Ectopic Adrenocorticotropic Hormone Research Articles

#2026 Hypokalemia associated to neuroendocrine carcinoma of the cervix

Abstract Background and Aims Hypokalemia is one of the most common electrolyte disorders seen in clinical practice. Hypokalemia can be caused by decreased intake of potassium, redistribution of potassium (K+) in cells or by excessive gastrointestinal losses or renal losses. In this setting, hypokalemia may also be caused by the paraneoplastic production of ectopic adrenocorticotropic hormone (ACTH) by some tumors. Cancer of the uterine cervix is the fourth common cancer affecting women worldwide and the fourth most common gynecologic cancer in Spain. Neuroendocrine carcinoma of the cervix represents about 2% of all cervical neoplasms. Method We report the case of a 44-year-old Peruvian woman with hypokalemia who was diagnosed with Cushing syndrome secondary to paraneoplastic production of ACTH by neuroendocrine carcinoma of cervix. Results Patient was overweight and affected by uterine myoma and anemia without further investigations. She was admitted to our hospital due to lower back pain, leg swelling and constipation. Blood pressure was normal, chest radiography did not show abnormal findings and ECG showed the U wave. Laboratory tests at admission revealed hypokalemia (2.3 mmol/L), metabolic alkalosis, anemia (hemoglobin 9.5 g/dL), hyperkaliuria (K+ urine/Creatinine urine 70 mmol/g) with an elevated transtubular potassium gradient (TTKG=12) and normal renal function. Laboratory data are presented in Table 1. She developed hypertension in the first day of hospitalization. Renin, aldosterone and cortisol tests was performed. Hypercortisolism was observed and confirmed with 24-hour urinary cortisol excretion. Because of an elevated ACTH (263 pg/mL), pituitary magnetic resonance imaging was performed without lesions. Whole-body computed tomography revealed a cervical mass. PET scan showed pelvic, adrenal, hepatic and local lymphadenopathy activity (see Fig. 1). After the histopathological study, diagnostic of small cell neuroendocrine carcinoma of the cervix was made. Chemotherapy therapy was initiated with cisplatin/etoposide regimen. The patient decide to return to Peru because of the poor prognosis of her illness. At discharge, potassium level was 3 mmol/L despite the treatment with spironolactone, ramipril, losartan and oral potassium chloride (160 mmol). Conclusion Hypokalemia is a common clinical disorder. In some patients it may be caused by an increased mineralocorticoid activity due to ectopic ACTH-secreting tumors. Applying diagnostic algorithms to electrolyte disorders, beyond their simple treatment, can unmask secondary causes and serious diseases.

A case of gallbladder neuroendocrine carcinoma complicated by ectopic adrenocorticotropic hormone syndrome and resulting in rapid fetal outcomes due to sepsis.

A 52-year-old woman presented to our hospital with chief complaints of upper abdominal bloating and lower leg edema. Computed tomography (CT) revealed liver metastasis from a gallbladder tumor. This tumor was diagnosed as neuroendocrine carcinoma (NEC) on performing a biopsy. Physical examination revealed a moon face. Blood tests revealed hypokalemia and high levels of adrenocorticotropic hormone (ACTH) and cortisol. Dexamethasone suppression test revealed that cortisol secretion was not suppressed, and the patient was diagnosed with gallbladder NEC and ectopic ACTH syndrome (EAS). Metyrapone was administered to suppress cortisol production; however, she developed septic shock due to cellulitis in the lower leg and died on the 16th day of admission. A pathological autopsy was performed, which revealed disseminated intravascular coagulation and acute respiratory distress syndrome as the cause of death. Only a few cases of EAS due to NEC originating from the gallbladder have been reported. The patient reported here succumbed shortly after diagnosis, thereby highlighting the challenges in treating gallbladder NEC complicated by EAS.

Difficult Diagnosis and Management of Concealed Cushing.

Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat. A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day. ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

Machine Learning May Be An Alternative To BIPSS In The Differential Diagnosis Of ACTH-Dependent Cushing's Syndrome.

