Christopher FletcherProfessor of Pathology at Harvard Medical School, Director of Surgical Pathology, Brigham and Women's Hospital, and Chief of Onco-Pathology, Dana-Farber Cancer Institute, Boston

Interview location: His office at Brigham & Women's Hospital, Boston.
Interview date: 20th November 2007


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SA:  Where did you grow up and what sort of family do you come from?

CF:   My father was a surgeon, and my mother was a social worker.  I grew up in the North of England.  I was partly educated in the north, and then went to Winchester public school and then did my medical training in London, at St. Thomas'-as-was – now, God knows: United Medical and Dental School of something, since it has merged with both Guy’s and King’s.

SA:  How influential were your parents in deciding your career?  Did you grow up under your father thinking you wanted to be a medic?

CF:  I probably never thought of doing anything else, actually -- which sounds terrible!  But my father was not impressed when I went into pathology.  From his point of view, being an old fashioned surgeon, he regarded the pathologist as one of the surgeon's handmaidens.  He decided I'd done okay by the time he retired, but originally he thought it was a terrible thing to do.

SA:  So when you say you'd never thought of anything else, what did you want to be originally?  A surgeon, a physician? 

CF:  Well, I didn't have any preconceptions.  But because my father was a very hard-working surgeon who I didn't see a great deal of when I was a child, I thought, "well, I like medicine, I enjoy what it's there for.  I think it serves a purpose.  But I don't want to end up being in the hospital 22 hours out of every 24."  And during medical school I discovered I did quite well at pathology (I did fine at the clinical things too, actually), but then something caught me about pathology. I won a couple of prizes at medical school, and it just seemed to be the thing.  So I chose it.  I end up now working far more hours than he used to as a surgeon, but that's beside the point! [Laugh]

SA:  Was pathology well taught at medical school?

[It] forms the underpinning of understanding all these different disease processesCF:  In those days it was very well taught.  It was a very important part of the medical course, and there was a whole block of three months during your clinical years when you were taught nothing but pathology.  All of that is largely disappearing around the world...[sighs].  But it forms the underpinning of understanding all these different disease processes.  I mean, I did relatively well in all my final exams at medical school based largely on what I'd learnt in pathology.  Because most of it's actually there in pathology, apart from which pills and which creams and things. So...

SA:  And did you have some inspiring teachers in pathology?

"Some amazing teachers"

CF:  It was a very strong department in those days, St. Thomas' was.  There was a well-known man called John Tighe, who was vice-president of the Royal College at the time, and who set very rigorous standards.  And a man called Michael Hutt, who was professor of geographical pathology.  He was very special because he had spent a lot of his time in Africa -- mainly because of his religious beliefs, I think, although you better not quote me!  But anyway, he set up one of the first medical schools in central Africa, in Uganda, and there were no pathologists so he had all these specimens sent from Africa.  We used to do all the stuff from Malawi and Tanzania and other places [at St. Thomas'], so we saw astounding pathology that you would never ever have seen in central London.  And he was very inspiring.We used to do all the stuff from Malawi and Tanzania and other places [at St. Thomas'], so we saw astounding pathology that you would never ever have seen in central London

Then there was another famous man called Herbert Spencer, who used to be the doyen of lung pathology, along with a man called Brian Corrin, who's currently professor at the Brompton in thoracic pathology.  So there were some amazing teachers in the department.

SA:  So did you immediately think, when you were doing pathology, "this is the area I want to be in"?

CF:  It's hard to remember in detail.  I remember at the very beginning being a bit bored, because when you don't know what you're doing and you haven't got enough to occupy you…I thought, "well this is a bit limp."

Traditionally, when you learnt pathology in England, you also had to go and learn some microbiology and chemical pathology -- you know, chemistry, and haematology The branch of medical science concerned with the blood and blood-forming tissues;  haematopathology is concerned with diseases of., and immunology.  And I didn't like those bits very much.  I got bored silly watching machines going round and printing out numbers, so I used to sneak back to histopathology the whole time -- which used to piss off the other departments! But within a year or eighteen months I discovered I loved it.  But the very first little bit?  I think it's true, actually, of any training: when you first start you think, "My god, this isn't what I imagined it would be."  And then you either cotton on or you don't.

SA:  When you did discover you loved it, what particularly thrilled you?

70-80 percent of clinical decisions in a hospital are based on either laboratory results or radiology results, and those account for only 7-8 percent of the hospital budget in any given city.  In other words, value for money is huge, in terms of impact on clinical care.
CF:  I think it was realising that it's the underpinning of so much medical care.  I mean, you're the one who's making the diagnosis.  Very often you're the one who's actually telling the surgeon, or the medical oncologist, what they need to do next.  They never tell the patients that, but half the time we're, if you like, guiding them to their clinical decision-making.  Of course they're the sort of infallible Alpha males sitting there with the patients, but actually they've often got no fuckin' idea until we tell them what it is! [Laughs].  Often they say, "Well gosh, what's that?  And what do I do about that?".  Particularly in the area that I've become so-called 'expert' in, which is soft tissue tumours and SarcomasA sarcoma is a cancer of the connective tissue (bone, cartilage, fat) resulting in mesoderm proliferation. of the limbs, they often are relatively clueless outside of specialist centres. So...

There's a wonderful statistic -- and the problem is I don't know where it comes from -- but it's something like: 70-80 percent of clinical decisions in a hospital are based on either laboratory results or radiology results, and those account for only 7-8 percent of the hospital budget in any given city.  In other words, value for money is huge, in terms of impact on clinical care.

Pathology in the doldrums…

SA:  Well then why has pathology managed to find itself in the doldrums?  As you say, it's the foundation of medical understanding and medical care...

CF:  Well, it varies around the globe, except that, the world over, patients have no clue what pathologists do, I don't think.  Most patients have no idea who makes the diagnoses, and they don't know whether or not the diagnosis is difficult either.  For them it's a black and white thing…But I think one thing that has screwed pathology, or academic medicine, in England is this dramatic division between research and clinical service, and 'never the twain shall meet'.  If you're a service person you better sign out a pile of cases in a given time.  And if you're a research person you better raise research funds, otherwise your medical school is failing.  And that completely kills any clinical or translational research at a stroke, and demoralises people terribly. 

The department I was in, there were no NHS appointments at the time, we were all senior lecturers, readers, professors and things, and we did the service work and the research.  And the idea that you can separate those -- and then decide that one group is more important than the other, depending on how the medical school views it -- is terribly destructive.

Then the media thing with Alder Hey clearly did a lot of harm.  I think that was very demoralising.  I don't think the NHS is a very supportive environment at the best of times.  They don't make the doctors feel good, and my feeling is that that hasn't changed. 

SA:  And what about here?  What is the status of pathology in the US?

High morale at Harvard

Christopher FletcherCF:  It's certainly not perceived negatively in any way, and there are no morale problems.  I mean, to give you an idea, we take 10 trainees a year from medical school to train in pathology and this year we have 470 applications.  So there's no shortage of people wanting to do pathology, and I think it's more widely appreciated how clinically important it is.

To give you some basic, practical examples.  We're mainly a tertiary centre, like a big teaching hospital or the Dana Faber Cancer Institute next door, who we do the pathology for.  If a patient comes from elsewhere with a diagnosis of X for treatment in the big centre, the clinicians here won't lay a finger on them until we've reviewed the pathology.  I mean, it's a hospital bylaw, you know, "Thou shalt not do anything until you really know the diagnosis is right."  When I left England it wasn't the norm to have the slides reviewed at all.  I believe it's beginning to be now, but it certainly wasn't a requirement then.  If somebody in Nottingham said it was X and the patient went to get treated in London, nobody thought "We'd better check whether Nottingham was right."

So there's a sense among clinicians here that pathology is very important. I think, actually, the concept of surgical pathology -- which is what you're really talking about, diagnostic HistopathologyHistopathology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining a thin slice (section) of tissue under a light microscope or electron microscope. -- was partly created in this country.  And it was created largely by surgeons, believe it or not, who wanted to have diagnostic answers.  Pathology was always a research thing, with a [diagnostic] report being a secondary phenomenon, and I wonder if in England that problem was never really addressed.  I mean, there were always these serious academic types that people respected, but maybe somehow the pathologist was never really integrated into the fabric of clinical care in the same way that they are here.  I really don't know…that's a tough question.

SA:  Looking at your own personal journey, when you started in pathology what really thrilled you?

CF:  Well making a diagnosis, influencing the decision-making, educating clinicians – and being a patient advocate.  I mean, nowadays, when there are all these tinier and tinier biopsies, and clinicians want black and white answers as fast as possible, it's kind of our job to say, "No actually you haven't given me enough tissue to decide whether it's benign or malignant."  Or "Well it's X, and you really need to be doing Y." Because there's a tendency, especially in this country, to over-treat.

