Navigating Familial Cancers: What Pathologists Need to Know to Diagnose MEN1

• CAP Endocrine Cancer Protocols
• For questions, please email us at CancerProtocols@cap.org

Becca Battisfore:

Welcome to the latest edition of the College of American Pathologists' CAPcast. I'm Becca Battisfore, content strategist with the CAP. Today we are going to talk with a pathologist and an oncologist who are on the front lines of diagnosing and treating patients with familial cancers.

More patients are surviving cancer today, thanks to better research, improved screening guidelines, enhanced pathology and more effective treatments, including immunotherapies. The American Association of Cancer Research estimates more than 18 million people are living with a history of cancer in the United States.

Before we begin to the questions, let's learn more about our host and guests, Dr. Paner, we'll start with you.

Dr. Gladell Paner:

Thank you, Becca. Good day everyone, and thank you for tuning into CAPcast. I am Gladell Paner. I'm a GU pathologist working at the University of Chicago and in the past seven years I had the pleasure of working with the CAP primarily through the Cancer Committee. And I'm your host for the CAPcast.

Dr. Vania Nosé:

Good afternoon everyone. It's my pleasure to be here and it's very nice to be talk about familial syndromes and I'm an endocrine pathologist and I do familial syndromes for many, many years. Many years. I work at Mass General Hospital in Boston and I'm here talking to you and discussing with the pleasure this topic. Thank you.

Dr. Mark Lewis:

Thank you so much for having me. So my name is Mark Lewis. I'm the director of gastrointestinal oncology at Intermountain Health, which is a multi-state healthcare system based in Salt Lake City, Utah. As we might discuss, I have both a personal and a professional interest in hereditary cancer syndromes.

Becca Battisfore:

Thank you all for joining Dr. Paner, I'll let you take it from here.

Dr. Gladell Paner:

Alright, thank you, Becca. With the advances in cancer diagnostics and treatment, we are fortunate to see more patients living with a history of cancer. And today our topic will be about multiple endocrine neoplasia or MEN1 and specifically we're can be talking about MEN1. So I would like to start with you, Dr. Nosé. Can you tell us what MEN1 is and honestly I lost track already. How many types of MEN are there and specifically about, describe to us MEN1 including the primary organs involved and the common tumors that are encountered.

Dr. Vania Nosé:

Sure, it's my pleasure. I just would like even to start with a little bit of a history so we understand what happened with all the syndromes and as a whole, what was the importance of a discovery of MEN1 to other syndromes to the discover of other syndromes. So imagine in 1903 Erdheim, he described the patient he found in autopsy that had the two tumors, the pituitary and the parathyroid glands. And I just described that in 1903. 50 years later, the Mayo Clinic describe eight patients with the tumors in three glands. I'm going to just mention that starts with a P. So it's pancreas, pituitary, parathyroid. They provided the overview of these eight patients and at the same time they said that the occurrence of a pituitary tumor islet cell normal, that was called in the parathyroid tumor, the same patient is extremely rare.

By that time they didn't notice genetic nature of the syndrome. So this was 1953, so 50 years after the first report of two tumors occurring in one patient. In one year later in New York, Werner, he described the association of these three diseases and associated with a familial and the gene can he described as being autosomal dominance. So MEN1, what we know today is an autosomal dominant disease that has numerous involvement of numerous endocrine organs and the mostly parathyroid even I can mention the amount of the percentage of involvement. So parathyroid is involved in 93 to 95% of a patients with the one syndrome. Then you have the parathyroid, you have microadenomatosis or multi glandular parathyroid disease. We don't call it anymore hyperplasia. We call it multi glandular parathyroid disease thyroid because it involves multiple glands and that these glands are neoplastic and hyperplastic. The other very important organ involved is the pancreatic duodeno area and you have their neuroendocrine tumors, you don't have adenocarcinomas, you have neuroendocrine tumors. And these are very, very interesting. They occurred up to 60% of all patients with MEN and they have multiple microdenomas. And the clue for the diagnosis that you find maybe macroadenoma in the adjacent pancreas has multiple microadenomas or we call microadenomatosis in the entire pancreas. That is really kind of a diagnostic of MEN1.

And then I'll say more about the other syndromes. And then the other very important thing is that they do also, there are multiple tumors and I have the beautiful tumors, multiple tumors in their duodenum, but they're all benign. All these tumors tend to be benign. They're neuroendocrine tumors, benign even pancreas or in the duodenum in the other organ that as part of the three primaries piece, so would be the pituitary gland. Usually they have another in up to 50% of the patients have pituitary adenoma. In the majority is about 60%, they produce prolactin, lactinoma. The others are less common. They have no functioning tumor that's also seen very much. Besides that there are many other organs involved like adrenal. You can have adenomacorticonoma or adrenal corticocarcinoma and other tumors. But the more interesting there other benign lesions, not endocrines that could alert clinicians for the occurrence of MEN1 that are multiple angiofibromas, collagenomas, lipomas gastric also. [Inaudible] So there are multiple other neuroendocrine tumors throughout the body that can be associated with...basically the syndrome is very complex.

Dr. Gladell Paner:

Thank you Dr. Nosé. So the way I understand is that these three Ps, these are the primary organs involved and there are other organs as well that are involved. But those are the kind of the minor involvements for MEN1. I'd like to switch to you Dr. Lewis and your experience with MEN1 is quite remarkable with you being an oncologist and also a cancer survivor with MEN1. So can you please share us a bit about your journey with MEN1 and your perspective as both a treating physician and a cancer survivor?

