Welcome to our webinar on Clinical Pearls from JCEM Case Reports. My name is Bill Young. I'm Editor-in-Chief of JCEM Case Reports. Our co-host for this webinar is Dr. Adina Turcu, who is the Deputy Editor for the journal. In this webinar, we will be highlighting three case reports that have been published in the journal this year. For each case, we'll have a presenter and a content expert. Our expert for this case is Dr. Mark Gurnell. He is Professor of Clinical Endocrinology at the University of Cambridge, UK. Our presenting author is Dr. Farhad Hasan from the Division of Endocrinology at Allegheny General Hospital in Pittsburgh, Pennsylvania. His case report is titled, Pituitary Apoplexy, Secondary to Gonadotropin-Releasing Hormone Agonists for Breast Cancer. Farhad, welcome, and we're looking forward to hearing about your case. Thank you, Dr. Young, and thank you, Dr. Turcu. Thank you for this invitation to participate in this exciting webinar. Okay, so I'm a Clinical Endocrinologist at Allegheny Health Network. My name is Farhad Hasan, and I'm the Associate Program Director for the Endocrine Fellowship here. So I and my fellows and my first author, Dr. Mastandrea, is a PGY3 resident with us. Dr. Voika has graduated, and Dr. Tetlay also was a resident with us who graduated, published this case recently at JCEM Case Reports. The title is Pituitary Apoplexy, Secondary to Gonadotropin-Releasing Hormone Agonist for Breast Cancer. So this is a patient of mine. She's a 52-year-old white female who presented to my clinic for evaluation of recurrent pituitary macroadenoma. Her presenting symptoms were worsening headaches and fatigue. She was originally diagnosed at an outside facility with a non-functioning pituitary macroadenoma at the age of 37. And she underwent transsphenoidal surgery at that facility, after which she was lost to follow-up. Unfortunately, we didn't get a pathology report, but according to the outside records, she had a 2-centimeter non-functioning pituitary mass that was resected due to vision compromise and compressive symptoms. On physical exam in my clinic, she was obese. Otherwise, exam was unremarkable, and she had no visual fields deficit. A pituitary MRI, given the history of the pituitary mass, a pituitary MRI was obtained showing recurrence of pituitary adenoma measuring 1.5 by 1.5 by 1.5 centimeter with abutment and slight displacement of the optic chiasm. On the A, figure A shows the MRI, the coronal T1 series post-contrast, and then we have the sagittal view on the right-hand side. Endocrine evaluation showed anterior pituitary hormones within reference range and normal morning serum cortisol with normal 24-hour urinary free cortisol. Due to borderline low serum free thyroxine and concerns about central hypothyroidism because TSH was within reference range, there was a concern, and she was therefore started on levothyroxine 50 mcg daily. This is a part of table 2 showing pre-apoplexy pituitary hormone panel, all being within reference range except for free T4. Because there was no immediate threat on our assessment, tumor and after consultation with neurosurgery, tumor surveillance was planned and repeat ophthalmologic evaluation was planned in six months. A few months after visit with me, she was diagnosed with left breast cancer that was ER PR positive with spread into regional lymph nodes, so she was T3, N2, and N0 on breast cancer tumor staging. She underwent partial mastectomy, adjuvant chemotherapy, and radiation, and endocrine adjuvant therapy was planned by her oncology team, and she received the first dose of intramuscular leuprolide 11.25 mg on June 9. She presented to the ER on June 12, which is four days later with acute onset, severe headache, photophobia, phonophobia, nausea, emesis, and blurry vision in her right eye. Diagnostic assessment in the hospital was concerning for apoplexy and MRI showed poor contrast enhancements within the lesion concerning for infarction and possible hemorrhage. She had in-house ophthalmologic evaluation that showed mild bilateral impairment in visual acuity and scotomas in her right eye on visual field testing. Fundoscopic exam revealed advanced cupping of the optic nerve head consistent with advanced glaucoma and no edema. Of note, she had been diagnosed with glaucoma even before presenting to us. Biochemical endocrine evaluation during hospitalization confirmed our fear that she had developed anterior hypopituitarism and the venous sample was drawn before she was given intravenous glucocorticoids because she was complaining of fatigue, myalgias, and headaches. Abnormal values are highlighted in bold. She had low cortisol, ACTH, low gonadotropins, IGF-1, and prolactin. TSH was probably inappropriately within reference range. Free T4, she was already on levothyroxine, so that might explain being in the reference range. In follow-up, during the stay, she was seen by