Introduction: The differential diagnosis between Cushing’s disease (CD) and ectopic ACTH syndrome (EAS) is complex, and bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold-standard test. However, BIPSS with corticotropin-releasing hormone (CRH) stimulation is rarely available.

Objective: This retrospective cohort study aimed to assess the accuracy of the inferior petrosal sinus to peripheral ACTH gradient (IPS:P) before and after desmopressin stimulation for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS), applying different cutoff values.

Methods: A total of 50 patients (48 with CD and 2 with EAS) who underwent BIPSS were included in this study. The sensitivity and specificity of IPS:P in BIPSS before and after desmopressin stimulation were evaluated. Various cutoff values for IPS:P were examined to determine their diagnostic accuracy.

Results: Using the traditional IPS:P cutoff, the sensitivity was 85.1% before stimulation, 89.6% after stimulation, and a combined sensitivity of 91.7%. Applying cutoff values of IPS:P >1.4 before and >2.8 after stimulation, the sensitivity was 87.2% and 89.6%, respectively, with a combined sensitivity of 91.7%. Receiver operating characteristic (ROC) curve analysis determined optimal cutoff values of 1.2 before stimulation and 1.57 after stimulation, resulting in a sensitivity of 93.6% and 93.8%, respectively, with a combined sensitivity of 97.9%. Specificity remained at 100% throughout all analyses. Among the 43 patients who responded positively to stimulation, 42 (97.7%) did so within the first three minutes, and all 43 (100%) did so within the first five minutes. None of the assessed clinical variables predicted the ACTH response to stimulation in BIPSS with statistical significance.

Discussion: ACTH stimulation with desmopressin during BIPSS improves the accuracy of IPS:P, making it a valuable tool for investigating ACTH-dependent Cushing’s syndrome. Considering the low risk of complications, we recommend the use of desmopressin stimulation during BIPSS for the differential diagnosis of ACTH-dependent CS.

Introduction

Cushing Syndrome (CS) is a rare disease that results from chronic exposure to elevated cortisol levels. It can be caused by either endogenous or exogenous factors, and its incidence is estimated to be 0.7-3.2 cases per million per year (1, 2). The mortality rate for CS is elevated and may remain higher than the general population even after remission of hypercortisolism (3, 4). The causes of endogenous CS are traditionally classified into two categories: ACTH-dependent (about 80-85% of cases) and ACTH-independent (15-20% of cases) (5). The most common cause of ACTH-dependent CS (75-80% of cases) is Cushing Disease (CD), which is characterized by a corticotropic pituitary adenoma. The remaining cases (15-20%) of ACTH-dependent CS are caused by ectopic ACTH syndrome (EAS), which occurs when tumors of various sites, histological differentiation, and aggressiveness produce ACTH. There are also exceptionally rare cases (<1%) of ectopic CRH-producing tumors (5, 6).

CS diagnosis is a complex and challenging pathway due to the variable pattern of hormonal findings, the non-specificity of clinical presentation, particularly in mild hypercortisolism states (7), and the technical limitations of diagnostic tests. Once CS is confirmed, it should be differentiated between ACTH-dependent or -independent cases (8). ACTH levels <10 pg/ml suggest an adrenal cause; ACTH levels >20 pg/ml suggest ACTH-dependent causes; and levels between 10-20 pg/ml are considered indeterminate, requiring additional tests to establish the etiology (5, 8). When ACTH-dependency is confirmed, the next diagnostic step is the differentiation between CD and EAS. In this step, non-invasive tests are initially recommended, such as the CRH test (CRH-t), the 8 mg dexamethasone suppression test (DST-8 mg), and a pituitary magnetic resonance imaging (MRI) (5, 8). These tests, however, presents heterogenous results, depend on the availability of CRH, restricted in many countries including Brazil, and present low discriminatory power (9, 10). An alternative to CRH-t is the use of desmopressin, which stimulates ACTH release in most patients harboring ACTH-secreting pituitary adenomas. The use of this stimulus for the differential diagnosis of CD vs EAS is controversial, since studies have demonstrated that EAS patients may present ACTH elevation following desmopressin administration (11–14). The DST-8 mg is widely available; however it also presents limitation due to the variability of criteria used; furthermore, it has shown insufficient discriminatory capacity in some studies (15, 16). Pituitary MRI fails to detect adenomas in CD patients in about 30-50% of cases even with modern technology equipment (17); moreover, it may also generate false-positive results since pituitary incidentalomas are common in the population, including macroadenomas (18). In cases of conflicting non-invasive test results and unavailability of other methods, bilateral inferior petrosal sinus sampling (BIPSS) should be performed to detect a central-to-peripheral ACTH gradient that allows the localization of the ACTH production (5). Some authors and guidelines recommend performing BIPSS in all patients with pituitary lesions < 6 mm demonstrated on MRI (5, 8, 19), whereas others suggest BIPSS should routinely be performed, especially to guide surgical therapy of CD (20–23). Thus, the procedure is considered the gold-standard in the differential diagnosis of ACTH-dependent CS, preferentially performed with CRH or, less frequently, with desmopressin. The use of CRH is a limiting factor since it is unavailable in many countries. On the other hand, although used in some medical centers, desmopressin as a stimulus for BIPSS is still poorly debated and assessed in the literature, and its utility in this setting remains uncertain since studies validating it in different populations and in larger series are still lacking (8, 24–26). A recent study evaluating desmopressin in a large cohort of patients proposed new diagnostic criteria, questioning the need of stimulus with the new cut-offs (27). Thus, the aim of this study is to assess the role of central-to-peripheral ACTH gradient after stimulus with desmopressin during BIPSS for the differential diagnosis of ACTH-dependent CS in a cohort of patients followed-up in a referral center for CS in Brazil.

