nm5253: right er c-, can i welcome you to this er academic er half day we've 
got some er very good er talks that er some of your colleagues have prepared 
and basically in er the time of well less than two hours we're meant to cover 
er most of the haematological malignancies so we're really going to be talking 
about patients with leukaemias and patients with lymphomas and i think er as 
part of your biological training to date you should have covered some of the 
molecular aspects of er malignancy er some of the aspects you'd have covered i 
believe in some of the basic science courses so today we're really going to 
concentrate on some of the clinical aspects of patients with leukaemias and 
lymphomas and see how that ties in and er builds together with what you've 
learnt from the biological sciences er so really i'm going to start off with er 
leukaemias and leukaemias are conditions whereby you have an abnormal 
proliferation of primitive er cells in the bone marrow the bone marrow's the 
site where different blood cells are made and there are a whole variety of 
different leukaemias acute and chronic would be the main types of leukaemias 
that we're going to be looking at and for a start we're going to have a 
presentation on er a patient who's recently been at Warwick Hospital presenting 
with er an acute leukaemia and i think we'll just go straight into that and 
have the presentation for a start and then we'll have a little bit of 
discussion about that afterwards so shall we have er candidate number one
sf5254: okay er i'm presenting acute myeloid leukaemia er it's not a classical 
presentation er but it's quite interesting er a female student from Stratford 
and she was admitted to Warwick Hospital on the twenty-eighth of May and er she 
was in for several weeks right up until the first of er July her presenting 
complaint was er anorexia and weight loss and she went from sixty-five 
kilograms to forty-eight in two months er she had fatigue and lethargy for five 
to six weeks and er abnormal blood results her haemoglobin was down white cell 
count was up and platelets down her history of the presenting complaint was a 
five week history of fatigue and lethargy er she was unable to socialise with 
her peers after school er which her mum said was unusual and participate in er 
sporting activities she'd sleep immediately after getting home from school er 
and started skipping meals and her appetite was reduced she had weight loss 
that we previously er discussed her mum booked a holiday to go to er Greece and 
the day that they the day before they were going her mum was really concerned 
that she hadn't actually got out of bed for several days and thought that she 
might have an eating disorder and took her to the er G-P who er did blood tests 
and they came abnormal and she was er admitted to Warwick Hospital er with 
suspected er leukaemia since she's been in er Warwick Hospital she had several 
complications er nausea vomiting and diarrohea predominantly with fever she 
also had candidiasis in the mouth and vagina and also quite bad mouth ulcers er 
she'd also had a severe candida-like infection er which was really hard to 
treat they couldn't get rid of this er and a maculopapular rash over the trunk 
and limbs and completely covered ninety per cent of her body er but we we'll 
talk about that a little bit more later and also hair loss er and these are 
mainly from chemotherapy and also her neutropenic state er she had no past 
medical history to note and a family history of diabetes and a cousin who died 
of leukaemia er who had it for fifteen to twenty years social history she was 
born in California and has lived here for four years attends Stratford High 
School a non-smoker non-drinker er she lives alone with her mother who's having 
financial difficulties at the moment er and they have to move out of their 
house at the end of August and they're in and out of hospital er quite 
frequently now Social Services have become involved and they're er looking for 
some sponsorship and er raising money to sort of help them through it er drugs 
and allergies she's on chemotherapy which is done in several rounds er it's 
goes on for ten days and then she has three weeks where she's in hospital in a 
neutropenic state so they give prophylactic er antibiotics Metro-, er 
Ciprofloxacin and also er prophylactic sort of anti-fungals Fluconozle er after 
the three weeks she's allowed home for s-, a couple of days and then back in 
for the next round er she had no drug allergy on physical examination on 
admission she was pale there was no jaundice cyanosis clubbing no palpable 
lymph nodes temperature was thirty-seven pulse ninety-eight B-P one oh three 
over sixty-eight her abdo was soft er non-tender no organomegaly and all of the 
systems were normal and now Will's going to tell you about rashes and things
sm5256: up there is an example of a maculopapular rash er this is the kind that 
you might see in children who have Rubella in this case er er Miss MM had it as 
a reaction to one of the drugs she was being given er and as you heard in this 
case it covered ninety per cent of her body and even after it cleared up it the 
this was about a couple of weeks two or three weeks ago the skin is still er 
sort of coming off er it's called desquamation afterwards er other skin 
conditions you might get in children er suffering from er leukaemia er here's 
an example of a seven year old boy who's got er petechiae er which is sort of 
pin pin prick er haemorrhages into the skin er they're not raised it's the kind 
of thing you might get in menigo-, er meningococcemia er and er basically er 
they're very small less than two millimetres but er haemorrhages into the skin 
larger than two millimetres are called purpura er here are some examples there 
er looking quite er quite er raw but they're actually flat lesions and don't 
break the skin and er when they're larger it's the same as bruising it's called 
ecchymoses and in this child it was actually the way they the twelve year old 
boy presented with acute myeloid leukaemia er diff-, differential diagnoses er 
actually it's difficult this was a a child of fifteen er and normally patients 
with A-M-L are you'd normally see them only in people over twenty er so some of 
the differentials might well be different in a child of this age but er in a 
normal case of A-M-L er other things that you might be thinking of er if there 
was lymphadenopathy as well you might me thinking of infections such as er 
infective mononucleosis or lymphoma er if the liver and spleen are enlarged you 
might be thinking of myeloproliferative disorders er or myelodysplasia er 
that's something you wouldn't get in a younger child er could have metabolic 
storage or autoimmune disorders and also rarely tropical disorders such a 
leishmaniasis er it says no peripheral leukaemic blasts er but there is 
pancytopenia er it might indicate there's er aplastic anaemia or infiltrated 
bone marrow involvement and in lymph-, if it's lymphoblastic lymphoma er you 
