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Abstract Background Endoscopic endonasal surgery is the main transsphenoidal approach for pituitary surgery in many centers, however few studies compare the endoscopic and microscopic surgical approach with regard to long-term follow-up. This single-center study aimed to compare the two techniques over 15 years. Methods Medical records and magnetic resonance images from 40 patients with primary transsphenoidal surgery for Cushing’s disease at Sahlgrenska University Hospital between 2003 and 2018 were reviewed. Fourteen patients who underwent microscopic surgery and 26 patients who underwent endoscopic surgery were included in this study. Results In the microscopic group, 12 of 14 patients achieved endocrine remission, compared to 19 of 26 patients in the endoscopic group (n. s.). Three patients in each group developed a late recurrence. Complications were seen in 5 patients in the microscopic group and in 8 patients in the endoscopic group (n. s.). No serious complications, such as carotid artery damage, cerebrovascular fluid leakage, epistaxis, or meningitis, occurred in any group. The postoperative hospital stay was shorter in the endoscopic than the microscopic group. Conclusion Endoscopic endonasal surgery for Cushing’s disease showed no difference in remission, recurrence, and complication rates compared to the microscopic approach. The endoscopic group had a shorter postoperative hospital stay than the microscopic group, which in part may be due to the minimal invasiveness of the endoscopic approach. References (0) Cited by (0) Recommended articles (6) Research article Identifying obstructive sleep apnea in patients with epilepsy: A cross-sectional multicenter study Seizure, Volume 100, 2022, pp. 87-94 Show abstract Research article Nursing Home Characteristics Associated with High and Low Levels of Antipsychotic, Benzodiazepine, and Opioid Prescribing to Residents with Alzheimer’s Disease and Related Dementias: A Cross-Sectional Analysis Journal of the American Medical Directors Association, 2022 Show abstract Research article Association between sensory impairments and restricted social participation in older adults: A cross-sectional study Collegian, 2022 Show abstract Research article Percutaneous Intervertebral-Vacuum Polymethylmethacrylate Injection for Foraminal Stenosis with Degenerative Lumbar Scoliosis World Neurosurgery, 2022 Show abstract Research article Predictors of Emergency Department service outcome for people brought in by police: A retrospective cohort study International Emergency Nursing, Volume 63, 2022, Article 101188 Show abstract Research article Interdisciplinary Care Coordination in Chronic Viral Hepatitis C The Journal for Nurse Practitioners, 2022 Show abstract Conflicts of interest The authors have no conflicts of interest. Author statements Conceptualization: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Data curation: Dan Farahmand, Erica Backlund, J. Carlqvist, T. Skoglund, T. Hallén, O. Ragnarsson, P. Trimpou. Formal Analysis: D. Farahmand, E. Backlund Funding acquisition: D. Farahmand Investigation: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Methodology: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Project administration: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Supervision: D. Farahmand Writing – original draft: Penelope Trimpou Writing – review & editing: E. Backlund, O. Ragnarsson, T. Skoglund, T. Hallén, G. Gudnadottir, J. Carlqvist and D. Farahmand. View full text From https://www.sciencedirect.com/science/article/abs/pii/S1878875022009640

Background Cushing’s disease (CD) is among the most common etiologies of hypercortisolism. Magnetic resonance imaging (MRI) is often utilized in the diagnosis of CD, however, up to 64% of adrenocorticotropic hormone (ACTH)-producing pituitary microadenomas are undetectable on MRI. We report 15 cases of MRI negative CD who underwent surgical resection utilizing a purely endoscopic endonasal approach. Methods Endoscopic endonasal transsphenoidal surgery (EETS) was performed on 134 CD cases by a single surgeon. Fifteen cases met inclusion criteria: no conclusive MRI studies and no previous surgical treatment. Data collected included signs/symptoms, pre- and post-operative hormone levels, and complications resulting from surgical or medical management. Data regarding tumor diameter, location, and tumor residue/recurrence was obtained from both pre- and post-operative MRI. Immunohistochemistry was performed to assess for tumor hormone secretion. Results Aside from a statistically significant difference (P = 0.001) in histopathological results between patients with negative and positive MRI, there were no statistically significant difference between these two groups in any other demographic or clinical data point. Inferior petrosal sinus sampling (IPSS) with desmopressin (DDAVP®) administration was performed on the 15 patients with inconclusive MRIs to identify the origin of ACTH hypersecretion via a central/peripheral (C/P) ratio. IPSS in seven, five and three patients showed right, left, and central side lateralization, respectively. With a mean follow-up of 5.5 years, among MRI-negative patients, 14 (93%) and 12 patients (80%) achieved early and long-term remission, respectively. In the MRI-positive cohort, over a mean follow-up of 4.8 years, 113 patients (94.9%) and 102 patients (85.7%) achieved initial and long-term remission, respectively. Conclusions Surgical management of MRI-negative/inconclusive Cushing’s disease is challenging scenario requiring a multidisciplinary approach. An experienced neurosurgeon, in collaboration with a dedicated endocrinologist, should identify the most likely location of the adenoma utilizing IPSS findings, followed by careful surgical exploration of the pituitary to identify the adenoma. Peer Review reports Introduction Cushing’s disease (CD) is the most common cause of hypercortisolism [1]. Left untreated, CD can result in multiple complications, most often cardiovascular disease or infection, and has a mortality rate 1.7–4.8-times higher than the general population [2,3,4]. Although MRI is the imaging modality of choice for identifying these tumors, imaging is often inconclusive [5]. Prior studies have shown that adrenocorticotropic hormone (ACTH)-producing pituitary microadenomas are undetectable on MRI in 36–64% of cases [5]. However, the development and widespread utilization of 3-T MRI (3TMRI) has led to much higher tumor detection rates [6, 7]. With a negative predictive value of approximately 19–94% and variable sensitivity and specificity, anywhere from 4 to 54% of MRIs are incorrectly reported, especially in the setting of ACTH-secreting pituitary adenomas [8, 9]. With such variation in radiographic appearance, reliance on imaging for the management of CD patients can cause significant uncertainty for neurosurgeons and endocrinologists alike. The choice approach in the surgical management of these adenomas is via an endoscopic endonasal transsphenoidal surgery (EETS) [2, 10, 11], resulting in overall post-operative remission rates of 64–93% globally and 50–71% for cases without a conclusive MRI [12,13,14,15]. Inconclusive MRIs pose a significant challenge in the surgical management of CD, with the decision to pursue surgery for MRI-negative CD remaining highly controversial [8, 10, 14, 16]. In this study, we report 15 cases of CD without positive MRIs who underwent adenoma resection via EETS. Patients, materials and methods Patients population Between January 2005 and December 2018, EETS was performed in 134 CD cases by a single surgeon at Loghman hakim and Erfan hospitals. Of those patients, 15 cases met inclusion criteria: inconclusive MRI studies and no prior surgical treatment. The population consisted of 12 women (mean age 32.5 years; range 14–65 years) and 3 men (mean age 35 years; range 22–60 years). Data collected included signs/symptoms, pre- and post-operative hormone levels, and complications resulting from surgical or medical management. Data regarding tumor diameter, location, and tumor residue/recurrence was obtained from both pre- and post-operative MRIs. Immunohistochemistry was performed to assess for tumor hormone secretion. Ethics approval and consent to participate All procedures performed in this study involving human participants were in accordance with the ethical standards and approved by the Shahid Beheshti Medical University (SBMU) Ethical Committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Also, a written informed consent was obtained from all subjects (or their parent or legal guardian in the case of children under 16). Imaging All patients underwent pre- and post-operative dynamic