NETS OVERVIEW Thor Halfdanarson, MD Mayo Clinic

NETS OVERVIEW Thor Halfdanarson, MD Mayo Clinic

November 7, 2019 1 By Jose Scott


I thank you very much sorry I have
to I have to actually lower than the mic here. it gives me great
pleasure to be here and talk to you about neuroendocrine tumors so I was given the task of talking about the neuroendocrine cancers, neoplasms, sort of a broad overview
the 30,000 foot view over this so I could stand here all day and talk about
it the way but there was only given 30 minutes 35 which is plenty well we’ll
make it through so let’s say so these are my disclosures so and let’s use to
move into the objective so what I hope to do here is to talk about the neuroendocrine neoplasms or NENs or NETs the common they are what are the
symptoms and sort of briefly talk about how we diagnose or work someone up and
then why we need medical oncologist like myself why this has to be a
multidisciplinary treatment and then talk about the multidisciplinary teams
per se so what our names were nets so neuroendocrine neoplasms or neuroendocrine tumors are a group of tumors that can really arise anywhere so what I wanted
to talk to you a little bit this slide is that the nomenclature the naming of
these things are changing so or they’re not called nets anymore well Nets is
only a part of the big family of an NENs so if you wouldn’t the neuroendocrine
neoplasm is a term that captures all of these tumors and nets are the most
common part of it so what is then the difference between a net and the NEM so
a neoplasm is really a an abnormal mass of tissue that that is growing and
there’s not the the cells are dividing when they’re sure when it shouldn’t then
they’re not dying when they should and the definition of a tumor is essentially
the same but for neuroendocrine neoplasm it’s a little different because in that
the context tumor and neoplasm are not necessarily the same thing it sounds a
little complicated we’ll go through it I’ll walk you through it and so what are NETs so these are cancers I think we need to we need
to be honest and we need to talk about these as cancers a lot of people have
been told that they have benign tumors and only a minority of them are benign
these are truly cancers they have the capacity to invade other organs and
spread to other organs and they most commonly happen in the happen severity
and the gastrointestinal tract lungs so small intestines pancreas and rectum but
they can really arise anywhere I don’t think there is an organ that that is
free of the risk of having neuroendocrine tumors I’ve seen pretty much every organ
in the body so they are extremely heterogeneous in the sense that that we
don’t in that any sense that no two neuroendocrine tumor cases are the same so when you meet someone who has a neuroendocrine cancer and odds are that that person has a very
different neuroendocrine tumor than the one that you .and we’ll go into that
a little bit more. so the behavior of the NETs varies greatly from one person
to the next. that’s why it’s so hard when you discuss this with other people with
neuroendocrine tumors there are all of these differences among different patients
that that dictate how this tumor will behave over the months or the years so
these can be among the slowest growing tumors that you find in humans and
tumors that don’t it may never ever need to be treated and in fact actually a lot
of people probably have them without ever knowing. there was a study very
fascinating study from Japan many many years ago that looked at patients who
died of old age in a nursing home and they had an autopsy that looked at their
pancreas and they found that 10% of these people dying in this particular
nursing home who have this kind of an autopsy had small pancreatic neuroendocrine tumors none of them knew that they had it during the lifetime so they are
probably much more common than we think and so gradet one tumors I sometimes showthis picture to th e patient they are slow growing generally and and then we
have the grade three tumors which are moving much much faster. but they are
on a spectrum.so it’s not like all grade three tumors move really fast. and all grade one tumors move really slow. and we’ll talk about tumor grade
in a little bit. so this is that busy I promise this is the busiest slide I will
have at the hand I test you at the end of the talk on this
so. really what I wanted to show you here this is the 2019 classification of
neuroendorine tumor so so this just came out last month or a month before that so the