So those are the things…I mean even now, when I'm essentially almost a full time administrator, it's diagnosing lumps and bumps in the evening that I still get most fun out of.



Setting up The Soft Tissue Tumour Unit

SA:  Before you came to the US, when you were in London, what sort of patient 'profile' did you have?

CF:  When I started out as a trainee, it was just the same as any large hospital, and I developed an interest in soft tissue tumours -- things in limbs and retroperitoneum and chest wall and things.  I continued to do general stuff, but that was my research interest.  Then I got a grant from the Cancer Research Campaign to establish a thing called "The Soft Tissue Tumour Unit", and we even set up a clinic at St. Thomas', with two orthopods [orthopaedic surgeons], me, and a general surgeon.  I used to go and see the patients with them as well, and patients started coming from all over. 

For some years I concentrated just on soft tissue things, and then one's reputation grows a bit and I now get an endless stream of weird lumps from all over the world.  They're mainly soft tissue.

SA:  So can you remember what interested you at first about these things?

CF:  Why did that happen?  Well that's a silly story!  There was a faculty member in histopathology at St. Thomas' at the time who was a skin pathologist (a dermatopathologist), and dermatologists the world over like to be able to 'sign out' their own pathology.  (In the US that's because it's a source of income, and in England I think it was more a historical thing).  There were some areas they were very ignorant in. And the skin pathologist at St. Thomas' …when I was a baby trainee, someone came to him from the skin world and said, "Will you please write a review article about how you diagnose SarcomasA sarcoma is a cancer of the connective tissue (bone, cartilage, fat) resulting in mesoderm proliferation.?" (Those are the malignant things in the limbs and what-have-you). He just went looking for a trainee, and he said, "Okay, somebody's going to write this… You can be first author, it'll be good for your CV ", sort of thing.  And for no special reason I said I'd do it.

I got very interested, and what was going to be one review article actually became a series of four, which were kind of well received.  And during the course of that I read and looked at lots and lots of cases that I found in the files.  I just discovered that I liked it, and we started doing little projects, and it just went exponentially from there.

SA:   So what was the state of knowledge of soft tissue tumours at the time?

By the time I left England I was getting about 1,500 cases a year, and I now get 4,500 a year.CF:  Well, it hadn't been a real focus of interest.  There were one or two sort of internationally recognised experts.  But there was no molecular biology at that time, no genetics, and because soft tissue tumours are relatively uncommon compared with things like breast cancer and lung cancer, people had difficulty gathering large numbers of cases sufficient to work out properly how they behaved, or what the prognostic factors were, or who's affected by them.

For every malignant one there are about 100 benign ones. Through getting referral cases, consultation cases, you gradually build that stuff up.  It's strange, I got my first consultation case in 1987, when I was still a registrar, believe it or not.  By the time I left England I was getting about 1,500 cases a year, which, in the UK, was huge.  You can get 100 of something that other people only see six of in a lifetime, and it helps you work out how they behave and so onThat was by far the biggest consultation for any type of pathology at the time.  And I now get 4,500 a year.  So you get enormous numbers of rare things, which enables you to put together definitive information on how a certain tumour behaves.  You know, you can get 100 of something that other people only see six of in a lifetime, and it helps you work out how they behave and so on.

SA:  And what exactly is soft tissue -- breast is also 'soft' tissue, so what's the difference?  Tell me about these cancers.

CF:  Well these are tumours of what we call Mesenchymal cellsFusiform or stellate cell's found between the ectoderm and endoderm of young embryos; the shape of the cell's in fixed material is indicative of the fact that in life they were moving from their place of origin to areas where they would become reaggregated and specialised; most mesenchymal cell's are derived from established mesodermal layers, but in the cephalic region they also develop from neural crest or neural tube ectoderm; they are the most strikingly pluripotential cell's in the embryonic body, developing at different locations into any of the types of connective or supporting tissues, to smooth muscle, to vascular endothelium, and to blood cells. .  So it's cells that make the connective tissue -- the supporting tissue like fibrous tissue, smooth muscle, skeletal muscle, adipose tissue, nerves, blood vessels, all those things.  That's what the pathology world means by 'soft tissue'.  And of course all of those things are ubiquitous, so you get tumours that will show those lines of differentiation [ie. composed of mesenchymal cells] in almost any anatomic site.  I mean, you can get a blood vessel tumour just as well in your heart or your leg or your bowel, as anywhere, because everywhere has got blood vessels.

SA:  And how common are these things?

Soft tissue things are notorious for the difficulty of separating the benign from the malignantCF:  Well, world over, for malignant ones, there's about the same incidence as testicular cancer and Hodgkin's Lymphoma.  They're about equal to that. But for every malignant one there are about 100 benign ones.  There's lots and lots of benign things.  And when one looks down a microscope one doesn't necessarily know intuitively whether it's benign or malignant.  There's quite a lot of the benign things that are rare, and that down a microscope can look malignant to somebody who doesn't see them very often.  Soft tissue things are notorious for the difficulty of separating the benign from the malignant. 

SA:  And you say your unit was the biggest in Britain…?

CF: Our referral practice became the biggest in any sort of pathology in Britain at that time.  For some reason sending cases as referrals or consultations hadn't been such a big thing.  It's not clear to me why.  Maybe people never used to worry about rare things. Or they used to show them to their pals down the hallway and they'd say, "Well, it's probably that", and that was good enough...I don't know.  But people in the 1980s began seeking second opinions for difficult or weird things.  And soft tissue is over-represented in that regard, in the sense that they're more difficult. 

Miseries of the marketplace

And that's why it became problematic for me. This was the time when Margaret Thatcher was trying to make healthcare market-driven.  The idea was, if I remember rightly (and  it’s almost 20 years ago), that if a patient went from Brighton to London to have their hip replaced, the health authority in Brighton had to pay the health authority in London for doing it.  In other words, if Brighton couldn't do a procedure, then they had to use some of their budget to pay someone else to do it.  And I ended up with this large consultation practice -- as I say, it grew to 1,500 cases a year -- which nobody had ever had in pathology before, and some administrator got the idea, "Oh here's the perfect example of market-driven. There are pathologists around the country saying, 'I need to send my cases there'.  So what we'll do is ask him to send bills for his services, and if what he does is worthwhile the health authorities will pay for it.  And with that money he'll be able to pay his support staff." 

Remember, nobody had ever sent a bill for a referral before.  And it was frightful --   people went berserk.  The government folks provided me with all this paper work that I was supposed to make people fill out -- forms they'd never heard of, forms that hospital administrators were only just learning about and getting to grips with.  And then because we were part of the European Community, they said, "Oh we can do it Europe-wide"!  (They were at that stage saying, "If an Italian tourist comes and has appendicitis in London, then the Italian government owes the English government something.")

SA:  Oh my goodness!  Did you get completely strangled by it?

I got crucified by my colleagues
CF:  I did, I got completely strangled.  I got crucified by my colleagues, who said, "How come you're charging for consultations when nobody else does? Where did this come from?  Never heard of this!  Fuck you, I'm never sending you a case again!"  That sort of thing.  It became quite a little cause celebre at the time.  The Royal College was supportive of me, and the president at the time, an immunologist named Peter Lachmann, came to visit and to show his support.

It ended up being on television.  Channel 4 made a documentary for the Dispatches series about "a group of specialist services that were being crucified", and I was the pathology one that was picked.  There was a bone-marrow transplant service, I think, for children at the Westminster, and they had an oncologist who said, "People can't get round the bureaucracy to enable them to send their child to us, so children are dying..." Of course it was dramatised for the sake of television.  And it was in the newspapers too.

SA:  So what would have happened if you hadn't charged?

CF:  They wouldn't let me do the work.  It was very simple. They said, "You're not going to spend your time doing that unless people pay for it."  And of course nobody did.  I mean, we collected peanuts.  There were a few pathologists... No, that's unfair -- many pathologists felt sorry for me.  A few of them felt motivated enough to bully their administrators to sort the forms out and make sure some money got sent between the two health authorities, but it was piddling.

SA:  And so did you find that the number of cases being sent to you dried up as well?

CF:  Oh well it was a funny combination, because I was getting better known, so it was  on an upward trajectory. But then some hospitals would say, "We're not going to engage in this," so it probably would have gone up faster if it hadn't happened.  And the people who worked for me, the hospital put them on monthly renewable contracts because of the uncertainty of my financial situation.

SA:  Oh how awful!

CF:  Well it was awful.

SA:  How long did that last for?

CF:  About two years.  At some point the administrative people began to realise the system wasn't working, so they were less draconian about it, and in the end kind of turned a blind eye and just assumed I was going to lose money.  I mean, they never took away the implicit threat.