get lymphomatous presentation er with less than twenty-five of blasts in the 
marrow er the definition of A-M-L which er er Doctor Rose is going to talk 
about more in er later on er talking briefly er acute leukaemia is a clonal 
malignant disorder er which affects er any age groups from infancy to old age 
in fact children can be born with leukaemia er but er like most cancers it er 
predominantly affects older ages er it's charac-, characterised by accumulation 
of abnormal white blood cells in the bone marrow which replace the normal 
tissue er which is why you get some of the effects er it's also replacing the 
haemopoietic precursor cells which is causing the anaemia et cetera it results 
in bone marrow failure er and peripheral blood involvement and it can 
infiltrate into various organs er the symptoms as i say er due to the bo-, bone 
marrow failure so anaemia because you can't make the red blood cells er 
infections because there's no white blood cells around to fight and haemorrhage 
due to platelet deficiencies and you can also get hyperleuccocytosis yeah so 
you can get an increase in white blood cells but they tend to be quite useless 
white blood cells er investigations for A-M-L er er i'll go through these in a 
bit of detail its full blood count obviously we're looking for a normochromic 
er normocytic anaemia so just because there's less red blood cells being made 
also thrombocytopoenia er you may also find that the white cell count is either 
decreased or significantly increased er differential white cell count is also 
often abnormal er with neutropenia and the presence of blast cells coagulation 
screening er could be abnormal er particularly in promyelocytic leukaemia er 
such as A-M-L type M-three which we'll go onto later er when granules from the 
leukaplast-, lu-, from leukaemic blasts er can have co-, coagulent activity 
biochemical screening can also be important er might er imply there's some 
renal impairment er chest x-ray er can also show that there's a mediastinal 
mass er which you might find of patients er with T-cell A-L-L er and in 
childhood acute lymphoblastic leukaemia can actually cause er bone olysis which 
you might see in the chest x-ray er bone marrow aspiration is er essential to 
confirm er the acute leukaemia er it's usually hypercellular with a 
predomination of the blast cells which are the immature cells er 
immunophenotyping er is basically the way they determine whether the leukaemia 
is lymphoid or myeloid er cytochemistry can also be useful to confirm myeloid 
or monocytic origin er cytogenetics and molecular studies will be talked about 
more later but they can er have a great impact on the prognostic and diagnostic 
values and also lumbar puncture er in acute leukaemias this isn't so useful in 
in chronic it might imply there's some involvement of the central nervous 
system by the leukaemic cells er incidence as i say this only accounts for 
about ten to fifteen per cent of childhood leukaemia most childhood leukaemia 
is A-L-L er it's the commonest leukaemia however in adults er particularly as 
it can er progress from other conditions as we can see there myeloproliferative 
disorders and preleukaemic conditions like myelodysplasia er the incidence 
increases with age and the median presentation age is sixty er future 
management just briefly they're giving a combination chemotherapy and also bone 
marrow transplantation either from a sibling she does have an older brother er 
or from a matched unrelated donor and that's the lot thank you
nm5253: right so the er presentation of er acute leukaemia as we've said you 
can er work out really from the blood blood results these patients are anaemic 
er and they have problems with breathlessness tiredness whatever er the white 
count is very low usually having a neutrophil count of less that 05and when 
you've got a neutrophil count like that you are at risk of both bacterial and 
fungal infection in particular er so gram-negative er septicemia is common er s-
, infections with staphylococcal er infections often from infected er Hickman 
lines which are the central lines which are inserted into patients so that they 
can have their treatment and chemotherapy is a common and er persistent problem 
for patients that are neutropenic er and patients who have low platelet counts 
as most patients with acute leukaemia do are at significant risk of bleeding 
and bruising so the principles of treatment are based on the management of 
these perimeters and patients with low platelet counts with platelet counts 
usually less than twenty times ten to the nine per litre would have a regular 
platelet transfusions and i was just wondering if anybody can tell me how long 
a platelet actually survives routinely in a normal circulation
su: seven to ten days
nm5253: seven to ten days good okay and what about a red cell how long would a 
red cell
nm5253: okay well in the presence of er severe infection where you've got 
consumption of er different blood products the survival of cells is 
significantly shorter but it does mean that patients with acute leukaemias do 
require to have platelet transfusions often on alternate days and blood 
transfusions er perhaps not as frequently but once or twice er a month in order 
to maintain their haemoglobin they do require to have antibiotic prophylaxis 
because er being neutropenic it's often the organisms that are within their own 
gastrointestinal tract that cause problems it's not so much what you and i er 
necessarily infect them with it's what they've actually got within their own er 
intestines so while they are neutropenic they are at risk of bacteremia and 
septicemia er patients who develop pyrexias of thirty-eight degrees for more 
than two hours if they're neutropenic would then be treated with intravenous 
antibiotics and it's important that er such patients do have regular monitoring 
of their temperature er because er if you let them drift and remain pyrexial 
for twenty-four hours you may well end up with er an overwhelming septicemia 
and er a significant mortality that could be avoided so they're the general 
principles of er management er on a day-to-day basis on the ward for patients 
with acute leukaemia the basic treatment that they receive is cytotoxic 
treatment which consists of er multiple chemotherapy agents because we know 
single agents are not as good as if we use multiple agents and we know that if 
we give repeated courses of treatment certainly up to four or five courses of 
treatment then the risk of relapse is significantly less and if we look at the 
overall prognosis for patients with acute myeloid leukaemia we would find that 
approximately forty per cent of patients with acute myeloid leukaemia are cured 
it means clearly that the majority of patients still are not curable although 
up to seventy to eighty per cent of patients will go into a remission in other 
words there'll be reconstitution of the normal blood counts there will however 
in many of these cases remain molecular evidence of disease and there are 