WHO the World Health Organization puts together these big sort of meetings
with people experts and they they sort of hash out what should be held how did
we define a neuroendocrine tumors however that how should swe call them house to be
classified in because we as scientists we want to classify everything and so
really what I wanted to show here and let’s see if I can make this, sorry again,
so I’m not sure if I have a pointer here but anyway so if so so essentially these
are three to three different grades and actually five different classes of
neuroendocrine tumors then a mixed …so so so really we have these
three different grades grade 1 grade 2 grade .3 but then we have these
large cell small cell. and we have the differentiation. and really the important
thing here when we grade them is to look at what’s called the ki-67 index
and the mitotic count and I’ll show you slides of each so moving on so
tumor grades so this is really a system for us to predict how a tumor will
behave over time. it’s not a perfect system but it’s it’s actually not bad
either.r so what we do is that we take a special tissue stain and we apply it to
slides of tissu.e and then we count the number of cells that stain positive. so
these are the cells that are actively replicating or dividing. and the stain
should not stain cells that are resting. and this tumor grade shows just purely the
number of cells that saying positive will fairly accurately predict how the
tumor will behave over the next month to years. so more dividing cells more
aggressive NETS or NEN so this is how it looks to the
pathologist so if you look at the this here on the left-hand side so this is a
grade one tumor or less than 3 percent of the cells stay in positive. you see that
there are the occasional little brown dots. this is fairly easy for us to call and then grade 2 — you can see that now up to
20% of them can be positive. so you can see that still a minority of them are
dividing or replicating. you see all of those faint blue dots here these are
resting cells they are not doing anything they’re just sitting there and
a grade 3 sometimes you can tell that all of the cells are actively dividing. so
those tend to be the most aggressive tumors and this is all done we’re mostly
done sort of computerized now. we just take this light we stick it into a
digital reader and it just scans this light and spits out a number which is
much faster and probably much more accurate than sitting there and counting
them just manually. so but not all grade 3 tumors are the same. we’ll get into
that a little bit more later. but so here we have a grade .. grade 1 grade 2
grade 3 and the grade 3 tumors are very very different from one person to the
next we can have a very slow-growing grade 3 – tumor and we can have a very
fast-growing grade 3 tumor. we can almost never we never see a fast-growing grade
one tumor. so the well differentiated and that’s what we get into the
differentiation and that’s the next slide so the well differentiated grade
3 neuroendocrine tumors probably for most parts behave like grade two neuroendocrine tumors but they move a little bit faster not much. and the poorly differentiated
grade three tumors move extremely fast and these are among the most aggressive
tumors we’ll see in humans and they need immediate therapy usually with
a combination of chemotherapy possibly with immunotherapy. what’s cool maybe
here about a little bit later today so the problem here is that we need we
still need an expert pathologist to look at these so the grade three tumors have
told you the greatest design or is assigned by a computer that reads the
slides but we still need a pathologist to look in the microscope and tell us
what is the differentiation of this tumor and that requires an expert
pathologist and this is something that people get wrong all the time so last
week actually this week I was in the clinic and I saw someone who is referred
to me as a pancreatic adenocarcinoma and referred for chemotherapy essentially
and we reread that as grade one neuroendocrine tumor. so what so means that the
pathologist who read the initial slide got it completely wrong. not only did it
get the grade wrong but the got the tumor type wrong. and so these
things happen. it can happen to any good pathologist if you have just having
a bad day and you’re reading these slides or if you’re not then a very
experienced pathologist so you really need a good pathology to look at this.