There was one special story that actually I haven't shared in public, but I suppose it doesn't matter now, since it’s so long ago.  One of the major family charitable foundations in the UK who were big backers of the Conservative Party thought this was a travesty.  Some small, dapper gentleman [check dead??] came to see me and said, "I just want to learn a little bit about what you do and what the programme is."  So I explained, and he said, "Oh, I think we'll go and look into this..." They went to see Virginia Bottomley, who was the health minister at the time, and said, "Look, you're destroying what this man does.  If you like, we'll endow it, we'll call it the Soft Tissue Unit; we'll give it a couple of million pounds and it can live off the interest.  Because what you're doing is not working, and it's silly, and it's actually making a fool of your attempts to make healthcare market- driven." 

Virginia Bottomley told them to fuck off.  She said, "If we admit that this is a failure, then it'll make us all look fools."  So this dapper little chap -- you know, expensive overcoat and everything -- came back a couple of months later and he said, "I'm terribly sorry, we've failed.  But we think this is awfully wrong so we'd just like to help you in the short term."  And he handed over a cheque for £50,000, which was a lot of money at the time.  He said, "I hope you can find that useful in some way or other." It was amazing!

SA:  So were you able to go on practicing good stuff during that time?

I got thicker and thicker skinned. When [Harvard] tried to recruit me, it wasn't very difficult to decide where I'd be better offCF:  Well yes, because I got thicker and thicker skinned.  I even started writing in some of my letters, "I'm enclosing this form as I am required to do.  Please return it if you can..."  I phrased it in some way that said, "I know this is bullshit", without saying that explicitly.  It started out being terribly stressful, because one thought, "We're just going to be closed down."  Then one realised that most people thought it was important, and that this was more of a political thing than anything else, and in the end I just gritted my teeth and thought,"Fuck it!"  But when [Harvard] tried to recruit me, it wasn't very difficult to decide where I'd be better off.

Cutting through the confusion of cancer categories

SA:  Absolutely.  But tell me a bit about some of the cases you saw.  I want to know about the sort of development of this as a speciality -- your research and your growing expertise in this. 

CF:  What you're really saying is, "What's changed in these 20 years?"  I now see so many it's hard to think back. Nowadays we average 25 new cases a day from all over the world.  And remember, these are cases where people [pathologists] have got stuck -- in other words, they're disproportionately difficult.  So it's somewhat divorced from reality because you get such a biased sub-set.  But what we've achieved over the 20 years is: we've defined or described for the first time lots of tumour types that were not formerly recognised.

SA:  Like what?

CF:  Well, to give you a general principle, it's things like tumours that were formerly thought to be malignant and you get enough cases and follow them up and discover they're not.  Things that were formerly confused -- you know, benign and malignant lumped together, and we've split them apart.

Probably the single biggest thing…  When I was a baby trainee in the 1980s, the commonest sarcoma (meaning malignant cancer in the soft tissues) for the preceding 20 years had been something called malignant fibrous histiocytoma, or MFH.  It was supposed to account for 65-70 percent of adult sarcomas, and they had variable behaviour, variable response to chemotherapy, and variable outcome.  And we showed over a period of time…

I published a paper in 1992 that said, "This actually doesn't exist."  It's like lumping lots of different kinds of dogs together and calling them all Mutt, and losing the fact that some are Pekingese and some are Irish wolfhounds. These tumours behave differently and respond differently to treatment.  And that has been a very hard thing to overturn.  Because if you think: all these patients all over the world have been diagnosed with something that everybody was rooted in for 25 years, and that the preceding generation of pathologists all firmly believed in

It just bothered me that no two looked quite the same.  They just had some overlapping things that they shared, but in sub-classifying them you found ones that were terribly aggressive versus ones that weren't particularly; ones that were very chemo-sensitive, versus ones that were not; ones that just had a very different outcome.  We published that in 1992, and in the 2002 World Health Organization classification it was acknowledged that MFH doesn't exist.  Now everybody is getting to learn this, and clinicians and so on.  That, I think, has probably had impact on patient care, so it's worth doing.

SA:  So before that, how did they used to treat these tumours?

CF:  Well, you know, surgery plus some radiation or chemotherapy.  But they wouldn't know which ones needed to be treated more aggressively than others.  They wouldn't be able to sit with a patient and say, "You're in trouble" versus "You should do okay".  I mean, they were all just lumped into a sort of, you know, "Fifty percent of you die and 50 percent of you don't, and we don't quite know which..."  It was just sort of dogma.

SA:  And how were you able to tease them apart?

A lot of that was done by looking down a microscope, not using modern molecular biologyCF:  Not using modern molecular biology.  A lot of that was done by looking down a microscope at lots of cases, and then using this technique immunohistochemistry, and electron microscopy.  So fairly ordinary tools.  Which is what I still use for a lot of what I do now.  I mean, I have the benefit here -- and the pleasure -- of being integrated with lots of geneticists, and we've done other things too.



Unhappy bed-fellows: basic research and clinical services

SA:  But it was literally just the number of times you saw these things...?

CF:  Observational mainly, yeah.  Which of course in the academic world is not hypothesis-driven, and therefore it's sort of trivialised.  That's one of the weird things about the sub-set of funded medical research that's relevant to health care -- it's negligible, as I'm sure you're beginning to discover.  In this country the NIH [National Institutes of Health], which hands out these billions of dollars in research funding, supports very good science that understands basic disease processes, but the amount of that that actually ends up being relevant to patient care is negligible.

SA:  And why is that?  Because it's hypothesis-driven?

CF: Yes, and it's basic science.  It's almost a self-propagating thing.  I mean, it's perceived as important, and for many people it's the be-all and end-all.  In fact that's the definition in many countries of what represents good pathology. In the traditional countries, England being clearly one of them, basic science was what gave you credibility. 

SA:  That's interesting.  Are you saying you come to research from a different angle – that what you're observing from more and more real cases is what raises the questions?

It's clinical research, it's not basic research.  But there's no question it has direct patient impact CF:  Yes, at least from my own perspective.  And then utilising tests to try and objectify that, so it's not witchcraft.  It's, you know, "I think that these may be showing a certain line of differentiation so let's see if they express these proteins to support that," or whatever. " And then let's see if that means anything in terms of behaviour."  It's clinical research, it's not basic research.  But there's no question it has direct patient impact.

SA:  And that's what you've been involved with most?

CF:  Yes.  And loved it.  Still do!

SA:  You say you get this stuff from all over the world -- are you seeing different things from different geographic locations?

CF:  Not dramatically different, no, there aren't huge geographic differences.  There are some.  I mean, it's quite interesting, this is not my area of expertise, but I think for example, gastric cancer is significantly different in Japan from here, and colon cancer's also very different.  Those are things that are driven by diet and environmental things.  With the soft tissue things that I deal with there are no data that they're environmentally influenced.

SA:  What do the data show?

The big taboo: cancer treatment as a cause of cancer


CF:  That we have no clue what causes most of them!  Just no clue at all.  There’s a subset that are associated with radiation -- usually for a prior malignancy, not because you live next door to a telephone pole or something, but because you've been radiated for some other cancer.  That probably accounts for 10 percent of them.  And that’s interesting, because we’re seeing more and more.  Nowadays ladies tend to have lumpectomies and radiation for breast cancer, instead of having mastectomies, so lots of women get radiation they wouldn’t have got 20 years ago.  And we’re seeing more and more radiation-induced vascular tumours of the skin of the breast. 

You try and tell the radiation people this and they don’t want to hear -- because again there’s so much dogma.  And breast cancer is such a politically sensitive issue with all these incredibly vehement advocacy groups, so I mean that’s a battle one’s never going to win.  But it’s quite striking.  As I travel around the place giving talks and meeting people, it’s quite clear everybody’s seeing the same thing -- these radiation-induced lesions in the skin.

And the problem is that it’s a swings and roundabouts thing.  It’s something nobody ever talks about in medicine.  You know how nowadays everyone proudly announces that they cure children of most of their cancers?  You see all these little bald children, and we all give money and stuff.  A huge proportion of them come back in their 20s and 30s with secondary malignancies induced by the treatment they had when they were little ones.  But that bit doesn’t get talked about so much.

That becomes a moral or ethical thing because after all, if you’ve given someone 20 years of life, I’m sure most people would say, “Well, that’s not a bad outcome is it?”  I mean, they all would have died if they hadn’t had the treatment.  And it’s question of whether they should have died at 18 months or aged 25 of something that the treatment caused.

SA:   What sort of secondary cancers do they tend to get?

CF:  Well by far the commonest one is because you’ve wrecked the bone marrow with chemotherapy, so they get what’s called myelodysplastic syndrome.  The screwed-up bone marrow predisposes to all sorts of leukaemias.  Of all those little children that get radiated, a significant subset will come with a radiation-induced cancer years later.

SA:  And that’s the sort of thing you’re seeing?

