Adrenalectomy Research Articles

Adrenalectomía laparoscópica bilateral sincrónica: técnica quirúrgica y resultados perioperatorios en 13 años de experiencia

Introduction and objectivesLaparoscopic surgery is the standard approach for the treatment of adrenal glands. Bilateral synchronous adrenalectomy is rarely performed, and evidence about this procedure is limited. Our objective is to report our 13-year experience with synchronous laparoscopic bilateral adrenalectomy, evaluating its feasibility, safety, and perioperative outcomes. Patients and methodsA total of 23 consecutive patients undergoing synchronous bilateral laparoscopic adrenalectomy between 2007 and 2020 in a single academic center were included. Variables evaluated were operative time, estimated blood loss, conversion to open surgery, postoperative complications, mortality, and postoperative length of stay. ResultsMean operative time was 189.3±48.9min. Mean estimated blood loss was 163.0±201.3ml. There were no conversions to open surgery. Five patients had postoperative complications, three of those were major. No patient died in the perioperative period. Median postoperative length of stay was three days (range 1-30). At pathology analysis, 15 patients had bilateral adrenal hyperplasia, 2 unilateral adrenal hyperplasia and a contralateral benign tumor, 1 unilateral adrenal hyperplasia and a normal contralateral gland, 1 unilateral adenoma, 3 bilateral pheochromocytomas and 1 bilateral myelolipoma. ConclusionSynchronous bilateral laparoscopic adrenalectomy is a feasible and safe technique. A multidisciplinary and experienced team involving anesthesiologists and endocrinologists is required.

Massive bilateral adrenal mass with adrenal insufficiency: a case report of primary adrenal lymphoma

Primary Adrenal Lymphoma (PAL) is extremely rare and usually occurs in men in the 6th-7th decade as bilateral, diffuse large B-cell lymphoma (DLBCL). Here, an 80-year-old patient admitted to the urology outpatient clinic with flank pain and bilateral adrenal mass detected on ultrasound is presented. Positron Emission Tomography-Computed Tomography (PET-CT) was planned for the patient who was referred to the endocrine outpatient clinic. The PET-CT scan revealed lobulated-contoured masses containing necrotic areas with a size of 7.4×5.5×9.8 cm, 19 Hounsfield Unit (HU), and SUVmax value of 23.9 the right adrenal, and with the size of 8.4×8.7×10.8 cm, 28 HU, SUVmax value of 27.3 in the left adrenal. These masses were reported to be not compatible with metastasis and suggested a tumor of the adrenal origin or bilateral adrenocortical carcinoma. In laboratory tests, since Adrenocorticotropic hormone level 291-592 pg/mL (high) and Cortisol level was 7.5-9.5 mcg/dL (low), bilateral adrenalectomy was performed considering adrenocortical cancer primarily. Diffuse large B cell lymphoma was determined as the result of the pathology. Postoperative hydrocortisone and fludrocortisone treatment was initiated for the patient immediately. The patient was transferred to the hematology inpatient clinic to receive Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone chemotherapy. In this case report, we aimed to emphasize that the differential diagnosis should be made well in massive bilateral adrenal masses. Although the diagnosis is challenging, clinicians should be alert in diagnosing lymphoma in bilateral, massive adrenal masses with adrenal insufficiency. Since this disease's prognosis is poor and aggressive, a histopathological diagnosis should be obtained, and treatment should be initiated as soon as possible.

18F-FDG PET/CT image findings of a dog with adrenocortical carcinoma

BackgroundIn human medicine, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been used to differentiate between benign and malignant adrenal tumors and to identify metastases. However, canine adrenocortical carcinomas identified by 18F-FDG PET/computed tomography (CT) have not been reported.Case presentationA 13-year-old, castrated male, Cocker Spaniel dog with severe systolic hypertension exhibited an adrenal mass approximately 3.6 cm in diameter on ultrasonography. There was no evidence of pulmonary metastasis or vascular invasion on thoracic radiography and abdominal ultrasonography, respectively. 18F-FDG PET/CT was performed to identify the characteristics of the adrenal mass and the state of metastasis. One hour after injection of 5.46 MBq/kg 18F-FDG intravenously, the peripheral region of the adrenal mass visually revealed an increased 18F-FDG uptake, which was higher than that of the liver, and the central region of the mass exhibited necrosis. The maximal standardized uptake value (SUV) of the adrenal mass was 3.24; and relative SUV, calculated by dividing the maximal SUV of the adrenal tumor by the mean SUV of the normal liver, was 5.23. Adrenocortical carcinoma was tentatively diagnosed and surgical adrenalectomy was performed. Histopathologic examination of the resected adrenal mass revealed the characteristics of an adrenocortical carcinoma. After adrenalectomy, systolic blood pressure reduced to below 150 mmHg without any medication.ConclusionThis is the first case report of 18F-FDG PET/CT findings in a dog with suspected adrenocortical carcinoma and may provide valuable diagnostic information for adrenocortical carcinoma in dogs.

