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  2. Abstract Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers. ACTH-dependent Cushing syndrome, ectopic ACTH, ectopic Cushing syndrome, glucocorticoid excess Issue Section: Case Report Introduction Even in the face of overt clinical signs and symptoms of hypercortisolism, diagnosing Cushing syndrome requires a high index of suspicion, and people with hypercortisolism experience a long road to diagnosis. In a recent meta-analysis including more than 5000 patients with Cushing syndrome, the mean time to diagnosis in all Cushing syndrome, including Cushing disease and ectopic adrenocorticotropin (ACTH) syndrome, was 34 months (1). Reasons for delayed diagnosis are multifactorial, including the nonspecific nature of subjective symptoms and objective clinical signs, as well as notorious challenges in the interpretation of diagnostic testing. Furthermore, the health care system's increasingly organ-specific referral patterns obfuscate multisystem disorders. Improving the recognition of and decreasing time to diagnosis in Cushing syndrome are critical factors in reducing morbidity and mortality. Here, we present the case of a patient who, despite classic signs of Cushing syndrome as well as progressive physical and mental decline, remained undiagnosed for more than 3 years while undergoing repeated evaluation by primary care and subspecialty providers. The case (1) highlights the lack of awareness of Cushing syndrome as a potential unifying diagnosis for multiorgan system problems; (2) underscores the necessity of continued education on the signs and symptoms of hypercortisolism, appropriate screening for hypercortisolism, and early referral to endocrinology; and (3) provides an opportunity for systemic change in clinical laboratory practice that could help improve recognition of pathologic hypercortisolism. Case Presentation In August 2018, a previously healthy 40-year-old man with ongoing tobacco use established care with a primary care provider complaining that he had been ill since the birth of his son 13 months prior. He described insomnia, headaches, submandibular swelling, soreness in his axillary and inguinal regions, and right-sided chest discomfort (Fig. 1). Previously, he had been diagnosed with sinusitis, tonsillitis, and allergies, which had been treated with a combination of antibiotics, antihistamines, and intranasal glucocorticoids. He was referred to otolaryngology where, in the absence of cervical lymphadenopathy, he was diagnosed with sternocleidomastoid pain with recommendations to manage conservatively with stretching and massage. A chest x-ray demonstrated a left apical lung nodule. Symptoms continued unabated throughout 2019, now with a cough. Repeat chest x-ray demonstrated opacities lateral to the left hilum that were attributed to vascular structures. Figure 1. Open in new tabDownload slide Timeline of development of subjective symptoms and objective clinical findings preceding diagnosis and surgical cure of ectopic Cushing syndrome. In May 2020, increasingly frustrated with escalating symptoms, the patient transitioned care to a second primary care provider and was diagnosed with hypertension. He complained of chronic daily headaches that prompted brain imaging with magnetic resonance imaging (MRI), which noted findings consistent with left maxillary silent sinus syndrome. He was sent back to otolaryngology, which elected to proceed with sinus surgery. During this time, he suffered a fibular fracture for which he was evaluated by orthopedic surgery. In the second half of 2020, he was seen by neurology to evaluate his chronic headaches and paresthesias with electromyography demonstrating a left ulnar mononeuropathy consistent with cubital tunnel syndrome. His primary care provider diagnosed him with fibromyalgia for which he started physical therapy, and he was referred to a pain clinic for cognitive behavioral therapy. Unfortunately his wife, dealing with her husband's increasing cognitive and personality changes including irritability and aggression, filed for divorce. At the end of 2020, the patient developed bilateral lower extremity edema and was prescribed hydrochlorothiazide, subsequently developing hypokalemia attributed to diuretic use. With worsening bilateral lower extremity edema and new dyspnea on exertion, he was evaluated for heart failure with an echocardiogram, which was unremarkable. Over the next several months, he gained approximately 35 pounds (∼16 kg). It was in the setting of weight gain that he was first evaluated for hypercortisolism with random serum cortisol of 22.8 mcg/dL (629 nmol/L) and 45.6 mcg/dL (1258 nmol/L) in the late morning and mid-day, respectively. No reference range was provided for the times of day at which these laboratory values were drawn. Although these serum cortisol values were above provided reference ranges for other times of day, they were not flagged as abnormal by in-house laboratory convention, and they were overlooked. The search for other etiologies of his symptoms continued. In early 2021, diuretic therapy and potassium supplementation were escalated for anasarca. He developed lower extremity cellulitis and received multiple courses of antibiotics. Skin biopsy performed by dermatology demonstrated disseminated Mycobacterium and later Serratia (2), prompting referral to infectious disease for management. Additional subspecialty referrals included rheumatology (polyarthralgia) and gastroenterology (mildly elevated alanine transaminase with planned liver biopsy). In July 2021, he was evaluated for edema by nephrology, where the constellation of subjective symptoms and objective data including hypertension, central weight gain, abdominal striae, fracture, edema, easy bruising, medication-induced hypokalemia, atypical infections, and high afternoon serum cortisol were noted, and the diagnosis of Cushing syndrome was strongly suspected. Emergent referral to endocrinology was placed. Diagnostic Assessment At his first clinic visit with endocrinology in June 2021, the patient’s blood pressure was well-controlled on benazepril. Following weight gain of 61 pounds (∼28 kg) in the preceding 2 years, body mass index was 33. Physical examination demonstrated an ill-appearing gentleman with dramatic changes when compared to prior pictures (Fig. 2), including moon facies, dorsocervical fat pad, violaceous abdominal striae, weeping lower extremity skin infections, an inability to stand without assistance from upper extremities, and depressed mood with tangential thought processes. Figure 2. Open in new tabDownload slide Photographic representation of physical changes during the years leading up to diagnosis of ectopic Cushing syndrome in June 2021 and after surgical resection of culprit lesion. Diagnostic workup for hypercortisolism included a morning cortisol of 33.4 mcg/dL (922 nmol/L) (normal reference range, 4.5-22.7 mcg/dL) and ACTH of 156 pg/mL (34 pmol/L) (normal reference range, 7.2-63 pg/mL) following bedtime administration of 1-mg dexamethasone, and 24-hour urine free cortisol of 267 mcg/24 hours (737 nmol/24 hours) (normal reference range, 3.5-45 mcg/24 hours). Morning serum cortisol and plasma ACTH following bedtime administration of 8-mg dexamethasone were 27.9 mcg/dL (770 nmol/L) and 98 pg/mL (22 pmol/L), respectively. Given concern for potential decompensation, he was hospitalized for expedited work-up. Brain MRI did not demonstrate a pituitary lesion (Fig. 3), and inferior petrosal sinus sampling under desmopressin stimulation showed no central-to-peripheral gradient (Table 1). He underwent a positron emission tomography–computed tomography 68Ga-DOTATATE scan that demonstrated a 1.2-cm left pulmonary nodule with radiotracer uptake (Fig. 4). Figure 3. Open in new tabDownload slide A, Precontrast and B, postcontrast T1-weighted sagittal magnetic resonance imaging of the sella. Images were affected by significant motion degradation, precluding clear visualization of the pituitary gland on coronal imaging. Figure 4. Open in new tabDownload slide 68Ga-DOTATATE imaging. A, Coronal and B, axial views of the chest after administration of radiopharmaceutical. Arrow in both panels indicates DOTATATE-avid 1.2-cm left lung lesion. Table 1. Bilateral petrosal sinus and peripheral adrenocorticotropin levels preintravenous and postintravenous injection of desmopressin acetate 10 mcg Time post DDAVP, min Left petrosal ACTH Left petrosal:peripheral ACTH Right petrosal ACTH Right petrosal:peripheral ACTH Peripheral ACTH Left:right petrosal ACTH 0 172 pg/mL (37.9 pmol/L) 1.1 173 pg/mL (38.1 pmol/L) 1.2 150 pg/mL (33.0 pmol/L) 1.0 3 288 pg/mL (63.4 pmol/L) 1.8 292 pg/mL (64.3 pmol/L) 1.8 162 pg/mL (35.7 pmol/L) 1.0 5 348 pg/mL (76.6 pmol/L) 1.8 341 pg/mL (75.1 pmol/L) 1.8 191 pg/mL (42.1 pmol/L) 1.0 10 367 pg/mL (80.8 pmol/L) 1.3 375 pg/mL (82.6 pmol/L) 1.3 278 pg/mL (61.2 pmol/L) 1.0 Abbreviations: ACTH, adrenocorticotropin; DDAVP, desmopressin acetate. Open in new tab Treatment The patient was started on ketoconazole 200 mg daily for medical management of ectopic ACTH-induced hypercortisolism while awaiting definitive surgical treatment. Within a month of initial endocrinology evaluation, he underwent thoracoscopic left upper lobe wedge resection with intraoperative frozen histopathology section consistent with a well-differentiated neuroendocrine tumor and final pathology consistent with a well-differentiated neuroendocrine tumor. Staining for ACTH was positive (Fig. 5). Postoperative day 1 morning cortisol was 1.4 mcg/dL (39 nmol/L) (normal reference range, 4.5-22.7 mcg/dL). He was started on glucocorticoid replacement with hydrocortisone and was discharged from his surgical admission on hydrocortisone 40 mg in the morning and 20 mg in the afternoon. Figure 5. Open in new tabDownload slide Lung tumor histopathology. A, The tumor was epicentered around a large airway (asterisk) and showed usual architecture for carcinoid tumor. B, The tumor cells had monomorphic nuclei with a neuroendocrine chromatin pattern, variably granulated cytoplasm, and a delicate background vascular network. By immunohistochemistry, the tumor cells were strongly positive for C, synaptophysin; D, CAM5.2; and E, adrenocorticotropin. F, Ki-67 proliferative index was extremely low (<1%). Outcome and Follow-up Approximately 12 days after discharge, the patient was briefly readmitted from the skilled nursing facility where he was receiving rehabilitation due to a syncopal event attributed to hypovolemia. This was felt to be secondary to poor oral intake in the setting of both antihypertensive and diuretic medications as well as an episode of emesis earlier in the morning precluding absorption of his morning hydrocortisone dose. Shortly after this overnight admission, he was discharged from his skilled nursing facility to home. In the first month after surgery, he lost approximately 30 pounds (∼14 kg) and had improvements in sleep and mood. Eight months after surgery, hydrocortisone was weaned to 10 mg daily. Cosyntropin stimulation testing holding the morning dose showed 1 hour cortisol 21.5 mcg/dL (593 nmol/L). Hydrocortisone was subsequently discontinued. In June 2022, 1 year following surgery, 3 sequential midnight salivary cortisol tests were undetectable. At his last visit with endocrinology in June 2023, he felt well apart from ongoing neuropathic pain in his feet and continued but improved mood disturbance. Though his health has improved dramatically, he continues to attribute his divorce and substantial life disruption to his undiagnosed hypercortisolism. Discussion Endogenous neoplastic hypercortisolism encompasses a clinical spectrum from subclinical disease, as is common in benign adrenal cortical adenomas, to overt Cushing syndrome of adrenal, pituitary, and ectopic origin presenting with dramatic clinical manifestations (3) and long-term implications for morbidity and mortality (4). Even in severe cases, a substantial delay in diagnosis is common. In this case, despite marked hypercortisolism secondary to ectopic ACTH syndrome, the patient's time from first symptoms to diagnosis was more than 3 years, far in excess of the typical time to diagnosis in this subtype, noted to be 14 months in 1 study (1). He initially described a constellation of somatic symptoms including subjective neck swelling, axillary and inguinal soreness, chest discomfort, and paresthesias, and during the year preceding diagnosis, he developed hypertension, fibular fracture, mood changes, weight gain, peripheral edema, hypokalemia, unusual infections, and abdominal striae. Each of these symptoms in isolation is a common presentation in the primary care setting, therefore the challenge arises in distinguishing common, singular causes from rare, unifying etiologies, especially given the present epidemics of diabetes, obesity, and associated cardiometabolic abnormalities. By Endocrine Society guidelines, the best discriminatory features of Cushing syndrome in the adult population are facial plethora, proximal muscle weakness, abdominal striae, and easy bruising (5). Furthermore, Endocrine Society guidelines suggest evaluating for Cushing disease when consistent clinical features are present at a younger-than-expected age or when these features accumulate and progress, as was the case with our patient (5). However, even when the diagnosis is considered, the complexities of the hypothalamic-pituitary-adrenal axis make selection and interpretation of screening tests challenging outside the endocrinology clinic. We suspect that in most such situations, a random serum cortisol measurement is far more likely to be ordered than a validated screening test, such as dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol per Endocrine Society guidelines (5). Although random serum cortisol values are not considered a screening test for Cushing syndrome, elevated values can provide a clue to the diagnosis in the right clinical setting. In this case, 2 mid-day serum cortisols were, by in-house laboratory convention, not flagged as abnormal despite the fact that they were above the upper limit of provided reference ranges. We suspect that the lack of electronic medical record flagging of serum cortisol values contributed to these values being incorrectly interpreted as ruling out the diagnosis. Cushing syndrome remains among the most evasive and difficult diagnoses in medicine due to the doubly difficult task of considering the disorder in the face of often protean signs and symptoms and subsequently conducting and interpreting screening tests. The challenges this presents for the nonendocrinologist have recently been recognized by a group in the United Kingdom after a similarly overlooked case (6). We believe that our case serves as a vivid illustration of the diagnostic hurdles the clinician faces and as a cautionary tale with regard to the potential downstream effects of a delay in diagnosis. Standardization of clinical laboratory practices in flagging abnormal cortisol values is one such intervention that may aid the busy clinician in more efficiently recognizing laboratory results suggestive of this diagnosis. While false-positive case detection is a significant downside to this approach, given the potential harm in delayed or missed diagnosis, the potential benefits may outweigh the risks. Learning Points People with Cushing syndrome frequently experience a prolonged time to diagnosis, in part due to lack of recognition in the primary care and nonendocrine subspecialty settings of the constellation of clinical findings consistent with hypercortisolism. Endocrine Society guidelines recommend against random serum cortisol as initial testing for Cushing syndrome in favor of dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol. Increased awareness of Cushing syndrome by primary care providers and specialists in other fields could be an important and impactful mechanism to shorten the duration of symptom duration in the absence of diagnosis and hasten cure where cure is achievable. We suggest clinical laboratories consider standardizing flagging abnormal cortisol values to draw attention to ordering providers and perhaps lower the threshold for endocrinology referral if there is any uncertainty in interpretation, especially in the context of patients with persistent symptoms and elusive diagnoses. Acknowledgments We are grateful to the patient for allowing us to present his difficult case to the community with the hopes of improving time to diagnosis for patients with hypercortisolism. Contributors All authors made individual contributions to authorship. J.M.E., E.M.Z., and K.R.K. were involved in the diagnosis and management of this patient. B.C.M., J.M.E., E.M.Z., and K.R.K. were involved in manuscript submission. S.M.J. performed and analyzed histopathology and prepared the figure for submission. All authors reviewed and approved the final draft. Funding No public or commercial funding. Disclosures J.M.E. was on the editorial board of JCEM Case Reports at the time of initial submission. Informed Patient Consent for Publication Signed informed consent obtained directly from the patient. Data Availability Statement Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study. References 1 Rubinstein G , Osswald A , Hoster E , et al. Time to diagnosis in Cushing's syndrome: a meta-analysis based on 5367 patients . J Clin Endocrinol Metab . 2020 ; 105 ( 3 😞 dgz136 . Google Scholar Crossref PubMed WorldCat 2 Park MA , Gaghan LJ , Googe PB , Klein KR , Mervak JE . Disseminated cutaneous Mycobacterium chelonae infection as a presenting sign of ectopic adrenocorticotropic hormone syndrome . JAAD Case Rep . 2021 ; 18 : 79 ‐ 81 . Google Scholar Crossref PubMed WorldCat 3 Reincke M , Fleseriu M . Cushing syndrome: a review . JAMA . 2023 ; 330 ( 2 😞 170 ‐ 181 . Google Scholar Crossref PubMed WorldCat 4 Puglisi S , Perini AME , Botto C , Oliva F , Terzolo M . Long-term consequences of Cushing's syndrome: a systematic literature review . J Clin Endocrinol Metab . 2024; 109 ( 3 😞 e901 ‐ e909 . Crossref PubMed WorldCat 5 Nieman LK , Biller BMK , Findling JW , et al. The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2008 ; 93 ( 5 😞 1526 ‐ 1540 . Google Scholar Crossref PubMed WorldCat 6 Scoffings K , Morris D , Pullen A , Temple S , Trigell A , Gurnell M . Recognising and diagnosing Cushing's syndrome in primary care: challenging but not impossible . Br J Gen Pract . 2022 ; 72 ( 721 😞 399 ‐ 401 . Google Scholar Crossref PubMed WorldCat Abbreviations ACTH adrenocorticotropin MRI magnetic resonance imaging © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com From https://academic.oup.com/jcemcr/article/2/3/luae034/7618559?login=false
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  4. Objective Postoperative data on Cushing’s disease (CD) are equivocal in the literature. These discrepancies may be attributed to different series with different criteria for remission and variable follow-up durations. Additional data from experienced centers may address these discrepancies. In this study, we present the results obtained from 96 endoscopic transsphenoidal surgeries (ETSSs) for CD conducted in a well-experienced center. Methods Pre- and postoperative data of 96 ETSS in 87 patients with CD were included. All cases were handled by the same neurosurgical team between 2014 and 2022. We obtained data on remission status 3−6 months postoperatively (medium-term) and during the latest follow-up (long-term). Additionally, magnetic resonance imaging (MRI) and pathology results were obtained for each case. Results The mean follow-up duration was 39.5±3.2 months. Medium and long-term remission rates were 77% and 82%, respectively. When only first-time operations were considered, the medium- and long-term remission rates were 78% and 82%, respectively. The recurrence rate in this series was 2.5%. Patients who showed remission between 3−6 months had higher longterm remission rates than did those without initial remission. Tumors >2 cm and extended tumor invasion of the cavernous sinus (Knosp 4) were associated with lower postoperative remission rates. Conclusion Adenoma size and the presence/absence of cavernous sinus invasion on preopera-tive MRI may predict long-term postoperative remission. A tumor size of 2 cm may be a supporting criterion for predicting remission in Knosp 4 tumors. Further studies with larger patient populations are necessary to support this finding. Key Words: Complete remission · Neuroendoscopy · Pituitary-dependant Cushing syndrome · Treatment outcome. Go to : INTRODUCTION Cushing’s disease (CD) is characterized by excessive secretion of adrenocorticotropic hormone (ACTH) by a corticotropic adenoma in the pituitary gland. In patients with CD whose hypercortisolism is inadequately corrected, morbidity and mortality can increase by up to 4.8 times due to Cushingrelated complications such as osteoporosis, hypertension, dyslipidemia, insulin resistance, and hypercoagulability [11,18]. Endoscopic transsphenoidal surgery (ETSS), the first-line treatment for CD [7], is performed to decrease complications while achieving remission and long-term disease control. Previous studies on CD have reported varying remission rates between 45% and 95% and recurrence rates ranging from 3−66% [2,4,9,16,21,30]. This wide range of differences can be primarily attributed to differences in surgical experience among centers: centers with higher surgical experience have fewer postoperative complications and higher remission rates [4,6]. However, despite initial remission, patients with CD may eventually experience recurrence. The mean recurrence rate at the 5-10-year follow-up is 23% for microadenomas and 33% for macroadenomas [19,23,30]. Since the postoperative rates in the literature are variable, additional data from experienced centers may be necessary to resolve these discrepancies. In this study, we present the medium- and long-term follow-up data from 96 operations for CD that were conducted in a center with a high level of experience for ETSS. Go to : MATERIALS AND METHODS The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Basaksehir Cam and Sakura City Hospital (No. 2022185). Informed consent was obtained from all patients. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This retrospective study included pre and postoperative data of 96 ETSS performed in 87 patients with CD (Fig. 1). CD was diagnosed based on unsuppressed cortisol levels (>1.8 µg/dL) following the 1-mg dexamethasone suppression test, high levels of urinary free cortisol, or late night salivary cortisol and plasma ACTH levels >20 pg/mL [28]. Between 2014 and 2022, all surgeries were conducted by the experienced neurosurgical team (Ö.G., O.T., B.E., E.A.) responsible for endoscopic transsphenoidal procedures at the Pituitary Research Center. The surgeries were performed under perioperative glucocorticoid coverage. Fig. 1. Number of operations and patients included in the study. Size, cavernous sinus invasion, sellar and suprasellar infiltration of adenoma on preoperative magnetic resonance imaging (MRI) scans, residual tumor on postoperative MRI scans, postoperative complications, pathology results, remission and recurrence status, and additional postoperative management were evaluated in addition to patients’ demographic data. For follow-up assessments, data obtained 3−6 months postoperatively and during the latest follow-up were included. Three different classifications obtained during radiologic evaluation using MRI were used for pituitary adenomas : 1) maximum size of tumor (MST) : 0−5 mm (group 1), 6−10 mm (group 2), 11−20 mm (group 3), and >20 mm (group 4); 2) Knosp classification : for evaluation of cavernous sinus invasion [22]; and 3) modified Hardy classification : for evaluation of sellar and suprasellar infiltrations [20,39]. In cases of CD without a lesion or with a lesion <6 mm on MRI, confirmation of the central origin and lateralization was provided by inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone stimulation [25,26,29]. Under neuronavigation guidance, pure ETSS surgical interventions were performed for all patients by a single surgical team using the Medtronic StealthStation™ S7 and S8 systems (Medtronic, Minneapolis, MN, USA) together with 4-mm 0°, 30°, and 45° rigid optical instruments and an endoscope. A nasal decongestant spray was administered 1 hour before the operation. The sphenoid ostium was detected from both nostrils, and a bi-nostril approach was used by resecting the posterior nasal septum. After sphenoidectomy, the standard sellar approach was used for lesions in the sellar region. The details of these surgical procedures are described in previous study [14]. Selective adenectomy with ETSS was performed for preoperatively localized and visible tumors, whereas hemihypophysectomy was performed for non-lesional cases. In cases with cavernous sinus-invading tumors, particularly Knops 3-4, the defect which was created by the tumor on the medial wall of anterior cavernous sinus was identified and, it was expanded for resection of the tumor tissue within the cavernous sinus. If a defect was not visible, blunt-ended hook-shaped dissectors were used to create a defect on the medial wall, allowing access for the tumor to enter the cavernous sinus. Hematoxylin and Eosin (H&E) and immunohistochemistry staining were performed for the specimens obtained during ETSS. Adenomas showing positive immunohistological staining for ACTH were diagnosed histologically as corticotropinomas. CD was considered to be in remission when the cases showed basal cortisol levels <5 µg/dL or suppressed cortisol levels (≤1.8 µg/dL) following the 1-mg dexamethasone suppression test, 3-6 months postoperation, and during the latest follow-up. The study protocol was approved by the ethics committee of our institution. Data were statistically analyzed using the SPSS 15.0 package (IBM Corp., Armonk, NY, USA). The chi-square test was used for categorical variables. Sample distribution was evaluated with the Kolmogorov-Smirnov test. Continuous independent variables with a normal distribution were compared using the Student’s t-test. Continuous variables with non-normal distributions were compared using the Mann-Whitney U test. p<0.05 was considered statistically significant. A Kaplan-Meier survival analysis was conducted to determine probability and time to recurrence in cases with initial remission. Go to : RESULTS Demographic data A total of 96 ETSS were performed for 87 patients with CD. Of the 87 patients, 68 (79%) were female, and 19 (21%) were male. The mean patient age was 42.2±12.9 years, and the mean duration of follow-up was 39.5±3.2 months. Of the 96 surgeries, 79 (82%) were performed for the first time, six (6%) were performed for residual tumors, and 11 (12%) were performed following a recurrence of the disease. Eight of the 17 patients who underwent reoperations had undergone their first operation at another center. Preoperative imaging Table 1 shows the maximum tumor size on preoperative pituitary MRI before each surgical procedure. Preoperative IPSS for lateralization was performed in 42 operations (44%), all of which were first-time cases. Knosp classification based on preoperative pituitary MRI and the modified Hardy classification is presented in Table 1. Table 1. Preoperative pituitary magnetic resonance imaging scans Number of tumors (n=96) Maximum tumor size  Group 1, 0−5 mm 41 (42.7)  Group 2, 6−10 mm 24 (25.0)  Group 3, 11−20 mm 20 (20.8)  Group 4, >20 mm 11 (11.5) Knosp classification  Grade 0 52 (54.2)  Grade 1 22 (22.9)  Grade 2 6 (6.3)  Grade 3 8 (8.3)  Grade 4 8 (8.3) Modified Hardy classification  0   A 41 (42.8)   B -   C -   D -   E -  1   A 14 (14.6)   B -   C -   D -   E 4 (4.2)  2   A 5 (5.2)   B -   C -   D -   E 5 (5.2)  3   A 1 (1.0)   B 2 (2.1)   C -   D -   E 1 (1.0)  4   A 1 (1.0)   B -   C -   D 1 (1.0)   E 3 (3.1)  NA 18 (18.8) Values are presented as number (%). Invasion : 0, sella normal; 1, sella focally expanded and tumor ≤10 mm; 2, sella enlarged and tumor ≥10 mm; 3, localized perforation of the sellar floor; 4, diffuse destruction of the sellar floor. Suprasellar extension : A, no suprasellar extension; B, anterior recesses of the third ventricle obliterated; C, floor of the third ventricle grossly displaced with parasellar extension; D, intracranial (intradural) : anterior, middle or middle fossa; E, into/beneath the cavernous sinus (extradural). NA : not available Postoperative results Remission was achieved between the 3rd and 6th months in 74 (77%) of the 96 operations, and long-term remission in 79 operations (82%). Among all 96 operations, eight (8%) concluded with a residual tumor. Regarding only first-time operations, five (6%) of the 79 concluded with a postoperative residual tumor. Of the 79 first-time operations, there were 62 cases (78%) of remission between 3 and 6 months. Two (2.5%) of these 79 operations involved recurrence during follow-up, while 60 (97%) showed sustained remission. Those with sustained remission had a median disease-free survival time of 31 months (interquartile range, 14-64) during long-term followup, two cases with recurrence had their recurrence 49 and 54 months after their operation. Survival analysis of cases with remisson and recurrence is presented in Fig. 2. CD persisted after 17 (21.5%) of the 79 first operations. Fig. 2. Survival analysis after the first operation in cases with remission at 3-6 months. Dashed line represents cases with recurrence and, straight line represents cases with sustained remission during long-term follow-up. Ten (13%) of the 79 cases underwent reoperation; two were due to recurrence, and eight due to disease persistence. In five cases (29%), the patients were initially unresponsive but showed remission later during the long-term follow-up. Remission was achieved with stereotactic radiosurgery (STRS) and medical treatment in one of these cases, with only STRS in two and only medical treatment in two cases. At the latest follow-up visit, the total number of cases showing remission after the first operation was 65 (82%). Additional details regarding the results of the first operations are provided in Fig. 3. Fig. 3. Results of the cases who had operation for the first time. Of the 18 reoperations, the results for one case were excluded since the patient was operated at another center. After the reoperation (n=17), the medium and long-term remission rates were 71% (n=12) and 77% (n=13), respectively. The 3-6-month remission rate did not differ significantly between first-time and reoperations (p=0.5). Residual tumors were present in three cases (18%) after reoperation. Of the early non-responders, one case showed remission after STRS, and none of the responders showed recurrence during long-term follow-up. Additional details regarding the results of reoperations are provided in Fig. 4. Fig. 4. Results of the reoperations in our center. Remission rates based on tumor size are presented in Table 2. The initial remission rates of the tumors in MST group 4 were significantly lower than those in the other MST groups (MST 1 vs. 4, p=0.01; MST 2 vs. 4, p=0.001; and MST 3 vs. 4, p=0.006). Comparisons of the other MST groups showed no significant differences. When adenomas were stratified using the 10-mm cut-off, the remission rates did not differ significantly (remission rate, 81% for adenomas <10 mm and 68% for adenomas ≥10 mm; p=0.2). Postoperative residual tumors were observed in five of the 11 tumors (46%) >2 cm (MST group 4) and in one tumor in each of MST groups 1-3 (2%, 4%, and 5%, respectively, p<0.001). Reoperation rate was 17% (n=7) for adenomas ≤5 mm, 18% (n=10) for adenomas ≥6 mm (p=0.9), and 27% (n=3) for adenomas >20 mm (among all grades, p=0.3). Table 2. Comparison of remission rates in preoperative pituitary magnetic resonance imaging scans 3−6-month remission Long-term remission Maximum tumor size  Group 1, 0−5 mm (n=41) 31 (75.6) 33 (80.5)  Group 2, 6−10 mm (n=24) 22 (91.7) 22 (91.7)  Group 3, 10−20 mm (n=20) 17 (85.0) 17 (85.0)  Group 4, >20 mm (n=11) 4 (36.4) 7 (63.6)  p-value 0.003* 0.200 Knops classification  0 (n=52) 41 (78.8) 44 (84.6)  1 (n=22) 21 (95.5) 21 (95.5)  2 (n=6) 4 (66.7) 3 (50.0)  3 (n=8) 7 (87.5) 7 (87.5)  4 (n=8) 1 (12.5) 4 (50.0)  p-value <0.001* 0.010* Modified Hardy classification  0   A (n=41) 32 (78.0) 34 (82.9)  1   A (n=14) 12 (85.7) 12 (85.7)  2   E (n=4) 3 (75.0) 3 (75.0)   A (n=5) 5 (100.0) 5 (100.0)  3   E (n=5) 2 (40.0) 2 (40.0)   A (n=1) 1 (100.0) 1 (100.0)   B (n=2) 2 (100.0) 2 (100.0)  4   E (n=1) 0 (0.0) 0 (0.0)   A (n=1) 1 (100.0) 1 (100.0)   D (n=1) 0 (0.0) 0 (0.0)   E (n=3) 1 (33.3) 3 (100.0)  p-value 0.10 0.06 Pathology result  Corticotropinoma (+) (n=71) 58 (81.7) 60 (84.5)  Corticotropinoma (-) (n=25) 16 (64.0) 19 (76.0)  p-value 0.07 0.30 Values are presented as number (%). Invasion : 0, sella normal; 1, sella focally expanded and tumor ≤10 mm; 2, sella enlarged and tumor ≥10 mm; 3, localized perforation of the sellar floor; 4, diffuse destruction of the sellar floor. Suprasellar extension : A, no suprasellar extension; B, anterior recesses of the third ventricle obliterated; D, intracranial (intradural) with anterior, middle, or middle fossa; E, into/beneath the cavernous sinus (extradural). * Statistically significant p-value Remission rates based on Knosp and Hardy classifications are presented in Table 2, respectively. The medium-term remission rates in Knosp group 4 were significantly lower than the rates in the other groups (Knosp 0 vs. 4, p<0.001; Knosp 1 vs. 4, p<0.001; Knosp 2 vs. 4, p=0.04; and Knosp 3 vs. 4, p=0.003). Additionally, the medium-term remission rate of tumors in Knosp group 2 was lower than that in Knosp group 1 (p=0.04). However, remission rates did not differ significantly among the other groups. Comparing invasive (Knosp 3 and 4) and noninvasive (Knosp 0, 1, and 2) tumors, remission rates within 3-6 months were 50% and 83% in the invasive and noninvasive groups, respectively. We further stratified cases with tumor size ≥20 mm (n=11) using