CG:  Yes absolutely, because some of them are sarcomas.  Nowadays the thoracic oncologists recognise that they’re seeing radiation-induced lung cancers in patients that had breast cancer treated 25 years ago and survived.  They’re getting lung tumours in the field behind the breast, and that sort of thing.  But again you’d say, “Well, hey, if they were going to die of breast cancer 25 years ago, it’s not a bad deal is it?”  But it’s not one of the things that really gets talked about a lot.

Challenging dogma

SA:  That’s very interesting.  I’ve actually heard others say that it’s very difficult to challenge dogma – sometimes people can’t get their papers published if they go against received wisdom.  Do you find that’s difficult, when you come up with some new knowledge which is really counter to what people are believing?

CF:  Well that thing I told you about, the MFH thing, that was very hard to get that published.  The norm when you submit things to most pathology journals, whether clinical or basic sciences, is that there are two peer reviews.  And then an editor looks at it and decides whether or not to accept it.  It took six reviews, I think, before they accepted the MFH paper, and then it took 18 months before it was published, and they claimed they’d lost the manuscript and all sorts of crap!

I think that’s changing a little bit, though.  One of the things I think is a strength, and what’s changed in diagnostic surgical pathology (I’m not talking now about basic science) in my career time, is that it’s become more objective -- it’s more reproducible, evidence-based.  Because one of the things that led the basic science guys to be critical of the clinical people (and I’m talking now 1960s and 70s) was that a lot of the clinical stuff -- before the introduction of technologies like immunohistochemistry, electron microscopy, molecular genetics -- was all a matter of opinion.  It was really almost who had the biggest balls.  You know, “I say it’s so and so”, and if you’re big and famous then it is so and so! 

Now it’s much, much more objective, and there is less dogma around than there was There was an awful lot of dogma associated with it.  And you’d go to meetings where famous people with different points of view would just sit and argue, but there was no right or wrong.  And it made me understand why basic scientists would say, “Well this is all bullshit.”  Now it’s much, much more objective, and there is less dogma around than there was.  There were lots and lots of dogmas when I was a baby pathologist.

SA:  What d’you think has changed that?  Is it the culture?

CF:  Yes, it’s that, plus ancillary techniques so that you can actually disprove nonsense – or prove truth, or whatever.  And then it’s much harder for people to argue.



Genetics springs some surprises

The more genetic information that’s discovered, the more you find that completely different tumours have identical genetic signatures It is interesting.  You’ll meet people during this process who'll tell you that, "Well molecular genetics are going to objectify things even more.  And you won’t need people like Fletcher anymore, because actually we’ll be able to decide by a pattern of gene expression or a chromosome translocation that it’s so and so.”  But what’s fascinating in my area, (and I think it’s also true in leukaemias), is that the more genetic information that’s discovered, the more you find that completely different tumours have identical genetic signatures.

SA:  Really?

CF:  Oh yes.  There are wonderful examples of that -- which the molecular genetics guys don’t like to talk about.  That’s another thing that gets pushed under the carpet.

SA:  But how?  I mean, give me an example.  That’s absolutely fascinating.

CF:  Well there’s one, ETV6-NRK3, it’s a gene fusion from a chromosome translocation that was thought to be specific for a thing called infantile fibrosarcoma in children.  It’s a tumour that grows in the limbs that looks hideous and you give it chemo and it disappears.  Exactly the same chromosome translocation has been found in a specific type of breast cancer which is actually rather aggressive.  And in a type of leukaemia.  So in other words, the same initiating chromosomal event, depending presumably on what cell type it happens in, gives you three completely unrelated tumours.  But if you didn’t have pathologists, and you said, “Okay, here’s a bit of DNA from this tumour – tell me what it is”, it could be any one of those three!  But people don’t like to talk about those things…

SA:  Goodness gracious!  That’s absolutely fascinating.  Did you discover those things?

CF:  We have discovered some similar things in the more recent past, but not as dramatic as that -- that’s the most dramatic example I can think of.  A lot of these things happen anecdotally, and anecdotes are not good to put in this, but I’ll give you an example.  I had a tumour from a child’s chest-wall in Oklahoma some time last year, which I thought was a certain type of cancer which is actually very indolent -- it has only a 2 percent risk of spreading, so if you’ve got to have cancer, this is a good thing to have.  You just cut it out.  The pathologist in Oklahoma had sent a piece of tissue for genetic testing which had come back with a result that suggested it was a thing called Ewing’s Sarcoma, which is a terribly aggressive tumour.  It's almost invariably fatal without chemotherapy, and the child would have to have two years of chemo as standard practice.  We probably see more of these soft tissue things than anybody in the world now, and it does give you a unique perspectiveSo, understandably, the man in Oklahoma said, “Well, I hope you don’t mind Dr Fletcher, but I think I ought to get some other opinions as well, because this is kind of a tough call. You say it’s one thing, and the genetics say it’s something else.”  They sent it to two famous pathologists who said, “Oh yes, this is definitely Ewing’s Sarcoma.”  I said, “I’m completely sure it’s not. This is not right at all.  I’m going to get some friends at the Memorial Sloan-Kettering Cancer Center in New York, and we’re going to sequence this gene thing and work out what it is."  Which we did, and it turned out it didn’t match with what you see in Ewing’s Sarcoma. 

But then, as part of that work, we screened 15 cases of the sort of cancer I thought it was. And 13 of the 15 cases -- which were all bona fide, no question cases [of this indolent type of cancer] -- all had exactly the same genetic event as the thing that I’d found in the Oklahoma one.  And it turns out – without going into enormous detail – that through that piece of serendipity, one actually discovered the genetic event which gives you this other, indolent type of cancer, which has since been validated in another study from Europe which will come out soon.  So that’s one of the things where the genetics would have completely misled the whole thing if one relied solely on looking for EWS gene rearrangement (as is often done in Ewing’s Sarcoma) – because the indolent sarcoma type had a quite different EWS fusion gene partner.

SA:  But what made you think it was not what the other pathologists thought?  What did you see that made you feel this was the indolent one?

I hate the sort of arrogance that often goes with expertise.  At the end of the day we all have things that we don’t know CF:  Okay, some people would say, “Oh it’s because he’s skilful”, but the reality, I think, is that the more you see…this happens to be my area, and you see a ridiculous number of cases.  I mean we probably see more of these soft tissue things than anybody in the world now, and it does give you a unique perspective.  One has to kind of share that in a nice way, because I hate the sort of arrogance that often goes with expertise.  At the end of the day we all have things that we don’t know what they are.  And in many ways…it sounds kind of sappy to say, but I feel it’s kind of a privilege.  They trust you, they say, “Oh I’m stuck, I’ll send it to you.”

And another thing to do with pathology practice, specially in the US -- often when people have cases sent as a referral they will send a letter back saying, “Dear Dr X, this is a so and so.” You know, just two lines.  And I tend to write long letters that say, “This is why I say it is what it is, and this is why it isn’t what you thought it might have been.”  Because I think there’s a kind of a mutual education process that goes with this.  And I think that’s maybe why people send more things – because they don’t feel patronised.  Someone hasn’t written back and said, “Hey you asshole, I know what this is, and you don’t”!  [We both laugh]  Which is how some of those letters can be received.

SA:  And I should imagine also that’s what makes people stick with the dogma, if it’s an unpleasant experience to admit you don’t know something.  People can easily get stuck in their ways.

CF:  Oh of course.  And it’s much easier too: black and white.  I think that’s another big change that’s happening in pathology and that I talk about in lectures nowadays. 

We all like to think of benign and malignant as black and white, and we all hope that pathologists can separate them.  But more and more we realise that there are a lot of tumours we can’t predict.  And we’re beginning to talk instead about things like risk assessment, instead of just a binary yes/no. 

But then what we’re also seeing – and again it’s through the bizarre nature of the materials I see – are things that look benign and banal down the microscope that then metastasise and kill people.  And you say, “Well how is that possible?”  In fact, most pathologist, when you tell them that, say, “Well don’t be silly, they’re just obviously misdiagnoses.  Somebody screwed up.”  But one realises over time – and it comes back to genetics again – it’s probable that these things, although they look the same down the microscope as quite common things, have had some other genetic event that says, “Okay, I’m capable of getting into a blood vessel and spreading now,”  which we don’t know how to recognise.
But only if one gathers outlying cases like that could one ever think, “Well, okay, let’s find what’s different genetically or molecularly between those and the other ones, because maybe that provides information about other sorts of cancer as well."  So even if those are terribly rare, ridiculously rare, they may provide valuable information for understanding the whole process.

The importance of sharing uncertainty

SA:  So it’s a sort of cumulative thing.  You need a great library of knowledge and samples, I presume?

