Grand Rounds-Pituitary Tumors: Pearls of Diagnosis and Technical Nuances for Transsphenoidal Resecti

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- Hello ladies and gentlemen, thank you for joining us. Today we're honored to have with us Dr. William Chandler from University of Michigan. He will be talking to us about pearls for diagnosis of pituitary tumors, and also his technical nuances for transnasal microsurgical removal of these tumors. Bill, thank you for joining us, and we're very excited to listen to your pearls.

- Thank you Aaron. First of all thank you, thank you and the ANS for putting together this wonderful series, I have had an opportunity to review some of the other programs that have been done, and I think it's a wonderful teaching tool, so I will try to add a few of my views with my experience over the years. So what we'll talk about, and you can see the title, I'm gonna move on, I don't have any disclosures in this area, one comment I would make is that, we see these patients with pituitary, and emphasize both pituitary and parasellar lesions in our clinics and of course the endocrinologists see these pearls, but remember that they present to oftentimes of course the emergency room, sometimes through their ophthalmologist, sometimes their neurologist with symptoms, sometimes even a psychiatrist with cushioning disease, and of course, most importantly here at the bottom are primary care providers and pediatricians see these people sort of out in the trenches and have to recognize what are oftentimes complicated endocrine symptoms. So I thought I would open, let me make a comment also that I've had the privilege of working with Dr. Barkin who is sitting in this picture, is a pituitary endocrinologist and Steve Sullivan who is next to him, he was a new member of our pituitary clinic who has been focusing on the endoscopic approaches, so I think the combined multidisciplinary clinic has been extremely helpful to our patients. The patients are always seen either by myself or Dr. Sullivan, along with Dr. Barkin at their first visit. So I'd like to go through just a few sort of pearls and pitfalls from the endocrine standpoint, so much of what we do is deciding who to operate on, and there's a few tricks along the way that I've certainly learned, and I'd like to share a few of those, the first one, and you can see this is a standard list of endocrine workup that's done in most pituitary patients, and the first thing that we see a lot of, is that patients come in with a normal TSH, but remember that in a secondary hypothyroidism, in other words, if it's coming from a sort of upstream and the pituitary the TSH which doesn't really have a lower limit may be normal, so it's very important to always check the free T4, and this oftentimes when patients come in, this has not been done. And I'm gonna show a couple of things, another sort of pearl is that when you see patients with symmetrical enhancement and you can see that on this patient, be aware, and I'll show you how this relates a little bit to the thyroid workup and to some other areas in the workup. So this was a woman who came in 28 years old, fatigue, headache, slightly elevated prolactin, presumably a stalk effect, hypothyroid, not too surprising, with a mass like this and a morning cortisol that was sort of not too low, but not too high, and she came in eager to have surgery and had been worked up, then I looked at this and realized that there's one thing, sort of a clue here, that this may not be a tumor, and that is, you can see the very symmetrical enhancement here, we don't see any pituitary gland around the edge, so what's missing from this picture, and what's missing, I can advance this, is that we have only a free T4, when a TSH was done it was greatly elevated, again, normal is up to seven, this was over 100 and this patient simply has primary hypothyroidism, this is a hypertrophy gland, this is what happens when the patient was simply put on Synthroid, so the treatment of this patient was Synthroid and not surgery. So, remember in primary hyper hype hyperthyroid, I'm sorry that should be hyperthyroidism, of course TSH goes up and the free T4 goes down, and secondary just the opposite which we covered. So the main message for the primary care doctors and all the folks that we talked to about to surgery, is to be sure and get both. Now, another area, and I sort of call this Pseudotumor tumor of hypothyroidism, and I've seen at least a half dozen cases like this in children and adults over the years. So, here's another situation, another sort of beware when you see this symmetrical enhancement, these are two different patients. I'll show you the first patient, and this is a patient who came in with this sort of enhancement, a mass, this patient did go to surgery a long time ago and was biopsy, and this turned out to be lymphocytic hypophysitis, so this is what this hypophysitis looks like. So this patient came in a few years later, again, referred in for surgery with what was believed to be a tumor, and you can see, I think there's an arrow over here pointing to this very small carotid artery, so this sort of mass lesion process at narrowed both carotids on the patient's, right, you can hardly even see the carotid. She was a young woman, fortunately without any neurovascular problems, but related to that, and I said, you know, this sort of looks like hypophysitis, looks like an inflammatory process, it's symmetrical, there's no normal glands. So we put her on prednisone, 40 milligrams a day for a month, and here's what her scan looked like, and she was on the prednisone for I think three or four months, came off of it, this has never changed, since then it's never come back. So this is a patient, with what we would call granulomatous hypophysitis. So again, beware when things look symmetrical, this is another thyroid related issue, that's sort of interesting, this patient came into our office with a hyperthyroid with elevated free T4 and a normal TSH and a black sort of hole in the middle of her pituitary gland, when I looked at this, I just thought she had hyperthyroidism, she was sort of nervous and jittery, but Dr. Barkin looked at this and realized that this is a problem, that the TSH was in the normal range, but with an elevated free T4 and the TSH should be ultra low, it should be almost barely measurable, so this patient, here's a CT scan showed this was a small calcified mass, I took that out and it was a TSH secreting microadenoma, and the patient had normal thyroid function after that treatment. So the Pearl is that when the free T4 is elevated, the TSH should be, go back to that should be almost unmeasurable. Now the workup of a patient looking at their ACTH levels, a patient who looks like this, who came in looking like the poor fellow had been at, locked in a closet for years was pan-hypopituitary and his 8 AM cortisol was less than one, so that's easy, here's what he looked like by the way two years earlier, so this is an example of someone with Panhypopituitarism, so, the message is that if you suspect hypocortisolemia simply get an 8 AM cortisol and you'll usually have the answer. If it's only moderately low this may be an a post-op patient or a patient you're working up, it may, if they're healthy enough, they can have an insulin hypoglycemia stimulation, stimulation test, and the cortisol should rise to up over about 20. So how do we work up patients with Cushing's disease, looking for hypercortisolism, and then of course the first thing, and this is again, back in their primary care office or the pediatrician's office is clinical suspicion, then when they have that, I think the best test to get is a 24 hour urine free cortisol. The over overnight dexamethasone suppression test is only about 80% reliable, and if you really suspect that a patient has Cushing's syndrome, let's say that they're hyper cortisol, you should get at least 24 hour urine free cortisol, and that we've found to be the best diagnostic test of hypercortisolism. So proving hypercortisolism, again, I think is what the 24 hour urine free cortisol, then if a patient has a normal imaging of their pituitary, if they have cortisolism, they look like they have Cushings and they have a pituitary tumor that's easy, you can proceed the surgery, but at the imaging, which is true and about 40% of Cushing's have normal imaging on MRI then the inferior patrol sinus sampling is of course the best way to prove pituitary origin, but remember that it only lateralizes about 70% of the time. Aaron did you have a question?