Dr. Mark Lewis:

The podcast, I view your discipline as absolutely integral to mine and true partners in care. So thank you for having me. So my interest in oncology and my own diagnosis, it turns out are very much intertwined. So we all have our reasons for entering the fields that we do. The reason I wanted to pursue cancer medicine is that my father died of cancer when he was 49 and I was 14. And so at a very early age I was interested in science. I saw his doctors frankly do fairly miraculous things to sustain his life, obviously not indefinitely. And it really drew me to the field, but absolutely no idea, and neither did my father crucially nor his doctors, that we had a hereditary predisposition to cancer. It seemed like bad luck. So I wanted to say two things, especially to any clinicians listening. I firmly believe in oncology, the word or phrase non-contributory almost never applies in taking a family history.

Usually when I see that word or phrase in the chart, it means it's shorthand for I didn't take a family history or I wasn't interested in taking one in sufficient detail. But the other thing I wanted to say, and again it relates is if two points make a line, then more points make a pattern. So what happened with me is I saw my father die when I was young and he was young too. And then a couple years later, his brother, my paternal uncle died of a pituitary tumor, actually a macroadenoma. So I thought, huh, that's strange. And then I was in medical school and actually learned about MEN1. I was taught the same mnemonic that Dr. Nosé told us about. But I didn't make the connection because my father's tumor had always been described to me and my family as lung cancer.

And it turns out it was actually a slightly incorrect term. The better term, which we've already heard today would've been a bronchial neuroendocrine tumor and in fact a neuroendocrine carcinoma. So with that detail now I had two points making a line and it turns out I was the final point in the pattern. So my very first day of oncology fellowship, I woke up with really serious abdominal pain and my differential was appendicitis or nerves. And it turns out neither were true. The true answer was elevated calcium, hypercalcemia. And one of the many things that that does is it can slow down your gut. So slightly embarrassing to admit on your podcast, but basically I had an ileus and the moment I was told that I had a high calcium level, that was my, hope it doesn't sound arrogant to say my eureka moment because everything clicked into place for me and I was like, oh my goodness, this is the pattern of MEN1.

So the part of my dad's history that then came flooding back to me was he had suffered from high calcium his entire adulthood. No one had given him a good explanation. It was blamed on things like excessive dairy intake, which frankly wasn't true. And even when he rigorously cut out all milk and cheese, his calcium was still high. And then when I realized I had high calcium as well, I thought, gosh, there's really only two conditions that I know of that can do this. One is entirely benign, familial hypercalcemia and the other is MEN1. And so in that pattern fit, I knew that I had it. I was going through my training at the Mayo Clinic, so we've already heard about Mayo today already. So it's almost a perfect place, perfect time to be diagnosed and it's a lens through which I've seen my entire career since.

So it's been a very valuable perspective I think for me as a clinician. And then you're very kind to mention my experience as a patient. We can certainly talk more about it. The biggest thing I've been through medically was I had the Whipple surgery to remove a dangerous pancreatic neuroendocrine tumor from the head of my pancreas in 2017. And that was a life-changing surgery. Ultimately I think a life-saving one, but boy has it left me with some comorbidities and again, hopefully some empathy I can share with my patients. So that's my perspective as both a patient and a son and now as an oncologist.

Dr. Gladell Paner:

Thank you, Dr. Lewis for sharing this experience. And it's really truly, as you mentioned, this is a life changing experience to have that and obviously it has an effect, a ramification on the way you see patients now. And when you see patients, you'll be seeing, you're treating the patient by seeing them through the lens of a patient. That's quite remarkable. So let's talk about the pattern of inheritance of MEN1, and I'd like to shift to Dr. Nosé. So in terms of the gene, what is the gene involved in MEN1? And can you explain to us about the pattern of inheritance of MEN1?

Dr. Vania Nosé:

Sure, sure. And I think that was a beautiful description that Dr. Lewis gave about his experience and I'm very proud of him because in the pathology side I'm always trying, although I don't have a personal, at least as far as I know so far, but I feel that these connections that are missing, I imagine how many patients we are missing in all these familial syndromes that we failed to diagnoses. And the Dr. Lewis was brilliant to put things together. But let's go to the syndrome. So this is an autosomal MEN1 syndrome is known to be an autosome dominant tumor syndrome caused by the germline mutation of the MEN gene. The MEN1 gene is very large and has multiple areas, multiple areas that can have mutations. And the important thing is that the MEN1 gene encodes a protein called menin. It's a protein with multiple functions and it's mostly like the tumor suppressor have this autosomal dominant inheritance, but 10% of the patients have the novo mutation. And these patients are harder to make a diagnosis than the ones that have familial history. Because one of the ways for us to make the diagnosis is by family history in case that you have the novel mutation that 10% of all the patients, these are basically difficult to make a diagnosis.

Nowadays in pathology can do even a minimal stain, we can do more things, but the molecular is the diagnosis and doing the molecular, the NGS for menin there are numerous mutations, numerous gene, I don't know the numbers exactly because they increase every day with the new publications. But there are mutations and these are all autosomal dominant, basically there is the transmission like Dr. Lewis perfectly explained and he mentioned on his particular case. So the diagnose would be very important, not that we have minimal malignant tumors, but the hormone disturbance that these lesions cause even if you don't have a large pancreatic lesion, but if you have other lesions, this mutation causes a lot of hormone overproduction and with the consequences of the hormone overprotection, not because all the tumors are malignant or just a few tumors are malignant. They protect against the overgrowth with the loss of menin. Let's say the insulin producing cells in the pancreas, they proliferate. That's why we have microadenomatosis. So not only one nodule, but the entire pancreas should have multiple small.

