Efficacy of whole-sellar gamma knife radiosurgery for magnetic resonance imaging-negative Cushing's disease.

BACKGROUND: Corticotroph adenoma delineation in Cushing's disease (CD) patients with previous surgery can be challenging. This study investigated the outcome of whole-sellar gamma knife radiosurgery (GKRS) in MRI-negative, but hormone-active CD patients with prior failed treatment attempts. METHODS: We retrospectively analyzed data of nine CD cases who underwent whole-sellar GKRS between April 2008 and April 2020 at a single center. Remission was determined as normal morning serum cortisol, normal 24-hour urinary free cortisol (UFC) or extended postoperative requirement for hydrocortisone replacement. RESULTS: Median age was 35.0 years, and most of the cases were female (89%). All subjects had undergone previous surgery. The mean pre-GKRS morning serum cortisol and 24-hour UFC were 27.5 µg/dL and 408.0 µg, respectively. Target volume varied from 0.6 to 1.8 cc, and the median margin dose was 28 Gy. The median duration of endocrine follow-up was 105 months, and initial endocrine remission was achieved in eight subjects (89%) at a median time of 22 months. The actuarial initial remission was 44% at two years, 67% at four years, and 89% at six years. The mean recurrence-free survival was 128 months. Age and pre-GKRS morning serum cortisol was found to be predictors for initial and durable endocrine remissions. New-onset hypopituitarism was observed in two of five patients (40%). None of the patients developed new neurological deficits and had GKRS-related adverse events during the follow-up. CONCLUSIONS: Whole-sellar GKRS is a safe and efficient method to manage MRI-negative CD and provides similar GKRS outcome rates as in MRI-positive CD.

Determinants of Clinical Behavior and Prognosis in Cushing's Disease: A Quest for Useful Biomarkers.

Abstract: Cushing's disease (CD) is the most common cause of endogenous hypercortisolemia. The clinical management of this condition is complex and entails multiple therapeutic strategies, treatment of chronic comorbidities, and lifelong surveillance for recurrences and complications. The identification of robust, practical, and reliable markers of disease behavior and prognosis could potentially allow for a tailored and cost-efficient management of each patient, as well as for a reduction of the medical procedure-associated stress. For this purpose, multiple clinical, biochemical, imaging, histopathological, molecular, and genetic features have been evaluated over the years. Only a handful of them, however, have been sufficiently validated for their application in the routine care of patients with CD. This review summarizes the current status of the established and potential biomarkers of CD, bases for their use, proposed and/or established utility, as well as advantages and barriers for their implementation in the clinic. (Rev Invest Clin. 2022;74(5):244-57).

Adrenocorticotropic hormone-producing pituitary adenoma with pituitary apoplexy treated by surgical decompression: a case report.

BACKGROUND: Pituitary-dependent hypercortisolism (PDH) is one of the most common endocrine disorders in veterinary medicine. However, there are few reports on pituitary tumor apoplexy (PTA) in dogs and no reports on its surgical intervention in veterinary medicine. Accordingly, the appropriate treatment is unknown. Herein, a case of PDH and PTA in a dog treated surgically is described. CASE PRESENTATION: A mongrel female dog (spayed; age, 8 years and 8 months; weight, 6.1 kg) with persistently elevated alkaline phosphatase underwent adrenocorticotropic hormone (ACTH) stimulation testing (post-stimulation cortisol: 20.5 µg/dL), abdominal ultrasonography (adrenal gland thickness: left, 5.7 mm; right, 8.1 mm), and brain magnetic resonance imaging (MRI) (pituitary-to-brain ratio [PBR], 0.61) at the referral hospital, resulting in a diagnosis of PDH (day 0). On day 9, the dog visited XXXX for the preparation of pituitary surgery to treat PDH. However, on days 10-15, the dog developed a loss of energy and appetite, bloody diarrhea, vomiting, and a decreased level of consciousness. However, on day 16, the dog's condition recovered. A preoperative MRI scan performed on day 52 (the day of surgery) showed apoplexy in the dorsal pituitary region (PBR, 0.68). Based on the PTA findings, the risks of surgery were described to the owner, and approval was obtained. At the time of trans-sphenoidal surgery, a partial pituitary resection was performed with preservation of the PTA area due to adhesions between the PTA area of the right side of the pituitary and surrounding tissues. The resected pituitary tissue was diagnosed as an ACTH-producing adenoma, with necrotic and hemorrhagic findings. As of day 290, endogenous ACTH and cortisol levels did not exceed the reference range. CONCLUSIONS: The acute signs that occurred on days 10-15 were most likely caused by PTA. Therefore, when signs similar to those detected in acute hypoadrenocorticism are observed in dogs with PDH, it is necessary to include PTA as a differential diagnosis. Trans-sphenoidal surgery may be effective in PDH-affected dogs that develop PTA, but careful attention should be paid to tissue adhesions secondary to hemorrhage that may occur after PTA.