- Yes, I may ask Bill, how do you use the cortisol level and the saliva in order to form a decision of who to operate, and who not to operate, is that the nuisance test?

- Yeah, to be honest, we do use that, patients come in, or oftentimes with salivary cortisol is usually done at night and if that's elevated, I think that's part of the picture, but, and it is very sensitive and that's probably a very good screening test, we still rely on the repeated 24 hour urine free cortisols to, you know, to make the diagnosis, now, there are patients with cyclic Cushings and this simply requires a number of checks and that's where the salivary cortisol can be helpful as well.

- Can you tell us a little bit about pseudo Cushing and how surgeons make sure they can differentiate that from really more surgically amenable form of Cushing's disease?

- Well, yeah, I honestly don't see a lot of pseudo Cushings, but again, I think you have to have repeated reliable evidence for hypercortisolism, there are patients who have other medical illnesses, who's going to have pseudo Cushings disease, but if the patient has the clinical signs and symptoms, and again, reliable 24 hour urine collections, then of course, we assume that they truly have Cushing syndrome and move on to further diagnosis, diagnose them with etiology and that's where, again, if MRI is helpful that's great, if not the patrol sinus sampling, in one example in men, you know, it's a little less likely to be pituitary origin, we had one gentleman where the patrol sinus sampling was negative and kept looking and looking, and he ultimately had serial sampling of the venous blood in every logo's lung because the CT scan it was long was negative, finally we found that at one lobule, it was very positive, so as the surgeons resected that and serial sectioning showed a very small tumor, so it can be difficult.

- So it seems like for you the 24 hour urine is the more, sort of the more sensitive test and it needs to be re repeated to determine Cushing's disease, is that correct? I know it's part of the picture, but in the big picture is one of the more important ones.

- Yeah, I think to these determine hypercortisolism again, now you can use the low and high dose TechSmith sown suppression test to further look for a pituitary origin, and again, the imaging and the patrol sinus sampling is quite accurate. Okay?

- Thank you.

