Researchers have identified a new, quick method for detecting ACTH-producing tumors – called Elecsys – that can improve the cure rates of Cushing’s disease patients undergoing surgery.
Transsphenoidal resection (TSR) – a surgical procedure performed through the nose and sphenoid sinus to remove a pituitary tumor – has been the method of choice for treatment for Cushing’s disease.
However, it often fails to localize the tumor with precision, leading to an incomplete resection (removal). This is likely a result of the preoperative methods used to guide surgeons before surgery, which include both magnetic resonance imaging (MRI) and a minimally invasive procedure called bilateral inferior petrosal sinus sampling (BIPSS) that measures ACTH in the veins that drain the pituitary gland.
However, both “suffer from suboptimal sensitivity and thus allow for incomplete resections, specially if pathological frozen sections fail to identify tumor,” researchers wrote.
MRI, for example, detects only 50 percent of Cushing’s adenomas, limiting surgeons’ ability to conduct curative TSR surgeries. Therefore, better diagnostic and tumor localization techniques are needed to increase the likelihood that initial surgeries can remove the entire tumor and cure patients.
A team of researchers at Yale School of Medicine evaluated a new method for guiding tumor localization during TSR. The method – a double-antibody sandwich assay for ACTH – is performed in the operating room in resected pituitary samples from patients. ACTH (adrenocorticotropic hormone) is a hormone produced in the pituitary gland in the brain, that simulated cortisol production in the adrenal glands. In patients with Cushing disease the pituitary gland releases too much ACTH.
In the new method – called Elecsys – samples are squeezed between sandwich-like system composed of two antibodies that recognize two sections of the ACTH protein. The three-step procedure is quick, allowing doctors to analyze samples in the operating room and determine if they have removed the entire tumors.
The performance and outcomes associated with the Elecsys were assessed by reviewing data of tissue samples from 14 patients with ACTH-secreting adenomas, who underwent TSR surgeries between 2009 and 2014.
“The intraoperative TSR protocol was modified with the introduction of the ACTH assay such that if either the assay or the frozen-section pathology returned results positive for tumor, that area of the gland was resected,” the researchers explained.
The new ACTH method detected tumor tissue and was capable of distinguishing it from normal tissue with a 95% sensitivity and 71.3% specificity. These values are comparable to those using the standard method for tumor localization, which requires frozen sections of the tumor. This suggests that the test can be used either in conjunction with or in place of frozen sections.
Also, 85.7% of the patients achieved long-term disease remission, with the remission rate exceeding the rate with previous methods (71.9%).
Overall, “these preliminary findings reflect the promising potential of tissue-based ACTH-antibody-guided assay for improving the cure rates of Cushing’s disease patients undergoing TSR. Further studies with larger sample sizes, further refinements of assay interpretation, and longer-term follow-ups are needed,” the study concluded.
Life was good! In fact, life was great! I was married to the love of my life. We had a beautiful little girl. My husband and I had both earned our graduate degrees. I earned my Doctorate in Clinical Psychology and was growing my clinical practice. I loved my work!
In October, 2006, my life was turned upside down when I gained 30 pounds in 30 days! I knew this was not normal at all. I sought answers but my doctor kept insisting that I wasn’t eating the right foods, that I wasn’t exercising hard enough, and finally that it was genetic. However, I was always a thin person, I ate pretty healthy foods, and I was pretty active. Red flags became even greater when my physician put me on prescription weight loss drugs and I STILL gained another 30 pounds. I knew my body and I knew something was wrong but I had no one to validate what was going on.
In January, 2010, to my surprise, I learned that I was miraculously pregnant with our second daughter. I was so sick during that pregnancy and, again, my doctors couldn’t figure out why. My OBGYN was very supportive, yet so concerned. Her solution was to put me on bed rest. I became so ill that she told me that “my only job was to sit still and wait to have a baby”. I did give birth to a healthy baby girl four weeks early. Little did I know, then, how much of a miracle she was.
