly larger lymphoid infiltrate
33:41which you can see here with CD3.
33:45These are the lymphoid cells and
33:47then this was CD 3 positive and
33:49this here is evil and here you
33:51can see with a double strain.
33:53These were not only CD 8.
33:54Positive,
33:55but these were also CD 56 positive
33:57CD 3 positive and CD 56 positive
34:00either positive cells and this is a
34:03classic example of a chronic active
34:06EBV infection of CD8 Gamma Delta type
34:09and we can see the viral levels of
34:12waxed and waned in this patient and
34:15patient did with conservative measures.
34:18Patient did quite well.
34:21So. We move on to a few other
34:24TB positive lymphomas, like.
34:25Here is I want to discuss about it.
34:27Be positive diffuse large B cell lymphoma.
34:31For the definition of EBV, positive,
34:33diffuse, large B cell lymphoma,
34:34there should be no history of a
34:37previous and informal or of any
34:39inborn or acquired immune deficiency.
34:41But age is not a criteria.
34:44And the the disease should not fulfill
34:47any criteria for other EBV positive news
34:50for proliferative disorders like you
34:52can't have limited granulomatosis or it
34:55should not be a plasmablastic lymphoma.
34:57So when you exclude all those things,
35:00what remains would be easy.
35:02Be positive. That would be be positive,
35:04diffuse large B cell lymphoma.
35:06Most of these patients are over the age
35:07of 50 years, but age is not a criterion.
35:10It can happen even in patients less
35:11than 50 years of age and a peak.
35:13Incidences in the 7th and the.
35:158 decades.
35:17More than 50% of the patients present
35:20with a high IPI and a High E Cox scope,
35:23and as I said earlier,
35:24they show a lower mutational burden
35:26as compared to maybe negative diffuse
35:28large B cell lymphoma's and frequently
35:31show over expression of PD L1 and
35:34they may also harbor structural
35:37variations in PDL one and PDL 2
35:40Chainz 2 subsets are identified,
35:43one is a polymorphous variant and
35:45other one is a monomorphic variant.
35:47The polymorphic variant is important
35:48to recognize because this can be
35:51misdiagnosed as a Hodgkin lymphoma.
35:52Other type of lymphomas.
35:54Here you have large transform cells,
35:56immuno blast including cells resembling Reed,
36:00Sternberg cells all inside predominant
36:01cells and these are seen in a very
36:05polymorphous background of small lymphocytes,
36:07plasma cells histiocytes.
36:08So you can see that there is an
36:10overlapping in overlap in the differential
36:13diagnosis with a polymorphous
36:15lymphoproliferative disorder.
36:16And other lymphomas.
36:17It can be also be mistaken for a
36:19T cell rich piece of lymphoma if
36:22the baby is not tested often,
36:23you see I'm just centric and the
36:26destructive areas and you have extensive
36:28coagulative necrosis and they can be CD 30.
36:31Positive City 15 can also be positive.
36:33Often you have a latency of
36:35type 2 and rarely of type 3.
36:38By type two I would mean that they
36:40should also be expressing LMP one and
36:42Type 3 in addition to Eber and LMP.
36:45One they would express.
36:47Who?
36:48Again, the impact on outcomes is
36:50not very clear in the Asian setting,
36:53EBV positive,
36:53diffuse large B cell lymphoma
36:55as adverse prognosis.
36:56The Neb negative diffuse large
36:58B cell lymphoma.
37:00Here is an example.
37:01He can see there are areas of neck
37:03regulative necrosis.
37:04Then here's the viability areas,
37:06and these cells can be
37:08quite polymorphic in nature.
37:10There are many other cells,
37:11including granulocytes,
37:13plasma cells,
37:14lymphocytes along with large atypical cells.
37:18Sorry and these are CD 20 positive,
37:21either positive and there are many
37:24histiocytes which are brought out
37:26by City 68 are here and then if you
37:29look light chain restriction study,
37:30there's a lot of background but these
37:33cells clearly show capital light
37:34chain restriction and they often have
37:36a non germinal center phenotype.
37:38Mum 1 positive there were negative for
37:41city 10 and possibly for BCL 6 and
37:44they have a high key 67 expression.
37:46In contrast to this,
37:48this is another EBV positive lymphoma,
37:50but in a completely different
37:52clinical context.
