MaryO

Highlights Aim to identify independent risk factors for postoperative delirium after pituitary adenoma surgery. Select matched subjects by Propensity Score Matching to reduce potential biases caused by variables. Enhance preoperative communication to minimize the occurrence of delirium, for patients at high risk of postoperative delirium. Minimize surgery duration and general anesthesia, optimize perioperative sedation regimen. Reducing unnecessary or excessive protective physical restraints. Abstract Objectives The primary aim of this study is to explore the factors associated with delirium incidence in postoperative patients who have undergone endoscopic transsphenoidal approach surgery for pituitary adenoma. Methods The study population included patients admitted to Tianjin Huanhu Hospital's Skull Base Endoscopy Center from January to December 2022, selected through a retrospective cohort study design. The presence of perioperative delirium was evaluated using the 4 'A's Test (4AT) scale, and the final diagnosis of delirium was determined by clinicians. Statistical analysis included Propensity Score Matching (PSM), χ2 Test, and Binary Logistic Regression. Results A total of 213 patients were included in this study, and the incidence of delirium was found to be 29.58 % (63/213). Among them, 126 patients were selected using PSM (delirium:non-delirium = 1:1), ensuring age, gender, and pathology were matched. According to the results of univariate analysis conducted on multiple variables, The binary logistic regression indicated that a history of alcoholism (OR = 6.89, [1.60–29.68], P = 0.010), preoperative optic nerve compression symptoms (OR = 4.30, [1.46–12.65], P = 0.008), operation time ≥3 h (OR = 5.50, [2.01–15.06], P = 0.001), benzodiazepines for sedation (OR = 3.94, [1.40–11.13], P = 0.010), sleep disorder (OR = 3.86, [1.40–10.66], P = 0.009), and physical restraint (OR = 4.53, [1.64–12.53], P = 0.004) as independent risk factors for postoperative delirium following pituitary adenoma surgery. Conclusions For pituitary adenoma patients with a history of alcoholism and presenting symptoms of optic nerve compression, as well as an operation time ≥3 h, enhancing communication between healthcare providers and patients, improving perioperative sleep quality, and reducing physical restraint may help decrease the incidence of postoperative delirium. Introduction In clinical practice, patients admitted to the intensive care unit (ICU) during the postoperative period after endoscopic transsphenoidal tumorectomy of pituitary adenoma often experience episodes of delirium. According to a recent retrospective analysis conducted at a single center, the incidence of postoperative delirium among these patients was found to be 10.34 % (n = 360) [1]. Delirium is a common complication following neurosurgery, characterized by acute distraction, confusion in thinking, sleep disorders, and cognitive decline. The incidence of delirium in admitted patients after neurosurgery has been reported to be 19 %, with a range of 12 % to 26 % depending on clinical features and the methods used for delirium assessment [2], [3], [4]. The incidence of postoperative delirium varied across different types of neurosurgical diseases, as reported in a meta-analysis [2]. Specifically, the incidences were 8.0 % for patients with neurological tumors, 20 % for those undergoing functional neurosurgery, 24.0 % for microvascular decompression patients, 19.0 % for traumatic brain injury patients, 42.0 % for neurovascular patients, and 17.0 % for the mixed population undergoing neurosurgery procedures. Furthermore, the incidence rates of delirium in intensive care units (ICUs), general wards, or both combined were found to be 24.0 %, 17 %, and 18 %, respectively. The aforementioned issue not only leads to prolonged hospital stays and increased healthcare costs, but also exerts a significant impact on patient consciousness and cognitive function. Therefore, early and accurate identification of delirium in post-neurosurgical patients is crucial. However, due to frequent co-occurrence with primary brain injury, related complications can also lead to cognitive impairment or even decreased levels of consciousness, posing challenges for timely and precise identification of delirium. Currently, the primary focus lies in the prevention of delirium within the neurosurgical ICU setting. Early identification and comprehensive pre-surgical assessment are positively significant measures for preventing postoperative delirium occurrence [5], [6]. In this study, a retrospective cohort design was employed to collect pertinent data and statistically analyze the incidence of delirium, as well as its associated influencing factors, among patients admitted to the neurosurgical ICU for pituitary adenoma treatment. And now it is reported as follows. Section snippets Patient selection A retrospective cohort study design was employed to select 213 pituitary adenomas admitted to the Skull Base and Endoscopy Center of Tianjin Huanhu Hospital between January 2022 and December 2022 as the subjects for investigation, with a review of their medical records. The mean age was (50.03 ± 15.72) years, ranging from 20–79 years old (Fig. 1). Informed consent was obtained from all patients or their families, ensuring compliance with the requirements stated in the Declaration of Helsinki. Inclusion criteria a. Propensity score matching The present study enrolled a total of 213 patients with pituitary tumors, among whom 63 exhibited symptoms related to delirium while the remaining 150 did not. Consequently, the incidence rate of delirium was determined to be 29.58 % in this cohort of patients admitted to the intensive care unit following pituitary tumor surgery. The univariate analysis revealed no significant differences in age (≥65y old, 23.8 % vs. 23.3 %, P = 0.940) and gender (male, 49.2 % vs. 56.7 %, P = 0.318) between the Background of perioperative delirium in transsphenoidal endoscopic pituitary adenoma surgery The pituitary gland is situated within the sella turcica and comprises two distinct components. The anterior pituitary, known as the adenohypophysis, functions as an endocrine organ responsible for secreting growth hormone, prolactin, adrenocorticotropic hormone, thyrotropin, follicle-stimulating hormone and luteinizing hormone. On the other hand, the posterior pituitary, referred to as the neurohypophysis, serves as a direct extension of the hypothalamus and acts as a storage site for Conclusions To enhance the evaluation of postoperative patients at risk of delirium, it is anticipated that optimizing doctor-nurse-patient communication and minimizing unnecessary and indiscriminate protective measures will mitigate the incidence of delirium following pituitary tumor surgery. This study is a single-center prospective study conducted at our institution, which has several inherent limitations. A large-scale multicenter prospective study is anticipated to further investigate the associated Limitations There are multiple factors that influence the occurrence of delirium following neurosurgery. This retrospective study solely focused on analyzing and comparing general patient data, medical history, and potential perioperative factors contributing to delirium, without considering any other known or unknown variables in this analysis. The pituitary gland functions as a neuroendocrine organ involved in the regulation of neuroendocrine processes. Changes in hormone levels following surgery for Funding All authors affirm that this study was conducted without any fund support from external organizations. CRediT authorship contribution statement Shusheng Zhang: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yanan Chen: Writing – original draft, Investigation, Data curation. Xiudong Wang: Validation, Supervision, Project administration, Methodology, Conceptualization. Jun Liu: Software, Formal analysis, Data curation. Yueda Chen: Validation, Supervision, Methodology, Investigation. Guobin Zhang: Writing – review & editing, Validation, Supervision, Methodology, Conceptualization. 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. References (21) G. Sousa et al. Postoperative delirium in patients with history of alcohol abuse Rev Esp Anestesiol Reanim (2017) M. Terzaghi et al. Sleep disorders and acute nocturnal delirium in the elderly: a comorbidity not to be overlooked Eur J Intern Med (2014) S. Lee et al. Opioid and benzodiazepine use in the emergency department and the recognition of delirium within the first 24 hours of hospitalization J Psychosom Res (2022) A.J. Slooter et al. Delirium in critically ill patients Handb Clin Neurol (2017) E. Wang et al. Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomized controlled trials and observational studies Br J Anaesth (2023) E. Rollo et al. Physical restraint precipitates delirium in stroke patients J Neurol Sci (2021) H. Chen et al. The incidence and predictors of postoperative delirium after brain tumor resection in adults: A cross-sectional survey World Neurosurg (2020) J. Liu et al. Identifying hormones and other perioperative risk factors for postoperative delirium after endoscope-assisted transsphenoidal pituitary adenoma resection: A retrospective, matched cohort study Brain Behav (2023) P.R. Kappen et al. Delirium in neurosurgery: a systematic review and meta-analysis Neurosurg Rev (2022) J. Wang et al. Risk factors for the incidence of delirium in cerebrovascular patients in a Neurosurgery Intensive Care Unit: A prospective study J Clin Nurs (2018) There are more references available in the full text version of this article. From https://www.sciencedirect.com/science/article/abs/pii/S0967586824001279