During the latter part of my pregnancy, while flipping through channels on television, I came across a Cushing’s episode on the health TV show, “Mystery Diagnosis”.
I knew right away that this diagnosis fit everything I had been experiencing: years of weird and unexplained symptoms, gaining 150 pounds for no reason, an onset of diabetes, high blood pressure, and an overall sense of doom.
You see, my friends and family witnessed me go from a vibrant young Clinical Psychologist in practice, to someone whose health deteriorated due to the symptoms of Cushing’s, as I tried for many years to get answers from professionals. As I continued to eat a healthy, 1000 calorie per day diet, engage in exercise with multiple personal trainers, and follow through with referrals to consult with dietitians; I continued to gain weight at a rate of 5 pounds per week and experience rapidly declining health. Finally, after watching that Cushing’s episode of Mystery Diagnosis, I found my answer! Ultimately, I sought the expertise of and treatment from a team of experts at the Seattle Pituitary Center in Seattle, WA. I had brain surgery in Seattle on November 16th, 2011. I want to tell you how I found the people who helped save my life…
On June 9, 2011, I went to my first MAGIC conference. I had never heard of them but someone on one of the online support groups told me about it. At that time, I was working but was very, very sick. We suspected at that time that I had been sick for years! My local endocrinologist was far from a Cushing’s expert. After watching the Cushing’s episode of Mystery Diagnosis, I told the same endocrinologist who had misdiagnosed me for years that I had found my answer. He swore that there was “literally no possible way that I had Cushing’s Disease!” He stated that my “hump wasn’t big enough”, “my stretch marks were not purple enough” and that “Cushing’s patients do not have children!” I told him that I was NOT leaving his office until he started testing me. He finally caved in. To his surprise, I was getting abnormal labs back.
At that time, there was evidence of a pit tumor but it wasn’t showing up on an MRI. So, I had my IPSS scheduled. An IPSS stands for Inferior Petrosal Sinus Sampling. It is done because 60 % of Cushing’s based pituitary tumors are so small that they do not show up on an MRI. Non Cushing’s experts do not know this so they often blow patients off, even after the labs show a high level of ACTH in the brain through blood work. An overproduction of the hormone ACTH from the pituitary communicates to the adrenal glands to overproduce cortisol. Well, the IPSS procedure is where they put catheters up through your groin through your body up into your head to draw samples to basically see which side of your pituitary the extra hormone is coming from, thus indicating where the tumor is. U of C is the only place in IL that does it.
So, back to the MAGIC convention; my husband and I went to this conference looking for answers. We were so confused and scared! Everyone, and I mean everyone, welcomed us with opened arms like we were family! There were brilliant presenters there, including an endocrinologist named Dr. William Ludlam. At that time, he was the director at the Seattle Pituitary Center in Seattle, WA. He is a true Cushing’s expert. Since then, he left in January, 2012 to have a significant impact toward the contribution of research of those impacted by Cushing’s Syndrome. His position was taken over by another brilliant endocrinologist, Dr. Frances Broyles.
I was scheduled to get an IPSS at U of C on June 28th, 2011 to locate the tumor. Two days after the IPSS, I began having spontaneous blackouts and ended up in the hospital for 6 days. The docs out here had no clue what was happening and I was having between 4-7 blackouts a day! My life was in danger and they were not helping me! We don’t know why, but the IPSS triggered something! But, no one wanted to be accountable so they told me the passing out, which I was not doing before, was all in my head being triggered by psychological issues. They did run many tests. But, they were all the wrong tests. I say all the time; it’s like going into Subway and ordering a turkey sandwich and giving them money and getting a tuna sandwich. You would be mad! What if they told you, “We gave you a sandwich!” Even if they were to give you a dozen sandwiches; if it wasn’t turkey, it wouldn’t be the right one. This is how I feel about these tests that they ran and said were all “normal”. The doctors kept telling us that they ran all of these tests so they could cover themselves. Yet, they were not looking at the right things, even though, I (the patient) kept telling them that this was an endocrine issue and had something to do with my tumor! Well, guess how good God is?!!!!