okay differentiation this is the concept I have the most difficulty explaining.so
this differentiation really means how much do the tumor cells look like the
the or cell of origin, that they started but the problem is that we don’t know
always what was the cell of origin so really what we’re looking at here is how
aggressive how angry-looking are these these tumors and so the well
differentiated tumor cells that tend to be all the same size very similar shapes
and they all look the same the poorly differentiated tumors are all like
different shapes and sizes some of them are dying others look very very
different so instead of showing the cells what are sometimes say this would
be a well differentiated tumor and this would be the poorly differentiated tumor
so you can actually see that when you look in the microscope as one of my
pathologist said these are the cells that you don’t want to meet in a dark
alley at night and so so you can really tell but then it gets a little bit more
complicated that because we have these grade three tumors what’s right here but
not all of them are poorly differentiated but all poorly
differentiated tumors are grade three so it’s getting a little complicated and
that’s why do we need neurons consumer specialist and pathologist to do this so
great and differentiation hopefully I didn’t make more complicated than it
should be but I’m let’s move on to the next important thing that determines
prognosis so we look at great differentiation and stage and so these
are the cancer stages so stage zero is something we almost never see a neureoendocrine tumor or localized tumor stage two or more advanced and then
after stages four so how does that really look in the body so let’s move on
to the next slide turn so this is just this is for colon cancer but the same
rules apply so here we have stage one or two so these are tumors here in this
case limited to the colon and they may either be just on the inside of the
colon or they may start growing through the wall of the colon but they haven’t
really gone anywhere beyond that stage 3 now we can see that the green things
here this is the this green vessels are lumpier outside of the colon these are
the lymph nodes now we can see that the tumor has gone from where it started in
the colon into the lymph node so this would be stage 3 and then stage four is
really when the tumor would started in the colon or in the small bowel or and
the pancreas has gone to the liver or gone to the lungs or bones or other
organs so that would be stage four. so there are only stated there are only
these these five stagges is essentially but stage zero something with we really
don’t talk about because we don’t really see that. so is this really a problem? so
why am or how big of a problem? are our NET so actually they turn out to be
quite a bit of a problem. so these numbers are rising so for all neuroendocrine tumors. we expect to see seven per 100,000 per year so in a city like
Rochester which has about 100,000 people we would this expect to see seven cases
a year so I’m horrible at math so I looked up
the the population of Illinois and I came up with a number close to 900 cases
in Illinois per year and take that with a grain of salt though. So these are the
most common origin: lung, small bowel, pancreas, rectum, appendix. and what I
wanted to show you here is that this curve here is the number of all cancers
in the US this goes down to back to 1973 and here we are 2012 and you can see
that in the 70s and the 80s the number of all cancers that are going up pop up
and then actually started to go down.and the reason for the number of cancers
going down is that we’re screening for colon cancer and people are not smoking
as much. but now we might actually see a little bit of an uptick again.
possibly because of obesity and if you look at the next curve this these are
the Nets so you can see that they have continued to increase as over-diagnosing
more and more and more so you can see that from the early 70s until now there
has been about six-fold increase in the number of new neuroendocrine tumor diagnosis do we think some of this is actually from from just better Diagnostics? we
have better scans people are getting more scans but I think there’s also a
real increase and how does this look for different neuroendocrine tumor types so if we look at the lung you can see that there is has been a steady increase in the
number of new lung cancer neuroendocrine tumors or no longer on the tumors and
this I think is largely due to more use of cross section limiting CT scans and
tones and for the small intestines a steady increase it’s a small bowel NET
and most common Nets and then for the pancreas down here really not much of a
change until very recently where we have we’ve seen a very noticeable uptick in
the number of new cases and we actually just shown and we have have a paper pen
thing showing that in the last 15 years there has been a three-fold increase and
the number of new pancreatic neuroendocrine cancer cases diagnosed possibly largely due to
more imaging so what are the symptoms o nonspecific as many of you know and sometimes just a little bit of diarrhea
a little bit of flushing. occasionally and and then different different tumors
have different the presenting features some are actually very quiet that don’t
cause any symptoms other causes some from bulky tumors that are causing
pain. and then they can make stuff they can make hormones or they can make
serotonin that make you sick so just a few of the symptoms from the tumor
itself so we have these obstructive symptoms so crampy abdominal pain this
is a common symptom of a small bowel pulmonary tumor, jaundice from biliary obstruction sometimes seen with pancreatic neuroendocrine tumors. cough or recurrent pneumonia always in the same part of the lung with
neuroendocrine tumors sometimes blood in the stools coughing up blood pain
things of that nature and then nonspecific symptoms just not feeling
unwell losing weight those kinds of things so carcinoid syndrome so this is