Happy Birthday, Harvey!

It's Sunday again, so this is another semi-religious post so feel free to skip it I'm sure that many would think that Abide With Me is a pretty strange choice for my all-time favorite hymn, especially since it often shows up at funerals and memorial services. My dad was a Congregational (now United Church of Christ) minister so I was pretty regular in church attendance in my younger years. Some Sunday evenings, he would preach on a circuit and I'd go with him to some of these tiny churches. The people there, mostly older folks, liked the old hymns best - Fanny Crosby and so on. So, some of my "favorite hymns" are those that I sang when I was out with my Dad. Fond memories from long ago. In 1986 I was finally diagnosed with Cushing's after struggling with doctors and trying to get them to test for about 5 years. I was going to go into the NIH (National Institutes of Health) in Bethesda, MD for final testing and then-experimental pituitary surgery. I was terrified and sure that I wouldn't survive the surgery. Somehow, I found a 3-cassette tape set of Reader's Digest Hymns and Songs of Inspiration and ordered that. The set came just before I went to NIH and I had it with me. At NIH I set up a daily "routine" of sorts and listening to these tapes was a very important part of my day and helped me get through the ordeal of more testing, surgery, post-op and more. When I had my kidney cancer surgery, those tapes were long broken and irreplaceable, but I had replaced all the songs - this time on my iPod. Abide With Me was on this original tape set and it remains a favorite to this day. Whenever we have an opportunity in church to pick a favorite, my hand always shoots up and I request page 700. When someone in one of my handbell groups moves away, we always sign a hymnbook and give it to them. I sign page 700. I think that many people would probably think that this hymn is depressing. Maybe it is but to me it signifies times in my life when I thought I might die and I was so comforted by the sentiments here. This hymn is often associated with funeral services and has given hope and comfort to so many over the years - me included. If you abide in Me, and My words abide in you, you will ask what you desire, and it shall be done for you. ~John 15:7 Abide With Me Words: Henry F. Lyte, 1847. Music: Eventide, William H. Monk, 1861. Mrs. Monk described the setting: This tune was written at a time of great sorrow—when together we watched, as we did daily, the glories of the setting sun. As the last golden ray faded, he took some paper and penciled that tune which has gone all over the earth. Lyte was inspired to write this hymn as he was dying of tuberculosis; he finished it the Sunday he gave his farewell sermon in the parish he served so many years. The next day, he left for Italy to regain his health. He didn’t make it, though—he died in Nice, France, three weeks after writing these words. Here is an excerpt from his farewell sermon: O brethren, I stand here among you today, as alive from the dead, if I may hope to impress it upon you, and induce you to prepare for that solemn hour which must come to all, by a timely acquaintance with the death of Christ. For over a century, the bells of his church at All Saints in Lower Brixham, Devonshire, have rung out “Abide with Me” daily. The hymn was sung at the wedding of King George VI, at the wedding of his daughter, the future Queen Elizabeth II, and at the funeral of Nobel peace prize winner Mother Teresa of Calcutta in1997. Abide with me; fast falls the eventide; The darkness deepens; Lord with me abide. When other helpers fail and comforts flee, Help of the helpless, O abide with me. Swift to its close ebbs out life’s little day; Earth’s joys grow dim; its glories pass away; Change and decay in all around I see; O Thou who changest not, abide with me. Not a brief glance I beg, a passing word; But as Thou dwell’st with Thy disciples, Lord, Familiar, condescending, patient, free. Come not to sojourn, but abide with me. Come not in terrors, as the King of kings, But kind and good, with healing in Thy wings, Tears for all woes, a heart for every plea— Come, Friend of sinners, and thus bide with me. Thou on my head in early youth didst smile; And, though rebellious and perverse meanwhile, Thou hast not left me, oft as I left Thee, On to the close, O Lord, abide with me. I need Thy presence every passing hour. What but Thy grace can foil the tempter’s power? Who, like Thyself, my guide and stay can be? Through cloud and sunshine, Lord, abide with me. I fear no foe, with Thee at hand to bless; Ills have no weight, and tears no bitterness. Where is death’s sting? Where, grave, thy victory? I triumph still, if Thou abide with me. Hold Thou Thy cross before my closing eyes; Shine through the gloom and point me to the skies. Heaven’s morning breaks, and earth’s vain shadows flee; In life, in death, O Lord, abide with me. https://youtu.be/i5nbq_VEea0 http://cushieblog.files.wordpress.com/2012/04/maryo-butterfly-script1.gif