PARTIAL ADRENALECTOMY - HOW FAR CAN WE GO?

Organ preservation and functional resections are the mainstays of most surgical sub-specialties at the present time. This is even more evident in endocrine surgery, where the product of secretion of these petit organs is of paramount importance. Partial adrenalectomy and cortical sparing techniques have evolved to actually compete with total adrenalectomy, the historical gold standard treatment. Much refined imaging techniques can readily identify smaller adrenal lesions that can be addressed surgically or percutaneously given the indication. The trend towards partial adrenalectomy is straightforward in bilateral disease where steroid replacement can be avoided while for unilateral disease, normal hormonal levels can be obtained. The reviewed publications offer deep insight into the advancement of partial or cortical sparing adrenal procedures from pioneering work to large cohort studies.

Diagnosis and Management of Cushing's Disease: A Survey of Endocrinologists from the Middle East and North Africa

Abstract Background Cushing's disease is the most prevalent cause of endogenous Cushing's syndrome. This study aimed to scope the current clinical practice pattern in managing Cushing's disease by endocrinologists in the Middle Eastern and North African (MENA) region. Methods A questionnaire dealing with diagnosis, treatment, and follow-up of patients with Cushing's disease was adopted and sent electronically to a convenience sample of endocrinologists from the MENA region. Results Out of 125 responses received, 88 were eligible for inclusion in the analysis. Most respondents selected the overnight dexamethasone suppression test (ONDST) and 24-hour urinary-free cortisol (UFC) as the best screening tests, 58 (66.7%) and 50 (57.5%) respectively, followed by midnight serum cortisol and midnight salivary cortisol. Measurement of serum adrenocorticotropic hormone (ACTH; 86.2%) and classic high-dose dexamethasone suppression test (40.2%) were selected for localization of the primary lesion. The primary choice of treatment was transsphenoidal pituitary surgery (98.8%). For the recurrence of Cushing's disease, medical therapy was the preferred modality followed by repeated pituitary surgery or bilateral adrenalectomy. In case of treatment failure following the first pituitary surgery and ketoconazole treatment, 36.9% selected pasireotide, while 32.1% chose bilateral adrenalectomy. Conclusion ONDST and UFC are the two most common tests used to screen an index case with features of hypercortisolism. Pituitary surgery is the primary choice of treatment in Cushing's disease. However, medical treatment by ketoconazole is preferred for recurrent cases. Bilateral adrenalectomy is followed by pasireotide may be chosen in case of treatment failure after pituitary surgery and ketoconazole.

Particular aspects in pheochromocytoma

We aim to address incomplete procedures of adrenalectomy for pheochromocytoma (PHEO) on a bases of a mini-review. Dopamine, adrenaline and noradrenaline – secretor tumors are rare in general population, representing a neuroendocrine neoplasia with a strong genetic driving force and uncertain profile concerning a malignant behavior which may be less or more predicted based on initial post-operative report. There is no linear correlation with the post-operative recurrence in terms of clinical presentation, timing and prognostic. The first laparoscopic – based PHEO removal was done in 1992; and since then, the open procedure was replaced in majority of cases by the new gold standard – laparoscopic adrenalectomy; a current conversion rate is of 5%; alpha and beta - blockade is mandatory for preoperative management since an adrenergic crisis might be triggered by higher intraabdominal pressure during laparoscopy; bilateral PHEO may be addressed through one time procedure; minimally invasive technique is done trans-peritoneal or retroperitoneal; robotic – assisted laparoscopic procedure is the next logical step from traditional laparoscopy; in children, minimally invasive procedure is less likely to be used as in adults. Partial adrenalectomy (in terms of cortical - sparing technique) should be rarely performed for unilateral PHEO; its potential utility is for cases with non-feasible total removal due to tumor anatomy (like advanced local disease) or bilateral adrenal involvement in hereditary syndromes (like MEN 2A, VHL), especially in children and young adults to overcome the need of life long glucocorticoid replacement due to chronic adrenal insufficiency. A meta-analysis focusing on recurrence after total adrenalectomy revealed a 3% ratio after 2 years in PHEO. The percent for partial procedure is more than 10% depending on study. In conclusion, a particular aspect in PHEO management is the recurrence after an adrenalectomy, typically after a partial procedure. Unless bilateral involvement or a clear diagnostic of a hereditary syndrome involving bilateral PHEO, partial adrenalectomy should be limited.