important techniques to actually try and identify er which patients have got 
persistent disease in terms of chromosome analysis it's important at diagnosis 
to look at the er er chromosome make-up because certain translocations are 
associated with a good prognosis and certain translocations are associated with 
a poor prognosis and for those patients who have good prognostic er features er 
in particular the chromosome analysis er these patients may be curable with 
chemotherapy alone so for example patients who have acute promylocytic 
leukaemia which is a type of acute myeloid leukaemia wh-, which we've heard 
about that is associated with increased granulation in the cytoplasm but can 
cause er disseminated intravascular coagulation due to the release of a 
thromboplastin-like material from the granules if these patients actually 
survive the first few days and don't go into D-I-C they actually have a 
significantly better er long term prognosis er and this particular type of 
leukaemia is associated with a translocation between chromosome's fifteen and 
seventeen the majority however of chromosome translocation's are usually 
associated with a poorer prognosis and it is really for these groups of 
patients that er one would consider more intensive forms of treatment and in 
particular bone marrow transplantation so patients with poor prognosis er we 
would consider bone marrow transplantation from a sibling donor er shortly 
after establishing the patient into remission with standard chemotherapy are 
there any questions that you want to ask quickly about this because we've got 
all the other leukaemias and lymphomas to go through er anything anybody's yeah
sm5260: you talk about having a pancytopenia but then you get times of hyper-
leukocytosis you talk about obviously replacing what's lacking if you like er 
transfusion wise but don't you risk hyperviscosity if there is say a what do 
you in a 
nm5253: well er you're right some er patients with acute leukaemia at 
presentation have extremely high white blood counts er due to large numbers of 
blast cells and primitive cells spilling out into the peripheral blood if that 
is the case then er it is er a matter of urgency to reduce the white count 
because at a certain level usually around about a white count of three-hundred 
times ten to the nine per litre you can run into problems with leukostasis er 
and you can either do one of two things you can try and treat them with 
chemotherapy er as soon as you can really or you can mechanically try and 
remove some of the cells er on a cell separator and that er can at least buy 
you some temporary time er but it is er a a difficult problem and er it's 
probably even more so er er a problem with patients with chronic myeloid 
leukaemia that can present with really very high white counts right so er we're 
going to move on now and er learn a little bit about about chronic myeloid 
leukaemia and er we'll be able to c-, contrast the presentation the clinical 
features er with the acute leukaemias thanks
sm5258: this was a forty-eight year old gentleman who was admitted to the C-C-U 
er with chest who's complaining of abdominal discomfort and feeling of 
tiredness the chest pain was of sudden onset radiating up the sternum and 
lasting twelve hours er when he was pres-, when he presented to the C-C-U er 
the chest pain was actually absent there was no associated nausea or vomiting 
er pain was worse on lying flat and it was constant in nature er he did have 
left-sided abdominal discomfort and he found it very difficult to describe this 
discomfort he did suffer from weight loss over the last few months er he was 
previously fit and healthy his past medical history nothing to note he was not 
on any other medication er no known drug allergies er he was a non-smoker no 
alcohol he lives with his wife and two children who are all fit and well and he 
doesn't have any living siblings okay family history there was no relevant 
family history no history of heart disease or leukaemia or any cancers okay on 
examination er this gentleman was pale he had a mild fever which was thirty-
seven-point-eight degrees c he was alert and not dehydrated there was no 
jaundice cyanosis er edema or lymphadenopathy er cardiovascular system no 
abnormality was found pulse rate was normal er regular rhythm and B-P was one-
forty over ninety his heart sounds one and two were present and there were no 
murmurs okay respiratory rate same again no abnormality was found here he had 
vesicular breath sounds and his chest was clear on examination of the abdomen 
he did have er it was soft and tender particularly in the left upper quadrant 
his spleen was enlarged and just below the left costal margin okay C-N-S no 
abnormality was found right investigations er the first investigation that was 
carried out was a full blood count his haemoglobin was eight-point-four and it 
should be between thirteen and eighteen so it was quite reduced in this bloke 
er his white cell count was one-five -nine as you can see it's significantly 
raised right it should be between four and eleven his platelet was three-two-
six and that's er more or less within the normal range chest x-ray was found to 
be normal and his E-C-G was he had sinus rhythm there was no changes no S-T 
elevation depression and also cardiac enzymes were not elevated okay er in this 
patient er heart disease or myocardial infarction or angina was ruled out 
because we couldn't find any changes on the E-C-G er so his chest pain was 
actually attributed to a hyperviscosity of the blood er secondary to a 
increased white cell count so i'm not going to talk about the chest pain any 
more i'll probably go off on one that's why okay a differential diagnosis er in 
this patient we thought he might have myelofibrosis which is a proliferative 
disorder of the myeloid cells and fibrosis of the bone marrow but you would 
find a white cell count of a betwee-, between fifty and sixty er could also be 
chronic lymphocytic leuk-, leukaemia which is proliferation of lymphocytes 
which is mainly characte-, characterised by small mature lymphocytes and the 
absence of many of the precursor cells which are found in chronic myeloid 
leukaemia er acute myeloid leukaemia Rachel and Will have already talked about 
sarcoidosis er is a restrictive deficit and er this is er and it usually can 
present with enlarged hilar and enlargement of the spleen and so we cou-, we 
did think it might be this reactive neutrophilia also known as a leukaemoid 
reaction and this usually occurs due to exaggerated response to infection so in 
this patient we was we were mainly looking at er chronic lymphocytic leukaemia 
and chronic myeloid leukaemia er okay er we carried out a few more 
investigations to narrow that down and the blood film showed an increased eso- 
eso-, whatever count and occasional blasts and nucleated red cells a B-M 
aspirate in the B-M aspirate we look for er we just look for chromosomal 
analysis and the aspirate was found to be hypercellular with the presence of a 