Abstract Avascular necrosis (AVN), also called osteonecrosis, stems from blood supply interruption to the bone and is often idiopathic. It has risk factors like trauma, alcohol, and corticosteroids. AVN in the talus (AVNT) is less common than in the femoral head. Most cases of talar osteonecrosis are associated with trauma, while a smaller proportion is linked to systemic conditions such as sickle cell disease or prolonged prednisone use. Glucocorticoids are a key nontraumatic cause. We report a middle-aged woman with Cushing’s syndrome symptoms, such as hypertension and moon face, since her youth. A few years ago, she experienced pain and swelling in her ankle, which was diagnosed as atraumatic AVNT and treated with hindfoot fusion. Years later, she was diagnosed with Cushing’s disease caused by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma in laboratory tests and imaging, which was resected in 2020. She experienced significant weight loss, and her Cushing’s syndrome symptoms were relieved after tumor resection. Mechanisms behind AVN in hypercortisolism involve fat cell hypertrophy, fat embolization, osteocyte apoptosis, and glucocorticoid-induced hypertension. Traditional X-rays may miss early AVN changes; MRI is preferred for early detection. Although there are some cases of femoral AVN caused by endogenous hypercortisolism in the literature, as far as we know, this is the first case of AVNT due to Cushing’s disease. AVNT treatment includes conservative approaches, hindfoot fusion, and core decompression. Cushing’s disease is a rare cause of AVNT, and a multidisciplinary approach aids in the rapid diagnosis of elusive symptoms. Introduction Avascular necrosis (AVN), also known as osteonecrosis, is a condition arising from the temporary interruption or permanent cessation of blood supply to a bone, leading to tissue necrosis or its demise. While AVN is frequently idiopathic, certain established risk factors are known including trauma, alcohol abuse, and the use of exogenous corticosteroids [1]. While not as prevalent as in the femoral head, AVN of the talus (AVNT) in the ankle presents a painful and disabling issue for patients and poses a challenging dilemma for orthopedic surgeons [2]. About 75% of cases of talar osteonecrosis stem from traumatic injuries, while approximately 25% of nontraumatic instances are typically associated with systemic conditions such as sickle cell disease or prolonged use of prednisone, which impede blood flow. [3] The use of glucocorticoids is one of the most important non-traumatic causes of AVN. Nevertheless, there are some case reports where AVN in the femoral head is reported as a manifestation of endogenous hypercortisolism, particularly associated with Cushing's syndrome [4-12]. In this article, we describe the case of a middle-aged woman who was diagnosed with idiopathic severe progressive AVNT for two years. She had retrogradely diagnosed masked symptoms of Cushing’s disease since her youth, but the diagnosis was confirmed after undergoing ankle arthrodesis. Case Presentation A 43-year-old woman visited our office in June 2018 with a complaint of severe pain and swelling in her left ankle, which had persisted for the past two years. She had hypertension since her youth and blurry vision since 2013 but had no other significant medical or family history. She was also diagnosed with major depressive disorder (MDD) in 2015 when she lost her husband. She had no history of smoking, alcohol consumption, or addiction. She had not experienced any significant trauma during this period and sought consultations from various specialties, including neurology, psychology, internal medicine, nephrology, rheumatology, and orthopedics. She had received a platelet-rich plasma (PRP) injection in the ankle, but it did not improve her symptoms. Despite undergoing various diagnostic workups, no precise diagnosis had been established. Back in 2013, she remembers suddenly experiencing blurry vision in her right eye. This condition underwent a misdiagnosis, which almost led to a loss of vision. She had been struggling with her eye problems until her last visit, during which she received intravitreal bevacizumab injections. Additionally, she previously had iron deficiency anemia, which was treated with ferrous sulfate before 2018. In our first visit, during the physical examination, the pain was localized in the ankle mortise with some posterolateral pain along the course of the peroneal tendons posterior to the fibula. Based on the physical examination and available ankle radiographs, we diagnosed AVNT. The patient subsequently underwent ankle arthroscopy through the standard anterior portals, the joint was cleaned, the synovium was shaved, and a small incision was conducted for peroneal assessment; this procedure revealed a subchondral collapse and extensive necrosis in the talus. Following the procedure, she experienced a partial improvement in her symptoms. However, six months later, she returned with a recurrence of symptoms (Figure 1). Upon further inquiry, she mentioned that her symptoms had recurred a month ago when she was dancing at a family party. Radiographs showed a stress fracture in her fibula and extensive AVNT. This diagnosis was confirmed through a CT scan, MRI, and bone scan (Figure 2). Figure 1: Ankle X-ray six months after arthroscopy Pain had reduced for four months, then pain increased with activity and disabled her after a night of dancing. Subchondral fracture and fibular stress fracture are evident (A and B, respectively). Figure 2: MRI, CT scan, and technetium-99m (Tc-99m) bone scan Coronal MRI confirmed avascular necrosis of the talar dome with subchondral fracture (A and B, respectively). CT scan (C) and Tc-99 bone scan (D) images also revealed the pathologies. In the second visit after arthroscopy, upon confirmation of a fibular stress fracture and significant subchondral collapse, and following a discussion of the next available options with the patient, the second procedure was performed as an ankle arthrodesis with an anterior approach. A 6 cm longitudinal incision was made anteriorly, and through the plane between the tibialis anterior and extensor hallucis longus, the ankle joint was accessed. Joint preparation was done with an osteotome, ensuring a bleeding surface on both sides. Then, manual compression with provisional pin fixation in the corrective position was performed. The fusion was planned at less than 5 degrees of valgus, 10 degrees of external rotation, and approximately 10 degrees of plantar flexion, suitable for the high-heeled shoes that she was using in her daily living activities. After confirming fluoroscopy in two planes, final 6.5 mm cannulated cancellous screws were used, and fixation was augmented with an anterior molded 4.5 mm narrow dynamic compression plate (DCP), according to our previously published anterior ankle fusion technique [13]. The foot was placed in a splint for 10 days, after which stitches were removed, and a cast was applied for four weeks. Then, walking with gradual, as-tolerated weight-bearing was initiated (Figure 3). Three months after surgery, she was pain-free, and by the sixth month, she could walk without any boot or brace, only using high-heeled shoes. Figure 3: Post-operative radiographies Six months after the ankle surgery, a huge osteonecrosis and fibular stress fracture were managed with an acceptable, painless ankle fusion (not solid) despite the remaining necrosis (A and B, respectively). In 2024, four years after the tumor resection, complete healing of talus necrosis and solid fusion were achieved (C and D, respectively). In 2020, two years after her ankle surgery, she was referred to an endocrinologist due to excessive weight gain and hirsutism. The biochemical assessment revealed the following: cortisol (8 AM) (chemiluminescence immunoassay (CLIA)) was 96 µg/dl (normal range: 4.82 - 19.5 µg/dl), and it was 22.1 µg/dl after overnight dexamethasone (normal range: < 1.8 µg/dl). Adrenocorticotropic hormone (ACTH) (CLIA) was 44.4 pg/ml (normal range: 7.2-63.3 pg/ml), and cortisol measured 5.7 µg/dl after the 48-hour low-dose dexamethasone suppression test (normal < 5 µg/dl). The results, along with symptoms (Table 1), are documented in the laboratory tests (Table 2). She was diagnosed with Cushing’s syndrome, which was subsequently confirmed as Cushing's disease due to an