- So another sort of pearl I guess, is that with Cushing's it's really all or none as you'll see in patients with acromegaly, if you take out 95% of the tumor they're a lot better, they may not be perfect, but with Cushing's my experience is you really get a perfect result, in other words the post-operative cortisol levels are subnormal, or you don't have success at all. The other thing I would say, and this says be willing to go back for a second look, and I'll show you an example on this slide, this is a patient where I took out at normal imaging, positive petrosal sinus sampling, I took out half the gland and the patient was not cured at all, so I went back, took out the rest of the gland, and you can see this tissue stain for ACTH, that's literally about one millimeter in size and the patient was cured, so that was it, so you can't see that at surgery and you can't see it on imaging. So the few patients, I think you just have to take out the gland, this is a patient where the first half of the gland that was taken out, showed hyperplasia and the treatment for that is to go back, I believe and take out the rest of the gland, So I think you need, I always tell patients that they might need two operations for Cushing's disease. So a few pearls with acromegaly, and I've summarized some of these, and the main one here is that, as many of you know that growth hormone may be normal, there's a nice picture from your book of Harvey Cushing, and a very tall fellow, but they actually may look normal as well, and another pearl that I learned in the process of seeing patients, a lot of folks don't know, is that estrogen will suppress IGF-1, I'll show you an example of that. So here interestingly, on your left side are acromegaly patients, 24 hour growth hormone levels, and on the right side these are normal controls, so you see all these spikes that we all have all the time, but if you look at the acromegaly patients, sort of the area under the curve is too high, and these patients both have clinical acromegaly elevated IGF-1 and as you can see normal growth hormone levels, whereas the normals have normal IGF-1 even though they have spikes. So IGF-1 is the gold standard.

- Is that correct, the source of estrogen is usually the contraceptive pills is that right? So you have to ask the patients to stop their pills before you get an accurate measurement.