Plurihormonal pituitary adenoma cosecreting ACTH and GH: a rare cause of Cushing's disease.

Plurihormonal pituitary adenomas are rare forms of pituitary adenomas that express more than one hormone. The most common association is with growth hormone (GH) and prolactin. Cosecretion of GH and adrenocorticotrophic hormone (ACTH) is rare with only 25 reported cases in literature. Most presented with features of GH excess, and only four presented with Cushing's disease. We report a case of a woman in her 30s with recurrent plurihormonal pituitary macroadenoma cosecreting GH and ACTH, diagnosed during workup for polycystic ovarian syndrome, and both times presenting uniquely with Cushing's disease. Biochemical testing showed GH excess and hypercortisolism. She underwent transsphenoidal surgery twice and immunohistochemistry showed positive staining for GH and ACTH on both occasions. We aim to raise more awareness of this rare type of pituitary adenoma, shed light on the importance of recognising rare presentations and highlight the necessity of rigorous follow-up given morbidity and potentially higher mortality risk.

Corticotroph tumor progression speed after adrenalectomy.

Objectives: After bilateral adrenalectomy in Cushing's disease, corticotroph tumor progression occurs in one-third to half of patients. However, progression speed is variable, ranging from slow to rapid. The aim was to explore corticotroph progression speed, its consequences and its risk factors. Design: A retrospective single-center observational study. Methods: In total,103 patients with Cushing's disease who underwent bilateral adrenalectomy between 1990 and 2020 were included. Clinical, biological, histological and MRI features were collected. Median duration of follow-up after bilateral adrenalectomy was 9.31 years. Results: In total,44 patients progressed (43%). Corticotroph tumor progression speed ranged from 1 to 40.7 mm per year. Progression speed was not different before and after bilateral adrenalectomy (P = 0.29). In univariate analyses, predictive factors for rapid corticotroph tumor progression included the severity of Cushing's disease before adrenalectomy as the cause of adrenalectomy, high ACTH in the year following adrenalectomy and high Ki67 immunopositivity in the tumor. During follow-up, early morning ACTH absolute variation was associated with corticotroph tumor progression speed (P-value = 0.001). ACTH measurement after dynamic testing did not improve this association. Conclusion: After adrenalectomy, corticotroph progression speed is highly variable and manageable with MRI and ACTH surveillance. Progression speed does not seem related to bilateral adrenalectomy but rather to intrinsic properties of highly proliferative and secreting tumors.

Cushing's disease: role of bilateral adrenalectomy.

INTRODUCTION: Laparoscopic bilateral adrenalectomy (BAD) is one of the treatments of Cushing's Disease (CD), but its indications and outcome is debated. METHODS: The literature on BAD was reviewed as part of a work performed for the Cushing's disease guideline. RESULTS: The surgical morbidity of BAD is reported between 10 and 18% and no mortality has been reported in the largest series. Because of the endocrine sacrifice it will be mostly performed after a multidisciplinary team discussion in selected cases of refractory CD (mostly after failure of pituitary surgery and/or medical treatment). It is also frequently discussed in female patients desiring pregnancy. Corticotroph tumor progression occurs in 40% of the patients but is in most patients manageable when detected early by a careful long term monitoring with pituitary MRI and ACTH assays after BAD. CONCLUSION: BAD is a safe and effective treatment of CD used in specific situations and requiring long term monitoring.