a syndrome that’s something we see in the small bowel neuroendocrine so this is
usually caused by a production of chemicals such as serotonin that result
in symptoms such as diarrhea and flushing. so the diarrhea is generally
cost by serotonin the flushing is not the cost by serotonin that’s caused by
some other chemicals that these tumors make if you take someone
give them IV infusion of serotonin they will have diarrhea but they may not
flush and then these are sometimes worsened by alcohol exercise emotional
upset that sort of stuff and and then these with time can actually damage the
heart valve so I’ll show you some some pictures of that as well so as for the
the pancreatic neuro endocrine tumors they can make stuff like insulin can’t repeat
blood sugar it can make gastrin which can cause stomach ulcers and that’s
called Zollinger Ellison syndrome just yesterday I saw a patient
with a classic Zollinger Ellison syndrome have been going to doctors
mostly for diarrhea. but then started having these stomach ulcers and and
there’s no one really put these these all of these things together. and then
when we saw her obviously the gastroenterology had made the diagnosis
they all seemed crystal clear to us. but if one symptoms had them happens like
it’s mild, and then there’s another symptom that comes on top of that, that’s
just hard sometimes for us to see the big picture it’s always very easy for us
in the ivory towers to say our address would have been seen the years ago but
if you’re the primary care doctor taking care of these patients actually
remarkably hard to make these diagnoses. so let’s move on here so this here I
wanted to show you so let’s first take a look at the left hand side so this is a
typical carcinoid flush I got this from a Canadian Medical Journal
so this flushing of the other skin here the face and what I wanted to show you
if we could play that video clip here on the right hand side if we just go back
one slight sorry you can see here see those veins here that there this is a
patient I saw a few months ago you can see the those pulsating veins so I was
just examining this person and he had a neuroendocrine tumor and I was thinking
oh this is this isn’t right so he had carcinoid heart disease and these are
the symptoms or signs that you can see if you really carefully examine patients
so let’s move on to the next slide so you here needs some help from tech and
let’s start this one so this is the Carcinoid heart disease you can see
here are the liver tumors making the serotonin which is flowing into the
bloodstream and to the heart and you can see the heart valves how they get
thicker and stiffer and instead of moving freely they’re like moving
sluggishly and they’re not closed saying so now the heart valves on the
right side started leaking and causing increased pressure that causes these
veins to bulge and then all sorts of other symptoms like swelling of the legs
and the shortness of breath and so on and so forth
so moving on so these tumors can sometimes cause skin rash this is a
patient with glucagonoma who had the characteristic skin rash and this is
another one who had the characteristic skin rash of the of the legs or started
on octreotide and the skin rash cleared up so this is something we see very
rarely but we see it occasionally okay so how do we make this diagnosis of NETs
so it’s a team effort so we need the pathology we need the radiology other
specialties gastroenterology clinical chemistry, pulmonary medicine, surgery,
endocrinology so this really is a team effort. it’s it’s a challenging
diagnosis to make so tumor markers I know that a lot of people are interested
in tumor markers so here’s my short take two slides on tumor markers generally
they are not very helpful with some exceptions though so 5 hiaa in
patients with carcinoid syndrome is helpful and they are helpful to monitor
treatment activity but in terms of making the diagnosis for most patients
with neuroendocrine tumor markers are not helpful and there is no perfect marker
and markers should almost never be used to determine therapy so just a quick
slide on Chromogranin A I’m not going to read all of this to you.
These are all of the things that can elevate chromogranin A that are not
neuroendocrine tumors and are not cancer. these are all of the things like medications
that can elevate chromogranin A these are all of the other cancers that can
elevate chromogranin A so this is just not a good test and so it although it
does have some some correlation with how long people they live it doesn’t really
help us diagnose and it doesn’t really help the determine who should get what
therapy so if the test is providing very little value should we really be
ordering it so tumor imaging this is really the exciting stuff for our us inn
neuroendocrine oncology–these things have changed a lot over the years– so we
have CT, which is probably the workhorse in our clinic that’s the study we use the
most MRIs, PETs and I was just going to show
you a few things here so this is a patient I saw two weeks ago three weeks
ago okay so this is a GP you can see that there’s there’s a tumor in the
liver this is an octreotide scan then at the same time there is nothing this is an
MRI than the following week we can see liver lesions this is a fused the Gallium 68 dotatate PET – MRI and we’re picking up a lot of lesions. these are ocretoscans and these are done like a couple of weeks apart. so to me and then we’ve
known these are three is conserved as well but octreoscans should be
pronounced dead. and they are they have served as well. but we have just moved on.e have much better imaging than Toctreoscans. so what about regular PETs? so a lot of people come in and say well my doctor did a PETand they
didn’t really find anything. well the regular PET, that’s what what’s called
that fdg-pet. so that looks at tumor metabolism look we’re giving you
radioactive sugar that the tumor cells gobble up and then we take a picture of
the body and we see where it went. so this is a patient with a low-grade
neuroendocrine tumor this is a regular pet there isn’t really not much going on.