Dr. Gladell Paner:

Thank you, Dr. Nosé. So it means that if one parent has the abnormal gene, then there's a risk of 50% of transmitting it to the children. And I agree the way Dr. Lewis described his experience, it's beautiful, it's very enlightening to us. As Dr. Nosé said, we as pathologists don't regularly see patients, that our diagnostic approach is from the other side. We encounter the tumor, multiple tumors, different kinds of tumor. We thought about a syndromic condition. So talking about the symptoms, and this is a condition that involve multiple organs and depending on the organs it'll have this type of symptoms. So we are expecting different types of symptoms and also the presentations will be at the different point in time. So Dr. Lewis, can you describe to us among these different symptoms, what is the most common clinical manifestations of MEN1 and having this multiple presentations along this timeline? When do you suspect MEN1 to be present in a patient?

Dr. Mark Lewis:

Yeah, absolutely. I think the multiple part is potentially a confounder because you have to think about multiple organ systems. But I think maybe the one thing that's in our favor here of making the diagnosis correctly, and as Dr. Nosé correctly said, it's actually harder. I think when it's de novo. You don't have the clues you can glean from family history. But the one feature that is almost as she already told us, almost a hundred percent penetrant is hyperparathyroidism. So I sometimes have people come to me and the reason for consultation is do I have MEN1? And you might say, well gosh, that's an easy question to answer. You can just do genetic testing. But there's two aspects. One is patients are still understandably hesitant to undergo germline testing. And we can certainly elaborate on the reasons for that. But the way I look at it is the Genetic Information Nondiscrimination Act of 2008 is a wonderful piece of legislation, but it leaves some porous protection against changes in insurance policies.

So without belaboring the point, what that really means is if you carry a germline mutation as I do and you disclose it, it can either drastically increase your life insurance policy or even disqualify you from life insurance. It can increase your disability premiums and it can certainly increase your long-term care. So what I'm getting at is in those cases, and because our genomic understanding is incomplete, so even if we do germline mutational analysis, we can't tell someone with a hundred percent certainty that they don't carry MEN1. Because of that, I actually rely a lot on phenotype. And so what I say to people is, if you make it to 60 years old and you have not had hypercalcemia from hyperparathyroidism, I find it very difficult to believe that you have MEN1. And I say that again to be reassuring most of the time, and most of us actually become symptomatic from our hypercalcemia by around age 30, which not coincidentally is when I became symptomatic.

So again, I would say hypercalcemia, which of course is an easy lab for almost any primary care physician to check is the number one lab abnormality that I would look for. And then the other part, which Dr. Nosé already mentioned, it goes outside the three P's mnemonic. I want to be clear, I really like that memory device. It's neatly alliterative. All the organs are aligned in the midline. It's easy for medical students to remember, and I think it's been on every board exam I've ever taken. However, it does not capture some of the more esoteric findings or what might seem more esoteric. So actually the second most penetrant finding are midfacial angiofibromas. And only with the benefit of hindsight, I realized I'd had this myself. So again, internists, you guys can make fun of us because you're a pathologist, but internists are famously great at internal medicine and not so great when it comes to dermatology. So when I developed these red spots on my nose in my mid twenties, I just thought it was like a form of refractory acne. I honestly didn't know what it was. And it turns out it was angiofibromas that frankly predated my symptomatic hypercalcemia. So again, in sort of order of prevalence or penetrance, number one is hyperparathyroidism. Number two is angiofibromas, but you have to know what you're looking for. Much less common, although still prevalent, are the pancreatic tumors that we've mentioned. The reason those are so variable in their presentation is, as Dr. Nosé mentioned, they can either be non-functional, so they may not produce any excess hormone at all, or they can produce any number of excess hormones ranging from insulin, typically that's the most benign, to gastroentoroglucagon and those are more serious and have more malignant potential.

And then just to round out the three Ps, and I have a family example for this too, let's talk about the pituitary. So I mentioned my paternal uncle died of a macroadenoma. So his manifestation, and he didn't realize what was happening to him either was he lost his peripheral vision. And the reason for that, of course was he had a tumor growing out of his sella turcica, pushing up in his optic chiasm and causing bitemporal hemianopsia. And the real problem here for him, he was a driving instructor, he actually lost his job. And this is almost darkly funny if it wasn't so tragic in the end, he was clipping the side mirrors of parked cars as he drove along the road, because he just couldn't see them. And the poor guy had no idea what was going on and it was because he had this massive pituitary tumor. He was also suffering, not surprisingly, from these terrible intractable headaches. So I would say there's lots more we could talk about. We kind of get into the more rare findings, but from head to toe, there's almost no part of the body that can't be affected by any in one, whether we're talking about pituitary gland, parathyroids, pancreas or skin.

Dr. Gladell Paner:

And in doing the test, ordering the test. So you start with a patient and say that patient turns out to be positive. So you go further to the family and test them as well. How do you?

Dr. Mark Lewis:

Yes. So you're talking about if their germline testing is positive? Yes. So that would set off a cascade. My biggest yield in doing this is I actually had a family from the upper Midwest where we identified the proband, the index patient, and sort of fanned out as a cascade through their family. We ended up identifying 20 affected relatives with MEN1 and they kind of walked into a buzz saw and no idea this was affecting their family. So this is the reason I think it's so important, again on my side of the table, to pick up these patterns is not only are you changing the management of the patient in front of you, but this has huge implications for their family. And like we said, autosomal dominance, it's a 50/50 chance of any child of an affected parent then inheriting the mutation. So as you can imagine, it's a tip of the iceberg phenomenon where if you identify that one patient, it can have a massive impact.

Dr. Gladell Paner:

I'm looking at the incidences of MEN1, so the incidence here says one to 5,000 to 30,000. So it's not really that super uncommon. I'm curious, Dr. Lewis, when you're ordering this germline testing, how many of the patients turn out positive in the ballpark?