This study aimed to develop machine learning (ML) algorithms for the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) based on biochemical and radiological features. Logistic regression algorithms were used for ML, and the area under the receiver operating characteristics curve (AUROC) was used to measure performance. We used Shapley Contributed Comments (SHAP) values, which help explain the results of the ML models to identify the meaning of each feature and facilitate interpretation. A total of 106 patients, 80 with Cushing's disease (CD) and 26 with ectopic ACTH syndrome (EAS), were enrolled in the study. The ML task was created to classify patients with ACTH-dependent CS into CD and EAS. The average AUROC value obtained in the cross-validation of the logistic regression model created for the classification task was 0.850. The diagnostic accuracy of the algorithm was 86%. The SHAP values indicated that the most important determinants for the model were the 2-day 2-mg dexamethasone suppression test, the > 50% suppression in the 8-mg high-dose dexamethasone test, late-night salivary cortisol, and the diameter of the pituitary adenoma. We have also made our algorithm available to all clinicians via a user-friendly interface. ML algorithms have the potential to serve as an alternative decision support tool to invasive procedures in the differential diagnosis of ACTH-dependent CS.

Bilateral Inferior Petrosal Sinus Sampling Without Lateralization Is Less Accurate for the Diagnosis of Cushing Disease.

During bilateral inferior petrosal sinus sampling (BIPSS), the side-to-side adrenocorticotropic hormone (ACTH) ratio, referred to as sampling lateralization, was used to predict pituitary adenoma localization. To investigate the potential different diagnostic accuracy of BIPSS for differentiating Cushing disease (CD) and ectopic ACTH secretory syndrome (EAS) patients with low lateralization (inferior petrosal sinus [IPS]:IPS ≤ 1.4) and high lateralization (IPS:IPS > 1.4). This single-center retrospective study (2011-2021) included (all patients had BIPSS results and confirmed pathologic diagnoses) 220 consecutive CD patients (validation set), 30 EAS patients, and 40 of the CD patients who had digital subtraction angiography (DSA) videos (discovery set). In the discovery set, the low-lateralization CD group (n = 11) had a higher median plasma ACTH concentration (62.2, IQR 44.7-181.0 ng/L) than the high-lateralization CD group (n = 29) (33.0, IQR 18.5-59.5, P = .013). Lower IPS to peripheral ratios were observed in the low-lateralization group during BIPSS, both before and after stimulation (P = .013 and P = .028). The sensitivity of BIPSS before stimulation in differentiating CD from EAS was lower in the low-lateralization group than the high-lateralization group (54.6% vs 93.1%, P = .003), as validated in the validation set. DSA videos revealed higher vascular area difference visible in the 2 sides of the pituitary in low lateralization (median 1.2 × 105 pixels, IQR 0.5-1.8) than the high-lateralization group (0.4 × 105 pixels, IQR 0.1-0.7, P = .008). The vascular area ratio of the 2 sides was also significantly higher in low (1.55, IQR 1.31-2.20) than high lateralization (1.19, IQR 1.07-1.35, P = .010). Our study suggested that low lateralization in CD patients may reduce the diagnostic sensitivity of BIPSS, which might be potentially associated with peripituitary vascular anatomy.

Ectopic ACTH Syndrome: Possibilities of Modern Diagnostics

The ectopic ACTH syndrome (EAS) is a constellation of clinical signs and symptoms caused by chronic excess production of cortisol by the adrenal glands due to stimulation by adrenocorticotropic hormone (ACTH) of extrapituitary origin. EAS is a rare pathology, it accounts for approximately 20% of all cases of ACTH-dependent hypercortisolism and up to 10% of all causes of endogenous autonomic cortisol production, however, it is often associated with severe hypercortisolism and is a life-threatening condition. The sources of ectopic secretion of ACTH are neuroendocrine tumors (NET), which differ in histological type, malignant potential, clinical course, and also have different, often difficult to detect localization. Early identification of ACTH -producing NET reduces the risk of death of the patient both from severe hypercortisolism and the tumor itself. The paper describes the features of the course of EAS, the possibilities of its diagnosis, and presents an algorithm for EAS diagnosis, created on the basis of the latest achievements of Russian and world medicine.