CF:  Oh absolutely.  You’ll have seen people with little sort of brown lumps on their lower legs?  They’re called dermatofibromas, and they’re terribly common, fantastically common. They’re banal and benign, and in fact some people believe they’re not even tumours.  It was realised, maybe five, six years ago, that once in a blue moon these things can actually spread and kill you.  And the first few reports, you could sense disbelief.  In fact people would write letters to the journal saying, "Well this case is clearly a misdiagnosis.  I can’t believe you published that" and all the rest of it.  It’s the dogma thing again -- "It can’t be, because it’s a benign thing…"  We now have 12 or 14 of those, and at some point we’ll have to try and work out how they differ.

SA:  Ones that have gone wild?

CF:  Yes, ones that have gone bad.  But only by gathering a reasonable number, with follow up, and then working with them will one ever discover what’s happened.  And then if you find out what it is that’s happened to them which we can’t see down the microscope, then maybe that enables one to find a readily applied test, or a stain, which says, “Okay the bad ones have lost expression of some protein.”  And if we then stain all the things that look the same, we might find one in a thousand or one in ten thousand that’s lost the protein, and then we could say, “Well that one might behave aggressively.”  I mean that’s very simplistic, but…

SA:  Yes, but of course looking down the microscope you’re looking at a point in time of an event, aren’t you?  And if you looked a week or a month later you might see something completely different.

CF:  Yes, absolutely right, yes.

SA:  So how do you get round that, and encourage people to question what they’re seeing?

There’s a significant subset of referral stuff where you have no idea what it is CF:  Well, it sounds stupid, but by writing long letters explaining why one thinks what one thinks, based on prior experience or whatever.  And the other thing is trying to be completely objective.  To turn it round another way, because we see all these things that people get stuck with, I write lots of letters every week which say, "I’m awfully sorry, I’ve got no idea what this is."  Sometimes I say, "I don’t know what the cell type is, and I’ve no idea whether it’s benign or malignant."  Other times I'll say, “It looks horrible, but I don’t now what it is.”  Or “Hey, it looks terribly benign, but I don’t know what it is.”  There’s a significant subset of referral stuff where you have no idea what it is. 

It was almost a sign of weakness to say “I don’t know.”
Twenty years ago experts didn’t like to say, “I don’t know.”  That’s a generalisation, but there was a general trend that it was almost a sign of weakness to say “I don’t know.” So they’d force it into some category and say, “This is an example of X”.  I can remember, as a baby trainee I’d see these reports, and I’d think, “How the hell did they call it that?  That’s very clever!  I must be deficient in some way.”  But now I routinely say, “I don’t know,” or “I think it’s this but I don’t know how it’ll behave.”

You know, if you’re willing to share uncertainty…I try to teach pathologists to share uncertainty with clinicians, because surgeons , as you know, are pretty dogmatic, and they want to know: "Benign or malignant?"  But life isn’t like that, and the more experienced ones know that. The surgeons and oncologists that understand pathology are much better doctors than the ones that don’t, because they have a much more realistic sense of what they’re dealing with, and the uncertainties that exist.  Of course there are some things that are hideously malignant and we all know they are, and at the opposite end they’re benign. But there’s a hell of a lot in the middle.

SA:  But do you find then, the more you are in pathology, that the more complex it gets?  And the more you realise you’re seeing differences the whole time?

There are personality types that go with specialties, aren’t there?
CF:  Yes.  And my goal is to try and get other pathologists to see that – and also to be brave enough to educate clinicians.  There are personality types that go with specialties, aren’t there?  You know, surgeons tend to be gung ho bullies – a generalisation! Orthopods are kind of big, grinning people with large hands who aren’t that aggressive; psychiatrists are kind of weird; and paediatricians are highly strung.  I think pathologists are some kind of combination of shy and retiring, or mentally atuned to being in a service role. In other words, we wouldn’t have a job unless people sent us tissue, and we’re doing our work for someone else -- we're not the ones who actually tell the patient it’s benign or malignant. (Although when you end up being a specialist, you have more and more patient interactions, but that’s an oddity.) I think there’s probably a personality type goes with this, and a Lot of pathologists don’t see it as their role to educate clinicians about the uncertainties or unpredictabilities
lot of pathologists don’t see it as their role to educate clinicians about the uncertainties or unpredictabilities, whereas I must say, I feel the reverse.  I feel quite strongly about it, and I’m sometimes a bit outspoken – but not in an excessively rude way! [He laughs] But it works. For example, in this hospital, pathology is a highly respected specialty and there’s a real sense of a need for what we do.  And I try and get the trainees to take the same approach.


The pathologist and the patient

SA:  So have you got good communication with the clinicians and do you think it’s important that there’s good interaction?

CF:  Terribly important.  Now, for every one of the things they call 'disease centres' in these big tertiary hospitals – if there’s a ‘head and neck group’ or a 'breast group' or whatever -- we have pathology representation in all of those.  And when people are designing clinical trials where they’re looking for end points that might involve taking a biopsy to see what’s changed, they’re all now learning that they have to come and talk to pathologists first, rather than it being an afterthought, because sometimes their expectations are unrealistic.  So I’d say we’re doing quite well on that front.  But it requires, for want of a better word, advocacy and education.  If you’re passive, or don’t provide answers, then of course they’re not going to respect you.

SA:  Okay, so tell me about your contact with patients, because, as you say, this is unusual.

CF:  Well in England it happened because we set up this clinic.  At the beginning people would send pathology slides saying, “What is it?”  And then it progressed to, “…and my surgeon says what should we do about it?”  So we got an orthopod and a general surgeon involved and I said, “Why don’t we have people send cases here?”  And so we gradually had more and more patients being sent to St. Thomas’.  When they started out, the two surgeons didn’t really know that much either, so I had to kind of get them interested -- which they became and they were wonderful.  Then I would see the patients with them.  I don’t know if we ever mentioned that I was a pathologist or not; we often mentioned that I was the one who made the diagnosis.

Some people do go into pathology to avoid patient care, but I loved it When the surgeon was on vacation, I would just see the patients on my own, for follow up and what have you.  And often when there was bad news to share with the patient it  got turfed to me to go and sit with them and say, “I’m awfully sorry, you know, you’ve got lung metastases,” or something.  Or when patients refused the surgery that was needed, it often ended up being my job to go and talk to them to explain what would happen if they didn’t – because it was supposed to be me that was the authority.

Some people do go into pathology to avoid patient care, but I loved it.  I loved contact with the patients.  I never had any problem with that.  But now, it’s interesting, the world’s changing with everything being electronic.  I get emails and phone calls from patients all over the world saying, “I’ve got this, what do I do about it?”  That’s becoming the norm, I think.  Or when people have sent the cases here for me to look at and I’ve sent my letter back to the pathologist, in this country it’s now the norm that the pathology report is given to the patients (or the patients all expect to see it),  so they know who I am, and they’ve got my address.  That’s becoming the norm in other countries too, I think.

There are all sorts of patients – they range from highly neurotic, silly requests to people who are just grateful.  I had an email just yesterday from a young man in California who said, “You diagnosed the lump in my throat, and they said I should get it radiated, but what do you think?”  And I said, “Well actually what you’ve got isn’t malignant, so I’d think twice about getting it radiated, because you don’t know what that may cause down the line.  How about going to a surgical oncologist to see if they can cut it out for you…”  I mean, one doesn’t give direct advice because you don’t want to undermine whoever their existing physician is.  And you don’t know the particular circumstances.  But you can provide general guidelines.  And people on the whole are very grateful.

SA:  But what do clinicians think?

CF:  Most of them are pretty grateful.  In fact more and more so – and maybe that’s just the luck of becoming perceived as an expert (because after all what’s an expert?  I’m not much better than I was 15 years ago but I wasn’t perceived as much of an expert 15 years ago).  If you’re perceived as such people are generally willing to listen.  And so in my letters I quite often say, “I think this should be treated such and such a way,” and they generally say, “Oh thank you, that’s great, that’s really helpful.”

And more and more letters come saying, “This is a lump in a 16 year old’s knee.  What is it?  And my clinicians would like to know what you would recommend for treating this.”  That I think is quite unusual.

 “Not enough hours in the day…”

SA:  So go back to where we were ages ago -- you ran your clinic in London and got strangled by the bureaucracy, and then what happened?

CF:  So this department at Brigham & Women’s was looking for a director of surgical pathology and I got asked to come and interview and was offered the position.  And that’s another wonderful thing in medicine – if you’re good at something then you get hired to be an administrator, and you spend all your time in committees!  So I came here, and now my main job is administrative.  We have a huge department.  We have 75,000 surgical specimens a year.  I have 60 odd faculty who work for me, and 40 odd trainees.  There are more than 100 doctors who are all in some way or another related to surgical pathology.

SA:  And do you mind doing administration rather than looking down a microscope?

CF:  I don’t mind.  It’s just that there aren’t enough hours in the day to do everything.  I enjoy doing the best I can, but I’m realising there has to be some implosion point because you can’t do everything.   Now, as you 'grow' young ones around you, they can become the front end of some of the academic productivity.  I can give projects to junior faculty or residents for the research things, and we can do them together, because I don’t get time to write as much as I used to.