Patients and methods

Patients

Between 1998 and 2020, 107 patients with ACTH-dependent CS were retrospectively evaluated at the Neuroendocrinology clinic of a tertiary center in Southern Brazil for BIPSS under desmopressin stimulation during initial diagnostic evaluation or after recurrence. Of these, 58 patients underwent BIPSS with desmopressin, 50 of which for the initial diagnostic evaluation, 7 after recurrence and 1 after emergency adrenalectomy. Eight patients who underwent BIPSS were excluded for insufficient data regarding final etiologic diagnosis (lack of histopatological confirmation, lack of biochemical remission 6 months after surgery, or lack of remission after radiotherapy). Finally, 50 patients were included in the analysis. The present study was conducted in compliance with the principles laid down in the Declaration of Helsinki and was approved by the Hospital de Clínicas de Porto Alegre Ethics Committee.

Diagnosis of CS and ACTH-dependency status

After exhaustive screening for exogenous glucocorticoid administration, CS diagnosis was based on the presence of at least two of the following conditions: cortisol after low-dose dexamethasone suppression test (either 1 mg overnight or 0.5 mg 6/6 hours for 48h) > 1.8 µg/dL (DST-1mg); 24-h urinary free cortisol (UFC) or late night salivary cortisol consistently elevated in at least two samples (8). Additionally, late night serum cortisol > 7.5 µg/dL (8) and a desmopressin test (DES-t) with a peak ACTH > 71.8 pg/mL or an increase in ACTH ≥ 37 pg/mL from baseline (28) were also considered suggestive of CS.

After clinical and biochemical diagnostic confirmation of CS, plasma ACTH measurement classified CS into ACTH-dependent (ACTH > 20 pg/dL) or ACTH-independent (ACTH < 10 pg/dL). Values between 10-20 pg/dL were considered indeterminate and new samples were obtained for correct classification (8).

Next, patients diagnosed with ACTH-dependent CS underwent pituitary MRI for the identification of an adenoma. Due to the unavailability of CRH-t, it was rarely performed. The DES-t for the differential diagnosis of CD and EAS was considered predictive of CD when the increase was > 20% in cortisol or >35% in ACTH after stimulus. In virtue of its low accuracy, DST-8 mg was only performed in a few cases. Patients with inconclusive or negative imaging, those with adenomas < 6 mm or those with adenomas > 6 mm but discordant non-invasive tests were submitted to BIPSS with sampling of ACTH at baseline and after desmopressin stimulus.

After investigation, patients with a suggestive diagnosis of CD underwent transsphenoidal surgery. Histological confirmation of a pituitary adenoma staining positive for ACTH was considered the gold-standard for diagnosis. Additionally, patients with inconclusive or absent histological specimen who exhibited clinical and biochemical remission 6 months after surgery or who remitted after pituitary radiotherapy were also considered diagnosed for CD. The EAS cases were confirmed based on surgical excision or biopsy of tumoral lesions confirming the presence of ACTH-staining neoplastic cells.