You see, Dr. Ludlam had given me his business card at the conference, which took place two weeks prior to the IPSS. I put it away for a while. But, something kept telling me to pull the card out and contact him. I am crying just thinking about it, Lord!
So, prior to my IPSS, I wrote Dr. Ludlam an e mail asking him some questions. At that time, he told me to send him ALL of my records including labs. I sent him 80 pages of records that day. He called me back stating that he concurred with all of the evidence that I definitely have Cushing’s Disease from a pituitary source. He asked me what I planned to do and I told him that I was having the IPSS procedure done in a few days at the University of Chicago. He told me once I got my results to contact him.
Fast forward, I ended up in the hospital with these blackouts after my IPSS. The doctors, including MY local endocrinologist told me there was no medical evidence for my blackouts. In fact, he told the entire treatment team that he even doubted if I even had a tumor! However, this is the same man who referred me for the IPSS in the first place! I was literally dying and no one was helping me! We reached out to Dr. Ludlam in Seattle and told him of the situation. He told me he knew exactly what was going on. For some reason, there was a change in my brain tumor activity that happened after my IPSS. No one, to this day, has been able to answer the question as to whether the IPSS caused the change in tumor activity. The tumor, for some reason, began shutting itself on and off. When it would shut off, my cortisol would drop and would put me in a state of adrenal insufficiency, causing these blackouts!
Dr. Ludlam said as soon as we were discharged, we needed to fly out to Seattle so that he could help me! The hospital discharged me in worse condition then when I came in. I had a blackout an hour after discharge! But get this…The DAY the hospital sent me home saying that I did not have a pit tumor, my IPSS results were waiting for me! EVIDENCE OF TUMOR ON THE LEFT SIDE OF MY PITUITARY GLAND!!!
Two days later, Craig and I were on a plane to Seattle. I had never in my life been to Seattle, nor did I ever think I would go. We saw the man that God used to save my life, Dr. William Ludlam, the same man who we had met at the MAGIC conference for the first time one month prior! He put me on a combo of medications that would pull me out of crisis. Within one month, my blackouts had almost completely stopped! Unfortunately, we knew this was a temporary fix! He was treating me to carry me over to surgery. You see, his neurosurgeon, Dr. Marc Mayberg was just as amazing. He is one of the top neurosurgeons in the US! Statistically, he has one of the highest success rates!
The problem was that our insurance refused to pay for surgery with an expert outside of IL, stating that I could have surgery anywhere in IL! Most people don’t know that pituitary surgeries are very complicated and need the expertise of a “high volume center” which is where they do at least 50 of these surgeries per year. Dr. Mayberg has performed over 5,000 of these surgeries! By this time, we had learned that we need to fight for the best care! It was what would give me the best chance at life! We thought I would have to wait until January when our insurance would change, to see if I could get the surgery I so desperately needed! I was holding on by a thread!
We began appealing our insurance. At the time the MAGIC foundation had an insurance specialist who was allowed to help us fight our insurance. Her name is Melissa Callahan and she took it upon herself to fight for us as our patient advocate. It was a long and hard battle! But…we finally WON!!!! On November 16th, 2011, Dr. Marc Mayberg found that hidden tumor on the left side of my pituitary gland! He removed the tumor along with 50% of my pituitary gland.
Recovery was a difficult process. They say that it takes about one full year to recover after pituitary surgery for Cushing’s. I was grateful to be in remission, nonetheless. However, about one year after my brain surgery, the Cushing’s symptoms returned. After seven more months of testing that confirmed a recurrence of the Cushing’s, I was cleared for a more aggressive surgery. This time, I had both of my adrenal glands removed as a last resort. By then, we had learned that I had hyperplasia, which is an explosion of tumor cells in my pituitary. It only takes one active cell to cause Cushing’s. Therefore, I could have potentially had several more brain surgeries and the disease would have kept coming back over and over.