Philadelphia Chromosome which Putri will talk about er soon er and that was 
present in the granular sized red blood cells and platelet precursors okay 
diagnosis this patient was diagnosed with er diagnosed with chronic myeloid 
leukaemia mainly due to the presence of the Philadelphia Chromosome he had a 
significantly increased white cell count he did have splenomegaly he had 
anaemia weight loss low grade fever and tiredness which are some of the classic 
signs of chronic myeloid leukaemia er this patient was managed on Hydroxyurea 
and Glivec which is a protein tyrosine kinases inhibitor and er a bone marrow 
transplant is going to be considered but Putri will mention that shortly as 
well okay
sm5257: right er i'm going to talk about er C-M-L the definition is it's an 
uncontrolled proliferation of myeloid stem cells the cells contain the 
Philadelphia Chromosome which is the diagnostic feature of C-M-L it's basically 
a reciprocal translocation from long arm of chromosome twenty-two to chromosome 
nine C-M-L is a progressive disease consisting of two phases a chronic phase 
and an accelerated advanced phase the chronic phase is actually signified by 
three it lasts for about three to four years and it might be characterised by 
systemic symptoms like weight loss amaemia fatigue er it i-, it is during this 
period that usually the diagnosis is made and treatment is offered to the 
patient but mainly on an er outpatient basis unfortunately every patient with C-
M-L does go into an accelerated or advanced phase it's er almost inevitable and 
this is when they stop responding to the treatment and they get increased 
anaemia and thrombocytopenia the prognosis is very poor at this stage and the 
only cure available at this moment of time well at this time is basically bone 
marrow transplant the incidence is one per a hundred-thousand per year and 
there's a slight male dominance over females er it's usually a middle-age 
disease and it occurs between the forty-fi-, forty to sixty-five year olds it 
constitutes twenty per cent of all leukaemias the clinical features are anaemia 
fever fatigue abdominal pain due to splenomegaly weight loss blurred vision or 
headaches this is due to the increased white cell count and bruising due to the 
decreased platelets the main investigations carried out are a full blood count 
in which you're mainly looking for the haemoglobin you're looking for platelet 
count and increased white cell count er U and E's er you'll do the blood film 
to look for an increased number of blasts and any mature granulocytes also er 
you're looking for a bo-, bone marrow aspirate to see hypercellularity and to 
check for the Philadelphia Chromosome which is again the main diagnostic 
feature you can also carry out an R-T-P-C-R which shows the expression of B-C-R-
A-B-L oncogene this is the oncogene responsible to produce tyrosine kinases 
which is required for the growth and proliferation of the cells er the 
treatment is oral hydroxyurea this is an orally active drug and it's a hydro 
carbamide but i'm not quite sure how it works er the other treatment is alpha 
interferons these these treatments are given during the chronic phase er this 
helps in haematological remission and aids in five to ten per cent of patients 
to get to get complete disappearance of the Philadelphia Chromosome Glivec or 
Imatinib is a protein tyrosine kinases inhibitor and it prevents growth and 
division of the leukaemic cells by blocking the signal transmission it also 
causes reduction of the Philadelphia Chromosome and the side effects are quite 
mild and easy to treat bone marrow transplant that's the only curative 
treatment for C-M-L using a matched sibling or unrelated match donor however 
it's restricted to younger patients below sixty years of age and there's an 
increased risk of relapse after transplantation autologous transplantation a 
lot of studies have been done on this trials have been done but the results 
have been quite disappointing so it's not used in daily practice so the 
prognosis of C-, C-M-L is variable but it the median survival is between three 
to five years and i'll pass it on to Doctor Rose
nm5253: er so chronic myeloid leukaemia is er a condition which er at the end 
of the day is really quite chronic and insidious in it's onset but at the end 
of the day is something which er ultimately will transform to a blast crisis 
and patients presenting with acute leukaemia following chronic myeloid 
leukaemia have a very poor prognosis indeed in fact it's just about universally 
fatal so the principles er of treatment and management are to try and prevent 
the er chronic phase of disease entering into the accelerated and then 
subsequent blast crisis so the standard treatments that are being used er such 
as hydroxyurea and er alpha interferon although we're not entirely sure the 
exact mechanism of how they work they do delay the phase er the chronic phase 
of disease er more recently er as we've heard already er we there has been a 
lot of er interest in the press about this tyrosine kinases er inhibitor this 
drug was basically built s-, specifically to er carry out the task of er er 
inhibiting the er B-C-R-A-B-L er gene from doing it's work and er this drug is 
now available and er if you look at the er chromosome level many of the 
patients who actually receive er Glivec er will go will er lose the er 
Philadelphia Chromosome and er it er certainly is a major step forward in terms 
of the management of a lot of patients with chronic myeloid leukaemia bearing 
in mind that only about twenty per cent of patients that you look for a 
transplant donor will you actually be able to find one er so the majority of 
the patients in the future are likely to be to be treated by Glivec and 
although it's unlikely to produce er molecular remission in a sustained manner 
it is a major er step forward in the treatment and management of patients with 
C-M-L er the drug itself i should say costs twenty-thousand pounds er a year 
and bearing in mind that many of the patients with chronic myeloid leukaemia 
might live fifteen years then as you accumulate these patients and they live 
longer so the finances get more and more stretched er but it is a major step 
forward in er in the management of er leukaemias er if you are in an exam and 
you er had a patient who had splenomegaly what would be your immediate er 
clinical er differential diagnosis it's the sort of thing you're bound to get 
in your finals isn't it so you need to be able to say something vaguely 
sensible about it right before i start picking on people er who's going to tell 
me what the differential somebody with a big spleen er would you like to tell 
us what you would er consider
sm5261: secondary to portal hypertension
nm5253: right okay so portal hypertension patients with chronic liver disease 
are a common reason to have splenomegaly and er er it would be sensible in your 
clinical exam to actually not just look at the spleen in sheer amazement that 