Bilateral inferior petrosal sinus sampling

The procedure was performed in the presence of documented hypercortisolism, in an angiography room, under sedation with fentanyl and midazolam, and by a qualified professional in interventional radiology. Initially, bilateral common femoral venipuncture was performed, maintained with 6 French (F) introducers. Then, ascending catheterization of the superior vena cava and internal jugular veins was performed with a 5F vertebral catheter and hydrophilic guidewire, with final positioning of the catheter tip at the level of the inferior petrosal sinuses. Angiographic confirmation was performed after injection of 10 ml of diluted nonionic contrast under digital subtraction, demonstrating bilateral sinus and sellar region opacification. In situations of fine-caliber inferior petrosal sinuses, a coaxial microcatheter was used for a better distal reach of the required topography. Heparinization was not usually necessary in this technique, only sequential washing of the catheters was performed between the sampling times with saline solution with 2 ml of heparin for each 1000 ml of solution. Samples were collected after washing the catheters at baseline. Then, 10 µg of desmopressin was administered intravenously and samples were collected after one, three, five, and 15 minutes. In some cases, the sampling times were slightly different, but always with one sampling at baseline and at least 3 samplings after stimulation. All samples were collected in ice-cold tubes, kept on ice and then centrifuged in a refrigerated centrifuge and frozen at -8°C until ACTH measurement, which occurred immediately after the end of the procedure. After the samplings, the catheters and introducers were removed, followed by manual compression of the inguinal region at the puncture site for 10 minutes, until complete hemostasis. After compression, a compressive dressing was placed at the puncture site and the patients remained at bed rest without flexing the thigh for 6 h. Our routine protocol in performing the BIPSS did not include the concomitant measurement of prolactin as suggested in some previous studies in the literature.

Hormone assays

Until April 2004, cortisol was measured using a commercially available radioimmunoassay (RIA) kit (Diagnostic Systems Laboratories, Webster, TX, USA). From May 2004 to March 2010, the method was modified to an electrochemiluminescence immunoassay (ECLIA) kit (Modular Analytics E 170; Roche, Mannheim, Germany). From March 2010 to February 2014, cortisol was measured by chemiluminescence immunoassay (ADVIA Centaur XP Immunoassay System, Tarrytown, NY, USA). From February 2014 to October 2019, the method was Competitive Electrochemiluminescence. (Roche e602 equipment line). From October 2019 until the end of the study, the method was Microparticle Chemiluminescent Immunoassay. (Abbott equipment line). ACTH measurements up to February 2000 were performed by commercially available RIA. From February 2000 to April 2015, the method was chemiluminescence with the Immulite 1000 equipment. From May 2015 to April 2018, the method was electrochemiluminescence with the Roche e602 equipment. From May 2018 to August 2019, the method was sandwich electrochemiluminescence using the Roche e602 equipment. From August 2019 until the end of the study, the method was chemiluminescent immunoassay in the Immulite 2000 equipment. These assay differences do not show a large variation from normal values and as samples collected from the same patient were always analyzed with the same assay, the calculations of different indexes of central versus peripheral samplings did not change as a result of the trials. Of the cases studied, ACTH was measured by RIA in 1 patient, by Immulite 1000 in 35 patients, by Roche e602 via electrochemiluminescence in 9 patients, by Roche e602 via sandwich electrochemiluminescence in 4 patients and by Immulite 2000 in 1 patient.

The basal ACTH and UFC values, therefore, are presented according to the percentage above the ULN according to each methodology used at each moment. For the calculation of the ACTH inferior petrosal sinus to peripheral gradient (IPS:P), however, absolute values were used since the ratios are calculated for the same patient using the same assay.

Statistical analysis

The Kolmogorov-Smirnov test was used to assess the distribution of variables. Continuous variables with normal distribution are presented as mean ± standard deviation (SD). Continuous variables with asymmetric distribution are shown as median and interquartile range (IQR). Categorical variables were compared using Fischer’s exact test. The comparison of continuous variables was performed using the Mann-Whitney test. ROC curves were used to assess the ability of the IPS:P gradient to discriminate between CD and EAS, and the Youden index was used to define optimal cutoffs. Sensitivity and specificity were calculated for the different criteria analyzed. Statistical analyzes were performed using the SPSS 24.0 program (statistical package software, SPSS Incorporation, Chicago, IL, USA). Differences were considered significant when p<0.05.