Long-Term Outcomes and Complications from Endoscopic Versus Microscopic Transsphenoidal Surgery for Cushing's Disease: A 15-Year Single-Center Study.

BACKGROUND: Endoscopic endonasal surgery is the main transsphenoidal approach for pituitary surgery in many centers; however, few studies compare the endoscopic and microscopic surgical approaches with regard to long-term follow-up. This single-center study aimed to compare the 2 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. 14 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 in the microscopic group. CONCLUSIONS: 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.

Role of Radiation in the treatment of Cushing Disease.

In Cushing disease (CD), radiation therapy (RT) is mostly used in the adjuvant setting in patients who have failed transsphenoidal surgery or have recurrent CD. Stereotactic radiotherapy (SRT) is administered as either single or several sessions, and the most commonly used modalities include photon source (Gamma Knife, CyberKnife, and LINAC) or heavy particles (protons). In multicenter studies, Gamma Knife SRT can lead to biochemical control in 80%, with medial time to remission approximately 15 mos, and 70% recurrence free at 10 years. Conventional RT (CRT) consists of administration of small daily fractions over six weeks, with cumulative dose of 45-50 Gy. Biochemical control is achieved in up to 64% of patients with CRT. Choice of radiation modality includes convenience for patients (SRT is more convenient) and proximity to critical structures. Both forms of RT can result in hypopituitarism. RT remains an important modality for the treatment of patients with CD.

Cushing's disease.

Cushing's disease (CD) is the most prevalent cause of endogenous hypercortisolism. CD is responsible for multiple co-morbidities and increased mortality. Accurate and prompt diagnosis and optimal treatment are essential to improve the prognosis of CD. However, the diagnosis of CD is probably one of the most difficult in endocrinology and, therefore, diagnostic workup should be performed in an experienced center. Transsphenoidal surgery performed by an expert surgeon is the only therapeutic option that can offer definitive cure and remains the first-line treatment in most patients. Second-line treatments include pharmacotherapy, pituitary radiotherapy and bilateral adrenalectomy. The second-line therapeutic strategy is complex, must be individualized and performed in a multidisciplinary expert center. Symptomatic treatments of persisting co-morbidities after remission, which are responsible for increased mortality and impaired quality of life is an important part of medical management.

Development of 68Ga DOTA-CRH for PET/CT Imaging of ACTH-Dependent Cushing's Disease: Initial Study.

Purpose: Adrenocorticotropic hormone (ACTH)-dependent Cushing's disease accounts for 75% cases of the endogenous Cushing's syndrome. The size of lesion is usually very small, which results in false-negative magnetic resonance imaging (MRI) even after biochemical confirmation of the disease. Corticotrophin-releasing hormone (CRH) the key controller of hypothalamus-pituitary--adrenal axis binds to CRH receptor R1 and R2. CRH R1 is overexpressed in pituitary adenomas. The present study aims to target these overexpressed receptors with 68Ga-DOTA-CRH for noninvasive imaging of ACTH-dependent pituitary adenomas. Materials and Methods: Custom-synthesized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-CRH peptide was purified by high performance liquid chromatography (HPLC) and characterized by mass spectra. Postradiolabeling optimization with 68Ga, quality control tests were carried out to ensure the suitability of 68Ga DOTA-CRH for intravenous administration. A pilot study consisting of 15 patients including 6 known cases of macroadenoma underwent 68Ga-DOTA-CRH regional brain positron emission tomography/computed tomography (PET/CT). The optimal imaging time and biodistribution studies were performed in five patients' whole-body and serial brain PET/CT imaging. Lesion activity was determined as SUVmax and correlated with CE-MRI and histopathology of excised tissue. Results: A retention time of 11.3 min and mass of 5145 Da was observed on HPLC and mass spectra. Radiolabeling yield of >98% was achieved under optimized conditions using 25-100 µg of conjugated peptide for 10-22 mCi of 68Ga. The quality control results were in agreement with acceptable criteria. 68Ga-DOTA-CRH was able to delineate ACTH secreting corticotropinoma in all 15 patients. Physiological uptake of radiotracer was observed in liver and spleen with diffused marrow activity. Excretion was noted by renal route. Imaging results were in correlation with CE-MRI and histopathology of excised tissue. Conclusion: 68Ga-DOTA-CRH PET/CT is a promising molecular imaging modality for detection of ACTH-dependent microadenoma.