As a last resort, my adrenal glands were removed so that no matter how much these cells try to cause my adrenals to produce excessive amounts of cortisol; the glands are not there to receive the message. As a result, I am Adrenally Insufficient for life, which means that my body cannot produce the life sustaining hormone, cortisol, at all. I had my Bilateral Adrenalectomy by world renowned BLA surgeon, Dr. Manfred Chiang, in Wisconsin on August 21st, 2013. I traded Cushing’s Disease for Addison’s Disease, one of the hardest decisions I have ever had to make in my life. However, I knew that I would die with Cushing’s. Recovery from my last surgery was difficult and involved weaning down to a maintenance dose of steroid to replace my cortisol. Now, on a maintenance dose; I still have to take extra cortisol during times of physical or emotional stress to prevent my body from going into shock.
I promised a long time ago that I would pay it forward…give back because so much has been given to me. This is why I have committed my life to supporting the Cushing’s community. I post videos on YouTube as a way of increasing awareness. My channel can be found at http://www.YouTube.com/drnkarenthames
Karen has made 2 videos about her experiences with Cushing’s:
and
Doc Karen will be our guest in an interview on BlogTalk Radio Friday December 2 at 11:00 AM eastern. The Call-In number for questions or comments is (323) 642-1665 .
The archived interview will be available through iTunes Podcasts (Cushie Chats) or BlogTalkRadio. While you’re waiting, there are currently 90 other past interviews to listen to!
1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
2National Institutes of Health, Bethesda, MD
Presentation Number: SAT-384
Date of Presentation: March 7, 2015
Abstract:Background: Urine free cortisol (UFC) has been traditionally used as one of the first steps in the diagnostic evaluation of Cushing’s syndrome (CS) (1). False positive results, especially values less than twice the upper limit of normal (ULN), can be seen in uncontrolled diabetes, obesity, depression, alcoholism, increased fluid intake, overcollection and stress. False negative results have also been reported with incomplete collection, in mild or cyclic CS and in patients with renal insufficiency (2-3). We evaluated the diagnostic accuracy of UFC and 24-hour urine 17-hydroxycorticosteroids (17OHCS) in patients with CS.Methods: Retrospective study of all CS patients evaluated at the National Institutes of Health (NIH) from 2009 to 2014. Screening tests used for CS included UFC, 17OHCS, late night salivary cortisol (LNSC), midnight serum cortisol and low dose (1mg overnight or 2-day 2mg/day) dexamethasone suppression test (DST). Values above reference range for UFC, 17OHCS and LNSC, a midnight serum cortisol ≥ 7.5 mcg/dL, and post-dexamethasone cortisol values ≥ 1.8 mcg/dL were considered abnormal. Hourly 24-hour sampling for cortisol was performed in a few cases with a mild clinical phenotype and equivocal test results. UFC was measured using liquid chromatography/tandem mass spectrometry (LC-MS/MS). 17OHCS was measured using colorimetric methodology with Porter-Silber reaction (reported as mg/g of creatinine). Mean of the first two UFC and 17OHCS values (appropriate collection by urine volume and creatinine) obtained within 30 days of initial NIH presentation were used for the purpose of this study.
Results: Seventy-two patients were diagnosed with CS (aged 18-77 years, 51 females). Of these, 51 had Cushing’s disease (CD), 10 had ectopic CS while 2 had an adrenal source of Cushing’s based on pathology. Biochemical tests including inferior petrosal sinus sampling (IPSS) suggested ectopic CS but no tumor was found (occult) in 6 patients. IPSS was indicative of a pituitary source in 2 patients with failed transsphenoidal surgery while one patient did not complete evaluation for ACTH-dependent CS. UFC results were available in all, 17OHCS in 70, LNSC in 21, midnight serum cortisol in 68 and DST results in 37 patients. UFC was falsely normal in six and only minimally elevated (< 2 x ULN) in 13 patients (normal renal function, no history of cyclicity, all had CD). Of these 19 patients, 24h 17OHCS was abnormal in all, LNSC was abnormal in 12, midnight serum cortisol was abnormal in 18 and DST was abnormal in 12 patients. Hourly 24-hour sampling for cortisol performed in 3 of these patients revealed abnormal nadir (> 7.5 mcg/dL) and mean daily serum cortisol (> 9 mcg/dL) levels.