Knosp classification; one case (9%) was Knosp 0, one case (9%) was Knosp 1, two cases (18%) were Knosp 3, and seven cases (64%) were Knosp 4 tumors. For ≥20 mm, all cases with Knosp 0, 1, and 3 tumors achieved remission within 3-6 months postoperatively, while none of the cases with Knosp 4 tumors had remission (p=0.01). All the cases with Knosp 0, 1, and 3 tumors sustained remission, and three cases with Knosp 4 tumor later achieved long-term remission (p=0.3). Of the cases that achieved long-term remission, two underwent STRS, and one had medical therapy with additional STRS. Of the 96 tissue specimens obtained during ETSS, 71 (74%) stained positive for ACTH and were histologically identified as corticotropic adenomas, while 25 (26%) were negative. Remission rates based on the pathology results are compared in Table 2. Of the lesions with conclusive findings on MRI (≥6 mm lesions), 89% (n=49) were pathologically confirmed as corticotropinomas, whereas 54% (n=22) of those with inconclusive MRI f indings were pathologically conf irmed (p<0.001). Among the lesions that showed negative results for both conclusive MRI findings (≤5 mm) and pathologic confirmation (negative for a corticotropinoma) (n=19), 12 (63%) showed remission at 3-6 months and 14 (74%) showed remission during long-term follow-up. During the exploration of the cavernous sinus in one patient (1%), postoperative lateral gaze paralysis of the eye developed due to right abducens nerve palsy. The patient was treated with anti-inflammatory doses of steroids, and the symptom completely resolved within 1 month. In three other patients (3%), severe epistaxis was observed in the postoperative period, 1 to 3 weeks after surgery. Nasal packing was applied for 3 days. Additionally, three patients (3%) experienced postoperative rhinorrhea. To address this issue, a reconstruction of the skull base was performed using fat tissue harvested from the leg, fascia lata graft, and tissue adhesive material. These patients were monitored with a lumbar drain for 1 week. Among the patients who developed rhinorrhea, one patient also developed meningitis and received intravenous antibiotic therapy for about 3 weeks and, the situation compeletly resolved during follow-up. The postoperative complications are summarized in Table 3. Comparison of various characteristics of the cases with and without medium and long-term remission are presented in Table 3, respectively. Table 3. Comparison of cases with and without remission, postoperative complications 3−6-month remission Long-term remission Number of cases (n=96) Remission (+) (n=74) Remission (-) (n=22) p-value Remission (+) (n=79) Remission (-) (n=17) p-value Operation 0.500 0.08  First time 62 (83.8) 17 (77.3) 66 (83.5) 13 (76.5)  Re-operation 12 (16.2) 5 (22.7) 13 (16.5) 4 (23.5) Tumor characteristics 0.003* 0.20  MST   Grade 1 31 (42.0) 10 (45.0) 33 (41.8) 8 (47.1)   Grade 2 22 (30.0) 2 (9.0) 22 (27.8) 2 (11.8)   Grade 3 17 (23.0) 3 (14.0) 17 (21.5) 3 (17.6)   Grade 4 4 (5.0) 7 (32.0) 7 (8.9) 4 (23.5)  Knosp classification <0.001* 0.01*   0 41 (56.0) 11 (50.0) 44 (55.5) 9 (53.0)   1 21 (28.0) 1 (4.5) 21 (26.5) 2 (12.0)   2 4 (5.0) 2 (9.0) 3 (4.0) 1 (6.0)   3 7 (10.0) 1 (4.5) 7 (9.0) 1 (6.0)   4 1 (1.0) 7 (32.0) 4 (5.0) 4 (23.0)  Hardy classification 0.09 0.06   0A 32 (43.2) 9 (41.0) 34 (43.0) 7 (41.0)   1A 12 (16.2) 2 (9.0) 12 (15.0) 2 (12.0)   1E 3 (4.0) 1 (4.5) 3 (4.0) 1 (6.0)   2A 5 (6.7) 0 (0.0) 5 (6.0) 0 (0.0)   2E 2 (2.7) 3 (14.0) 2 (3.0) 3 (17.0)   3A 1 (1.4) 0 (0.0) 1 (1.0) 0 (0.0)   3B 2 (2.7) 0 (0.0) 2 (3.0) 0 (0.0)   3E 0 (0.0) 1 (4.5) 0 (0.0) 1 (6.0)   4A 1 (1.4) 0 (0.0) 1 (1.0) 0 (0.0)   4D 0 (0.0) 1 (4.5) 0 (0.0) 1 (6.0)   4E 1 (1.4) 2 (9.0) 3 (4.0) 0 (0.0)   NA 15 (20.3) 3 (13.5) 16 (20.0) 2 (12.0) Postoperative  Complication 0.900 0.30   (+) 10 (13.5) 3 (13.6) 12 (15.2) 1 (5.9)   (-) 64 (86.5) 19 (86.4) 67 (84.8) 16 (94.1)  Pathologic diagnosis 0.070 0.30   Corticotropinoma 58 (78.4) 13 (59.1) 60 (75.9) 11 (64.7)   Negative 16 (21.6) 9 (40.9) 19 (24.1) 6 (35.3)  Remission during long-term F/U <0.001*   (+) 72 (97.3) 7 (31.8)   (-) 2 (2.7) 15 (68.2)  Residual tumor 0.001*   (+) 3 (3.8) 5 (29.4)   (-) 76 (96.2) 12 (70.6)  Remission during long-term F/U <0.001*   (+) 72 (91.1) 2 (11.8)   (-) 7 (8.9) 15 (88.2) Postoperative complication  DI-temporary 4 (4.2)  DI-permanent 4 (4.2)  Meningitis 1 (1.0)  CSF leak 3 (3.1)  Epistaxis 3 (3.1)  Cranial nerve palsy, transient 1 (1.0) Hypopituitarism 4 (4.2)  Hypocortisolism 2 (2.1)  Hypothyroidisim 2 (2.1) Values are presented as number (%). *Statistically significant p-values. MST : maximum size of tumor, NA : not available, F/U : follow up, DI : diabetes insipidus, CSF : cerebrospinal fluid Go to : DISCUSSION This study reported an overall postoperative 3-6 month remission rate of 77% and a long-term remission rate of 82% after 3 years of follow-up. The initial and long-term remission rates after first operations were 78% and 82%, respectively, with a recurrence rate of 2.5% over a follow-up period of 3-3.5 years. Additionally, our findings revealed that tumor size >2 cm and extended tumor invasion of the cavernous sinus (Knosp 4) might be associated with lower postoperative remission rates. Patients who showed remission within 3-6 months showed higher rates of long-term remission than those in patients without initial remission. Pituitary surgery is the first-line treatment modality for CD. ETSS is a safe and less invasive method for treating pituitary adenomas; therefore, it has been increasingly preferred in CD [5,15]. However, the postsurgical outcomes in patients with CD have shown variable remission and recurrence rates [2,4,9,16,17,21,30]. These discrepancies may be attributable to differences in population and number of cases involved in the studies, tumor characteristics, criteria for remission and recurrence used by the centers, laboratory parameters, time of evaluation and followup durations, surgical and imaging techniques used by different centers, and neurosurgical expertise. In this study, we present the medium- and long-term postoperative results of 96 ETSS procedures performed in 87 patients. The medium-term results (obtained 3-6 months postoperation) were preferred to immediate results since a subset of cases may show delayed remission, and immediate postoperative results could be misleading in almost 6% of cases [37]. The overall medium-term remission rate was 77%, consistent with the results published by Serban et al. [34], who reported an overall remission rate of 77% 2 months postoperation. A larger series of 1106 cases reported an immediate remission rate of 72.5% within 7 days postoperation; however, this rate decreased to 67% after delayed remission rates and recurrences 56 months postoperation were considered [12]. The long-term remission rate obtained over a median period of 3 years was 82% in our series. The increased long-term remission rate was attributed to reoperations, additional medical therapies, and the use of STRS in those who did not show remission initially. Of the 96 procedures, 79 were performed for the first time. The medium-term remission rate after first operations was 78%. Recent studies have reported remission rates of 74-82% after first operations [12,34]. The recurrence rates reported previously varied between 3% and 66% [5,12,34]. However, the duration of follow-up differed among the studies. Dai et al. [12] and Brady et al. [5] reported recurrence rates of 12% and 3%, respectively, after a follow-up period of 2 years. In contrast, Serban et al. [34] reported a recurrence rate of 17% after a longer followup duration of 6 years. In this series, after a median follow-up period of 3 years, the overall recurrence rate was 2.5%. Residual tumors were observed in five cases (6%), and the reoperation rate after the first operation was 13%. Including the eight patients admitted for reoperation after having undergone their first surgery in another center, 17 cases involved reoperations in our center. Of these cases, 71% (n=12) showed remission between 3-6 months postoperation, while none showed recurrence; thus, the long-term remission rate was 77%. Residual tumors were detected in three cases (18%), and the disease persisted in four (24%) of these 17 reoperated cases. Previous studies have reported remission rates of 22-75% after repeated surgery in CD [5,12,34,38]. Although the success rates after reoperations were lower than those in first-time operations in some studies [38], the remission rates after the first and reoperations did not differ significantly in our study. Tumor size has been reported to contribute to the success of transsphenoidal surgery [12,34], with microadenomas showing a higher success rate after surgery [5,12,34]. Our remission rates for micro- and macroadenomas were similar to those reported by Dai et al. [12] : 81% for adenomas <10 mm and 68% for adenomas ≥10 mm. However, the statistical significance of our study differed from that in the series presented by Dai et al. [12] (p=0.2 vs. p=0.002). This may be due to the large difference in the number of cases included in the two studies and the differences in size scales for tumors ≥10 mm. In our series, when the tumors were stratified further by the tumor size, the medium-term remission rate further decreased to 36% for tumors ≥20 mm in size, although the remission rates for other groups <20 mm were all above 75% (p=0.003). Sharifi et al. [35] classified pituitary MRI scans in CD showing a tumor size <6 mm as “inconclusive” because incidentalomas are frequent among tumors in this size range, and this size is not indicative of CD. Previously published series reported that the rate of inconclusive MRI scans in CD was 36-64%, and the remission rates varied between 50% and 71% for those with an inconclusive MRI scan [10,24,27,32,33]. In our series, 54% of the preoperative MRI scans were inconclusive. In the series presented by Sharifi et al. [35] and some other series [8,12,32,36], no significant difference was observed between the remission rates of CD cases with and without a conclusive MRI.This finding is controversial since other studies showed decreased remission rates with preoperative inconclusive MRIs [13,40]. Similar to the results reported by Sharifi et al. [35], we did not find a statistically significant difference between the remission rates of tumors <6 mm and those between 6-20 mm. However, a significant difference was observed between tumors <6 mm and those ≥20 mm. Residual tumors were more frequent after operating tumors >20 mm compared to those <20 mm, but the number of reoperations did not differ among the groups. Additionally, tumors >20 mm were primarily Knosp 4 (64%), probably contributing to lower remission rates in this group. Interestingly, two Knosp 3 cases had postoperative remission within 3-6 months without additional intervention. In these two cases, the surgical team explored the cavernous sinus and could resect the tumor. However, complete excision was not feasible with Knosp 4 tumors, where there is a complete encasement of the intracavernous internal carotid artery. Thus, a tumor size of 20 mm may be supportive data in predicting non-remission in the presence of complete cavernous sinus infiltration. Cavernous sinus invasion, determined by the Knosp classification, and sellar invasion and/or suprasellar extension, determined by the Hardy-Wilson classification, indicate the radiologic status of local invasion in cases of pituitary tumors [20,22,39]. Invasion to surrounding structures and tissues may be a limiting factor for postoperative remission of pituitary tumors. In the series presented by Dai et al. [12], remission rates of corticotropinomas with Knosp grade 4 (definitive cavernous sinus invasion) dropped to 53% from a remission rate of 77% for corticotropinomas with less likely or no cavernous sinus invasion (p<0.001). Similarly, our results showed that both medium- and long-term remission rates for Knosp grade 4 tumors decreased to 13% and 50%, respectively, and were lower than the remission rates in other grades (p<0.001 and p=0.01, respectively). While remission rates in Knosp group 3 were not inferior to noninvasive tumors, remission rates in Knosp group 4 were lower than all the other groups. In this regard, the extent of invasion may be more determinative. In contrast, in our series, the modified Hardy classification did not show a significant effect on postoperative remission rates in medium- and long-term follow-up assessments. Araujo-Castro et al. [3] had previously shown that for pituitary adenomas, the Hardy-Wilson classification lacked utility in predicting postoperative remission compared to the Knosp classification. The difference in the utility of these classifications for predicting postoperative remission may be due to differences in accessing tissues during surgery. In the present series, 74% (n=71) of tissues were histologically proven to be corticotropinomas, while 26% (n=25) did not show histologic confirmation. Medium- and long-term remission rates did not differ between histologically proven and unproven CD cases (medium-term remission rates, 82% vs. 64%, p=0.07; long-term remission rates, 85% vs. 76%, p=0.3). A conclusive finding of an adenoma on MRI increased the rate of histologic proof of corticotropinoma in our series, implying that adenomas showing a ≥6-mm lesion on MRI more frequently stained positive for ACTH. In previous studies 12-53% of CD did not have postoperative pathologic identification and the rate increased in those with a preoperative inconclusive MRI [25,31,38]. However, this did not have a significant influence on our remission rates. The remission rates did not decrease even for CD cases that were not conclusively detected on MRI and could not be histologically proven. On the other hand, in previous studies, ACTH positivity was higher, and the lack of proof for a corticotropinoma decreased the remission rates [1,12,31,32,34]. The higher remission rates despite reduced localization with MRI and/or lower rates of histologic confirmation in our series may be explained by the successful preoperative IPSS lateralization, surgical exploration, and hemi-hypophysectomy procedure. Furthermore, tumor tissues might have been aspirated along with blood and other materials through the suction tube, potentially resulting in less histological confirmation despite postoperative remission of CD. Additionally, tumor tissues might have been aspirated along with blood and other materials through the suction tube, potentially resulting in less histological confirmation despite postoperative remission of CD. The total rate of complications in this series was 20%, and the most frequent complication was diabetes insipidus (DI; 8%, both permanent and temporary). The incidence of hypopituitarism was relatively lower (4%), mainly involving hypocortisolism and hypothyroidism. Recent studies have shown postoperative DI rates of 25-66% and hypothyroidism rates of 11-23% [5,34]. Although our neurosurgical team was experienced in conducting pituitary surgeries, other factors may have resulted in these differences. Since not all the cases were postoperatively followed in our center, with some patients lost to follow-up, there may be missing data. Comparing cases with and without remission in the medium term, cases of remission frequently involved adenomas >20 mm and less cavernous sinus invasion. Additionally, cases that achieved medium-term remission showed long-term remission more frequently. In the long term, those showing remission had less cavernous sinus invasion and residual tumors compared to those without remission. Therefore, we may conclude that a tumor size of 20 mm may predict medium-term remission, while the absence of/less cavernous sinus invasion, early remission, and absence of residual tumor may predict long-term remission. This study had limitations. First, the retrospective nature of the study and the limited number of cases, which was inevitable due to the low incidence of CD, may have distorted our results. Although the same neurosurgical team operated on all patients, they were followed up pre and postoperatively at different endocrinology centers, causing difficulty in obtaining the full postoperative data of certain cases. Lastly, some patients recently underwent ETSS; thus, they had a shorter follow-up period. However, we intend to present the longer-term outcomes of all patients in a separate study. Although ETSS is the first-line treatment for CD, previous studies on the use of ETSS for CD have reported a wide range of remission and recurrence rates, which can be primarily attributed to differences in the surgical experience levels among centers. This trend highlights the need for additional data from experienced centers to resolve the discrepancies in the existing data. Therefore, we present medium- and long-term follow-up data from 96 operations for CD conducted in a center with a high level of experience for ETSS. We believe our study makes a significant contribution to the literature because the findings reconfirm the usefulness of ETSS for the treatment of CD and highlight the importance of the size of the adenoma and presence/absence of cavernous sinus invasion on preoperative MRI in predicting long-term remission postoperatively. Go to : CONCLUSION ETSS is a safe and effective method for the treatment of CD. Some characteristics of adenomas, such as size, cavernous sinus invasion, and postoperative residue, may predict long-term remission. A tumor size of 2 cm may be a supporting criterion for predicting remission status in the presence of complete cavernous sinus infiltration. Further studies with larger patient populations are necessary to support this finding. Go to : Notes Conflicts of interest No potential conflicts of interest relevant to this study exist. Informed consent Informed consent was obtained from all individual participants included in this study. Author contributions Conceptualization : BE, MB, EH; Data curation : EA, OH, DT, MM; Formal analysis : LŞP, DAB, DT, İÇ; Funding acquisition : OT, ÖG, DAB; Methodology : LŞP, İÇ, MM, ÖG; Project administration : BE, SÇ, EH; Visualization : EA, OT, OH; Writing - original draft : BE, MB, SÇ; Writing - review & editing : BE, EH Data sharing None Preprint None Go to : Acknowledgements This manuscript was edited by a certified English Proofreading Service (Editage). Go to : References 1. Acebes JJ, Martino J, Masuet C, Montanya E, Soler J : Early post-operative ACTH and cortisol as predictors of remission in Cushing’s disease. Acta Neurochir (Wien) 149 : 471-477; discussion 477-479, 2007 2. Aranda G, Enseñat J, Mora M, Puig-Domingo M, Martínez de Osaba MJ, Casals G, et al : Long-term remission and recurrence rate in a cohort of Cushing’s disease: the need for long-term follow-up. Pituitary 18 : 142-149, 2015 3. 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J Neurosurg 109 : 751-759, 2008 32. Salenave S, Gatta B, Pecheur S, San-Galli F, Visot A, Lasjaunias P, et al : Pituitary magnetic resonance imaging findings do not influence surgical outcome in adrenocorticotropin-secreting microadenomas. J Clin Endocrinol Metab 89 : 3371-3376, 2004 33. Semple PL, Laws ER Jr : Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing’s disease. J Neurosurg 91 : 175-179, 1999 34. Serban AL, Del Sindaco G, Sala E, Carosi G, Indirli R, Rodari G, et al : Determinants of outcome of transsphenoidal surgery for Cushing disease in a single-centre series. J Endocrinol Invest 43 : 631-639, 2020 35. Sharifi G, Amin AA, Sabahi M, Echeverry NB, Dilmaghani NA, Mousavinejad SA, et al : MRI-negative Cushing’s disease: management strategy and outcomes in 15 cases utilizing a pure endoscopic endonasal approach. BMC Endocr Disord 22 : 154, 2022 36. Sun Y, Sun Q, Fan C, Shen J, Zhao W, Guo Y, et al : Diagnosis and therapy for Cushing’s disease with negative dynamic MRI finding: a singlecentre experience. Clin Endocrinol (Oxf) 76 : 868-876, 2012 37. Valassi E, Biller BM, Swearingen B, Pecori Giraldi F, Losa M, Mortini P, et al : Delayed remission after transsphenoidal surgery in patients with Cushing’s disease. J Clin Endocrinol Metab 95 : 601-610, 2010 38. Valderrábano P, Aller J, García-Valdecasas L, García-Uría J, Martín L, Palacios N, et al : Results of repeated transsphenoidal surgery in Cushing’s disease. Long-term follow-up. Endocrinol Nutr 61 : 176-183, 2014 39. Wilson CB : A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg 61 : 814-833, 1984 40. Yamada S, Fukuhara N, Nishioka H, Takeshita A, Inoshita N, Ito J, et al : Surgical management and outcomes in patients with Cushing disease with negative pituitary magnetic resonance imaging. World Neurosurg 77 : 525-532, 2012 From https://jkns.or.kr/journal/view.php?doi=10.3340/jkns.2023.0100
  5. I would have hoped that you could get better answers in the UK. I'm in the US - Virginia. Our doctors aren't very good, either
  6. Earlier
  7. Hi I’m located in Bradford in the United Kingdom..where are you located?
  8. Oh no, Shagufta! I cannot imagine what you're going through. Where are you located?
  9. YOU’RE INVITED! Webinar on Dr. Theodore Friedman’s update on medical treatment for Cushing’s disease In this informative webinar, Dr. Friedman will discuss What medicines to use to treat Cushing’s disease Side effects and timing of the medicines The use of ketoconazole for a medication trial before surgery Longer-term treatment for Cushing’s How to determine when a patient should go to surgery Sunday • March 31 • 6 PM PDT here to join the meeting or https://us02web.zoom.us/j/4209687343?pwd=amw4UzJLRDhBRXk1cS9ITU02V1pEQT09&omn=88672684111 OR +16699006833,,4209687343#,,,,*111116# US (San Jose) OR Join on Facebook Live https://www.facebook.com/goodhormonehealth Slides will be available on the day of the talk here. There will be plenty of time for questions using the chat button. For more information, email us at mail@goodhormonehealth.com
  10. YOU’RE INVITED! Webinar on Dr. Theodore Friedman’s update on medical treatment for Cushing’s disease In this informative webinar, Dr. Friedman will discuss What medicines to use to treat Cushing’s disease Side effects and timing of the medicines The use of ketoconazole for a medication trial before surgery Longer-term treatment for Cushing’s How to determine when a patient should go to surgery Sunday • March 31 • 6 PM PDT here to join the meeting or https://us02web.zoom.us/j/4209687343?pwd=amw4UzJLRDhBRXk1cS9ITU02V1pEQT09&omn=88672684111 OR +16699006833,,4209687343#,,,,*111116# US (San Jose) OR Join on Facebook Live https://www.facebook.com/goodhormonehealth Slides will be available on the day of the talk here. There will be plenty of time for questions using the chat button. For more information, email us at mail@goodhormonehealth.com
  11. Abstract Cushing’s syndrome is a constellation of features occurring due to high blood cortisol levels. We report a case of a 47-year-old male with a history of recurrent olfactory neuroblastoma (ONB). He presented with bilateral lower limb weakness and anosmia and was found to have Cushing’s syndrome due to high adrenocorticotropic hormone (ACTH) levels from an ectopic source, ONB in this case. Serum cortisol and ACTH levels declined after tumor removal. Introduction Olfactory neuroblastoma (ONB), or esthesioneuroblastoma, is a rare malignancy arising from neuroepithelium in the upper nasal cavity. It represents approximately 2% of all nasal passage tumors, with an incidence of approximately 0.4 per 2.5 million individuals [1]. ONB shares similar histological features with small round blue cell neoplasms of the nose. Ectopic hormone secretion is a very rare feature associated with these tumors. Five-year overall survival is reported to be between 60% and 80% [2,3]. The age distribution is either in the fifth to sixth decade of life [4,5], or in the second and sixth decades [6]. Features of Cushing’s syndrome (moon face, buffalo hump, central obesity hypertension, fragile skin, easy bruising, fatigue, muscle weakness) are due to high blood cortisol levels [7]. It can be either primary (cortisol-secreting adrenal tumor), secondary (adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, also called Cushing disease), or ectopic ACTH secretion (from a non-pituitary source). All three types share similar features [8]. Ectopic ACTH syndrome (EAS) is due to an extra pituitary tumor, producing ACTH. It accounts for 12-17% of Cushing's syndrome cases [9]. Most cases of EAS-producing tumors are in the lungs, mediastinum, neuroendocrine tumors of the gastrointestinal tract, and pheochromocytomas [9]. Ectopic ACTH secretion from an ONB is very rare. As of 2015, only 18 cases were reported in the literature [10]. Here, we report such a case. Case Presentation Our patient is a 47-year-old Bangladeshi male, with a history of recurrent ONB that was resected twice in the past (transsphenoidal resection in 2016 and 2019) with adjuvant radiotherapy, no chemotherapy was given. He also had diabetes mellitus type 1 (poorly controlled) and hypertension. He presented with bilateral lower limb weakness, anosmia, decreased oral intake, loss of taste for one week, and bilateral submandibular swelling that increased in size gradually over the past two years. There was no history of fever, cough, abdominal pain, or exposure to sick contacts. The patient reported past episodes of similar symptoms, but details are unclear. The patient's family history is positive for diabetes mellitus type 1 in both parents. Lab tests in the emergency department showed hypokalemia and hyperglycemia as detailed in Table 1. He was admitted for further workup of the above complaints. Test Patient Results Reference Range Unit Status Hemoglobin 14.7 13-17 g/dL Normal White blood cell (WBC) 17.9 4-10 10*9/L High Neutrophils 15.89 2-7 10*9/L High Lymphocytes 1.07 1-3 10*9/L Normal Sodium 141 136-145 mmol/L Normal Potassium 2.49 3.5-5.1 mmol/L Low (Panic) Chloride 95 98-107 mmol/L Low Glucose 6.52 4.11-5.89 mmol/L Elevated C-reactive protein (CRP) 0.64 Less than 5 mg/L Normal Erythrocyte sedimentation rate (ESR) 2 0-30 mm/h Normal Creatinine 73 62-106 µmol/L Normal Uric acid 197 202.3-416.5 µmol/L Normal Alanine aminotransferase (ALT) 33.2 0-41 U/L Normal Aspartate aminotransferase (AST) 18.6 0-40 U/L Normal International Normalised Ratio (INR) 1.21 0.8-1.2 sec High Prothrombin time (PT) 15.7 12.3-14.7 sec High Lactate dehydrogenase (LDH) 491 135-225 U/L High Thyroid-stimulating hormone (TSH) 0.222 0.27-4.20 mIU/L Low Adrenocorticotropic hormone (ACTH) 106 ≤50 ng/L Elevated Cortisol (after dexamethasone suppression) 1750 Morning hours (6-10 am): 172-497 nmol, Afternoon hours (4-8 pm): 74.1-286 nmol nmol/L Elevated (failure of suppression) 24-hour urine cortisol (after dexamethasone suppression) 5959.1 <120 nmol/24 hrs nmol/24hr Elevated (failure of suppression) Table 1: Results of blood test at the time of hospitalization. Hypokalemia and high values of adrenocorticotropic hormone and cortisol were confirmed. On examination, the patient's vital signs were as follows: blood pressure was 154/77 mmHg, heart rate of 60 beats per minute, respiratory rate was 18 breaths per minute, oxygen saturation of 98% on room air, and a temperature of 36.7°C. The patient had a typical Cushingoid appearance with a moon face, buffalo hump, purple striae on the abdomen, central obesity, and hyperpigmentation of the skin. Submandibular lymph nodes were enlarged bilaterally. The examination of the submandibular lymph nodes showed a firm, fixed mass extending from the angle of the mandible to the submental space on the left side. Neurological examination showed weakness in both legs bilaterally (strength 3/5) and anosmia (checked by orthonasal smell test). The rest of the neurological exam was normal. Laboratory findings revealed (in Table 1) a marked hypokalemia of 2.49 mmol/L and hyperglycemia of 6.52 mmol/L. The serum cortisol level was elevated at 1587 nmol/L. Serum ACTH levels were raised at 106 ng/L (normal value ≤50 ng/L). Moreover, the high-dose dexamethasone suppression test failed to lower the serum ACTH levels and serum and urine cortisol. Serum cortisol level after the suppression test was 1750 nmol/L, while 24-hour urine cortisol after the test was 5959.1 nmol/24hr. Serum ACTH levels after the test also remained high at 100mg/L. This indicated failure of ACTH suppression by high-dose dexamethasone, which points towards ectopic ACTH production. Other blood tests (complete blood count, liver function tests) were insignificant. A computed tomography scan with contrast (CT scan) of the chest, abdomen, and pelvis, with a special focus on the adrenals, was negative for any malignancy or masses. CT scan of the neck showed bilaterally enlarged submandibular lymph nodes and an enlarged right lobe of the thyroid with nodules. Fine needle aspiration (FNA) of the thyroid nodules revealed a benign nature. Magnetic resonance imaging (MRI) of the brain showed a contrast-enhancing soft tissue lesion (18x18x10mm) in the midline olfactory groove area with extension into the frontal dura and superior sagittal sinus, suggesting recurrence of the previous ONB. There was evidence of previous surgery also. The pituitary gland was normal (Figures 1-2). Figure 1: A brain MRI (T1-weighted; without contrast; sagittal plane) shows a soft tissue lesion located in the midline olfactory groove area. Dural surface with extension into anterior frontal dura. MRI: Magnetic resonance imaging Figure 2: A brain MRI (T2-weighted; without contrast; axial plane) shows a soft tissue lesion located in the midline olfactory groove area. MRI: Magnetic resonance imaging Octreotide scintigraphy showed three focal abnormal uptakes in the submandibular cervical nodes. Additionally, there was a moderate abnormal uptake at the midline olfactory groove with bilateral extension (Figure 3). Figure 3: Whole-body octreotide scan (15 mCi 99mTc-Octreotide IV) demonstrates three focal abnormal uptakes: the largest (5.2 x 2.4 cm) in the left submandibular region, and two smaller ones on the right, suggestive of lymph node uptake. Additional abnormal uptake was seen along the midline of the olfactory groove region with bilateral extension. No other significant abnormal uptake was identified. On microscopic examination, an excisional biopsy after the transcranial resection surgery of the frontal skull base tumor showed nests and lobules of round to oval cells with clear cytoplasm, separated by vascular and hyalinized fibrous stroma (Figures 4A-4B). Tumor cells show mild to moderate nuclear pleomorphism, and fine chromatin (Figure 4C). A fibrillary neural matrix is also present. Some mitotic figures can be seen. Immunohistochemical stains revealed positive staining for synaptophysin (Figure 4D) and chromogranin (Figure 4E). Stains for CK (AE1/AE3), CD45, Desmin, and Myogenin are negative. Immunostaining for ACTH was focally positive (Figure 4F), while the specimen of the cervical lymph nodes showed the same staining, indicating metastases. The cytomorphologic and immunophenotypic features observed are consistent with a Hyams grade II ONB, with ectopic ACTH production. Figure 4: Histopathological and immunohistochemical findings of olfactory neuroblastoma. A (100x magnification) and B (200x magnification) - hematoxylin and eosin (H-E) staining shows cellular nests of round blue cells separated by hyalinized stroma. C (400x magnification) - nuclei show mild to moderate pleomorphism with fine chromatin. D (100x magnification) - an immunohistochemical stain for synaptophysin shows diffuse, strong cytoplasmic positivity within tumor cells. E (200x magnification) - tumor cells are positive for chromogranin. F (400x magnification) - ACTH cytoplasmic expression in tumor cells. ACTH: adrenocorticotropic hormone For his resistant hypokalemia, he had to be given intravenous (IV) and oral potassium chloride (KCL) repeatedly. The patient underwent transcranial resection of the frontal skull base tumor. The patient received cefazolin for seven days, and hydrocortisone for four days. After transcranial resection, his cortisol level decreased to 700 nmol/L. Furthermore, ACTH dropped, and serum potassium also normalized. Subsequently, the patient was transferred to the intensive care unit (ICU) for meticulous monitoring and continued care. In the ICU, the patient developed one episode of a generalized tonic-clonic seizure, which aborted spontaneously, and the patient received phenytoin and levetiracetam to prevent other episodes. A right-sided internal jugular vein and left transverse sinus thrombosis were also developed and treated with enoxaparin sodium. Following surgery, his low potassium levels improved, resulting in an improvement in his limb weakness. His other symptoms also gradually improved after surgery. Three weeks following the primary tumor resection, he underwent bilateral neck dissection with right hemithyroidectomy, for removal of the metastases. The patient opted out of chemotherapy and planned for an international transfer to his home country for further management. Other treatments that he received during hospitalization were ceftriaxone, azithromycin, and Augmentin®. Insulin was used to manage his diabetes, perindopril to regulate his blood pressure, and spironolactone to increase potassium retention. Omeprazole was administered to prevent GI bleeding and heartburn/gastroesophageal reflux disease relief after discharge. Discussion ONB was first described in 1924, and it is a rare neuroectodermal tumor that accounts for 2% of tumors affecting the nasal cavity [11]. Even though ONB has a good survival rate, long-term follow-up is necessary due to the disease's high recurrence rate [2]. ONB recurrence has been approximated to range between 30% and 60% after successful treatment of the primary tumor [12]. Recurrent disease is usually locoregional and tends to have a long interval to relapse with a mean of six years [12]. The first reported case of ectopic ACTH syndrome caused by ONB was in 1987 by M Reznik et al., who reported a 48-year-old woman with ONB who developed a Cushing-like syndrome 28 months before her death [13]. The occurrence of Cushing’s syndrome due to ectopic ACTH can occur either in the initial tumor or even years later during its course or after recurrence [3,6,9,14]. Similar to the case of Abe et al. [3], our patient also presented with muscle weakness due to hypokalemia, which is a feature of Cushing’s syndrome. Hypokalemia is present at diagnosis in 64% to 86% of cases of EAS and is resistant to treatment [9,14], as seen in our case. In our patient, the exact time of development of Cushing’s syndrome could not be ascertained due to the non-availability of previous records. However, according to the patient, he started developing abdominal obesity, pigmentation, and buffalo hump in 2021 about two years after his second surgery for ONB. The distinction between pituitary ACTH and ectopic ACTH involves utilizing CT/MRI of the pituitary, corticotropin-releasing hormone (CRH) stimulation test with petrosal sinus blood sampling, high dose dexamethasone suppression test, and checking serum K+ (more commonly low in ectopic ACTH) [2,15,16]. In our case, a CRH stimulation test was not available but CT/MRI brain, dexamethasone test, low serum potassium, plus the postoperative fall in cortisol levels, all pointed towards an ectopic ACTH source. Conclusions In conclusion, this case highlights the rare association between ONB and ectopic ACTH syndrome, which developed after tumor recurrence. The patient's unique presentation of bilateral lower limb weakness and hypokalemia can cause diagnostic challenges, emphasizing the need for comprehensive diagnostic measures. Surgical intervention proved crucial, with postoperative cortisol values becoming normal, highlighting the efficacy of this approach. The occurrence of ectopic ACTH production in ONB patients, although very rare, is emphasized, so that healthcare professionals who deal with these tumors are aware of this complication. This report contributes valuable insights shedding light on the unique ONB manifestation causing ectopic ACTH syndrome. The ongoing monitoring of the patient's clinical features will further enrich the understanding of the course of this uncommon phenomenon in the medical literature. References Thompson LD: Olfactory neuroblastoma. Head Neck Pathol. 