pituitary MRI via a superconducting 1.5-T scanner. Prior to gadolinium injection, T1-weighted Spin Echo (SE) and T2-weighted turbo SE images, followed by coronal dynamic acquisition (T1-weighted turbo SE), were obtained in the coronal plane using the following protocol: TR/TE, 400/20 ms; 288 · 192 matrix; two excitations; 18 · 18 cm field of view (FOV); 3 mm in thickness with 0.3-mm intersection gap. Afterwards, with simultaneous gadolinium injection, coronal and sagittal T1-weighted SE images were obtained 2 minutes following injection. All images were independently reviewed by both a radiologist and a neurosurgeon. MRIs studies were categorized into direct and indirect signs of CD. Direct signs consisted of any inhomogeneity found in the pituitary, such as a lesions with diminished enhancement. Indirect signs included pituitary stalk deviation and bulging or erosion of the sellar contour. MRI studies were considered negative (normal) if no direct or indirect signs were identified. In some cases, small lesions with diameters under 6 mm may be seen on MRI however are not considered indicative of CD due to the high prevalence of incidentalomas in this region. MRIs in which these lesions were present were classified as inconclusive. Any uncertainty in interpreting the MRIs by any of the reviewers resulted in exclusion of the image from this study. Pre-operative endocrine examination All cases were ACTH-dependent Cushing syndrome showing clinical features including weight gain, proximal myopathy, and wide base purple striae. Furthermore, all cases demonstrated laboratory abnormalities consistent with CD, including increased 24-hour urinary free cortisol (UFC) excretion, loss of the cortisol circadian rhythm, high basal ACTH level, failure of low-dose dexamethasone to suppress cortisol secretion in addition to serum suppression or 24-hour UFC after high-dose dexamethasone. Additionally, pre- and post-operative levels of anterior pituitary hormone including prolactin, growth hormone (GH), insulin-like growth factor I (IGF-I), thyroid stimulating hormone (TSH), free/total Triiodothyronine (T3)/ Thyroxine (T4), follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and free/total testosterone (men) or estradiol (premenopausal women) were measured. The 15 cases of MRI negative CD were diagnosed and categorized according to their endocrine profile in order to distinguish the ACTH-dependent CD from pseudo-cushing syndrome. Bilateral inferior petrosal sinus sampling (BIPSS) All 15 cases of MRI-negative ACTH-dependent Cushing’s syndrome underwent bilateral inferior petrosal sinus sampling (BIPSS). To confirm that the elevated ACTH secretion originated from the pituitary, BIPSS was simultaneously performed with central/peripheral (C/P) ACTH gradient measurement, utilizing the calculations described by Oldfield et al. [17]. No significant complications occurred in performing the procedures. A petrosal to peripheral ACTH ratio ≥ 2.0 in the basal state, a peak ratio ≥ 3.0 after desmopressin (DDAVP®) administration, or a normalized IPS:P ratio > 0.8 were considered diagnostic of CD. Additionally, tumor lateralization was specified when the interpetrosal gradient ratio of ACTH was ≥1.4 [18]. Endoscopic Endonasal Transsphenoidal surgical approach All patients underwent surgery by a single neurosurgeon and otolaryngologist (ENT) with extensive experience in pituitary tumor excision via EETS. Exposure to the sellar floor was provided by an ENT surgeon while drilling of the sella was performed by the neurosurgeon. Extensive drilling of the sellar floor laterally up to the carotid artery bilaterally provided a wide view of the medial wall of the cavernous sinus as well as exposure of the anterior and posterior intercavernous sinuses was performed in all cases. The dura was then opened to expose the pituitary gland. Following tumor identification, adenomectomy was performed with selective removal of a rim of normal pituitary tissue. In cases where a tumor was not visualized on initial exposure of the pituitary, the pituitary gland was explored laterally via a horizontal paramedian incision on the IPSS suggesting side. If a tumor was not visualized at this stage, a vertical paramedian incision was then performed. In some cases, a cream-like substance was drained from the pituitary incision. Although this was suspicious of a tumor and tissue biopsy was obtained, it was not considered a definite tumor diagnosis and thus surgical exploration (EXP) was done in the same manner on the other side of the pituitary. In the scenario where no distinct adenoma was found, both sides of the pituitary gland underwent EXP with emphasis on lateralizing sides distinguished by IPSS. However, we did not rely solely on IPSS lateralization, as whole gland EXP was performed in all cases. Although ACTH secreting pituitary adenomas are the most common cause of Cushing syndrome, pituitary adenomas can also be ectopic, forming outside of the sella turcica with no direct connection to the pituitary gland [19]. After EXP of each side of the gland, ipsilateral periglandular inspection with visualization of the medial wall of the cavernous sinus and diaphragm was performed to identify a potential ectopic microadenoma in the periglandular region. Although the exact origin of ectopic ACTH-producing pituitary adenomas is unclear, they likely emerge from remnants of Rathke’s pouch during its development course [20]. As a result, these tumors can be discovered in the nasopharynx, sphenoid sinus, cavernous sinus, clivus, or suprasellar area [21]. Detecting an adenoma at this stage may prevent further unnecessary EXP of pituitary gland. If a visible tumor was still not detected, a vertical medial incision was made on the pituitary gland adjacent to the pituitary stalk and neurohypophysis. If a tumor could not be reliably identified by extensive EXP of the entire pituitary gland or BIPSS failed to localize a pituitary adenoma, we did not progress to performing incomplete or complete hypophysectomy. Figures 1 and 2, respectively, demonstrate the surgical management algorithm and pituitary incisions for MRI-negative CD. Fig. 1 Eight-step MRI negative Cushing’s disease surgical management Full size image Fig. 2 Schematic illustration of 8 steps in endoscopic endonasal approach to MRI inconclusive Cushing’s disease (Resembling half Georgia flag) Full size image If an ectopic ACTH-secreting adenoma is not easily found, permanent destructive or ablative surgeries such as bilateral adrenalectomy and hypophysectomy may be required [20]. Despite the danger of Nelson syndrome, bilateral adrenalectomy remains a feasible option in the management of refractory CD [22, 23]. Histological examination All intraoperative tissue specimens obtained underwent histological examination by a pathologist. Pituitary specimens were fixed in buffered 10% formalin and embedded in paraffin wax. All specimens were first examined by Hematoxylin and Eosin (H&E) staining to detect regions which had loss of acinar organization. Additionally, reticulin and periodic Acid-Schiff (PAS) staining was implemented for a more accurate histopathologic diagnosis. Immunohistochemistry staining was used to identify cytokeratin and anterior pituitary hormones, including ACTH, in the case of a pituitary adenoma not being detected by H&E staining. The presence of ACTH-secreting cells was examined via immunocytochemistry using specific anti-ACTH antibodies. Post-operative endocrinologic assessment and follow up Serum cortisol and ACTH levels were monitored for 2–5 days following surgery. Initial follow-up occurred 2 weeks post-operatively with a subsequent visit occurring 3 months postoperatively, during each visit a complete pituitary hormonal evaluation was performed. This evaluation was repeated every 3 months for up to 2 years and every 6 months after that. An initial postoperative pituitary MRI was typically performed within 3 months after surgery. For patients to be considered to be in initial post-operation remission, a basal plasma cortisol level lower than 140 nmol/L (5 μg/dL) or adequate suppression of plasma cortisol (≤56 nmol/L) (≤1.8 μg/dL) following the 1-mg dexamethasone suppression test was necessary during the first month following surgery. Long term remission was defined as a plasma cortisol lower than 84 nmol/L (3 μg/dL) after a 1-mg dexamethasone suppression test at the final visit. Recurrence was defined as a recurring case of hypercortisolism with insufficient suppression of plasma cortisol (> 140 nmol/L) after a 1-mg dexamethasone suppression test. Clinical criteria for remission included significant symptomatic improvement or resolution without additional therapy (radiotherapy, adrenalectomy). Patients achieving remission