neurosurgery colleagues and ophthalmology and conservative treatment was elected after assessment and patient was ultimately discharged on hydrocortisone 15 mg in the form of 10 and 5 and levothyroxine 75 mcg per day. A repeat pituitary MRI when she followed with me in three months showed a partially empty sella as shown here. She followed up with glaucoma specialists after discharge for her visual symptoms and trabeculectomy was performed a few months after discharge and visual fields remain intact. She continues to follow with me and she continues to require glucocorticoids and levothyroxine replacement. In our case report, we also reviewed the literature and we found at least five other cases of females presenting with apoplexy after receiving GnRH agonists. For the sake of time, I'm not going to go over these cases and I will leave that to the discussion, but it is well described in our article. Thank you very much. I will stop sharing here. Farhad, thank you very much for sharing that fantastic case. Very clear presentation. I reread your article before the webinar today and it's beautifully written, beautifully organized. It's a great example of how to do a case report. Adina, did you have any questions for Farhad? Yes, I would also like to thank you for sharing this interesting case with us. What I thought was interesting is that she had pituitary surgery for a large adenoma, presumably, although we don't have all of the details, when she was relatively young at age 37. I was wondering, were there any other elements to suggest a genetic cause or multiple endocrinoplasia syndrome in her when she was younger or later after the diagnosis of her initial adenoma? Thank you for the question. Not that we are aware of. The only outside record we got indicated that she had a pituitary macroadenoma that was resected two centimeters without further details. She didn't have any other biochemical or family information that would make us suspect a syndrome like MEN1. She didn't have any calcium disorders and her prolactin was within reference range when she presented initially. Farhad, you shared a post apoplexy three-month MRI scan. I assume more time has passed. Have you gotten another follow-up MRI or what's your plan for follow-up? Correct. Very good question. When you see a recurrent tumor, you get worried about further recurrences. We did get an MRI. I think the latest MRI was from late last year and it showed further shrinkage. There is no evidence of tumor recurrence. I did inform my patient that to have the peace of mind, perhaps in two to three years we should get another MRI. Farhad, in your experience and review of the literature, did you find that perhaps history of pituitary surgery is a risk for developing apoplexy in the future? Since we're talking about making the vasculature in the area vulnerable? Very good question. Not that I came across, although biologically it's possible. If you have an anatomically compromised area, it could, but not that I'm aware of. At this point, I'd like to ask Dr. Mark Grinnell to join us. Thanks a lot for making time for this session. Dr. Gurnell is a professor at the University of Cambridge. Welcome. We'd like to ask you, what do you think, in your experience, is a history of pituitary surgery a risk for developing apoplexy, sometimes in the future? I think that's a really interesting question. I think it probably speaks to the fact that there is unfortunately not a great deal of evidence in this area. I think a larger part depends on what we're actually left with after the surgery, is the honest answer to that. If we've undergone surgery and then, as in this case, there is a sizable remnant or there is regrowth of a remnant, then I think that actually does clearly present a potential risk of apoplexy. I think that probably leads us on to thinking more broadly about which patients actually with pituitary tumours are at particular risk. Actually, one of the things that I often say to my fellows is that there are what I often think of as three phases of awareness for a risk of apoplexy. The first one I refer to is when you know that you have a patient with a macroadenoma. For very good reasons, you may be deciding to pursue a conservative approach or a surveillance approach where there isn't going to be some intervention. Whilst we don't want to make our patients unduly anxious about things, I think there are certain things we do need to increase their awareness about and that of our colleagues. In particular, for example, if they were to develop any symptoms, such as nicely presented here in this case, that are suggestive of apoplexy, they need to be aware of that. They also have a need to know that certain things that may come up in life, such as interventions, for example, a patient who's going for cardiac surgery, we're probably changing the risk of this kind of event happening in that sort of