you've found it but to actually have some sort of plan as to how you're going 
to impress the examiner one point if you're going to talk about the 
differential diagnosis of portal hypertension would then to have been made 
clear that you've looked for other signs clinical signs of liver disease so if 
you find you're asked to examine an abdomen and you find a spleen then it would 
be very useful to actually er look for other signs of chronic liver disease 
okay so that is one reason what other haematological reasons might we what are 
you likely to have
nm5253: some blood so would you like to be a little bit more specific it's 
likely to be chronic problems aren't they because we're not going to produce 
people with acute leukaemia to sit in the outpatient area's and and have 
hundreds of people pummel their stomachs so i think chronic myeloid leukaemia 
that we've just been talking about is a good differential diagnosis so somebody 
with an isolated splenomegaly and the other condition that we've mentioned 
already is myelofibrosis whereby you get er extra medullary haematopoiesis the 
spleen will set itself up as a factory it'll produce er er or attempt to 
produce increasing numbers of haemopoyetic cells and er the spleen will enlarge 
and these patients have increased fibrosis in their bone marrow so particularly 
large spleens perhaps the first thing you would say is myelofibrosis portal 
hypertension would come close second chronic myeloid leukaemia would be in 
there and one other group of conditions that you would consider for somebody 
with an enlarged spleen
nm5253: well infections yes er you certainly can get increased splenomegaly 
certainly with things like glandular fever the splenomegaly in patients with 
glandular fever is usually tender again in er an exam situation these things 
are often transient they are not likely to be there er unless you've got some 
person who's come from abroad and has some form of chronic infection
nm5253: so you could have someone with a haemoglobinopathy er certainly some 
patients er with thalassemia would have er splenomegaly if they've still 
managed to retain their spleen and it hasn't been removed
nm5253: er yes some of the haemolitic anaemias again where you have er 
splenomegaly i think the other group that we're going to go on and talk about 
are patients with lymphomas and er er if you want to really impress your 
examiners again er when you've found the spleen not only do you look for 
evidence of chronic liver disease and you can say well this patients got 
splenomegaly there aren't any signs of chronic liver disease the other thing 
that would impress them would be if you actually went and were seen to be 
examining as to whether the patient had any enlarged lymph glands because if 
the patient has something like chronic lymphocytic leukaemia or the patient has 
a lymphoma then you might score some extra points by actually showing that you 
actually are thinking one step ahead so as part of your clinical examination 
for an enlarged spleen you have a differential diagnosis a myelofibriosis 
chronic myeloid leukaemia lymphomas and er chronic liver disease so i think 
they're worth all considering right we're going to er go on now and er discuss 
some of the er clinical situation r-, relating to lymphoma patients and we're 
firstly going to have a case of a patient with a high grade non-Hodgkin's 
lymphoma
sf5255: okay Paul and i are going to be talking about lymphoma and we'll try 
and keep it as brief as possible er the two main different types of lymphomas 
are divided by Hodgkin's and non-Hodgkin's lymphoma Hodgkin's is characterised 
by Reed-Sternberg cells and every other lymphoma falls into non-Hodgkin's 
lymphoma basically it's a cancer of the lymphoid tissue and it can be 
characterised on their biological features and also on the clinical behaviour 
and once you work this out you're able to f-, put them into a classification 
and then stage them on the disease our patient was a twenty year old girl 
presented in September two-thousand-one with shortness of breath chronic cough 
and anaemia she subsequently had a chest x-ray which revealed wide mediastinum 
and left hilum shadowing which is of huge medical emergency in this age group 
er there was no significant past medical history the only medication she was on 
was an oral contraceptive pill which was for contraception reasons er at the 
time she was living with her parents taking her A-levels and this obviously 
affected how she did in her exams and i think she had to postpone them for a 
while er she didn't take dr-, well she didn't smoke and she doesn't drink and 
there was no significant family history the significant findings on examination 
were the anaemia the stridor er an increased respiratory rate and actually no 
splenomegaly or hept-, heptaomegaly er as she had no splenomegaly or 
heptaomegaly i thought i'd just look at the causes of lymphadenopathy which has 
sort of been discussed already however the best way to probably divide them is 
through infection and malignancy er infection could be then subdivided into 
viral bacterial and protozoal and at this age group you're probably thinking 
along the lines of glandular fever er also malignancy which we've had two of 
the cases discussed already and obviously she falls into the non-Hodgkin's 
lymphoma category the most likely causes for this patient will be non-Hodgkin's 
lymphoma and sarcoidosis and the investigations have already been kind of 
discussed by Will in great depth so the main thing's that we'd be looking 
looking for on our investigations were the biopsy to actually type the lymphoma 
and also the C-T scan to actually stage the disease so she had a mediastinal 
lymph node biopsy which is not typical but as she had no other lymphadenopathy 
anywhere else we had to biopsy the lymph node when i say we they did and the 
histology revealed that it was sclerotic and necrotic tissue an atypical 
lymphoid population indicative of a high grade N-H-L the er immunology showed C-
D-twenty and C-D-seventy-nine-A which i believe are B cell markers and the C-T 
scan indicated that she was stage one by Ann Arbor staging which just means 
that she had er one lymph node group above the diaphragm and so therefore she 
was diagnosed with non-Hodgkin's B Cell Lymphoma the treatment was quite 
extensive which isn't always true for all non-Hodgkin's patients she we-, 
underwent six cycles of C-H-O-P and then had a C-T scan which revealed there 
was no real progress so then she under went two more cycles of E-S-H-A-P a 
positron emissions tomography revealed then that she still needed further 
treatment which was Chemo B-E-A-M er therapy after this once she was in the 
clear she had autologous peripheral stem cell rescue er the good thing about er 
this type of non-Hodgkin's lymphoma is the fact that it's got a curable rate 
and using ch-, in-, intensive er chemotherapy twenty to forty per cent of the 
patients under the age of sixty will actually be cured