- Yes, those are relatively low levels, I'll give you an example here, this is a woman who has a nice control, brought her twin sister with her, although I'm not sure you could pick out which one is an acromegaly, the both have sort of square jaws, but the woman with the circle here has an obvious pituitary tumor, they had identical rings, they were given since they were twins, she had had her ring increased in size, the twin sister had not, so wonderful control. But look at her values are slightly elevated, IGF-1 normal would be about 250, growth hormone three, which isn't terribly low but within the normal range, she was taking estradiol, so she was actually, excuse me, on estrogen treatment for something and not just birth control pills, so Dr. Barkin had her stop this and her IGF-1 went to 1300. So, estrogen actually can be used, it's not a standard treatment, but it can be helpful in patients who are not cured with surgery, so, again, it's a nice little pearl to be aware of that fact. So, I already mentioned that reducing the tumor is oftentimes helpful in these patients, and another thing to remember is that it may take days to weeks even a month or so, for the IGF-1 to reach its lowest level to come down, post-operatively. So, the other thing is that today, most postoperative failures, and if you have sizable tumors, you're gonna have about 40% failures because they're invasive, the first line is, is somatostatin analog, such as Sandostatin LAR Somatuline and then pegvisomant which somavert, which is receptor blocker. And then if that fails, then focused radiation, either fractionated or stereotactic radio surgery is still very helpful in these patients. So a couple of pearls about prolactin secreting adenomas, obviously in every patient need with a pituitary tumor needs their prolactin measured, and most of these are treated medically, now is cabergoline of dopamine, and then I think many people are aware, we published a case in this many years ago, the so called hook effect and I'll mention that, so this I put in here not to give up on cabergoline, some people would see this and say, my gosh, this has to have surgery, it's probably too big to be treated medically, here's this patient a few months later with the prolactin down to 72, which is a fraction of where it started and the tumor nicely shrunken. Here's another phenomenon that I've seen on several occasions, oftentimes in Akron Miguel Alix and prolactinomas the tumors grow downward like this not upward, and you treat a patient like this medically, and they develop a CSF rhinorrhea, and then that has to be treated surgically because they simply, the tumor disappears, the skull based has been eroded through by the tumor. Here is a patient, a classic example of a fellow that we published this case with a very large tumor, the entire skull base, it wasn't clear what this was, his prolactin was only 40, he was hyperthyroid, he was hypo pituitary, actually had proptosis from this tumor getting into his orbits, so I operated on him, and the pathology stained very positively for prolactin, repeat prolactin was 45, and Dr. Barkin said, you know, let's dilute it down and see, so they finally diluted this a one to 1000, and his proactive is 280,000. So the so-called hook effect is essentially this, there's a nice little hook, as in the assay, as the value gets very high, it overwhelms the asset, hooks back down, and it may read as being very low. So the thing to learn from that is if you have a large tumor, you don't see this in small tumors, you have a large tumor with a normal prolactin, always ask your lab laboratory to dilute the specimen to check for prolactin, and it may not show up, until you get to one to 50, one to 100, this case one to 1000, so always ask for serial donors. Now, a few comments about sort of pearls of surgery, and then I think we'll move onto a couple of your videos. The approaches of course are basically sub frontal or trans nasal, I used to do a lot of sub label, but that stopped quite a while ago, and most of these are done trans nasal. I think it's really a personal choice, whether you prefer the microscope of the endoscope going trans nasally or a combination of the two, you know, I'll just make a couple of comments on that, so here's the approach, very straightforward. What I do with this, well here just shows that you can treat of course, a very small tumor or a very large tumor with the same approach, I simply use the Kilian speculum, which is a common ENT instrument. I put this, I don't go submucosal at all until I get to the very back of the nose, another nice little pearl is that, the inferior turbinate is very easy to see, the middle turbinate is easy to see, and if your speculum is in line with the middle of turbinate, although I always use lateral fluoroscopy, it's virtually always pointing at the cellar, it works every time. This is a little trick, I take a little, cut a little piece of a finger off of a glove and put it around here, so that as you Bovie down deep, you don't make any burns on the entrance to the nearly here, and that has worked well, so obviously lateral fluoroscopy you don't go too high or too low, this is the, the speculum is down now against the Andrew walls, smino and sinus I simply use the Bovie to take the mucosa off of here, here's an opening looking into the smino and sinus, and then what you wanna do is enlarge this, so you have a nice opening and you need to then break across the midline, what I'm using now is a drill, this this very nice sort of curved drill, and I'm not supporting any particular manufacturer, but this one with a gentle curve on it works extremely well, what I used to do is use an angle comparison to cut under there, and it works very nicely, but the drill is probably a little bit faster. So this just shows how this is drilled or sort of getting away, and then you come right up here, you do, when you're coming in on, I usually come in on the patient's right side because of where I stand, so you are always looking a little bit across the left, and you have to remember that, although I have not had any problem getting a full exposure here, this is a view once the parasanal sinus is open, here's drilled away, the anterior wall of the cellar, I usually make a horizontal and vertical cut down, or they try not to open the upper half, unless I have to, it's a big tumor you wanna do that, but looking for a microadenoma that when you get into the upper half, you're more likely to get CSF, which is prone to leak right along this upper edge up here, those little folds of rack right now, so, there's a nice little pituitary tumor, microadenoma. So, this is another pearl, and I'll show you an example of this, and this is probably true in any surgery we do, is be willing to swallow your pride, stop and back out, and also use frameless navigation, very liberally, I've done nearly a couple of 1000 of these tumors, and I still find that the frameless is very helpful, certainly on any very small tumor or on any redo. Now, here's an example, I did have a fellow, with who I didn't really appreciate so much, he has sort of complicated, Sphenoidal sinus septa in here, he has Cushing's with a normal imaging of the pituitary. So I got up here, I got some bleeding, nothing bad, but I just couldn't be entirely sure where I was, so I stopped, backed out, got a stealth CT scan, and you can see, I was actually headed off here a little bit, he had a funny septum coming in from this side and here's the carotid artery right there, so had I kept going on that track and not recognize that this needed to be drilled away, it could have been a problem. So we put him in the frameless navigation system, here's going back in now, we correct the trajectory and drill this away, and everything worked out fine. Just one comment, I like the system that we actually bought two of these for our spine folks, and it turns out you can spin this thing and generate essentially by one spin, there's a camera up here that sees infrared detectors here, as well as here, and with one spin of this, you generate a CT scan and it registers into the stealth system, so I use that, so we have the stealth system here and then of course lateral fluoroscopy, and you can make sure these correlates. So this shows you the midline, which in a small tumor is very helpful. When I finished the case, if there's any degree of CSF, I'll put a piece of bone in a lot of times, I'll take a little piece of iliac crest bone, and and fit that in there, since I don't take any bone on the way in, and then I put some tissue glue over that fat, little more glue, and then a pack, and then it looks like that, just a little tape, we pull that out and virtually all of our patients go home the next morning and they can actually breathe, even with that pack in there, since it's a small pack up high. One comment about the extended transformational approach, and this is where I'll comment that the endoscope in the scopic systems that are used are very helpful in this, you can of course treat chordoma's, you can go up above here for craniopharyngiomas are a few, there's an old feels talked about a few Cushing's patients with tumor applause installed, and then you can go further forward from angiomas which I personally don't recommend, I like doing central cranially, so the extended approach is the endoscope is very helpful for that, it is two dimensional and cushioning, work with you. I have some thoughts that the extended approach, the endoscope may, for some of these tumors that invade the cavern science that may prove to be helpful. Couple of slides on intercranial surgery, don't give up on that, it's very straightforward, here's a patient with a craniopharyngioma, which I do not do these from below, but coming in with this standard perianal approach, here's of course the carotid, the optic nerve, the assisted craniopharyngioma, and here afterwards, you can see the stalk of the Vaser artery in this come up, very nicely from above, this is a left sided use, maybe a little hard to see at first, this is the optic nerve, the very large meningioma, here it is partly out and here it is pretty much completely out, but you can see this optic nerve is sort of pale, and this is a damaged nerve from the tumor, hopefully not from the surgery, may not have a high likelihood of getting better. So, I think maybe I'll stop there, if you have some cases.