context. And also thinking about medications that patients might be prescribed, that's what this case is all about. But there are other medications that we know are probably going to slightly increase the risk of somebody experiencing apoplexy. So again, we think about the presence of antiplatelet drugs and anticoagulants. It's debated whether they increase the risk, but certainly if you're on those agents and you have apoplexy, that's a concern. So that's the first phase of awareness. The second phase of awareness, I think, is the acute presentation. It's both patients and clinicians being aware that this type of presentation means that somebody needs to think about the possibility of apoplexy. And then the third, which I also think feeds into your question, the phase of awareness, Adina, is actually what happens after the event. Even in a case where you think you have really excellent resolution, either as a consequence of intervention or, as in this case, conservative management with a really favorable outcome, that doesn't mean that's the end of the story. And there are really reported cases of patients having further events. So I think it's never say never, but there are certain scenarios where the risk is probably slightly higher. And as I say, without causing undue angst to our patients, I think we do need to raise awareness. And they're often the best person, actually, because we might not know as here that there's been a change in their health otherwise that potentially increases the risk. So, Mark, I have a question for you. Let's say you saw a patient six months ago and you diagnosed a 1.1 centimeter non-functioning pituitary adenoma. It was discovered, incidentally, on an MRI done for something else. In the interim, she's diagnosed with breast cancer, as in this case. The oncologist calls you up and says, we're going to start a GnRH agonist. Would you do anything different? What action would you take at that point? The oncologist wants to start that GnRH agonist. Yeah. So, I mean, I think, again, we always very much focus on cases such as this where something very dramatic happens and we see the outcome. But to be honest, there are probably patients out there with undiagnosed lesions who are having treatments who aren't coming to grief. And, of course, what we have to do always as clinicians is balance up what is the greatest benefit for the patient. Here it's different because we know there's a lesion. So I think this is all about how we counsel that patient and discuss with them. And also discussing with our colleagues, is this part of the medical treatment of this patient a crucial part? If we were trying to weigh up, for example, if we omitted this, would it dramatically alter the outcome from an oncological perspective? That would be really important to know. But if actually the feeling is that this treatment really needs to go through in its entirety and that's a core part of it, then I think it's a case of actually saying, OK, make sure we have up-to-date imaging. Make sure we have an up-to-date endocrine assessment. Make sure we have an up-to-date visual assessment. And then warning the patient that there is a small risk that this is recognized, it has been described. And the patient needs to understand, I think, what the consequences are. But I don't think that I could say to a patient, you must not have this treatment because there are these reports of this event happening. Because we might deny them a treatment which on the benefit for them overall would be better to go forward with. I think actually there was another really very interesting feature in this case. And I was really very glad, Dr Hassan, that you mentioned that during the assessment of the patient when they first came to you with their first recurrence, that you checked the urinary free cortisol. I think that's another really interesting aspect of this case. If you look at the laboratory results when she represented with her headache and fatigue, in the absence of the pathology being available and indeed the information from the prior centre, then actually the endocrinology would make me concerned about the possibility that this wasn't a straightforward non-functioning pituitary adenoma of an SF1 lineage actually. I think I would have been concerned with the impairment of the thyroid axis and not knowing obviously quite where to situate the gonadotropins in a perimenopausal lady. That with really good preservation of the adrenal axis, you just would have wondered about the possibility of this being a corticotrophic tumour. Now whilst that doesn't necessarily change things from the apoplexy risk perspective, if it's a macro adenoma, I think that's another really nice teaching point from this case. And I was very glad to see that that assessment for cortisol excess had been completed. Mark, in the very nice review of the literature that Dr Hassan and his team