had to meet both laboratory and clinical criteria to be classified as such. Glucocorticoids were not given postoperatively except when there was laboratory evidence of hypercortisolism and/or clinical manifestations of glucocorticoid insufficiency. Additionally, 4 to 6 weeks post-operatively, thyroid and gonadal axis function was assessed by measuring free T4, TSH, FSH, and LH levels in addition to end-organ hormones (estradiol in women and testosterone in men). Statistical analysis SPSS software (version 26, Chicago, IL) was used to analyze the data. For continuous data, we calculated descriptive statistics, mean and standard deviation (SD), and for categorical variables, frequency and percentages were calculated. The chi-square or Fisher’s exact test was used to analyze categorical data, while the student’s t-test or Mann- Whitney U test was used to analyze continuous variables’ means, depending on the distribution’s normality. Statistical significance was defined by a p value of < 0.05. Results Demographic and clinical data of 134 patients with CD who underwent EETS are shown in Table 1. Fifteen (11.2%) of the 134 CD patients who underwent EETS were MRI-negative and 119 patients (88.8%) were MRI positive. The female/male ratio in the MRI-negative group was four to one while this ratio in the MRI-positive cohort was 2.6. With regards to sex distribution, Fisher’s exact test found no statistically significant difference between these two groups (P = 0.565). All patients had clinical manifestation of Cushing’s syndrome including obesity, hirsutism, glucose intolerance, and hypertension. As shown in Table 1, pre-operative ACTH level was 134.02 ± 21.78 ng/l and 151.76 ± 44.17 ng/l in MRI-negative and MRI-positive patients, respectively, and no statistically significant difference was observed between these two groups (P = 0.781). As demonstrated in Table 1, UFC was 462.3 ± 43.98 μg/24 h and 478.4 ± 73.02 in MRI-negative and MRI-positive patients, respectively, and no statistically significant difference was observed between these two groups (P = 0.832). Table 1 Demographic and clinical data Full size table IPSS with DDAVP® administration was performed on the 15 MRI-negative patients to identify the origin of ACTH hypersecretion via the C/P ratio. Seven patients showed right-sided lateralization and five patients showed left-sided lateralization. In remaining three patients, IPSS did not show an ACTH interpetrosal gradient ratio greater than the cutoff point, which was interpreted as an ACTH hypersecretion with central origin. On EXP, adenomas were found in 2 of the 3 patients, with no adenoma being found in the 3rd. The IPSS results were in concordance with our observations during EXPs in 60% of patients. However, in 13% of patients, no adenoma was detected, and in 26% an adenoma was found on the opposite side of the pituitary where pre-operative IPSS results initially reported a tumor or was suggestive of one being present. In 60% of MRI-negative patients, histological examination demonstrated an adrenocorticotropic pituitary adenoma, but in 40% no adenoma was found after pathological examinations. In MRI-positive patients, positive histology was observed in 112 patients (94.1%), while in 7 patients (5.9%) histopathological studies were negative. Fisher’s exact test revealed that the difference between MRI-negative and MRI-positive patients in terms of histopathological result was statistically significant (P = 0.001). In all four patients who had discordant IPSS results as well as the patients who had negative or inconclusive findings on EXP, tissue samples were obtained from suspicious sites during EXP and were sent for histopathological examination. Histopathology demonstrated adrenocorticotropic adenoma tissues in 3 of them on the opposite side of the IPSS suggested region, while in 1 of them the histological results were inconclusive. This patient (case 10) achieved initial remission, however she experienced recurrence after 25 months, and similarly to her initial presentation, MRI findings were negative and IPSS suggested right sided lateralization. She underwent revision surgery, and a distinct adenoma was detected on the right side, which was confirmed by histological examination, after which she went into remission following selective adenectomy (Table 2). Table 2 Presents summary of patients’ demographics, IPSS and surgical exploration results Full size table Among the patients with inconclusive MRI, 14 (93%) achieved initial remission, 12 of which (80%) went on to long term remission with a mean follow up of 5.5 years. Two patients (cases 10 and 11) developed recurrence following initial remission; according to the IPSS suggested side, partial hypophysectomy was performed in both cases however neither was able to achieve remission afterwards. One patient (case 13) was unable to achieve initial remission following the initial surgery and thus required continued medical management. With a mean follow-up of 4.8 years among the 119 patients with positive MRI, 113 patients (94.9%) and 102 patients (85.7%) achieved initial and long-term remission, respectively. There were no statistically significant differences between these two groups in terms of either initial (P = 0.767) or long-term remission (P = 0.457). Among the 102 patients who achieved long-term remission, 12 patients (11.7%) experienced disease recurrence. With regards to recurrence rate, there was no statistically significant difference between patients with either positive or negative MRI (P = 0.542). In two patients (cases 2 and 6) the adenoma was not found during EXP, however tissue samples obtained from the IPSS suggested side demonstrated adrenocorticotropic pituitary adenoma in both patients on histopathological examination. Diabetes insipidus (DI) was the most frequent complication associated with CD. Transient DI occurred in seven cases with resolution prior to discharge. There was one case of permanent DI diagnosed in follow-up. Additionally, one patient developed symptomatic adrenal insufficiency requiring glucocorticoid replacement. Two patients developed hypothyroidism requiring hormone replacement. Panhypopituitarism was not seen following the initial surgeries however occurred in one case following revision surgery (partial hypophysectomy) which required hormone replacement therapy. Cerebrospinal fluid (CSF) leak resulting in meningitis was seen in one patient, however no other complications occurred during the post-operative period. None of our patients demonstrated clinical or endocrinological signs of gonadal insufficiency in follow-up aside from the aforementioned case of panhypopituitarism following revision partial hypophysectomy. In the MRI-positive cohort, 51 patients showed transients DI (42.8%), with 4 of the patients (3.4%) experiencing DI till last follow-up. Partial anterior pituitary insufficiency and complete anterior pituitary insufficiency was observed in one (0.8%) and two (1.6%) patients, respectively. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion was observed in 3 patients (2.5%). Discussion In this study we present the outcomes of pure endoscopic endonasal surgical treatment of fifteen patients with MRI-negative Cushing’s disease. Due to the arduous nature of treatment in this patient population, we used a precise method of EXP as described above, resulting in initial remission in 93% of patients post-operatively. Based on the work of Bansal et al., patients with a definite adenoma on MRI who underwent microscopic transsphenoidal surgery had a statistically significant greater rate of early remission and lower rates of persistent disease than those with negative/equivocal findings [24]. However, in terms of late remission and recurrence, there was no statistically significant difference between these two groups [24]. Negative/equivocal MRI results and the incidence of macroadenoma, particularly in patients with cavernous sinus invasion, were found to predict poor remission rates [24]. According to some investigations, MRI-negative CD patients had a poorer remission rate [25, 26]. In other studies, however, there was no statistically significant difference in remission between those who had MRI-negative CD and those who had a MRI-positive CD, which is consistent with our result [14, 27,28,29,30,31,32]. Recurrence occurred in 2 patients, while 12 patients showed no clinical or endocrinological signs of recurrence during the mean follow-up of 5 years, and one patient did not go to remission. Aside from one CSF leak leading to meningitis and one case of permanent DI, there were no major surgery related complications. Pituitary CD is a common and potentially lethal condition that, if left untreated, can lead to sequelae