sf5255: Paul will be discussing C-H-O-P in great de-, detail and E-S-H-A-P is 
just another chemotherapy regime which i don't know what the letters stand for 
but i'm sure if you ask er Doctor Rose he'll actually go through that with you 
er thank you so three days post-transplant she developed a fever which was 
treated appropriately with antibiotics and I-V fluids however on administrating 
the I-V fluids through her Hickman line er they noticed that she was developing 
a swollen neck and anterior chest so on investigation they found that it was a 
fibrosed sub-, er superior vena cava and also thrombosis in the subclavian 
vessels one of the main complications of chemotherapy is fertility and ovarian 
dysfunction and unfortunately is had an early onset of menopause which is 
currently being treated by hormonal therapy she recently er visited outpatients 
in June two-thousand-three and seems to be cured as she has no symptoms or 
signs of recurrent lymphoma her L-D-H and F-B-C are both normal and she's off 
to university in September two-thousand-three er the prognosis for this girl is 
actually very good and age is a huge thing that er influences your prognosis so 
what i've done is use the age adjusted I-P-I instead and this is just based on 
your L-D-H levels your extra nodal involvement and the stage and so her score 
actually came out as a zero which is a really good prognosis and it corresponds 
to eighty-three per cent five year overall survival and that is it and you can 
ask questions now to Doctor Rose instead of me
nm5253: so p-, patients with er high grade lymphomas er are potentially curable 
and er although high grade lymphomas have a much faster cell turnover and er er 
contrast to patients with a low grade lymphomas er they do in some respects in 
for younger patients you could say have a in some ways a better prognosis er 
patients treated with high dose treatment er are potentially curable er 
patients with er treatment with chemotherapy if they've not relapsed usually 
within two years of finishing their chemotherapy are likely to be cured this 
does contrast with patients with Hodgkin's disease because patients with 
Hodgkin's disease can relapse anything up to ten fifteen years after their 
initial chemotherapy er so it is important to er be aware of that i think one 
or two other things recently that have come out about we're talking about 
Hodgkin's disease now for a few minutes are that patients with Hodgkin's 
disease despite their initial chemotherapy up to five ten fifteen per cent of 
these patients are developing second malignancies er these malignancies vary 
from er acute leukaemias through to patients developing er problems with er 
bone marrow function where they develop myelodysplasia through to patients 
female patients er developing er problems with er breast cancer and er some 
very high percentage of patients who've been treated with er Hodgkin's disease 
are now actually g-, develop subsequent breast cancer and it is recommended 
that patients with Hodgkin's disease now are screened on a regular basis really 
female patients er with mammography thereafter er the overall chances of going 
into remission with er different stages of Hodgkin's disease do depend on the 
actual stage of disease if you have localised disease er then this is 
potentially curable with a radiotherapy to those particular sites for patients 
who have stage four disease and by that we mean have extra nodal disease or 
bone marrow involvement these patients have a significantly worse prognosis 
with approximately fifty per cent long term survival so for a disease that we 
tend to think of as very curable if you happen to have stage four disease at 
presentation there are still a lot of patients who require very intensive 
treatment and for these patients if they relapse they would require to have a 
stem cell bone marrow transplant er er in order to try and salvage these 
patients er for patients with er the low grade lymphomas we'll hear the 
treatments are very different and these diseases behave in a entirely different 
indolent manner again so it is important to actually make the right diagnosis 
and the most important thing in terms of management of patients with lymphomas 
is to actually get a proper histological assessment and diagnosis er and the 
histological assessment can be aided again by a chromosome analysis er as 
certain lymphomas associated again with certain specific er chromosomal 
translocations er so it's important to make the er accurate histological 
diagnosis it's important to have chromosome analysis again wherever possible 
right well we're going to hear a case now of er low grade non-Hodgkin's 
lymphoma and we'll just contrast the clinical presentation with patients with 
high grade disease i think the only other thing i want to say about the high 
grade lymphoma was with this particular case was the fact that this patient 
presented with a mediastinal mass and er young people presenting with 
mediastinal masses do represent medical emergencies they can cause er stridor 
and if you remember stridor is an inspiratory wheeze so if you get a young 
patient who comes in with a leukaemia or lymphoma it's important to get a chest 
x-ray that day because these tumors can grow really quite rapidly and some T 
cell acute lymphoblastic leukaemias and high grade er T cell lymphomas can 
result in you know er compression of your airways really quite quickly so it's 
important and that would be again represented er an urgent clinical 
presentation of a lymphoma thanks
sm5259: okay er so i'm just going to do a case presentation on a low grade 
patient who had follicular lymphoma right so a thirty-eight year old gentleman 
he presented to his G-P er January last year he had a swollen right leg which 
he'd had for six months and he also had bilateral inguinal masses er the reason 
why he'd waited six months before he went to see his G-P about it was that he'd 
previously fractured his femur and thought it was i-, in some way related to 
that and also he said that he'd recently put on weight and thought it might 
just be something related to that as well er but as it turned out he he saw his 
GP and he referred him on to the haematologist via the two week cancer referral 
scheme er additional history er as i said he had fractured right femur 
following an R-T-A he was on no medication no significant family history er 
he's married and he has three children he works as an engineer lecturer and he 
says that he previously worked in the petroleum industry and there is said to 
be some association with exposure to ben-, er i think it's benzine and 
developments of lymphoma er and yeah he was a non-smoker so significant points 
in this patient er he had unilateral lymphoedema er with his lymph nodes they 
were enlarged greater than one centimetre they were firm rubbery and non-tender 
and he'd had these for six months significant er negatives were the fact no 
recent history of long haul flights no recent trauma no source of infection and 
no signs of inflammatory or connective tissue disease okay so differentials so 
