Hormones Functional/Nonfunctional Tumor, and Carcinoid Syndrome, Joe Dillon, MD, University of Iowa

Hormones  Functional/Nonfunctional Tumor, and Carcinoid Syndrome, Joe Dillon, MD, University of Iowa

well thank you very much for the
invitation and to come and and thanks for sticking it out this to the
afternoon so that for for this session here so I’m going to talk about the I’ve
been asked to talk about functional tumors non functional tumors and
carcinoid syndrome so that the functionality here relates to the
presence of hormonal secretions so as previous speakers have mentioned
there are neuro endocrine cells widely widely spread throughout the body and
indeed any of these can any of these areas can can produce a neuroendocrine
tumor so whether we’re talking about the lungs stomach pancreas abdomen ovaries
in women prostate in men parrot ganglia lots of lots of areas were neuro
endocrine cells hang out a neuro endocrine cell actually when you this is
a this is a low-power microscope view of the lining of the of the small bowel and
what they’ve done here is they’ve they’ve just put on a stain for
serotonin so they’re showing the serotonin producing cells they say it’s
1% it looks like less than 1% to me so these are very rare cells in the normal
bowel if you cone down further on one single
cell you can show what’s what’s being shown here in a in a high-powered
microscope version view of one of those one of those cells is this is that the
nucleus where the genes are these little brown spots are serotonin granules
that’s that’s what it looks like under high power microscopy so neuro endocrine
so what is a neuro and can sell it’s got the Nero thing it’s
got the endocrine thing what’s that all about so just a cartoon of a
neuroendocrine cell to introduce you to what’s going on
there’s blood supply coming in there also nerve supplies coming in and hence
the neuro part but I’m not going to talk about that at the moment there’s blood
leaving this area there are a variety of hormones being being made in neuro
endocrine cells there are over 20 different hormones chemicals that have
been shown to come from neuro endocrine cells and tumors in the normal neuro
endocrine cells they’re being produced in themselves they’re their jettison
their jettisoning their cargo out into the blood and having effects downstream
so also in neuro endocrine cells these are normal neuroendocrine cells there are
somatostatin receptors on the outside of the cells so so those somatostatin
receptors are responding to somatostatin and other and other chemicals that are
coming on the on the blood coming coming inwards so neuroendocrine tumors then as
we as we mentioned neuro and consumers can be quite widespread in the body but
this this slide separates neuro and the consumers into a relatively old schema
which is forged mid gut hindgut forgat includes interestingly enough the lungs
the the stomach the pancreas and the the first part of the that the duodenum the
mid gut is where most of the neuro endocrine tumors over 55% of them are in
the small intestine which is mid gut and then the hindgut is rectum and and part
of the colon but this division into four got Midgut and hindgut allows me to
just highlight one aspect of neuro endocrine tumors which is that different
tumors in different places can have different hormones being produced so
that the the foregut the lung and the stomach for example can
produce a lot of histamine serotonin in the lung and thymus can produce adrenal
stimulating hormone the pancreas although it’s a for gut organ it it’s a
very specialized organ with a lot of different potential for four different
hormones it can produce insulin which is probably best known for in terms of in
terms of hormones but can also produce gastrin glucagon etc and then the mid
gut produces mainly serotonin it also produces another set of hormones called
tackykiins which I’ll mention again so what is a
functional tumor a functional tumor is a tumor that produces either sudden or
sustained production of certain chemicals which we call hormones into
the bloodstream those those chemicals from the tumors produce specific
symptoms which we will talk about in a moment the specific symptoms really
depend on which hormones are related by the tumors and which hormones are
related by the which hormones are released by the tumors really there
varies by the tumor site and the the type of tumor so the the the most well
known syndrome or hormonal syndrome present in functional tumors is of
course the carcinoid syndrome and we’ll speak mostly about this these come from
small bowel but you can get carcinoid syndrome from lung and stomach you can
even rarely get it from pancreas tumors produces serotonin but also other
hormones that I’ll mention again but there are a variety of other of other
hormonal syndromes somebody has mentioned is zollinger-ellison i think
it was Dr. Hafdanarson this morning producing gastrin you’ll notice that a
lot of the other syndromes are from pancreas here some of them also act up
Cushing’s syndrome coming from lung and thymus down here invisible is
pheochromocytoma and paraganglioma so what is carcinoid syndrome well I think
I should I should ask you all to define carcinoid syndrome at this stage because
you’ve you’ve heard it in a number of other a number of other talks but
essentially one or more of the following symptoms so eighty or ninety percent of
people with carcinoid syndrome would would have either flushing or diarrhea
but otherwise, other things are wheezing, palpitations, heart failure associated
with carcinoid heart disease and and other symptoms they’re caused by the
hormones as I mentioned mostly when people have liver tumors as well as the
primary tumor there are some there are some tumors that that can cause
carcinoid syndrome with without liver metastases about twenty percent of
people have these tumors initially they do tend to the the number of people who
have carcinoid syndrome tends to increase over time just with tumors
getting bigger so how do patients come to present with how do they get
diagnosed with neuroendocrine tumors? well many patients get diagnosed with
neuroendocrine tumors because it’s either an incidental finding turn 50
have you colon screening with colonoscopy and neuroendocrine tumors
found have have an x-ray because you’ve fallen and hurt your back and something
else is found have abdominal symptoms such as abdominal pain chest pain those
all of those ways of presenting are non far from non-functional tumors about 20%
of people have the hormonal syndromes so those are the functional tumors and the
issue about this is that people with non-functional tumors have a big problem