2009, 3:252-9. 10.1007/s12105-009-0125-2 Abdelmeguid AS: Olfactory neuroblastoma. Curr Oncol Rep. 2018, 20:7. 10.1007/s11912-018-0661-6 Abe H, Suwanai H, Kambara N, et al.: A rare case of ectopic adrenocorticotropic hormone syndrome with recurrent olfactory neuroblastoma. Intern Med. 2021, 60:105-9. 10.2169/internalmedicine.2897-19 Yin Z, Wang Y, Wu Y, et al.: Age distribution and age-related outcomes of olfactory neuroblastoma: a population-based analysis. Cancer Manag Res. 2018, 10:1359-64. 10.2147/CMAR.S151945 Platek ME, Merzianu M, Mashtare TL, Popat SR, Rigual NR, Warren GW, Singh AK: Improved survival following surgery and radiation therapy for olfactory neuroblastoma: analysis of the SEER database. Radiat Oncol. 2011, 6:41. 10.1186/1748-717X-6-41 Elkon D, Hightower SI, Lim ML, Cantrell RW, Constable WC: Esthesioneuroblastoma. Cancer. 1979, 44:3-1087. 10.1002/1097-0142(197909)44:3<1087::aid-cncr2820440343>3.0.co;2-a Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125 Chabre O: Cushing syndrome: physiopathology, etiology and principles of therapy [Article in French]. Presse Med. 2014, 43:376-92. 10.1016/j.lpm.2014.02.001 Isidori AM, Lenzi A: Ectopic ACTH syndrome. Arq Bras Endocrinol Metabol. 2007, 51:1217-25. 10.1590/s0004-27302007000800007 Kunc M, Gabrych A, Czapiewski P, Sworczak K: Paraneoplastic syndromes in olfactory neuroblastoma. Contemp Oncol (Pozn). 2015, 19:6-16. 10.5114/wo.2015.46283 Finlay JB, Abi Hachem R, Jang DW, Osazuwa-Peters N, Goldstein BJ: Deconstructing olfactory epithelium developmental pathways in olfactory neuroblastoma. Cancer Res Commun. 2023, 3:980-90. 10.1158/2767-9764.CRC-23-0013 Ni G, Pinheiro-Neto CD, Iyoha E, et al.: Recurrent esthesioneuroblastoma: long-term outcomes of salvage therapy. Cancers (Basel). 2023, 15:1506. 10.3390/cancers15051506 Reznik M, Melon J, Lambricht M, Kaschten B, Beckers A: Neuroendocrine tumor of the nasal cavity (esthesioneuroblastoma). Apropos of a case with paraneoplastic Cushing's syndrome [Article in French]. Ann Pathol. 1987, 7:137-42. Kadoya M, Kurajoh M, Miyoshi A, et al.: Ectopic adrenocorticotropic hormone syndrome associated with olfactory neuroblastoma: acquirement of adrenocorticotropic hormone expression during disease course as shown by serial immunohistochemistry examinations. J Int Med Res. 2018, 46:4760-8. 10.1177/0300060517754026 Clotman K, Twickler MTB, Dirinck E, et al.: An endocrine picture in disguise: a progressive olfactory neuroblastoma complicated with ectopic Cushing syndrome. AACE Clin Case Rep. 2017, 3:278-83. 10.4158/EP161729.CR Chung YS, Na M, Ku CR, Kim SH, Kim EH: Adrenocorticotropic hormone-secreting esthesioneuroblastoma with ectopic Cushing’s syndrome. Yonsei Med J. 2020, 61:257-61. 10.3349/ymj.2020.61.3.257 From https://www.cureus.com/articles/226080-olfactory-neuroblastoma-causing-cushings-syndrome-due-to-the-ectopic-adrenocorticotropic-hormone-acth-secretion-a-case-report?score_article=true#!/
  12. Hi I’m a Cushings survivor..post Pitituary surgery 20 years since..Cushings came back in 2008 after 2004 three times surgery..Was put on medication until 2012 when I had gamma knife radiotherapy..Still have health issues which I know are related to my cushings disease..Arthritis and blood pressure and kidney cyst issues..Now suffering from gout since last year which I’m controlling with herbal remedies..Lost over 20kg since a few months doctors cannot find the solution and suffering from anxiety and depression..I think these problems are all because of my Cushings disease but doctors are not helping me or doing anything.. Need help desperately so posting here as I know Cushings survivors will understand and help..Regards Shagufta
  13. Abstract Background The aim of this study was to investigate the clinical features and treatment options for pediatric adrenal incidentalomas(AIs) to guide the diagnosis and treatment of these tumors. Methods The clinical data of AI patients admitted to our hospital between December 2016 and December 2022 were collected and retrospectively analyzed. All patients were divided into neonatal and nonneonatal groups according to their age at the time of the initial consultation. Results In the neonatal group, 13 patients were observed and followed up, and the masses completely disappeared in 8 patients and were significantly reduced in size in 5 patients compared with the previous findings. Four patients ultimately underwent surgery, and the postoperative pathological diagnosis was neuroblastoma in three patients and teratoma in one patient. In the nonneonatal group, there were 18 cases of benign tumors, including 9 cases of ganglioneuroma, 2 cases of adrenocortical adenoma, 2 cases of adrenal cyst, 2 cases of teratoma, 1 case of pheochromocytoma, 1 case of nerve sheath tumor, and 1 case of adrenal hemorrhage; and 20 cases of malignant tumors, including 10 cases of neuroblastoma, 9 cases of ganglioneuroblastoma, and 1 case of adrenocortical carcinoma. Conclusions Neuroblastoma is the most common type of nonneonatal AI, and detailed laboratory investigations and imaging studies are recommended for aggressive evaluation and treatment in this population. The rate of spontaneous regression of AI is high in neonates, and close observation is feasible if the tumor is small, confined to the adrenal gland and has no distant metastasis. Peer Review reports Background The incidence of adrenal incidentaloma (AI) is increasing due to the increased frequency of imaging and improved imaging sensitivity [1]. AI is relatively common in adults, and several organizations, such as the American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons and the European Society Endocrinology, have proposed specific protocols to guide the evaluation, treatment, and follow-up management of AI in adults [2]. Although AI, a nonfunctioning adrenocortical adenoma, is most common in adults, neuroblastoma is the most common incidental tumor of the adrenal gland in children. In addition, in the neonatal period, which is a more complex stage of childhood, the biology of adrenal masses found in this age group is also more specific, and the nature of these masses can range from spontaneous regression to rapid progression to aggressive disease with metastatic dissemination and even death. Given that AI is the most common malignant tumor, the management of AI in children cannot be simply based on the measurements used in adult AI. In this study, we retrospectively analyzed the clinical data of pediatric AI patients in a single center to investigate the clinical characteristics and management of AI in children. Methods A total of 66 children with adrenal tumors were diagnosed and treated at the Department of Urology of the Children’s Hospital of Nanjing Medical University from December 2016 to December 2022. A total of 55 cases were detected during physical examination, or the patients were diagnosed and received treatment for diseases other than adrenal disease after excluding adrenal tumors detected due to typical clinical manifestations or signs such as centripetal obesity and precocious puberty. Research protocols involving human materials were approved by the Medical Ethics Committee of the Children’s Hospital of Nanjing Medical University. All clinical information, radiological diagnosis, laboratory test results, intervention results, and follow-up data were collected from the department’s database. All the children underwent ultrasonography and CT scanning, and 11 children underwent MRI. In addition to routine tests such as blood routine and biochemical indexes, the examination and evaluation of adrenal endocrine hormones and tumor markers included (1) plasma cortisol and ACTH levels, (2) plasma catecholamine and metabolite determination, (3) plasma renin and plasma aldosterone, (4) urinary vanillylmandelic acid/homovanillic acid(VMA/HVA), and (5) AFP, CEA, NSE, and CA19-9. Five patients underwent a low-dose dexamethasone suppression test. Seventeen of the 55 patients were treated with watch-waiting therapy, 4 of the 17 ultimately underwent surgery, 4 of the 38 patients underwent tumor biopsy, and 34 underwent adrenalectomy. The data were analyzed using Graph Pad Prism 8. The measurement data are expressed as ‾x ± sd. The maximum diameter of the tumors, age of the patients with benign and malignant tumors, and maximum diameter of the tumors between the laparoscopic surgery group and the open surgery group were compared using paired t tests, and the percentages of the count data were compared using Fisher’s exact test. Results In this study, all patients were divided into two groups according to their age at the time of consultation: the neonate group and the nonneonate group. Neonate group: There were 7 male and 10 female patients, 7 of whom were diagnosed via prenatal examination and 10 of whom were diagnosed after birth. Five patients were diagnosed with lesions on the left side, 12 patients were diagnosed with lesions on the right side, and the maximal diameters of the masses ranged from 16 to 48 mm. The characteristics of the AIs in the neonate group are presented in Table 1. Table 1 Characteristics of AI in the neonates group Full size table Among the 17 patients, 8 had cystic masses with a maximum diameter of 16∼48 mm, 5 had cystic-solid masses with a maximum diameter of 33∼39 mm, and 4 had solid masses with a maximum diameter of 18∼45 mm. Two patients with solid adrenal gland masses suggested by CT scan had obvious elevations in serum NSE and maximum diameters of 44 and 45 mm, respectively. These patients underwent adrenal tumor resection, and the pathology diagnosed that they had neuroblastomas(NB). In one patient, the right adrenal gland was 26 × 24 × 27 mm in size with slightly elevated echogenicity at 38 weeks after delivery, and the mass increased to a size of 40 × 39 × 29 mm according to the 1-month postnatal review. MRI suggested that the adrenal gland tumor was associated with liver metastasis, and the pathology of the tumor suggested that it was NB associated with liver metastasis after surgical resection (stage 4 S, FH). One child was found to have 25 × 24 × 14 mm cystic echoes in the left adrenal region during an obstetric examination, and ultrasound revealed 18 × 11 mm cystic solid echoes 5 days after birth. Ultrasound revealed 24 × 15 mm cystic solid echoes at 2 months. Serum NSE and urinary VMA were normal, and the tumor was excised due to the request of the parents. Pathology suggested a teratoma in the postoperative period. A total of 13 children did not receive surgical treatment or regular review via ultrasound, serum NSE or urine VMA. The follow-up time ranged from 1 to 31 months, with a mean of 9.04 ± 7.61 months. Eight patients had complete swelling, and 5 patients were significantly younger than the previous patients. Nonneonate group: There were 24 male and 14 female patients in the nonneonate group; 24 patients had lesions on the left side, 14 patients had lesions on the right side, and the maximal diameters of the masses ranged from 17 to 131 mm. Most of these tumors were found during routine physical examinations or incidentally during examinations performed for various complaints, such as gastrointestinal symptoms, respiratory symptoms, or other related conditions. As shown in Table 2, abdominal pain was the most common risk factor (44.7%) for clinical onset, followed by routine physical examination and examination for respiratory symptoms. Table 2 Clinical presentations leading to discovery of AI in non-neonate group Full size table Among the 38 patients, 10 had NBs with maximum diameters ranging from 20 to 131 mm, 9 had ganglion cell neuroblastomas with maximum diameters ranging from 33.6 to 92 mm, 9 had ganglion cell neuromas with maximum diameters ranging from 33 to 62 mm, 2 had adrenal adenomas with maximum diameters ranging from 17 to 70 mm, 1 had a cortical carcinoma with a maximum diameter of 72 mm, 2 had adrenal cysts with maximum diameters ranging from 26 to 29 mm, 2 had mature teratomas with maximum diameters of 34 and 40 mm, 1 had a pheochromocytoma with a diameter of 29 mm, 1 had a nerve sheath tumor with a diameter of 29 mm, and 1 patient with postoperative pathological confirmation of partial hemorrhagic necrosis of the adrenal gland had focal calcification with a maximum diameter of 25 mm (Table 3). Table 3 Distribution of different pathologies among AI with various sizes in non-neonate group Full size table The mean age of children with malignant tumors was significantly lower than that of children with benign tumors (57.95 ± 37.20 months vs. 105.0 ± 23.85 months; t = 4.582, P < 0.0001). The maximum diameter of malignant tumors ranged from 20 to 131 mm, while that of benign tumors ranged from 17 to 72 mm, and the maximum diameter of malignant tumors was significantly greater than that of benign tumors (65.15 ± 27.61 mm v 37.59 ± 12.98 mm; t = 3.863, P = 0.0004). Four biopsies, 5 laparoscopic adrenal tumor resections and 11 open adrenal tumor resections were performed for malignant tumors, and 16 laparoscopic adrenal tumor resections and 2 open procedures were performed for benign tumors. The maximum diameter of the tumors ranged from 17 to 62 mm in 21 children who underwent laparoscopic surgery and from 34 to 99 mm in 13 children who underwent open resection; there was a statistically significant difference in the maximum diameter of the tumors between the laparoscopic surgery group and the open surgery group (35.63 ± 10.36 mm v 66.42 ± 20.60 mm; t = 5.798, P < 0.0001). Of the 42 children with definitive pathologic diagnoses at surgery, 23 had malignant tumors, and 19 had benign tumors. There were 15 malignant tumors with calcification on imaging and 5 benign tumors. The percentage of malignant tumors with calcifications in was significantly greater than that of benign tumors (65.22% v 26.32%; P = 0.0157). In the present study, all the children underwent CT, and 31 patients had postoperative pathological confirmation of NB. A total of 26 patients were considered to have neurogenic tumors according to preoperative CT, for a diagnostic compliance rate of 83.97%. Three children were considered to have cortical adenomas by preoperative CT, and 1 was ultimately diagnosed by postoperative pathology, for a diagnostic compliance rate of 33.33%. For 4 patients with teratomas and adrenal cysts, the CT findings were consistent with the postoperative pathology. According to our research, NB 9-110HU, GNB 15-39HU, GB 19-38HU, ACA 8HU, adrenal cyst 8HU, and cellular achwannoma 17HU. Discussion According to the clinical practice guidelines developed by the European Society of Endocrinology and European Network for the Study of Adrenal Tumors, AI is an adrenal mass incidentally detected on imaging not performed for a suspected adrenal disease [3]. The prevalence of AI is approximately 4%, and the incidence increases with age [4]. Most adult AIs are nonfunctioning benign adrenal adenomas (up to 75%), while others include functioning adrenal adenomas, pheochromocytomas, and adrenocortical carcinomas [5]. In contrast to the disease spectrum of adult AI cases, NB is the most common tumor type among children with AI, and benign cortical adenomas, which account for the vast majority of adult AI, accounting for less than 0.5% of cases in children [6]. According to several guidelines, urgent assessment of an AI is recommended in children because of a greater likelihood of malignancy [3, 7]. When an adult patient is initially diagnosed with AI, it should be clear whether the lesion is malignant and functional. In several studies, the use of noncontrast CT has been recommended as the initial imaging method for adrenal incidentaloma; a CT attenuation value ≤ 10 HU is used as the diagnostic criterion for benign adenomas; and these methods have a specificity of 71-79% and a sensitivity of 96-98% [8, 9]. A CT scan of tumors with diameters greater than 4 to 6 cm, irregular margins or heterogeneity, a CT attenuation value greater than 10 HU, or a relative contrast enhancement washout of less than 40% 10 or 15 min after administration of contrast media on enhanced CT is considered to indicate potential malignancy [7]. As the most common AI in children, NB often appears as a soft tissue mass with uneven density on CT, often accompanied by high-density calcified shadows, low-density cystic lesions or necrotic areas. CT scans can easily identify more typical NBs, and for those AIs that do not show typical calcified shadows on CT, it is sometimes difficult to differentiate neurogenic tumors from adenomas. In these patients, except for the 1 patient with adrenal cysts who had a CT value of 8 HU, very few of the remaining AI patients had a CT value less than 10 HU. Therefore, the CT value cannot be used simply as a criterion for determining the benign or malignant nature of AI, and additional imaging examinations, such as CT enhancement, MRI, and FDG-PET if necessary, should be performed immediately for AI in children. Initial hormonal testing is also needed for functional assessment, and aldosterone secretion should also be assessed when the patient is hypertensive or hypokalemic [7]. Patients with AI who are not suitable for surgery should be observed during the follow-up period, and if abnormal adrenal secretion is detected or suggestive of malignancy during this period, prompt adrenal tumor resection is needed. For adult patients with AI, laparoscopic adrenal tumor resection is one of the most effective treatments that has comparative advantages in terms of hospitalization time and postoperative recovery speed; however, there is still some controversy over whether to perform laparoscopic surgery for some malignant tumors with large diameters, especially adrenocortical carcinomas, and some studies have shown that patients who undergo laparoscopic surgery are more prone to peritoneal seeding of tumors [10]. The maximum diameter of an adult AI is a predictor of malignancy, and a study by the National Italian Study Group on Adrenal Tumors, which included 887 AIs, showed that adrenocortical carcinoma was significantly correlated with the size of the mass, and the sensitivity of detecting adrenocortical carcinoma with a threshold of 4 cm was 93% [11]. According to the National Institutes of Health, patients with tumors larger than 6 cm should undergo surgical treatment, while patients with tumors smaller than 4 cm should closely monitored; for patients with tumors between 4 and 6 cm, the choice of whether to be monitored or surgically treated can be based on other indicators, such as imaging [12]. A diameter of 4 cm is not the initial threshold for determining the benign or malignant nature of a mass in children. In a study of 26 children with AI, Masiakos et al. reported that 9 of 18 benign lesions had a maximal diameter less than 5 cm, 4 of 8 malignant lesions had a maximal diameters less than 5 cm, and 2 had a diameter less than 3 cm. The mean maximal diameter of benign lesions was 4.2 ± 1.7 cm, whereas the mean maximum diameter of malignant lesions was 5.1 ± 2.3 cm. There was no statistically significant difference between the two comparisons; therefore, this study concluded that children with AI diameters less than 5 cm cannot be treated expectantly [6]. Additionally, this study revealed that malignant lesions occurred significantly more frequently than benign lesions in younger children (mean age 1.7 ± 1.8 years v 7.8 ± 5.9 years; P = 0.02). In the nonneonatal group of this study, 20 patients with malignant tumors had maximum diameters ranging from 20 to 131 mm, 10 had malignant tumors larger than 60 mm, and 3 had tumors smaller than 40 cm; 18 patients with benign tumors had maximum diameters ranging from 17 to 70 mm, 5 had diameters ranging from 40 to 60 mm, and 5 had diameters larger than 60 mm. Therefore, it is not recommended to use the size of the largest diameter of the tumor to decide whether to wait and observe or intervene surgically for children with AI. Instead, it is necessary to consider the age of the child; laboratory test results, such as whether the tumor indices are elevated or not; whether the tumor has an endocrine function; etc.; and imaging test results to make comprehensive judgments and decisions. Preoperative aggressive evaluation and prompt surgical treatment are recommended for nonneonatal pediatric AI patients. Adrenal hematoma and NBs are the most common types of adrenal area masses in children, while pheochromocytoma, adrenal cyst, and teratoma are rarer masses [13]. In clinical practice, adrenal hematoma and NB are sometimes difficult to differentiate, especially when adrenal masses are found during the prenatal examination and neonatal period, and such children need to be managed with caution. The Children’s Oncology Group (COG ANBL00B1) implemented the watchful waiting treatment for children under 6 months of age with a solid adrenal mass < 3.1 cm in diameter (or a cystic mass < 5 cm) without evidence of distant metastasis, and if there is a > 50% increase in the adrenal mass volume, there is no return to the baseline VMA or HVA levels, or if there is a > 50% increase in the urinary VMA/HVA ratio or an inversion, surgical resection should be performed [14]. Eighty-three children in this study underwent expectant observation, 16 of whom ultimately underwent surgical resection (8 with INSS stage 1 NB, 1 with INSS stage 2B, 1 with INSS stage 4 S, 2 with low-grade adrenocortical neoplasm, 2 with adrenal hemorrhage, and 2 with extralobar pulmonary sequestration). Most of the children who were observed had a reduced adrenal mass volume. Of the 56 patients who completed the final 90 weeks of expectant observation, 27 (48%) had no residual mass, 13 (23%) had a residual mass volume of 0–1 ml, 8 (14%) had a mass volume of 1–2 ml, and 8 (14%) had a volume of > 2 ml; ultimately, 71% of the residual masses had a volume ≤ 1 ml and 86% had a residual volume ≤ 2 ml. In this study, a total of 16 patients were included in the watchful waiting treatment group; 3 patients underwent surgical treatment during the follow-up period, and 13 patients ultimately completed watchful waiting treatment. After 1–31 months of follow-up, 8 patients’ swelling completely disappeared, and 5 patients’ swelling significantly decreased. After strict screening for indications and thorough follow-up review, AIs in the neonatal period can be subjected to watchful waiting treatment, and satisfactory results can be achieved. For benign adrenal tumors, laparoscopic surgery is superior to open surgery in terms of successful resection, whereas the feasibility of minimally invasive surgery for AI with preoperative suspicion of malignancy is controversial. The European Cooperative Study Group for Pediatric Rare Tumors recommends that minimally invasive surgery be considered only for early childhood tumors and should be limited to small, localized tumors; additionally, imaging should suggest no invasion of surrounding tissue structures or lymph nodes; and this strategy requires surgeons with extensive experience in oncologic and adrenal surgery [15]. NB is the most common pediatric AI, and open tumor resection remains the mainstay of treatment. For small, early tumors without evidence of invasion on preoperative examination, laparoscopic resection may be considered if the principles of oncologic surgery can be adhered to. If the patient responds to chemotherapy, the decision to perform laparoscopic tumor resection can also be re-evaluated after chemotherapy. According to the current study, the recurrence and mortality rates of laparoscopic surgery are comparable to those of open surgery [16, 17]. The relative contraindications for laparoscopic NB resection include a tumor diameter greater than 6 cm, venous dilatation, and the involvement of adjacent organs or blood vessels [18]. Patients who undergo open adrenalectomy have higher overall survival and recurrence-free survival rates than patients who undergo laparoscopic adrenalectomy [19]. Open adrenalectomy remains the gold standard for surgical resection of adrenocortical carcinoma, whereas laparoscopic adrenalectomy should be reserved for highly selected patients and performed by surgeons with appropriate expertise [20]. Cortical tumors are particularly rare among children with AIs and are sometimes not clearly distinguishable from neurogenic tumors on preoperative imaging; in such patients, the presence of subclinical Cushing’s syndrome needs to be carefully evaluated preoperatively; otherwise, a perioperative adrenal crisis may occur [21]. In patients in whom the possibility of an adrenocortical tumor was considered preoperatively, the assessment for subclinical Cushing’s syndrome mainly involved assessing the serum dehydroepiandrosterone sulfate level and performing an overnight dexamethasone suppression test. A procedure for evaluating pediatric AI is shown in Fig. 1. Imaging is the first step in the evaluation of AI in children. CT can be used to clarify the nature of most tumors. MRI can be used to evaluate imaging risk factors (IDRFs) for NB. Bone marrow cytomorphology is recommended for all children with AI, along with microscopic residual neuroblastoma testing and further bone scanning if the bone marrow examination is positive. In addition, serum tumor marker levels and other relevant tests should be performed, and hormone levels should be evaluated. If adrenal adenomas cannot be completely excluded during the preoperative examination, a 1 mg overnight dexamethasone suppression test should be performed to exclude subclinical Cushing’s syndrome. In patients with hypertensive hypokalemia, the presence of aldosteronism should be evaluated by testing plasma aldosterone concentrations and plasma renin activity. Adrenal masses found in the neonatal period can be observed if the tumor is small, confined to the adrenal gland and shows no evidence of distant metastasis, while tumors that increase significantly in size during the follow-up period or that are associated with persistently elevated tumor markers require aggressive surgical treatment. Fig. 1 Algorithm for the evaluation and management of a pediatric adrenal incidentaloma. *DST overnight :20µg/kg dexamethasoneweight ˂40 kg,1 mg dexamethasone if ≥ 40 kg. CT = computed tomographic;MRI = magnetic resonance imaging;NSE = neuron-specific enolase;AFP = alpha-fetoprotein;CEA = carcinoembryonic antigen;CA19-9 = cancerantigen19-9;ACTH = adrenocorticotropic hormone;PAC = plasma aldosterone concentration; PRA = plasma renin activity;DST = dexamethasone suppression test Full size image Data availability The datasets analyzed during the current study are not public, but are available from the corresponding author on reasonable request. Abbreviations CT: computed tomographic MRI: magnetic resonance imaging ACTH: adrenocorticotropic hormone VMA: vanillylmandelic acid HVA: homovanillic Acid AFP: alpha-fetoprotein CEA: carcinoembryonic antigen NSE: neuron-specific enolase CA19-9: cancerantigen19-9 FH: favorable histology HU: Hounsfiled Unit COG: Children’s Oncology Group INSS: International Neuroblastoma Staging System References Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol. 2003;149(4):273–85. Article CAS PubMed Google Scholar Maas M, Nassiri N, Bhanvadia S, Carmichael JD, Duddalwar V, Daneshmand S. Discrepancies in the recommendedmanagement of adrenalincidentalomas by variousguidelines. J Urol. 2021;205(1):52–9. Article PubMed Google Scholar Fassnacht M, Tsagarakis S, Terzolo M, et al. 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Int J Urol. 2023;30(10):818–26. Article CAS PubMed Google Scholar Download references Acknowledgements We would like to express our deepest gratitude to all the patients and their parents who participated in this study. Their patience and cooperation were instrumental to the success of this research. We thank our colleagues in the Department of Radiology for their invaluable contributions in diagnosing and monitoring the progression of adrenal incidentalomas. We sincerely appreciate the hard work of the pathologists in diagnosing and classifying tumors, which laid the foundation for our study. Finally, we would like to thank our institution for providing the necessary resources and an enabling environment to conduct this research. Funding Not applicable. Author information Authors and Affiliations Department of Urology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, Jiangsu, China Xiaojiang Zhu, Saisai Liu, Yimin Yuan, Nannan Gu, Jintong Sha, Yunfei Guo & Yongji Deng Contributions X.J.Z. and Y.J.D designed the study; S.S.L., Y.M.Y., N.N.G., and J.T.S. carried out the study and collected important data; X.J.Z. analysed data and wrote the manuscript; Y.F.G. and Y.J.D.gave us a lot of very good advices and technical support; All authors read and approved the final manuscript. Corresponding author Correspondence to Yongji Deng. Ethics declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate Ethics approval for this study was granted by the Ethics Committee of Children’s Hospital of Nanjing Medical University. Informed written consent was obtained from all the guardians of the children and we co-signed the informed consent form with their parents before the study. We confirmed that all methods were performed in accordance with relevant guidelines and regulations. Conflict of interest There are no conflicts of interest. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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  14. This article costs $70 to buy https://doi.org/10.1136/bcr-2024-259687 Doctors should suspect Cushing’s syndrome when they see patients with purple stretch marks and metabolic conditions such as diabetes, even if those symptoms aren’t the reasons for a medical visit, physicians in Japan wrote in a case study describing how they reached that diagnosis for a woman in her early 30s.
  15. Abstract Purpose To assess coronary inflammation by measuring the volume and density of the epicardial adipose tissue (EAT), perivascular fat attenuation index (FAI) and coronary plaque burden in patients with Cushing’s syndrome (CS) based on coronary computed tomography angiography (CCTA). Methods This study included 29 patients with CS and 58 matched patients without CS who underwent CCTA. The EAT volume, EAT density, FAI and coronary plaque burden were measured. The high-risk plaque (HRP) was also evaluated. CS duration from diagnosis, 24-h urinary free cortisol (UFC), and abdominal visceral adipose tissue volume (VAT) of CS patients were recorded. Results The CS group had higher EAT volume (146.9 [115.4, 184.2] vs. 119.6 [69.0, 147.1] mL, P = 0.006), lower EAT density (− 78.79 ± 5.89 vs. − 75.98 ± 6.03 HU, P = 0.042), lower FAI (− 84.0 ± 8.92 vs. − 79.40 ± 10.04 HU, P = 0.038), higher total plaque volume (88.81 [36.26, 522.5] vs. 44.45 [0, 198.16] mL, P = 0.010) and more HRP plaques (7.3% vs. 1.8%, P = 0.026) than the controls. The multivariate analysis suggested that CS itself (β [95% CI], 29.233 [10.436, 48.03], P = 0.014), CS duration (β [95% CI], 0.176 [0.185, 4.242], P = 0.033), and UFC (β [95% CI], 0.197 [1.803, 19.719], P = 0.019) were strongly associated with EAT volume but not EAT density, and EAT volume (β [95% CI] − 0.037[− 0.058, − 0.016], P = 0.001) not CS was strongly associated with EAT density. EAT volume, FAI and plaque burden increased (all P < 0.05) in 6 CS patients with follow-up CCTA. The EAT volume had a moderate correlation with abdominal VAT volume (r = 0.526, P = 0.008) in CS patients. Conclusions Patients with CS have higher EAT volume and coronary plaque burden but less inflammation as detected by EAT density and FAI. The EAT density is associated with EAT volume but not CS itself. From https://link.springer.com/article/10.1007/s40618-023-02295-x This is a preview of subscription content, log in via an institution to check access.