such as morbid obesity, hypertension, and diabetes mellitus. Diagnosis and treatment of CD is more challenging than other functional pituitary adenomas. Currently, trans-sphenoidal pituitary EXP is considered the standard of care for CD [33,34,35]. CD is typically diagnosed by endocrinologist through clinical symptoms, and supported by laboratory tests such as the 8 AM blood or saliva cortisol level, 24 hours urinary free cortisol level, low- and high-dose dexamethasone suppression tests, and the corticotropin-releasing hormone (CRH) stimulating test [36,37,38]. When ACTH-dependent CD is diagnosed, or clinical signs and symptoms are highly suggestive of it, MRI imaging of the pituitary is often the next step to identify the causative agent i.e., a pituitary adenoma. With regards to pituitary lesions, MRI is considered the most sensitive imaging modality, however reported sensitivity varies significantly between studies, with reported rates ranging from 22 to 92% [39,40,41]. The rate of MRI-negative microadenomas is reported to be between 36 to 63% [5]. Hofmann et al. reported no identified tumor in 49.3% of 270 MRIs [29]. Yamada et al. reported a lower frequency (17%) of MRI-negative CD in their series [42]. In our series, only 15 out of 134 (11.19%) CD patients were MRI-negative. In general, negative-MRIs could be explained by several factors such as field strength, technique (the correct pulse sequence and parameters), radiologist interpretation errors, or tumor size. Identifying tumors smaller than 3 mm in diameter is difficult in MRIs with 2.5- to 3-mm-thick image sections [29]. Dynamic MRI and 3-TMRI can result in a higher sensitivity in identifying ACTH-secreting microadenomas [6, 7, 43]. In addition, spoiled gradient-recalled echo sequence (SPGR) view can help to increase sensitivity [44]. The relatively low number of negative-MRIs in our study can be attributed to the more extensive review of MRI images, utilization of high-field strength MRI (1.5 T), as well as the implementation of SPGR dynamic studies with 1.5- to 2.0-mm-thick sections, in addition to standard methods. Additionally, assessment of images by experienced pituitary neuroradiologists may have reduced the negative-MRI rate in our series. Although small tumor size is a likely factor in MRI-negative CD, prior studies have reported examples of MRI-negative microadenomas 4-6 mm in size, typically large enough to be easily identified on EXP [42]. If MRI is unable to identify the tumor definitively, the next best step is venous sampling to confirm CD. There are various indication for BIPSS, including patients who have clinical and laboratory findings of CD but normal or inconclusive MRI results [45], cases that do not have a clear hormone test response, or cases where there are inconsistencies between laboratory and imaging results [46]. BIPSS is also recommended by some as standard for any case of confirmed ACTH-dependent Cushing’s syndrome [47, 48]. In our institution, BIPSS is reserved for MRI-negative Cushing’s patients. Newell-Price et al. reviewed 21 studies with 569 total patients, and found that BIPSS with CRH stimulation had a 96% sensitivity and 100% specificity in separating CD from pseudo-Cushing’s states [49]. Most studies report a 90–100% sensitivity and specificity for BIPSS [50,51,52]. In the majority of cases of CD, a pituitary microadenoma can be found eccentric to one side of the pituitary, having venous drainage directly into the ipsilateral inferior petrosal sinus (IPS) [53]. This phenomenon is the basis for utilizing BIPSS as a means of lateralizing ACTH secreting pituitary tumors. There are many instances where EXP fails to detect a pituitary adenoma, despite conformation of pituitary origin of ACTH secretion via BIPSS. Evidence of lateralization prior to surgery can convince the surgeon to perform a guided hemi hypophysectomy. In our series, the accuracy of BIPSS for lateralizing adenomas was 60%, similar to the reported accuracy in the literature of approximately 70% [17]. Inaccurate lateralization from BIPSS has been attributed to asymmetrical venous drainage with shunting of blood toward the dominant side. Thus, BIPSS appears to be a superior diagnostic tool compared to other means of lateralization, and neurosurgeons should be wary of making operative decisions solely from BIPSS data [49]. The standard of care for MRI-negative CD is highly disputed. There is evidence suggesting surgical exploration is more problematic than watchful waiting [8], or that it is not indicated in MRI-negative CD [54]. Many advancements have led to the widespread adoption of transsphenoidal approach during the last three decades, especially the endoscope [31]. Regardless of the width or depth of access, the endoscopic approach allows the surgeon to have a large panoramic view. Many cases in the literature have reported successfully treating functional pituitary tumors via endoscopic surgery [27, 31, 55,56,57,58]. The results suggest that they are on par with, if not superior to, traditional microscopic approaches. When patients were operated on utilizing a microscopic technique assisted by a pre-operative ACTH gradient, the overall rate of partial adenomectomy (partial hypophysectomy) was 30%, including 19% in patients with positive MRIs and 40% in those with negative MRIs [28]. However, endoscopic visualization of pituitary adenomas has allowed for the need for partial adenomectomy to be reduced to less than 2%, limiting the damage to the normal pituitary gland during operation [28]. A recently published meta-analysis demonstrated that although there was no statistically significant differences between EETS and microscopic endonasal transsphenoidal surgery in the sub-analysis with regards to recurrence rate, remission rate, and persistence rate, the recurrence rate in the microscopic endonasal transsphenoidal surgery group was almost three times higher than in the EETS group [11]. As a result, EETS appears to be a possible suggested therapeutic method, while more studies are needed to establish the therapeutic method of choice [59]. In general, pituitary surgery is not advisable in cases of MRI-negative CD where IPSS is not able to prove a central origin of ACTH secretion [42]. However, when IPSS demonstrates central ACTH secretion, surgical intervention has been proposed as a first line treatment in MRI-negative CD [25, 32, 42, 60]. The outcome of surgical intervention in MRI-negative patients is variable in the literature. Some reports indicated lower remission rate in these patients [42, 61], while others have concluded that EXP results in greater complications in this population [8, 15]. Additionally, several studies have shown no significant difference in outcomes of pituitary surgery between MRI-negative and MRI-positive patients [14, 25, 32]. Pivonello et al. found the lack of tumor detection on pre-operative MRI operation to be a negative prognostic factor in surgical management [62]. In the present study, surgery was performed for all MRI-negative Cushing’s patients with positive IPSS results. We achieved 93% initial remission and 80% long term remission rates, comparable to mean remission rates in patients with preoperative identification of tumor, as reported in the literature, ranging from 52.6–100% [62]. Failure to identify an adenoma on EXP or in histologic examination is not uncommon in the surgical management of CD. Intraoperative detection of the adenoma has been shown to be a factor of favorable prognosis [63,64,65]. Similarly, failure to identify an adenoma on histopathology has been found to be a negative prognostic indicator. Specifically, remission rates were significantly lower in cases where no histological tumor identification could be provided [14, 63, 66]. In our study, two cases revealed no adenoma on EXP, however the tissue samples subsequently obtained from the IPSS suggesting side were consistent with pituitary adenoma on histologic examinations. In six cases, a cream-like substance was identified within the pituitary following incision, however histologic examination failed to demonstrate adrenocorticotropic adenoma in any of them. Nonetheless, 5 of the 6 patients went into remission following surgery, potentially due to the small size of tissue samples obtained which in turn made accurate histopathological assessment more difficult [14, 67]. In cases where EXP does not result in localization of an adenoma, surgical decision making becomes complicated. Generally, total hypophysectomy is not advisable due to high rates of endocrine complications as well as failing to provide significantly increased remission rates over partial hypophysectomy [62, 68]. In this scenario, multiple studies have recommended partial hypophysectomy