ACTH-producing pituitary adenoma observed in the MRI and Brain CT (Figure 4). Sign/symptom Severity Weight Gain Severe Hirsutism Severe Hypertension Severe Easy bruising Severe Depression Severe Moon face Moderate (masked with makeup) Lethargy Moderate Headache Moderate Peripheral edema _ Buffalo hump _ Myopathy _ Acne _ Purple striae _ Table 1: Cushing's disease symptoms and signs The hyphens in the table indicate that the patient does not have those symptoms or signs. Laboratory test Result Reference range Cortisol (8 AM) (CLIA) 96 µg/dl 4.82-19.5 µg/dl Cortisol (8 AM) (after overnight dexamethasone) (CLIA) 22.1 µg/dl <1.8 µg/dl ACTH (CLIA) 44.4 pg/ml 7.2-63.3 pg/ml Cortisol after 48 hours of LDDST (CLIA) 5.7 µg/dl < 5 µg/dl Table 2: Laboratory tests CLIA: chemiluminescence immunoassay; ACTH: adrenocorticotropic hormone; LDDST: low-dose dexamethasone suppression test Figure 4: Brain MRI Finally, a pituitary adenoma was diagnosed using a Brain MRI as the cause of Cushing’s disease symptoms (A and B). Finally, she underwent a tumor resection and had a dramatic response after treatment (30 kg weight loss). She revealed that she had Cushing’s syndrome symptoms since she was young. These symptoms included a puffy face, which she covered with makeup, high blood pressure, and hirsutism. In January 2024, four years after her brain surgery, during our last visit, her symptoms had significantly improved. She reported no problems with her ankle, and talus necrosis was completely healed, with a solid fusion achieved in radiographs (Figure 3). Discussion As far as we are aware, this case presentation represents the first instance of AVNT attributed to Cushing’s disease in the existing literature. Nevertheless, some individuals with endogenous Cushing's syndrome have been reported to experience AVN of the femoral head [4-12]. Cushing's syndrome is an uncommon endocrine condition marked by manifestations of hypercortisolism. The predominant cause is often an adenoma in the anterior pituitary gland that produces ACTH, referred to as Cushing's disease [14]. The presentation of Cushing's syndrome can vary significantly in both adults and children, influenced by the extent and duration of hypercortisolemia. However, the typical signs and symptoms of Cushing's syndrome are widely known [15]. Although some individuals may perceive these alterations as normal and physiological, the disease can go unnoticed for an extended period, as in our case, in which it remained undiagnosed for more than 20 years. However, it is known that steroid use is a significant contributing factor to the occurrence of bone osteonecrosis, accounting for up to 40% of non-traumatic instances of AVN [16]. The mechanisms leading to AVN due to either endogenous hypercortisolism or excess exogenous glucocorticoids are not completely understood. There are just some hypotheses that suggest that the hypertrophy of fat cells, embolization of fat, and osteocytes' apoptosis result in impaired blood flow in the bone, ultimately causing ischemic tissue necrosis [17]. An alternative proposed theory suggests that elevated levels of glucocorticoids may cause insulin resistance and subsequently contribute to AVN [18]. Traditional X-rays often fail to detect the initial changes of AVN (as observed in our case). MRI stands as the preferred method for identifying AVN in its early phases, providing an opportunity for timely therapeutic interventions [19,20]. In an analysis of 321 cases of AVNT, the predominant treatment modalities included conservative therapies (n = 104), hindfoot fusion (n = 62), and core decompression (n = 85) [21]. These approaches reflect the primary methods employed in contemporary clinical practice for addressing AVNT. After all, we confirmed the AVNT diagnosis using MRI and bone scan and managed it with hindfoot fusion. Subsequently, the underlying issue, endogenous hypercortisolism due to an ACTH-producing pituitary adenoma, was identified and treated through resection of the tumor (Figure 5). Figure 5: Case report timeline * Avascular necrosis in the talus Conclusions Cushing’s syndrome is a rare endocrine disorder characterized by excessive cortisol levels, commonly caused by an ACTH-producing adenoma in the pituitary gland, known as Cushing’s disease. Cushing’s disease may be one of the rare causes of AVNT. To the best of our knowledge, this is the first instance of AVNT due to Cushing’s disease described in the literature. Since atraumatic AVNT is rare in itself, a multidisciplinary approach can lead us to a more rapid and proper diagnosis, as each symptom may be masked or considered rare within its subspecialty field. References Chang CC, Greenspan A, Gershwin ME: Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum. 1993, 23:47-69. 10.1016/s0049-0172(05)80026-5 Zhang H, Fletcher AN, Scott DJ, Nunley J: Avascular osteonecrosis of the talus: current treatment strategies. Foot Ankle Int. 2022, 43:291-302. 10.1177/10711007211051013 Parekh SG, Kadakia RJ: Avascular necrosis of the talus. J Am Acad Orthop Surg. 2021, 29:e267-78. 10.5435/JAAOS-D-20-00418 Belmahi N, Boujraf S, Larwanou MM, El Ouahabi H: Avascular necrosis of the femoral head: an exceptional complication of Cushing's disease. Ann Afr Med. 2018, 17:225-7. 10.4103/aam.aam_75_17 Salazar D, Esteves C, Ferreira MJ, Pedro J, Pimenta T, Portugal R, Carvalho 😧 Avascular femoral necrosis as part of Cushing syndrome presentation: a case report. J Med Case Rep. 2021, 15:287. 10.1186/s13256-021-02882-7 Alaya Z, Braham M, Bouajina E: Aseptic femur head necrosis revealing Cushing's disease: a rare presentation. J Clin Surg Res. 2020, 1:10.31579/2768-2757/002 Phillips KA, Nance EP Jr, Rodriguez RM, Kaye JJ: Avascular necrosis of bone: a manifestation of Cushing's disease. South Med J. 1986, 79:825-9. 10.1097/00007611-198607000-00011 Koch CA, Tsigos C, Patronas NJ, Papanicolaou DA: Cushing's disease presenting with avascular necrosis of the hip: an orthopedic emergency. J Clin Endocrinol Metab. 1999, 84:3010-2. 10.1210/jcem.84.9.5992 Modroño N, Torán CE, Pavón I, Benza ME, Guijarro G, Navea 😄 Cushinǵs syndrome and avascular hip necrosis: presentation of two patients [Article in Spanish]. Rev Clin Esp (Barc). 2014, 214:e93-6. 10.1016/j.rce.2014.05.003 Camporro F, Bulacio E, Gutiérrez Magaldi I: Bilateral osteonecrosis of the hip secondary to endogenous Cushing's syndrome due to a recently-diagnosed carcinoid tumour of the lung [Article in Spanish]. Med Clin (Barc). 2016, 147:228. 10.1016/j.medcli.2016.03.042 Ha JS, Cho HM, Lee HJ, Kim SD: Bilateral avascular necrosis of the femoral head in a patient with asymptomatic adrenal incidentaloma. Hip Pelvis. 2019, 31:120-3. 10.5371/hp.2019.31.2.120 Anand A, Jha CK, Singh PK, Sinha U, Ganesh A, Bhadani PP: Avascular necrosis of femur as a complication of Cushing's syndrome due to adrenocortical carcinoma. Am Surg. 2023, 89:2701-4. 10.1177/00031348221129510 Gharehdaghi M, Rahimi H, Mousavian A: Anterior ankle arthrodesis with molded plate: technique and outcomes. Arch Bone Jt Surg. 2014, 2:203-9. Lindholm J, Juul S, Jørgensen JO, et al.: Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001, 86:117-23. 10.1210/jcem.86.1.7093 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 Konarski W, Poboży T, Konarska K, Śliwczyński A, Kotela I, Hordowicz M, Krakowiak J: Osteonecrosis related to steroid and alcohol use-an update on pathogenesis. Healthcare (Basel). 2023, 11:1846. 10.3390/healthcare11131846 Chan KL, Mok CC: Glucocorticoid-induced avascular bone necrosis: diagnosis and management. Open Orthop J. 2012, 6:449-57. 10.2174/1874325001206010449 Hartmann K, Koenen M, Schauer S, Wittig-Blaich S, Ahmad M, Baschant U, Tuckermann JP: Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev. 2016, 96:409-47. 10.1152/physrev.00011.2015 Kaste SC, Karimova EJ, Neel MD: Osteonecrosis in children after therapy for malignancy. AJR Am J Roentgenol. 2011, 196:1011-8. 10.2214/AJR.10.6073 Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA: Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med. 2015, 8:221-7. 10.1007/s12178-015-9279-6 Gross CE, Haughom B, Chahal J, Holmes GB Jr: Treatments for avascular necrosis of the talus: a systematic review. Foot Ankle Spec. 2014, 7:387-97. 10.1177/1938640014521831 From https://www.cureus.com/articles/221491-talus-avascular-necrosis-as-a-rare-complication-of-cushings-disease-a-case-report?score_article=true#!/