Results

Patient characteristics are shown in Table 1. During the study period, 50 patients with a confirmed diagnosis of ACTH-dependent CS whose etiology could be confirmed through histopathological or biochemical data (remission after 6 months of surgery or after radiotherapy) who had undergone the BIPSS were included. The mean age (SD) at diagnosis was 38.22 (15.56) years, 39 patients (78%) were female, and 48 patients had CD and 2 EAS.

In the imaging results, 23 (46%) were microadenomas, among which 15 were < 0.6cm (65.2% of microadenomas), 8 were macroadenomas (16%), and 19 had negative or inconclusive imaging (38%). One of the patients with EAS had an image suggestive of a 0.4 cm microadenoma on MRI. Regarding macroadenomas, the indication for BIPSS was proposed based on the following situations: 3 presented with a clinical picture of EAS, including 2 with systemic lesions suspicious for neoplasia, 3 presented imaging characteristics that were somewhat atypical for adenomas, 1 was associated with a brainstem vascular lesion and one was a recurrent disease with postsurgical alteration and residual lesion.

BIPSS was performed in 44 patients who had not yet undergone investigation or treatment and in 6 patients who had been previously treated for CD but had relapsed during follow-up. No complications were recorded in any of the cases submitted to BIPSS. There were no thromboembolism events related to the procedure.

At baseline (before stimulation), 49 patients were evaluated (1 patient with CD had samples collected, but his results were not properly recorded). The median IPS:P gradient at baseline was 6.62 (IQR 2.46-11.36) in patients with CD and 1.14 (IQR 1.10-1.14) in patients with EAS (p=0.01). Using the IPS:P>2 gradient criteria, 40 of 47 patients with CD were positive and none of the 2 patients with EAS were positive, resulting in 85.1% sensitivity (95% confidence interval (CI) 71.1-93.3%) and 100% specificity.

After stimulation with desmopressin, all 50 patients were evaluated. The median SPI:P gradient after stimulation was 29.46 (IQR 15.39-61.50) in patients with CD and 1.26 (min-max 1.25-1.28) in patients with EAS (p=0.01). In patients with EAS, the highest ACTH peak was 537 pg/mL (109.5% increase from baseline), while in patients with CD, the lowest increase from baseline was 19.48%. Using the IPS:P gradient criteria > 3, 43 of 48 patients with CD were positive, and none of the 2 patients with EAS were positive, resulting in 89.6% sensitivity (95%CI 76.5-96.1%) and 100% specificity. When evaluating patients who were positive at baseline and/or after stimulation in a combined manner, 44 of 48 CD patients were positive, whereas no EAS patients were positive. The overall sensitivity, therefore, was 91.7% (95%CI 79.1-97.3%), and the specificity was 100%. Of the 9 negative patients at baseline, 3 (33.33%) became positive after stimulation. Among the 43 patients who tested positive after the stimulus, 42 (97.7%) had already tested positive up to the third minute, and 100% of the patients were positive up to the fifth minute (Figure 1), totaling 86% of the total sample. Of the 3 patients whose stimulation was necessary, 2 had microadenomas and 1 had macroadenomas. In the two patients with EAS, the time of peak of ACTH was at 1 minute for patient 1 (31.1% increase from baseline) and at 3 minutes for patient 2 (109.5% increase from baseline).