37:52This is a patient at 7070 year old lady
37:56who presented with an adrenal mass
37:58so that hemorrhagic mass and there
38:00was a a pseudo cyst with brown fluid,
38:03and when we accept when we examine
38:06multiple blocks from the pseudo cyst,
38:08there were some areas where we see
38:10these kind of large atypical cells
38:12and these large atypical cells.
38:14As you can see here, these were all.
38:16Keep a positive and they are they
38:18had a non germinal center phenotype.
38:21They were seen in 20 probably Mum 1
38:23positive but negative for CD 10 and
38:24six and a very high K 67 expression.
38:27It's important not to call these AB
38:30positive diffuse large B cell lymphoma.
38:32This is a fibron associated EBV positive
38:36large B cell lymphoma that these have
38:39a very different disease cause most
38:41of these don't require any chemotherapy.
38:44They do exceedingly well.
38:47Rarely be negative cases have
38:49also been described here.
38:51These two muscles are sit
38:54within the mesh of fibrin.
38:56And you can also get these in in
38:59catheters and whenever you have a
39:01thrombus within within that thrombus,
39:04we can get these EBV positive large B cells.
39:07So it occurs in specific clinical context and
39:10one has to be careful not to over diagnosis.
39:14Inflammation is very little as you can,
39:16as you saw in this particular case
39:18they have immuno plastic features
39:20and they have a non GC phenotype.
39:23The CD ten negative mum 1 positive
39:26six can be positive in some cases.
39:28And they can rarely express City 138,
39:31and they have a very favorable outcome.
39:34And accession alone is sufficient
39:36in most of these cases.
39:38In contrast to this season,
39:40here is a very aggressive
39:41EBV positive lymphoma.
39:43The Plasmablastic lymphoma,
39:44which is got diffused in a plastic
39:46which shows diffused in a plastic
39:48proliferation of tumor cells,
39:50which I've got plasmacytic features,
39:52typically occurs in an extranodal
39:53setting occurring in the oral cavity
39:56and other mucosal sites rarely
39:57can also occur in in lymph nodes,
40:00it classically occurs.
40:03It typically occurs in the
40:04HIV positive patient,
40:05but can also occur outside the HIV study.
40:08And can also occur in
40:10post transplant patients.
40:11It can also occur in in elderly people.
40:14Some may occur as a transformational event.
40:18In a previous case of follicular
40:20lymphoma or CLL and rarely following
40:22CD 19 CAR T cell therapy again.
40:25Patients present with advanced stage
40:27with advanced with a high IPI.
40:30Nearly 60% of Kesari be associated
40:33and those which are EBR associate
40:35typically have latency type one
40:37or type 280% of the cases of
40:40associated case or HIV positive.
40:42And rarely we can get in
40:45between negative cases.
40:46You running HIV studying rarely.
40:48It can be even be negative and
40:49milk translocation is present in
40:51nearly 80% of these patients.
40:53In of these cases,
40:55they typically suppress the Bissell
40:57program that negative facility,
40:5920 packs file and city 45 and they
41:02expressed a plasma cell program.
41:04The positive facility 138 city
41:0738 blimp one mom one XBP one
41:10and they express light chains.
41:11They express imina globulin.
41:13They you can demonstrate your globulin.
41:16Restriction like chain restriction and
41:19they can rarely also express CD 56,
41:21so often one would think the CD 56
41:24expression would be a good way to
41:26distinguish this from plasmablastic myeloma,
41:28but they can rarely be positive,
41:30or city 56 cyclin D1 expression would
41:32be negative in these cases and that
41:35could be a useful marker if present.
41:37They are more indicative of a
41:39plasmablastic myeloma mic is often
41:41positive because these carry MC
41:43transportation. PDL one is often positive.
41:46They show loss of MHC Class 2 expression
41:49and K 67 expression is usually very high.
41:52This is a classic example of
41:55Blossom plasmablastic lymphoma.
41:56You can see these are blast immuno
41:59blaster plasmablasts and these
42:01are typically as I said CD 138
42:04positive and it can very easily
42:06demonstrate like to instructions.
42:07Yet scapolite chin restricted.
42:11As against the Plasmablastic lymphoma,
42:13you have the. Just create associated.
42:17Sorry before I go into situate associated
42:19lymphoma is worthwhile to discuss
42:22situate associated Castleman disease.
42:26This occurs usually in HIV positive patients.
42:28Nearly 80% of them are HIV positive.
