NETs and GIST
Welcome back to the Deep Dive.
Today, we're tackling a really interesting and honestly, pretty complex group of tumors.
They seem to live in two completely different worlds, almost.
Sometimes they're this slow growing chronic issue you manage..
Other times, they're incredibly aggressive.
We're talking about neuroindocrine tumors nets and also gastrointestinal stromol tumors, GI cyst.
Kind of related, but different.
They really are a challenge, and I think the sources show that difficulty comes right from their biology.
They're complicated.
So what's our plan for today?
How do we make sense of this?
Our mission, really, is to give you a solid framework.
We'll focus on three main axes .
Function what hormones were they making, if any, grade, how fast are they growing, and distribution where are they located?
Okay.
Function grade distribution.
Got it.
Exactly.
And just to define nets quickly, they're rare tumors.
They come from these specialized cells scattered around, mostly in the gut and pancreas , And these cells are weird partner-on, part endocrine gland, dual personality, almost.
And that's key, isn't it?
That dual nature?
They're not like your standard colon cancer, for example.
Not at all.
Often slower growing, yeah.
But the big thing is that some of them make hormones , lots of hormones.
And those hormones can cause major symptoms way before you'd ever notice the tumor itself.
Okay, let's dive into that functional part.
When these nets actually make hormones, the symptoms aren't subtle, are they?
No, not at all.
They can be really dramatic.
Debilitating, even, and very specific to the hormone involved.
It's like the body's normal physiology just gets cranked up to 11 with no off switch.
Right.
No feedback loop.
Precisely.
So let's talk specifics.
Carcoid syndrome.
That's probably the one people have heard of.
Flushing , diarrhea, sometimes wheezing.
What's driving that?
Yeah, the classic carcid, usually from the midgut pumps out mainly serotonin and inalicrane.
Sotonin hits the gut hard, increases motility, increases secretions.
That's where the really bad watery diarrhea comes from.
Makes sense.
And the calic .
That activates a pathway Brady Keenan.
Brady Keenan is a potent vodilator.
It opens up blood vessels.
That causes the sudden episodic flushing.
Okay, so serotonin for diarrhea, Brady Keenan for flushing, that covers the immediate symptoms.
But the sources also mention this serious long term issue heart damage, specifically rightsided heart failure .
How does serotonin cause that?
Yeah, that's carcid heart disease.
Serotonin over time, causes fibrosis, scarring, basically.
On the heart valves.
Exactly.
It promotes fibr blast growth.
But here's the really interesting physiological part.
It almost always affects the right side of the heart .
Tricustid regurgitation, pomonic stenosis.
Why only the right side?
That seems odd.
Because the lungs act like a filter, a shield, almost, when blood carrying all that serotonin p passes through the lungs, the medators get metabolized, broken down, inactivated.
So the left side of the heart is protected?
Pretty much.
The lungs clean the blood before it gets there.
You really only see left-sided damage if there's a hole in the heart , a right to left, or maybe huge lung bypassing that breakdown process.
Wow.
So even if someone feels okay, we need to check their heart.
Oh, absolutely.
Routine echoes are standard for anyone with a functional mid gut carcid.
That heart damage can be insid.
Okay.
Let's shift to the pancreas.
Inoma, Whipple's triad comes up here.
Right.
Insaloma means the tumor is just pumpingping out insulin regardless of blood sugar, doesn't care if your glucose is already low.
So low blood sugar.
What does that do?
Well, the brain needs glucose.
When it doesn't get enough, you get neuroglycopanic symptoms, confusion , maybe acting strangely, even seizures.
Scary.
And at the same time, the body panics, it releases stress hormones, catacines, that causes theergic symptoms, tremors, palpitation, sweating.
In Whipple's triad ties it all together.
Yep.
The triad is one, having those symptoms, two, documenting low blood glucose during the symptoms, and three, the symptoms go away when you give glucose.
It's diagnostic gold.
Okay.
Then there's gastronoma.
Zollinger Ellison syndrome.
Sounds like extreme heartburn.
Oh, it's way beyond heartburn.
It's relentless acid production, nonstop.
Driven by gastron from the tumor.
Exactly .
So much acid floods the duodenum that it overwhelms the normal bicarbonate buffer..
It gets severe, recurring ulcers, often in weird places like the junum further down.
And does that cause diarrhea, too?
Yes, for two reasons.
The acid itself is irritating, but it also inactivates pancreatic lipase.
The fat digesting enzyme.
Right.
So fat digestion fails.