they have tumor growth there they’re proud
is related to to tumour where that the tumor grows where the tumor is is is
present people who have functional tumors have two problems they have the
same tumor growth problem that the that people with non-functional tumors have
but they also have these hormonal symptoms and the hormonal symptoms are a
big deal so this is a nice study and it’s been repeated a number of times
it’s a study from the folks in MD Anderson looked at over 600 patients to
see you know what really made a difference to them was it was it how big
their tumor was or whether was metastatic or not or or whether was that
they had symptoms related to functionality or the the hormones of
their tumor and what they found was that when they looked at people who had
increasing amounts of carcinoid syndrome as manifested by increasing bowel
movements those folks had increased anxiety increased depression decreased
overall physical function and they had essentially the same data when they
looked at Flushing which is the other big symptom of of carcinoid syndrome so
so the the symptoms really make a difference in how one lives one’s life
as many of you know how do we treat folks with hormonal symptoms well we
treat them by I think there’s sort of three conceptual pots that I put the
treatment in one is attack the tumor just as the same as if it were a non
functional tumor to is stopped the hormone being produced by the tumor and
three is try to block the action of the hormone even if it is already produced
by the tumor attacking the tumor attacking the tumor is all that you’ve
heard about up to now today so the you go to see Dr. Keutgen are are to see
doctor how and get the tumor removed as much as possible that’ll take care of
the functional the the the symptoms you starve it with with embolization
therapies that we’ll hear about next you burn it out with ablation therapies you
radiated with PRRT with either the lutathera or if it’s a pheochromocytoma
with MIBG or Axedra you poison it with now this is I should put an asterisk it
because as Dr. Chandra sakina’s has mentioned everolimus doesn’t decrease symptoms related to carcinoid syndrome
but actually ever almost actually does a does an interestingly good job at
decreasing some of the symptoms of insulin producing neuroendocrine tumors
the specific treatments and these are the I’m going to focus more on the stop
the hormone production and block the action of the hormone today so that
stopping the hormone production is octreotide and Landreotide that
decreases all of the hormones that come from these neuro endocrine tumors you
can also stop the hormone production by using two telotristat that blocks one
of the hormones but the main hormone that comes from these tumors serotonin
and then for people with with other forms of not carcinoid but pancreatic
neuroendocrine tumors producing insulin diazoxide blocks insulin production
Metyrosine bocks adrenaline production pheochromocytoma so there are
a group of medications which block the production of hormone there are also a
group of medications which block the actions of hormones and and when you’re
getting to this stage of blocking the actions of hormones you’re you’re a
little bit off the grid in terms of in terms of controlled clinical trials so
ondansetron which you might know as zofran a very good nausea medication but
it is an inhibitor of a partial inhibitor of serotonin and has been and has been used as such in in carcinoid syndrome they’re
their agents which block histamine they’re agents that block gastrin etc so
there are certain medications which can block the action of hormone but as I say
you’re off the grid in terms of in terms of clinical trials and it’s a it’s on a
on a case by case basis in a experimenting with one thing or another
so let’s focus on carcinoid syndrome a little bit the main the main hormonal
syndrome that that comes from neuro endocrine tumors they’re more than 20
hormones that are made by neuroendocrine tumors the the the major hormone that’s
related to carcinoid syndrome is is serotonin it’s certainly the the the
best the best known hormone of the of the carcinoid syndrome it is the main
hormone that causes carcinoid diarrhea it is not the main hormone that causes
flushing as was was mentioned already serotonin is is very important in our
normal bowel activities irrespective of of neuro endocrine tumors without
serotonin we would have a bowel which does not contract but serotonin then
when when when present in excess gives rise to carcinoid diarrhea but serotonin
actually gives rise to about 50% of the of the of the diarrhea that occurs with
carcinoid tumors there are other hormones that that that cause other
parts of the diarrhea so how do we going back to our little three three pronged
attack here how do we treat carcinoid diarrhea well actually before I get
there I should mention that before before talking about the specific
treatments for for carcinoid syndrome diarrhea I should point out and others
have have mentioned this before I think doctor how there are certain things that
you might notice can cause your exacerbation of carcinoid syndrome and
and if you can avoid those situations or takes them out treat at 30 minutes
before those situations you can avoid the symptoms of carcinoid carcinoid
diarrhea are carcinoid carcinoid flushing I’ve got a small asterisk here
with eating there are there are a lot of many people have have certain triggers
for their for their carcinoid syndrome if you have never seen a podcast or a
video by Leanne Burns who is the dietician at New Orleans for a long time
should check out her stuff great advice on on what to eat and what not to eat in
in in a patient in a person with with carcinoid syndrome so starting off with
with treatments octreotide, lanreotide and Sandostatin improves both flushing and diarrhea in about 60 to 80 percent of people it affects all of the hormones
that are produced by these by these by these tumors this is just a couple of
the trials that have been shown this is the the urine level of five hiaa which
is which is the urinary product of serotonin from the blood these patients
were were given lanreotide as as part of the major lanreotide trial a
clarinet it normalized the the urinary serotonin and it goes up slowly whereas
placebo it just keeps on rising because these tumors keep on growing and
similarly we can show that octreotide or Sandostatin can decrease the number of
bowel movements per day either of them over a period of many weeks and there’s
similar data with with flushing so so these agents
take care of diarrhea and flushing one thing that I should mention and that dr.