The role of bilateral inferior petrosal sinus sampling in determining the preoperative localization of ACTH-secreting pituitary microadenomas in Cushing's disease: Experience of a tertiary center.

INTRODUCTION: Bilateral inferior petrosal sinus sampling (BIPSS) is an important procedure in the diagnostic work-up of Cushing's syndrome (CS). In this study, we investigated the diagnostic performance of BIPSS in detecting the source of adrenocorticotropic hormone (ACTH) secretion in Cushing's disease (CD) without radiological evidence. METHODS: Thirty-five consecutive patients who underwent BIPSS due to ACTH-dependent CS between 2010 and 2019 in our clinic and subsequently underwent transsphenoidal surgery were included. The indication for BIPSS was biochemically proven ACTH-dependent CS but normal or ≤6 mm pituitary lesion in pituitary magnetic resonance imaging (MRI). Corticotropin releasing hormone (CRH) stimulation was applied to all patients during the BIPSS procedure. BIPSS data, MRI results, pathological findings, and follow-up results were analyzed. The diagnostic performance of BIPSS was calculated. RESULTS: A total of 35 patients, 6 (17%) males and 29 (83%) females, were included in the study. Pituitary MRI was normal in 12 (34.3%) and revealed lesions ≤ 6 mm in 23 (65.7%) patients. BIPSS lateralized the right side in 13 (37.1%) and left side in 18 (51.4%) patients, while no lateralization was observed in the remaining 4 (11.5%) patients. BIPSS showed lateralization in the same direction with pituitary adenoma in 21 (60%) patients before CRH injection and in 29 (83%) patients after CRH injection (p = 0.034). The sensitivity of the BIPSS procedure was 88%. Accurate localization of the pituitary lesion was more frequent when based on BIPSS results than on MRI (83% vs. 51%, P = 0.005). CONCLUSION: BIPSS appears to be a valuable and safe diagnostic tool in patients who are diagnosed with CD biochemically but do not have clear radiological evidence of ACTH-producing lesion.

Apoplexy of Crooke cell tumour leading to the diagnosis of severe Cushing disease; a case report.

BACKGROUND: Patients with Crooke cell tumours present with features of Cushing syndrome or mass effect. There are few reports of patients with Crooke cell tumours presenting due to apoplexy. All of them had silent tumours. Patients with Cushing syndrome caused by Crooke cell tumours have not been reported to present with apoplexy. CASE PRESENTATION: A 35-year-old female presented with sudden onset headache and visual loss for 1 week. She had secondary amenorrhoea for 10 years. There were features of Cushing syndrome including central obesity, multiple monomorphic acne, dorso-cervical and supraclavicular fat pads, hypertension, proximal weakness, pigmentation and refractory hypokalaemia. She was found to have markedly elevated serum cortisol, central hypothyroidism and hypogonadotropic hypogonadism. There was a mass in the sellar region (4.7 cm × 1.9 cm × 5.3 cm) suggestive of a pituitary tumour extending to the suprasellar region. Imaging showed evidence of bleeding and compression of the optic chiasm. She underwent urgent trans-sphenoidal excision of the tumour. Histology was compatible with a pituitary neuroendocrine tumour. There was margination of ACTH reactivity to the cell periphery and ring like positivity in most of the cells in the cytokeratin stain. Features were in favour of a Crooke cell tumour. After surgery she improved gradually and became eucortisolaemic. CONCLUSIONS: This is a unique presentation of an apoplexy of Crooke cell tumour causing Cushing syndrome. Delayed health seeking behaviour of this patient despite severe Cushing disease could have led to this presentation which has not been reported before.