Clinical features and risk factors for postoperative recurrence in patients with Cushing's syndrome of different etiologies

The clinical characteristics of Cushing’s syndrome (CS) vary with etiology, and few studies have investigated the risk factors affecting CS recurrence after surgery. This retrospective study involved 202 patients diagnosed with CS between December 2012 and December 2022. The patients were divided into three groups according to etiology: Cushing's disease (CD), adrenocortical adenoma (ACA), and ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Of the patients with CS, 41.9% had hypokalemia and 15.0% had hypophosphatemia. The cortisol levels were negatively correlated with blood potassium, blood chlorine, and blood phosphorus. Moreover, 22.4% of patients had an abnormal heart structure, 11.2% had centripetal remodeling, 5.6% had centripetal hypertrophy, and 5.6% had centrifugal hypertrophy. The overall recurrence rate of CS caused by pituitary tumors and adrenal adenoma was 25.7%. The recurrence times were longer in the ACA group versus the CD group, in patients < 50 years of age versus in patients ≥ 50 years old group, and in patients with CD with tumors ≥ 1 cm versus tumors < 1 cm. Age, preoperative cortisol level, postoperative cortisol level, and absolute neutrophil value were closely related to postoperative recurrence, and etiology was an independent predictor of tumor recurrence in patients with CS. The results of this study showed that CS caused by different etiologies showed different clinical manifestations, blood electrolyte characteristics, and that CS could affect patient cardiac structure and function. Etiology is an independent predictor of tumor recurrence in patients with CS.

Diverse presentations of Cushing's syndrome during pregnancy - A case series.

Cushing's syndrome (CS) encompasses various causes of hypercortisolism including adrenocorticotropic hormone (ACTH) secreting pituitary adenoma with or without bilateral adrenal hyperplasia, an adrenal adenoma or carcinoma, ectopic ACTH or corticotrophin-releasing hormone (CRH) secretion by a neoplasm or exogenous corticosteroid therapy. The diagnosis of CS in pregnancy presents a challenge due to overlapping clinical features of pregnancy (weight gain, striae, acne). If untreated, CS in pregnancy is associated with increased risk of maternal and fetal complications. With fewer than 250 cases currently published, we aim to review the clinical presentations, diagnostic methods, management, and outcomes of patients with CS in pregnancy to help optimise our clinical practice. This is a single-centre, retrospective review of woman with documented hypercortisolism receiving antenatal care at a tertiary maternity hospital in Perth between 2006 to 2022. Data were collated from electronic and chart reviews. OMNI calculator was used for birthweight calculations. Local ethics and patient consent were obtained. Five women and seven pregnancies were identified. Four women had a pituitary source of ACTH-dependent CS as confirmed by brain magnetic resonance imaging. One woman had an ectopic source of ACTH. Two women were diagnosed during pregnancy. All pregnancies occurring prior to treatment of the Cushing's disease were complicated by secondary hypertension and diabetes. CS represents a rare and difficult to diagnose condition in pregnancy. When untreated, maternal and fetal outcomes are compromised. Close monitoring of the associated complications with involvement of a multidisciplinary team are recommended.

Uncommon presentation of small cell lung carcinoma with ectopic adrenocorticotropic hormone secretion and resistant hypokalemia: A case report

Paraneoplastic syndromes can serve as initial indicators of malignancy, with small cell lung cancer accounting for 13% of new lung cancer diagnoses. The most prevalent paraneoplastic syndrome associated with small cell lung cancer is inappropriate antidiuretic hormone syndrome, followed by ectopic adrenocorticotropic hormone-mediated Cushing’s syndrome. Cushing’s syndrome manifests as hypercortisolemia and presents with diverse symptoms, including central obesity, plethora, menstrual irregularities, hypertension/diabetes mellitus, ecchymoses, osteoporosis, muscle weakness, virilization/hirsutism, skin atrophy, decreased libido, and infertility. This case report details the uncommon presentation of small cell lung carcinoma manifesting with ectopic adrenocorticotropic hormone secretion (EAS), leading to resistant hypokalemia and rhabdomyolysis. This case emphasizes the importance of considering EAS in severe cases of Cushing's syndrome and highlights the diagnostic and therapeutic challenges associated with this condition.