Chandra sir Caron mentioned in regards to progression of tumors is that there
are some data showing that that just increasing the dose of octreotide or lanreotide will improve carcinoid syndrome so this was a this was a
retrospective study from Dr. Strosburg. over 200 patients but almost 200 of them had either flushing or diarrhea in the
in the three months before before going up on their dose of Sandostatin mostly
going up from 30 to 40 but sometimes up farther than that
essentially 80% of people get benefit benefit from taking more octreotide or
our lanreotide some people will use short-acting octreotide in addition to
that the monthly injection as an alternative for this so increasing the
dose is is one opportunity to get rid of the symptoms so starting at a lower dose
increasing the dose of insufficient control of symptoms that the dose can be
increased in in terms of milligrams or we can decrease the time from four weeks
to three weeks to two weeks if your insurance company allows it and
sometimes adding on the the short acting is is helpful Xermelo, telotristat, a
different medication which is helpful in in diarrhea this is your dietary protein
gets broken down into tryptophan an amino acid eventually a small amount
goes to serotonin in in carcinoid syndrome lots of it goes to serotonin so
less of it goes to protein or niacin vitamin b3 Zermelo or telotristat blocks that blocks that effect and and and gets the decreases the serotonin
back towards normal and what this what what happens when
when when a person takes Zermelo is that the the number of bowel
movements decrease that when compared to placebo a
couple of practical points to remember about Zermelo or telotristat it’s
used in addition to octreotide it’s better absorbed when taken with food
short-acting octreotide can decrease its absorption discontinued it if
constipation arises if there are side effects starts lower it can take six to
ten weeks for it to really have its effect there are differences between telotristat and sandostatin both decrease serotonin they both decrease
diarrhea telotristat does not influence any other hormone it I’m not
sure that it influences flushing at all maybe very occasionally it it may very
well decrease carcinoid heart disease that’s a an area of current research
because serotonin causes heart disease there are Studies on whether it
influences tumor growth we know that octreotide does influence
tumor growthn very important point not all diarrhea is carcinoid syndrome
and this has been mentioned already so there are people who have bile salt
diarrhea because they’ve they’ve lost their gallbladder or ileum small bowel
bacterial overgrowth need antibiotics they don’t need more octreotide the side
effects of these medications they need pancreas enzymes they don’t need more
octreotide other drugs that people are on I have many patients who who after
going through a lot of this we discover or I realize that they’re taking their
they’re taking something like metformin for their diabetes the diabetes that the
Sandostatin and Lanreotide I’d have increased and when we take them off the
metformin their diarrhea goes away so important to reconsider what’s what’s
going on as I mentioned there are some sort of off-label uses for other
medications which may have an influence on diarrhea also
diarrhea there are nonspecific anti diarrheal switch I use all the time as
long flushing flushing is is a more specific carcinoid syndrome effect and
it’s actually also frequently more difficult to manage because I think we
have we have less medications for it this is just points out that in in the
the foregut in the in in flushing that occurs it from the from a long
neuroendocrine tumors stomach these people kind of flushing for hours they
can lacrimation tearing swelling around their eyes and that is a histamine
effect the mid gut tumors the more common tumors the ilium tumors tend
to be that the kinds tend to have a shorter effect how do we treat flushing
again attack the tumor same deal octreotide and Lanreotide same deal
off-label use for clonidine as a trial block the action of the hormone
histamine blockade can be helpful in in in some people I use zertac and zantac
because I can remember the double Z cetirizine and ranitidine also remember
not all flushing is carcinoid syndrome so a bunch of drugs can cause carcinoid
syndrome so has its it’s important to reevaluate things before before jumping
into going further in in in carcinoid treatment other hormonal symptoms
syndromes I mentioned to some of these other hormonal syndromes stopping the
hormone production octreotide or lanreotide will will do that
I mentioned the dioxide my tyrosine and then blocking the action of the hormone
so in in in gastronoma– blocking the the the eventual the eventual issue
which is the acid dietary effects on on insulinoma including using
raw cornstarch which is a very slowly slowly absorbed glucose and that is the
last slide and thank you very much for your attention

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