  16. Cushing’s syndrome (CS) secondary to adrenocorticotropic hormone (ACTH) producing tumours is a severe condition with a challenging diagnosis. Ectopic ACTH-secretion often involves neuroendocrine tumours (NET) in the respiratory tract. ACTH-secreting small intestine neuro-endocrine tumours (siNET) are extremely rare entities barely reported in literature. This review is illustrated by the case of a 75-year old woman with fulminant ectopic CS caused by a ACTH-secreting metastatic siNET. Severe hypokalemia, fluid retention and refractory hypertension were the presenting symptoms. Basal and dynamic laboratory studies were diagnostic for ACTH-dependent CS. Extensive imaging studies of the pituitary and thorax-abdomen areas were normal, while [68Ga]Ga-DOTATATE PET-CT revealed increased small intestine uptake in the left iliac fossa. The hypercortisolism was well controlled with somatostatin analogues, after which a debulking resection of the tumour was performed. Pathological investigation confirmed a well-differentiated NET with sporadic ACTH immunostaining and post-operative treatment with somatostatin analogues was continued with favourable disease control. © Acta Gastro-Enterologica Belgica. ABOUT THE CONTRIBUTORS B alliet, c severi, t veekmans, j cuypers, h topal, c m deroose, t roskams, m bex, j dekervel B Alliet Department of Gastroenterology, UZ Leuven, Leuven, Belgium. C Severi Department of Gastroenterology, ZOL, Genk, Belgium. T Veekmans Department of Pathology, UZ Leuven, Leuven, Belgium. J Cuypers Department of Endocrinology, AZ Turnhout, Turnhout, Belgium. H Topal Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium. C M Deroose Department of Nuclear Medicine, UZ Leuven, Leuven, Belgium. T Roskams Department of Pathology, UZ Leuven, Leuven, Belgium. M Bex Department of Endocrinology, UZ Leuven, Leuven, Belgium. J Dekervel Department of Gastroenterology – Digestive Oncology, UZ Leuven, Leuven, Belgium. From https://www.physiciansweekly.com/fulminant-ectopic-cushings-syndrome-caused-by-metastatic-small-intestine-neuroendocrine-tumour-a-case-report-and-review-of-the-literature/
  17. Highlights Phaeochromocytoma with ectopic ACTH secretion. Its clinical presentation is varied, and diagnosis is challenging. Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing’s syndrome. Removal of the primary tumour often leads to full recovery. Abstract Introduction The occurrence of hypercortisolism resulting from adrenocorticotropic hormone (ACTH)-secreting pheochromocytoma is exceedingly uncommon, with limited documented instances thus far. Presentation of case We present a case of ectopic ACTH-secreting pheochromocytoma in a patient who suffered from severe metabolic disorders. Our clinical case outlines the diagnostic history, preoperative correction of the patient's metabolic disturbances and surgical strategy for management of a rare ectopic ACTH producing pheochromocytoma. Discussion Ectopic adrenocorticotropic hormone-secreting pheochromocytoma displays multifaceted clinical features and requires prompt diagnosis and multidisciplinary management in order to overcome the related severe clinical derangements. Conclusion The combination of biochemical and hormonal testing and imaging procedures is mandatory for the diagnosis of ectopic ACTH secretion, and in the presence of an adrenal mass, the possibility of an ACTH-secreting pheochromocytoma should be taken into account. Keywords Hypokalemia Adrenal gland Pheochromocytoma Ectopic cushing's syndrome Cushing's syndrome 1. Introduction Neuroendocrine tumors such as Pheochromocytoma and paraganglioma (PPGL) are an uncommon occurrence. The prevalence of PPGL has been estimated to be between (2–8)/1 million, with a population rate of 1:2500–1:6500 [1], and it is associated with symptoms such as headache, irregular heartbeats, profuse sweating, high blood pressure, nausea, vomiting, nervousness, irritability, and a sense of imminent mortality [2]. Hypercortisolism is also a rare disorder with an incidence of 5/1 million, <10 % of patients with hypercortisolism are caused by ectopic secretion of ACTH [3], and these are most commonly seen in APUD tumors such as small cell bronchopulmonary carcinoma, pancreatic islet carcinoma, medullary thyroid carcinoma, pheochromocytoma, and melanoma [4]. Tumors that secrete both ACTH and catecholamines are much rarer. Here, we present a case of ectopic ACTH-secreting pheochromocytoma with severe metabolic disorders. The case report is compliant with SCARE Guidelines [5]. 2. Case report The patient is a 46-year-old male who presented to our hospital with recurrent symptoms of pheochromocytoma. He reported that he experienced unexplained symptoms such as panic attacks, headache, sweating, nausea, vomiting, and a feeling of imminent death, which could be alleviated by rest. His blood pressure was around 160–220/110–120 mmHg, and he was taking oral antihypertensive drugs regularly, with poor control of his blood pressure. The patient was admitted with a body temperature of 36.7 °C, heart rate of 130 beats/min, respiratory rate of 20 cycles per minute, blood pressure of 138/88 mmHg, height of 175 cm, weight of 67 kg, Body Mass Index (BMI): 21.88, normal physical examination, emaciated body type, thin subcutaneous fat, self-reported weight loss of 20 kg within 10 months, and history of diabetes mellitus of >1 year. Laboratory tests showed that the blood potassium levels were within the normal range, while the blood sugar and beta-hydroxybutyrate levels were elevated (Table 1). Hormonal analysis showed plasma levels of free catecholamine and its metabolites were much higher than normal, in addition to a severe excess of cortisol secretion with circadian rhythm disorders and elevated serum ACTH (Table 2). Small dose dexamethasone suppression test (1 mg) yielded cortisol levels of over 1750 nmol/L (negative: no decrease in blood cortisol), thus confirming the presence of ACTH-dependent hypercortisolism. The results of electrocardiogram, chest computerized tomography (CT), cardiac ultrasound and thyroid ultrasound showed no obvious abnormality. Enhanced CT of the adrenal glands (Fig. 1) revealed the presence of a right adrenal tumor measuring approximately 5.3 ∗ 4.7 cm. Despite undergoing cranial MRI, no pituitary lesion was detected, thereby ruling out the possibility of Cushing's disease. The patient was further considered for possible ectopic ACTH syndrome and suspected ectopic ACTH-secreting pheochromocytoma. Table 1. Laboratory test results. Laboratory test Result Reference value Unit White blood cell 17.03 3.5–9.5 109/L Red blood cell 5.06 3.8–5.1 1012/L Hemoglobin 147 115–150 g/L Platelets 206 125–350 109/L Glucose 12.13 3.9–6.1 mmol/L β-Hydroxybutyric acid 8.680 0–0.30 mmol/L Creatinine 55.30 40–105 umol/L Calcium 2.47 2.2–2.7 mmol/L Phosphate 1.26 0.85–1.51 mmol/L Potassium 3.66 3.5–5.5 mmol/L Sodium 147.1 137–147 mmol/L Table 2. The patient's adrenal hormone results Empty Cell Preoperative Postoperative Reference value Unit Norepinephrine, free 11,900 118 217–1109 pg/ml Adrenaline, free 3940 <24 <95 pg/ml Dopamine 207 <18 <20 pg/ml Methoxy norepinephrine 4130 87.80 <145 pg/ml Methoxy adrenaline 1850 <12 <62 pg/ml Adrenocorticotropic hormone (8:00) 544 10.60 7.2–63.3 pg/ml Cortisol (8:00) >1750 246.00 166–507 nmol/L Adrenocorticotropic hormone (16:00) 647 33.50 – pg/ml Cortisol (16:00) >1750 536.00 73.8–291 nmol/L Adrenocorticotropic hormone (00:00) 566 – – pg/ml Cortisol (00:00) >1750 – nmol/L Renin 2.82 3.10 2.4–32.8 pg/ml Aldosterone 81.51 73.56 16–160 pg/ml Aldosterone/renin concentration ratio 28.90 23.73 0–25 Download : Download high-res image (184KB) Download : Download full-size image Fig. 1. Adrenal CT showed a 53 ∗ 47 mm mass in the right adrenal gland. In response to the patient's pheochromocytoma symptoms and improve preoperative preparation, we used α-blocker (Phenoxybenzamine 20 mg q8h) to lower blood pressure and increase blood volume, antihypertensive medication (nifedipine 30 mg q12h, olmesartan tablets 20 mg q12h) to assist in lowering blood pressure, and β-blocker (metoprolol 47.5 mg q12h) to control the heart rate. On the 4th day in hospital, the patient was lethargic and had weak limbs. Urgent blood workup showed severe hypokalemia (2.85 mmol/L) as well as hyperglycemia (10.26 mmol/L). Patient was transferred to intensive care to correct intractable hypokalemia and diabetic ketoacidosis. After the patient was transferred to ICU, a deep vein cannulation was performed with intravenous potassium chloride supplementation, and the patient's blood potassium was maintained at normal levels prior to surgery through a large amount of potassium supplementation (Fig. 2A). For diabetic ketoacidosis, insulin administration, rehydration, ketone elimination and other treatments were given and the amount of access was recorded, and it was found that the patient was polyuric, with the highest urine volume of 21,800 ml in a single day (Fig. 2B), and the amount of urine did not decrease by taking oral desmopressin tablets 0.1 mg bid. Download : Download high-res image (255KB) Download : Download full-size image Fig. 2. Changes in blood potassium and urine volume during the patient's hospitalization. A: Blood potassium level. B: Daily urine vlume. Eventually, the patient underwent laproscopic right adrenal tumor resection. Intraoperative changes in blood pressure and heart rate are shown in Fig. 3. On day 1 after surgery, the morning (8:00) ACTH level was 10.60 pg/ml, antihypertensive medications were discontinued, and his blood pressure was 100–120/60–90 mmHg. The patient's daily urine output and blood glucose gradually returned to normal levels after surgery. Pathology (Fig. 4😞 Adrenal pheochromocytoma with ACTH immunopositive staining, cellular heterogeneity was unremarkable, nuclear schizophrenic images were rare, no pericytes, choroidal invasion and necrosis were seen. The patient was discharged from the clinic in a satisfactory condition with adrenal insufficiency compensated by daily intake of Prednisone Acetate Tablets (20 mg), discontinued 6 months after surgery. No signs of recurrence were noted upon frequent follow-up examinations. Download : Download high-res image (295KB) Download : Download full-size image Fig. 3. Changes in patient's intraoperative blood pressure and heart rate. Download : Download high-res image (313KB) Download : Download full-size image Fig. 4. Immunohistochemistry. A: hematoxylin and eosin staining B: ACTH. 3. Discussion We share the management of a patient with ectopic ACTH-secreting pheochromocytoma with severe metabolic disturbances, where, in addition to the rare etiology, perioperative management of the clinical complications of catecholamines and hypercortisolism is very challenging [6]. Patients suffering from ectopic ACTH syndrome caused by pheochromocytoma commonly exhibit severe Cushing's syndrome (CS), significant diabetes mellitus, hypertension, and hypokalemia [7]. Additionally, a retrospective study revealed that the majority of patients presented with Cushing's syndrome [8], whereas another report indicated that only 30 % of patients presented with typical Cushing's syndrome, but weight loss was frequently observed [9]. Our patient's recent weight loss may be attributed to the body's hypermetabolic condition caused by catecholamines. Recent reports claim that catecholamines directly reduce subcutaneous and visceral fat [10]. Rapid onset of cortisolism appears to be a feature of ACTH-secreting pheochromocytomas, because of the rapid onset of severe hypercortisolism, and our patient did not exhibit typical Cushing's symptoms [8]. Despite the absence of typical Cushing-like symptoms, this patient displayed persistent hypokalemia, a prevalent metabolic manifestation of Cushing's syndrome, particularly in ectopic ACTH syndrome, where hypokalemia is observed in 74 %–95 % of patients, in contrast to 10 % of patients with Cushing's disease [11]. Glucocorticoids have the ability to interact with aldosterone receptors, resulting in specific aldosterone-like reactions, while ectopic ACTH syndrome typically generates a higher amount of cortisol compared to Cushing's disease, ultimately causing more pronounced hypokalemia [7]. The perioperative management of patients with ACTH-secreting pheochromocytomas poses a significant challenge due to severe hypokalemia, and our patient's potassium levels remained within the normal range through extensive central venous potassium supplementation, without the need for cortisol secretion inhibition medications. The severity of hypertension in patients with ACTH-secreting pheochromocytomas seems to surpass that of patients with pheochromocytomas alone [12]. Hypercortisolism amplifies catecholamine-induced hypertension [13]. In the case of hypertension in patients with pheochromocytomas, alpha-blockers are favored for reducing blood pressure and enlarging blood volume, while for individuals whose blood pressure is not adequately managed with alpha-blockers alone, a combination of medications is recommended. Proper preoperative readiness for expanding the volume is crucial for a successful surgical procedure. Patients with ACTH-secreting pheochromocytoma have a greater prevalence and intensity of diabetes mellitus compared to those with pheochromocytoma alone [14], and our patient displayed a combination of severe diabetes mellitus and ketoacidosis. Insulin exhibits swift action and adaptable dosage, effectively averting hypoglycemia and effectively addressing hyperglycemia, rendering it the preferred medication for regulating blood glucose levels in individuals with ectopic CS [6]. Managing the water-electrolyte balance in this patient proved to be an arduous task, and the diabetes insipidus may have been one of the complications, with a maximum urine output of 21,800 ml in a single day (Fig. 2), and we hold the belief that the patient's diabetes insipidus is caused by a range of factors, such as hypokalemia, hypercortisolism, and severe diabetes mellitus. Indeed, hypokalemia may cause renal impairment, which reduces the ability to concentrate urine and lack of response to antidiuretic hormone (ADH), leading to nephrogenic diabetes insipidus [15]. Cortisol increases renal plasma flow and glomerular filtration rate, and also inhibits the secretion of antidiuretic hormone, leading to neurogenic diabetes insipidus [16]. For hypercortisolism, surgery to target the cause is the first-line treatment, and surgical removal of primary tumor may lead to 40 % radical treatment and 80 % complete remission of ectopic ACTH syndrome [17]. 4. Conclusion Preoperative diagnosis and management of pheochromocytoma, an extremely rare cause of ectopic ACTH syndrome, is challenging. Proper preoperative recognition of complications of both hypercortisolism and catecholamines excess is the key to prevent the morbidity and mortality of an ACTH-producing pheochromocytoma. If diagnosed successfully and managed intensively, they are curable. Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Ethical approval Shandong Provincial Hospital Affiliated to Shandong First Medical University does not require ethical approval for publication of case reports. Signed consent from the patient has been received. Funding No funding was received for this research. Author contribution Shangjian Li: study concept or design, data collection, data analysis or interpretation, writing the paper Xudong Guo: study concept or design, data collection, data analysis or interpretation, writing the paper Hanbo Wang: study concept or design, data analysis or interpretation Ni Suo: study concept or design, data analysis or interpretation Xiuqing Mi: study concept,data collection Shaobo Jiang: study concept or design, data analysis or interpretation, writing the paper Guarantor Shangjian Li Xudong Guo Shaobo Jiang Conflict of interest statement All authors declare no conflict of interest. Acknowledgements None. References [1] A. Jain, R. Baracco, G. Kapur Pheochromocytoma and paraganglioma-an update on diagnosis, evaluation, and management Pediatr. Nephrol., 35 (2020), pp. 581-594 View article CrossRefView in ScopusGoogle Scholar [2] F.A. Farrugia, A. Charalampopoulos Pheochromocytoma Endocr. Regul., 53 (2019), pp. 191-212 View article CrossRefView in ScopusGoogle Scholar [3] M. Gadelha, F. Gatto, L.E. Wildemberg, et al. Cushing’s syndrome Lancet, 402 (2023), pp. 2237-2252 View PDFView articleView in ScopusGoogle Scholar [4] O. Ragnarsson, C.C. Juhlin, D.J. Torpy, et al. A clinical perspective on ectopic Cushing’s syndrome Trends Endocrinol. Metab. (2023) Google Scholar [5] C. Sohrabi, G. Mathew, N. Maria, et al. The SCARE 2023 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg., 109 (2023), pp. 1136-1140 View article CrossRefView in ScopusGoogle Scholar [6] M.F. Birtolo, E.M. Grossrubatscher, S. Antonini, et al. Preoperative management of patients with ectopic Cushing’s syndrome caused by ACTH-secreting pheochromocytoma: a case series and review of the literature J. Endocrinol. Investig., 46 (2023), pp. 1983-1994 View article CrossRefView in ScopusGoogle Scholar [7] J.N. Gabi, M.M. Milhem, Y.E. Tovar, et al. Severe Cushing syndrome due to an ACTH-producing pheochromocytoma: a case presentation and review of the literature J Endocr Soc, 2 (2018), pp. 621-630 View article CrossRefView in ScopusGoogle Scholar [8] P.F. Elliott, T. Berhane, O. Ragnarsson, et al. Ectopic ACTH- and/or CRH-producing pheochromocytomas J. Clin. Endocrinol. Metab., 106 (2021), pp. 598-608 View article CrossRefView in ScopusGoogle Scholar [9] J.E. Paleń-Tytko, E.M. Przybylik-Mazurek, E.J. Rzepka, et al. Ectopic ACTH syndrome of different origin-diagnostic approach and clinical outcome. Experience of one clinical centre PLoS One, 15 (2020), Article e0242679 View article CrossRefView in ScopusGoogle Scholar [10] L.N. Krumeich, A.J. Cucchiara, K.L. Nathanson, et al. Correlation between plasma catecholamines, weight, and diabetes in pheochromocytoma and paraganglioma J. Clin. Endocrinol. Metab., 106 (2021), pp. e4028-e4038 View article CrossRefGoogle Scholar [11] J. Young, M. Haissaguerre, O. Viera-Pinto, et al. Management of endocrine disease: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion Eur. J. Endocrinol., 182 (2020), pp. R29-r58 View article CrossRefView in ScopusGoogle Scholar [12] H. Falhammar, M. Kjellman, J. Calissendorff Initial clinical presentation and spectrum of pheochromocytoma: a study of 94 cases from a single center Endocr. Connect., 7 (2018), pp. 186-192 View article CrossRefView in ScopusGoogle Scholar [13] E.L. Alba, E.A. Japp, G. Fernandez-Ranvier, et al. The Mount Sinai clinical pathway for the diagnosis and management of hypercortisolism due to ectopic ACTH syndrome J Endocr Soc, 6 (2022), Article bvac073 View in ScopusGoogle Scholar [14] L. Foppiani, M.G. Poeta, M. Rutigliani, et al. Catastrophic ACTH-secreting pheochromocytoma: an uncommon and challenging entity with multifaceted presentation Endocrinol. Diabetes Metab. Case Rep., 2023 (2023) Google Scholar [15] S. Khositseth, P. Uawithya, P. Somparn, et al. Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus Sci. Rep., 5 (2015), Article 18311 View PDF This article is free to access. View in ScopusGoogle Scholar [16] M.M. Hammami, N. Duaiji, G. Mutairi, et al. Case report of severe Cushing’s syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration BMC Cancer, 15 (2015), p. 624 View PDF This article is free to access. View in ScopusGoogle Scholar [17] A. Ferriere, A. Tabarin Cushing’s syndrome: treatment and new therapeutic approaches Best Pract. Res. Clin. Endocrinol. Metab., 34 (2020), Article 101381 View PDFView articleView in ScopusGoogle Scholar From https://www.sciencedirect.com/science/article/pii/S2210261224001226
  18. Abstract Context Patients with Cushing’s disease (CD) face challenges living with and receiving appropriate care for this rare, chronic condition. Even with successful treatment, many patients experience ongoing symptoms and impaired quality of life (QoL). Different perspectives and expectations between patients and healthcare providers (HCPs) may also impair well-being. Objective To examine differences in perspectives on living with CD between patients and HCPs, and to compare care goals and unmet needs. Design Memorial Sloan Kettering Pituitary Center established an annual pituitary symposium for pituitary patients and HCPs. Through anonymous pre-program surveys distributed at the 2020 and 2022 symposia, patients and HCPs answered questions related to their own sense, or perception of their patients’ sense, of hope, choice, and loneliness in the context of living with CD. Participants From 655 participants over two educational events, 46 patients with CD and 116 HCPs were included. Median age of both groups was 51 years. 78.3% of the patients were female vs. 53.0% of the HCPs. Results More patients than HCPs reported they had no choices in their treatment (21.7% vs. 0.9%, P < 0.001). More patients reported feeling alone living with CD than HCPs’ perception of such (60.9% vs. 45.5%, P = 0.08). The most common personal care goal concern for patients was ‘QoL/mental health,’ vs. ‘medical therapies/tumor control’ for HCPs. The most common CD unmet need reported by patients was ‘education/awareness’ vs. ‘medical therapies/tumor control’ for HCPs. Conclusions CD patients experience long term symptoms and impaired QoL which may in part be due to a perception of lack of effective treatment options and little hope for improvement. Communicating experiences and care goals may improve long term outcomes for CD patients. Introduction Patients with rare diseases face challenges receiving appropriate care. Cushing’s disease (CD), a condition associated with excess endogenous glucocorticoids due to an ACTH-secreting pituitary tumor, is a rare disease, occurring in 0.7 to 2.4 per million per year [1]. Patients with CD are at high risk for metabolic, cardiovascular, and psychiatric disease, in addition to long-term symptom burden and impaired quality of life (QoL), despite adequate treatment [1,2,3]. A critical aspect of effective patient care is communication and mutual understanding between healthcare provider (HCP) and patient. Patients with pituitary tumors experience significant anxiety associated with their diagnosis, in large part due to difficulties interacting with healthcare systems and limited communication of information [4]. Many pituitary patients express concern regarding the complexity of their care, and satisfaction improves with the delivery of more information by the HCP [4]. Patients with pituitary tumors, and CD specifically, require multidisciplinary care which necessitates effective communication in order to provide the best possible outcomes [5]. Similar to acromegaly patients [6], CD patients’ long-term well-being may be adversely affected by different perspectives and expectations between patients and HCPs, especially after treatment [7]. While HCPs primarily use biochemical data to define successful treatment, patients rely more on their symptoms and ability to regain normal functioning [7]. Despite achieving biochemical remission, CD patient perception of having persistent disease negatively impacts QoL [8]. In addition, 67.5% of Cushing’s syndrome patients report receiving insufficient information from their HCPs regarding the recovery experience after surgery despite the fact that all HCPs report providing this information [9]. Improved communication between HCPs and CD patients is vital to optimizing patients’ QoL and long term outcomes. Recently there has been a growing emphasis on the use of internet-based platforms for healthcare delivery and education [10]. With the goals of offering HCP and patient education and assessing pituitary patients’ needs, since 2019 the pituitary center at Memorial Sloan Kettering (MSK) has offered annual virtual educational programs for pituitary patients, caregivers, HCPs, and members of the pharmaceutical industry. For the current study, we gathered deidentified information from 2020 to 2022 MSK program participants on CD patients’ and HCPs’ attitudes about CD, related to their sense of hope, choice, and loneliness, through anonymous pre-program surveys. Our specific aims were to: (1) Assess differences in perspectives between patients’ and HCPs’ responses in the pre-program survey; (2) Compare patients’ and HCPs’ perceived care goals and unmet needs. Methods Educational program enrollment The MSK program was offered to patients with any type of pituitary tumor as well as HCPs, family members, caregivers, and members of industry. The role of the registrant as a patient, caregiver/family member, HCP, and/or member of industry was determined for all registrants of the virtual programs. Any patient with a pituitary tumor treated at our center and outside institutions, inclusive of patients at all points along their treatment journey, were invited to register for the virtual education program. HCPs, including endocrinologists, neurosurgeons, otolaryngologists, radiation oncologists, neurologists, ophthalmologists, neuro-oncologists, family medicine and internal medicine physicians, physicians in training and other allied health professionals who treat and manage patients with pituitary diseases were also invited to register. Invitations were sent through email to neuroendocrine experts and endocrinologists, patient support groups on social media, direct messaging to patients with pituitary tumors by their treating physicians and via patient databases, advertisements through endocrine societies, brochure/postcard mailing, and Eventbrite, a virtual platform for live events. Study participants Registrants from MSK virtual programs held on December 5, 2020, (n = 328) and April 9, 2022, (n = 327) were included in the pool of subjects, among which the qualifying participants were determined. Of the 655 total registrants from the 2020 and 2022 programs, 320 (48.9%) were patients or caregivers and 309 (47.2%) were HCPs (Fig. 1). Of the 147 providers (88 in 2020 and 59 in 2022) that attended and filled out a pre-program survey 31 were excluded from our analysis. Eight filled out surveys in both 2020 and 2022, 4 were members of industry, 3 did not fill out any responses, and 1 was not in the healthcare field. In addition, 12 providers had at least three fields missing in the survey and 3 had filled out two surveys for the same year, so they were also excluded. A total of 116 providers (72 from 2020 to 44 from 2022) were included in the analysis. Fig. 1 Enrollment flowchart Full size image Among the 320 pituitary patients who attended the programs (157 from 2020 to 163 from 2022), 53 identified as ‘patients with Cushing’s’ and submitted surveys (34 participants from 2020 to 19 from 2022). Seven patients were excluded from the 2022 surveys as they had also filled out surveys in 2020, leaving a final group of 46 patients who were included in the analysis. Virtual education programs For each program, there was a single day of live interactive programming, meaning that all participants attended at the same time. The programs were recorded and made available for several weeks as enduring material for registrants on an online website. After joint sessions in the morning, both programs consisted of two tracks in the afternoon: the ‘provider/clinical track’ and the ‘patient/caregiver track’. During the programs, an ongoing chat reeled through the virtual program which allowed patients to continually ask questions. Faculty experts answered these questions in written responses directly within the chat and/or in spoken responses during one of the live broadcasted Q&A sessions. Additionally, the programs both included panel discussions answering patient questions and moderated patient discussions with invited patient speakers. Study procedures Through anonymous pre-program surveys distributed at the 2020 and 2022 symposia, patients and HCPs answered questions related to their own sense, or perception of their patients’ sense, of hope, choice, and loneliness in the context of living with CD. This survey was developed by a multidisciplinary team and has been reported previously [11]. Demographic and clinical information was also assessed including year of diagnosis, prior treatments, and current medications (for patients) and specialty and practice type (for providers), as shown in Tables 1 and 2. Multiple-choice questions assessing patients’ attitudes toward their disease included possible answers of ‘I have no hope for improvement,’ ‘I have some hope for improvement,’ and ‘I have a lot of hope for improvement;’ and ‘I have no choice in my treatment,’ ‘I have some choices in my treatment,’ and ‘I have many choices in my treatment.’ Patients were also asked to respond ‘TRUE’ or ‘FALSE’ to the following statements: ‘I feel alone living with my Cushing’s,’ ‘Hearing the journeys of other patients helps me better understand my own,’ and ‘I feel anxious about my Cushing’s diagnosis.’ Table 1 Patient demographic data Full size table Table 2 Provider demographic data Full size table Multiple-choice questions assessing providers’ attitudes about their patients' Cushing’s included possible answers of ‘I have no hope for their improvement,’ ‘I have some hope for their improvement,’ and ‘I have a lot of hope for their improvement;’ and ‘my patients have no choice in their treatment,’ ‘my patients have some choices in their treatment,’ and ‘my patients have many choices in their treatment.’ Providers were also asked to respond ‘TRUE’ or ‘FALSE’ to the following statements: ‘my patients feel alone living with their Cushing’s,’ ‘Hearing the journeys of other patients helps will help my patients better understand their own,’ and ‘my patients feel anxious about their Cushing’s diagnosis.’ Additionally, patients were surveyed on care goals and unmet needs related to their treatment. Specifically, patients were asked, ‘What are the healthcare outcomes/goals that matter to you the most?’ and ‘What do you think are unmet needs for the diagnosis or treatment of your condition?’ The first question was intended to refer to the patient specifically, while the second question was meant to examine how the condition is treated in general. Survey responses were submitted as free text and subsequently grouped by the authors (AH and EBG) into nine different categories: (a) Quality of life (QoL)/Mental Health; (b) Medical Therapies/Tumor Control; (c) Education/Awareness; (d) Communications/Multidisciplinary Care; (e) Insurance/Access; (f) Fertility; (g) Controlling Comorbidities; (h) Support System and (i) none. Responses could receive multiple designations if applicable. AH coded the free text themes independently, then EBG reviewed each answer and corresponding grouping to confirm accuracy. If there was disagreement or confusion, coding from our prior work [11] was reviewed. HCPs were also surveyed on care goals and unmet needs related to their patient’s treatment. Providers were asked, ‘What are the healthcare outcomes/goals that matter to you the most?’ and ‘what do you think are unmet needs for the diagnosis or treatment of your patient’s condition?’ The first question was intended to refer to the provider and their goals related to Cushing’s, while the second question was meant to examine how the condition is treated in general. Survey responses were submitted as free text and subsequently grouped by the authors (AH and EBG) into nine different categories: (a) Quality of life (QoL)/Mental Health; (b) Medical Therapies/Tumor Control; (c) Education/Awareness; (d) Communications/Multidisciplinary Care; (e) Insurance/Access; (f) Fertility; (g) Controlling Comorbidities; (h) Support System and (i) none. Responses could receive multiple designations if applicable. Statistical analysis Descriptive statistics were presented as counts and percentages for categorical variables and as medians and interquartile range (IQR) for continuous variables. The Chi-square test or Fisher’s exact test was used to compare gender and survey responses between the CD patient group and the HCP group. All statistical tests were two-tailed, and a P-value of < 0.05 was considered statistically significant. SAS Software® (version 9.4; SAS Institute Inc., Cary, NC) was used for all analyses. Results Between the 2020 and 2022 events, there was combined representation from 25 different countries. A map and a full list of the countries is shown in Fig. 2. Fig. 2 Map of registrant locations. Locations (listed alphabetically): Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Greece, Hong Kong, India, Israel, Jamaica, Latvia, Malaysia, Netherlands, New, Zealand, Oman, Peru, Philippines, Qatar, Romania, Saudi Arabia, Singapore, UK, US Full size image From a total of 655 participants over two educational events, 46 patients with CD and 116 HCP caring for CD patients were included in the analysis. The demographic data of the patients and HCPs are outlined in Tables 1 and 2, respectively. Median age of the patients and HCPs was 51 years. 78.3% of the CD group was female vs. 53.0% of the HCP group (P = 0.003). CD patients ranged from newly diagnosed to being diagnosed 33 years prior. The HCPs who filled out the pre-program surveys were in practice for a mean duration of 18.5 years, with a range from 1 to 54 years. As shown in Table 1, CD patients had a mean duration of suspected active disease prior to diagnosis of 5.26 years, as defined by onset of CD symptoms until diagnosis, and a mean duration of disease since diagnosis of 5.9 years. 42 (91%) had undergone surgical treatment of their Cushing’s. For those who underwent surgery, the mean number of surgeries was 1.17 (range 0–4). 20% had received pituitary radiation. Overall, 31% of patients were on medical therapy for Cushing’s. Metyrapone was the most used CD therapy (in 11%), followed by ketoconazole (in 9%). Of those requiring pituitary hormone replacement, 34.8% had one pituitary hormone deficiency and 21.7% had multiple hormone deficiencies. Thyroid hormone replacement (37%) and adrenal replacement (30%) were the most common. As shown in Table 2, the majority of the HCPs were endocrinologists (72%) followed by neurosurgeons (9%) and nurses (8%). There was a total of 9 different specialties represented by the provider group. 16% of the providers worked in private practice, 16% were hospital based, and 16% worked in ‘unspecified clinical care.’ 38% of the providers practice type was ‘unspecified.’ Based on the pre-program survey responses, we identified different attitudes between patients and HCPs in several domains. Table 3 depicts pre-program survey responses from CD patients and HCPs assessing their attitudes about CD. 21.7% of patients reported they had no choices in their treatment, compared to 0.9% of HCPs (P < 0.001). Almost all HCPs (99.1%) reported that CD patients had least some choice in their management. In addition, less than half (45.7%) of patients reported they had a lot of hope for improvement whereas 71.3% of HCPs had a lot of hope for their patients’ improvement. Surprisingly, fewer CD patients reported feeling anxious about their diagnosis compared to HCPs’ perceived patient anxiety (65.2% vs 94.6%, P < 0.001). However, more patients tended to feel more alone living with CD than HCPs’ perception of such (60.9% vs. 45.5%, P = 0.08). Both CD patients and HCPs agreed that hearing the journeys of other CD patients would help patients better understand their own disease (97.8% vs 100%). Table 3 Patient and provider attitudes by pre-program survey Full size table CD patients and HCPs were also surveyed on their personal care goals and unmet needs, results of which are shown in Figs. 3A, B and 4A, B. The most common personal care goal concern for patients was ‘QoL/mental health’ which was reported by 70%, followed by ‘controlling comorbidities’ (39%) and ‘medical therapies/tumor control’ (24%). HCPs prioritized the same three care goals as patients but ‘medical therapies/tumor control’ was the most common (44%). ‘Controlling comorbidities’ and ‘QoL/mental health’ were the second and third most often HCP reported care goals (31 and 22% respectively). ‘Education/awareness’ was the most common perceived CD unmet need by patients (59%). HCPs reported both ‘medical therapies/tumor control’ and ‘education/awareness’ to be the most common unmet needs (35 and 26%, respectively). Examples of patient and provider responses, and how they were coded, are shown in Supplemental Table 1. Fig. 3 A Care goals according to participants with Cushing’s who completed pre-program survey. This pie graph represents the free-text survey response from patients regarding their personal care goals as categorized by topic. B Care goals according to providers who completed pre-program survey. This pie graph represents the free-text survey response from providers regarding their personal care goals as categorized by topic Full size image Fig. 4 A Unmet needs for the field of Cushing’s disease according to participants with Cushing’s who completed pre-program survey. This pie graph represents the free-text survey response from patients regarding unmet needs in Cushing’s as categorized by topic. B Unmet needs for the field of Cushing’s disease according to providers who completed pre-program survey. This pie graph represents the free-text survey response from providers regarding unmet needs in Cushing’s as categorized by topic Full size image Discussion This study examined the differences between patients and HCP-reported perceptions of living with CD. We identified several differences in disease outlook between CD patients and HCPs. We found that more patients than HCPs reported they had no choices in their treatment. Furthermore, less than half of patients reported they had a lot of hope for improvement whereas most (71.3%) of HCPs had a lot of hope for their patients’ improvement. Interestingly, fewer CD patients reported feeling anxious about their diagnosis compared to HCPs’ perceived patient anxiety, although a higher percentage of patients reported feeling alone living with CD compared to the HCPs’ perception of patient loneliness. We also identified HCP and patient differences in reported personal care goals and perceived unmet needs in the field. The most common personal care goal concern for patients was ‘QoL/mental health,’ whereas it was ‘medical therapies/tumor control’ for HCPs. ‘Education/awareness’ was the most commonly perceived unmet need by patients, whereas it was ‘medical therapies/tumor control’ for HCPs. Our findings support prior work demonstrating a discrepancy between patients and HCPs regarding the need for improved multidisciplinary care [12]. 43% of patients listed ‘communication/multidisciplinary care’ as an unmet need in the field, compared to 3% of providers. Pituitary centers of excellence provide expert multidisciplinary care in the neuroendocrine, neurosurgical, and radiation oncology domains, but often lack expertise in mental and physical health domains salient for CD patients, who suffer from depression, anxiety, myopathy and joint pain. In order to offer comprehensive care, psychiatrists, psychologists, social workers, pain medicine experts, physical therapists, and nutritionists with expertise in CD should be included in the pituitary center multidisciplinary team [13]. Our findings suggest that pituitary centers of excellence should take into account the most important personal care goal reported by CD patients, which is Qol/mental health, and provide expert treatment in this domain. It is not surprising that Qol/mental health is the personal care goal most reported by CD patients. Prior assessment of acromegaly patients demonstrated the same finding: QoL/mental health was the most common personal care goal concern [11]. While surgical [14] and medical [15,16,17,18] treatment of Cushing’s improves QoL, QoL has been shown to remain impaired over time after treatment [19]. Several factors may contribute to long-term Qol impairments, including the presence of persistent disease, imperfect treatment modalities which themselves may be associated with burden and adverse side effects, and persistent comorbidities including depression, anxiety, fatigue, and overweight. Perception of disease status may also play a role in QoL. In surgically remitted CD patients, there may be discordance between biochemical remission and perceived disease status [8]. Specifically, this study found that of those with self-identified persistence of disease, 65% were in fact biochemically remitted. This group had lower QoL scores than the concordant group who self-identified as in remission with biochemical evidence of remission. CD patients’ outlook on their condition, including their perception of choices and hope for change, has not been previously well described, despite the fact that these perceptions likely inform long term Qol. Patient outlook may be a modifiable target that if addressed, could improve long term patient well-being and outcomes. Aside from continuing progress in the development of new therapies for CD patients which can offer patients more objective choices in their treatment, other modalities should be considered. Prior work has shown that virtual educational programs improve acromegaly patients’ hope for improvement, perception of having choices in their treatment, and sense of loneliness [11]. Educational programs have also been shown to result in improved physical activity and sleep, and reduced pain levels in CS patients [20]. More work is needed to develop effective education programming tailored for CD patients to provide the appropriate support that these patients need. Difference in HCP and patient disease perceptions may also play a role in Cushing’s patients’ quality of life and outcomes. Among a cohort of patients who underwent surgical resection for Cushing’s, 32.4% reported not receiving information from their doctors about the recovery experience, despite the fact that all physicians surveyed reported giving information about the recovery process [9]. Furthermore, 16.1% of patients in this cohort reported that not enough medical professionals were familiar with the symptoms of Cushing’s. Recovery time was also reported to be longer by patients than providers [9]. Similarly, discordance was found between acromegaly patients and HCPs regarding reported severity of symptoms, with patients more frequently reporting symptoms as severe compared to HCPs, and many patients reporting symptoms which were not reported by HCPs [6]. Improving communication between HCP and patients may positively affect CD patient outlook and QoL. We identified a similar disparity between CD patients and HCP regarding care goals and unmet needs. 70% of patients surveyed considered QoL/mental health to be a top care goal, but only 22% of provider shared this goal. 59% of patients reported education/awareness as an unmet need, compared to 26% of HCPs. These findings support data shown by Acre et al. in which Cushing’s patients report a lack of symptom recognition by their providers [9]. HCPs should be aware that their patients may have different treatment priorities. Our finding that more HCPs reported patient anxiety living with CD compared to patients themselves needs further exploration. This could reflect inadequate communication between HCP and patient, or skewed HCP perceptions of CD. This, and other findings in our study should be viewed in light of the small cohort, and as such, needs confirmation in larger cohorts and more in-depth symptom assessments. Additional limitations of our study include lack of paired patient-HCP responses as the HCPs included were not providing care for this specific CD cohort. Since this was a pituitary educational forum, likely most or all patients who identified as having Cushing’s had CD. However, our survey did not specify the type of surgery patients underwent or the etiology of their Cushing’s. Additionally, we used multidisciplinary team agreed upon measures and not validated assessments. Further work should consider validating a tool to assess patient-provider discordances. Our findings may also be confounded by selection bias, given that the patients participating in our virtual education programs are more likely to be under the care of experts in the field and may not represent the attitudes of all patients living with CD. Finally, the included HCPs were representatives from a range of specialties with different levels of experience taking care of patients with CD which may also affect their responses. Our findings highlight the importance of understanding CD patients’ outlook and perspective in their condition, and that they may differ from their HCP. More than half of CD patients did not have a lot of hope for improvement and reported feeling alone, and many patients felt they had no choices in their treatment. QOL/mental health was the most commonly reported care goal for patients, which was not the case for HCPs. Comprehensive multidisciplinary care for CD patients should include mental health professionals with expertise in CD. Regular open communication between HCPs and CD patients will help bridge perception differences and facilitate personalized care, which will ultimately improve long-term outcomes for CD patients. Data availability The data that support the findings of this study are available from the authors upon request. References Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. 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Endocrine 53:199–209. https://doi.org/10.1007/s12020-015-0737-0 Article CAS PubMed Google Scholar Download references Acknowledgements The authors would like to thank the HCP and patient participants who attended the events, the MSK faculty, invited speakers, Leslie Edwin of Cushing’s Support and Research Foundation, Amy Edouard and the MSK CME team, and Recordati Rare Diseases, Inc., Amryt Pharma (previously Chiasma, Inc.), Crinetics, Sparrow Pharmaceuticals, Corcept Therapeutics, and Xeris Biopharma (previously Strongbridge Biopharma) for providing educational grants for these educational activities. Funding This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Author information Authors and Affiliations Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA Amanda Halstrom Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA I.-Hsin Lin Multidisciplinary Pituitary & Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA Andrew Lin, Marc Cohen, Viviane Tabar & Eliza B. Geer Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA Andrew Lin Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Andrew Lin, Marc Cohen & Eliza B. Geer Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Marc Cohen & Viviane Tabar Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Eliza B. Geer Contributions A.H. and E.B.G. wrote the manuscript text and prepared the figures. All authors reviewed the manuscript. Corresponding author Correspondence to Eliza B. Geer. Ethics declarations Competing interests The authors declare no competing interests. Ethical approval As an educational quality initiative project using de-identified data, it was determined that our project did not constitute human subjects research and thus did not require IRB oversight. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 15 kb) Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions From https://link.springer.com/article/10.1007/s11102-024-01381-4
  19. Highlights EAS should be considered in patients presenting with rapid progression of ACTH-dependent hypercortisolism causing severe clinical and metabolic abnormalities. Ectopic ACTH secretion by a pheochromocytoma should be suspected in cases of ACTH-dependent Cushing syndrome in the presence of an adrenal mass. If required, medical management with steroidogenesis inhibitors can be initiated at the time of EAS diagnosis to control clinical and metabolic derangements associated with severe hypercortisolemia In patients with ACTH-dependent Cushing syndrome from an ectopic source, inhibiting steroidogenesis should be reserved for cases where the initial diagnosis is unclear or patients who are not suitable candidates for surgery. Unilateral adrenalectomy is indicated in the management of ACTH/CRH-secreting pheochromocytomas and is typically curative. Catecholamine blockade should be started prior to surgical removal of catecholamines-secreting pheochromocytomas. A multidisciplinary approach is required to diagnose and manage this condition. Abstract Background/Objective Ectopic co-secretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in silent (i.e., noncatecholamine-secreting) pheochromocytoma is a rare cause of Cushing Syndrome (CS). Case Report A 57-year-old woman rapidly developed hypercortisolism, clinically manifesting as fatigue, muscle weakness, weight gain, and worsening hypertension, and biochemically characterized by hypokalemia and marked elevation of serum cortisol and plasma ACTH. This acute presentation suggested a diagnosis of ectopic ACTH syndrome (EAS). Imaging studies revealed a right adrenal mass that enhanced after administration of the radioisotope 68Ga-DOTATATE. Plasma metanephrines were normal in two separate measurements. The possibility of a silent pheochromocytoma was considered. After controlling her hypercortisolism with metyrapone and surgical preparation with alpha blockade, the patient underwent elective right adrenalectomy. Pathology revealed a pheochromocytoma that stained focally for ACTH and CRH. Postoperatively, cortisol levels normalized, the hypothalamic–pituitary–adrenal (HPA) axis was not suppressed, and clinical symptoms from hypercortisolism abated. Discussion Patients who exhibit a rapid progression of ACTH-dependent hypercortisolism should be screened for ectopic ACTH syndrome (EAS). The use of functional imaging radioisotopes (such as gallium DOTA-peptides), improves the detection of ACTH-secreting tumors. Preoperative treatment with steroidogenesis inhibitors helps control clinical and metabolic derangements associated with severe hypercortisolemia, while alpha blockade prevents the onset of an adrenergic crisis. Conclusion We present a rare case of EAS due to a silent pheochromocytoma that co-secreted ACTH and CRH. Pheochromocytoma should be considered in patients with EAS who have an adrenal mass even in the absence of excessive catecholamine secretion. Key words ectopic ACTH syndrome Cushing Syndrome non-catecholamine-secreting pheochromocytoma Abbreviations EAS ectopic ACTH syndrome CS Cushing Syndrome CRH corticotropin-releasing hormone ACTH adrenocorticotropic hormone DHEA-S dehydroepiandrosterone sulfate UFC urine free cortisol PRA plasma renin activity Introduction Cushing Syndrome (CS) is rare, with an estimated incidence of 0.2-5.0 per million people per year, and prevalence of 39-79 per million (1). Ectopic ACTH Syndrome (EAS), a type of CS originating from extra-pituitary ACTH-secreting tumors, is uncommon. The prevalence of CS due to ACTH-secreting adrenal medullary lesions is not well established. However, EAS is observed in approximately 1.3% of all identified cases of pheochromocytoma (2). Recognizing EAS can be challenging due to its rarity, leading to delayed diagnosis. Neuroendocrine neoplasms can produce CRH, which can lead to the secretion of ACTH by the pituitary. In certain cases, co-secretion of ACTH and CRH by an adrenal neoplasm has been observed. Only two published cases have provided definitive biochemical and immunohistochemical evidence of exclusive CRH secretion (3). Case Report A 57-year-old woman with a history of well-controlled hypertension sought care due to a two-month history of 60 lb weight gain, facial rounding, easy bruising, muscle weakness, lower extremity edema and acne. Her blood pressure control had worsened, and laboratory tests showed a markedly low serum potassium level of 1.8 mmol/L while taking hydrochlorothiazide. To manage her blood pressure, she was prescribed a calcium channel blocker, an angiotensin receptor blocker, and potassium supplements. However, her symptoms worsened, and she was referred to our emergency department. Blood pressure at presentation to our hospital was 176/86 mmHg. She had characteristic features of CS, including face rounding, supraclavicular fullness, dorsocervical fat accumulation, pedal edema, oral candidiasis, multiple forearm ecchymoses, and acneiform skin eruptions. No visible abdominal striae were present. She had no family history of pheochromocytoma, or multiple endocrine neoplasia type 2. Serum cortisol level was 128 mcg/dL (normal range: 4.6-23.4) at 5 PM, with an ACTH level of 1055 pg/mL (normal range: 6-50); serum DHEA-S level was elevated at 445 mcg/dL (normal range: 8-188). Her 24-hour urine cortisol was at 12,566 mcg (normal range: 4.0-50.0). Plasma metanephrines were normal at <25 pg/mL (normal range: <57), and plasma normetanephrine was 44 (normal range: <148). A second plasma metanephrine measurement showed similar results. Serum aldosterone level and plasma renin activity were low at 2 ng/dL (normal range: 3-16) and 0.11 ng/mL/h (normal range: 0.25-5.82), respectively. Dopamine and methoxytyramine levels were not measured. An abdominal CT revealed a 4.8 x 4.5 x 5 cm right heterogeneously enhancing adrenal mass with a mean Hounsfield Unit of 68 in the non-contrast phase, and an absolute percentage washout of 30% (Fig 1A). The left adrenal gland appeared hyperplastic (Fig 1B). An Octreoscan, which was the in-hospital available nuclear medicine imaging modality, confirmed a 5.1 cm adrenal mass that was mild to moderately avid, with diffuse bilateral thickening of the adrenal glands and no other focal radiotracer avidity. A pituitary MRI did not show an adenoma, and EAS was suspected. Further evaluation with 68Ga-DOTATATE PET/CT (Fig 2) performed after her admission demonstrated an avid right adrenal mass consistent with a somatostatin receptor-positive lesion. No other suspicious tracer uptake was detected. These findings were consistent with a neuroendocrine tumor, such as pheochromocytoma. Download : Download high-res image (261KB) Download : Download full-size image Fig. 1. Preoperative abdominal computed tomography scan showing a 4.8 x 4.5 x 5 cm right heterogeneously enhancing adrenal mass with irregular borders (A) and a hyperplastic left adrenal gland (B). Download : Download high-res image (219KB) Download : Download full-size image Fig 2. 68Ga-DOTATATE PET/CT showing an avid right adrenal mass. To control her symptoms while undergoing workup, the patient received oral metyrapone 500 mg thrice daily and oral ketoconazole 200 mg twice daily. Ketoconazole was stopped due to an increase in transaminases. The dosage of metyrapone was increased to 500 mg four times daily and later decreased to alternating doses of 250 mg and 500 mg four times daily. Within 3 weeks of starting medical therapy, serum cortisol level normalized at 20 mcg/dL. The 24-hour UFC improved to 246.3 mcg/24h. She experienced gradual improvement in facial fullness, acne, and blood pressure control. The possibility of a silent pheochromocytoma was considered, and a-adrenergic blockade with doxazosin 1 mg daily was started 1 month prior surgery. She underwent surgery after two months of metyrapone therapy. With an unclear diagnosis and a large, heterogeneous adrenal mass, the surgical team elected to perform open adrenalectomy for en bloc resection due to concerns for an adrenal malignancy. The tumor was well-demarcated and did not invade surrounding structures (Figure 3A). H&E-stained sections showed classic morphologic features of a pheochromocytoma (Figure 3B), with immunohistochemistry demonstrating strong immunoreactivity for synaptophysin and chromogranin, and negative SF- I and inhibin stains excluding an adrenal cortical lesion. The sections analyzed by QuPath (4) revealed that approximately 4% of ce11s were ACTH cells, often found in isolation, and had a clear, high signal-to-noise staining (Figure 3C). CRH cells were less prevalent, comprising about 2.4% of the total analyzed cells, and tended to cluster together (Figure 3D). These cells had more background staining, resulting in a lower signal- to-noise ratio. Download : Download high-res image (663KB) Download : Download full-size image Figure 3. Gross and Histopathological analysis of the patient’s pheochromocytoma. (A) Image of the gross excised specimen. (B) H&E staining (200x final magnification) demonstrates prominent vascularity and cells with finely granular, eosinophilic cytoplasm and salt-and-pepper chromatin. (C) ACTH staining (200x final magnification) shows clear and isolated positive cells, representing about 4.0% of the section analyzed by QuPath. (D) CRH staining (200x final magnification) reveals tight clusters of positive cells, accounting for 2.4% of the total cells. Positive (human placenta and hypothalamus) and negative (thyroid gland) control tissues performed as expected (data not shown). The patient's postoperative recovery was uneventful, with a short course of hydrocortisone which was stopped 1 week after surgery after HPA axis evaluation showed normal results. After one month, hypercortisolism had resolved, as shown by a normal 24-hour UFC at 28 mcg. Administration of dexamethasone at 11 PM resulted in suppression of morning cortisol to 0.8 and 0.6 mcg/dL 1 and 7 months after surgery, respectively. Her liver function tests normalized, and blood pressure was well-controlled with amlodipine 10 mg daily and losartan 100 mg daily. Genetic testing for pheochromocytoma predisposition syndromes is currently planned. Discussion EAS accounts for 10-20% of cases of ACTH-dependent CS (5). This condition can be caused by several neuroendocrine neoplasms that produce bioactive ACTH (6) In the literature, we have found 99 documented cases of EAS caused by a pheochromocytoma. Of these, 93% showed ACTH expression. Only two cases have been reported with dual staining of ACTH and CRH (7). Exclusive CRH production has only been reported in two cases (8:9). However, the true prevalence of CRH-producing pheochromocytomas might be underestimated, as most cases testing for CRH expression was not performed. Although the clinical presentation of EAS may be highly variable, there is often a rapid onset of hypercortisolism accompanied by severe catabolic symptoms. The diagnostic process should focus on identifying the location of a potential neuroendocrine neoplasm responsible for the ACTH secretion. Sometimes the peripheral origin of ACTH must be confirmed by inferior petrosal sinus sampling (IPSS). In this case, given the clinical presentation consistent with EAS, negative pituitary MRI, and the presence of an adrenal mass that needed to be removed independently, IPSS was not performed. Neuroendocrine neoplasms express somatostatin receptors on their surface, which allow functional imaging using [11 lln]-pentetreotide (Octreoscan). However, Octreoscan has a low sensitivity in detecting occult EAS. In cases where the tumor is in the abdomen and pelvis, Octreoscan has limited utility in locating the source of ACTH (10). This increased risk of false negatives is caused by physiological tracer uptake by the liver, spleen, urinary tract, bowel, and gallbladder. The use of Gallium-68 labeled somatostatin receptor ligands (PET/CT 68Ga-DOTATATE) is more effective in detecting somatostatin receptors (SSTR2) than [11lln]-pentetreotide due to its higher spatial resolution and affinity (11)_ This test was performed after discharge form the hospital to rule out the presence of a second, smaller neuroendocrine tumor that the Octreoscan might have missed. A new molecular imaging technique targeting CRH receptors (68Ga CRH PET/CT) has shown potential in identifying tumors expressing CRH, but its availability remains limited (12). In our patient's case, both the Octreoscan and 68Ga- DOTATATE successfully identified the adrenal tumor as a potential ACTH/CRH secretion source. According to relevant guidelines, presurgical adrenergic blockade is recommended for patients with biochemical evidence of catecholamine excess (13, 14). Conversely, silent pheochromocytomas can generally be operated without alpha blockade (15). Despite this, we opted to administer pre-operative alpha blockade as a precautionary measure for this patient. Pathology examination confirmed the diagnosis of pheochromocytoma. ACTH and CRH staining demonstrated that clear and significant populations of two separate ACTH and CRH positive cells were present in the excised pheochromocytoma. ACTH/CRH cells were dispersed throughout various regions of the pheochromocytoma rather than being well-defined, separate histological entities. As a result, there is no indication that this resulted from collision tumors, but rather random mutation and expansion of tumor cells into ACTH or CRH secreting cells. These results have limitations, including variation in ACTH and CRH expressing regions due to tumor heterogeneity, nonspecific binding of polyclonal antibodies, and normal low-rate false negative/positive detection using QuPath. Post-surgical normal HPA activity was likely due to the de-suppression of the HPA axis by medical therapy, but it may also be explained by chronic stimulation of corticotroph cells induced by ectopic CRH secretion. The standard approach to managing EAS involves surgical intervention. However, surgery may not be a viable option in cases where the source of ACTH production is unknown. Medical therapy to reduce or block excess cortisol can be used in such circumstances. Conclusions In conclusion, a pheochromocytoma causing EAS should be considered even in the absence of elevated plasma metanephrines. These tumors may simultaneously express ACTH and CRH.CRH. References 1 C. Steffensen, A.M. Bak, K. Zøylner Rubeck, J.O.L. Jørgensen Epidemiology of Cushing’s syndrome Neuroendocrinology, 92 (2010), pp. 1-5 View PDF This article is free to access. CrossRefView in ScopusGoogle Scholar 2 H. Falhammar, J. Calissendorff, C. Höybye Frequency of Cushing’s syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center Endocrine, 55 (2020), pp. 296-302 Google Scholar 3 K.B. Lois, A. Santhakumar, S. Vaikkakara, S. Mathew, A. Long, S.J. Johnson, et al. 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Cushing in silent pheochromocytoma Clinical Relevance This case highlights the importance of considering ectopic ACTH secretion by a pheochromocytoma in patients presenting with rapid progression and considerable clinical hypercortisolism concomitant with an adrenal mass and elevated plasma ACTH. This represents an unusual manifestation of a specific subtype of ACTH/CRH-secreting pheochromocytoma that did not exhibit catecholamine secretion The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper ∗ These 2 authors contributed equally to this work From https://www.sciencedirect.com/science/article/pii/S2376060524000075
  20. Abstract Acromegaly is very uncommon, as is non-iatrogenic Cushing syndrome; we discuss a patient who was found to have both a pituitary adenoma causing acromegaly and a cortisol-producing adrenal adenoma causing Cushing syndrome within 1 year. She was a healthy, 44-year-old woman who presented with visual changes and was found to have bitemporal hemianopsia and a 3.3-cm pituitary mass along with central hypogonadism, central hypothyroidism, and suppressed adrenocorticotropin and discrepant cortisol. After transsphenoidal resection she had declining, but persistently elevated, insulin-like growth factor 1 (IGF-1), raising concern for persistent acromegaly. She also was experiencing several cushingoid symptoms and was found to have elevated salivary and urinary cortisol. An abdominal computed tomography scan showed a 3.1-cm adrenal adenoma, and she subsequently underwent adrenalectomy. Following adrenalectomy, her cortisol levels normalized, and her IGF-1, growth hormone, and oral glucose tolerance test showed substantial improvement consistent with previous reports linking hypercortisolism and elevated IGF-1 levels. Combinations of pituitary and adrenal disease are seen in a handful of genetic syndromes; however, her clinical presentation and genetics do not fit with known syndromes. This case describes two rare endocrine tumors in one patient and associated limitations of routine laboratory testing. acromegaly, adrenal Cushing syndrome, IGF monitoring Issue Section: Case Report Introduction Acromegaly resulting from a pituitary adenoma is a very uncommon occurrence, with roughly 30 to 70 individuals affected per million people [1]. Cushing syndrome from an adrenal adenoma is even rarer, with approximately 0.6 individuals affected per million people [2]. Based on these statistics, the chances of both co-occurring in an individual patient would be astronomically low; however, several genetic syndromes can link these 2 diseases, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4, Carney complex, and McCune-Albright syndrome. In addition to the challenge of diagnosing both conditions simultaneously, the presence of both causes a laboratory dilemma. Biochemical control following treatment of a somatotroph adenoma is characterized by growth hormone (GH) suppression during an oral glucose tolerance test (OGTT) and normalization of age-adjusted insulin-like growth factor 1 (IGF-1) levels [3]. There is limited information on how hypercortisolism affects these tests, but there are some study data that suggest patients with Cushing syndrome have elevated IGF-1 compared to controls [4, 5]. Patients with multiorgan endocrine involvement need to be monitored for confounders in laboratory testing. Case Presentation A 44-year-old woman presented to her optometrist for progressive blurring of vision and was found to have bitemporal hemianopsia. Her medical history consisted of only mild hypertension for which she was not taking any medications. She reported no contributory family history. A pituitary magnetic resonance imaging scan was obtained showing a 2.1 × 2.5 × 3.3-cm macroadenoma with invasion into the right cavernous sinus, and with upward displacement and flattening of the optic chiasm (Fig. 1). Figure 1. Open in new tabDownload slide Initial magnetic resonance imaging scan of the pituitary showing a large 2.1 × 2.5 × 3.3-cm macroadenoma with invasion into the right cavernous sinus and with upward displacement and flattening of the optic chiasm. A, Sagittal view. B, Coronal view. She had significant elevation of IGF-1 to 610 ng/mL (79.7 nmol/L) (49-240 ng/mL; 12.3-31.4 nmol/L), with an elevated GH level of 23 ng/mL (23 μg/L) (0.01-3.61 ng/mL; 0.01-3.61 μg/L) consistent with acromegaly. She also had coexisting pituitary deficiencies including hypogonadotropic hypogonadism and central hypothyroidism (Table 1, column 2). Morning adrenocorticotropin (ACTH) was low at less than 5.0 pg/mL (<1.1 pmol/L) (7.2-63 pg/mL; 1.6-13.9 pmol/L) on multiple occasions with morning cortisol within normal limits at 18 μg/dL (497 nmol/L) (4-23 μg/dL; 111-1630 nmol/L). When the patient was seen by endocrinology she confirmed several symptoms and signs consistent with acromegaly including amenorrhea, arthralgias, skin tags, coarsening facial features, increased teeth spacing, hair thinning, increased ring and shoe size, hair loss, and new prediabetes. She also reported a 30-pound weight gain, but lost most of this weight by following an intensive weight-loss program consisting of a restrictive diet. Her menstrual periods ceased only 2 months prior to presentation. She associated most of her symptoms to changes in her routine and stressors during the COVID-19 pandemic and did not seek medical evaluation early for these symptoms. Due to uncertainty regarding her low ACTH level in conjunction with normal cortisol levels, she was started on perioperative glucocorticoids as well as thyroid replacement. She underwent a transsphenoidal resection of her pituitary macroadenoma, and the surgical pathology revealed a sparsely granulated somatotroph adenoma that was PIT1 positive, GH weakly positive, keratin cAM 5.2 positive, Ki67 index 1.2%, and was negative for prolactin, ACTH, and TPIT. She had repeat laboratory tests after a hydrocortisone taper was completed (see Table 1, column 3). Table 1. Pituitary laboratory values before intervention, 6 weeks after pituitary resection, and 4 weeks after adrenalectomy (6 months after pituitary resection) Parameter Initial labs 6 weeks post pituitary resection 4 weeks post adrenalectomy* Reference range (non-pregnant premenopausal females) ACTH < 5.0 pg/mL (1.1 pmol/L) < 5.0 pg/mL (1.1 pmol/L) < 5.0 pg/mL (1.1 pmol/L) 7.2-63 pg/mL (1.6-13.9 pmol/L) Serum AM Cortisol 18 μg/dL (497 nmol/L) 16 μg/dL (443 nmol/L) <1 μg/dL (27.6 nmol/L) 4-23 μg/dL (111-1630 nmol/L) LH <0.3 mIU/mL (0.3 IU/L) <0.3 mIU/mL (0.3 IU/L) 6.3 mIU/mL (6.3 IU/L) 0.5-76.3 mIU/mL (0.5-76.3 IU/L) FSH <0.3 mIU/mL (0.3 IU/L) <0.3 mIU/mL (0.3 IU/L) 1.8 mIU/mL (1.8 IU/L) 1.5-33.4 mIU/mL (1.5-33.4 IU/L) Estradiol <12 pg/mL (44 pmol/L) <12 pg/mL (44 pmol/L) 40 pg/mL (146.8 pmol/L) 17-200 pg/mL (62.4-734 pmol/L) GH 23 ng/mL (23 μg/L) 1.81 ng/mL (1.81 μg/L) 0.88 ng/mL (0.88 μg/L) 0.01-3.61 ng/mL (0.01-3.61 μg/L) OGTT GH 0.49 ng/mL (0.49 μg/L) 0.2 ng/mL (0.2 μg/L) 0.01-0.4 ng/mL ** (0.01-0.4 μg/L) IGF 1 610 ng/mL (79.7 nmol/L) 385 ng/mL (50.3 nmol/L) 290 ng/mL (37.9 nmol/L) 49-240 ng/mL (12.3-31.4 nmol/L) Prolactin 9.1 ng/mL (9.1 μg/L) 3.9 ng/mL (3.9 μg/L) 2.8-29.2 ng/mL (2.8-29.2 μg/L) TSH 1.69 mIU/L (1.69 μIU/mL) 0.29 mIU/L (0.29 μIU/mL) 0.05 mIU/L (0.05 μIU/mL) 0.47-4.68 mIU/L (0.47-4.68 μIU/mL) T4, free 0.7 ng/dL (9.0 pmol/L) 0.8 ng/dL (10.3 pmol/L) 1.5 ng/dL (19.4 pmol/L) 0.8-2.2 ng/dL (10.3-28.4 pmol/L) Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI). Abbreviations: ACTH, Adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicular stimulating hormone; GH, growth hormone; IGF, insulin like growth factor; TSH, thyroid stimulating hormone; T4, thyroxine. *6 months post pituitary resection. **2 hours following glucose load. Open in new tab Her IGF-1 had improved to 385 ng/mL (50.3 nmol/L) (49-240 ng/mL; 12.3-31.4 nmol/L) but it was still elevated, her gonadotropins were still undetectable, and her ACTH was still suppressed with normal morning cortisol levels. She also had a robust response on an ACTH stimulation test. A 3-month postoperative pituitary magnetic resonance imaging scan showed a lobular, hypoenhancing soft tissue in the dorsal aspect of the sella concerning for possible residual tumor. By this time, her most recent IGF-1 was still elevated at 427 ng/mL (55.8 nmol/L). Her 2-hour OGTT using ultrasensitive GH suppressed partially from 1.01 ng/mL (1.01 μg/L) to 0.49 ng/mL (0.49 μg/L) (0.01-0.4 ng/mL; 0.01-0.4 μg/L 2 hours following glucose load) (Table 2). She continued to complain of symptoms such as weight gain, poor sleep, and facial and ankle swelling. Testing for hypercortisolism was finally undertaken and was consistent with Cushing syndrome with midnight salivary cortisol elevated more than 4 times the upper limit of normal on 3 successive tests: 730 ng/dL, 502 ng/dL, 404 ng/dL (2012 nmol/L, 1384 nmol/L, 1114 nmol/L] (<100 ng/dL; < 276 nmol/L). She was also found to have elevated 24-hour urinary free cortisol of 817 μg/24 hours (2254 nmol/day) (3.5-45 μg/24 hours; 9.7-124.2 nmol/day) (Table 3). Dehydroepiandrosterone sulfate was low at less than 5 μg/dL (0.13 μmol/L) (75-410 μg/dL; 1.95-10.66 μmol/L). Table 2. Oral glucose tolerance tests performed 3 months post transsphenoidal surgery and 6 weeks post adrenalectomy (6 months post transsphenoidal surgery) Post pituitary resection (3 mo) Post adrenalectomy (6 weeks)* Glucose GH Glucose GH Initial 107 mg/dL (5.93 mmol/L) 1.01 ng/mL (1.01 μg/L) 79 mg/dL (4.38 mmol/L) 0.88 ng/mL (0.88 μg/L) 30 min 129 mg/dL (7.16 mmol/L) 0.34 ng/mL (0.34 μg/L) 60 min 164 mg/dL (9.16 mmol/L) 0.29 ng/mL (0.29 μg/L) 90 min 165 mg/dL (9.16 mmol/L) 0.21 ng/mL (0.2 μg/L) 120 min 149 mg/dL (8.27 mmol/L) 0.49 ng/mL (0.49 μg/L) 142 mg/dL (7.88 mmol/L) 0.20 ng/mL (0.20 μg/L) Reference GH 2 hours after glucose load 0.01 -0.4 ng/mL (0.01 -0.4 μg/L). Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI). Abbreviations: GH, Growth Hormone. *6 months post pituitary resection. Open in new tab Table 3. Initial testing for hypercortisolism Parameter Value Reference range Midnight salivary cortisol 730 ng/dL (2012 nmol/L) 502 ng/dL (1384 nmol/L) 404 ng/dL (1114 nmol/L) <100 ng/dL (276 nmol/L) 24-h urine free cortisol 817 mcg/24 h (2254 nmol/day) 3.5-45 mcg/24 h (9.7-124.2 nmol/day) DHEA sulfate <5 μg/dL (0.13 μmol/L) 75-410 μg/dL (1.95-10.66 μmol/L) Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI). Abbreviations: DHEA, Dehydroepiandrosterone. Open in new tab A computerized tomography scan of the abdomen was obtained showing a 3.1-cm, lipid-rich left adrenal adenoma (5 Hounsfield units), which confirmed the likely source of her coexisting adrenal Cushing syndrome (Fig. 2). Figure 2. Open in new tabDownload slide Computed tomography of the abdomen showing a 3.1-cm, lipid-rich adrenal adenoma (5 Hounsfield units). A, Axial view. B, Coronal view. Treatment The patient underwent laparoscopic left adrenalectomy with pathology consistent with adrenal adenoma. Outcome and Follow-up In the following weeks after surgery, the patient reported considerable symptomatic improvement including better sleep, improved ankle swelling, and weight loss. To our astonishment, follow-up laboratory tests in the following months showed recovery of the hypothalamic-pituitary-gonadal axis (see Table 1, column 4), with return of menses, and improvement in the IGF-1 level to normal levels, and successful suppression of GH level on a 2-hour OGTT: 0.88 ng/mL to 0.20 ng/mL (0.88 μg/L to 0.20 μg/L). This was consistent with biochemical remission of acromegaly (see Table 2). Despite hydrocortisone wean attempts, the patient's hypothalamic-pituitary-adrenal axis has not recovered fully to date. However, there is promising early detection of the ACTH level, which is no longer suppressed. The patient did undergo genetic testing and is heterozygous for a variant of unknown significance detected in the PTCH1 gene, which has no established connection to the development of acromegaly or adrenal Cushing syndrome. Discussion The definition of biochemical control of acromegaly after resection has been redefined over time [6]. Broadly, it is defined as GH suppression during an OGTT and normalization of age-adjusted IGF-1 level 3 to 6 months postoperatively [6, 7]. However, it has been estimated that up to 30% of patients could have discrepant results between IGF-1 and GH levels. Suppression was traditionally defined as GH nadir of less than 1.0 ng/mL (<1.0 μg/L) after OGTT, but now with ultrasensitive assays, the consensus for suppression is a GH level of less than 0.4 ng/mL (<0.04 μg/L) [6]. There was also a retrospective study of postsurgical patients with a mean follow-up of 39 months that suggests a 3-month IGF-1 level less than 1.25 times the upper limit of normal is associated with long-term remission [3]. There are also other factors that can affect GH and IGF-1 levels, such as pregnancy, diabetes, oral estrogen (not transdermal estrogen), and critical illness [7]. There is limited literature on the effects of hypercortisolism on IGF-1 levels, but higher IGF-1 levels were identified in patients with Cushing syndrome as early as 1993 [4]. There was also a retrospective case-control study, published in 2019, measuring preoperative and postoperative IGF-1 levels in Cushing disease patients to matched controls that found a significantly higher proportion of Cushing patients with elevated serum IGF-1 above the reference range compared to controls [5]. In addition, among the patients who achieved remission of their Cushing, IGF-1 levels decreased significantly postoperatively. Though this study did not involve acromegaly patients and included patients with pituitary Cushing disease rather than adrenal Cushing syndrome, we observed in our case a similar phenomenon by which the IGF-1 normalized after cure of the overt hypercortisolism. This is a rare case, but similar cases have been reported, the most similar of which was published in 2011 and detailed the presentation of a patient with acromegaly who was found to have hypercortisolism from an adrenal adenoma 6 years after the resection of her pituitary adenoma. The authors reported that, post adrenalectomy, the patient needed significantly less pegvisomant for biochemical control of her acromegaly [8]. Our case is different in that our patient had overt Cushing syndrome, whereas this patient had mild autonomous cortisol secretion. Because of suppressed ACTH and the focus on GH excess in association with a macroadenoma, we did not initially look for cortisol excess as a cause of our patient’s symptoms. Also, because most visits were conducted by televideo during this time, and there were still COVID restrictions and more limited access in the health care setting, not all clinical features were immediately evident, and in addition, the overlap of symptoms for these 2 different conditions made the diagnosis challenging. During our patient’s workup, genetic testing was completed to identify a unifying genetic syndrome explaining the co-occurrence of 2 different endocrine tumors. Here genes were analyzed using next-generation sequencing and Sanger sequencing. During analysis, the coding domains and a portion of flanking regions were searched; notably, the promotor genes and a portion of the untranslated regions were not reported. The only remarkable finding in her genes was PTCH1, a variant of unknown significance that has no reported relationships to acromegaly or Cushing syndrome. The known syndrome that overlaps the most with her disease would be MEN1 syndrome. Most defects in the MEN1 gene would have been caught with this approach to analysis; however, a portion of the promoter and untranslated genes was not reported. Genes in these regions may be responsible for 5% to 25% of MEN1 gene dysfunction [9]. However, she had no evidence of primary hyperparathyroidism, which has a high penetrance in MEN1 and is most often the first presentation in MEN1 (>93% penetrance and first manifestation in >67%) [10]. Carney complex is another disease process that could be considered, but our patient did not have primary pigmented nodular adrenocortical disease. McCune-Albright syndrome is unlikely given that she had no fibrous dysplasia of bone or café au lait skin macules on examination. This case raises the question of whether we should be actively searching for additional endocrine abnormalities in patients diagnosed with one endocrine problem. We believe that actively searching for other endocrine abnormalities should be evaluated on a case-by-case basis. While identifying other abnormalities early could be lifesaving in a subset of cases, it comes at a cost. Endocrine testing in patients with dysfunction of another endocrine organ may be difficult to interpret, and false positives could result in unnecessary invasive testing. Given the questionable net benefit, each patient should be evaluated on a case-by-case basis. As genetic testing continues to improve, we suspect there may be additional subsets of patients who warrant further evaluation. Overall, this case serves as a reminder that we should keep a high index of suspicion for concomitant endocrine abnormalities and in those cases our gold-standard testing may be insufficient. Learning Points In patients with rare endocrine tumors, consider a genetic endocrine syndrome, as other endocrine tumors are more common in these patients than in the general population. Gold-standard testing can be undermined by metabolic or physiologic abnormalities. While televideo visits are a tremendous asset to medicine, at times the lack of a comprehensive physical exam can limit appropriate evaluation. Contributors All authors made individual contributions to authorship. S.S.W., N.C., and K.B. were involved in the diagnosis and management of this case and text editing. J.G. and S.S.W. were involved in manuscript preparation and submission. J.G. was involved in table and figure preparation. All authors reviewed and approved the final draft. Funding No public or commercial funding. Disclosures The authors do not have any conflicts of interest. Informed Patient Consent for Publication Signed informed consent obtained directly from the patient. Data Availability Statement Original data generated and analyzed for this case report are included in this published article. The laboratory that performed the genetic testing described (Ambry Genetics) deposits variant-level data to ClinVar (http://www.clinvar.com/), a public repository that aggregates information about human genomic variation. Abbreviations ACTH adrenocorticotropin GH growth hormone IGF-1 insulin-like growth factor 1 MEN1 multiple endocrine neoplasia type 1 OGTT oral glucose tolerance test Author notes Jacob Gabbay and Samantha Steinmetz-Wood contributed equally to this work. © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. From https://academic.oup.com/jcemcr/article/2/1/luad145/7479271?login=false
  21. Abstract Ectopic adrenocorticotropin (ACTH)-secreting tumors are among the causes of ACTH-dependent Cushing syndrome. When surgical resection of the primary lesion is not feasible, medications such as metyrapone, mitotane, and ketoconazole have been used to control hypercortisolism. This report presents a case treated with the novel drug osilodrostat, wherein the patient's adrenal glands exhibited shrinkage following the initiation of this drug. The case involves a 68-year-old man diagnosed with small cell lung cancer and ectopic ACTH-producing Cushing syndrome. Initially, metyrapone was administered to manage hypercortisolism, but its effect proved insufficient. Subsequently, osilodrostat was initiated while gradually decreasing metyrapone, leading to full suppression of blood cortisol levels. With continued osilodrostat treatment, the adrenal glands reduced in size, suggesting the potential to reduce the osilodrostat dosage. ectopic ACTH-producing tumor, Cushing syndrome, osilodrostat, adrenal shrinkage Issue Section: Case Report Introduction Ectopic adrenocorticotropin (ACTH)-secreting tumors represent a rare cause of Cushing syndrome, with an estimated annual incidence of 2 or 3 cases per 1 000 000 (1). Cushing syndrome is categorized into ACTH-independent and ACTH-dependent forms. Ectopic ACTH-dependent Cushing syndrome arises from autonomous ACTH secretion by tumors located outside the pituitary gland, comprising approximately 15% of Cushing syndrome cases (1). Notably, small cell carcinomas of the lung are the most common cause of biochemical hypercortisolism (1). Treatment of ectopic ACTH-secreting tumors typically necessitates primary tumor removal, chemotherapy, radiation therapy, and somatostatin analogues (1). Alongside surgical intervention, medications such as metyrapone, mitotane, and ketoconazole have been employed to reduce blood cortisol levels. However, metyrapone's limitations in terms of its potency and dosing frequency have prompted the search for a more effective drug. Osilodrostat has emerged as a promising option for managing Cushing syndrome. It inhibits the enzyme 11β-hydroxylase, which converts 11-deoxycorticosterone (DOC) to corticosterone and 11-deoxycortisol (11-DOF) to cortisol (2). Osilodrostat has a longer biological half-life than metyrapone, allowing for once-daily or twice-daily dosing. Evidently, osilodrostat possesses superior potency against 11β-hydroxylase (2). Case reports suggest that osilodrostat rapidly controls blood cortisol levels in patients with ectopic ACTH-producing tumors. The dosage of osilodrostat typically commences at 2 mg and is gradually adjusted based on cortisol levels and patient response. Although some cases have seen an increase to more than 10 mg initially, the dosages are eventually reduced to 1 to 5 mg. This case presents a unique scenario in which the patient's adrenal glands shrank during osilodrostat treatment, enabling dosage reduction. Case Presentation A 68-year-old man presented to our hospital with complaints of enlarged right hilar lymph nodes, fever, back pain, dizziness, and diarrhea. His height was 171.0 cm, and his weight was 63.1 kg. His vital signs were as follows: heart rate of 102 beats/min and blood pressure of 181/86 mm Hg. He did not have any cushingoid features. A comprehensive evaluation, including blood tests and a computed tomography (CT) scan of the chest and abdomen, was conducted. His blood tests showed hypokalemia and hyperglycemia. CT revealed the presence of a tumor in the right hilar region, along with swelling of the mediastinal and right supraclavicular lymph nodes and enlargement of the bilateral adrenal glands (Fig. 1A-1C). Tumor markers such as neuron specific enolase and pro–gastrin-releasing peptide were markedly elevated; thus, small cell lung cancer was suspected (details are shown in Table 1). Figure 1. Open in new tabDownload slide Progress of lung tumor and adrenal grand in computed tomography. Upper row (A, D, G): progression of small cell lung cancer. There were no changes in the progress. The density in HU of the lung cancer was 31 on day 1, 40 on day 58, and 34 on day 128. Middle row (B, E, H): progression of the size of the adrenal grand. The adrenal grand progressively shrank. Lower row (C, F, I): Each volume of the right adrenal gland was 11.7 mL on day 1, 7.5 mL on day 58, and 4.4 mL on day 128. Each volume of the left adrenal gland was 14.2 mL on day 1, 8.8 mL on day 58, and 4.9 mL on day 128. The density of the right adrenal gland was 30 HU on day 1, 13 HU on day 58, and 30 HU on day 128. The density of the left adrenal gland was 31 HU on day 1, 18 HU on day 58, and 19 HU on day 128. Table 1. Laboratory data on administration Blood tests Results Reference ranges Red blood cell 4.0 10^12/L 4.35-5.55 10^12/L 400 10^4/mcL 435-555 10^4/mcL White blood cell 8.7 10^12/L 3.3-8.6 10^12/L 87 10^4/mcL 33-86 10^4/mcL Differential count  Neutrophils 91.1%  Lymphocytes 6.0%  Eosinophils 0.0% BUN 6.8 mmol/L 2.9-7.1 mmol/L 19 mg/dL 8.0-20 mg/dL Creatinine 72.5 mcmol/L 57.5-94.6 mcmol/L 0.82 mg/dL 0.65-1.07 mg/dL eGFRCre 72 mL/min/1.73 m2 >90 mL/min/1.73 m2 Sodium 152 mmol/L 138-145 mmol/L 152 mEq/L 138-145 mEq/L Chloride 97 mmol/L 101-108 mmol/L 97 mEq/L 101-108 mEq/L Potassium 1.6 mmol/L 3.6-4.8 mmol/L 1.6 mEq/L 3.6-4.8 mEq/L Calcium 2.00 mmol/L 2.20-2.52 mmol/L 8.0 mg/dL 8.8-10.1 mg/dL Blood glucose 15.1 mmol/L 3.9-6.9 mmol/L 272 mg/dL 70-125 mg/dL HbA1c 52 mmol/mol 27-44 mmol/mol 6.9% 4.6%-6.2% ACTH 170 pmol/L 1.6-14.0 pmol/L 770 pg/mL 7.2-63.3 pg/mL Cortisol 2436 nmol/L 196-541 nmol/L 88.3 mcg/dL 7.1-19.6 mcg/dL DHEA-S 10.43 mcmol/L 0.35-7.15 mcmol/L 385 mcg/dL 13-264 mcg/dL SCC 1.7 mcg/L <2.3 mcg/L 1.7 ng/mL <2.3 ng/mL CYFRA 4.2 mcg/L <3.5 mcg/L 4.2 ng/mL <3.5 ng/mL Pro GRP 147 204 ng/L <81 ng/L 147 204 pg/mL <81 pg/mL NSE 205 mcg/L <12 mcg/L 205 ng/mL <12 ng/mL Abnormal values are shown in bold font. Values in the upper row are International System of Units (SI). Abbreviations: ACTH, adrenocorticotropin; BUN, blood urea nitrogen; CYFRA, cytokeratin 19 fragment; DHEA-S, dehydroepiandrosterone sulfate; eGFRCre, estimated glomerular filtration rate from creatinine; HbA1c, glycated hemoglobin A1c; NSE, neuron specific enolase; Pro GRP, pro–gastrin-releasing peptide; SCC, squamous cell carcinoma antigen. Open in new tab Diagnostic Assessment Although his physical findings did not include cushingoid features, the patient's severe hypokalemia, hypertension, and hyperglycemia and the existence of small cell lung cancer indicated that he had ectopic Cushing syndrome due to small cell lung cancer. Next, we examined his plasma ACTH and serum cortisol levels. Both were markedly elevated. Based on the CT scan and blood test data, there was a strong suspicion of ectopic ACTH-producing small cell lung cancer. Pituitary magnetic resonance imaging could not detect obvious tumors in the seller turcica within the visible range. Diagnostic tests for Cushing disease, such as the corticotropin-releasing hormone (CRH) challenge test and arginine vasopressin challenge test, are needed to definitively diagnose ectopic Cushing syndrome. However, we determined that the hypercortisolism should be corrected as soon as possible. A needle biopsy confirmed the lung tumor as small cell carcinoma on day 10. Immunohistochemical analysis revealed the tumor's negativity for chromogranin A, ACTH, and CRH but positivity for proopiomelanocortin (POMC), indicating its potential to produce pro-big ACTH and result in ectopic Cushing syndrome (Fig. 2). Figure 2. Open in new tabDownload slide Immunostaining of the small cell lung cancer. Figures show each immunostaining analysis: A, chromogranin A; B, adrenocorticotropin (ACTH); C, corticotropin-releasing hormone (CRH); D, proopiomelanocortin (POMC). Chromogranin A, ACTH, and CRH are negative in small cell lung cancer, but POMC is positive. This means that small cell lung cancer produces big-ACTH and can result in ACTH-dependent Cushing syndrome. Treatment Without confirming the diagnosis, we initiated the administration of metyrapone at a dose of 500 mg per day since we were familiar with metyrapone rather than osilodrostat. The dose of metyrapone was gradually increased, reaching 2000 mg per day by day 7. An overview of the clinical course is depicted in Fig. 3. Initially, the cortisol level was extremely high, so we did not consider the replacement of any steroids. Subsequently, we used hydrocortisone with metyrapone osilodrostat from day 10. Chemotherapy with etoposide and carboplatin was also started on day 10. Figure 3. Open in new tabDownload slide Changes of adrenocorticotropin (ACTH) and cortisol during metyrapone and osilodrostat, and chemotherapy. Cortisol was suppressed following an increase in the metyrapone and osilodrostat dosage. ACTH was not suppressed after chemotherapy for small cell lung cancer. As 2000 mg of metyrapone failed to sufficiently lower the patient’s serum cortisol level and metyrapone needed to be taken 6 times a day, we introduced osilodrostat at a daily dose of 1 mg starting from day 25. With close monitoring of the patient's serum cortisol and plasma ACTH levels, we gradually increased the osilodrostat dose to 20 mg per day while concurrently decreasing the metyrapone dose. This approach resulted in full suppression of the serum cortisol levels, enabling the discontinuation of metyrapone 20 days after the initiation of osilodrostat. Outcome and Follow-up Subsequently, we gradually decreased the dose of osilodrostat while following the patient's serum cortisol levels (see Fig. 3). Sixty-six days after the initiation of osilodrostat treatment, the patient was successfully maintained on a reduced daily dose of 1 mg without any increase in serum cortisol levels. A plain CT scan conducted after 33 days of osilodrostat treatment demonstrated that the primary lung tumor had somewhat decreased in size, but the density of lung cancer ranged from 30 to 40 HU, which indicated that there was no necrotic change in his lung cancer (Fig. 1D). The scan also revealed a slight reduction in the volume of the bilateral adrenal glands compared to that on day 1 (Fig. 1E and 1F). The patient was readmitted on day 91 for chemotherapy due to small cell lung cancer. Osilodrostat administration was discontinued after day 128. However, the patient's serum cortisol level remained below 4.0 mcg/dL (110 nmol/L). A plain CT scan on day 128 showed a marked reduction in the volume of the bilateral adrenal glands (Fig. 1H and 1I). The patient died of small cell lung cancer on day 143. We analyzed the adrenal steroid profile using residual serum samples on day 48 by liquid chromatography–mass spectrometry. Serum DOC and 11-DOF levels were elevated above the normal range (Table 2). This means that bioactive ACTH was definitely present in excess in the patient's serum, and his adrenal glands were stimulated. We also measured the plasma ACTH using test kits provided by Roche and Tosoh Corporation using residual plasma samples on day 132. The Tosoh test kit has a higher detection sensitivity for pro-ACTH than that of Roche. The ACTH levels were 924 pg/mL (203 pmol/L) and 1257 pg/mL (277 pmol/L), respectively. These results indicate that while some pro-ACTH was present in the patient's plasma, mature ACTH was also present to some extent. Table 2. Hormone levels on day 48 Hormone tested Results Reference ranges ACTH 142 pmol/L 1.6-14.0 pmol/L 646 pg/mL 7.2-63.3 pg/mL Cortisol 41.4 nmol/L 196-541 nmol/L 1.5 mcg/dL 7.1-19.6 mcg/dL DOC 2.18 nmol/L 0.24-0.85 nmol/L 0.72 ng/mL 0.08-0.28 ng/mL 11-DOF 4.34 nmol/L 0.12-3.35 nmol/L 1.50 ng/mL 0.04-1.16 ng/mL Abnormal values are shown in bold font. Values in the upper row are International System of Units (SI). Abbreviations: 11-DOF, 11-deoxycortisol; ACTH, adrenocorticotropin; DOC, 11-deoxycorticosterone. Open in new tab Discussion In our case, we observed 2 significant aspects. First, the patient's adrenal glands exhibited shrinkage despite the plasma ACTH levels not decreasing. Second, the osilodrostat dose was reduced while the adrenal glands shrank. Our search for publications on osilodrostat and ACTH-dependent Cushing syndrome yielded 57 relevant articles as of May 23, 2023, with 47 cases of ACTH-dependent Cushing syndrome, including 38 cases of ectopic ACTH-producing tumors and 9 cases of Cushing disease (3‐10). Thirty-seven out of 47 cases with ACTH-dependent Cushing syndrome were managed with osilodrostat monotherapy, while the remaining 10 patient cases received a combination of osilodrostat, ketoconazole, and cabergoline, among other drugs. In the 37 cases of osilodrostat monotherapy, 2 different strategies for initiating osilodrostat were observed: the titration strategy and the block and replacement with hydrocortisone strategy (see Fig. 4). Twenty-two of 37 cases received the titration strategy, starting with a low initial dose of 1 to 10 mg daily, with only 2 cases initially starting with a higher initial dose (20 mg daily). Twelve patients initially treated with the titration strategy transitioned to the block and replacement strategy during follow-up. On the other hand, 15 of 37 patient cases received the block and replacement strategy, with initial osilodrostat doses varying from 2 to 60 mg daily, supplemented with hydrocortisone from the outset. In our patient case, osilodrostat was initiated in combination with metyrapone but was subsequently switched to monotherapy, with the dose titrated up to 20 mg daily and then tapered to 1 mg. Figure 4. Open in new tabDownload slide Reported strategy of treatment with osilodrostat. Thirty-seven patients received osilodrostat monotherapy. Twenty-two cases had a titration strategy. Twelve of 22 patient cases with a titration strategy were switched during follow-up to a block and replacement strategy. Fifteen patient cases had a block and replacement strategy initially. Notably, none of the 47 cases of ACTH-dependent Cushing syndrome obtained from PubMed mentioned changes in adrenal gland size. Although metyrapone and osilodrostat both attenuate 11β-hydroxylase enzymatic activity, metyrapone-induced adrenal shrinkage has not been reported. Therefore, the inhibition of 11β-hydroxylase by osilodrostat is unlikely to be the cause of the adrenal gland size reduction. The mechanism by which osilodrostat reduces adrenal volume remains unknown, making it imperative to closely monitor adrenal size in patients undergoing osilodrostat treatment. As indicated in previous reports, most patients attempt dose reduction or discontinue osilodrostat successfully. Thus, if the adrenal glands shrink, reducing the osilodrostat dose may be feasible without compromising blood cortisol level control. Hence, tracking adrenal size through imaging studies, such as CT and magnetic resonance imaging, in osilodrostat-treated patients becomes essential, and assessing the adrenal pathology in these individuals is equally crucial. In addition to the former hypothesis, there is another hypothesis that the hormones produced by small cell lung cancer change from ACTH to big-ACTH, which has much less potency to increase plasma cortisol levels, due to chemotherapy or progression to undifferentiated carcinomas of small cell lung cancer. However, the CT scan after osilodrostat administration showed that the density of lung cancer did not change and ranged from 30 to 40 HU, which indicated there was no necrotic change in the patient's lung cancer. In addition, the difference in ACTH measurement results between the 2 kits suggested that bioactive ACTH was present in the plasma, and the elevation of serum DOC and 11-DOF indicated that the patient's adrenal glands were stimulated by ACTH. We experienced a case of ectopic ACTH-dependent Cushing syndrome treated with osilodrostat. In this case, a reduction in the osilodrostat dose was needed to maintain serum cortisol levels in the appropriate range, and a concomitant reduction in adrenal gland size was observed. It is important to follow-up not only ACTH and cortisol levels but also adrenal size on imaging studies in patients treated with osilodrostat. Evaluation of the adrenal pathology in these patients is also needed. Learning Points To treat ectopic ACTH-producing Cushing syndrome, osilodrostat is currently available. We found that osilodrostat was able to fully control the blood cortisol levels, and the dose of osilodrostat could be reduced after the patient's blood cortisol level was controlled. In our ectopic Cushing syndrome patient, the enlarged adrenal glands had shrunk in the course of treatment with osilodrostat. Through an unknown mechanism, osilodrostat decreases the size of adrenal glands; this effect enabled us to reduce the dosage of osilodrostat. Acknowledgments We thank Dr Yuki Sakai, Dr Chika Kyo, Dr Tatsuo Ogawa, Dr Masato Kotani, and Dr Tatsuhide Inoue for their extensive literature review and management of this patient. We also appreciate Dr Yuto Yamazaki and Dr Hironobu Sasano for conducting the pathological diagnosis. Contributors All authors made individual contributions to this study. F.S. was involved in the writing, submission, and preparation of tables and images. R.H. was involved in the diagnosis and management of this patient. R.K. was involved in the diagnosis and management of this patient and was responsible for overseeing the study. H.A. was responsible for the original idea and writing the first draft of the manuscript. All authors were involved in writing and reviewing the case report and approving the final draft. Funding No public or commercial funding was received. Disclosures The authors declare no conflicts of interest. Informed Patient Consent for Publication Signed informed consent obtained directly from the patient. Data Availability Statement Original data generated and analyzed during this study are included in this published article. Abbreviations 11-DOF 11-deoxycortisol ACTH adrenocorticotropin CRH corticotropin-releasing hormone CT computed tomography DOC 11-deoxycorticosterone POMC proopiomelanocortin © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com From https://academic.oup.com/jcemcr/article/2/2/luae008/7590573?login=false
  22. Abstract Pituitary surgery, a critical intervention for various pituitary disorders, has sparked ongoing debates regarding the preference between endoscopic and microscopic transsphenoidal approaches. This systematic review delves into the outcomes associated with these techniques, taking into account the recent advancements in neurosurgery. The minimally invasive nature of endoscopy, providing improved visualization and reduced morbidity, stands in contrast to the well-established track record of the conventional microscopic method. Examining outcomes for disorders such as Cushing's disease and acromegaly, the review synthesizes evidence from Denmark, Bulgaria, and China. Noteworthy advantages of endoscopy encompass higher resection rates, shorter surgery durations, and fewer complications, endorsing its effectiveness in pituitary surgery. While emphasizing the necessity for prospective trials, the review concludes that endoscopic approaches consistently showcase favorable outcomes, influencing the ongoing discourse on the optimal surgical strategies for pituitary disorders. Introduction & Background Pituitary surgery is a critical intervention for various pituitary disorders, and the choice between endoscopic and microscopic transsphenoidal approaches has been a subject of ongoing debate within the medical community. This systematic review aims to explore and analyze the outcomes associated with endoscopic and microscopic transsphenoidal pituitary surgery. As advancements in surgical techniques continue to shape the field of neurosurgery, understanding the comparative effectiveness of these two approaches becomes imperative. The endoscopic approach, characterized by its minimally invasive nature, has gained popularity for pituitary surgery in recent years [1]. Proponents argue that it provides enhanced visualization, improved maneuverability, and reduced patient morbidity. On the other hand, traditional microscopic transsphenoidal surgery has been the conventional method for decades, known for its familiarity among surgeons and established track record [2]. Several studies have investigated the outcomes of these approaches in treating pituitary disorders, including but not limited to Cushing's disease, pituitary adenomas, and other tumors. For instance, a systematic review and meta-analysis by Chen et al. compared endoscopic and microscopic transsphenoidal surgery specifically for Cushing's disease, shedding light on the effectiveness of these approaches in managing this specific condition [3]. Moreover, Møller et al. reported promising results for endoscopic pituitary surgery based on the experiences of experienced microscopic pituitary surgeons, indicating a potential shift towards the adoption of the endoscopic technique [1]. Guo et al. conducted a meta-analysis comparing the effectiveness of microscopic and endoscopic surgery for treating pituitary disorders, contributing valuable insights into the overall efficacy of these approaches [4]. This review aims to contribute to the ongoing discourse on pituitary surgery by providing a comprehensive analysis of the outcomes associated with endoscopic versus microscopic transsphenoidal approaches. By synthesizing the existing evidence, we strive to offer valuable insights that can guide both clinicians and researchers in making informed decisions regarding the optimal surgical approach for pituitary disorders. Review Materials and methods This systematic review strictly adheres to the established Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, employing a comprehensive approach to investigate the outcomes of endoscopic versus microscopic transsphenoidal pituitary surgery. The subsequent sections delineate the criteria for study inclusion, the search strategy utilized, and the methodology employed for data synthesis. Search Strategy We conducted a meticulous search across prominent electronic databases, including PubMed, Embase, and the Cochrane Library, to identify pertinent articles. Our search strategy comprised a combination of Medical Subject Headings (MeSH) terms and keywords related to pituitary surgery, encompassing both endoscopic and microscopic approaches. Boolean operators (AND, OR) were strategically employed to refine the search and identify studies meeting our predetermined inclusion criteria. The search string used for PubMed was ("Outcomes" OR "Treatment Outcome" OR "Surgical Outcome") AND ("Endoscopic Transsphenoidal Pituitary Surgery" OR "Endoscopic Pituitary Surgery" OR "Endoscopic Hypophysectomy") AND ("Microscopic Transsphenoidal Pituitary Surgery" OR "Microscopic Pituitary Surgery" OR "Microscopic Hypophysectomy" OR "Endoscopy"[Mesh] OR "Endoscopy, Surgical"[Mesh] OR "Transsphenoidal Hypophysectomy"[Mesh] OR "Microsurgery"[Mesh] OR "Microscopic Hypophysectomy"[Mesh]). Eligibility Criteria Stringent inclusion criteria were predefined to ensure the selection of high-quality and relevant studies. The included studies focused on investigating the outcomes of endoscopic versus microscopic transsphenoidal pituitary surgery. Only articles published in peer-reviewed journals within the timeframe from the inception of relevant databases until October 2023 were considered. Exclusion criteria encompassed studies on other interventions, those lacking sufficient data on surgical outcomes, and studies solely involving animal cells. Additionally, only studies in the English language with full-text availability were included, and gray literature was not considered eligible. Data Extraction and Synthesis Two independent reviewers meticulously screened titles and abstracts to identify potentially eligible studies. Subsequently, full-text articles were retrieved and evaluated for adherence to inclusion criteria. Discrepancies between reviewers were resolved through discussion and consultation with a third reviewer. Relevant data, including study design, patient characteristics, interventions, and surgical outcomes, were systematically extracted using a predefined data extraction form. Data Analysis A narrative synthesis approach was employed to summarize findings from included studies due to anticipated heterogeneity in study designs and outcome measures. Key themes and patterns related to the outcomes of endoscopic versus microscopic transsphenoidal pituitary surgery were identified and presented. Results Study Selection Process Following four database searches, 97 articles were initially identified. After eliminating eight duplicates, the titles and abstracts of the remaining 89 publications were evaluated. Subsequently, 17 potential studies underwent eligibility verification through a thorough examination of their full texts. Ultimately, three articles satisfied the inclusion criteria. No additional studies meeting the eligibility criteria were found during the examination of references in the selected articles. The entire process is visually depicted in the PRISMA flowchart (Figure 1). Figure 1: PRISMA flow diagram of the selection of studies for inclusion in the systematic review. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Characteristics of Selected Studies Overall, three papers met the inclusion criteria. Two studies were randomized controlled trials (RCTs), one each from Bulgaria and China. One study was an observational study from Denmark. The main findings and characteristics of the included studies are mentioned in the following tables (Table 1 and Table 2). Author Year Country Study type Sample size No. of participants in the endoscopic group No. of participants in the microscopic group Main findings Møller et al. [1] 2020 Denmark Observational study 240 45 195 The study comparing endoscopic and microscopic transsphenoidal pituitary surgery revealed that the endoscopic technique exhibited advantages, achieving a higher rate of gross total resection (39% vs. 22%) and shorter surgery duration (86 minutes vs. 106 minutes). Complications within 30 days were lower with the endoscope (17% vs. 27%), and grade II complications or higher were significantly reduced (4% vs. 20%) compared to the microscopic approach. Pituitary function outcomes favored the endoscope, with fewer new deficiencies in the HPA axis (3% vs. 34%) and TSH-dependent deficiencies (15% vs. 38%). The HPG axis also showed better normalization in the endoscopic group (32% vs. 19%). Visual field impairment and postoperative improvement did not significantly differ between the two techniques. Overall, the findings suggest that endoscopic transsphenoidal pituitary surgery may offer superior outcomes compared to the microscopic approach, particularly in terms of resection rates and complication profiles. Vassilyeva et al. [5] 2023 Bulgaria RCT 83 43 40 The study compared endoscopic and microscopic transsphenoidal pituitary surgery in acromegaly patients, revealing comparable demographic profiles between the groups. Endoscopic surgery demonstrated advantages with shorter anesthesia and surgery times, as well as a reduced postoperative hospital stay. Complete tumor removal was more frequent with endoscopic adenomectomy, while microscopic surgery showed a higher rate of sub-total removal. Both techniques led to a tendency for somatic improvement, with more pronounced visual function improvement in the endoscopic group. Complications, such as liquorrhea and endocrine disorders, were generally low, with endoscopic surgery showing mainly mild complications. Disease remission rates were similar between the groups at various follow-up intervals. In conclusion, while both techniques proved effective in achieving remission, endoscopic surgery exhibited favorable outcomes in terms of efficiency and some aspects of complication profiles. Zhang et al. [6] 2021 China RCT 46 23 23 Endoscopic transsphenoidal pituitary surgery for the treatment of Cushing's disease showed comparable efficacy to microscopic transseptal pituitary surgery but with the added benefits of shorter operative time, reduced estimated blood loss, shorter hospital stays, and fewer complications. Table 1: Summary of the studies included in this systematic review. RCT: randomized controlled trial; HPA: hypothalamic-pituitary-adrenal; TSH: thyroid-stimulating hormone; HPG: hypothalamic-pituitary-gonadal Technique Møller et al. [1] Vassilyeva et al. [5] Zhang et al. [6] Male-to-female ratio (endoscopic) 25:20 17:26 13:10 Male-to-female ratio (microscopic) 107:88 16:24 12:11 Mean age in years (endoscopic) 61 43.26 55.6 Mean age in years (microscopic) 58 44.12 53.2 Functional tumors (endoscopic) 15 All functional All functional Non-functional tumors (endoscopic) 29 - - Functional tumors (microscopic) 69 All functional All functional Non-functional tumors (microscopic) 115 - - Microadenoma size (mm) (endoscopic) - 4 19 Macroadenoma size (mm) (endoscopic) - 39 4 Microadenoma size (mm) (microscopic) - 3 18 Macroadenoma size (mm) (microscopic) - 37 5 Mean operative time (min) (endoscopic) 86 142 108 Mean operative time (min) (microscopic) 106 176 174 Mean hospital stay (days) (endoscopic) - 5 2.8 Mean hospital stay (days) (microscopic) - 7 5.1 Postoperative complications (endoscopic) 2 15 3 Postoperative complications (microscopic) 39 10 8 Table 2: Summary of demographics, tumor characteristics, and postoperative outcomes of the studies included in this systematic review. The quality assessment of the selected studies was done using the Newcastle-Ottawa Quality Assessment Scale. All three studies included in this study turned out to be of high quality with a rating of 9/9 stars (Table 3). Author Selection Comparability Outcome Total stars Møller et al. [1] ★★★★ ★★ ★★★ ★★★★★★★★★ Vassilyeva et al. [5] ★★★★ ★★ ★★★ ★★★★★★★★★ Zhang et al. [6] ★★★★ ★★ ★★★ ★★★★★★★★★ Table 3: Quality assessment of the included studies using the Newcastle-Ottawa Quality Assessment Scale. Discussion This systematic review thoroughly assesses the effectiveness and results of endoscopic transsphenoidal pituitary surgery in comparison to microscopic transsphenoidal surgery, with a specific focus on pituitary adenomas, including Cushing's disease and acromegaly. The results contribute significant insights into the evolving landscape of pituitary surgery, highlighting the benefits and limitations of both surgical techniques. The selected studies offer valuable insights into the comparative outcomes. Møller et al.'s observational study in Denmark suggests that endoscopic surgery exhibits superior outcomes with higher gross total resection rates, shorter surgery duration, and fewer complications [1]. Vassilyeva et al.'s RCT in Bulgaria, focusing on acromegaly patients, indicates endoscopic advantages such as shorter anesthesia and surgery times, reduced postoperative stay, and comparable remission rates [5]. Zhang et al.'s RCT in China, specifically for Cushing's disease, suggests comparable efficacy with added benefits favoring endoscopy [6]. The endoscopic approach has been advocated for its panoramic visualization and superior mobility, which are crucial in resecting tumors while preserving normal structures [7,8]. Studies have shown a higher remission rate in endoscopic procedures for endocrine-active tumors, like growth hormone or adrenocorticotropic hormone (ACTH)-secreting adenomas, compared to the microscopic approach [9,10]. Patient comfort and recovery play a significant role in evaluating surgical methods. The endoscopic technique, by avoiding submucosal excision of nasal tissues, typically results in less postoperative pain and rhinological dysfunction. Studies, including ours, have reported shorter operative times and hospital stays with endoscopic surgery, attributed to fewer intraoperative and postoperative complications and a reduced need for wound management [11-13]. Safety is paramount to any surgical intervention. The endoscopic method has shown a decrease in common complications such as cerebrospinal fluid (CSF) leak, pituitary hormone dysfunction, and diabetes insipidus. Additionally, the endoscopic procedure exhibited fewer complications, which could be attributed to the enhanced visualization allowing for more precise tumor excision and preservation of vital structures [14-16]. In the context of acromegaly patients, the endoscopic technique has demonstrated increased radicality in tumor removal. Our review aligns with these findings, showing a higher rate of total tumor resection in endoscopic patients compared to those undergoing microscopic surgery. This improved outcome is likely due to better illumination and a wider angle of vision provided by endoscopic operations [5,17]. The endoscopic technique has shown a statistically significant improvement in visual function post surgery compared to the microscopic method. However, the frequency of certain postoperative complications, such as intraoperative liquorrhea, was higher in microscopic surgery. These differences underline the importance of the surgical technique in influencing the outcomes and complications of pituitary surgery [5,18]. Despite these findings, it is important to recognize the limitations inherent in these studies. Factors such as tumor size, density, and localization significantly influence surgical outcomes and procedure times. Additionally, the retrospective nature of many studies introduces potential biases, underscoring the need for more prospective, randomized trials for a comprehensive understanding of the long-term outcomes of these techniques. Conclusions This systematic review comparing endoscopic and microscopic transsphenoidal pituitary surgery outcomes indicates consistent evidence favoring the endoscopic approach. Notable studies from Denmark, Bulgaria, and China reveal superior results with endoscopic surgery, demonstrating higher resection rates, shorter surgery duration, and fewer complications. Endoscopy's benefits extend to patient comfort, as evidenced by shorter operative times and hospital stays. Safety considerations also support endoscopy, showing a decrease in common complications such as CSF leaks and hormonal dysfunction. Despite these strengths, the review underscores the need for prospective, randomized trials to address limitations and provide a comprehensive understanding of long-term outcomes. References Møller MW, Andersen MS, Glintborg D, Pedersen CB, Halle B, Kristensen BW, Poulsen FR: Endoscopic vs. microscopic transsphenoidal pituitary surgery: a single centre study. Sci Rep. 2020, 10:21942. 10.1038/s41598-020-78823-z Gao Y, Zhong C, Wang Y, et al.: Endoscopic versus microscopic transsphenoidal pituitary adenoma surgery: a meta-analysis. World J Surg Oncol. 2014, 12:94. 10.1186/1477-7819-12-94 Chen J, Liu H, Man S, et al.: Endoscopic vs. microscopic transsphenoidal surgery for the treatment of pituitary adenoma: a meta-analysis. Front Surg. 2022, 8:806855. 10.3389/fsurg.2021.806855 Guo S, Wang Z, Kang X, Xin W, Li X: A meta-analysis of endoscopic vs. microscopic transsphenoidal surgery for non-functioning and functioning pituitary adenomas: comparisons of efficacy and safety. Front Neurol. 2021, 12:614382. 10.3389/fneur.2021.614382 Vassilyeva N, Mena N, Kirov K, Diatlova E: Comparative effectiveness of endoscopic and microscopic adenoma removal in acromegaly. Front Endocrinol (Lausanne). 2023, 14:1128345. 10.3389/fendo.2023.1128345 Zhang T, Zhang B, Yuan L, Song Y, Wang F: Superiority of endoscopic transsphenoidal pituitary surgery to microscopic transseptal pituitary surgery for treatment of Cushing's disease. Rev Assoc Med Bras (1992). 2021, 67:1687-91. 10.1590/1806-9282.20210732 Yadav Y, Sachdev S, Parihar V, Namdev H, Bhatele P: Endoscopic endonasal trans-sphenoid surgery of pituitary adenoma. J Neurosci Rural Pract. 2012, 3:328-37. 10.4103/0976-3147.102615 Louis RG, Eisenberg A, Barkhoudarian G, Griffiths C, Kelly DF: Evolution of minimally invasive approaches to the sella and parasellar region. Int Arch Otorhinolaryngol. 2014, 18:S136-48. 10.1055/s-0034-1395265 Broersen LH, Biermasz NR, van Furth WR, de Vries F, Verstegen MJ, Dekkers OM, Pereira AM: Endoscopic vs. microscopic transsphenoidal surgery for Cushing's disease: a systematic review and meta-analysis. Pituitary. 2018, 21:524-34. 10.1007/s11102-018-0893-3 Torales J, Halperin I, Hanzu F, et al.: Endoscopic endonasal surgery for pituitary tumors. Results in a series of 121 patients operated at the same center and by the same neurosurgeon. Endocrinol Nutr. 2014, 61:410-6. 10.1016/j.endoen.2014.07.002 Zubair A, M Das J: Transsphenoidal hypophysectomy. StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL); 2023. Pan X, Ma Y, Fang M, Jiang J, Shen J, Zhan R: Improvement in the quality of early postoperative course after endoscopic transsphenoidal pituitary surgery: description of surgical technique and outcome. Front Neurol. 2020, 11:527323. 10.3389/fneur.2020.527323 Aiyer RG, Upreti G: Endoscopic endo-nasal trans-sphenoidal approach for pituitary adenomas: a prospective study. Indian J Otolaryngol Head Neck Surg. 2020, 72:36-43. 10.1007/s12070-019-01725-8 Oertel J, Gaab MR, Linsler S: The endoscopic endonasal transsphenoidal approach to sellar lesions allows a high radicality: the benefit of angled optics. Clin Neurol Neurosurg. 2016, 146:29-34. 10.1016/j.clineuro.2016.04.016 Hanson M, Li H, Geer E, Karimi S, Tabar V, Cohen MA: Perioperative management of endoscopic transsphenoidal pituitary surgery. World J Otorhinolaryngol Head Neck Surg. 2020, 6:84-93. 10.1016/j.wjorl.2020.01.005 Qiao N: Endocrine outcomes of endoscopic versus transcranial resection of craniopharyngiomas: a system review and meta-analysis. Clin Neurol Neurosurg. 2018, 169:107-15. 10.1016/j.clineuro.2018.04.009 Nie D, Fang Q, Wong W, Gui S, Zhao P, Li C, Zhang Y: The effect of endoscopic transsphenoidal somatotroph tumors resection on pituitary hormones: systematic review and meta-analysis. World J Surg Oncol. 2023, 21:71. 10.1186/s12957-023-02958-2 Butenschoen VM, Schwendinger N, von Werder A, Bette S, Wienke M, Meyer B, Gempt J: Visual acuity and its postoperative outcome after transsphenoidal adenoma resection. Neurosurg Rev. 2021, 44:2245-51. 10.1007/s10143-020-01408-x From https://www.cureus.com/articles/213241-navigating-the-surgical-landscape-a-comprehensive-analysis-of-endoscopic-vs-microscopic-transsphenoidal-pituitary-surgery-outcomes#!/
  23. Abstract We present a patient with Cushing syndrome secondary to accidental intake of corticosteroid tablets—a 66-year-old woman with a history of well-controlled hypertension, who over the course of a few weeks developed full-blown Cushing syndrome with uncontrolled blood pressure, typical central fat accumulation, and easy bruising. The clinical features further worsened upon increase of the dosage of her antihypertensive medication because of rising blood pressure. Biochemical analyses showed low cortisol and ACTH concentrations. Inspection of the patient's medications revealed that she had accidentally been taking corticosteroids tablets, prescribed for her husband, instead of antihypertensives, ie, dexamethasone 4 mg and then 8 mg, instead of candesartan at the same dose. This case highlights the necessity of a thorough review of the medications taken by patients suspected to have exogenous Cushing syndrome, including inspection of the original packaging, and not just relying on information from the patient and electronic health records. This case also highlights the need of special labeling on the packaging for the easy identification of corticosteroid-containing medications given their widespread availability. Cushing syndrome, accidental intake, exogenous Cushing syndrome, differential diagnosis Issue Section: Case Report Introduction Cushing syndrome (CS) is a disorder caused by prolonged and excessive exposure to glucocorticoids. The most common cause of CS is exogenous or iatrogenic, ie, CS caused by administration of glucocorticoids due to inflammatory, autoimmune, or neoplastic diseases. Endogenous CS is a rare condition, caused by either hypersecretion of ACTH from the pituitary gland, ectopic ACTH production, or hypersecretion of cortisol from the adrenal glands. It is of great importance to exclude exogenous CS in all patients who present with signs and symptoms compatible with the syndrome. The following case highlights the need to rule out exogenous CS via a face-to-face review of the medications taken by a patient with CS, rather than only relying on the patient's history and electronic health record. Case Presentation A 66-year-old woman was referred to our department for investigation of suspected CS. She was diagnosed with essential hypertension a couple of years earlier and was prescribed tablet candesartan 4 mg daily. Apart from an otherwise well-controlled hypertension, the patient had a history of bilateral hip replacement, the first performed in 2020 and the second 2 years later. During the 6 weeks prior to our evaluation, the patient had noticed an increasing fat accumulation around her abdomen, upper back, neck, and over the collar bones, despite minimal increase of her body weight. Moreover, the patient had developed a rounded face and increased growth of facial hair, especially on the chin, as well as thin and fragile skin that bruised easily. About 1.5 weeks before she was referred to our clinic, the dose of candesartan was increased by her general practitioner from 4 to 8 mg daily because of rapidly worsening hypertension, confirmed by monitoring 24-hour ambulatory blood pressure. Diagnostic Assessment The physical examination of the patient revealed central obesity and multiple bruises that the patient could not recall. Increased growth of fine hairs on the chin and facial plethora was present. Blood pressure was 165/88 mmHg. The patient did not have any signs of abdominal stretch marks, nor did she have any obvious muscle wasting in the arms and legs (Fig. 1). When comparing to photographs taken about 6 months prior to the examination, the differences were obvious (Fig. 2). Figure 1. Open in new tabDownload slide The patient few weeks prior to admission for evaluation of Cushing syndrome. Figure 2. Open in new tabDownload slide The patient many months before the onset of Cushing syndrome. Biochemical evaluation revealed unmeasurable plasma cortisol at 12:00 PM, 4:00 PM, and 6:00 AM (<28 nmol/L, reference 102-535 nmol/L; <1.01 μg/dL, reference 3.69-19.39 μg/dL). Serum ACTH was also undetectable (<0.2 pmol/L, reference 1.6-13.9 pmol/L; <0.91 pg/mL, reference 2.27-63.18 pg/mL), which raised suspicion of exogenous CS. The patient firmly denied any intake of anything other than her candesartan tablets. She even stated that she avoided any analgesics after the hip replacement previously the same year, nor had she received any intra-articular cortisone injection. The patient gave a very trustworthy and consistent impression, which inevitably led us to proceed to further investigation of the adrenal glands and the pituitary gland to exclude rarer forms of CS, such as cyclic CS and/or pituitary apoplexy of an ACTH-producing pituitary adenoma. The magnetic resonance imaging of the pituitary and the computed tomography of the adrenal glands were normal. Except for the low cortisol and ACTH levels, endocrine workup was unremarkable (Table 1). Table 1. Biochemical evaluation of the patient with Cushing syndrome at baseline, ie, at admission Hormone tested Value Normal Range Plasma cortisol at 08:00 AM <1.01 mcg/dL (<28 nmol/L) 3.70-19.39 mcg/dL (102-535 nmol/L) ACTH <0.91 pg/mL (<0.2 pmol/L) 7.27-63.18 pg/mL (1.6-13.9 pmol/L) TSH 1.0 mIU/L (1.0 mIU/L) 0.4-3.7 mIU/L (0.4-3.7 mIU/L) Free T4 1.01 ng/dL (13 pmol/L) 0.76-1.32 ng/dL (9.8-17 pmol/L) IGF-1 142 ng/mL (18.60 nmol/L) 38-162 ng/mL (4.98-21.22 nmol/L) Prolactin 374 mIU/L (17.58 mcg/L) 63-561 mIU/L (2.96-26.37 mcg/L) FSH 90 mIU/mL (90 IU/L) 27-133 mIU/mL (post-menopausal) (27-133 IU/L) LH 16 mIU/mL (16 IU/L) 5.2-62 mIU/mL (post-menopausal) (5.2-62 IU/L) SHBG 6.07 mcg/mL (54 nmol/L) 2.25-17.42 mcg/mL (20-155 nmol/L) Testosterone 8.65 ng/dL (0.30 nmol/L) 11.53-34.58 ng/dL (0.4-1.2 nmol/L) Estradiol <19.07 pg/mL (<70 pmol/L) <28.06 pg/mL (<103 pmol/L) (post-menopausal with no hormone substitute) Aldosterone 9.05 ng/dL 0.251 pmol/L <23.61 ng/dL (recumbent position) <655 nmol/L Renin 8.25 mIU/L 2.8-40 mIU/L (recumbent position) DHEAS 14.81 mcg/dL (0.4 µmol/L) 29.63-181.48 mcg/dL (0.8-4.9 µmol/L) HbA1c 45 mmol/mol (6.3 %) 31-46 mmol/mol (5-6.4 %) Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI). Abbreviations: ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; T4, thyroxine; IGF-1, insulin-like growth factor 1; FSH, follicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; DHEAS, dehydroepiandrosterone sulfate; HbA1c, glycated hemoglobin. Open in new tab On day 3 after admission, we noted that plasma cortisol at 8:00 AM was measurable, though still low, at 134 nmol/L (4.86 μg/dL), which reinforced our first suspicion of exogenous CS and prompted a more thorough review of the patient's medication. At this time, we asked the patient to show us the tablets that she had been taking at home and that she still carried in her purse. To the patient's frank surprise, it turned out that she was indeed carrying tablets containing 4 mg dexamethasone in the belief that they were candesartan 4 mg tablets. The dexamethasone 4 mg tablet the patient had (generic) was white, scored with a diameter of 6 mm (Fig. 3A). The candesartan 4 mg tablet the patient had been dispensed (generic) was also white, scored and with a diameter of 7 mm (Fig. 3B). Figure 3. Open in new tabDownload slide A. Tablet Dexamethasone 4 mg. White, scored, diameter 6 × 6 mm. B. Tablet Candesartan 4 mg. White, scored, diameter 7 × 7 mm. Treatment The patient was discharged with the same antihypertensive medications as prior to the deterioration and referred to her general practitioner for follow-up of blood pressure. Upon clinical evaluation 5 months after discharge, she showed no signs or symptoms of CS (Fig. 4). Figure 4. Open in new tabDownload slide The patient 5 months after the resolution of Cushing syndrome. Outcome and Follow-up Thus, the patient had accidentally been taking her husband's medication, with which the patient had been aiding her husband, and developed a surreptitious iatrogenic CS. In hindsight, the severity of the clinical features had been worsening and resulted in rapid deterioration alongside the increase of the dosage of the antihypertensives from 4 to 8 mg because of the rising blood pressure. By day 5 after admission, the patient's plasma cortisol and ACTH concentrations had normalized, as had her blood pressure. Discussion Exogenous hypercortisolism is the most common cause of CS, though seldomly published in the literature, and is mainly iatrogenic because of prolonged use of high doses of synthetic glucocorticoids prescribed for the treatment of nonendocrine diseases (1). A recent study has shown that as many as every seventh resident in western Sweden received a glucocorticoid prescription between 2007 and 2014 (2). The rising use of generic medications during the past decade has resulted in corticosteroids being available in different forms, shapes, and packages that make them less easily recognizable. In many countries, corticosteroids are available over-the-counter in almost any form, whereas a variety of agents such as herbal preparations, tonics, and skin-bleaching creams may also contain corticosteroids to the unawareness of the people using them (3, 4). There are no large studies regarding how common the unintentional use of medicines or products that contain corticosteroids. However, studies on traditional Chinese medicine have shown that illegally impure herbs and medicines containing corticosteroids are widely used, suggesting that the accidental intake of corticosteroids is more frequent than we may think (3, 5). Many cases of factitious CS have been reported as a cause of exogenous CS, which makes the diagnosis even more challenging (6-8). The Endocrine Society Clinical Practice Guidelines for the diagnosis of CS recommend that exogenous CS be always excluded before starting the investigation of endogenous CS (9). However, a specific and definitive approach for diagnosing, respectively excluding, exogenous CS is currently lacking. In a recent review, the authors recommend that in addition to asking the patient which medicines they take, the physician should review the electronic health record and ask particularly for medications that are administered via nonoral routes, as well as over-the-counter agents as mentioned earlier (10). If not confirmed by history, the physician is advised to proceed to the measurement of ACTH and/or dehydroepiandrosterone sulfate as well as screening for synthetic glucocorticoids (10). The results usually show low ACTH, dehydroepiandrosterone sulfate, and cortisol levels even though the clinical picture suggests CS. The cross-reactivity of hydrocortisone or cortisone, which is similar to endogenous steroids, in immunoassay-based measurements of plasma and urinary cortisol may show variable levels of cortisol. These measurements combined with low ACTH can make the diagnostic workup much more complex (7). Screening for exogenous substances with the help of high-performance liquid chromatography is usually positive and constructive (7). It is increasingly clear that the risk of accidental ingestion of potent medicines can have deleterious effects on health. This leads us to conclude that thorough face-to-face review of the packaging of medications taken by the patient is mandatory and can spare both physicians and patients from a series of unnecessary investigations. Given the high availability, easy access, and catastrophic adverse effects of the unintentional use of corticosteroids, we therefore propose that all corticosteroid-including medications and agents be marked with a recognizable label. Learning Points Exogenous CS should be always excluded before starting investigation of endogenous CS. Concerning exogenous CS, practitioners should always think broadly and ask for use of herbal preparations, skin-bleaching creams, and any over-the-counter products. Unintentional use of corticosteroids can still be the case even after a thorough review of the electronic records; practitioners should always inspect the medicines the patient has taken. Contributors All authors (K.K., O.R., P.T.) made equal contributions to authorship. K.K., O.R., and P.T. were involved in the diagnosis and management of this patient, as well as in manuscript submission. K.K. and P.T. authored the manuscript draft. All authors (K.K., O.R., P.T.) reviewed and approved the final draft. Funding No public or commercial funding. Disclosures None declared. Informed Patient Consent for Publication Signed informed consent was obtained directly from the patient. © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. From https://academic.oup.com/jcemcr/article/2/1/luad160/7504969?login=false
  24. Abstract Purpose This study was undertaken to assess the unmet needs within the endogenous Cushing’s syndrome (CS) care paradigm from the endocrinologist’s perspective, including data abstracted from patient charts. The study evaluated endocrinologists’ perceptions on burden of illness and treatment rationale along with the long-term clinical burden of CS, tolerability of CS treatments, and healthcare resource utilization for CS. Methods Retrospective medical chart data from treated patients with a confirmed diagnosis of CS was abstracted using a cross-sectional survey to collect data from qualified endocrinologists. The survey included a case report form to capture patient medical chart data and a web-enabled questionnaire to capture practitioner-level data pertaining to endocrinologists’ perceptions of disease burden, CS treatments, and treatment attributes. Results Sixty-nine endocrinologists abstracted data from 273 unique medical charts of patients with CS. Mean patient age was 46.5 ± 13.4 years, with a 60:40 (female:male) gender split. The mean duration of endogenous CS amongst patients was 4.1 years. Chart data indicated that patients experienced a high burden of comorbidities and symptoms, including fatigue, weight gain, and muscle weakness despite multi-modal treatment. When evaluating treatments for CS, endocrinologists rated improvement in health-related quality of life (HRQoL) as the most important treatment attribute (mean score = 7.8; on a scale of 1 = Not at all important to 9 = Extremely important). Surgical intervention was the modality endocrinologists were most satisfied with, but they agreed that there was a significant unmet treatment need for patients with CS. Conclusion Endocrinologists recognized that patients with CS suffered from a debilitating condition with a high symptomatic and HRQoL burden and reported that improvement in HRQoL was the key treatment attribute influencing their treatment choices. This study highlights unmet needs for patients with CS. Patients with CS have a high rate of morbidity and comorbidity, even after treatment. Introduction Endogenous Cushing’s syndrome (CS) is a rare, debilitating disorder caused by chronic overproduction of cortisol [1,2,3]. CS has an estimated incidence of 0.7 to 2.4 cases per million per year, with a majority of cases (~ 70%) occurring in women [1, 4, 5]. Active CS is characterized by a variety of signs and symptoms, including muscle weakness, obesity, depression, menstrual changes, facial redness, decreased libido, hirsutism, acne, ecchymoses, hypertension, diabetes, and neurocognitive deficits [6]. Because of the diverse constellation of associated symptoms, many of which are common in the general population, CS can be challenging to diagnose and patients often seek input from multiple specialists (i.e., orthopedists, rheumatologists, gynecologists, and endocrinologists) prior to receiving a correct diagnosis [6]. Current treatment options for CS include surgery as the first line of treatment, followed by pharmacotherapies as the second line option and radiation therapy, among other treatments, as a potential third line option. Pharmacotherapies include steroidogenesis inhibitors (e.g., ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane), glucocorticoid receptor antagonists (e.g., mifepristone), and medications that inhibit tumoral ACTH secretion (e.g., pasireotide, cabergoline) [6,7,8,9,10]. These pharmacotherapies can be administered as monotherapy or in combination. The impact of CS on overall health-related quality of life (HRQoL) has been previously described [11]. However, studies reporting both the patient burden (via medical charts) and physician perceptions of burden are lacking, and studies examining healthcare resource utilization (HCRU) and the economic burden of CS are limited. The current study reviewed medical charts of patients with CS to characterize the overall burden of CS (including symptoms, treatments, and HCRU) as well as physician perceptions of available treatments for CS and the rationale behind associated treatment decisions. Methods Study design and recruitment This quantitative, cross-sectional study was conducted to collect disease burden data pertaining to patients with CS from qualified physician respondents. All study materials were reviewed and granted exemption by a central Institutional Review Board (IRB) prior to study execution (Advarra; Columbia, MD; https://www.advarra.com/). HCPs were recruited via a physician panel through an independent recruitment partner (Toluna) and received an appropriate honorarium for their time participating in the study. This study was fielded between May 26 and July 27, 2021, and involved the abstraction of retrospective medical chart data from patients with a confirmed diagnosis of CS by endocrinologists. The survey included a 45–60-min web-enabled questionnaire, including a case report form (CRF) component, to capture patient medical chart data and health care practitioner (HCP)-level data in order to assess perceptions of CS disease burden, treatments, and attributes associated with treatments. Considering the rarity of CS, each HCP was required to abstract information from a minimum of 2 patient charts, and a maximum of 8 patient charts. Selection of study population HCPs were able to participate in the study if they: 1. Were board-certified or board-eligible in endocrinology in the United States. 2. Had been in practice for more than 3 years and less than 35 years post residency. 3. Spent at least 25% of their professional time providing direct patient care. 4. Had treated or managed at least 40 unique patients (of any condition) in an average month. 