Paraneoplastic isolated adrenocorticotropic hormone deficiency revealed after immune checkpoint inhibitors therapy: new insights into anti-corticotroph antibody.

A recently discovered facet of paraneoplastic adrenocorticotropic hormone (ACTH) deficiency exists in two forms: a paraneoplastic spontaneous isolated ACTH deficiency (IAD) and an immune checkpoint inhibitor (ICI)-related hypophysitis. Autoantibodies against corticotrophs, such as circulating anti-proopiomelanocortin (POMC) antibodies are considered disease markers. However, the number of identified cases was limited, implying that the characteristics of these autoantibodies are not fully understood. We investigate circulating autoimmune autoantibodies in detail through a novel case of IAD that developed as a paraneoplastic autoimmune ACTH deficiency. The patient developed IAD after 25 weeks of ICI therapy for metastasis of large-cell neuroendocrine carcinoma at 69 years of age. Ectopic ACTH expression and infiltration of CD3+, CD4+, CD8+, and CD20+ lymphocytes were observed in the tumor tissues and circulating anti-POMC antibodies were detected specifically in the patient's serum. Moreover, detailed analyses of immunofluorescence staining using patient serum revealed that the recognition site of the autoantibody was ACTH25-39, which had not been identified in previous cases of paraneoplastic autoimmune ACTH deficiency. This case involved a combination of paraneoplastic spontaneously acquired IAD and ICI-related hypophysitis occupying the middle ground. Moreover, our study reveals new aspects of anti-POMC antibodies in patients with paraneoplastic ACTH deficiency. This report expands our understanding of the immunological landscape and provides new insights for the identification of antibodies associated with paraneoplastic autoimmune ACTH deficiency.

THU517 Aggressive Cushing’s: A Rare Case Of Pancreatic ACTHoma In A Young Female

Abstract Disclosure: O.C. Reyes: None. A. Sison: None. M. Villa: None. D. Dimayuga: None. Introduction: Adrenocorticotropic hormone-producing pancreatic neuroendocrine neoplasm (ACTHoma) is a rare type of pancreatic neuroendocrine tumor that causes ectopic adrenocorticotropic hormone syndrome. Cushingoid manifestations and metabolic abnormalities can occur rapidly. High index of suspicion is required for early diagnosis. Case: A 31-year-old Filipino female presented with facial and ankle swelling that occurred 6 weeks before the visit. She also had acne, easy bruising, amenorrhea and frequent mood swings. There was reported weight gain of 3 kg a month prior. She had no history of hypertension and diabetes, and had no unusual family history. At the time of admission, vital signs were blood pressure of 130/80mmHg, pulse of 92/min, respiratory rate 20/min and body temperature of 37.2C. Her body mass index was 28kg/m2. She had muscle atrophy of the upper and lower extremities, facial flushing, posterior cervical fat pad, abdominal violaceous striae, and skin pigmentation. Her external genitalia was normal, Tanner Stage 5 consistent with adult pattern. Neurologic exam was unremarkable. She was examined for Cushing’s syndrome. On initial tests, glucose was 406 mg/dl, HbA1C 10.7%, thyroid stimulating hormone 0.122 (NV: 0.55-4.78), Free T3 0.77 (NV: 2.3-4.2), Free T4 0.58 (NV: 0.89-1.76). Creatinine was 0.86 mg/dL, sodium was 140 mEq/L, potassium was 2.1 mEq/L showing hypokalemia. There was leukocytosis on her blood count, white blood cells 15,310/mm3 (neutrophils 94%, lymphocytes 3%). In the low-dose dexamethasone suppression test (DST), the serum cortisol concentration was 991.03nmol/L. Her adrenocorticotrophic hormone (ACTH) level was elevated at 577pg/mL. After high-dose DST, the serum cortisol concentration was &amp;gt; 1750 nmol/L. No tumor was observed on pituitary magnetic resonance imaging. On abdominal computed tomography (CT), a large, lobulated, heterogeneously-enhancing mass arising from the pancreatic body and tail measuring 7.5cm x 10cm x 10.9cm was seen. The mass had infiltrated the gastric fundus, and encased the splenic artery. Multiple non-calcified subcentimeter pulmonary nodules were observed on chest CT. CT-guided biopsy of the pancreatic mass was done. On microscopic examination, numerous atypical cells arranged with small clusters and sheets and scattered singly were found in the tumor. The cells had small to enlarged, hyperchromatic, ovoid to round nuclei and scant to ample delicate cytoplasm. On immunohistochemical staining, the tumor cells were stained positive for synaptophysin and chromogranin A, which are both neuroendocrine markers, as well as ACTH. However, the patient died prior to any definitive management. Conclusion: ACTHoma is a very rare disease that causes hypercortisolemia. Reporting of similar cases will provide insight into its clinical features, immunohistochemical characteristics, diagnosis, therapy, and prognosis. Presentation: Thursday, June 15, 2023