conducted, they found a discrepancy in the prevalence of this entity between men and women. With women being rarely affected. So I was wondering, do you think there is a role of sex steroids that play into the predisposition for apoplexy? We normally think of estrogens and progesterone having a role in the endothelium. So I was curious, why did you think men are more prone to this? Yeah, again, I think it's really quite difficult. I think, I mean, it's an excellent review of the literature, I agree. But I think when you look at the literature in this way, the first note I'd have to say is a slightly cautionary note about saying that there's definitely a sex difference on the available information that we have. It's really tricky, I think, when we don't know what the reporting biases are, in which cases do or don't make it into the literature. But accepting all of that, I think the honest answer is I don't actually know really for certain why there would be a bias, for example, with a slightly higher rate in males than females. As you mentioned, there are differences in the biology of the vascular endothelium, depending on whether we're talking about testosterone, whether we're talking about estrogen, progesterone. But I don't honestly have an answer to that at this stage, Adina, I'm not sure. I mean, I think the pathophysiology of apoplexy is fascinating. Because if you think about it, at the end of the day, almost certainly, it is the imbalance between the metabolic requirements which are being imposed on the cells and the actual blood supply at that stage. And actually, if you look at the pathology of pituitary tumours, they can look really quite different to each other in terms of the degree of vascularity of those tumours. And I don't really, I'm afraid, have enough knowledge of that from a pathological perspective to definitely explain that. But I think the very fact that we see this after not, for example, just GnRH testing, but it's also reported with the other hypothalamic hormone stimulatory testing, I think just confirms that there comes a point where the metabolic stress versus the blood supply is clearly imbalanced. Mark, do you have any concluding pearls for us on a patient who presents with apoplexy to the emergency department, and what actions the endocrinologist should take? So I think the most important thing, I think, really is almost we need to have prepared people as much as we possibly can. Because actually, sometimes it's almost before the endocrinologist becomes involved that the most important opportunities need to be picked up. But let's assume that that diagnosis has been made. Then critically, there is no way that this patient can be properly assessed without the clinician actually being there with the patient and actually assessing them. And that is a combined clinical assessment from the endocrine perspective. But clearly, there's a really important assessment of that patient's neurological status as well. And that means actually sharing the care, I think, of these patients with the other members of the Pituitary Tumor Centre of Excellence, for example. Because at some point in time, we're going to need to make some key decisions for the endocrinologist. The first and foremost is, do I have the blood sample? Do I actually know the glucocorticoid needs to be going into this patient pretty quickly and early on so that I've made sure this patient is safe? That then gives me and my colleagues the time to make the decision as to whether we're actually going to pursue a pathway, which will have almost certainly a balance between intervention, as one could have actually seen happening in this case, versus are we going to go for conservative management? I was very impressed here that this case actually had such a thorough ophthalmic assessment, that it would have been very easy here to assume that the visual problem was a direct consequence of the tumour, which had caused a visual problem in the past. But here, a really good thorough assessment identified another cause, which would never have been remediated by surgical intervention. And then could the surgeons have achieved a better surgical outcome? Well, my best friends are surgeons, but I'd have to say that they may have to say that their results probably may not have been any better in terms of looking at the MRI appearances afterwards. So I think the endocrinologist needs to be there at the heart of things, needs to take control of what has happened here, and then that gives the best chance of making the right decisions for each individual case. Well, with that, I'd like to thank Dr. Mark Gurnell for being our content expert today, Dr. Farhad Hassan for presenting his really interesting case, and this will conclude our webinar. Thank you for joining us.

webinar

Dr. Farhad Hassan

case report

Pituitary Apoplexy

Gonadotropin-Releasing Hormone Agonists

Breast Cancer