SA:  And do you have some good juniors?

CF:  Oh wonderful.  This is regarded as one of the strongest departments in the country, so there are some fabulous people.  Seventy percent of our trainees have PhDs in addition to their medical degrees before they even start in pathology, so they’re very impressive.


A medical mystery: how do tumours arise?

SA:  What are you researching at the moment?

CF:  God, we have about 20 or 30 projects going at any time!  They range from describing more tumour types that we’ve identified – things that people had never imagined that are going to cause a certain amount of controversy. 

On a quite separate note, here’s a really anal example: most people have traditionally thought, naively, that tumours arise from their normal cellular counterparts.  So if you’ve got a smooth muscle cell then you can have a smooth muscle tumour.  Or if you’ve got a fat cell then you can have a tumour made of fat cells.  And in the soft tissue things I've been talking about, the truth is we’ve no idea at all what cells they arise from.  I mean, most tumours showing skeletal muscle differentiation arise at sites where there isn’t any skeletal muscle…  So it was obviously nonsense all along. 

SA:  So do you mean you just get a little clump of foreign cells in a foreign site?

Your finger tip has got the gene in it that made your pituitary gland as well CF:  Well no, what it is I think…My humble belief is that you can take almost any cell type and if it undergoes a sort of genetic catastrophe that says, “You can go bad now” , it can then reprogramme and show a different line of differentiation.  Because remember, if you think about it, every one of your cells has got your entire genome in it.  Your finger tip has got the gene in it that made your pituitary gland as well.  It’s just that during embryogenesis that gene was switched off because that was going to make a finger cell, not a pituitary gland cell.  But the information is there.

So to give you an example (and nothing as bizarre as growing a pituitary in your finger tip!)…Anywhere that you make secretions, like the breast or salivary gland, you have ducts, and around those ducts there are things called myoepithelial cells -- they’re the things that actually make the ducts squeeze so that saliva comes, or breast milk comes or whatever.  Normal myoepithelial cells are only ever found around ducts in organs like that, but we started finding myoepithelial tumours in all sorts of ridiculous places -- in deep soft tissue of people’s legs and things -- where there are no ducts of any kind.  And it was interesting, they must always have been there, but it’s just that people didn’t recognise them -- they had the blinders on, because, you know, "You can't possibly have a myoepithelial tumour there". 

Within less than three or four years, 100 more cases of something that didn’t exist before in theory

All of a sudden you have 100 of something that half the world says is impossible
We started describing those in the late 1990s, and it was almost like a revelation to people.  They said, “Oh I never thought that could happen!”  And I was then sent, within less than three or four years, 100 more cases of something that didn’t exist before in theory.  Of course it existed, it’s just that none of us were open eyed to it, and all of a sudden you have 100 of something that half the world says is impossible.  We now have way more than that.  And we’ve now gathered a whole series of malignant ones in little children which are very aggressive -- and they’re a type of tumour that people never even thought children could get, let alone in these bizarre places.  That’s one of the things which is being published at the moment.

SA:  So children who had got them before they were even recognised, what happened?  They just died and nobody knew what of?

CF:  Well they died, and they were probably just forced into categories that weren’t correct because they couldn’t think of anything else.

SA:  So when did the scales fall from your eyes?

It keeps happening all the time. “That looks weird; it reminds me of these other things …”
CF:  Well that’s the sort of thing I like about this – it keeps happening all the time.  You see something and you think, “That looks weird; it reminds me of these other things …”  And you sort of put them away in the back of your mind.  These things happen over a period of years. You think, “I’m sure we’ve seen seven or eight of those now,” and then, thank God for computer data bases, you can find them. (In the old days you had to find them all in those little books [he gestures towards a row of well-used hard back exercise books on his shelf], they’re all hand written.)  You gather things together, and then you usually wait for some follow up, because without follow-up data it’s not really valid.  And then you present the stuff. 

It’s what I love, when you go backwards and say, “Okay, let’s find all of those things that I’ve been seeing…” Usually when I start recognising them I’ll call them something like -- you know, it sound ridiculous! -- ‘distinctive gelatinous thing’.  It’s not a diagnosis, just a way of remembering them when I don’t know what they are.  And then I say, “Okay let’s get out all those things that I called ‘distinctive gelatinous thing’.”  And it’s a wonderful sensation, because nine times out of 10 you look back and they all look exactly the same, even though you’ve collected them over a 10 or 15 year period.  Then you say, “Okay, let’s find the follow up and work out what they are.”

The cancer without a name

It’s a real thrill. And when it’s clinically useful

– I mean, to me that’s what matters 
It’s very pleasurable. Oh yes, it’s a real thrill. And when it’s clinically useful – I mean, to me that’s what matters.  For example, we’ve got a thing which we haven’t published yet – and I don’t know how we’re ever going to persuade people to recognise this – which we see in young patients.  They develop multiple nodules, usually in one limb, in the skin, or muscle or bone.  Lumps and bumps. And then if you use some fancy scan you usually find they’ve got 10 or 15 lumps.  Down the microscope they look like a thing called epithelioid sarcoma, which is a nasty type of cancer.  And so we used to think they were some funny variant of that for a while. 

Then after a bit you realised you could recognise them just down the microscope without knowing that there were multiple bumps.  And then you knew that was valid because I'd say in my letters, “I’ve seen cases like this where they’d subsequently develop multiple lumps.  Please scan the limb.”  They’d scan the limb and say, “Wow, you’re right. We’ve got eight or 10 lumps!”  So that’s kind of the first thing that tells you you’re on to something.  Then you’d think intuitively and you’d say “Well, right now we don’t have any follow up data, but my gut feeling is this isn’t good.”  Apart from anything else, to treat them you’re going to have to cut the limb off, because if they’re all over, in the bones and things, there’s no way you can cut them all out. People have to treat them quite radically. 

You assume that this must represent a pattern of spread in some strange way, not that the patient has suddenly grown 10 identical tumours at the same time.  Therefore you intuitively think this must be bad.  But, 'touch wood', we now have about 25 of these cases and not a single patient has developed distant disease.  Not one of them.

SA:  So it just stays within the limb?

CF:  Yeah.  So it’s clinically distinctive, intuitively horrible, and yet turns out to be – I won’t say ‘benign’ because I think we have to follow them for a long long time.  I don’t believe they’re 10 different tumours – though they might be!  This might be some limb-wide genetic defect!  Who knows?

SA:  So is that one of the things you’re investigating?

CF:  Yes, absolutely.

SA:  And what are you trying to find out?

You could pull every medical text book off the shelves and you’d not find it.  They don’t even have a name CF:  What the hell they are!  I mean, they don’t 'exist' right now.  You could pull every medical text book off the shelves and you’d not find it.  They don’t even have a name.  (I’ve got a name I call them in my letters.)  We’ve had a couple of patients here with this disease, and people will say, “Well, hey, how do you know what this is? And what do I do about it?”  I go and sit with the family over in Dana Faber and say, “Look, we’ve seen 20 cases and they seem not to spread, but I can’t promise you they don’t spread.”  I mean right now we’ve only got two, three, four years of follow up, and we’ve all learnt that cancer can be a long-term disease.  20 years ago people used to say that if you survived five years you were cured, and of course it’s absolute nonsense – lots of things come back later.

SA:  But do they still always remove the limb?

CF:  We had one adolescent boy who refused.  He said “I’m not having this done, it's not right.”  He kept growing new lumps and then he came back and asked to have his limb removed because they were painful.

SA:  So until people decide not to have the limb removed and see what happens you won’t know?

CF:  No.  These patients may come back with spread later anyway, because sometimes things spread long after they’re cut out.  Who knows?  But it’s an example of something that one would never ever have understood without having this extraordinary material that gets sent in consultation.  And then, as Gonzales-Crussi says, you have to actually recognise it.  If you just said, “Don’t know”, and forgot about it, you’d never move on.  Part of it is the pleasure of actually recognising those things.  And then them being validated.  It’s a lot of fun, yes.

SA:  Have you got wonderful archives of things?

[He pulls out a drawer and shows me the files.] There are over 40,000 of them, letters to people going right back to 1987 or whatever, from all around the world.  And we have all the slides in the next room and another room down the hallway.

SA:  What has been the most exciting thing you’ve done – can you remember some special moments?

You have to be kind of a fetishist to want to listen about soft tissue tumours for a whole week, there you can talk about rarer things, or weirder things or difficult things
CF:  In truth it’s more a question of just enjoying what one does.  And it’s not just looking at lumps, it’s educating others to recognise them, whether it’s common things that matter, or rare things that only the more sophisticated pathologists are turned on by.  We have all these trainees here who I just try to teach the general principles of being a good pathologist and how to influence a surgeon or whatever.  And then I do a course once a year where we just teach about soft tissue all week.  You have to be kind of a fetishist to want to listen about soft tissue tumours for a whole week, so you have 50 people in a room who are all interested.  And there you can talk about rarer things, or weirder things or difficult things.