- Thank you Bill, I think those were very helpful. One thing that I have personally learned, and a couple of times the hard way, is if you don't know what's going on do back out, it's very simple and very usual for neurosurgeons to not to be able to back away, and say, no, no, I can do this, I've done this a lot, those septations in the cellar can be extremely confusing, can really limit your view and can really push you in the wrong way, and you can open the carotid artery and not know where you are and really enter a very devastating hemorrhage without any control. So I think the most important pearl that I have learned in pituitary surgery, that location is the most important thing, and number two, is operating on the right person, if any time there is this homogeneous enhancement, that is very symmetric, usually there's something else going on, especially girls who are going through puberty. By the way, one second, we froze, which was a good time to freeze, let me go out and come back, just hang on one second.

- Okay.

- Okay, we are good now, it stopped. So I'll start from, if you don't mind I apologize. So Bill thank you so much for these very important pearls, one thing that I have learned a couple of times in a hard way is, if you don't know where you are and if things don't seem very usual to you, I think it's best to back out and repeat a CT scan, just like you mentioned, and come back with a strategic CT later, it is very easy just to not have your ego or have your ego get on your way, continue removing tumor, ending up at a location of a carotid artery or cavernous sinus, causing an injury to a large vessel, have a lot of hemorrhage, not be able to control and really make a relatively strict award operation to a very dangerous one for the patients. So I think knowing where you are in cellar, specially when the septations of the cellar are very complex, it is extremely easy for people who are very experienced to get lost, I cannot emphasize that, and I'm not consumed myself necessarily very experienced, but I have seen that happen. Also wanted to mention the issue of homogeneous enhancement and symmetric enhancement of tumors, you don't wanna operate on someone who doesn't need surgery and remove piece of their tumor and piece of their normal pituitary gland, potentially causes CSF leak, have them have a meningitis, and it really, it becomes a cascade event after that, when you do a new to operate on somebody who didn't need it, very often, girls who are going through puberty have hypertrophied glance, pregnant woman can have obviously hypertrophy glance, and this can be easily mistaken for a pituitary tumor, end up in a surgeon's office, who for some reason, who was always used to seeing patients with pituitary tumors, look at it as a regular pituitary tumor, goes and does a biopsy of a normal hypertrophied gland in a girl who's going through puberty, looks very hard, sends multiple specimens, it comes back negative, cause a CSF leak after surgery, the patient has a CSF leak, has a meningitis, and it just goes down after that, I think those pearls are some of the most common pitfalls of surgeons getting into trouble, don't you agree?

- I do, and particularly you mentioned the young women in 16 to 20 year olds, we say that with some frequency and oftentimes people come in, of course have headaches and they may actually push you to do surgery, because they're unhappy with their headaches, and the best thing first is to just resist, and the last thing you wanna do is injure a normal gland.

- On a pregnant, on a young woman who is looking forward to a pregnancy, is it correct that if you do a pituitary tumor in a young woman, and they have a injury to their pituitary gland, does that put their pregnancy in the future at risk?

- Well, yeah certainly, although the reality is with today's sort of endocrine technology, a woman without a pituitary gland at all, can still have a pregnancy, and that's really different certainly than it was 20, 25 years ago. But obviously those are only patients who have tumors and needed surgery in the first place.

- Sure. Well, I wanna thank you again and I think this was very useful, and again, we appreciate all your thoughts.

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