this is a dotatate otPET–lots of tumors in the liver
there’s the primary tumor not seen on the regular pet. here here it is again
and this is the regular PET CT you can see there is really not what’s going on
in this liver here’s the door at a pet every month I probably see two or three
patients with a low-grade nen and the tumor will come in with an fdg-pet CT
for a low-grade neuroendocrine tumor that is a near it’s it’s it’s not a useless test
but it it’s a very limited utility. it’s incredibly important for high-grade
neuroendocrine tumors. so I’m not saying we should never do it. but you just have to
pick those imaging studies very carefully. okay so moving on so why do we
need better drug therapy that’s because of patients like this this is one of my
patients had a lot of tumors from a pnet not even doctor how could I think
we remove all of these tumors although possibly so we treated with it with
chemotherapy in this instance and this is another patient who was referred to
me for few liver metastases and for
consideration of surgery. Indeed there are some liver metastases here but these
are all bone metastase.s so this person instead of coming in for surgery
actually went home on a medical therapy with injections. actually happens to be
doing just fine two or three years . and on octreotide line real tight
so I’m going to skip over this one here just in the interest of time and so talk
a little bit about the the the the main concepts of therapy does anyone or
everyone with a neuroendocrine tumor need to be treated? absolutely no. so we
definitely observe a lot of patients. I have a number of patients now on
observation. they come in every three to six months, and they have never seen
therapy yet we have a biopsy proven grade one neuroendocrine tumor and we’re just watching so treatment consideration so why do we treat should we treat to
relieve symptoms of the carcinoid syndrome formal pancreatic neuroendocrine tumors
or symptoms from bulky tumors or metastases so that’s one thing so we
treat to make people feel better.we also treat to make people live longer and
that’s to prolong survival but keep in mind that not all treatments have been
shown to prolong survival and some treatments are toxic they’re painful
they have side effects and they have what we call now financial toxicity with
many of you may be aware these are not cheap drugs and they may not always be
completely covered so we have to be mindful of that does the patient need to
be treated what should we treat them with and so on and so forth don’t forget
that every person is unique so it’s this is not like a one-size-fits-all so we
here that’s that’s the reason for for the multidisciplinary teams so things to
consider before starting therapy so it’s treatments really need it or they’re
troublesome symptoms or there is the rapid tumor growth and then where did
this neuroendocrine tumors start because a pancreatic tumor is treated very
differently from a small bowel neuroendocrine tumor and then what’s the stage? and then
obviously, the grade differentiation so the team approach is
incredibly important and there is generally with the exception of
high-grade poorly differentiated neuroendocrine carcinomas there is no rush and starting therapy so we usually have time to get all of the team together
and discuss these and it’s better to get these net experts involved early so
that’s why we have tumor boards so tumor boards are meetings which can be so
occasionally like virtual can be most often in person you have a lot of
different specialties surgery oncology radiology, nuclear medicine,
interventional radiology, pathology, gastroenterology, genetics. and we sit
together and we discuss how we should suit you to treat patients and why do we
do this we do this because we think that more brain power. more CPU is better. so
having more brains together as better and and then also the initial approach
may change and it’s been shown scientifically that medical oncologists
are really bad about predicting how if patients may be candidates for surgery
or not this actually been scientifically shown that we are just not good that’s
saying who or the patient is you have surgery and then sometimes there are
several reasonable approaches and then we have to go back to the patient they
say well these are the options we have which one fits your goals and and even
we have to consider there are financial things we have to consider and then
probably most importantly for a lot of our patients especially those who travel
from afar we can actually in a team report we can get 30 different
specialties take a look at the case without the patient having coming it
having to come in for 30 different visits so that the maybe one visit case
presented to board I call a patient with a plan so we are making it to the end so
I’m won’t talk too much about the treatment other than just treatment of
symptoms with source open set and analogs and then all sorts of symptoms
we have for for diarrhea and so on and so forth we’ll hear a lot more of that
later today so ask for the anti tumor therapy this is it’s gonna be my last
slide so there’s a lot of options we have for anti tumor therapy that’s where
the rest what the rest of the day is for and the subsequent speakers will really
talk about that so what they said not to go into into all of those details so
that brings me to the end so thank you very much for listening and gladly take
some questions thank you.