Thanks to AI, this year I was able to see a whole lot of zebras outside a hospital

Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of medications to treat severe endocrinologic, oncologic, metabolic and neurologic disorders by modulating the effects of the hormone cortisol, today announced completion of enrollment in GRADIENT, a Phase 3 trial of its proprietary selective cortisol modulator relacorilant in patients with Cushing’s syndrome (hypercortisolism) caused by an adrenal adenoma or adrenal hyperplasia. “Hypercortisolism with adrenal etiology affects many patients and is associated with serious cardiometabolic comorbidities, including hypertension and hyperglycemia, and increased risk of premature death,” said Bill Guyer, PharmD, Corcept’s Chief Development Officer. “GRADIENT is the first prospective placebo-controlled study to be conducted exclusively in these patients with Cushing’s syndrome. We expect data from GRADIENT in the fourth quarter of this year.” GRADIENT is a randomized, double-blind, placebo-controlled trial conducted at sites in the United States, Europe and Israel. One-hundred thirty-seven patients were randomized 1:1 to receive relacorilant or placebo for 22 weeks. Primary endpoints are improvement in glucose metabolism and hypertension. About Cushing’s Syndrome (Hypercortisolism) Cushing’s syndrome is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. Symptoms vary, but most patients experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system and can be lethal if not treated effectively. About Relacorilant Relacorilant is a selective cortisol modulator that binds to the glucocorticoid receptor (GR), but does not bind to the body's other hormone receptors. Corcept is studying relacorilant in a variety of serious disorders, including ovarian, adrenal and prostate cancer and Cushing’s syndrome. Relacorilant is proprietary to Corcept and is protected by composition of matter, method of use and other patents. Relacorilant has orphan drug designation in the United States and the European Union for the treatment of Cushing’s syndrome. About Corcept Therapeutics For over 25 years, Corcept’s focus on cortisol modulation and its potential to treat patients across a wide variety of serious disorders has led to the discovery of more than 1,000 proprietary selective cortisol modulators. Corcept’s advanced clinical trials are being conducted in patients with hypercortisolism, solid tumors, amyotrophic lateral sclerosis (ALS) and liver disease (NASH). In February 2012, the company introduced Korlym, the first medication approved by the U.S. Food and Drug Administration for the treatment of patients with Cushing’s syndrome. Corcept is headquartered in Menlo Park, California. For more information, visit Corcept.com. Forward-Looking Statements Statements in this press release, other than statements of historical fact, are forward-looking statements based on our current plans and expectations that are subject to risks and uncertainties that might cause our actual results to differ materially from those such statements express or imply. These risks and uncertainties include, but are not limited to, our ability to operate our business; risks related to the study and development of Korlym as well as relacorilant, miricorilant, dazucorilant and our other product candidates, including their clinical attributes, regulatory approvals, mandates, oversight and other requirements; and the scope and protective power of our intellectual property. These and other risks are set forth in our SEC filings, which are available at our website and the SEC’s website. In this press release, forward-looking statements include those concerning the development of relacorilant as a treatment for Cushing’s syndrome, and design, timing and expectations regarding our GRADIENT trial. We disclaim any intention or duty to update forward-looking statements made in this press release. From https://finance.yahoo.com/news/corcept-completes-enrollment-phase-3-120000179.html