SA:  So going back to the story about these cells that appear in sites that they shouldn’t, Gonzales Crussi was telling me about teratomas, is that the same sort of thing?

CF:  Well that’s slightly different, because teratomas are tumours that are derived from things called germ cells, which are the things that make babies, basically.  Germ cells have the potential to be everything -- they’re the only cells in the body that are 'totipotential', meaning they can be anything.  So in that context anything is fine, because that’s what they do for a living, yes? 

There’s some cell in there that in some way has flipped -- it’s turned into another cell type during the course of going bad What I'm talking about – and the problem is, I can’t offer you any science to support it because it’s not something people have pursued…All the cells that make limbs, for instance, used to be considered to be ‘terminally differentiated’, meaning you went through embryogenesis, you decided to make a skeletal muscle, there’s your muscle, that's it -- if you damage it it’ll scar, or whatever, but you can’t repair muscle. It’s not like liver that re-grows.  And once a skeletal muscle, always a skeletal muscle.  Most of these sarcomas that I see arise in the middle of skeletal muscle, and most of them do not show skeletal muscle differentiation. 

They show all sorts of other types.  Meaning there’s some cell in there that in some way has flipped -- it’s turned into another cell type during the course of going bad.  It will need lots of cleverer people than me to sort that out. You either need something that’s terribly common or kills children – those are the things that attract money!
But the truth is that my tumours aren’t common enough for people to invest that much money, research money, into sorting them out.  That’s part of the problem.  You either need something that’s terribly common or kills children – those are the things that attract money!  That’s just the nature of society.

The changing face of cancer

SA:  So when we talk about 'cancer', are you finding more and more and more weird things that the cells can do?

Hell, I’m not even sure that we used to see things like that 25 years ago!
CF:  Yeah. And one of the things that is strange – this is a really out-of-the-box thing  – but I think that tumour types vary over time.  That's well-documented for some of the environmentally-related things like gastric cancer.  Lots of people died of gastric cancer in the 1940s, '50s, and '60s; now it’s relatively much less common.  It was a combination of food, smoking, alcohol, and probably what was in the cigarettes, and so on.  But I sometimes wonder…Some of these tumour types that we see seem so distinctive that you think, “I can’t believe we didn’t see those before”.  You know the famous expression “There’s nothing new under the sun”?  I’m sure there’s a lot of truth in that – it’s whether you’re open to seeing it.  But some of these tumours seem so strikingly distinctive that you think, “What did people call those 25 years ago?”  And I’ve now been at it long enough to think, “Hell, I’m not even sure that we used to see things like that 25 years ago!”  And I worry, purely hypothetically, that maybe we’re constantly developing new tumour types because of things that we don’t know about – whether it’s environmental exposures, or it’s genetic events that we don’t understand.

Then there are other tumours that were reportedly quite common a long time ago that now we hardly ever see, and there’s no rational explanation for why they should have gone away.

SA:  Like what?

Christopher Fletcher & colleaguesCF:  Well the trouble is none of them are very common things.  But for example there’s a thing known as calcifying aponeurotic fibroma that’s supposed to occur in the hands, mainly of kids and young adults.  In the 1940s and '50s two quite large series of cases were published – 40 to 50 cases, which in those days was huge, because they didn’t have big referral practices.  But in this huge file I’ve got, I’ve only ever seen 10 or 15 cases.  And 50 years ago there never were case collections as huge as I have now; they simply didn’t exist.  And I’m thinking, “How could a little hospital somewhere have 50 of those and I’ve only seen 10?"  There’s something wrong.  So has the tumour disappeared?  Or were those 50 all misdiagnoses?  God knows; you never can answer those questions, but…

SA:  Fascinating, yes!  So looking across those lovely hand-written books of yours now, do you see patterns?  Are you getting a real sense of this?

CF:  I keep getting a sense of new things coming, not necessarily of things disappearing.  Some terribly distinctive things.  There’s a man in Italy called Juan Rosai.  He described, around 1990, a tumour that’s called desmoplastic small round cell tumour, which basically 90 percent of the time occurs in the tummies of boys. They present with multiple lumps within the tummy, and they’re all dead within a couple of years.  They’re horrible things.  But it’s such a distinctive tumour, both down the microscope and clinically.  I mean, everybody in a paediatric hospital would remember if they’d seen boys presenting with these things.  Anyway, it had never been described before Juan, and now everybody accepts it as a specific tumour type.  The baby trainees all recognise it!  I mean, it’s not like it’s rare as hen’s teeth.  It has a specific genetic signature and all the rest of it.  Now where the hell was that before?  I don’t know the answer to that.  Maybe it was buried in lots of other tumour types as misdiagnoses, but you’re always left wondering.

SA:  And what have you seen recently that you think, “I’ve never seen this before”?

It doesn’t exist in text books.  It’s not in any of the journals – nobody’s described it – and we’ve had nearly 30 cases now CF:  Well this thing I’ve just described to you – the multiple nodules in the legs.  That doesn’t exist in the literature.  It doesn’t exist in text books.  It’s not in any of the journals – nobody’s described it – and we’ve had nearly 30 cases now, I think.

SA:  When did you start to see them?

CF:  I think the first one was about 1995.  And the only reason I cottoned on, actually, was that we had another one terribly similar within a year.  And I thought, “That’s strange!  I remember we had a thing like that”.  And then bit by bit we’ve been accumulating data. 

SA:  So has that kind of thing happened quite a lot across your career?

If I took any credit, it’s more for being open minded than anything else – not trying to force things into existing categories CF:  Well yes, but only because I’m so lucky in seeing all these amazing, funny cases.  And I suppose, if I took any credit, it’s more for being open minded than anything else – not trying to force things into existing categories.

SA:  Yes, what do you think are your strengths in doing this?  What do you think has allowed you to build up your expertise?

CF:  That’s a tough question to answer honestly!  It’s mostly open-mindedness.  And I’m not very fond of dogma.  Dogma kind of irritates me.  And then the luck of seeing all this material.  Presumably one has some aptitude, but I’ve no idea how you measure that.


Motivation: "I'm probably a doctor at heart"

SA:  Do you still get a thrill seeing the material?

The fun bit is seeing lumps and working out what they are.  And feeling as though you’re helping patients -- I mean, I think I’m probably a doctor at heartCF:  Yeah, absolutely. The best bit of the day is that. I get a lot of pleasure from running this part of the department, and I like seeing the trainees do well.  And I don’t mind doing all this admin.  But the fun bit is seeing lumps and working out what they are.  And feeling as though you’re helping patients -- I mean, I think I’m probably a doctor at heart.

SA:  Yes, I was going to ask, what d’you think your motivation is?

CF:  I’m first and foremost a physician. I think of pathologists as physicians, and I don’t like pathologists who aren’t willing to be engaged in clinical care. I think that’s cowardly.

One of my most memorable visits from a patient here was a lady who came from Wisconsin and she just wanted to come and say thank you.  You never know what’s going to show up until they do…She was probably 60ish, and she and her husband were bikers.  They were border-line morbidly obese bikers!  So these two huge people arrived in this leather gear with studs all over it [we both laugh] -- and they were charming, I mean, they were lovely.  I normally think, Oh god, those bikers look kind of scary, and they were delightful.

SA:  And what had you done for them?

CF:  Actually I’d told her she had cancer whereas somebody else had told her she had a benign thing, and she was saying, “If you hadn’t said that, I wouldn’t have got the right treatment.”  It turned out I was right unfortunately, because it spread.  But she came to say thank you.  So…Human beings are complicated things!

SA:  But it’s interesting, you obviously feel at ease with talking to patients – d’you think that was because of your background?  You grew up in a medical household where it wasn’t difficult to talk to people?

CF:  Probably.  Because we had to do all those terrible things like…My father was quite traditional, so he would cart me and my sister round the hospital sometimes when we were little. You know, on a Saturday morning he’d say… Actually I suppose in real life it was probably my mother saying, “Can you take the kids out of the house for a bit? I’ve had no peace all week,” sort of thing.  And then things like Christmas time, when I was young they would have surgeons come to carve the turkeys on the wards on Christmas day (sounds so old fashioned, doesn’t it?), and families were expected to show up too.  They’d usually make the surgeons dress up and things, and then we’d have to traipse round behind them – you know, the adults drinking endless sweet sherries and all becoming progressively inebriated!  When you were a small child it was very unnerving, but as you became a young adult you just drank the sweet sherry as well!  [We both laugh].

But I don’t know.  I think it’s probably one of those things where you either like it or you don’t.  And another big part of my job is I’ve ended up being kind of a mentor to a lot of the trainees when they want help finding jobs, so it’s a never-ending stream of people with needs, and it’s the same principle really. 