Dr. Mark Lewis:

So it's all about pre-test probability, right? And again, there's enormous selection bias coming to my clinic. I would say when I order it, if I think that they MEN1, the germline testing confirms my suspicion probably something like 80% of the time. And I always wonder in that remnant 20% if either our understanding of the germline mutation is just incomplete. So for instance, if I had gotten smarter and I had gone and tested myself before 2007, my family's particular mutation was not even indexed in the database until our Swedish colleagues actually added it that year. So as Dr. Nosé mentioned, this is iterative and we're learning all the time what's truly pathogenic and what might be a variant of unknown significance and what might be completely benign. So that's part of it.

The other part of it is we might discuss, you hinted at this earlier, is there are other MEN syndromes. Actually, I always think it's really unfortunate that MEN1 and MEN2 are named a number the way they are because MEN2 is a completely different disease affecting a different gene and frankly with potentially much earlier more lethal manifestations with medullary thyroid cancer affecting some children in their first year of life. It's a horrible, horrible thing for some parents and infants to have to contend with. But my real point is that I think that MEN4, which we might briefly discuss is it's not a waste basket diagnosis at all. But again, it's a separate syndrome that almost phenotypically mixes MEN1 and MEN2. And there's been some work retrospectively patients who looked like they had MEN1 phenotypically, but when we tested their germline, we didn't find it. Some of those patients actually have problems, germline mutations I should say with cyclin-dependent kinases that actually can lead to MEN4. And there's even this nomenclature of MENX, meaning that we may continue adding germline mutations to the MEN family, but that's how I would describe the Bayesian likelihood of finding MEN1 when you order it.

Dr. Gladell Paner:

Thank you, Dr. Lewis. And I'd like to turn this question to you, Dr. Nosé. This is regarding the things that we discussed with Dr. Lewis about genetic testing. My question is currently are these types of MEN, are they defined by the gene mutation, by the type of the gene mutation, or not yet?

Dr. Vania Nosé:

Thank you so much for the question and I think this is an amazing discussion. So there are three ways to make the diagnosis of MEN. One is genetic, the other one is familial and the other one is individual. So the individual way to make the diagnosis, you need to have a patient who has the three diseases at least, or like he mentioned, Dr. Lewis mentioned, angiofibromas or the lesions that are less common. But having two of the three major lesions or microadenomatosis is one of the, let's say the individual criteria. The other criteria is the familial. There are index patients. Index patient is like it's the asymptomatic patients of the first degree relative of a patient with the MEN1 variant or symptomatic first degree relatives of a patient with the syndrome, like discuss the parathyroid like microadenomatosis is another sign in patients under 30 years of age.

That's the criteria used. And also the germline is another way to confirm all these things. And the germline, it's really a confirmatory test and mostly for the asymptomatic family members of one person, that diagnosis, like initially there are multiple mutations, I don't know, 400, 500 mutations described already. And these mutations are very important and the dependence of one gene is very high with over 90% care in these mutations. So when to do the testing, any patient that's suspicious has one of these criteria. And the MEN1 has really been well studied. They have done criteria for diagnosis and like I said, the non criteria are individual, familial and the genetic and the genetic condit line test is the ones that really confirming patients with diseases or people from the family if the test is really negative. 10% of these patients that have been believed for many, many years to be MEN1 had tests negative, had pancreas. They have what is called now MEN4. And I think this is really an important finding, although it's phenotypically basically similar, it's called dose by different gene. It's also dominant and it has the same kind of transmission, at least the progress of NGS and the discovery and novel genes associated with this. Finding these clinical findings and the morphological find. That's why I always say the morphologist is fantastic because if you find all these microadenomatosis, if you find multi glandular parathyroid disease, these are all clues for you to make a diagnosis. Mostly all of them young patient. And also in this cases, these patients, they have multiple organs involved. And the involvement of these multiple organs, I feel that's very important. Usually like I always say, multiple organs multifocal and the bilateral is the for pathological diagnosis of syndromes.

Dr. Gladell Paner:

Thank you Dr. Nosé for that beautiful insight there. Thinking about the tests from our experience and when it comes to genetic testing, usually the test comes from the clinicians, not from the pathologist. And this is just my curiosity, Dr. Nosé, from your experience looking at diagnostic specimens, have you ever or have you thought of ordering the test yourself?

Dr. Vania Nosé:

I'm the one, the worst one to order the tests. And I talk to the clinician because I really feel that if you have a main tumor and you have the remainder of the organ, don't just study the main tumor, study the entire organ. And the problem is that the majority of the residents, the fellows, they learn how to make diagnosis of that tumor and they forget everything else. And they keep teaching because I feel that we are missing so much if we don't look everything. So I described as many pathological findings in the tumor thyroid, in the adrenal and the pancreas because I feel that if you have a clue, if you see where they are, if you see what's going everywhere in the side, you make a diagnose correctly, you suspect syndrome, let's consider thyroid that's not in case of MEN1, but let's consider thyroid. When you see multiple thyroid, no multiple follicular adenomas dens with nodes. You think in PTEN one you think, and I ordered the test and I would talk to the clinician and [inaudible] for the patient and I ordered and I tell the clinician, this is highly suspicious for PTEN syndrome. To be honest, I have done also multiple times correct diagnosis in this sense of being modest, but in the sense that you feel that you are right and why not help this family, this patient, this family to look for the other tumors because one, let's say they know much, they're all benign, but the patient may have other tumors, the places that are family, the children. So it is always important. I really like to work with the clinicians.

Dr. Gladell Paner:

Thank you, Dr. Nosé. So I'd like to switch now to the treatment side of MEN1, and this is for you, Dr. Lewis and I, we don't want to guess your age right now, but we would like to know since you were diagnosed with MEN1, can you describe to us the advancement in treatment for MEN1 and if there's any impact in the prognosis different than you were diagnosed and to is it now?