42:31Rarely it can occur in HIV negative
42:34setting in in specific areas,
42:36but most of them are HIV positive.
42:38Typically these patients are in.
42:41That early 40s in middle aged
42:43patients and have relatively low
42:46or undetectable HIV viral loads.
42:48So CD 4 counts are reasonably OK.
42:50These patients milk there's a huge male
42:53predominance and different morphologies.
42:55Those of Castleman disease
42:57of plasmacytic type,
42:58other mixed mixed pattern and they are
43:01you classically see plasmablasts which
43:04are medium to large sized lymphoid cells
43:07with nuclei and amphiphilic cytoplasm,
43:10and these cells are.
43:11Being typically in the mantle zones,
43:13but rarely they can be seen
43:15in into follicular interest.
43:16They can be intrafollicular,
43:18perifollicular, and these lymph nodes.
43:20One it's important to recognize
43:22that many of these lymph nodes
43:24can have foci of Kaposi sarcoma.
43:26When these patients are treated with anti CD,
43:3020 Kaposi sarcoma tends to explode so
43:32it's important to recognize that if
43:35the patients also have Kaposi sarcoma.
43:38Alchemize also concomitantly treated.
43:42This the the,
43:43the number and the density of
43:45copper brass can be very variable.
43:47It can be few or it can form large
43:50sheets like what people used to
43:52describe as micro infamous in the
43:53past and these plasmablasts our
43:55mum one and blimp and positive.
43:57But they often are negative for CD,
44:0020 have very low expression of CD 20 and
44:03they typically laxity 1:30 at expression.
44:06The express IG M and they are Lambda
44:08light chain restricted though there
44:10are Lambda light chain restricted.
44:12They are not born.
44:13Well, there polyclonal,
44:14so they're monotypic,
44:15but polyclonal and patients
44:17usually have a detectable plasma,
44:20which case which we are judged
44:22by DNA and that's a useful
44:24marker outside of the Histology.
44:25Here is a typical case where you
44:28can see castlemans like features.
44:30You got follicles which somewhat
44:32resemble the they had in vascular
44:34type of Castleman disease.
44:35But more importantly you have
44:37plasma cells in the inter,
44:39follicular and medullary areas.
44:41These plasma cells are.
44:43Are not plasmablasts,
44:44they're reactive plasma cells,
44:46which are both Kappa and
44:47Lambda light chain positive,
44:49but the typical plasmablasts are
44:50seen here in the mantle zone.
44:53As you can see here,
44:54and these are huge,
44:568 positive and CD 21 will highlight
44:58this FTC meshworks and here with you
45:01can identify plasmablasts in the mantle
45:04cell and these are IG M positive and
45:06their Lambda light chain restricted,
45:08whereas the plasma cells in
45:10the interfollicular area.
45:11Those are normal reactive plasma cells.
45:15Siri 20 this patients respond extremely
45:18well for anti CD 20 treatment.
45:21So one of the questions is always been if
45:23these plasma Blaster CD twenty negative.
45:24How do they respond?
45:25So we went on to do some double
45:27stains and here you can show that
45:29while most of the plasma blasts are
45:31negative like here is positive plasma
45:33blast which is negative for CD20.
45:36A good proportion of them
45:38show expression of CD 20
45:40and some of them can be quite weak.
45:43Then we also went on to look at.
45:46In these lymph nodes,
45:47many of these lymph nodes show
45:49follicular dendritic cell mesh works.
45:52Here is Brown is in the HV
45:54Atlanta one and red is CD 20,
45:58city 21 and you can see many of
46:01the follicular dendritic cell
46:02processes also show the Lana protein.
46:05So obviously the nuclei of these
46:08are negative for Lana one,
46:10it's only the cytoplasmic processes
46:11that are showing Lana one positive ITI.
46:14So there by suggesting that you have.
46:16In a subset of metric Castleman disease,
46:18that is presentation of Lana,
46:20one on the FTC's.
46:22So then we went on to look at,
46:24make some associations.
46:25We showed that those cases will have
46:28a lower load of huge positive plasma
46:32blasts are more likely to have HSV
46:36positivity in the FDC processes,
46:39and these cases also had fewer CD 3
46:41positive T cells within these follicles.
46:43So there was an inverse correlation
46:46between the number eventuate.
46:47All the new cells.