You get steria, fatty stools, and diarrhea.
Jeez.
Okay, one more functional one.
Vipoma sounds very dehydrating.
It is. Devastatingly so.
Very VIP vactive intestinal peptide is incredibly potent.
It makes the intestines pour out chloride and water and potassium.
Massive amounts.
So just huge volumes of watery diarrhea.
Exactly.
Cious.
Leading to severe dehydration and dangerously low potassmia.
It's sometimes called WD syndrome.y diarrhea, hypmia,lorhydria, a true medical.mergency.
Wow.
But you mentioned earlier, most nets don't do this.
They're non-functional.
That's right.
The majority are silent in terms of hormones.
They still might be growing.
They could still be malignant, but they don't cause these dramatic syndrome.
So how do they show up?
Often light .
Maybe vague belly pain or a bowel obstruction if the tumor gets big enough, or sometimes they're just found by accident on a scan done for something else entirely Incidental.
Okay, so if the hormones are the key for functional tumors, diagnoses must involve tracking those hormones.
Yeah.
Right.
Finding their fingerprints and then figuring out where the tumor actually is.
Exactly.
Biomarkers and imaging.
They go hand in hand.
Let's start with biomarkers .
Chrom and A often gets mentioned as a general net marker.
It is.
CGA.
Chroman A. It's stored in those little secret bubbles, the granules, along with the hormones in many nets.
So generally, more tumor means more CGA.
It's a decent marker for overall tumor burden.
But there's a catch, isn't there?
Something about heartburn meds.
A huge catch.
You absolutely have to know if the patient is on a proton pump inhibitor, PPIs .
Like Eprazol, Lapol..
Very common drkes.
Extremely.
PPIs indirectly stimulate certain cells in the stomach, ECL cells to release a ton of CGA.
It has nothing to do with the net.
So you can get a sky high CGA level just from taking a PPI.
Absolutely.
A massive false positive makes the test basically useless if someone's on chronic PPI therapy.
You have to stop the PPI for a couple of weeks, if possible, before testing CGA.
Wow, okay.
That's a critical point.
What about for carcinoid syndrome specifically?
5HIAA?
Right.
Five hydroxy endal acetic acid.
That's the main breakdown product, the metabolite of serotonin.
We met measure it in a 24 hour urine collection.
And that's the gold standard for mid-gut carcinides?
It is.
Especially if there are liver mets, the levels are usually very high.
It reflects the total serotonin output.
But there's another twist based on where the tumor started.
Embryology matters.
Okay.
Forget carcids stomach, lung, maybe esophagus.
They often lack a key enzyme.
It's called AD, aromatic amino acid decy.
AAD.
And without that enzyme.
They can't efficiently convert the precursor, 5HTP into serotonin, they get stuck.
So someone could have a lungcinoid, maybe even making some mediators, but they're 5 HIAA tests could be normal.
Exactly.
Normal, or maybe just slightly up.
It can hide the diagnosis biochemically .
It's a really important distinction based on the tumor's origin, for gut versus midgut.
So, given these issues with CGA and 5HIA, why not just measure the specific hormones directly, like insulin, gastro, VIP?
We do that, too, Abs. But hormone release can be episodic, not constant, so a random blood draw might miss it.
Oh, okay.
That's why we often need provocative tests.
For insulinoma, it's the supervised 72 fast.
We're trying to force the tumor to reveal itself by letting the blood sugar drop and seeing if insulin stays inappropriately.
And for gastron.
The Secretin stimulation test .
Normally, Secretin tells the stomach G cells to stop making gas., but in a gastronoma, Secretin paradoxically makes the tumor release more gast, levels way up.
Okay, that makes sense.
Let's switch to imaging.
I suspect a net, do I jump straight to the fancy PT scam?
No, you need anatomy first.
Start with a high quality CT or MRI scam.
Which one is better?
Often MRI is preferred, especially for looking at the liver.
Liver are common and gives great detail there.
But a good multif CT is also.
And what if the tumor is really small maybe in the pancreas?
That's where endoscopic ultrasound US comes in.
It's critical.
Okay.
ES puts an ultrasound probe right next to the pancreas via an endcope.
It gives the best resolution for tiny lesions, maybe less than two centimeters, that CT or MRI might miss entirely.
Plus, you can biopsy right then and .
Very cool.
And then we talk about the specialized P scan, the Dotetate scan.
Yes, the Gallium 68 Dotetate PE CT.
That's become a cornerstone.
Why is it so good for nets?