Stereotactic radiosurgery before bilateral adrenalectomy is associated with lowered risk of Nelson's syndrome in refractory Cushing's disease patients.

BACKGROUND: Nelson's syndrome is a rare but challenging sequelae of Cushing's disease (CD) after bilateral adrenalectomy (BLA). We sought to determine if stereotactic radiosurgery (SRS) of residual pituitary adenoma performed before BLA can decrease the risk of Nelson's syndrome. METHODS: Consecutive patients with CD who underwent BLA after non-curative resection of ACTH secreting pituitary adenoma and had at least one follow-up visit after BLA were studied. Nelson's syndrome was diagnosed based on the combination of rising ACTH levels, increasing volume of the pituitary adenoma and/or hyperpigmentation. RESULTS: Fifty patients underwent BLA for refractory CD, and 43 patients (7 men and 36 women) had at least one follow-up visit after BAL. Median endocrine, imaging, and clinical follow-up were 66 months, 69 months, and 80 months, respectively. Nine patients (22%) were diagnosed with the Nelson's syndrome at median time after BLA at 24 months (range: 0.6-119.4 months). SRS before BLA was associated with reduced risk of the Nelson's syndrome (HR = 0.126; 95%CI [0.022-0.714], p=0.019), while elevated ACTH level within 6 months after BLA was associated with increased risk for the Nelson's syndrome (HR = 9.053; 95%CI [2.076-39.472], p=0.003). CONCLUSIONS: SRS before BLA can reduce the risk for the Nelson's syndrome in refractory CD patients requiring BLA and should be considered before proceeding to BLA. Elevated ACTH concentration within 6 months after BLA is associated with greater risk of the Nelsons' syndrome. When no prior SRS is administered, those with a high ACTH level shortly after BLA may benefit from early SRS.

A human ACTH-secreting corticotroph tumoroid model: Novel Human ACTH-Secreting Tumor Cell in vitro Model.

BACKGROUND: Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models. METHODS: To characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures. FINDINGS: scRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months. INTERPRETATION: Our human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD. FUNDING: This work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation.

Paediatric Cushing's disease: Epidemiology, pathogenesis, clinical management and outcome.

Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70-100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.

Postoperative Day 1 Morning Cortisol Value as a Biomarker to Predict Long-term Remission of Cushing Disease.

CONTEXT: Recurrence of Cushing disease (CD) can occur even decades after surgery. Biomarkers to predict recurrence of CD after surgery have been studied but are inconclusive. OBJECTIVE: The aim of our study was to identify specific biomarkers that can predict long-term remission after neurosurgery. DESIGN: Identification of specific biomarkers to predict long-term remission of CD was performed by logistic regression analysis followed by Kaplan-Meier survival analysis, using recurrence as the dependent variable. SETTING: A total of 260 patients with CD identified from our institutional research patient data registry search tool and from patients who presented to our longitudinal multidisciplinary clinic between May 2008 and May 2018 underwent statistical analysis. INTERVENTIONS: Data on clinical features, neuro-imaging study, pathology, biochemistry, and treatments were collected by reviewing digital chart records. MAIN OUTCOME MEASURE: Postoperative cortisol as a biomarker to predict long-term remission after surgical treatment for CD. RESULTS: By logistic regression analysis, postoperative day 1 (POD1) morning (5-10 am) serum cortisol, female sex, and proliferative index had significant association with CD recurrence (odds ratio [OR] = 1.025, 95% CI: 1.002-1.048, P = .032). In contrast, the postoperative nadir cortisol (OR = 1.081, 95% CI: 0.989-1.181, P = .086), urinary free cortisol (OR = 1.032, 95% CI: 0.994-1.07, P = .098), and late night salivary cortisol (OR = 1.383, 95% CI: 0.841-2.274, P = .201) had no significant correlation with recurrence. A significant association between POD1 morning serum cortisol and long-term CD remission was verified by Kaplan-Meier analysis when using POD1 morning serum cortisol <5 µg/dL as the cut-off. CONCLUSIONS: The POD1 morning serum cortisol level has a significant association with CD recurrence.