46:49And presence of antigen on the
46:52left and this this positively
46:54correlated with the number of T
46:56cells within the folly truths.
46:58As I said,
46:59there can be microscopic Kaposi sarcoma.
47:01Here is the lymph node capsule of a
47:03patient with multicentric Castleman disease
47:05showing microscopic Kaposi sarcoma.
47:11A good a good proportion of patients
47:13of multicentric Castleman disease also
47:15present with primary effusion lymphoma,
47:17and typically these are serious effusions,
47:19but some cases and more,
47:21and many of them will not have any solid
47:24tumor analysis but a subset of them
47:26present with solid tumor masses and
47:28and these may not have any effusions,
47:31and these are called extra cavitary,
47:32primary fusion infamous,
47:34and these patients usually have
47:36a low CD 4 count in contrast to
47:38multicentric Castleman disease.
47:40And though most of these are seen in HIV,
47:43positive patients rarely just can
47:45be seen in other immune suppression
47:47settings like the post transplant setting
47:50operations with immune sentences,
47:52and again typical ages 40 to 50.
47:54Rarely you can see this outside of
47:56the HIV setting in the in endemic
47:59areas like the Sub Saharan Africa
48:01and Mediterranean,
48:02and they're accompanied by at the
48:04same time by Kaposi sarcoma and the
48:06Multicentric Castleman disease.
48:08In nearly one half of cases.
48:12Here the self the important thing about
48:14this entity is they are dually infected
48:17both with HHV 8 and Epstein Barr virus,
48:20but largely the malignant
48:22process is driven by.
48:25So by Minister chemistry you can
48:28demonstrate edges and by in situ
48:30hybridization you can identify Eva.
48:31You usually the EBV latency is type one,
48:34so you'll be LMP.
48:36One is usually absent in these cells.
48:38This again a large amount of plastic
48:41cells are plastic plastic cells and
48:43they show prominent and aplasia cells
48:45can resemble Reed Sternberg cells.
48:47And again,
48:47like in the plasmablastic lymphoma,
48:49there is suppression of the bezel
48:51program and what you see is often
48:53a plasma cell program with.
48:55It's only 138 mum one and blimp,
48:58but unlike the plasmablastic lymphomas,
49:00these do not express immunoglobulin so
49:03the immuno globulin negative and some of
49:06them can express aberrant T cell antigens.
49:09Nearly a third of them do that.
49:11And here is a typical case of an
49:13extra cavitary primary effusion.
49:15Lymphoma showing on a plastic or
49:17even a plastic type cells which
49:19are positive for in this case it
49:21was CD 45 positive but most often
49:23city 45 is also negative.
49:25CD 38 and mum one were positive and you
49:28can see there is minimal expression
49:31of 79 and a proportion of cells.
49:33Express CD 30.
49:35Most importantly,
49:36these cells are dually infected with EBV,
49:39demonstrated by Eva and Batch
49:41were demonstrated by LENOVA.
49:45And more, many of them
49:48also overexpressed PDL 1.
49:50So we do not know whether all of these
49:53carry structural abnormalities in PDL one,
49:56but most of them have overexpression of PDL.
50:01There is also another entity
50:02known as the case.
50:03Such great positive diffuse
50:04large B cell lymphoma.
50:06Most of these men can
50:08develop in patients who.
50:10Have been of who had medical
50:12centric Castleman disease.
50:14These patients are
50:15profound immune deficiency.
50:16The most of them are HIV positive.
50:18Rarely it occurs in other other immune
50:21compromised settings are very rarely.
50:23It can occur.
50:24Non immune compromised setting and
50:26this is singley infected with HPV.
50:28There is no infection in these
50:30patients and characteristically
50:31involves lymph nodes and spleen.
50:33Same areas where Multicentric
50:36Castleman disease presents.
50:38They are variably positive of 45 and 20.
50:41Unlike the Multicentric Castleman disease,
50:43they express AGM and Lambda light chains.
50:48So this is quite a rare disease.
50:50You can and look if we
50:52move on to the next entity,
50:54which is extremely exceedingly uncommon,
50:57but it's important to know about this
50:59because this is a perfectly benign disease.
51:03Here we got cake and EBV positive.
51:08This can be again Dooley infected by EBV
51:11and what's known as the Associated German
51:15or Tropic lymphoproliferative disorder.
51:17Most of these patients are HIV negative.