Dr. Mark Lewis:

Certainly. No, I have no problem disclosing my age. So I was 30 when I was diagnosed. I'm 44 now. And my pancreas surgery was almost exactly halfway between those two. So I was 37 when I had my Whipple. So I think the biggest change I've seen honestly is on the diagnostic side, but here I'm going to bring in yet another partner specialty, which is radiology. So it's been really interesting to me. So as an oncologist, I often tell my trainees, listen, you're not doing your patients a proper service unless you actually look at the images yourself. So our radiology colleagues are wonderful and they obviously give us synoptic reports and text much as you do. But I think it's really important to see the images and in fact, the tumor board, when a pathologist shows us the slides, when a radiologist shows us the scans, it's definitely a case of a picture is worth a thousand words.

So what I'm getting at is when I was first diagnosed, the imaging for neuroendocrine tumors with or without MEN1 was pretty primitive. So not that long ago we were using Octreoscan, which is a form of somatostatin receptor scintigraphy, it's based on indium 111. And the best description I can give you visually, I know this is an audio format, it was like a snowstorm. There was this kind of very, very blurry kind of black and white picture of the body. It was actually very difficult to discern any anatomic detail. And what's happened in the years since is we now have dotatate PET that is far more, far more precise, especially in regard to anatomic correlate. I've likened it, my best analogy is it's the difference between the way TV used to look when we had a big box that we plugged into the wall and the way it looks now when it's flat screen and it's high def, it really feels to me like that difference in resolution.

And the reason that matters is with that increased diagnostic acumen on that particular type of scan, we now have a whole new field of treatment. Now to your question, I actually have not required this treatment myself, but I prescribe it all the time and it is peptide receptor radionuclide therapy. So the reason I love the PET scans is it's not an academic exercise. They show me disease that I can almost always act upon. So the way I explain it to the patients is you go for your PET scan, this isotope is placed into your circulation, it binds to your tumors, and it shows us that on their surface they have somatostatin receptors. Ergo, we can target those same receptors now, not with a diagnostic isotope like gallium or copper. We can actually target those with a therapeutic isotope like lutetium. So for five plus years now, the FDA has approved such as therapy in the United States, and it's been, I don't think hyperbolic to say, a game changer.

So that to me has been the biggest advance. The one thing I have benefited is increasingly less invasive approaches to the pancreas. So when I was first diagnosed, again, I've mentioned I was at Mayo. Mayo among other things is well known for its surgical expertise and rightly so. But it was interesting to me. I was given three different surgical opinions and basically almost a menu if you will, as to what to do. I've told other people it felt like a la carte medicine. So the first option, and the surgeon literally said this to me, he said, Mark, I can just take out your entire pancreas problem solved. That's great for me, tumor risk reduction perspective. It's not great from having a no pancreas perspective. And I definitely did not want then or now to have pancreato-diabetes. So I passed on that.

The next option I had was the Whipple. And we are getting better and better understanding of when to operate. Basically, this is the key. If you look hard enough at most MEN1 patient's pancreas, it is very, very easy to find tiny, tiny tumors or tumor lids throughout the entire parenchyma. That's not the issue. The issue is at what point are those going to grow or secrete excess hormone or both to the point that they actually are harmful to the patient's health. So I think what I'm getting at, because the third surgeon offered me an observation, and that's the option I took. We're getting better at knowing when to intervene. So the reason I had my Whipple halfway between when I was diagnosed and how old I am now is I was being followed every year with a means that required no radiation exposure whatsoever, was endoscopic ultrasound. And the year that we saw the dominant tumor in my pancreatic head, more than double in size, that's when we knew its behavior was changing and it needed to be removed. So I think that that's the biggest advance I've lived through personally while witnessing professionally that imaging in this whole field of theranostics, the coupling almost like a lock and a key it have a scan to the treatment that's been wonderful. And nuclear medicine has been an absolute godsend for NET patients and MEN1 patients, not just on the diagnostic side, but on the therapy side.

Dr. Gladell Paner:

It's very interesting when the tumors or the lesions are being monitored by this scan, I would suspect that there's certain cutoff for the size that they follow and then it reaches size, then they have to take it out or something like that.

Dr. Mark Lewis:

That's exactly right. So here I have to sort of tip my hat to our Dutch colleagues. So one of the great things about certain countries, especially in northern Europe, is not just socialized medicine but rigorously kept records and national databases. And the Dutch in particular have done a phenomenal job at this. So they're following an unbelievable number of MEN1 patients and families. And what they've been able to do both retrospectively, but now prospectively is just to your point, ask the question, when is a pancreatic tumor, at what size does it truly become dangerous? And the answer is for a non-functional tumor. So this is the key. So now you have to bring in some lab work and see if the patient has a hormone excess or not. But if it's non-functional, the magic number where you need to do something is three centimeters. And that's exactly when I have my Whipple and my tumor doubled in size in a year, which obviously indicated a faster growth rate and went from under three to over three.

That's when I knew as a medical oncologist that as much as I didn't want to, I needed the Whipple. And so that's the cutoff that I look for. We haven't really discussed this and there's a reason why it is vanishingly rare that you would see an actual cancer, an actual malignancy in the pituitary or the parathyroids. Thankfully that is the farthest thing from a common manifestation of MEN1. So truly the big malignancy risk associated with the three Ps at least comes from the pancreas. So if you're mitigating that, I often tell patients that I can keep them alive and then we're going to deal with the hormonal excesses of the other organs as we've already mentioned.