THU531 A Case Of Cushing Syndrome Due To Ectopic ACTH Secreting Lung Neuroendocrine Tumor Treated With Cryoablation

Abstract Disclosure: S. Paknikar: None. J. McHugh: None. K. Rachmasari: None. I. Bancos: None. Introduction: Ectopic secretion of adrenocorticotropic hormone (ACTH) is a rare and severe form of Cushing Syndrome (CS) that requires an urgent specialized approach for diagnosis and management. Clinical Case: A 50-year-old woman was referred to endocrinology due to concern for CS. Over the previous year she had developed progressive weakness, edema, weight gain with abdominal fat redistribution, hypertension, and multiple compression fractures. On exam, she had a profound proximal myopathy, reported 10/10 pain along the spine, and was hypertensive (170/105 mm Hg) with normal other vitals. The patient's sodium was 141mmol/L [reference range 135-145 mmol/ L], potassium 4.1 mmol/L [3.6-5.2 mmol/L] while on spironolactone, and creatinine was 0.57 mg/dL [0.59-1.04 mg/dL]. Due to the severity of her symptoms, she was admitted to the hospital. Hormonal work up was consistent with an ACTH dependent CS: ACTH was 121pg/mL [7.2-63 pg/mL] and 24-hour urine cortisol was 645 mcg/24 hr [3.5-45 mcg/24 hr]. Workup for ACTH secreting tumor included a pituitary MRI which showed a 3 mm area of delayed enhancement in the pituitary gland, felt to be artifactual. A chest computed tomography (CT) showed a 1.3 cm low-density nodule in the right upper lobe concerning for a neuroendocrine tumor. A Gallium-68 DOTATATE Positron emission tomography/CT scan was performed and demonstrated that the nodule was highly DOTATATE avid (Krenning score of 3, scale of 0-4). These findings supported a diagnosis of ectopic CS caused by an ACTH secreting lung neuroendocrine tumor. Management of ectopic CS was twofold: addressing the underlying ACTH secreting lesion and urgent treatment of hypercortisolism and its consequences. In this case, this was achieved with CT-guided cryoablation of the right upper lobe nodule. The ACTH levels were monitored postoperatively, and when decreased (9.3pg/mL [ 7.2-63 pg/mL], glucocorticoid replacement therapy was initiated. As a result of prolonged hypercortisolism, the patient experienced multiple compression fractures and debility. Physical therapy was recommended for recovery from the compression fractures as well as proximal myopathy. Enoxaparin was initiated due to risk of venous thromboembolism from CS. From an osteoporosis standpoint, she was continued on calcium and vitamin-D supplementation and treated with weekly alendronate. Her hypertension improved allowing medication reduction. Postoperatively, she received education on adrenal insufficiency and biochemical monitoring for adrenal insufficiency recovery was implemented. Conclusion: Ectopic ACTH secreting tumors represent a rare cause of CS and effective management requires consideration of medical comorbidities to determine the approach: surgical, cryoablative, or medical therapy alone, mitigation of Cushing syndrome sequelae, and prompt recognition and treatment of glucocorticoid withdrawal. Presentation: Thursday, June 15, 2023