51:19They present with neck,
51:21lymph adenopathy and they are asymptomatic.
51:23Here the germinal centers are partially
51:26or completely replaced by large blasts
51:28which are as I said ebb and positive.
51:31They are mum 1 positive.
51:33They've got many features which
51:35could be similar to the similar to
51:39the primary effusion lymphoma but
51:41these cells are right within the.
51:45In the germinal centers and the important
51:47difference from the primary effusion,
51:48enforma is that they express
51:51monotypic immunoglobulin expression
51:52is seen in nearly 2/3 of cases,
51:54whereas in primary effusion lymphoma you
51:57can't demonstrate him in a globe date,
51:59and if you do PCR study for immuno
52:02globulin gene rearrangement,
52:04they're calling clonal and
52:05expressing itself is sufficient,
52:07and prognosis is excellent in these patients.
52:11There's another entity which
52:12people need to be aware of.
52:14Many of the patients are nearly
52:16one in 10 patients of MULTICENTRIC.
52:18Castleman disease can develop
52:20hemophagocytic invoice cytosis,
52:22and if you get a spleen,
52:23or if you get one metal in these patients,
52:25you can explain.
52:26You can see this in the red bulk you
52:29have active phagocytosis occurring
52:31and you also see this positive
52:33plasma blast in the surrounding
52:35areas and the same thing happens
52:38also in the bone marrow you can see.
52:41Active phagocytosis along with presence
52:43of these kind eventuate positive
52:46plasmablasts and this these patients
52:48can have if they are not treated well.
52:52They can have pork survival.
52:54I just want to touch for the next
52:56few couple of minutes on HTLV one,
52:58which is quite a rare entity,
53:00but people have to recognize
53:02that this is underdiagnosed in.
53:04In 2018 there was a a study came
53:06out from the National Cancer
53:08Database which showed that mycosis
53:11fungoides occurring in patients.
53:13I'm sorry,
53:14330 positive proteinous infamous
53:15occurring in African American
53:17patients have portal survival.
53:20This could be true,
53:20but in all none of these patients
53:22they still be one was tested.
53:24Around the same time you had,
53:26there was another study which came
53:27out from the Miami group which showed
53:30that ATL is indistinguishable from
53:32many of the common teasel informers.
53:34So any T cell lymphoma one has to
53:37keep in mind that the likelihood of
53:39HTLV one and exclude the possibility
53:42of HTLV 1 by serology.
53:44Otherwise one could easily miss,
53:47diagnose and aitl as some other
53:50T cell lymphoma.
53:51ATL is divided into four groups.
53:54When he was a cute group
53:55and their infamous group,
53:56then you have the chronic group
53:58and the smoldering type of aitl,
53:59the genomic.
54:00They're all genomic differences
54:02between these four groups
54:04and the genomic differences also have
54:07an implication on outcomes like the IRF
54:094 mutations has a very patient of ATL,
54:12which I had a four mutations
54:13have a very poor survival.
54:15Those will start 3 mutations are
54:17typically seen in the indolent type of
54:19ATL and they have a much better survive.
54:22So again, now people have come
54:24up with genomic skills in ATL.
54:26Much of this work has come from Japan
54:29and the genomic subsets also correlate
54:32with the clinical subsets and and and
54:36there are clear indicators of survival.
54:39I'll just, I think this is the
54:41last case I'm going to show and
54:43I will end with this here.
54:44The HIV positive patient who was
54:46referred for an allogeneic transplant.
54:48This was in London and patient had
54:50already received two courses of ice,
54:52and when bullmer investigations
54:53were being done,
54:54we saw these kind of abnormal cells
54:57and these cells were CD 3 positive.
54:59There were CD 4 positive in 25
55:01positive and most of them were CD,
55:03eight negative and on flow you
55:05can see that these were having
55:08lower expression of CD3 or CD to.
55:10Positive and there were no CD 4
55:12positive but CD eight negative and
55:14you can see City 25 was positive in
55:17these cells and CD seven was negative.
55:20So these for ATL cells and these
55:22sometimes can be difficult to
55:23diagnose in peripheral red where you
55:25have the question of whether it's
55:27an ATL or a chronic HTLV 1 carrier.
55:29In contrast to that case,
55:31here is a peripheral blood from a
55:32patient with cousin STLV 1 carrier.
55:34Here are the blue cells you can
55:36see with lower expression of CD
55:38three and these for CD 4 positive.