Dr. Gladell Paner:

Thank you, Dr. Lewis. So you mentioned about the malignant potentials of these tumors. I'm going to loop this question to Dr. Nosé. So in MEN1, we're dealing with these multiple different types of tumors, different organs. So among these tumors, and this is an advice to pathologists making the diagnosis, which of these tumors have the highest risk to being malignant?

Dr. Vania Nosé:

Ones that are more malignant really are the more rare ones that are the adrenal cortical carcinoma that occurs in rarely cases. But the pancreatic neuroendocrine tumor are the ones that when we start to grow, there is a size that you cannot let it grow more in the sea. And basically the diagnosis of malignancy is based on factors like mitosis or proliferative end necrosis. But there are lots more rare than the known neuroendocrin tumors in or maybe the dynamic, the pulmonary are more malignant usually. But as we have more tumors in the pancreas, then all the organs, the pancreas would be the one that within the more common ones. But the more dangerous would be the adrenal and lung get the time.

Dr. Gladell Paner:

And how about say, so these tumors also arises in a sporadic setting in nonfamilial setting. And in terms of if we compare these tumors from the familial side and the sporadic setting, are there any difference when it comes to behavior?

Dr. Vania Nosé:

Behavior? No, some tumors are even more benign than this sporadic. So they don't think behavior. The problem is the multi centricity. So in cases people looking for primary tumor in think that's metasis, that means that's really poor prognosis. And these are all little benign little tumors in the, so the prognosis, as far as I know, no, doesn't change. It is not the difference. What is different is pathology, the pathology between sporadic and familial cases. But between, I think the prognosis, depending on it is worse just because of the hormonal overproduction. And in cases of a lack of a diagnosis like in Dr. Lewis' family before you have adenoma and you have no idea that you are part of a familial syndrome. But I think nowadays, if we pay more attention to all the details and family history and association of tumors, I go to the clinical history to try to find family history and so forth. We have to pay more attention to all these details and takes more time for us to sign. So much easier for me to sign on and know it's not next, but we have to carefully try to think about falo syndromes all the time because they're much more common than what we think.

Dr. Gladell Paner:

That's a very good point, the multifocality. And when we look at the specimen we look, we only look at that specimen that we diagnosed for that time for the patient. And it's important also to look back if this patient have the same previous tumor in a different organ, for example, parathyroid, it turns out to be multifocal and that could be a hand that we're looking into if familial syndrome. That's a very good point. And I'd like to switch to Dr. Lewis, and this is something to do about the counseling of the patients you are living with MEN1. So in terms of counseling the patients and also in terms of surveillance, can you share your experience to us and can you also share to us what are the challenges?

Dr. Mark Lewis:

Yeah, great question. So first of all, I'm happy to say the prognosis is improving. I think that if I had to point to one year or decade where things started to change for the better, it would be the 1990s. So prior to 1990, the number one cause of death for MEN1 patients was truly horrendous peptic ulcer disease. So in the initial kindred described by Dr. Nosé and Dr. Wermer's pedigree, essentially half of that family, that Italian immigrant family he was following in New York, were dying of either horrendous GI bleeding, gastric perforation, or both,.I mean horrible ways to go. And then in the 1990s we really developed effective and I would argue prophylactic acid suppression in the forms of H2 blockers in proton pump inhibitors. So that has actually shifted prognosis now where back to the pancreas, the number one threat to mortality in a patient like myself or an MEN1 patient I would follow is actually the pancreas not forgetting, as Dr. Nosé very rightly said, that the more esoteric sites of tumor development can actually be the most lethal, including the adrenal gland and the lungs and the thymus.

So the way I counsel patients is based on current medicine. We'll see where we go with CRISPR, this is an incurable lifelong condition. There's nothing I have to offer that's a cure. So what I try to do without being dismissive is get them to accept this as a chronic illness. If they go to their primary care doctor and they're diagnosed with hypertension or diabetes, barring some phenomenal change in lifestyle or risk modification, they're probably always going to have diabetes or high blood pressure. And again, I'm not trying to minimize in making this comparison, but my point is, every single person who comes to the oncologist, their first question usually is, am I going to die and related, how long am I going to live?

And the answer is, most one patients now thankfully lived decades after diagnosis, which brings me to the other answer to your question is first do no harm. So I've already mentioned on the surgical side, I think a good surgeon knows how to operate and I think a great surgeon knows when not to operate. And I've certainly benefited from surgeons that have been very judicious in taking out the right tumor at the right time and leaving me with organs and functional preservation for as long as possible. So that's one part of it. On my side of it, if I get too overzealous and order a lot of scans that contain ionize and radiation, I'm potentially harming my patient. That is a legitimate concern for iatrogenic harm. So one of the things that I do when I surveil them is I try my best to avoid anything that contains radiation.

So for instance, I follow myself with MRIs of the abdomen and MRIs of the pituitary. The only radiation I incur with any regularity is about every five years I get a CT of my chest. It's obviously very difficult to MRI the lungs because of respiratory motion. And then even the dotatate PET scans I mentioned earlier actually carry less radiation than if you were CTing the patient chest, abdomen, and pelvis because you have a very fleeting isotope that decays rather than all the X-ray exposure that's associated with traditional CT. So the long-winded answer to your question is I tell people, listen, your prognosis is generally favorable. I will tell you if I'm ever worried about your liver function in particular, the number one way my patients die if I'm being blunt and then I say, listen, the way I follow you, I don't want to hurt you. That goes against all medical ethics. But I also want to be picking things up in a timely fashion so we can intervene before they become too problematic or even incurable or deadly. And again, I think pancreatic monitoring is probably the thing that saves the most lives in MEN1. The other technique that I kind of glanced over is endoscopic ultrasound. It's more invasive. It requires a subspecialized gastroenterologist, but it's enormously helpful because they can get an ultrasound probe right next to the pancreas in the first sweep of the duodenum. They can both see and sometimes even biopsy the pancreas from there. And again, you're incurring no radiation with that approach, even though of course it's an invasive procedure and you usually have to travel to a tertiary center.