FRI216 A Rare Case Of Cushing Syndrome Secondary To Adenocarcinoma Of The Lung

Abstract Disclosure: S.M. Alheraki: None. M.H. Horani: None. F.Z. Alharraki: None. Cushing syndrome is one of the endocrine diseases that is mainly due to the high levels of cortisol. An overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma or an ectopic, paraneoplastic foci (small cell lung cancer) is the primary cause of secondary hypercortisolism. While small cell lung cancer and carcinoids cause the majority of ectopic ACTH syndromes, in this article, we describe a case of Cushing syndrome secondary to lung adenocarcinoma. It is highly likely that patients with malignancies are suffering from ectopic ACTH syndrome if they exhibit clinical signs such as weakness, hypertension, or lab values indicating hyperglycemia, hypokalemia, or metabolic alkalosis. Presentation: Friday, June 16, 2023

Emerging diagnostic methods and imaging modalities in cushing's syndrome.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by prolonged glucocorticoid excess. Timely diagnosis is critical to allow prompt treatment and limit long-term disease morbidity and risk for mortality. Traditional biochemical diagnostic modalities each have limitations and sensitivities and specificities that vary significantly with diagnostic cutoff values. Biochemical evaluation is particularly complex in patients whose hypercortisolemia fluctuates daily, often requiring repetition of tests to confirm or exclude disease, and when delineating CS from physiologic, nonneoplastic states of hypercortisolism. Lastly, traditional pituitary MRI may be negative in up to 60% of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (termed "Cushing's disease" [CD]) whereas false positive pituitary MRI findings may exist in patients with ectopic ACTH secretion. Thus, differentiating CD from ectopic ACTH secretion may necessitate dynamic testing or even invasive procedures such as bilateral inferior petrosal sinus sampling. Newer methods may relieve some of the diagnostic uncertainty in CS, providing a more definitive diagnosis prior to subjecting patients to additional imaging or invasive procedures. For example, a novel method of cortisol measurement in patients with CS is scalp hair analysis, a non-invasive method yielding cortisol and cortisone values representing long-term glucocorticoid exposure of the past months. Hair cortisol and cortisone have both shown to differentiate between CS patients and controls with a high sensitivity and specificity. Moreover, advances in imaging techniques may enhance detection of ACTH-secreting pituitary adenomas. While conventional pituitary MRI may fail to identify microadenomas in patients with CD, high-resolution 3T-MRI with 3D-spoiled gradient-echo sequence has thinner sections and superior soft-tissue contrast that can detect adenomas as small as 2 mm. Similarly, functional imaging may improve the identification of ACTH-secreting adenomas noninvasively; Gallium-68-tagged corticotropin-releasing hormone (CRH) combined with PET-CT can be used to detect CRH receptors, which are upregulated on corticotroph adenomas. This technique can delineate functionality of adenomas in patients with CD from patients with ectopic ACTH secretion and false positive pituitary lesions on MRI. Here, we review emerging methods and imaging modalities for the diagnosis of CS, discussing their diagnostic accuracy, strengths and limitations, and applicability to clinical practice.

Ectopic Cushing’s Syndrome as the First Presenting Sign of Small Cell Lung Carcinoma

A 67-year-old man with a history of hypertension, hyperlipidemia, coronary artery disease, and former smoking presented with fatigue, lower extremity edema, and a new tremor over the course of one month. Workup was notable for hypokalemia, metabolic alkalosis, and extremely elevated adrenocorticotropic hormone (ACTH) and cortisol levels. He was ultimately diagnosed with ectopic Cushing’s syndrome (CS) secondary to new metastatic small cell lung carcinoma. About 5-10% of CS cases are caused by ectopic ACTH production. The most commonly implicated malignancies are small cell lung cancer (SCLC) and neuroendocrine tumors, with SCLC accounting for up to three-fourths of cases. ACTH production is a poor prognostic sign in SCLC, associated with more extensive disease and decreased response to first-line treatment. Tumor-associated ACTH production is often so rapid that patients do not have time to develop classic Cushingoid physical exam findings, instead presenting with acute-onset hyperglycemia, pseudohyperaldosteronism, and generalized weakness. Prompt diagnosis and treatment are essential to improve outcomes.