based on IPSS lateralization as the next best step in management [63, 69]. Carr et al. suggested the advantage of 2/3 gland resection on remission rate in MRI-negative CD [60], but as previously discussed, IPSS may incorrectly lateralize adenomas, and thus surgeons should be hesitant when making decisions regarding tumor lateralization based solely on BIPSS data [17, 49]. Moreover, both adenomectomy and hypophysectomy are not without risks and potential complications. Surgical aggressiveness is correlated with increased likelihood of pituitary loss-of-function, supported by literature showing that the larger the amount of resection, the higher the rate of hypopituitarism. It has been reported that patients undergoing adenomectomy, hemi-hypophysectomy, and-total hypophysectomy had mean rates of hypopituitarism of 6.6, 20.2, and 80.2%, respectively [63, 70, 71]. As most CD patients are females of reproductive age, preserving child-bearing capacity is an important consideration, one which results in reluctance to perform hemi-hypophysectomy. In our series, we performed selective adenectomy when distinct adenomas were found, and in the cases where no adenoma was detected, meticulous EXP of pituitary gland bilaterally was performed. Subsequently, if EXP was inconclusive, a vertical median incision was made near the pituitary stalk to explore central part of the gland, which is believed to be the nest for adrenocorticotropic cells. Although an important step in localizing the adenoma, this also likely explains the high rate of postoperative DI in our study. No additional hemi-hypophysectomy was performed during the initial surgery in our study. With this technique, we achieved acceptable results with regards to remission rates, and none of our patients experienced panhypopituitarism in postoperative follow-ups. In one patient where CD recurred 2 years post-operatively, inadequate bony exposure and limited visualization of the medial wall of the right cavernous sinus resulted in failure to identify the adenoma during the initial surgery, further supporting the strategy of creating extensive exposure of the operative field in MRI-negative CD. Another possible reason for recurrence in this patient would be growth of a previously undetected microadenoma. Conclusion Surgical treatment of MRI-negative Cushing’s disease is a demanding scenario necessitating multidisciplinary management. An experienced neurosurgeon working in collaboration with an endocrinologist should specify the most likely region of the tumor via IPSS. Additionally, surgical exploration of the pituitary is an invaluable tool in identifying adenomas while reducing the need for aggressive hypophysectomy, thus decreasing the likelihood of complications. 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Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successfuI treatment. Clin Endocrinol. 1993;38(1):73–8. CAS Article Google Scholar Download references Acknowledgments We are grateful to all those who have helped us to accomplish and fulfil this project. Funding None. Author information Authors and Affiliations Department of Neurosurgery, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Guive Sharifi, Amir Arsalan Amin & Seyed Ali Mousavinejad Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Guive Sharifi, Amir Arsalan Amin, Nader Akbari Dilmaghani & Seyed Ali Mousavinejad Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran Mohammadmahdi Sabahi Department of Neurosurgery, Rutgers-New Jersey Medical School, Newark, NJ, USA Nikolas B. Echeverry Department of Otolaryngology, Head and Neck Surgery, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Nader Akbari Dilmaghani Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Majid Valizadeh Department of Endocrinology, Loghman Hakim Hospital, Shahid Beheshti Medical University, Tehran, Iran Zahra Davoudi Department of Neurological Surgery, Pauline Braathen Neurological Center, Cleveland Clinic Florida, Weston, Florida, USA Badih Adada & Hamid Borghei-Razavi Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Director of Minimally Invasive Cranial and Pituitary Surgery Program, Research Director of Neuroscience Institute, Cleveland Clinic Florida Region, 2950 Cleveland Clinic Blvd. Weston, Cleveland, FL, 33331, USA Hamid Borghei-Razavi Contributions Guive Sharifi, Mohammadmahdi Sabahi and Amirarsalan Amin have given substantial contributions to the conception and the design of the manuscript, Mohammadmahdi Sabahi, Nikolas B. Echeverry, Nader Akbari Dilmaghani, Ali Mousavi Nejad, and Zahra Davoudi to the acquisition, analysis, and interpretation of the data. All authors have participated in drafting the manuscript. Mohammadmahdi Sabahi, Majid Valizadeh, and Badih Adada revised it critically. Hamid Borghei-Razavi supervised this project. All authors read and approved the final version of the manuscript. All authors contributed equally to the manuscript and read and approved the final version of the manuscript. Corresponding author Correspondence to Hamid Borghei-Razavi. Ethics declarations Ethics approval and consent to participate All procedures performed in this study involving human participants were in accordance with the ethical standards and approved by the Shahid Beheshti Medical University (SBMU) Ethical Committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Also, informed consent to participate in this study was obtained from participants included in the (or their parent or legal guardian in the case of children under 16). Consent for publication Not applicable. Competing interests All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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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 Cite this article Sharifi, G., Amin, A.A., Sabahi, M. 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). https://doi.org/10.1186/s12902-022-01069-5 Download citation Received27 January 2022 Accepted26 May 2022 Published09 June 2022 DOIhttps://doi.org/10.1186/s12902-022-01069-5 From https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-022-01069-5#Sec13

This article was originally published here Front Surg. 2022 Feb 2;8:806855. doi: 10.3389/fsurg.2021.806855. eCollection 2021. ABSTRACT PURPOSE: Currently, endoscopic transsphenoidal surgery (ETS) and microscopic transsphenoidal surgery (MTS) are commonly applied treatments for patients with pituitary adenomas. This meta-analysis was conducted to evaluate the efficacy and safety of ETS and MTS for these patients. METHODS: A computer search of Pubmed, Embase, Cochrane library, Web of Science, and Google Scholar databases was conducted for studies investigating ETS and MTS for patients with pituitary adenomas. The deadline is March 01, 2021. RevMan5.1 software was used to complete this meta-analysis after literature screening, data extraction, and literature quality evaluation. RESULTS: A total of 37 studies including 5,591 patients were included. There was no significant difference in gross tumor removal (GTR) and hormone-excess secretion remission (HES remission) between two groups [RR = 1.10, 95% CI (0.99-1.22), P = 0.07; RR = 1.09, 95% CI (1.00-1.20), P = 0.05]. ETS was associated with lower incidence of diabetes insipidus (DI) [RR = 0.71, 95% CI (0.58-0.87), P = 0.0008], hypothyroidism [RR = 0.64, 95% CI (0.47-0.89), P = 0.007], and septal perforation [RR = 0.32, 95% CI (0.13-0.79), P = 0.01] than those with MTS. CONCLUSION: This meta-analysis indicated that ETS cannot significantly improve GTR and HES remission. However, ETS could reduce the incidence of DI, hypothyroidism, and septal perforation without increasing the rate of other complications. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/#myprospero, identifier: CRD42021241217. PMID:35187049 | PMC:PMC8847202 | DOI:10.3389/fsurg.2021.806855