SA:  What about your mother – how much of an influence was she?

CF:  She was an extremely caring, thoughtful woman.  I mean, everybody says that about their mother, don’t they?  But she was very affectionate; she was very uncritical; she was very supportive.  My father was more sort of Victorian – well not Victorian, that’s too harsh.  He was a more traditional father.

SA:  Were you close to your dad?

CF:  Um, closer to my mother, because I didn’t see so much of him when I was little.  I mean, I always looked up to him.  He was certainly very successful in what he did, and in the society where we lived, North Yorkshire, he was very well-thought of, and when he died hundreds of people showed up.  But he wasn’t particularly sharing of personal things.  But that’s generational, I think.

SA:  So was it quite a strict upbringing?

CF:  Not terribly.  I mean, relatively formal, but not strict. I went to boarding school when I was about nine or 10.  When I first started boarding I was terribly homesick. But in the end it was fine. I had a very good education, I think, and I view that as a strength.  I mean, even down to silly things like just getting a bit of Latin and Greek so you understand where words came from.  I don’t remember any Latin or Greek now really, but it helps you work out all sorts of things subconsciously, which the young kids now don’t at all.  We used to have cold baths at 7 o’clock in the morning in my prep school, and then half an hour of Latin grammar before breakfast.

Lessons of pathology: "We're all completely dispensible…"

SA:  At this stage in your life, how would you say that being a pathologist has shaped you?  What has it taught you about life particularly?

Life is very much a lottery...
CF:  Probably the two most important things are the recognition that life is very much a lottery, and the fact that disease and death can happen to anybody at any time – which is something that bothers me more as I get older, because I think when one was younger one acknowledged that but thought, “It doesn’t happen to our generation, does it?”

And at some point one thinks, "How am I going to get time to have my own life back again?"  One of the problems I have now is that the demand for all of the things we’ve talked about is essentially limitless, and I have to work harder and harder and harder.  I mean, you just get so far behind. Once upon a time I had a table you had meetings at!  [He gestures at the table beside us piled high with papers and things – no room for anything around that today!]   The job just gets bigger.  And at some point I think one has to reclaim one’s own life, because I don’t want to drop dead having done nothing else.

SA:  Have you got kids?

CF:  I’ve got three women. They’re grown now, they’re in their 20s, my daughters. 

SA:  And were you a more present dad than your own father?

CF:  Oh yes, very much so.  When they were little the deal was I would get home, I can’t remember, around six or six fifteen and it was my job to bath the children and put them to bed.  In other words, one wasn’t an absentee father, sort of thing.  And pathology enabled that, because you didn’t get called out of hours very often.  And it was fun.  I liked it a lot, and I have a much closer relationship with my children than I had with my own parents.

Some people like to be demagogues, but I mean it’s all bullshit, we’re all dispensible!
But no, what I’ve learnt from the job is that "there but for the grace of God go all of us", day after day.  And the other thing is, what’s painfully true, is that we’re all completely dispensible.  In other words, if I were to drop dead tomorrow, people would find other people to send their lumps to. 

The thing that really struck me in that regard -- one of the most famous pathologists in the world was chairman of this department, the man who recruited me, a man called [Ramzi S] Cotran, who used to edit the standard student textbook worldwide.  I mean, it’s used everywhere across the world.  Cotran  had melanoma and he died seven or eight years ago, and until the time he died, anyone who was looking to make a senior appointment almost anywhere in the US would call him up and say, “D’you think we should hire so and so?  Is so and so a good person?” or whatever.  He was sort of Pope-like and very, very widely respected.  And within this hospital, of course, he made pathology very powerful.  And after he died, for the first three months it was, “Well, what would Cotran have done?”  Or, “Cotran would have done this” and everyone would do the same.  But after six months it was, “Well he’s dead now…” you know?  After a year he didn’t feature in the conversation at all.  And now, seven or eight years later, the young ones, half of them, will say, “Who’s Cotran?”

And of course, it’s true for every one of us, yes?  Some people like to be demagogues, but I mean it’s all bullshit, we’re all dispensible!

SA:  So has it made you more humble, recognising just how incredibly…

To effect change you probably have to be out on a limb a little bit CF:  What a lottery it is?  I find I get more broadminded and tolerant, and humble if you want to use the word, the older I get.  You know, I was regarded as much more opinionated when I was in my 20s than I am now.  And I think that’s probably the way it has to be, because that’s probably the only time you have the balls to challenge things, to make change, yes?  Because at some point, if you start understanding everybody’s point of view, nothing changes!  [Laughs] So I think to effect change you probably have to be out on a limb a little bit.

SA:  As a pathologists, seeing so much of death, have you become more at ease with the idea of dying, or are you just as worried about it as the next person?

The majority seem not to be scared when they get to that point, which I find reassuring CF:  Good question.  I don't worry too much about dying.  This is a generalisation, but from personal experience, having taken care of dying people and then having talked to dying people, and having watched one's own family members die, I've never actually had the sense that… the majority seem not to be scared when they get to that point, which I find reassuring.  I'm not personally too troubled by it.


SA:  You say you'd like to 'reclaim' your life at some point – to do what?

CF:  I like to travel and I like to read.  And I've got engaged in some philanthropic things.  When I first came I used to be terribly offended that people were always asking for money. You'd get letters from a charitable thing, or from the Boston Symphony Orchestra, or the Museum of Fine Arts, "We need some money".  And I used to think this was rude and weird, because I didn't realize they're not all paid for by the state, like those in the UK are.

Those things give me a lot of pleasure So the average American gives away something like four percent of their income. But what I like is getting other people to part with their money for causes that I think matter.  There's a music school I support which is for underprivileged children.  They're nearly all black or Hispanic, most of them have only one parent, and many of them come from a very underprivileged social environment.  In this school -- it's called a Charter School, and it has its own sort of ethos about what it's trying to do -- every child is made to learn the violin.  These are children who may come out of these kind of hell-hole neighbourhoods where everyone takes drugs, and 80 percent of the murders occur, and they all learn: a) to play the violin, b) that they have to take care of the violin.  They have to take it home with them and see that it doesn't get smashed.  They have to practice, and they have to play with other people, so they learn a kind of interactive thing.  They learn to perform.  They learn to listen when the other children perform.  And the social enhancement – I don't think they turn into musicians particularly -- but the other benefits are huge.  And when you go and see it it's really very moving.

So anyway they have these fundraising events every couple of years and I cart all these people along, and the last two years in a row I got every person round the dinner table to buy a violin each!  For me that's a good evening.  If at the end of the evening the other nine people have all agreed to pay for a violin, I think, "Hey, that was a good evening!"

Then we have a couple of pathologists in the department who go out and work in Malawi for a few months each year.  The same sort of principle – they're actually helping with malaria and malaria research and things.  Part of it is actually making sure you provide an enabling environment for them to do that.  One could say, "I'm not having any of you wasting your time doing that."  But I think it's a good thing.

It's interesting, again it's the opportunity to influence young people without knowing you're doing it.  One of the young women who graduated from the programme last year and went to a faculty position wrote me a nice letter when she left.  Then I had a letter from this music school I've just told you about and it said, "We thought you should know that this young woman made a donation to the school in your name and said that she'd never thought about the social relevance of philanthropy before that…" I was astonished!  But sometimes when I'm supposed to be working I say, "I'm awfully sorry, I have to go for a couple of hours because I've got this concert…"  And me being perceived as a workaholic, they think, "This is weird!  What's he really doing?"  So those things give me a lot of pleasure.

Autopsies on the decline

SA:  One last question I wanted to ask you: people have said that one of the problems for pathology here is the readiness of people to sue, and this is one of the reasons for the decline in the autopsy rate – everyone's worried that something will be found that was missed while the person was alive.  Is that true?  Is there a problem with autopsies here?

CF:  There is but it's not that.  It's the same as it is in England.  It's a combination of social distaste; the belief that radiology has found things that only pathologists could find before; a reluctance of the junior doctors who are around in the middle of the night to ask families. I think people just shy away from asking.  There's another thing too – health care has changed, as has happened in England.  If you or I were in hospital 20 years ago the young doctor, the houseman -- you would see the same one day after day, so you knew and trusted that person.  Now it's a different one every eight hours and you don't form that bond.  They don't really know you or the family well enough to say, "Well, grandmother died, can we do an autopsy?" I think a lot of that's been eroded.  In the old days, a week in hospital and you were just about family friends by the end, and that's all gone.

See again, the litigation thing is massively overstated.  Touch wood, I've now been here 13 years and let's say the average over the years has been 50,000 specimens a year – that's 650,000 specimens, and we haven't been sued once.  And my sense is that the medical-legal environment here is no different from England.  Now in Florida I gather it's much more dramatic – I gather there's a lot of litigation in Florida.  But here it's not an issue I think about at all.  People don't seem to practice defensive medicine here [in Boston].