55:40And you can see reduced expression
55:43of CD5 and importantly these four
55:45CD 25 positive and CD 26 negative
55:48and also CD seven negative.
55:51So this is for the patient with
55:52chronic HSV 1 carrier and that
55:54distinction can be quite difficult.
55:56One may have to do southern blot for STL.
55:58We want to show that there is a
56:00monoclonal HTLV one or they're in the
56:03process from a chronic infection to ATL,
56:06that is integration of the virus.
56:08It can be a single integration,
56:09sometimes there can be more
56:11than one integration.
56:12And that's important to recognize the ATL
56:15and distinguish that from chronic carrier.
56:19So in the last couple of minutes I
56:21just want to give you an update on
56:23The Who classification of tumors.
56:25So this is in general about
56:28the classification of tumor.
56:29This is managed by the classification
56:31of tumours,
56:32editorial board and this has got
56:34a chair or the head of the WHL
56:37classification of tumors. Dr.
56:38Ian Cree, who is a pathologist himself.
56:41Then it has got.
56:42Standing members,
56:43these are standing members are common
56:46across different globe books and
56:48these are nominated by major societies
56:50and involving cancer diagnosis
56:52and they serve on a 3 year term.
56:55Then you have the expert editorial
56:57board members for each
56:59of these, each of the blue books and the
57:02current guideline for these for being an
57:04expert member is that people can't be
57:06on this board for more than two books.
57:09That's the maximum if you serve on one book,
57:11you can. So when a second book, but we can't.
57:14So beyond two books and all members
57:17have equal status and this is the
57:20decisions are made more by consensus.
57:22There is it's not,
57:24there is no hierarchy within the
57:27tutorial board and members are
57:28chosen based on their expertise and
57:30and also geography if possible.
57:32Like there is a positive attempt
57:34is made to be inclusive to include
57:36people from across the world.
57:39And the current WHO classification
57:41has 25 expert editors and one of
57:44them and has about 380 authors,
57:47and these authors include not just
57:50hematopathologist, but they have clinicians,
57:52hematologists, oncologists.
57:53We got, geneticists, epidemiologists.
57:56All of them are authors. Most of the major.
58:00Major chapters have got.
58:06Otters are beyond just being
58:09hematopathologist and across these I mean,
58:11these 380 authors come from 31 different
58:14countries, so there's a much wider
58:17representation of across the world,
58:18so the the timelines and the way
58:21we are progressing. This was fast.
58:23We, you know, the editorial board,
58:25at least the editorial board members
58:27were contacted. In February,
58:29we had a very pre meet in April 2021.
58:32That was the first time we got
58:34to know who were the other.
58:35In total board members and then we had a
58:38content meeting which happened in November,
58:40so part of it we could not complete.
58:42So the T cell lymphomas could not
58:45be discussed because we had three
58:46full days 12 hour meetings each day
58:48for three days and we are still left
58:50with some chapters which were left
58:53and that's being discussed next week.
58:56And I mean that was the November
58:582224 meeting.
58:59So we have a third editorial
59:01meeting in in in January,
59:03but we are likely to have another
59:05meeting sometime in in spring and
59:08we are hoping that the towards the
59:10end of the of the year we will
59:12have the publication coming out.
59:14So possibly by October November we
59:17should be having the 5th edition
59:19of The Who classification.
59:22I'll stop that and I'm happy to
59:25take questions.
59:28Sorry, I think I took a little
59:30longer than I expected. I would thank
59:32you. So thank you so much for
59:35that overview and really,
59:37really fascinating case.
59:39Needed cases. Allow all the
59:42people currently onto to essence,
59:46especially trainees.
59:47Please feel free to pop up
59:49with question with question.
59:56See, there's something on the chat,
59:58see if there's any question.
60:00Those oh those are CME credits. OK so I have
01:00:05a question why that was a a great talk.
01:00:08I really appreciated that
01:00:10my my question is about
01:00:12you know the latency versus
01:00:14lytic cycles of EBV,
01:00:15and that how that plays into lymphoma,
01:00:17Genesis, and I know historically,
01:00:20we've always talking about these latency
01:00:22programs and eborn Debnath course or latency.
01:00:25Genes, but recently there's been a
01:00:27lot more suggestion that the lytic
01:00:29replication of the virus in the near
01:00:31term before you know diagnosis is actually,
01:00:34you know, very relevant for
01:00:37for lymphoma Genesis.