Decreased visual functions and severe headache may be signs of a brain tumor. The pituitary gland is a pea-sized gland located in the bone structure at the base of the brain called Sella Turcica. The pituitary gland, which has a great effect on our body, is a vital organ that regulates the secretion of many hormones such as growth hormone, prolactin hormone, and thyrotropin. Head of Department of Brain and Nerve Surgery, Yeni Yüzyıl University Gaziosmanpaşa Hospital, Assoc. Dr. Mete Karatay said, 'Tumors in the pituitary gland cause many disorders. Therefore, the symptoms should be taken into account and the tumor should be intervened before it grows. ' He gave information about the subject. Pituitary adenomas take the 3rd place after all tumors located in the head, after those originating from the brain itself and its membrane. So it is a relatively common tumor. The reasons for its occurrence are not fully understood. Rarely, they are seen together with inherited diseases. Tumors arising in the pituitary gland show symptoms either due to excessive hormone secretion or due to excessive growth and compression and spread to the surrounding tissues. Adenomas that do not secrete hormones usually grow slowly and can remain asymptomatic for years. Those who secrete hormones show early symptoms due to the effects of hormones in the body. In pituitary adenomas, headache, weakness, decreased visual clarity, vision loss, limitation of eyeball movements, double vision, drooping of the eyelid or visual field (especially loss of the outer quadrants of the eye) can be seen, and brain tumors such as pituitary adenoma should come to mind in these cases. . Other common complaints are the following complaints that develop due to the hormone secretion of the pituitary gland. In excess of prolactin; menstrual irregularities, milk secretion from breast tissue, development in breast tissue, sexual dysfunction in men, decrease in sperm quantity In excess of growth hormone; excessive elongation in adolescence; In adulthood, it causes elongation of the extremities of the body parts such as the chin, tip of the nose, hands and feet, heart problems, sweating, high blood sugar and joint problems. Cushing's - In ACTH excess; fat in abnormal areas of the body, muscle weakness, high blood pressure and blood sugar, skin oily and acne development, stretch marks, psychological problems In excess of TSH; weight loss, palpitations, bowel problems, sweating, restlessness, and irritability In the excess of FSH - LH; menstrual irregularities, sexual function problems, infertility The treatment of pituitary adenomas is done by the endocrinology and neurosurgery units. From an endocrinological standpoint, it is important to restore the body's hormonal balance. Neurosurgeons focus on relieving the pressure on nerve structures. Therefore, these patients are usually treated with a team of endocrinologists and neurosurgeons. Surgery is usually performed in the nasal cavity and is considered one of the difficult neurosurgical operations. The surgeon uses what we call a microscope and endoscope to reach and remove the tumor. Today, the method we call endoscopic surgery is used more frequently. With this method, there is no external scar and shortens the length of stay in the hospital. From https://www.raillynews.com/2021/05/gorme-kaybi-beyin-tumorunun-habercisi-olabilir/

Zarina Brady, Aoife Garrahy, Claire Carthy, Michael W. O’Reilly, Christopher J. Thompson, Mark Sherlock, Amar Agha & Mohsen Javadpour BMC Endocrine Disorders volume 21, Article number: 36 (2021) Cite this article 160 Accesses Metricsdetails Abstract Background Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing’s disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. Methods A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012–February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol < 138 nmol/L within 7 days of surgery, with improvement in clinical features of hypercortisolism. A strict cut-off of < 50 nmol/L at day 3 post-op was also applied, to allow early identification of remission. Results A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol < 50 nmol/L). Three patients had an early repeat ETSS for persistent disease (day 3 cortisol 306-555 nmol/L). When the outcome of repeat early ETSS was included, the remission rate was 92% (36/39) overall. Remission rate was 94% (33/35) when patients with macroadenomas were excluded. There were no cases of CSF leakage, meningitis, vascular injury or visual deterioration. Transient and permanent diabetes insipidus occurred in 33 and 23% following first ETSS, respectively. There was one case of recurrence of CD during the follow-up period of 24 (4–79) months. Conclusion Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus. Peer Review reports Introduction With an estimated annual incidence of 1.7 per million [1], Cushing’s disease is rare. Untreated, it poses serious complications including osteoporosis, hypertension, dyslipidaemia, insulin resistance, and hypercoagulability [2] and is associated with a 4.8 fold increase in mortality rate [3,4,5]. Patients who are in remission from CD have a mortality rate which decreases towards (although not reaching) that of the general population [6]. Endoscopic transsphenoidal surgery (ETSS) offers patients potential remission from Cushing’s disease, although long term surveillance is required as recurrence rates range from 5 to 22%% [7,8,9,10,11,12]. Since the first report in 1997 [13], the selective removal of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma by endoscopic transsphenoidal surgery has gained popularity as the first line treatment for Cushing’s disease. The primary goal of ETSS treatment in Cushing’s disease is to produce disease remission and to provide long-term control, while minimising complications. Remission rates are dependent on tumour size, preoperative MRI, cavernous sinus invasion, intraoperative visualisation of the tumour and pre- and postoperative ACTH and cortisol concentration [11]. Several studies also report pituitary neurosurgeon experience as a major factor for operative success [2, 14, 15]. Reported remission and recurrence rates after TSS for CD vary widely according to the criteria utilised to define remission [11], and in some studies due to limited patient numbers or short follow-up periods. Indeed, there is no clear consensus on how best to define post-operative remission; an early morning serum cortisol concentration < 138 nmol/L (5μg/dl) within 7 days of TSS is quoted in the 2015 Endocrine Society Clinical Practice Guideline as indicative of remission [16]. A more strict day 3 cut-off of 50 nmol/L (1.8 μg/dl) has been reported in paediatric studies [17], and also included in the Endocrine Society Guideline [16]; the literature suggests this cut-off is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. The main objective of this study was to assess the outcomes of endoscopic transsphenoidal surgery for Cushing’s disease in a tertiary pituitary centre; remission using two widely accepted criteria [16], recurrence and postoperative complications. Methods Study design This is a retrospective analysis of a prospectively-maintained database of patients operated on by a single neurosurgeon (MJ), via image-guided endoscopic transsphenoidal approach for Cushing’s disease. Patient data was gathered over 8 years (January 2012 to February 2020) and identified from the institution’s prospective database. Clinical and biochemical data during the follow-up period was reviewed. Approval was granted by the Hospital Audit Committee. Study population Patients were screened for Cushing’s syndrome by the presence of typical clinical features, together with failure to adequately suppress cortisol to < 50 nmol/L following overnight dexamethasone suppression test (ONDST) and/or elevated late night salivary cortisol (LNSF) concentration and/or elevated 24 h urinary free cortisol measurements. As per standard guidelines, Cushing’s disease was diagnosed on the basis of elevated serum ACTH measurements, along with confirmatory hormone responses to peripheral corticotropin releasing hormone (CRH) test and inferior petrosal sinus sampling (IPSS). Patients with previous TSS prior to the study period were excluded. Surgical procedure A single neurosurgeon subspecialising in endoscopic pituitary and anterior skull base surgery, M.J, carried out all ETSS surgical procedures. The surgical technique has been described in detail in publications by Cappabianca et al. (1998, 1999) and Jho et al. (1997, 2000, 2001) [13, 18,19,20,21]. In summary, the procedure consists of a binostril endoscopic transsphenoidal approach. A selective adenomectomy was performed on patients with adenomas noted on pre-operative MRI. In cases of negative pre-operative MRI, exploration of the pituitary gland was performed. To confirm the diagnosis of ACTH-secreting adenoma or hyperplasia, all specimens removed underwent histopathological and immunohistochemical staining for pituitary hormones. Postoperative assessment Patients received empiric oral hydrocortisone on day 1 and on the morning of day 2 post-operatively, prior to assessment of 0800 h serum cortisol on day 3. A blood sample for serum cortisol was drawn at 0800 h on the morning of day 3, if clinically stable, prior to administration of hydrocortisone. The Endocrine Society Clinical Practice Guideline define post-operative biochemical remission as morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively [16], ‘standard criteria’. In our institution, we also apply a biochemical cut-off of < 50 nmol/L (1.8 μg/dl) at day 3 postoperatively to allow early