Dr. Gladell Paner:

And in terms of imaging, the protocols of the imaging, do you do a yearly scan at least?

Dr. Mark Lewis:

Yes. So there are actually updated international guidelines from Thacker, et al. And Dr. Thacker for years has sort of led this global counsel of providers. And again, it's sort of the principle of no or minimal ionizing radiation and frequent enough surveillance of the key organs. So the way I do it is I get an MRI of my abdomen, in my patient's abdomens every year. That's essentially a hard and fast rule. How often you image the pituitary has actually been shifting a little bit. A lot of us feel comfortable imaging the pituitary with a dedicated MRI of the cell probably every three years. But there are certainly clinical clues like we've already talked about, the vision loss. Certainly if a man develops galactorrhea, that's a huge red flag, even intractable headache. I would say in an MEN1 patient, I have a pretty low bar for MRI of the brain and then that leaves us with the middle ground, which again is the chest.

This may be the most debatable, but I like getting a CT of the chest every five years and or a dotatate PET scan every five years because in both cases you're catching the thorax. And one thing that we haven't touched on that's interesting is there is actually, it seems a gender difference in the types of nets that develop in the chest for MEN1 patients. We don't really understand why this is the case, but for women it seems like there's a true predilection probably like eight to one for true bronchial neuroendocrine tumors, whereas men have the opposite for thymic tumors. So much so that in hindsight, I've actually wondered often if my father really even had a bronchial NET, maybe he had a thymic NET, whatever it was, it grew in his anterior mediastinum. But my point is that you can't forget about the chest and this whole business of three Ps mnemonic again is wonderful provided it's not too reductive.

I've seen great doctors, great doctors, great clinicians, completely forget about the adrenal glands, which by the way, you'll see on the MRI of the abdomen completely forget about the chest because you're not usually MRI that part of the body. And again, sometimes even underestimate just how harmful to quality of life. Some of the non-malignant tumors can be, for instance, pituitary macroadenoma or unchecked hyper parathyroidism. I can tell you at least from the latter, it is miserable. You feel horrible when you're hypercalcemic chronically. And so I think that's the final piece of the puzzle is prognosis is one thing, but we also want our patients to not just have longevity but really good, rich, full lives that they can enjoy.

Dr. Gladell Paner:

Thank you, Dr. Lewis. I really like the way you counsel the patient. So this is basically tell them that you have a chronic disease and this require a long-term follow-up. I'd like to shift to Dr. Nosé. And Dr. Nosé, this is for our surgical pathologist listener for today. Do you have any advice for the pathologists, for the surgical pathologist regarding their roles in the recognition of MEN1?

Dr. Vania Nosé:

So yes, I love to say the pathologists play a very, very, very important role on diagnosing familial cancer syndromes of or hereditary syndromes. All glands, I mean every single gland, if there are multiple, like I mentioned, the duodenum that has multiple little tumors, you cannot think they're multi focal like paragangliomas. If they're multi focal, they're not metastatic, they're multi focal. So this is a clue for diagnosis of familial syndrome. And in the end, the pancreas is a major, the duodenum is another major clue. When you have this multiple microadenomatosis disease, a clue, really an important clue, don't look at the larger tumor like over three centimeters only make that diagnose. Make that diagnose correct. But please do look at no involved grossly no involved [inaudible]. And again, if there are more focal tumors in one organ or if there are tumors, multiple words, always think and adrenal cortical tumor, the majority of people think, oh, is it resectable?

And they just like the survival is very poor, but never think about syndrome. And adrenal cortical carcinomas are very commonly associated with syndromes, not only with the one but multiple other syndromes. So what I feel is that every time that you have pay attention to the age of the patient, the gender to see the correct gender for the tumor. But the age is crucial. And then always look at the whole specimen as a whole, not only one section like parathyroid. If you look at parathyroid, which is multi multinodular, multiple glands involved, people just say, oh, hypercellular, parathyroid next. No, if they're multi nodule, parathyroid glands, the multiple nodules, usually we call now we even change the name of the last because we feel that it's really, they are [inaudible] for thinking in MEN1, let's say, or MEN4. But there are multiple nodus in each parathyroid.

And these nodus are very unique morphologically. They don't distinguish, we don't distinguish from others as a whole. You see that they're different because there are four glands involved. They have different sizes. And I think these are close to the pathology to always pay attention. Always, always, always for any case, but always clinical history and contacting the clinician is crucial also. And don't forget, look at the family history. I found cases and cases that looking and said, oh yeah, my sister had, my brother had, oh yeah, my mom used to have. We have really, as pathologists, we play a very important role. And I feel if we don't keep talking to other pathologists, to the young pathologist, the young pathologists are really fascinating about making the diagnosis of the main lesion, but they forget exactly what to look for. And we are teachers, we are leaders in the field, so we have to teach them how to make the correct diagnosis for the disease. So anyway, one, we have to think two, four now three or five. So we have already five MENs where Carney Complex almost was called me and also coming from Mayo Clinic. But just look, carefully, every single piece of tissue that we get.

Dr. Gladell Paner:

Thank you Dr. Nosé, that's an excellent advice and couldn't agree more. And as you said, it's important for us for pathologists to communicate even the hint for the suspicion of these findings to communicate it to the clinicians because there are additional information that we may not be aware of and could help lead to the findings or the diagnosis of that men in general. Dr. Lewis, we are aware that you have been very active in sharing awareness on men, one in public venues and social media. And having said that, I just followed you on Twitter, on X. So please can you share with us some of your activities?