5. Had managed (i.e., had an appointment with) at least 3 patients with CS in the past year. 6. Had access to confirmed CS patient chart(s) at the time of the study. Each HCP who qualified to participate provided information via chart abstraction from the medical records of 2–8 patients with CS. The selected medical charts were from patients ≥ 21 years of age who had received a physician confirmed diagnosis of CS at least 3 months before the time of the study, and had received at least one therapy (surgical, radiological, or pharmacological) to treat their CS within the past 12 months. Patients who were diagnosed with adrenal or pituitary carcinomas were excluded. Data analysis The data analysis was conducted in SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and Q Research Software 5.6. (Q Research Software, New York, NY). After pilot interviews and throughout the fielding, quality control checks of all the case report forms were conducted to ensure that charts with logical inconsistencies were removed from the sample. Descriptive statistics (such as means, medians, and frequencies) were used to describe the study population across various patient and physician level metrics. Results Endocrinologists’ demographics and practice characteristics Endocrinologists’ demographic information and practice characteristics are presented in Table 1. A total of 69 endocrinologists were surveyed and they provided information on 273 unique patient charts. The majority of the 69 endocrinologists surveyed (53/69, 73%) were male. The mean (± SD) time in practice was 17.3 (± 7.6) years. The majority of endocrinologists (35/69, 51%) worked in urban practices and were in private practice settings (47/69, 68%) (Table 1). The sample was almost equally distributed between physicians from the northern (26%), southern (29%), eastern (25%) and western (22%) regions of the United States. The mean (± SD) estimated number of patients with endogenous CS seen in the last 6 months was 30 (± 34.4) patients. Table 1 Endocrinologist demographics and practice characteristics Full size table aEndocrinologist were allowed to select multiple practice settings, if applicable Patient demographics Patient demographics and clinical characteristics at the time of the survey are shown in Table 2. The majority of patients (165/273, 60%) were female with a mean (± SD) age at diagnosis of 40.2 (± 12.3) years and a mean (± SD) age at the most recent visit of 46.5 (± 13.4) years. Mean (± SD) BMI was 33.3 (± 8.3) kg/m2, with 50.5% of patients categorized as obese, 33.0% of patients categorized as overweight, 14.7% of patients categorized as normal or healthy weight, and 1.8% of patients categorized as underweight (Table 2). Most patients (167/273, 61%) had private or commercial health insurance. Patient demographics and clinical characteristics at disease diagnosis are shown in Table 2. A majority of patients (194/273, 79%) originally saw their primary care physician (PCP) prior to diagnosis and were diagnosed in a private practice setting (182/273, 67%). At the time of diagnosis, 46/273 patients (17%) had poor health, 107/273 patients (39%) had fair health, 68/273 patients (25%) had neutral health, 45/273 patients (16%) had good health, and 7/273 patients (3%) had excellent health, according to the responding physician. Table 2 Patient demographics, clinical characteristics and therapy experience at diagnosis and time of the study Full size table Treatment of endogenous Cushing’s syndrome The patient treatment experience at the time of the study is presented in Table 2. Of the 273 patients, 79 (28.9%) underwent surgery only, 11 patients (4.0%) underwent surgery and radiation therapy, 4 patients (1.4%) underwent radiation therapy and pharmacotherapy, 5 patients (1.8%) underwent surgery, radiation therapy, and pharmacotherapy, 85 patients (31.1%) underwent surgery and pharmacotherapy, 2 patients (< 1%) underwent radiation alone and 87 patients (31.9%) underwent pharmacotherapy alone. Symptomatic burden of endogenous Cushing’s syndrome At diagnosis, 34% of patients presented with 1–3 symptoms, 33% of patients presented with 4–6 symptoms, 20% of patients presented with 7–9 symptoms, 8% of patients presented with 10–12 symptoms, and 5% of patients presented with > 13 symptoms (Fig. 1). Symptoms of CS at the time of diagnosis are shown in Fig. 2. The top 10 most common symptoms of CS at the time of diagnosis (Fig. 3) included fatigue, weight gain (in the midsection and upper back), acne, muscle weakness, facial weight gain (i.e., facial roundness), decreased libido, headache, edema, emotional lability, and hirsutism. Although symptoms decreased post-treatment, a large proportion of subjects still exhibited these symptoms post-treatment (Fig. 3). The most commonly reported comorbidities observed in patients with CS at the time of CS diagnosis (i.e., those affecting ≥ 20% of patients) included obesity, hypertension, depression, diabetes, dyslipidemia, anxiety, and impaired glucose tolerance (Table 2). Fig. 1 Number of CS symptoms reported at diagnosis Full size image Fig. 2 Symptoms of CS at diagnosis (N = 273) Full size image Fig. 3 Top 10 symptoms of CS over time. Responses were restricted for Erectile Dysfunction and Irregular Menstrual Periods. Hirsutism was not restricted to females only. All denominators in the table reflect the entire patient cohort, while the metrics below are based on only the affected genders: Female Only Hirsutism: 19% of the cohort (= 52/273), 32% of the females (= 52/165), Erectile Dysfunction: 6% of the cohort (= 17/273), 16% of the males (= 17/108) and, Irregular Menstrual Period: 11% of the cohort (= 30/273), 18% of the females (= 30/165) Full size image Economic burden of Cushing’s syndrome Healthcare resource utilization was assessed (Table 3). Patients required a mean (± SD) of 1 (± 1.4) hospitalization annually with a mean (± SD) length of impatient stay of 4.3 (± 3.1) days. Patients required a mean (± SD) of 0.6 (± 1.3) annual emergency room (ER) visits, and 4.3 (± 6.3) outpatient visits. Table 3 Healthcare resource utilization Full size table Endocrinologists’ perceptions of disease burden Endocrinologists were asked if they agreed with a series of statements regarding their perception of CS burden and impact on a scale of 1–9, where 1 = Not at all agree and 9 = Completely agree (Fig. 4). The highest proportion of endocrinologists responded “Completely agree” with the statements “CS patients can have reduced ability to function at work or school due to their condition” (percent of endocrinologists who responded “Completely agree” = 35%), “patients with CS feel the impact of their condition every day” (30%), that “CS is a debilitating condition” (28%), “patients with CS often have impaired health-related quality of life” (28%), and “CS results in sleep disturbances that adversely impact patient’s HRQoL” (26%). Fig. 4 Physicians’ perceptions of CS burden and impact. On a scale of 1–9, where 1 = Not at all agree and 9 = Completely agree Full size image Endocrinologists’ treatment perceptions Endocrinologists were asked for their perceptions of the most important treatment attributes on a scale of 1 to 5, where 1 = the least important and 5 = the most important (Table 4). The two most important treatment attributes included treatments that were efficacious post-surgery (mean score = 4.0) and efficacious as a combination therapy (3.7). Endocrinologists were asked to rank satisfaction with currently available treatments for CS including surgical intervention, pharmacotherapy, and radiological or other interventions on a scale of 1–9, where 1 = Not at all satisfied and 9 = Extremely satisfied (Table 5). Overall, endocrinologists reported highest satisfaction with surgical intervention with regards to initial efficacy (mean score = 7.2), durability (6.9), safety (6.3), side effects (6.2), tolerability (6.4), and patient’s overall experience (6.9). Endocrinologists also ranked pharmacotherapy higher than radiation therapy for the treatment of CS for initial efficacy (5.9 versus 5.2), safety (5.9 versus 5.4), side effects (5.3 versus 5.2), tolerability (5.7 versus 5.5), and patient’s overall experience (5.9 versus 5.4). Table 4 Top 5 highest rated treatment attributes Full size table Table 5 Physicians’ satisfaction across therapeutic categories Full size table Endocrinologists’ attitudes toward treatments and interventions Key factors for evaluating and selecting a CS treatment were rated on a scale of 1–9, with 1 = Not at all important and 9 = Extremely important (Fig. 5). Improving HRQoL (mean score = 7.8) was rated as the most important attribute. Similarly, improving cardiovascular complications/events (e.g., myocardial infarction, stroke, embolism) (7.6), psychiatric symptoms (e.g., depression, anxiety, mood changes) (7.6), skeletal/muscular symptoms (e.g., muscular weakness, decrease in bone mineral density, bone fractures) (7.5), and neurologic symptoms (e.g., headaches, memory, and cognitive difficulties including brain fog) (7.5) were ranked as key factors when choosing CS treatment. While factors in the survey such as “causes high rate of adrenal insufficiency” and “label contains a warning against use in CS” were ranked as less important, none of the factors listed were considered unimportant by physician respondents for choosing CS treatment. Fig. 5 Key factors for evaluating CS treatments that influence medication selection. On a scale of 1–9, where 1 = Not at all important and 9 = Extremely important Full size image Endocrinologists were asked if they agreed with a series of statements regarding CS treatment and intervention attitudes on a scale of 1–9, where 1 = strongly disagree and 9 = strongly agree (Table 6). The three highest scoring statements were “there is a significant clinical unmet need for patients with endogenous CS” (mean score = 6.6), “better patient support services for CS medications often leads to better patient adherence” (6.5), and “patient out of pocket cost is a significant burden for CS patients on a pharmacological therapy” (6.5). The lowest scoring statement was “patient out of pocket cost is not a significant factor when prescribing pharmacological therapy for my CS patients” (4.6). Table 6 Physicians’ attitudes toward CS treatment and intervention Full size table Discussion This study provides valuable information on the physician’s perspective of unmet needs and treatment goals for patients with CS. Endocrinologists in our sample strongly agreed that patients with CS suffered from a debilitating daily condition with a high HRQoL burden. Endocrinologists also strongly agreed with the view that “there is a significant clinical unmet need for patients with endogenous CS” and ranked prescribing treatments to improve HRQoL, cardiovascular events, depression, and anxiety as key factors influencing treatment decisions. The importance providers place on the availability of post-surgery treatment options reflects the inability of many patients with CS to achieve complete post-surgical symptom resolution and suggests all symptoms in patients with CS are not currently addressed with available treatments. Multiple treatment modalities were utilized by endocrinologists in the care of patients with CS, including surgery, pharmacotherapy, and/or radiation therapy. Improvement in HRQoL was the key treatment attribute influencing CS treatment choices, followed by the goal of reducing cardiovascular complications, and decreasing psychiatric symptoms. However, the prevalence of comorbidities after CS treatment as well as endocrinologists’ perceptions and attitudes regarding an unmet need for CS treatments and ongoing disease burden showed that few therapies are able to improve patients’ ongoing disease burden. New CS treatments are needed that have long-term efficacy, fewer side effects, and effective reimbursement. Patients with CS have a high symptomatic disease burden at diagnosis. This study and others have demonstrated that many of these signs and symptoms (e.g., hypertension, obesity, and depression) persist even after receiving treatment aimed at normalizing cortisol levels [12,13,14,15]. Results from the present study show that many patients continue to experience fatigue, weight gain, muscle weakness, and emotional lability even after treatment, indicating an unmet need for CS treatments that can effectively manage these persistent symptoms. The persistence of symptoms after treatment for CS is likely multifactorial, and may, at least in part, be due to complications of prolonged hypercortisolism, given diagnostic and treatment delays; however, the ability to predict which patients will continue to experience persistent symptoms after treatment is challenging [14, 16, 17]. Additionally, the effects of inadequate cortisol control, symptoms due to glucocorticoid withdrawal, and side effects from medications taken to address comorbidities may contribute to persistent symptoms after treatment for CS. Although there are currently established reference values and treatment guidelines used to stratify patients, there are no current clear guidelines on management of ongoing symptoms after cortisol levels have been addressed [18]. Additionally, the present study indicated that only 32% of patients were diagnosed at the first presentation of their CS symptoms, underscoring the importance of increasing awareness of CS and its presentation among PCPs to expedite diagnosis and treatment. The economic burden of illness from CS includes both the direct impact on HCRU, and the indirect impact on the patient due to loss of work productivity. The present study determined that the mean (± SD) annual number of hospitalization among patients with CS was 1 (± 1.4) day with an average length of inpatient stay of 4.3 days, similar in duration to the mean length of stay for all hospitalizations in the US [19]. However, the average number of outpatient visits among patients with CS was 4.3 visits per year, slightly lower than described in a recent study of patients with CS [11], but almost twice the rate of the average American, indicating a substantial direct cost burden [20]. Patients’ reduced ability to function at work or at school could limit their full economic potential, not only for themselves, but for family members and caregivers, indicating an indirect economic cost. The degree of concordance between patients’ chart data and the perceptions of providers regarding disease symptoms is an important issue raised, but not directly addressed, by this study. Although endocrinologists agreed that there was a high HRQoL burden attributable to CS, this study did not analyze patients’ perceptions of HRQoL burden of CS. Discordance between patients’ perceptions and the perceptions of their healthcare providers, as well as the tendency of providers to perceive disease burden as less impactful or severe than is perceived by patients, has been reported in other medical conditions such as acromegaly, rheumatoid arthritis and chronic pain. The result of this is often worse medical outcomes for patients with rheumatoid arthritis or worse pain and functioning in patients with chronic pain [21,22,23,24]. Further study is necessary to analyze the concordance between the perceptions of physicians and patients with CS. A recent cross-sectional web-enabled survey burden of illness study and a recent systemic literature review [11, 25, 26], conducted by the authors of this study, elucidated both the burden of CS as well as unmet needs in the healthcare system for patients with CS. The results of the current study corroborate the findings of both of these studies, confirming that patients experience a substantial and complex burden of cumulative CS symptoms that impacts their HRQoL. Similar to prior studies, the current results also demonstrate that although symptoms improve with treatment, some symptoms such as weight gain, pain, and anxiety persist even after treatment interventions, including surgery, pharmacotherapy, and radiation therapy. Patients with CS have previously been shown to have worse HRQoL scores compared to healthy counterparts [26], underscoring the long-term effects of CS despite treatment. This study and others have demonstrated that current therapies do not completely mitigate this HRQoL burden and indicate an unmet need among many patients with CS for additional treatments to control symptoms after cortisol level normalization. Study limitations During the time in which this study was conducted, additional CS treatments could have been approved, potentially changing the treatment landscape, and thereby altering the proportion of patients that continued to have symptoms after treatment (Fig. 3) or the proportion of patients with a particular comorbidity after treatment. Physician response may have been subject to recall bias; although this may have been mitigated by the use of patient chart data the possibility that details were omitted at the time of patient visits exists. Additionally, when physicians were asked about working in a Center of Excellence, the term was not explicitly defined which may have led to varying interpretations by respondents. Due to the nature of the method used (i.e., a survey given to endocrinologists treating patients at the present time), we have limited historical chart data on the entire medical journey of each patient and all important medical events may not have been captured. For example, treatments administered to patients prior to this study (i.e., those administered by previous doctors or from a different hospital) may not be present in the patients’ charts and were not captured by our survey. Additionally, we did not capture biochemical data to make definitive statements on disease status based on patient cortisol levels. Updated guidelines on cortisol levels indicative of disease severity have recently been issued by the Pituitary Society [18], and a shift toward standardized clinical guidelines may help physicians provide timely and appropriate treatment for patients with CS. Future patient-centered research in CS should focus on identifying biomarkers associated with persistent symptoms after initial treatment, which could influence the development of guidelines for managing ongoing symptoms as current treatments are focused on cortisol management. The cohort of patients with CS included in our study is also not representative of the full spectrum of patients with CS as they were required to have received at least one pharmacological therapy to be eligible for the study. This requirement was added to our eligibility criteria as the aim of our study was to evaluate the burden of illness faced by patients with Cushing’s Syndrome, post-treatment, in the real world. Future studies evaluating concordance between patient chart data and physician perceptions of CS symptoms are also likely to be of interest. 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Pituitary 23(2):140–148 Article PubMed Google Scholar Panda M et al (2006) The influence of discordance in pain assessment on the functional status of patients with chronic nonmalignant pain. Am J Med Sci 332(1):18–23 Article PubMed Google Scholar Page-Wilson GO, Maguire A, O'Hara M, Moloney S, Eliza G (2022) Patient-reported burden of illness in endogenous Cushing’s syndrome Page-Wilson GO, Bhagyashree O, Silber A, Meyer J, O'Hara M, Geer E (2022) Physician perceptions on the treatment and health-related quality of life burden of endogenous Cushing’s syndrome Download references Acknowledgements Medical editorial assistance was provided by Amal Gulaid, MPH from Trinity Life Sciences. Medical writing assistance was provided by Iona Bartek, PhD. Funding for this study was provided by Strongbridge Biopharma plc, a wholly owned subsidiary of Xeris BioPharma Holdings, Inc. Target Journal Pituitary. Funding Funding for this study was provided by Strongbridge Biopharma plc, a wholly-owned subsidiary of Xeris Biopharma Holdings, Inc. Gabrielle Page-Wilson, MD and Eliza B. Geer, MD were contracted by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to provide expert guidance for this study. Bhagyashree Oak, PhD, Abigail Silber, MPH, and Mathew O’Hara, MBA are employees of Trinity Life Sciences, which was commissioned by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to conduct the current study. James Meyer, MBA, PharmD is an employee and shareholder of Xeris Pharmaceuticals, Inc. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Author information Authors and Affiliations Division of Endocrinology, Columbia University Irving Medical Center, New York, NY, USA Gabrielle Page-Wilson Trinity Life Sciences, Waltham, MA, USA Bhagyashree Oak, Abigail Silber & Matthew O’Hara Xeris Pharmaceuticals, Inc, Chicago, IL, USA James Meyer Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA Eliza B. Geer Contributions All authors contributed to the study conception and design. Study material preparation, data collection, analyses, and manuscript development were conducted by BO, AS, and MO. JM provided overall strategic guidance. GP-W and EBG provided expert reviews of the work. All authors read and approved the final published version. Corresponding author Correspondence to Eliza B. Geer. Ethics declarations Conflict of interest Funding for this study was provided by Strongbridge Biopharma plc, a wholly-owned subsidiary of Xeris Biopharma Holdings, Inc. Gabrielle Page-Wilson, MD and Eliza B. Geer, MD were contracted by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to provide expert guidance for this study. Bhagyashree Oak, PhD, Abigail Silber, MPH, and Mathew O’Hara, MBA are employees of Trinity Life Sciences, which was commissioned by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to conduct the current study. James Meyer, MBA, PharmD is an employee and shareholder of Xeris Pharmaceuticals, Inc. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Ethical approval This was an observational study conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. As this was not a randomized clinical trial, the study was not registered as such. The ADVARRA Institutional Review Board (Columbia, MD; https://www.advarra.com/) has granted the study exemption from IRB oversight using the Department of Health and Human Services regulations found at 45 CFR 46.104(d)(2). The IRB also completed the necessary additional limited review considerations as set forth under the Revised Common Rule, 45 CFR 46.104(d). Informed consent Informed consent was obtained from all participants included in the study during the screening process and this was required to successfully enroll into the study. Participants were able to exit the study at any time or refuse to answer any questions. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions From https://link.springer.com/article/10.1007/s11102-023-01371-y
  25. Summary Background Paediatric endogenous Cushing syndrome is a rare condition with variable signs and symptoms of presentation. We studied a large cohort of paediatric patients with endogenous Cushing syndrome with the aim of describing anthropometric, clinical, and biochemical characteristics as well as associated complications and outcomes to aid diagnosis, treatment, and management. Methods In this prospective, multisite cohort study, we studied children and adolescents (≤18 years at time of presentation) with a diagnosis of Cushing syndrome. Patients had either received their initial diagnosis and evaluation at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, MD, USA) or been referred from other centres in the USA or outside the USA. We collected participants’ clinical, biochemical, and imaging findings and recorded their post-operative course until their latest appointment. Findings Of 342 paediatric patients with a diagnosis of Cushing syndrome, 193 (56%) were female and 149 (44%) male. 261 (76%) patients had corticotroph pituitary neuroendocrine tumours (Cushing disease), 74 (22%) had adrenal-associated Cushing syndrome, and seven (2%) had ectopic Cushing syndrome. Patients were diagnosed at a median of 2 years (IQR 1·0–3·0) after the first concerning sign or symptom, and patients with adrenal-associated Cushing syndrome were the youngest at diagnosis (median 10·4 years [IQR 7·4–13·6] vs 13·0 years [10·5–15·3] for Cushing disease vs 13·4 years [11·0–13·7] for ectopic Cushing syndrome; p<0·0001). Body-mass index z-scores did not differ between the diagnostic groups (1·90 [1·19–2·34] for adrenal-associated Cushing syndrome vs 2·18 [1·60–2·56] for Cushing disease vs 2·22 [1·42–2·35] for ectopic Cushing syndrome; p=0·26). Baseline biochemical screening for cortisol and adrenocorticotropin at diagnosis showed overlapping results between subtypes, and especially between Cushing disease and ectopic Cushing syndrome. However, patients with ectopic Cushing syndrome had higher urinary free cortisol (fold change in median cortisol concentration from upper limit of normal: 15·5 [IQR 12·7–18·0]) than patients with adrenal-associated Cushing syndrome (1·5 [0·6–5·7]) or Cushing disease (3·9 [2·3–6·9]; p<0·0001). Common complications of endogenous Cushing syndrome were hypertension (147 [52%] of 281 patients), hyperglycaemia (78 [30%] of 260 patients), elevated alanine transaminase (145 [64%] of 227 patients), and dyslipidaemia (105 [48%] of 219 patients). Long-term recurrence was noted in at least 16 (8%) of 195 patients with Cushing disease. Interpretation This extensive description of a unique cohort of paediatric patients with Cushing syndrome has the potential to inform diagnostic workup, preventative actions, and follow-up of children with this rare endocrine condition. Funding Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health. Introduction Paediatric endogenous Cushing syndrome is a rare disorder accounting for 5–7% of all reported cases of endogenous Cushing syndrome.1, 2, 3 In children older than 5–7 years and adolescents, endogenous Cushing syndrome is most commonly caused by corticotroph pituitary neuroendocrine tumours (PitNETs) and is termed Cushing disease. By contrast, Cushing syndrome in children younger than 5 years is often associated with adrenal disorders and is termed adrenal-associated Cushing syndrome.4 Albeit rare, a third type termed ectopic Cushing syndrome is caused by neuroendocrine tumours outside the hypothalamic–pituitary axis that secrete adrenocorticotropin or corticotropin-releasing hormone.5, 6 Thus endogenous Cushing syndrome is caused by either adrenocorticotropin-dependent sources (pituitary or ectopic) or adrenocorticotropin-independent (adrenal) hypercortisolemia. Patients with adults-onset Cushing syndrome typically present with weight gain, skin manifestations (striae, hirsutism, acne, and easy bruising), and abnormal fat deposition.7, 8, 9 Paediatric Cushing syndrome differs from adult-onset Cushing syndrome in aspects including effects on growth (weight gain with concomitant height deceleration), atypical physical presentation (such as lack of centripetal obesity or typical striae), delayed or suppressed puberty, and variable mental health problems and neurocognitive function deficits.10 Diagnosis of paediatric Cushing syndrome is therefore challenging, and delayed evaluation is common. Research in context Evidence before this study Endogenous Cushing syndrome is a rare endocrine condition. Diagnosis can be challenging and delay treatment. We searched PubMed for articles published in English on paediatric Cushing syndrome using terms “Cushing” AND “children” from database inception to May 5, 2023. Although several case series of paediatric Cushing disease were identified, only a few studies of the various causes of paediatric endogenous Cushing syndrome were available. Added value of this study To our knowledge, this cohort of paediatric endogenous Cushing syndrome of various causes is one of the largest sources of cumulative clinical, anthropometric, and biochemical data on the presentation, diagnosis, and management. We confirm that baseline biochemical data cannot aid differential diagnosis of Cushing syndrome subtypes. However, evidence suggests that minimally invasive stimulation tests could be a safe alternative to interventional sampling procedures such as inferior petrosal sinus sampling. We provide the prevalence of complications related to Cushing syndrome. Long-term outcomes of paediatric patients with pituitary corticotroph tumours recurrence is possible up to 8 years after initial remission. Implications of all the available evidence Data from this large paediatric cohort inform the evaluation, diagnosis, and long-term care of patients with paediatric Cushing syndrome. We recommend an algorithm for the diagnosis of patients and screening of complications. Screening for recurrence in patients with Cushing disease is indicated for this age group, at least for the first decade after surgery. We have evaluated a large cohort of children and adolescents with endogenous Cushing syndrome of various causes. The aim of the study was to document anthropometric, clinical, and biochemical characteristics, complications, and outcomes of paediatric endogenous Cushing syndrome to aid clinicians in the diagnosis and management of these patients. Section snippets Study design and participants In this prospective, multisite cohort study, we screened participants who, from 1995 to 2023, had enrolled in studies under protocols 97-CH-0076 (clinicaltrials.gov, NCT00001595), 95-CH-0059 (NCT00001452), and 00-CH-0160 (NCT00005927) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, Bethesda, MD, USA). Paediatric patients (18 years or younger at time of presentation) with a diagnosis of Cushing syndrome were eligible for inclusion in the study. We Results 342 patients with paediatric Cushing syndrome were included in the study (table 1). 278 patients were referred from centres in the USA, and 64 patients were referred from centres outside of the USA. 261 (76%) patients were diagnosed with Cushing disease, 74 (22%) patients were diagnosed with adrenal-associated Cushing syndrome, and seven (2%) patients were diagnosed with ectopic Cushing syndrome. Patients with adrenal-associated Cushing syndrome were diagnosed at a younger age than patients Discussion We present extensive and unique data on presentation, diagnosis, and follow-up of paediatric patients with three diagnostic types of endogenous Cushing syndrome. Clinical and anthropometric characteristics were similar across subtypes of Cushing syndrome, but biochemical tests differed. We also present extensive information on complications; hypertension, insulin resistance, dyslipidaemia, and elevated ALT were common. Long-term follow-up of patients revealed excellent postoperative prognosis, Data sharing The data that support the findings of this study are available from the corresponding author upon reasonable request. Declaration of interests CAS holds patents on the function of the PRKAR1A, PDE11A, and GPR101 genes and related issues; his laboratory had received research funding on GPR101, and on abnormal growth hormone secretion and its treatment by Pfizer. CAS receives support from ELPEN and has been consulting for Lundbeck Pharmaceuticals and Sync. CT reports receiving research funding on treatment of abnormal growth hormone secretion by Pfizer. References (38) OA Hakami et al. Epidemiology and mortality of Cushing's syndrome Best Pract Res Clin Endocrinol Metab (2021) HL Storr et al. Paediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances Trends Endocrinol Metab (2007) C Tatsi et al. Neonatal Cushing syndrome: a rare but potentially devastating disease Clin Perinatol (2018) CA Stratakis An update on Cushing syndrome in pediatrics Ann Endocrinol (Paris) (2018) JL Shaw et al. Validity of establishing pediatric reference intervals based on hospital patient data: a comparison of the modified Hoffmann approach to CALIPER reference intervals obtained in healthy children Clin Biochem (2014) MB Lodish et al. Effects of Cushing disease on bone mineral density in a pediatric population J Pediatr (2010) L Meloche-Dumas et al. Role of unilateral adrenalectomy in bilateral adrenal hyperplasias with Cushing's syndrome Best Pract Res Clin Endocrinol Metab (2021) M Fleseriu et al. Consensus on diagnosis and management of Cushing's disease: a guideline update Lancet Diabetes Endocrinol (2021) MS Broder et al. Incidence of Cushing's syndrome and Cushing's disease in commercially-insured patients <65 years old in the United States Pituitary (2015) O Ragnarsson et al. The incidence of Cushing's disease: a nationwide Swedish study Pituitary (2019) From https://www.sciencedirect.com/science/article/abs/pii/S235246422300264X
  26. Dr. Theodore Friedman will be giving a brief update on growth hormone replacement, then answer your questions about endocrine issues. He can not give specific medical advice and this does not replace making an appointment, but he can answer your questions on any endocrine topic including: Cushing's disease Adrenal insufficiency/Addison's Hypothyroidism/Hashimoto's Graves' Disease Menopause PCOS Growth hormone deficiency Hypopituitarism For both existing and potential patients. Sunday • January 21, 2024 • 6 PM PST Please join using the links below https://www.facebook.com/goodhormonehealth/ or Via Zoom Click to join the meeting meeting ID 420 968 7343, passcode 111116 Slides will be available on the day of the talk here. For more information, email us at mail@goodhormonehealth.com
  27. Dr. Theodore Friedman will be giving a brief update on growth hormone replacement, then answer your questions about endocrine issues. He can not give specific medical advice and this does not replace making an appointment, but he can answer your questions on any endocrine topic including: Cushing's disease Adrenal insufficiency/Addison's Hypothyroidism/Hashimoto's Graves' Disease Menopause PCOS Growth hormone deficiency Hypopituitarism For both existing and potential patients. Sunday • January 21, 2024 • 6 PM PST Please join using the links below https://www.facebook.com/goodhormonehealth/ or Via Zoom Click to join the meeting meeting ID 420 968 7343, passcode 111116 Slides will be available on the day of the talk here. For more information, email us at mail@goodhormonehealth.com
  28. Abstract We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing's disease. Introduction Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors with an incidence of 1/1000, and pituitary corticotroph tumors (corticotroph PitNETs) account for approximately 15% of all PitNETs. Most corticotroph PitNETs are functional tumors with clinical manifestations of Cushing's disease characterized by central obesity, hypertension, diabetes mellitus, and psychosis (Cui et al., 2021). The increased cortisol due to the overproduction of adrenocorticotropic hormone (ACTH) significantly reduces the overall quality of survival and life expectancy of patients (Sharma et al., 2015; Barbot et al., 2018). Currently, treatment of corticotroph PitNETs mainly relies on surgery resection, pharmacologic therapy or radiotherapy may be considered for patients with residual tumors or those who are unable to undergo surgery. While several agents, such as cabergoline and pasireotide, are clinically approved, the effect is unsatisfactory, and potentially serious side effects exist. Therefore, there is an urgent need to develop novel therapeutic drugs for corticotroph PitNETs. Metformin is a biguanide hypoglycemic agent for the treatment of type 2 diabetes. In addition to its hypoglycemic effect, numerous studies identified the therapeutic role of metformin in the prevention and treatment of various tumors including small cell lung cancer, colorectal cancer, breast cancer, ovarian cancer, and neuroendocrine tumors (Lu et al., 2022; Kamarudin et al., 2019; Wang et al., 2019; Thakur et al., 2019), making metformin a promising adjuvant drug in the therapy of cancers. Besides, it has been reported that metformin improves metabolic and clinical outcomes in patients treated with glucocorticoids. However, to date, limited studies explore the potential anti-cancer effect of metformin in corticotroph PitNETs. Recent studies report the use of metformin for blood glucose and body weight control in patients with Cushing's disease (Ceccato et al., 2015), while the role of metformin on ACTH secretion and tumor growth in corticotroph PitNETs remains to be elucidated. In the current study, we investigated the effect of metformin in corticotroph PitNETs and performed RNA-sequencing to identify the potential mechanisms of metformin. We found that metformin inhibited cell proliferation and ACTH secretion of AtT20 cells in a dose-dependent manner. Besides, metformin induced cell cycle arrest via decreased ERK1/2 phosphorylation and increased P38 phosphorylation. Our results revealed that metformin is a potential drug for corticotroph PitNET therapy. Section snippets Cell culture The ACTH-secreting mouse pituitary tumor cell line AtT-20 was purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA). Cells were cultured in F-12K medium (ATCC; Catalog No. 30-2004), supplemented with 15% fetal bovine serum (FBS; Gibco), and 2.5% horse serum (Gibco) as suggested. AtT20 cells were cultured in a humidified incubator at 37 °C in 5% CO2. Reagents and drugs Metformin and Ulixertinib were purchased from MedChemExpress (MCE), Metformin was dissolved in sterile H2O and prepared as a Results Metformin inhibits cell proliferation and ACTH secretion, and leads to cell cycle arrest in AtT20 cells. We used CCK-8 assay to detect the cell viability of AtT20 cells after treatment with different concentrations of metformin at 24 h, 48 h, and 72 h. The results showed that metformin significantly inhibited the proliferation of AtT20 cells in a dose-dependent manner (Fig. 1A). Similarly, prolonged (6 days) treatment of AtT20 cells with a lower concentration (400 μM) of metformin also inhibited Discussion Metformin, acting by binding to PEN2 and initiating the subsequent AMPK signaling pathway in lysosomes, is the most commonly used oral hypoglycemic agent (Hundal et al., 2000; Ma et al., 2022). Previous reports demonstrated metformin as a potential anti-tumor agent in cancer therapy (Evans et al., 2005). Metformin, either alone or in combination with other drugs, has been shown to reduce cancer risk in a variety of tumors including pituitary neuroendocrine tumors (PitNETs) (Thakur et al., 2019; Conclusion Our study demonstrated that metformin suppressed cell proliferation and decreased ACTH secretion in AtT20 cells via the MAPK pathway. Our results revealed that metformin is a potential anti-tumor drug for the therapy of corticotroph PitNETs, which deserves further study. Funding This study was supported by the National Natural Science Foundation of China (82072804, 82071559). CRediT authorship contribution statement Yingxuan Sun: Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Jianhua Cheng: Data curation, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. Ding Nie: Formal analysis, Writing – review & editing. Qiuyue Fang: Data curation, Formal analysis, Writing – review & editing. Chuzhong Li: Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Funding acquisition. Yazhuo Zhang: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We thank Mr. Hua Gao (Cell Biology Laboratory, Beijing Neurosurgical Institute, China) for support with the techniques. References (30) K. Jin et al. Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells Mol. Cell. Endocrinol. (2018) R. Krysiak et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia Eur. J. Intern. Med. (2016) X. Liu et al. Combination treatment with bromocriptine and metformin in patients with bromocriptine-resistant prolactinomas: pilot study World neurosurgery (2018) J. Sinnett-Smith et al. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: dependence on glucose concentration and role of AMPK Biochem. Biophys. Res. Commun. (2013) C.R. Triggle et al. Metformin: is it a drug for all reasons and diseases? Metab., Clin. Exp. (2022) J.C. Wang et al. Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation J. Exp. Clin. Cancer Res. : CR (2019) J. An et al. Metformin inhibits proliferation and growth hormone secretion of GH3 pituitary adenoma cells Oncotarget (2017) M. Barbot et al. Diabetes mellitus secondary to Cushing's disease Front. Endocrinol. (2018) F. Ceccato et al. Clinical use of pasireotide for Cushing's disease in adults Therapeut. Clin. Risk Manag. (2015) M. Cejuela et al. Metformin and breast cancer: where are we now? Int. J. Mol. Sci. (2022) From https://www.sciencedirect.com/science/article/abs/pii/S0303720723002915
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