he had unilateral leg swelling so you'd be thinking venous disease and 
lymphatic disease er in terms of his er lymphadenopathy it'd be very similar to 
what Jo said in terms of the infections so you think viral bacterial and 
protozoal and also primary and secondary malignancies can cause that okay so he 
was referred on to the haematologist and on examination he noted there was 
generalised lymph node enlargement er there was no sign of splenomegaly 
although subsequently he's developed that er and he had no history of night 
sweats fever or recent weight loss er and these are so-called B signs okay er 
so the investigations that he had he had an ultrasound of his right leg to rule 
out a thrombus er he had microbiology to rule out any infection er they all 
came back negative for any pathology so he had some more investigations he had 
er a inguinal lymph node biopsy histology indicated this to be a non-Hodgkin's 
low grade follicular lymphoma and it was positive for C-D-ten C-D-twenty and 
also this B-C-L-two protein which is overexpressed due to a translocation from 
chromosome fourteen and eighteen er which results in overexpression of this 
oncogene er and that's present in this patient er he had a C-T scan and that 
indicated that he had diffuse bulky disease he had a bone marrow aspirate and a 
core biopsy of the right iliac crest er and this helped stage the condition and 
it indicated that it was er diffuse infiltration with small lymphoid cells in 
the bone marrow so this patient was discussed at the M-D-M and he was diagnosed 
with bulky disease stage four so treatment right he was started on C-O-P which 
is cyclophosphamide vincristine prednisolone er he had four cycles of that and 
this was all done as an outpatient er with three weeks in between each cycle 
after the first four cycles he had a C-T scan and that indicated er there was 
no significant reduction in er lymph node size so he had four more cycles 
following that he had two month break from chemotherapy er during inguinal node 
er re-enlargement so he started back on C-H-O-P which is a more aggressive 
chemotherapy and added to that was this er Rituximab er and the difference 
between C-O-P and C-H-O-P is that you have er one chemoth-, chemotherapy agent 
called doxorubicin hydrochloride and the significance of the er Rituximab is 
that it's a monoclonal antibody er which causes slices of B cell er B 
lymphocytes and it's specific to C-D-twenty which this patient was positive for 
er right future treatment options so patient responded well to this er final 
course of C-H-O-P he had six cycles of that and he went into remission 
following it however although he's in remission now it's not curative there 
isn't actually any cure for low grade lymphomas and when it does reoccur it 
they're going to have to require er more aggressive chemotherapy er that type 
of chemotherapy's going to re-, result in bone marrow destruction therefore at 
the present he's having er peripheral stem cell harvest so that that can be 
stored and er later on he can have that infused and er used as a bone marrow 
transplant unfortunately he had a sister but she wasn't a suitable er 
transplant patient okay and that's it
nm5253: so er low grade lymphomas are often slow growing but indolent they 
don't respond very well to a particularly to aggressive treatment and the more 
aggressive you are with them sometimes the more resistant they are they do 
respond to er low grade er treatment with er oral chemotherapy certain 
alkalating agents in particular chlorambucil er is a useful agent and er these 
are not curable conditions so if you have a patient presenting with diffused 
lymphadenopathy in middle age who hasn't got a particularly high lymphocyte 
count to exclude chronic lymphocytic leukaemia then the likelihood would be 
that they've got a a low grade er diffused non-Hodgkin's lymphoma in terms of 
the classification of lymphomas over the last twenty years there have been 
something like fifty different classifications of non-Hodgkin's lymphomas and 
er you could look through er most pathology and histology text books over the 
last er er few years and you will find a different classification in every text 
book there is a er an agreed classification at present which is the W-H-O 
classification which is worth looking at at least to give you some idea as to 
what the current nomenclature is in terms of classification of different 
lymphomas but basically on a clinical level you need to be able to distinguish 
between high grade and low grade non-Hodgkin's lymphomas you need to be able to 
identify the patients who have Hodgkin's disease in terms of immunological 
diagnosis it is important to differentiate B cell conditions from T cell 
conditions in general T cell disorders carry a worse prognosis certainly 
patients with chronic T cell lymphomas er do particularly badly they're often 
associated with skin infiltration and er again are indolent and tend to be 
rather resistant to treatment are they any questions you've had an hours worth 
of being drilled with information about high and low grade lymphomas patients 
with acute and chronic leukaemias so i think yeah
sf5262: er i think this was mentioned before but can you say again the 
difference between Hodgkin's and non-Hodgkin's
nm5253: right well Hodgkin's disease is characterised by the presence of Reed-
Sternberg cells in the bone marrow er these are large cells which have an owl-
like appearance and er er are read-, usually readily identified on er 
histological examination er they are believed to be the malignant cell in 
patients with er Hodgkin's disease and they probably are an early B cell er 
malignancy
nm5263: about half of them are positive
nm5253: right yes er 
nm5263: can i can i ask a question somebody mentioned B B signs what are A signs
nm5253: sorry the A-A signs sorry B-B in terms of the clinical signs you've got 
er you can classify somebody as being A or B and it really means absence or 
present and the B clinical signs are the presence of fever drenching night 
sweats so it's not somebody just feeling a bit hot and you know bit of a clammy 
night and coming in and it's drenching night sweats so that they have to change 
their bedding they have to change er their nighty or whatever er and it's 
significant weight loss so something like a stone in the last six months in 
weight er and loss of of appetite so the you need to be a little bit er firmer 
about when you're actually attributing somebody to have B symptoms patients 
often also have fever and it's important to identify the type of fever that 
they've got er in Hodgkin's disease you can get this Pel-Ebstein fever which 
the temperature remains elevated for two or three days goes down and then comes 
up again or sometimes you can just get a persistently raised er high 
temperature with it sorry er yes you were going to
sf5264: er i was just wondering if there were like diagnostic criteria do you 
need all three or would you maybe just get the one or two