Wow - a lot has happened since I first shared this post. If you look at the timestamp, I'm writing this at 4:20 am and I've been awake for an hour, even though I'm exhausted. I have been back on Growth Hormone although it doesn't seem to do me any good. I also had my knee replaced last March and I shared more about that in Bee’s Knees: TKR, Finally! I plan to get the other one done, presumably after next summer.

Comment from the blog: Thank you Mary. I had surgery to remove pituitary tumor caused by Cushings in 2013. I am just starting to see some returning symptoms. Chronic stiff neck bloating belly gummy eyes. It feels like I am wearing a bras that is 5 times too small for me but I don’t have a bras on. A tightness across my back. 4 days ago one red spot showed up that I know is bleeding under the skin but I never knew the name of it. Now I know it is purpura because of this diagram. I know enough now that anything that looks strange on my body I take pictures of to show the doctor. Having your site is reassuring. I am still learning from it.

Even though this was from two years ago, I don't think that there have been any significant changes in the many symptoms of Cushing's. Today's News Item proclaimed loftily But will enough doctors actually allow patients to get that far or will they still blow them off?

PET/MRI could become the diagnostic method of choice over MRI alone for identifying small pituitary tumors associated with Cushing disease, according to a study published March 21 in the Journal of Nuclear Medicine. In patients diagnosed with the disease yet who had inconclusive MRI results, PET/MRI was positive in 100% of cases, noted lead author Ilanah Pruis, a doctoral student at Erasmus University Medical Center in Rotterdam, Netherlands. “This multimodal imaging technique provides a welcome improvement for diagnosis, planning of surgery, and clinical outcome in patients with Cushing disease,” the authors wrote. Cushing disease is characterized by small tumors in pituitary glands, which causes them to secrete excess cortisol, the authors explained. While it is a rare disease, over time it can cause severely disabling conditions, such as high blood pressure or type II diabetes. Currently, guidelines recommend the use of MRI and inferior petrosal sinus sampling (IPSS) to diagnose these tumors. IPSS is an invasive procedure in which cortisol hormone levels are sampled from the veins that drain the pituitary gland. In up to 40% of patients, however, MRI is inconclusive, as the lesions are smaller than 10 millimeters in diameter. Even advanced MRI techniques, such as dynamic perfusion imaging, can leave small lesions undetected in up to one third of patients, the authors noted. In preclinical work, PET imaging using a radiotracer named F-18 FET has been shown to bind with high affinity to a molecular target in pituitary tumors, and in this study, the researchers aimed to test this technique combined with MRI in a multimodal approach. The researchers analyzed results from 22 patients (68% women; mean age 48 years) who underwent F-18 FET PET/MRI at Erasmus MC between February 2021 and December 2022. All patients showed a clear pituitary tumor F-18 FET-PET/MRI, whereas reading of the MRI alone yielded a suspected lesion in only 50%, the authors found. T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine. Importantly, 16 patients underwent treatment based on the results -- either surgery, Gamma Knife, or CyberKnife therapy -- with 12 of these patients achieving short-term remission, the authors noted. “[F-18 FET-PET/MRI] is of great clinical value because it allows precision surgery and targeted Gamma Knife or CyberKnife therapy,” the group wrote. The researchers noted that only one previous study evaluated F-18 FET-PET/MRI in these patients and that their study was limited, given the relatively small number of patients. “Future studies will be directed at head-to-head comparisons of the performance of F-18 FET- PET and other diagnostic techniques, including advanced MRI sequences… preferably in patients at the time of initial clinical presentation,” the authors concluded. A link to the full study can be found here. From https://www.auntminnie.com/clinical-news/molecular-imaging/article/15667496/petmri-may-improve-diagnosis-of-cushing-disease