Dr. Mark Lewis:

Certainly. So lemme tell you how this came about. So I kind of glossed over this too, but the very first surgery I had, which may not surprise you based on what we were just discussing, is I had a subtotal thyroidectomy again when I was still at Mayo. And the endocrine surgeon, who was absolutely wonderful, actually came to me before the procedure and he said, Mark, I have a strange request. He said, I want to videotape your surgery. And I said, by all means, you can do that. It's fine by me. And he said, the reason I want to is most hyperparathyroidism is driven by a single gland, a single adenoma. But as Dr. Nosé has very nicely told us, it's the multi glandular architecture here, which of course makes sense in a germline setting that really should alert everybody to the fact that something is going on on a deeper level with a germline milieu.

So my point is he videotaped my subtotal parathyroidectomy basically to show trainees and other people at Mayo. And I was totally fine with that. So fast forward several years and it's coming time for me to need my Whipple in 2017. And that whole experience of opening up the operating room and allowing cameras in that had stuck in my mind. And I thought, well, maybe there's actually an even more modern way of doing this where rather than ending up on a VHS tape and the Mayo Clinic library, what if I can share this with more people? And I've been accused of being an exhibitionist, and I guess that might be fair. So I arranged with my surgeon and my institution's social media team to live tweet the entire surgery from pre-op to surgery to post-op. It is an amazing experience for me at least.

It's actually how my wife got updates. So traditionally the surgeon has to come out of the OR every couple hours and tell the family things are going. My wife could literally see if she chose to step by step every part of my operation. And I'll tell you why I did it. Well, first of all, I didn't anticipate this, but the public support was just amazing. There's lots of negative things on social media, of course. But I woke up and 3 million people had been following my surgery and almost all of them had nice things to say afterwards, which was really lovely. But the more important part is the Whipple surgery is a really daunting operation. And in my practice, both with neuroendocrine tumors and with the more conventional pancreatic adenocarcinoma, I see patients who are operable and decline the surgery because they are afraid of it. And I'm a firm believer that monsters are more scary in the dark.

So I thought, well, if I can convince one person, one person, that this is actually a surmountable obstacle, that the surgeon with the right amount of expertise and following these steps can perform this successfully and there's life on the other side of the Whipple, then I felt like maybe my experience could help someone beyond me, and I'd like to believe that's been the case. One beautiful thing that's happened is this feedback loop where, because I've advertised that online neuroendocrin tumor patients with and without MEN1 now come to me because they want quote a doctor who gets it. I tell them right off the bat, I'm like, listen, my experience is going to necessarily be different than yours. I haven't had chemo, I haven't had radiation. I certainly might at some point. I said, so far all I can tell you is I know what it's like to have cancer.

I know what it's like to have a family history. I know what it's like to have life-changing decisions. And that's kind of the bedrock of empathy that we build from. But the final reason I do it, honestly, and you mentioned earlier some of the statistics around MEN1, it is generously estimated that one in 5,000 Americans might have it. I think the number is probably somewhere between one and 20,000, one 30,000 regardless, it's not everybody by any means. It is profoundly lonely to be diagnosed with a rare condition. And when I was first diagnosed, social media was really in its infancy. I didn't know anybody else who had any MEN syndrome. All my relatives had passed. I felt like I didn't have anybody to talk to. So again, with all the necessary caveats, and there's certainly some horrible trolls on social media, I would say 99 times out of a hundred, my interactions on the have been positive.

And you really kind of find your tribe. You find kindred spirits and you realize you're not going through this alone. That's happened both professionally. Net experts who I've met online and patients and patient advocates. And it's just been a beautiful, beautiful thing. And frankly, at least my interactions like this one outside of tumor board, I'm almost ashamed to admit I never venture out and seek out my pathologists. I love this dialogue. I think a conversation like today's shows me that we're all in this together a couple of times. Dr. Nosé, you've sort of framed this I think very appropriately as a mystery. And I like to think that we're all assembling our clues together. There's forensic evidence, there's circumstantial evidence, there's gut instinct, but together we can arrive at the correct diagnosis. The correct diagnosis tends to lead to the correct treatment. And then finally, the real, to me, weight of identifying hereditary syndrome, as we've already discussed, is the cascade effect on the family. My family is very small. I'm an only child, so I have not propagated any in one beyond my own son. But I have to tell you, these huge kindreds that are out there, many of whom remain undiagnosed or unrecognized, that's what keeps me up at night. It's like, how do we figure out who's got this? I am living walking through that. If you catch it early enough, there's things you can do that can prolong your life.

Dr. Gladell Paner:

Thank you, Dr. Lewis. What you're doing is really novel and commendable. Thank you. You're bringing man one to our attention, not only for the patients of course, but also for the diagnosticians like us. And I'm looking at clear and giving to your Twitter account, and you have a big number of pathologists, followers. So we are on the other side of the fence. We're making this diagnosis. So yeah, so as you mentioned, conversation like this brings MEN1 to our attention. So that's very helpful. So unfortunately, this is the time we have. This is a very interesting discussion. I would like to thank both of you for your insights and expertise about MEN1 and Dr. Lewis about sharing your personal experience about men. One, this is truly very informative and I would like to pass this now to Becca.

Becca Battisfore:

Thank you, Dr. Paner, for leading the conversation to our guests for shining a light on MEN syndromes and other familial cancers.

And I want to thank you all for listening to this CAPcast. You can find links to the CAP's Cancer Protocols in the show notes, including nine endocrine protocols available to support pathologists in reporting out cases. If you have questions or comments about any of the protocols, please email CancerProtocols@cap.org. And for more information about the cap, visit, cap.org.

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