Site-specific performance of 68Ga-DOTATATE PET/CT in detecting tumors with ectopic adrenocorticotropic hormone secretion.

The aim of this study was to assess the detection ability of 68Ga-DOTATATE in pulmonary versus extrapulmonary tumors with ectopic adrenocorticotropic hormone secretion (EAS). Images of 68Ga-DOTATATE PET/CT from 74 patients with suspected EAS were retrospectively reviewed. EAS tumors were confirmed in 39 patients through surgical resection or biopsy. Image findings were compared with the histopathological results. EAS tumors were pathologically confirmed via surgery or biopsy in 39 patients. Among those 39 patients, 25 were with pulmonary neuroendocrine tumors (NETs), and the remaining 14 were with extrapulmonary NETs. 68Ga-DOTATATE PET/CT correctly identified the tumor in 26 patients, rendering an overall detection rate of 66.7%. On a site-based analysis, 68Ga-DOTATATE PET/CT correctly identified the EAS tumor in 13 of 25 patients with pulmonary NETs, yielding a detection rate of 52%; for the 14 patients with extrapulmonary NETs, 68Ga-DOTATATE PET/CT correctly identified the EAS tumor in 13, yielding a detection rate of 92.9%. The detection rate of 68Ga-DOTATATE was significantly higher in extrapulmonary NETs than in pulmonary NETs (92.9%% vs. 52%, P = 0.013). For the 13 patients with positive pulmonary NETs, the tumor SUVmax ranged from 1.1 to 7.4 with an average SUVmax of 3.1 ± 2.1. For the 13 patients with positive extrapulmonary NETs, the tumor SUVmax ranged from 2.7 to 21.8 with an average SUVmax of 9.9 ± 6.3. The tumor SUVmax was significantly higher in extrapulmonary tumors than pulmonary tumors (P = 0.015). The tumor size was smaller in pulmonary tumors than in extrapulmonary tumors, while the difference was not significant (P = 0.516). 68Ga-DOTATATE showed site-specific difference in detecting tumors with EAS secretion. Specifically, 68Ga-DOTATATE performed better in the extrapulmonary EAS tumors than in pulmonary ones with both higher detection rate and uptake. Combination of anatomic imaging techniques are necessary for the correct diagnosis of pulmonary EAS tumors.

A clinical case of ectopic ACTH syndrome: diagnostic difficulties

Ectopic adrenocorticotropic hormone (ACTH-ectopic syndrome) secretion is a rare variant of endogenous hypercortisolism. Development of severe complications in various organs, systems and complex differential diagnoses characterizes the complexity of disease. Also, surgical intervention requires rapid, confirmed diagnosis and localisations of tumours. The presented clinical case is a case with multiple comorbidities presented with hypercortisolism complicating the diagnostic process and demonstrates the difficulties in managing patients with this nosology.

Typical Carcinoid Tumor Cases Causing Ectopic ACTH Syndrome: Dramatic Response to Surgery.

Although Cushing's Syndrome (CS) is usually caused by pituitary/adrenal adenomas, in the remaining few cases, Adrenocorticotrophic hormone (ACTH) is secreted by extrapituitary neuroendocrine tumors (NET). In typical pulmonary / bronchial carcinoid tumors leading to ectopic ACTH syndrome (EAS). The main principle of treatment is the localization of the ACTH-secreting tumor and its surgical removal. In this case report, we aimed to present two typical carcinoid cases, whose ACTH and cortisol levels returned to normal after lung surgery for ectopic ACTH. One of the cases, a 32-year-old female patient with CS symptoms and signs, was referred to our department after detecting a lesion in the left lower lobe in the thorax CT, which did not show an obvious focus on cranial MRI. The other patient, a 36-year-old male, had previously undergone adrenalectomy for Cushing's syndrome and was admitted to the emergency department due to adrenal insufficiency. The lesion seen in the right lower lobe on thorax CT was evaluated as an ectopic ACTH focus. After the tumors of the patients were resected according to surgical principles, CS clinic regressed, and ACTH and cortisol values returned to normal. Pathological examinations of the surgically resected tumors were reported as typical carcinoid. With surgically removed typical carcinoids tumors, excellent longterm survival results can be achieved and hypercortisolism can be controlled.