Bilateral Synchronous Adrenal Tumors in Lynch Syndrome

A 65-year-old Hispanic male with Lynch Syndrome and a history colon cancer was incidentally found to have bilateral adrenal tumors by CT scan. A PET scan revealed marked FDG avidity of both adrenal masses; with an SUV of up to 24.5. The patient was asymptomatic at the time. The patient underwent bilateral adrenalectomy and left nephrectomy. Final pathology demonstrated high-grade malignant spindle cell neoplasm with sarcomatoid features. Immunohistochemistry for the MMR proteins showed decreased protein expression of MLH1, negative staining for PMS2, and intact tumor staining of MSH2 and MSH6.

Morbidity and mortality in Cushing's syndrome

Endogenous Cushing's syndrome is arare endocrine disorder that is fatal if left untreated. It can be distinguished into adrenocorticotropic hormone (ACTH)-dependent (central and ectopic Cushing's syndrome) and ACTH-independent subtypes (unilateral or bilateral adrenal adenomas). The clinical presentation of patients includes typical stigmata of cortisol excess with physical symptoms of catabolic metabolism (myopathy, striae, parchment skin, osteoporosis) and components of metabolic syndrome (diabetes mellitus, obesity, arterial hypertension, hypercholesterolemia). Biochemical diagnosis is performed in three steps: 1.Confirmation of the diagnosis by 1‑mg dexamethasone suppression test, 24‑h urine free cortisol, and measurement of late-night salivary cortisol. 2.Differentiation of ACTH-dependent Cushing's syndrome from ACTH-independent adrenal Cushing's syndrome by measurement of plasma ACTH. 3.Further subtyping by corticotropin-releasing hormone (CRH) test, inferior petrosal sinus sampling, and imaging modalities. Therapeutic decisions are made on an interdisciplinary basis. First-line therapy for all subtypes is surgery when possible; additional options for all forms include drug therapy and bilateral adrenalectomy. Despite adequate treatment, Cushing's syndrome is associated with increased long-term morbidity and mortality. Interdisciplinary and multimodal therapy management is necessary in the long term to positively influence mortality and reduced quality of life.

Adrenalectomy improves glycemic responses in congenic obese LA/Ntul//-cp RATS

To determine the effects of adrenalectomy on typical insulin-mediated glycemic responses in male obese rats, groups (n=6 -12 rats/phenotype) of normally reared congenic lean and obese animals were fed a Purina chow diet from 6 to 9 weeks of age, and the Chow diet plus a highly palatable cafeteria diet from 9 to 12 weeks of age. The congenic LA/Ntul//-cp rat strain is noted for its longevity and early expression of the obese trait but remains non-diabetic throughout much if not all of its normal lifespan. Subgroups of obese animals were subjected to bilateral adrenalectomy (ADX) at 6 weeks of age to remove glucocorticoid contributions to glycemic parameters. Measures of weight gain (WG )and of glucose tolerance (OGT) were obtained in the three treatment groups at 6, 9 and 12 weeks of age. WG on ADX-obese rats was similar to that of their lean littermates at 6 and 9 weeks of age on the chow diet but increased to twice that observed in their lean littermates from 9 to 12 weeks of age. OGT responses after 30 to 60 minutes and the area under the OGT curve were impaired but not diabetic in obese animals at all ages compared to lean littermates and returned toward those of normally lean rats after ADX. The Insulin to glucose ratio (I:G) was also consistent with insulin resistance in obese but not in ADX-obese or lean rats at 12 weeks of age. In conclusion, ADX resulted in normalization of OGT and glycemic parameters in the obese phenotype at 9 and 12 weeks of age. These results are consistent with normalization of typical insulin-mediated components of glycemic parameters and glucose uptake in peripheral tissues following adrenalectomy of congenic obese rats. The results further suggest that the counterregulatory effects of insulin and glucocorticoid hormones may be contributory to the impaired glycemic responses in the obese phenotype of the LA/N//-cp (corpulent) rat and are consistent with a receptor-mediated element in the development of insulin resistance and glucose uptake in peripheral tissues commonly associated with the early development of obesity in this strain.