Please join in a Virtual Town Hall Meeting on Cushing's Awareness Day! Mark your calendars for Monday, April 8, 2024, from 7 - 8 pm EST as we shed light on Cushing's syndrome with two incredible people who are living with this condition. Gain valuable insights, hear personal stories, and learn more about Cushing's syndrome from those who understand it firsthand. Don't miss this opportunity to connect, learn and show your support. Register now to secure your spot: https://www.eventbrite.com/.../cushings-awareness-day.... Let's come together to raise awareness and foster understanding. #CushingsAwareness

Comment from https://cushieblog.com/2024/04/01/day-1-cushings-awareness-challenge-2016/ Great post which sums up the doctor patient relationship quite well. And by extension my marital relationship as my husband believed the doctor. I finished my memoir and am happy to say I covered all those points. An agent read my first chapter and asked me to send her the full manuscript. I am waiting for her to read it and get back to me. I’m with you. More people need to know about this illness. I’m hoping to get my story published. You are doing such a wonderful job of awareness. Thank you for your tireless work Mary O.

Somehow, the fact that April 1 was fast approaching slipped my mind this year but here we are. Every month seems to be Cushing’s Awareness Month as more and more people are learning about Cushing's. It doesn’t seem like the diagnostic process is getting any easier, though. I read posts on here, on Facebook, in my inbox and people still aren’t getting the answers they need from doctors. I’ve had my license tags (CUSH1E) for many years and just last week someone mentioned them - and I could share about Cushing’s once again. They make is so easy to start a conversation. While American actress Amy Schumer is spreading the word about Cushing’s in general, I think that in some ways she is hurting things for everyone else. CBS News reports that “she says she now feels ‘reborn’ after her diagnosis, and while some forms of Cushing can be fatal, she has a type that ‘will just work itself out.’” How many others will try to get diagnosed and only be told not to worry, that it “will just work itself out”?

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

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. Araujo-Castro M, Acitores Cancela A, Vior C, Pascual-Corrales E, Rodríguez Berrocal V : Radiological Knosp, revised-Knosp, and Hardy-Wilson classifications for the prediction of surgical outcomes in the endoscopic endonasal surgery of pituitary adenomas: study of 228 cases. Front Oncol 11 : 807040, 2022 4. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, et al : Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 93 : 2454-2462, 2008 5. Brady Z, Garrahy A, Carthy C, O’Reilly MW, Thompson CJ, Sherlock M, et al : Outcomes of endoscopic transsphenoidal surgery for Cushing’s disease. BMC Endocr Disord 21 : 36, 2021 6. Brichard C, Costa E, Fomekong E, Maiter D, Raftopoulos C : Outcome of transsphenoidal surgery for cushing disease: a single-center experience over 20 years. World Neurosurg 119 : e106-e117, 2018 7. Broersen LHA, Biermasz NR, van Furth WR, de Vries F, Verstegen MJT, Dekkers OM, et al : Endoscopic vs. microscopic transsphenoidal surgery for Cushing’s disease: a systematic review and meta-analysis. Pituitary 21 : 524-534, 2018 8. Cebula H, Baussart B, Villa C, Assié G, Boulin A, Foubert L, et al : Efficacy of endoscopic endonasal transsphenoidal surgery for Cushing’s disease in 230 patients with positive and negative MRI. Acta Neurochir (Wien) 159 : 1227-1236, 2017 9. Chandler WF, Barkan AL, Hollon T, Sakharova A, Sack J, Brahma B, et al : Outcome of transsphenoidal surgery for cushing disease: a singlecenter experience over 32 years. Neurosurgery 78 : 216-223, 2016 10. Ciric I, Zhao JC, Du H, Findling JW, Molitch ME, Weiss RE, et al : Transsphenoidal surgery for Cushing disease: experience with 136 patients. Neurosurgery 70 : 70-80; discussion 80-81, 2012 11. Clayton RN, Raskauskiene D, Reulen RC, Jones PW : Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 96 : 632-642, 2011 12. Dai C, Feng M, Sun B, Bao X, Yao Y, Deng K, et al : Surgical outcome of transsphenoidal surgery in Cushing’s disease: a case series of 1106 patients from a single center over 30 years. Endocrine 75 : 219-227, 2022 13. Doglietto F, Maira G : Cushing disease and negative magnetic resonance imaging finding: a diagnostic and therapeutic challenge. World Neurosurg 77 : 445-447, 2012 14. Erkan B, Barut O, Akbas A, Akpinar E, Akdeniz YS, Tanriverdi O, et al : Results of endoscopic surgery in patients with pituitary adenomas : association of tumor classification grades with resection, remission, and complication rates. J Korean Neurosurg Soc 64 : 608-618, 2021 15. Fang J, Xie S, Li N, Jiang Z : Postoperative complications of endoscopic versus microscopic transsphenoidal pituitary surgery: a meta-analysis. J Coll Physicians Surg Pak 28 : 554-559, 2018 16. Feng M, Liu Z, Liu X, Bao X, Yao Y, Deng K, et al : Diagnosis and outcomes of 341 patients with Cushing’s disease following transsphenoid surgery: a single-center experience. World Neurosurg 109 : e75-e80, 2018 17. Fleseriu M, Hamrahian AH, Hoffman AR, Kelly DF, Katznelson L; AACE Neuroendocrine, Pituitary Scientific Committee : American Association of Clinical Endocrinologists and American College of Endocrinology Disease state clinical review: diagnosis of recurrence in Cushing disease. Endocr Pract 22 : 1436-1448, 2016 18. Hakami OA, Ahmed S, Karavitaki N : Epidemiology and mortality of Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab 35 : 101521, 2021 19. Hameed N, Yedinak CG, Brzana J, Gultekin SH, Coppa ND, Dogan A, et al : Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience. Pituitary 16 : 452-458, 2013 20. Hardy J, Vezina JL : Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neurol 15 : 261-273, 1976 21. Juszczak A, Ertorer ME, Grossman A : The therapy of Cushing’s disease in adults and children: an update. Horm Metab Res 45 : 109-117, 2013 22. Knosp E, Steiner E, Kitz K, Matula C : Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33 : 610-617; discussion 617-618, 1993 23. Lambert JK, Goldberg L, Fayngold S, Kostadinov J, Post KD, Geer EB : Predictors of mortality and long-term outcomes in treated Cushing’s disease: a study of 346 patients. J Clin Endocrinol Metab 98 : 1022-1030, 2013 24. Lüdecke DK, Flitsch J, Knappe UJ, Saeger W : Cushing’s disease: a surgical view. J Neurooncol 54 : 151-166, 2001 25. Mamelak AN, Dowd CF, Tyrrell JB, McDonald JF, Wilson CB : Venous angiography is needed to interpret inferior petrosal sinus and cavernous sinus sampling data for lateralizing adrenocorticotropin-secreting adenomas. J Clin Endocrinol Metab 81 : 475-481, 1996 26. McCance DR, McIlrath E, McNeill A, Gordon DS, Hadden DR, Kennedy L, et al : Bilateral inferior petrosal sinus sampling as a routine procedure in ACTH-dependent Cushing’s syndrome. Clin Endocrinol (Oxf) 30 : 157-166, 1989 27. Netea-Maier RT, van Lindert EJ, den Heijer M, van der Eerden A, Pieters GF, Sweep CG, et al : Transsphenoidal pituitary surgery via the endoscopic technique: results in 35 consecutive patients with Cushing’s disease. Eur J Endocrinol 154 : 675-684, 2006 28. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al : The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 93 : 1526-1540, 2008 29. Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, et al : Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 325 : 897-905, 1991 30. Petersenn S, Beckers A, Ferone D, van der Lely A, Bollerslev J, Boscaro M, et al : Therapy of endocrine disease: outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. Eur J Endocrinol 172 : R227-R239, 2015 31. Prevedello DM, Pouratian N, Sherman J, Jane JA Jr, Vance ML, Lopes MB, et al : Management of Cushing’s disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. 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