Catastrophic ACTH-secreting pheochromocytoma: an uncommon and challenging entity with multifaceted presentation.

Cushing's syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) by a pheochromocytoma is a challenging condition. A woman with hypertension and an anamnestic report of a 'non-secreting' left adrenal mass developed uncontrolled blood pressure (BP), hyperglycaemia and severe hypokalaemia. ACTH-dependent severe hypercortisolism was ascertained in the absence of Cushingoid features, and a psycho-organic syndrome developed. Brain imaging revealed a splenial lesion of the corpus callosum and a pituitary microadenoma. The adrenal mass displayed high uptake on both 18F-FDG PET/CT and 68Ga-DOTATOC PET/CT; urinary metanephrine levels were greatly increased. The combination of antihypertensive drugs, high-dose potassium infusion, insulin and steroidogenesis inhibitor normalized BP, metabolic parameters and cortisol levels; laparoscopic left adrenalectomy under intravenous hydrocortisone infusion was performed. On combined histology and immunohistochemistry, an ACTH-secreting pheochromocytoma was diagnosed. The patient's clinical condition improved and remission of both hypercortisolism and catecholamine hypersecretion ensued. Brain magnetic resonance imaging showed a reduction of the splenial lesion. Off-therapy BP and metabolic parameters remained normal. The patient was discharged on cortisone replacement therapy for post-surgical hypocortisolism. EAS due to pheochromocytoma displays multifaceted clinical features and requires prompt diagnosis and multidisciplinary management in order to overcome the related severe clinical derangements. A small but significant number of cases of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome are caused by ectopic ACTH secretion by neuroendocrine tumours, which is usually associated with severe hypercortisolism causing severe clinical and metabolic derangements. Ectopic ACTH secretion by a pheochromocytoma is exceedingly rare but can be life-threatening, owing to the simultaneous excess of both cortisol and catecholamines. The combination of biochemical and hormonal testing and imaging procedures is mandatory for the diagnosis of ectopic ACTH secretion, and in the presence of an adrenal mass, the possibility of an ACTH-secreting pheochromocytoma should be taken into account. Immediate-acting steroidogenesis inhibitors are required for the treatment of hypercortisolism, and catecholamine excess should also be appropriately managed before surgical removal of the tumour. A multidisciplinary approach is required for the treatment of this challenging entity.

Should We Use Prolactin Adjustment in Bilateral Inferior Petrosal Sinus Sampling to Diagnose Cushing Disease? A Joint Meta-Analysis of Head-to-Head Diagnostic Tests Accuracy Studies

ObjectivePrevious studies have shown inconsistent results regarding the usefulness of prolactin adjustment in bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (CS). This meta-analysis compared the diagnostic accuracy of prolactin adjustment versus no adjustment in BIPSS. MethodsThis study searched the PubMed, Embase, Web of Science, Cochrane library, and WanFang databases for published data as of March 2022 on the use of prolactin adjustment in BIPSS to differentially diagnose ACTH-dependent CS. A Bayesian joint bivariate model was used in the head-to-head comparison of the diagnostic accuracy. ResultsThis meta-analysis included a total of 10 studies with 300 patients. The combined sensitivity and specificity for BIPSS without prolactin adjustment were 94.47% (95% CI, 88.67%-98.44%) and 91.14% (95% CI, 57.17%-99.80%), respectively. The combined sensitivity and specificity after prolactin adjustment were 99.97% (95% CI, 99.03%-100.00%) and 80.69% (95% CI, 50.27%-97.82%), respectively. After the prolactin adjustment, the sensitivity of BIPSS to diagnose Cushing disease was improved with a statistically significant difference (difference in sensitivity, 5.39%; 95% CI, 1.37%-11.26%), whereas the decrease in specificity was without a statistically significant difference (difference in specificity, −9.20%; 95% CI, −42.02% to 26.61%). ConclusionThis meta-analysis indicated that prolactin adjustment in BIPSS might help to recognize Cushing disease among patient with ACTH-dependent CS. However, prolactin adjustment may not help identify ectopic ACTH syndrome in BIPSS.