Conclusion: UFC can be falsely normal or only minimally elevated in mild CS. Multiple collections and use of complimentary screening tests including 24-hour urine 17OHCS and LNSC can help make a diagnosis and prevent delay in treatment.
(1) Newell-Price J, et al. Cushing’s syndrome. Lancet. 2006;367(9522):1605-17. (2) Alexandraki KI, et al. Is urinary free cortisol of value in the diagnosis of Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes. 2011;18:259–63. (3) Kidambi S, et al. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007;157(6):725-31
Nothing to Disclose: STS, LKN
Sources of Research Support: This research was in part supported by the intramural research program of NICHD/NIH
Hello all, I’m Michelle mother of 3 beautiful children, I work part-time, 33yrs young, non-smoker, non-drinker, overall health is good for the most part…..Where do I even begin.
I just recently received the diagnosis of cyclic Cushing’s. I’m not really sure how long I have actually had Cushing’s because I have had a diagnosis of PCOS since I was 17 yrs. old ( I’m now the ripe young age of 33). However looking back through labs with my endocrinologist who I see every 6 months, my ACTH levels have been elevated for a bit over 1 yr. It was not until recently January of 2015- things were going terribly wrong.
Starting in January I started to feel genuinely unwell, on a regular basis. I cant really explain all my symptoms there were so many different sensations and feelings that were seemingly different daily. However the red flag was I was having blood pressure spikes from really high, to very low back to back. I never had any blood pressure issues so this was a concern that led me to see a cardiologist. Upon tons of testing the cardio MD felt that something was telling my otherwise very healthy heart to do this and I should see a endocrinologist. (thank goodness for him) I contacted my endo and let him know…. the testing began.
I did every test: the midnightcortisol saliva test, dex suppression, 24 hr urine test, CRH stimulation testing. And I did them more than once. Each time it was a different response either, inconclusive, normal high, or high. I was then referred to the head of the Cleveland clinics pituitary department Dr. Kennedy. He said he is having a hard time believing when he looks at me that its Cushing’s. However all my labs say it is. I will say I do fit the mold of PCOS to a tee- which symptoms of that do coincide with Cushing’s but he still said we have to be sure its Cushing’s. To add to the mix I did have a normal MRI as well.
Dr. Kennedy started me on a 2 week midnight cortisol saliva test- Upon completion we noted levels of cortisol all over the place, some Normal, normal on high range, high, and really high. He confirmed with all the other tests this is Cushing’s. Now we are trying to figure out what is next…. and where is this damn little tumor at. he feels that it is most likely in the pituitary from my test results, but we still are not ruling out else where. He is thinking that the next step would be exploratory neurosurgery or the IPSS. I’m not sure what to think of all this, except I want to hope for the best like everyone- and just be cured!!
On a side note during all of this I also had episodes of severe pain in my chest and nausea. I went to see a GI who did an upper endo scope. They found I had eosinpphilic esophagitis. I also have never had any GI problems until now; and they came on suddenly. Im also having pain in my pancreas area- not sure if any of the two are related at all to Cushing’s. But once again I was fine until recently with all these issues at once it seems.
wish me luck on further testing, treatment, and ultimately a CURE!!
Michelle was our guest in an interview on BlogTalk Radio Wednesday, May 13, 2015.
The archived interview is available now through iTunes Podcasts (Cushie Chats) or BlogTalkRadio. There are currently 83 other past interviews for your listening pleasure!
SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.
The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.
Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.
A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).
The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.
At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.
MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.
Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.
“We did not find any difference in localization rates by measurement of prolactin during IPSS,” she said. The small size of the study and its retrospective design invite further research in a more robust study.
Dr. Sharma reported having no financial disclosures.
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