indication of biochemical remission, ‘strict criteria’. If serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical sequalae of hypercortisolaemia made (such as improvement in blood pressure or glycaemic control), before repeat endoscopic transsphenoidal surgery is considered. Transient cranial diabetes insipidus (DI) was defined as the development of hypotonic polyuria postoperatively requiring at least one dose of desmopressin [22], which resolved prior to discharge. Permanent DI was confirmed by water deprivation test according to standard criteria [23]. Thyroid stimulating hormone (TSH) deficiency was defined by low fT4 with either low or inappropriately normal TSH. Growth hormone (GH) deficiency was confirmed using either Insulin Tolerance Test or Glucagon Stimulation Test [24]. Gonadotrophin deficiency was defined in premenopausal women as amenorrhoea with inappropriately low FSH and LH concentration, and in postmenopausal patients as inappropriately low FSH and LH concentration. Recovery of hypothalamic-pituitary-adrenal axis was assessed by short synacthen (250 μg) test or insulin tolerance test 3 months post-operatively, and every 3–6 months thereafter in cases of initial fail or borderline result. Patients were assessed annually for recurrence of Cushing’s disease, recurrence was defined by failure to suppress cortisol to < 50 nmol/L following an 1 mg overnight dexamethasone suppression test, an elevated late night salivary cortisol (LNSF) or urinary free cortisol (UFC) in patients no longer taking hydrocortisone. Laboratory analysis Prior to 2019, serum cortisol was measured using a chemiluminescent immunoassay with the Beckman Coulter UniCel Dxl 800. Intra-assay CV for serum cortisol was 8.3, 5 and 4.6% at concentrations of 76, 438 and 865 nmol/L, respectively. From January 2019 onwards, serum cortisol was measured using Elecsys® Cortisol II assay on the Roche Cobas e801; intra-assay precision for serum cortisol was 1.2, 1.1 and 1.6% at concentrations of 31.8, 273 and 788 nmol/L, respectively. Statistics Data are expressed as median (range) and number (%). The Fishers Exact test was used to compare categorical variables between groups. All p-values were considered statistically significant at a level < 0.05. Statistical analysis was performed using GraphPad Prism 8 statistical software (GraphPad Software, La Jolla, California, USA). Results Demographics Forty-three endoscopic transsphenoidal procedures were performed in 39 patients. Demographics are summarised in Table 1. Median (range) age was 37 years (8–75), 30 were female. Median (range) duration of symptoms was 24 months (6–144), 72% (28/39) had hypertension, and 28% (11/39) had type 2 diabetes. Table 1 Summary of demographics and post-operative outcomes Full size table Preoperative imaging and IPSS Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). No adenoma was identified in 17 patients (44%). IPSS was carried out in 33 (85%) patients. Postoperative remission Post-operative outcomes are summarised in Table 1 and Fig. 1. Using standard criteria (0800 h serum cortisol < 138 nmol/l within 7 days of operation and improvement in clinical features of hypercortisolism), postoperative remission rates for initial surgery were 87% (34/39) for the entire group and 89% (31/35) when patients with macroadenomas were excluded, Fig. 1. Three patients had an early repeat ETSS for persistent disease; day 3 serum cortisol ranged from 306 to 555 nmol/L and interval to repeat ETSS from 10 days–3 months. When the outcome of early repeat ETSS was factored in, overall remission rate was 92% (36/39) overall, and 94% (33/35) when patients with macroadenomas were excluded. Fig. 1 Schema of patients who underwent ETSS. *Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids Full size image Using strict criteria of early remission (day 3 serum cortisol concentration < 50 nmol/L), postoperative remission rates were 58% (22/38) overall, and 62% (21/34) excluding macroadenomas. Including the three patients with early repeat ETSS, remission rate was 61% (23/38) overall, and 65% excluding macroadenomas (22/34). Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids. Eleven patients (28%) had a cortisol measurement between 50 and 138 nmol/L on day 3, seven of whom had received metyrapone therapy prior to ETSS. Six patients had serial measurements of 0800 h cortisol up to a maximum follow-up of 14 days post-op, serum cortisol concentration fell after day 3 in all six patients. Ten (91%) were glucocorticoid-dependent at 3 months based on synacthen/ITT; 0800 h cortisol had fallen to < 50 nmol/L in six patients. Predictors of remission No statistical difference was found in the rates of remission in those patients with or without tumour target on preoperative MRI, using either strict criteria for remission (12/21 target vs 10/17 no target, p > 0.99) or standard criteria (19/22 target vs 15/17 no target, p > 0.99). Similar results were found when the four patients with macroadenoma were excluded. Persistent disease Five patients (13%) had persistent hypercortisolaemia after the initial endoscopic transsphenoidal surgery (Table 2). Three patients underwent a repeat early endoscopic transsphenoidal surgery, Fig. 1. Remission rate after repeat early ETSS was 67% (2/3) using standard criteria, and 33% (1/3), using the strict criteria. Of the patients with persistent disease following repeat ETSS, one received radiosurgery, while the other has been commenced on medical therapy, with a view to refer for radiotherapy. Table 2 Outcome of five patients with persistent hypercortisolaemia after initial ETSS Full size table Postoperative complications The rate of transient diabetes insipidus after first ETSS was 33% (13/39), while permanent diabetes insipidus occurred in 23% (9/39). Postoperatively, there were five cases of new thyroid stimulating hormone deficiency (13%) and four cases of gonadotrophin deficiency (10%) (in pre-menopausal females). There were no cases of postoperative CSF leak, no cases of meningitis and no visual complications. There were no other complications. Recurrence No patients were lost to follow-up. Over a median (range) duration of follow-up of 24 (4–79) months, one patient had recurrence of Cushing’s disease. Pre-operative MRI had shown a macroadenoma; serum cortisol on day 3 after the initial ETSS was 71 nmol/L, which fulfilled standard criteria for remission, but not the more strict criteria. The patient underwent a second ETSS 13 months later. No tumour was visible intra-operatively so no tissue was removed, day 3 serum cortisol concentration was 308 nmol/L and the patient was commenced on a trial of metyrapone. Recovery of the hypothalamic-pituitary-adrenal axis Recovery of the hypothalamic-pituitary-adrenal axis occurred in nine patients (27%), at median 13 (3–27) months post-operatively. There was no statistical difference in rates of recovery of HPA axis in patients with day 3 cortisol < 50 nmol/l, and those who only passed standard criteria for remission (< 138 nmol/l) [7/20 (follow-up 25 (3–59) months) versus 2/11 (follow-up 16 (3–79) months) respectively, p = 0.43]. One patient died 5 weeks post-operatively; post-mortem revealed bilateral haemorrhagic adrenal necrosis. Discussion Reported remission rates following ETSS in patients with Cushing’s disease (CD) vary widely, predominantly due to differences in criteria used to define remission [11]. There is no uniform consensus on the criteria used to define ‘remission’, with institutions using a combination of biochemical and clinical criteria; this makes comparing surgical outcome studies challenging. The normal corticotroph cells of the pituitary gland are suppressed due to sustained hypercortisolaemia, therefore following successful removal of the ACTH-secreting adenoma, serum ACTH and cortisol concentrations should fall postoperatively. A morning serum cortisol concentration < 138 nmol/L (5 μg/dl) within 7 days of ETSS is usually indicative of remission, and this biochemical cut-off is quoted in the Endocrine Society Clinical Practice Guideline [16], and many surgical outcome studies [8, 11, 25]. Other studies have applied a more strict serum cortisol cut-off of < 50 nmol/L (1.8 μg/L) at day 3 postoperatively to allow early indication of biochemical remission [10, 11, 26,27,28]; the literature suggests this cutoff is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. Our practice is to apply this latter approach; if serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical signs of hypercortisolaemia made, before repeat endoscopic transsphenoidal surgery is considered. It is important to ensure that serum cortisol has reached a nadir, before further intervention is considered. In this single-centre