01:00:38So just your thoughts on sort of how
01:00:41that sort of might integrate into
01:00:43these classifications or pathogenesis.
01:00:46Yeah, good that you asked the question,
01:00:49if you use the one you see proportion
01:00:52of cells which are in the lytic phase.
01:00:56And the question that comes up is.
01:00:58Those cells which are in the lytic phase.
01:01:00Can they infect other cells?
01:01:03And can you have multiple EBV
01:01:07positive lymphoma clones occurring
01:01:10within a particular tumor?
01:01:13In most of the. B cell lymphoma's.
01:01:16At least people have not much work
01:01:18has actually happened, though.
01:01:19People have shown that there is a subset
01:01:22of cells which are in the lytic phase.
01:01:24But how that would impinge on
01:01:27the evolution of the tuba.
01:01:29I think it is far from clear.
01:01:34I'm probably the lytic.
01:01:36Phase is important also because
01:01:38if you follow these patients.
01:01:40It is only latent TB you wouldn't
01:01:43see arising EBV viral level in the
01:01:46serum and the very fact that the
01:01:48plasma levels keep increasing and
01:01:50correlates with the tumor load.
01:01:52It means that there is a subset of cells
01:01:54where they are lytic infected exactly.
01:01:57Yeah and also the the fascinating
01:01:59question also comes up is if
01:02:01there was a way to convert the
01:02:03latent virus into a lytic virus.
01:02:05Can you steal the kill the lymphoma
01:02:07cell instead of treating patient with
01:02:09all the chemotherapeutic agents?
01:02:11If you can just trigger.
01:02:12And change the latency into lytic,
01:02:15or whether the baby itself
01:02:16can kill the tumor cells.
01:02:18But that has been just
01:02:19a fascinating question,
01:02:20but nobody has ever done it.
01:02:24Thank you, thank you. I
01:02:27have a question. This is Jeff Squire.
01:02:31You described the mutations
01:02:34in EBV in EBV genome,
01:02:36in Burkitt's. And wondering whether there are
01:02:40mutations? Found another
01:02:42EBV associated lymphomas
01:02:45and also you described cytokine
01:02:49suppression in Burkitt's,
01:02:50and I wonder how widespread that
01:02:53is among other. Yeah, that's us.
01:02:57Regarding the Abner 3B mutations,
01:02:59which we showed,
01:03:00we showed that across not just Burkitt
01:03:02lymphoma but also in diffuse large B
01:03:05cell lymphoma and in post transplant
01:03:07lymphoproliferative disorders so that actors,
01:03:09even outside of the bucket, look firmer.
01:03:12Whereas this cytokine thing that
01:03:13I showed you was purely in in the
01:03:16mouse model we have not been able to
01:03:20show SL 10 differences in patients.
01:03:27OK, so that's a rather dramatic
01:03:29finding, so it seems to be a
01:03:32consistent mutation and ended
01:03:363833 B mutations we have.
01:03:37We have been able to show
01:03:38outside of the work as well
01:03:40and and how. How prevalent
01:03:42is that? Is it a friend?
01:03:44Most cases? Yeah, we evaluated in about
01:03:4640 cases and if I remember correctly.
01:03:49More than half of them had mutations
01:03:52and these patients were from.
01:03:54All over the world now.
01:03:56I mean, we had patients from
01:03:58Australia to UK to Africa,
01:04:00collected from different
01:04:02parts of the world and also.
01:04:04One of The thing is important.
01:04:06Recently my my friend Lorenzo Lucchini.
01:04:09He showed a variety of lymphomas
01:04:12where using RNA scope they could
01:04:15show remnants of EB virus even even
01:04:17in those which were ever negative.
01:04:20So there is a possibility
01:04:22not only mutations occur,
01:04:23but eventually many tumors
01:04:25may lose the baby virus.
01:04:27So what we currently consider
01:04:29as EBV negative disease,
01:04:30a subset of them may not be be
01:04:33negative when from inception, yes.
01:04:36Thank you, thank you.
01:04:46So I think we're over 6 minutes over.
01:04:49I just wanted to thank you so much for
01:04:53took a little long I could have.
01:04:55Cut down on my great thank you. Thank you
01:04:59to the next meeting.
01:05:00Thank you, thank you. Thank you very much.
01:05:03Thank you, bye.