Surgical adrenalectomy during rescue Extracorporeal Life Support for pheochromocytoma induced cardiogenic shock: a case report

Introduction : Pheochromocytoma, a rare catecholamine-producing tumor, has been described to provoke stress-induced Takotsubo-like cardiomyopathy and even severe refractory cardiogenic shock. In this case report, venoarterial extracorporeal membrane oxygenation (VA-ECMO) was used for hemodynamic stabilization and was continued during the resection of a large neuroendocrine tumor. Description : A 69-year old male, recently diagnosed with a pheochromocytoma, was referred to our center because of severe cardiogenic shock after induction of anesthesia for resection of the mass. Despite adequate alpha-and beta-adrenergic blockade for one month, he developed malignant hypertension with subsequently hemodynamic collapse. After successful cardiopulmonary resusci-tation he developed pulmonary oedema with severe hypoxemia and persistent hemodynamic lability. On arrival in our hospital, echocardiography revealed significant left ventricular impairment. Decision was made to commence him on VA-ECMO for a refractory cardiogenic shock with severe pulmonary oedema. Because of persistent blood pressure swings despite VA-ECMO and beta-adrenergic blockade, we decided to remove the tumor on mechanical circulatory support by an open surgical approach the next day. After clamping of the adrenal circulation, the patient experienced profound hypotension requiring high doses of epinephrine and a methylene blue infusion. Surgical resection was successful but complicated by a postoperative bleeding for which the patient underwent an emergent endovascular embolization of an adrenal artery. Over the next days, there was progressive cardiac recovery and the patient was weaned off VA-ECMO on the fourth postoperative day. The patient was discharged from the intensive care 27 days after admission and left the hospital on day 30. Discussion: VA-ECMO seems to be a feasible last resort therapy in refractory cardiogenic shock induced by pheochromocytoma crisis as suggested by a high survival rate in literature. Despite its support benefit during this type of shock, surgical removal of the tumor is rarely done with mechanical circulatory support and heparinization.

Severe Ectopic Cushing's Syndrome: Feasibility of Bilateral Simultaneous Retroperitoneoscopic Adrenalectomy and Risk of Thromboembolic Events

Severe Ectopic Cushing's Syndrome: Feasibility of Bilateral Simultaneous Retroperitoneoscopic Adrenalectomy and Risk of Thromboembolic Events

Functioning Crooke Cell Adenomas: Case Series and Literature Review

Crooke cell adenomas (CCAs) are rare, potentially aggressive pituitary adenomas. Data regarding prevalence and clinical course are sparse. We performed a retrospective review of 59 consecutive functioning corticotroph adenomas operated on between October 2017 and November 2020 and a literature review of CCA publications since1991. The prevalence of CCAs among functioning corticotroph adenomas at our institution was 8.5% (5/59). In the 4 other surgical case series, prevalence of CCAs was 0%-6.8%. Our patients (4 women and 1 man, mean age 46 ± 11 years) presented with hypercortisolism (3/5), with vision loss (1/5), and incidentally (1/5). All patients had elevated adrenocorticotropic hormone (151 ± 54 pg/mL) and urinary free cortisol (830 ± 796.5 μg/day). Radiologically, 3 tumors were macroadenomas and 2 had cavernous sinus invasion. All patients achieved biochemical remission at 3 months postoperatively. One patient with a giant pituitary adenoma underwent fractionated radiation for residual tumor. During follow-up (range, 3.1-31.0 months), no patients had evidence of radiological or biochemical recurrence. The literature review identified 22 functioning corticotroph adenomas with outcome data. Additional treatments included reoperation (50%), radiation (59%), bilateral adrenalectomy (23%), and temozolomide (36%). We found a higher CCA prevalence among functioning adrenocorticotropic hormone adenomas after implementation of the 2017 World Health Organization classification. In our series and the literature, most CCAs were macroadenomas with high adrenocorticotropic hormone levels. Postoperative outcomes were excellent in our series, while some cases from the literature were refractory to standard treatments. Larger clinical and molecular studies are needed to identify patients at risk.

Medullary thyroid cancer with ectopic Cushing's syndrome: A multicentre case series.

Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. Retrospective cohort study in three German and one Swiss referral centres. Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment forECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.