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

Oh no, Shagufta! I cannot imagine what you're going through. Where are you located?

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

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#!/

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. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2023;189(1):G1–42. Article PubMed Google Scholar Young WFJr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601–10. Article Google Scholar Rowe NE, Kumar R, Schieda N, et al. Diagnosis, management, and follow-up of the incidentallydiscoveredadrenalmass: CUAguidelineendorsed by the AUA. J Urol. 2023;210(4):590–9. Article PubMed Google Scholar Masiakos PT, Gerstle JT, Cheang T, Viero S, Kim PC, Wales P. Is surgery necessary for incidentally discovered adrenal masses in children?J. Pediatr Surg. 2004;39(5):754–8. Article Google Scholar Lee JM, Kim MK, Ko SH et al. Clinical guidelines for the management of adrenal incidentaloma. Endocrinol Metab. 2017;32(2). Terzolo M, Stigliano A, Chiodini I, et al. AME position statement on adrenal incidentaloma. Eur J Endocrinol. 2011;164(6):851–70. Article CAS PubMed Google Scholar Boland GW, Blake MA, Hahn PF, Mayo-Smith WW. Incidental adrenal lesions: principles, techniques, and algorithms for imaging characterization. Radiology. 2008;249(3):756–75. Article PubMed Google Scholar Payabyab EC, Balasubramaniam S, Edgerly M, et al. Adrenocortical cancer: a molecularlycomplexdiseasewheresurgerymatters. Clin Cancer Res. 2016;22(20):4989–5000. Article CAS PubMed Google Scholar Angeli A, Osella G, Alì A, Terzolo M. Adrenal incidentaloma: an overview of clinical and epidemiological data from the National Italian Study Group. Horm Res. 1997;47(4–6):279–83. Article CAS PubMed Google Scholar Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (incidentaloma). Ann Intern Med. 2003;138(5):424–9. Article PubMed Google Scholar Zhang K, Zhang Y, Zhang Y, Chao M. A retrospective analysis of the clinical characteristics of 207 hospitalized children with adrenal masses. Front Pediatr. 2023;11:1215095. Article PubMed PubMed Central Google Scholar Nuchtern JG, London WB, Barnewolt CE, et al. A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children‘s oncology group study. Ann Surg. 2012;256(4):573–80. Article PubMed Google Scholar Virgone C, Roganovic J, Vorwerk P, et al. Adrenocortical tumours in children and adolescents: the EXPeRT/PARTNER diagnostic and therapeutic recommendations. Pediatr Blood Cancer. 2021;68(suppl 4):e29025. Article PubMed Google Scholar Chang S, Lin Y, Yang S, et al. Safety and feasibility of laparoscopic resection of abdominal neuroblastoma without image-defined risk factors: a single-center experience. World J Surg Oncol. 2023;21(1):113. Article PubMed PubMed Central Google Scholar Zenitani M, Yoshida M, Matsumoto S, et al. Feasibility and safety of laparoscopic tumor resection in children with abdominal neuroblastomas. Pediatr Surg Int. 2023;39(1):91. Article PubMed Google Scholar International Pediatric Endosurgery Group. IPEG guidelines for the surgical treatment of adrenal masses in children. J Laparoendosc Adv Surg Tech A. 2010;20(2):vii–ix. Google Scholar Nakanishi H, Miangul S, Wang R, et al. Open versuslaparoscopicsurgery in the management of adrenocorticalcarcinoma: a systematicreview and meta-analysis. Ann Surg Oncol. 2023;30(2):994–1005. Article PubMed Google Scholar Gaillard M, Razafinimanana M, Challine A, et al. Laparoscopic or openadrenalectomy for stage I-IIadrenocorticalcarcinoma: a retrospectivestudy. J Clin Med. 2023;12(11):3698. Article PubMed PubMed Central Google Scholar Utsumi T, Iijima S, Sugizaki Y, et al. Laparoscopic adrenalectomy for adrenal tumors with endocrine activity: perioperative management pathways for reduced complications and improved outcomes. 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. 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Reprints and permissions From https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-024-04673-7

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.