single-surgeon study, we report two very different remission rates using these two widely accepted criteria. Our remission rate, including those patients who had an early second ETSS, using standard guidelines, is 92%, on par with other larger studies [7, 8, 11, 25, 29]. When patients with corticotroph macroadenomas were excluded, the remission rate was even higher at 94%. In comparison, when we applied the more strict criteria of day 3 cortisol < 50 nmol/L, the remission rate was considerably lower at 61%. This criteria is in place in our institution so that we can safely identify patients who have early signs of remission to facilitate discharge on day 3 post-operatively; however reporting these rates in isolation lead to a misleadingly low remission rate compared to the more lenient criteria proposed by the Endocrine Society [16]. Evidence has suggested that higher day 3 cortisol concentration is associated with greater risk of recurrence of CD. A recent retrospective cohort analysis of 81 ETSS for CD by Mayberg et al. reported significantly higher recurrence rates in patients with post-operative cortisol nadir between 58 and 149 nmol/L (2.1–5.4 μg/dL) compared with those with cortisol < 55 nmol/L (2 μg/dL) (33% vs 6%, p = 0.01) [30]. Recurrence of CD was low in our series at 3%, and occurred in a patient with a corticotroph macroadenoma, which have been shown to be associated with higher rates of recurrence [31]. On post-operative assessment, serum cortisol fell between the two criteria for remission and if remission was strictly defined as a day 3 cortisol < 50 nmol/L, then this patient had in fact persistent hypercortisolaemia. This case highlights the difficulty when comparing studies reporting ETSS outcomes in CD – the distinction between persistent post-operative hypercortisolism and early recurrence of CD is not always clear-cut, and is dictated by the local protocol. Whilst our recurrence data are encouraging in comparison to other reports on CD recurrence, which published rates of up to 22% [11], longer term follow-up is necessary before recurrence rates can be accurately defined. The criteria used to define long term recurrence of CD also varies widely in the literature; a large systematic review (n = 6400) by Petersenn et al. (2015) reported decreased recurrence rates when studies used UFC with ONDST vs. UFC only, and UFC with morning serum cortisol vs. UFC only [11]. This highlights the requirement for standardization of remission and recurrence criteria, for consistency in clinical practice and in the literature. The post-operative surgical complication rate in our series was very low, with no cases of CSF leak, vascular injury or visual compromise. Other published case series have reported incidence rates for CSF leakage and meningitis of 0–7.2% and 0–7.9% [2, 12, 32, 33] respectively. Postoperative meningitis is strongly associated with CSF leakage [34]. Some studies suggest that the endoscopic approach results in higher rates of carotid artery injury compared with the microscopic approach, which could be attributed to the nature of the extended lateral approach [35]. However, in this series of 43 ETSS, we report no cases of surgical related carotid artery injury, similar to other studies reporting 0% serious morbidity or mortality due to carotid artery injury [33, 36]. Finally, postoperative visual disturbance is a major concern, as it can be life changing for patients. Factors linked with visual complications include tumour size, patient age and any pre-existing visual conditions [37,38,39]. Visual deterioration after TSS for Cushing’s disease has been reported to occur in some large case series at rates of 1.9% [32] and 0.86% [12]. There were no cases of postoperative visual disturbance in our series. While the surgical complication rate was low, our endocrine complication rate was higher than that reported in other studies, particularly the rate of DI. Transient DI occurred in 33% of cases, and permanent DI in 23%. These relatively high rates of transient DI may be due to the diagnostic criteria used in our protocol; we defined transient post-operative DI as one episode of hypotonic polyuria in the setting of normal or elevated plasma sodium concentration, requiring at least one dose of desmopressin. In contrast, some studies discount any polyuria which lasts less than 2 days [10], while others require the documentation of hypernatremia for the diagnosis of DI [40]. These more stringent criteria will not capture cases of mild transient DI; therefore it is not surprising that the rates of transient DI reported in a 2018 meta-analysis were lower than that in our study, 11.3% [29]. The rates of permanent DI in our study merits particular attention. TSS for CD has been shown to be associated with a higher risk of post-operative DI [41, 42]. It may be that a more aggressive surgical approach resulted in high remission rates, but at a cost of higher rates of DI. All patients are reviewed post-operatively in the National Pituitary Centre, where there is a low threshold for water deprivation testing and/or 3% saline testing. We did not routinely re-test patients for resolution of DI after their initial water deprivation test at 3 months, and it is possible that some cases subsequently resolved after 3 months [41, 43]. Regardless, the rate reported in this study is significant, and emphasises the importance of counselling the patient about the risk of DI long-term. Strengths and limitations The reporting of two remission rates based on widely accepted criteria is a strength of this study, and allows for direct comparison of our outcomes with other studies. All ETSS were performed by a single pituitary surgeon; while this removes bias from surgeon experience, the disadvantage of this is that the sample size is relatively low. Furthermore, because we included patients who were recently operated on to maximise numbers for analysis of surgical complications, the follow-up period is relatively short. A longer follow-up is required to comment accurately on recurrence of CD. We did not have full ascertainment of longitudinal post-operative data including dexamethasone suppression tests, and this has highlighted the need for protocolised follow-up to allow for consistency when reporting our results. Conclusion Endoscopic transsphenoidal surgery in patients with Cushing’s disease offers excellent remission rates and low morbidity. Remission rates are much higher when standard criteria [morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively] are used compared with day 3 cortisol < 50 nmol/l. Higher remission rates were found for patients with microadenomas. Patients should be counselled regarding risk of post-operative endocrine deficiencies, in particular permanent diabetes insipidus. Longer follow-up is required to accurately assess recurrence rates. Availability of data and materials The data that support the findings of this study are not publicly available due to restrictions by General Data Protection Regulation (GDPR), but are available from the corresponding author on reasonable request. Abbreviations TSS: Transsphenoidal surgery ACTH: Adrenocorticotropic hormone CD: Cushing’s disease ETSS: Endoscopic transsphenoidal surgery ONDST: Overnight dexamethasone suppression test LNSF: Late night salivary cortisol CRH: Corticotropin releasing hormone IPSS: Inferior petrosal sinus sampling DI: Diabetes insipidus TSH: Thyroid stimulating hormone GH: Growth hormone UFC: Urinary free cortisol References 1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1):117–23. CAS PubMed PubMed Central Google Scholar 2. Broersen LHA, van Haalen FM, Biermasz NR, et al. 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Presented by Ahmad Sedaghat, MD, PhD - Associate Professor and Director of the Division of Rhinology, Allergy and Anterior Skull Base Surgery in the Department of Otolaryngology - Head and Neck Surgery at the University of Cincinnati College of Medicine and UC Health. Norberto Andaluz, MD, MBA, FACS - Professor of Neurosurgery and Otolaryngology/Head and Neck Surgery - Director, Division of Skull Base Surgery University of Cincinnati College of Medicine and University of Cincinnati Gardner Neuroscience Institute - UC Health Click here to attend Date: Wednesday, Sept 23, 2020 Time: 3:00 PM Eastern Daylight Time Learning objectives: 1. To understand the surgical steps of endoscopic pituitary surgery 2. To understand how the surgical steps of endoscopic pituitary surgery translate to post-operative outcomes 3. To understand surgical factors that can modify post-operative outcomes after endoscopic pituitary surgery 4. To understand post-operative care that can modify post-operative outcomes after endoscopic pituitary surgery