Effect of adrenalectomy and glycemic status on caloric efficiency and adiposity in the congenic LA/Ntul//-cp (corpulent) rat

Obesity develops in the obese phenotype of the congenic LA/Ntul//-cp (corpulent) rat strain by 6 weeks of age.1 To gain insight into the contributors to the expression of obesity in the obese phenotype of this strain, groups [n=12-20 rats/phenotype] of congenic male lean and obese LA/Ntul//-cp (corpulent) rats were fed an ad libitum standardized Purina chow diet (CHOW) from 6 to 12 weeks or age, and subgroups (n=6 rats / subgroup) were overfed with a highly palatable cafeteria diet (CAFÉ) from 9 to 12 weeks of age (WOA). A subgroup of obese rats (n=6) were subjected to bilateral adrenalectomy (ADX) at 6 WOA and followed the same dietary regimen and treatment schedule. BW of lean and obese animals were similar at 6 WOA and increased by 88% in lean phenotype and 281% in obese phenotype during the 6 weeks study, while in ADX obese rats, BW were similar at 6 and 9 WOA but BW increased to 2.5-fold above starting weights and 1.8-fold above 9-week weights between 9 and 12 WOA. The CAFE supplement was without significant effect on final body weights in the lean phenotypes, but was associated with significantly greater body weights at ages 9 and 12 WOA in the obese phenotype (p=<0.05) and in the obese-ADX at 12 WOA. CE (kcal/gram gain of BW per day) remained relatively constant in lean and obese-ADX rats throughout the study, but CE was more efficient in the obese phenotype at all ages studied and was more efficient with the CAFE supplement feeding regimen. Fasting I:G ratios at 12 weeks of age were 4.2-fold greater in obese than lean and were partially normalized in obese-ADX to 1.7-fold increase at 12 WOA. Relative adiposity of obese rats was 3.8-fold greater in obese than lean phenotype, with the greatest increase in the SQ depot. Resting VO2 (RMR) was lower in obese than lean rats at each age studied and was increased by ADX. Thermogenic interscapular brown adipose tissue (IBAT) mass was greater in obese and obese-ADX than lean rats. The results of this study indicate that CE is associated with the predisposition for the expression and development of adiposity in the obese phenotype of this strain and is associated with an increased I:G ratio and IBAT mass that is consistent with insulin resistance and an impaired capacity for energy expenditure and became normalized on the Chow but not the CAFE diet following ADX. These observations implicate likely multiple metabolic factors that contribute to a greater efficiency of energy storage, utilization and or energy conservation in the obese than in the lean phenotype of this strain and which is partially corrected in the obese phenotype by ADX. The metabolic impact of added caloric intake was associated with an additive impact on the CE of weight gain and adiposity in the obese phenotype of this congenic rodent strain and was partially corrected via ADX

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.

Proton Stereotactic Radiotherapy for Treatment of Nelson's Syndrome

Nelson's syndrome is a rare disorder that may arise as a complication of treating Cushing's disease through bilateral adrenalectomy. It is characterized by growth of remaining pituitary adenoma and elevation of adrenocorticotropic hormone (ACTH) levels. Prior studies have established radiation therapy (RT) as a method of treating Nelson's syndrome. In this study, we evaluated the efficacy of proton stereotactic radiosurgery (PSRS) on decreasing ACTH levels and achieving disease remission in patients with Nelson's syndrome treated with SRS.A retrospective analysis of eight patients with Nelson's syndrome who received PSRS between 2007 and 2017 at our institution was conducted. All patients previously underwent bilateral adrenalectomy for treatment of Cushing's disease. Patients received PSRS at a total dose of 15 or 20 Gy(RBE) delivered in one fraction. The median clinical target volume was 5.7 cc (range 3.7-9.0 cc). ACTH levels, disease status, and post-treatment complications were followed post-SRS to assess for endocrine remission.The median follow-up was 80 months (range 35-126 months) from the end of SRS treatment. The median ACTH level decreased from 761.5 pg/mL pre-SRS to 38 pg/mL post-SRS at time of latest follow-up. Endocrine remission was achieved among six patients (75%) at a median time of 47 months (range 12 -126 months) from SRS. Three patients (38%) developed pituitary deficits (two with TSH and gonadal deficiency and one with pan-pituitary deficiency) post-SRS.SRS can be an effective treatment to achieve endocrine remission in patients with Nelson's syndrome. SRS can lead to pituitary deficits in some patients and longer follow-up is warranted to assess long-term disease control and treatment toxicity.D.W. Kim: None. G. Lee: None. E. Cai: None. B. Swearingen: None. P.H. Chapman: None. M.R. Bussiere: Consultant; American College of Radiology. A. Klibanski: None. J.S. Loeffler: None. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital.