Because most well-derentiateated nets have loads of sematin receptors on their surface, specifically subtype 2 SST2.
Okay.
Dotetate is basically a sematin molecule tagged with a radioactive tree tracer, Gallum 68.
It binds specifically to those SSTR2 receptors.
So it lights up wherever the net cells are.
Exactly.
It's incredibly sensitive for finding tumors anyone in the body, great for staging .
And really importantly, it tells us if the patient is a candidate for certain targeted therapies.
Like what?
Like seatin analog drugs, like octotide and landriotide, which bind the same receptors and also PReptide receptor,ucrapy.
PRT.
Yeah.
That's where you attach a much stronger radioactive particocol to theatin analog.
It delivers targeted radiation right to the tumor cells that express the receptor, so the Dotetate scan confirms the target is there.
So the scan directs therapy.
Brilliant.
But what if the net is really aggressive?
Poorly differentiated?
Does Dototate still work?
Often, no, really aggressive tumors, what we call neocrine carcinas or NECs.
They tend to lose those somatatin receptors as they become more poorly differentiated.
So dodate would be negative.
Could be.
Or only weekly positive.
For those aggressive ones, we often turn to a different PT scan , FDGPT.
The standard Cancer PT scan.
Right.
These aggressive NECs are growing so fast, they chew up a lot of sugar, glucose.
FDGPT measures glucosetake.
So, often aggressive NCs are dotate negative, but FDG positive.
It reflects their different biology.
Okay, so the biopsy is obviously key, not just to say, yes, this is a net by looking for markers like chromanine or syneptapism.
Right.
Those confirm the neuroendocrine linear.
But the biopsy also tells us how fast it's growing.
That's the Kai 67 part.
Exactly.
Kai 67 and the mitotic count.
Those are the measures of the tumor's tempo.
It's proliferation rate.
How does Kai 67 work?
K 67 is a protein that's present in cells that are getting ready to divide .
So the 67 index is simply the percentage of tumor cells that stain positive for this protein.
It tells you what fraction of the tumor is actively cyc.
And that gives us the grade?
Yes.
The WHO grading system relies heavily on it.
Grade is low, 67, less than equal to 2%.
These are typically slow growing.
Grade 2 is intermediate K 67 between 3 and 20% .
And grade 3 is high grade Kai 67, greater than 20%.
The mitot count, how many cells are actually caught in the act of dividing under the microsopeope is also factored in.
And this grating seems absolutely crucial.
It's the fork in the road between calling something a net versus an NEC.
It is the critical distinction.
It dictates prognosisis and treatment more than almost anything else.
So explain that difference again, net versus NEC.
Okay.
If the tumor cells still look relatively organized, somewhat like the tissue they came from, we call that weld differentiated, even if the 67 is high , like in grade 3, it's still classified as a neurontumer, a net, G1,2, and well-diated G3 are all nits.
And these nets, even high grade ones, are managed differently?
Generally, yes.
They tend to be somewhat more indolent, relatively speaking, and often still have targets like theastatin receptor.
But if the tumor cells, they completely disorganized, very abnormal, ugly , under the microscope, we call that poorly differentiated, and the 67 is usually very high, often over 50%, then it's classified as a neurocrine carcinoma, an NEC.
And an NEC is just a different disease entirely.
Totally different beast.
NCs behave much more like other aggressive carcomas, like small cell lung cancer that grow fast, spread early.
So the treatment approach must be radically different.
Radically different.
Low or intermediate grade nets might be watched or treated with surgery or someatin analogues or PRT .
It's often managed more like a chronicisease.
Poor differenti's usually systemic chemotherapy right away.
Platin-based, like small cell lung cancer, is ticking.
Okay, so let's pull it all together for management.
We've got function, Hormones, grade, net versus NECE, Kai 67, and distribution, localized metastatic.
How do these guide treatment choices?
It's all about integrating those three. Axes.
If a net is localized, caught early, surgery is the goal, potentially curative.
Makes sense.
Cut it out.
Yep.
But if it's unresceptable or already metastatic, then it depends.
Fordiets, especially if they're causing hormone symptoms or are grade 1 or , we usually start with some analogs, octotide orotide injections.
And those do two things, right?
Control symptoms and maybe slow growth.
Exactly.
They block hormone release, controlling the fleshing or diarrhea, and they have an anti-proliferative effect on tumors with SSTR receptors.
What if the tumor grows despite the analogs?
Then we escalate.
If the dotate scam is positive, PRRT is a major option, targeted radiation.
For pancreatic nets, specifically, there are also targeted pills like Eamus or Sunatanib.