nm5253: you may just get one or two but if er you're getting drenching night 
sweats then that patient would be er classified er as a as a B type patient and 
it does seriously affect the prognosis to these patients because if you have B 
symptoms your prognosis in general er whether you've got Hodgkin's or non-
Hodgkin's disease is significantly worse and often when patients relapse you 
may not necessarily even be aware of any lymph glands or something like that 
but the first thing that they actually notice is that their drenching night 
sweats have come back or er the most disappointing thing is between courses of 
chemotherapy if they come along and tell you that they're still getting 
drenching night sweats after a fortnight after the chemotherapy's finished and 
you're pretty well sure that the treatment patients are resistant to it and you 
need to be thinking of changing your management
sf5265: can i just ask er you were talking about er prognosis er and you were 
saying that you looked at full blood count i can understand er that but L-, L-D-
H as well er 
nm5253: yeah the L-, L-D-H er is er it's a liver enzyme er but it it's also 
very useful er it's also present in red cells but it is has also been shown to 
be of er good prognostic er value in patients with lymphoma and it's also 
particularly useful in monitoring response to treatment so er round about 
thirty to forty per cent of patients with high grade lymphomas will have a 
raised L-D-H and er these patients you can use it to monitor the management and 
er also in patients who are again otherwise well if they come to clinic and you 
check their L-D-H and it's suddenly shot up then again that's often an early 
indication that the disease is shortly to become active
su: i was wondering if they've used er umbilical cord stem cells for treatment 
in this country
nm5253: if we take for example a patient with chronic myeloid leukaemia chronic 
myeloid leukaemia can affect patients at all ages and er er i'll give you an 
example round about seven or eight years ago we had a mother with chronic 
myeloid leukaemia who did not have er a sibling transplant donor and er she was 
pregnant and she did have her stem cells harvested er on the basis that they 
might be er potentially useful er in those sort of situations er you know there 
may be er a situation there that you would actually use er er you know cord 
cells they're not commonly or routinely collected and it isn't routine practice 
in the U-K er usually for patients who haven't got a a sibling donor you would 
look on the computer systems in the U-K and further afield to look for a 
matched unrelated donor there are one or two places certainly in Bristol they 
are collecting er lots of er er stem cells from er you know foetal stem cells 
er but it isn't er part of the routine practice but i think if you had a mother 
who was pregnant who had a baby then you might seriously think about 
potentially using them
su: do you know how successful it is in other countries
nm5253: er i mean they have been done with some success but they're not it's 
certainly not mainstream or or routine practice by any means
nm5263: the thing about cord blood er is if it is for of of somebody else it's 
just like any other and the cord blood is very rich in stem cells and if you 
take er cord blood from your child of course that's that's an donor the same as 
your sister would be the thing about about cord blood if if you can think ahead 
sufficiently so that you score it against the risk of your developing leukaemia 
in later life er that may be very valuable because of course that'd be er er an 
autograph but you've got to think ahead or your parents have to anyway
nm5253: i think the other thing to say about bo-, transplantation is that most 
people would believe that er transplantation is successful and and cures 
patients really because it induces graft-versus-host disease and er it is that 
graft-versus-host disease effect which is important actually in the treatment 
er for example where patients have had transplants from identical twins these 
patients er more commonly relapse with the er original disease so people have 
tried to look at ways of er mimicking or instituting you know graft-versus-host 
disease er in order to you know as actually part of the er experimental regimes 
in terms of management of patients with leukaemias
nm5263: so generally graft-versus-host or is it graft-versus-tumor
nm5253: well it's graft-versus-tumor
nm5263: yeah nice distinction isn't it
nm5253: it is right there must be lots of other questions any-, anybody want to 
ask any of this distinguished panel any question before you leave
sm5260: it is a bit of a er off the beaten track but you mentioned D-I-C 
earlier in the talk
nm5253: yes
sm5260: er there's a bit of confusion from what i've read that people say 
you'll have to er use thrombolysis because of all the clots around the body and 
other people argue you can't do that you have to give F-F-P what is 
nm5253: yeah er er i don't think that there would be anybody who would 
seriously consider giving thrombolysis to somebody with overwhelming er 
disseminated intravascular coagulation you could er er bearing in mind that 
most of these patients er not only are thrombosing but they also bleed and they 
bleed because they're got severe thrombocytopoenia at the same time they do get 
er er consumption of the coagulation factors so they can thrombose but at the 
same time er eventually they end up with er quite a severe bleeding diathesis 
and to actually routinely talk about using er er lysis of clots er is not er 
you know would be v-, highly dangerous and most of these patients would bleed 
to death quicker than they will do otherwise er so the aims of treatment would 
be to really to damp down the process of consumption of clotting factors so 
replace clotting factors in fresh frozen plasma but particularly to give 
platelet transfusions because the reason most of these patients die is because 
they bleed because of the thrombocytopoenia
sm5257: what's the prognosis like if you give er platelet transfusions because 
apparently the patients don't respond to it after a while
nm5253: er platelet refractoriness is is a serious problem and many of the 
patients do develop antibodies and can become refractory to er platelet 
transfusions er you can give H-L-A matched er platelets er for those who don't 
get an adequate increment after you've given er standard platelet er donations 
er but it is a er quite problem actually er and certain many of the patients 
with acute leukaemias who have repeated and recurrent courses of chemotherapy 
and then you want to go on and g-, have a bone marrow transplant if they've got 
antibodies then it's all the more difficult for them to actually go through 
that right any-, anything more are you all dead or you're all you've had enough 
you're right well c-, can i just say er thank you very much to er all all of 
you who have taken part er this evening and er thank you very much for coming