Successful spontaneous pregnancy after transphenoidal surgery and bilateral adrenalectomy for Cushing’s disease: A case report

Successful spontaneous pregnancy after transphenoidal surgery and bilateral adrenalectomy for Cushing’s disease: A case report

Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization

To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study

GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions. The bilateral nature of this disease suggests germline genetic predisposition. We aimed to identify the genetic driver event responsible for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. We conducted a multicentre, retrospective, cohort study at endocrine hospitals and university hospitals in France, Canada, Italy, Greece, Belgium, and the Netherlands. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production and those with GIP-dependent unilateral adrenocortical adenomas were used as control groups. We performed whole genome, whole exome, and targeted next generation sequencing, and copy number analyses of blood and adrenal DNA from patients with familial or sporadic disease. We performed RNA sequencing on adrenal samples and functional analyses of the identified genetic defect in the human adrenocortical cell line H295R. 17 patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome were studied. The median age of patients was 43·3 (95% CI 38·8-47·8) years and most patients (15 [88%]) were women. We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients. None of the 29 patients in the control groups had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions. Global gene expression analysis showed GIP receptor upregulation with a log2 fold change of 7·99 (95% CI 7·34-8·66; p=4·4 × 10-125), and differential regulation of several other G protein-coupled receptors in GIP-dependent primary bilateral macronodular hyperplasia samples compared with control samples. In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells. We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis. Genetic testing and counselling should be offered to these patients and their relatives. Agence Nationale de la Recherche, Fondation du Grand défi Pierre Lavoie, and the French National Cancer Institute.

Median 10 years follow-up of patients with covert Cushing\u2019s syndrome: a case series

BackgroundEctopic adrenocorticotropic hormone secretion syndrome occurs in 10% of all patients with adrenocorticotropic-hormone-dependent hypercortisolism. It is usually associated with overt malignancies or with occult and indolent tumors. This study aims to confirm the source of ectopic adrenocorticotropic hormone in four patients with ectopic Cushing’s syndrome over time.Case presentationA 38-year-old Iranian man with Cushing’s syndrome underwent bilateral adrenalectomy since the source of ectopic adrenocorticotropic hormone secretion was not localized and pituitary imaging was normal. A whole-body scan revealed a right-lung tumoral mass with mediastinal lymph node metastasis. The mass was assumed a lung carcinoid tumor with mediastinal adenopathy. Right-lung mid-zone lobectomy and mediastinal lymphadenectomy were done. In a 47-year-old Iranian man with Cushing’s syndrome, whole-body computed tomography scan revealed a pulmonary nodule in the posterior segment of the left lower lobe of the lung. The third case was a 25-year-old Iranian man who presented with symptoms and signs of Cushing’s syndrome. Pituitary magnetic resonance imaging revealed a microadenoma 5 × 9 mm. Whole-body scan showed abnormal focal somatostatin receptors analog avid lesion in the posterior aspect of inferior third of right lung, highly suggestive of ectopic adrenocorticotropic-hormone-producing tumor. The last case was a 43-year-old Iranian woman with Marfan syndrome with a history of mitral and aortic valve replacement and chronic dissection of the aorta, who presented with symptoms and signs of Cushing’s syndrome. She underwent bilateral adrenalectomy 1 year later owing to failure to locate ectopic adrenocorticotropic hormone syndrome. Whole-body scan showed abnormally increased radiotracer uptake in the midline of the skull base and posterior aspect of the middle zone of left hemithorax and bed of left lobe of thyroid.ConclusionThe clinical spectrum of ectopic adrenocorticotropic hormone secretion syndrome is wide, and distinguishing Cushing’s disease from ectopic adrenocorticotropic hormone secretion syndrome is difficult. Initial failure to identify a tumor is common. Pulmonary carcinoid or occult source of ectopic adrenocorticotropic hormone secretion syndrome is usually the cause. In occult cases of ectopic adrenocorticotropic hormone in which the tumor cannot be localized, serial follow-up with serial computed tomography, magnetic resonance imaging, or scintigraphy is recommended for several years until the tumor can be localized and treated.