Okay, but for the NECs, the poorly differentiated ones.
Chemotherapy.
Systemic chemo is the primary treatment.
It's treated like a widespread aggressive cancer from the start.
Got it.
Now, before we leave NE, we have to touch on carcid crisis.
You hear about this happening during surgery or procedures.
It sounds terrifying.
It is.
It's a sudden massive release of all those mediators, serotonin, bridian, histamine, others, all at once.
Triggered by stress , anesthesia, handling the tumor.
All of the above.
And it causes profound hypotension.
Blood pressure plummets, severe flushing, sometimes bronosasm It can be fatal.
How do you manage it?
Because the patient is crashing.
Here's the absolutely critical counerintuitive point.
You must avoid standard catacoline vasopressors . Drugs like epine,, dopamine.
Wait, the go-to drugs for low blood pressure will make it worse.
Yes.
It's throwing gasoline on the fire.
Those catacomines can actually trigger the cells to release even more mediators.
So what do you use?
High doose intervenous octotide , then infusion.
Octotide directly blocks the release of metators from the tumor cells.
That's the antidote,'s a lifaving distinction.
Wow.
That's crucial to know.
And just to close the loop, that carcid heart disease we talked about earlier, that's the long-ter damage from chronic mediator release.
Precisely.
The fibrosis on the rightsided valves usually tricuspid regurg, is the hallmark of long-term uncontrolled serotonin exposure from a functional carcinoid tumor.
It just highlights how managing the function is as important as managing the tumor itself.
Okay, let's completely switch gears now.
GIS, gastrointestinalomal tumor, the most common misenchal tumor in the GI tract.
How is this fundamentally different from a net?
Fundamentally different origin, different biology, different treatment, world apart.
Okay.
Where do they come from?
Not neuroendocrine cells.
No.
They arise from the interstitial cells of Kajal.
ICCs.
The pacemaker cells.
Exactly.
The cells in the muscle wall of the gut that control peristalsis, gut motility, GS's kind. Come from those.
So, no hormones involved?
None.
They are never functional in that sense.
No flesing, no hypoglycemia, none of that.
Symptoms are usually from mass effect bleeding, pain, obstruction.
And the underlying cause is different, too.
It's a specific mut .
Yes.
It's usually driven by an activating mutation in a gene for a receptor tyene.
Most commonly, it's the gene, which codes for the CD-17 receptor you see on staining, or another related gene called PDR.
These mutations basically jam receptors on switch, telling the cell to grow constantly.
And histologically, they look different, too.
Yeah.
Typically spindle cells, long, thin cells, seeing spindle cells that stain positive for Kit, CD-17, and often another marker called DOG1, is pretty much diagnostic for GS.
And this unique biology leads to different behavior and treatment.
Absolutely.
One key thing.
G rarely spread to lymphodes.
Unlike many carcinomas, routine limphode removal.
Okay. Is the treatment revolution. Mut usually kit , we have a specific drugs.
Ib.
Belvic.
That's the one.
Mibb is a tene inhibitor, a TKI.
It directly blocks the abnormal signaling from the mutated kit or PDGRA receptor.
So it turns off the growth signal?
Precisely.
And it was transformative.
It turned GS, which used to be a highly lethala, into often a manageable chronic condition for many patients.
It's like the poster child for successful molecularly targeted therapy and cancer.t So wrapping up this deep dive, I think the main takeaway for neurocrinumors is that you really have to integrate those three axes we started with.
Function, grade, and and distribution.
Right.
Is it making hormones?
How fast is it growing?
Where is it?
Exactly.
And the answers dictate whether the best path is surgery or controlling hormones with analogues or targeted radiation like PR.RRT or if it's aggressive NC needing chemo, it's very individualized.
It really is a complex landscape for nets, and then you can trraft it with gist.
Right.
GIST provides that almost elegant example of find finding the specific driver mutation, kit , and hitting it with a targeted drug imm with incredible success.
Which does leave you wondering, doesn't it?
It does.
It raises a provocative thought for you, the listener.
We see this amazing success with targeted therapy for gist, hitting that one key pathway.
Will we ever find something similar for nuts ?
A kind of unifying target that could simplify treatment across all those different grades and functions.
Or is the very nature of nets that neuro endocrineuality, the complexity, always going to demand this more intricate, multi-pronged approach involving surgery.y, hormone control, maybe PRT, maybe chemo.
Is a single magic bullet like imatinib for just even possible for the diverse world of nets?
Something to think about .