When assessing only the 23 patients with microadenoma, 20 of 22 patients with CD were positive at baseline, and the patient with EAS and 0.4 cm microadenoma was negative, resulting in 90.9% sensitivity (95%CI 69.37-98.4%), while maintaining 100% specificity. After stimulation, all 22 patients with CD were positive and the only patient with EAS and microadenoma was negative, resulting in 100% sensitivity (95%CI 81.5-100%) while maintaining 100% specificity. When only microadenomas < 0.6 cm were evaluated, 12 of 14 CD patients were positive at baseline, and the patient with EAS and 0.4 cm microadenoma was negative, resulting in 85.7% sensitivity (95%CI 56.2-97.5), with 100% specificity. After stimulation, all 14 patients with CD were positive, and the patient with EAS and microadenoma was negative, resulting in a sensitivity of 100% (95%CI 73.2-100%) while maintaining 100% specificity. All eight patients with microadenomas >0.6cm were already positive at baseline and remained positive after stimulation (100% sensitivity and 100% specificity). Thus, only patients with microadenoma <0.6 cm improved sensitivity after stimulation. Among the 8 patients with macroadenoma, sensitivity was 75% at baseline and remained the same after stimulation. However, when assessed for need for stimulation, only one patient with macroadenoma benefited, but sensitivity did not increase because a patient who was positive at baseline became negative after stimulation. Assessing all patients with positive imaging on MRI (micro or macroadenomas, n = 31), 26 of 30 CD patients were positive at baseline, and the patient with EAS and microadenoma was negative, resulting in 86.7% sensitivity and 100% specificity. After stimulation, 28 of 30 CD patients were positive and the patient with EAS and microadenoma remained negative, resulting in 93.3% sensitivity and maintaining 100% specificity. The combined sensitivity (baseline or after stimulus) in this group of patients was 96.7%.

Among the 19 patients with negative imaging, 18 had baseline results and were evaluated. Baseline sensitivity was 82.4%. After stimulation, data from 19 patients were evaluated and resulted in a sensitivity of 83.3%. When the patients with negative imaging (n=19) and those with microadenomas <0.6 cm (n=15) were analyzed together, which represent the most difficult cases in clinical practice, we observed that the IPS:P gradient >2 at baseline resulted in sensitivity of 83.9% and 100% specificity. After stimulation, the IPS:P >3 gradient had a sensitivity of 90.6% while maintaining 100% specificity.

After assessing the traditionally proposed criteria, the analysis was performed using the criteria proposed by Chen et al. (27). Using the IPS:P gradient at baseline > 1.4, 41 of 47 CD patients were positive and none of the EAS patients were positive, resulting in 87.2% sensitivity (95%CI 73.5-94.7%) while maintaining 100% specificity. After stimulation, using the IPS:P>2.8 gradient criteria, 43 of 48 patients with CD were positive, resulting in 89.6% sensitivity (95%CI 76.5-96.1%), strictly the same as the traditional criteria maintaining 100% specificity. When evaluating patients who were positive at baseline and/or after stimulation, 44 of 48 patients with CD were positive, and no patient with EAS was positive, resulting in 91.7% overall sensitivity (95%CI 79.1-97.3%), the same as the traditional criteria. Finally, only 2 of 49 patients who were negative at baseline became positive after stimulation.

To establish institution-specific cut-off points, a ROC curve was performed to assess the accuracy of the central/peripheral ACTH gradient in BIPSS in our cohort of patients. For the IPS:P gradient at baseline, the cut-off point with the highest accuracy was 1.2, whereas for the IPS:P gradient after stimulation, the cut-off point with the highest accuracy was 1.57 (Figure 2). Using these cut-off points, 44 of 47 CD patients were positive at baseline and no EAS patients were positive, resulting in 93.6% sensitivity (95%CI 81.4-98.3%), while maintaining 100% specificity. After stimulation, 45 of 48 CD patients were positive and no EAS patients were positive, resulting in 93.8% sensitivity (95%CI 81.8-98.4%), with 100% specificity (Figure 3). When evaluating patients who were positive at baseline and/or after stimulation, 47 of 48 CD patients were positive and no EAS patients were positive, resulting in an overall sensitivity of 97.9% (95%CI 87.5-99.9%) With 100% specificity. Finally, only 2 patients who were negative at baseline became positive after stimulation.

In the comparison between the traditional criterion and our study criterion, the baseline sensitivity changed from 85.1 to 93.6%. After stimulation, baseline sensitivity changed from 89.6 to 93.8%, respectively. A summary of the sensitivity results with the different diagnostic criteria is presented in Table 2.

Technical difficulties or anatomical variations were found in 6 patients undergoing BIPSS. Among the 43 cases with a positive IPS:P gradient, 3 had anatomical variations and 1 had some technical difficulty. Of the 5 cases in which the IPS:P gradient did not occur (false-negatives), 1 presented anatomical variation and 1 presented some technical difficulty during the test. Among the 6 patients who underwent BIPSS after recurrence, all had a final diagnosis of CD, and only 1 was negative on BIPSS.

Of the 50 patients evaluated, 43 had undergone DES-t as part of the diagnostic workup, of which 41 were later diagnosed with CD and 2 with EAS. Forty patients were considered responsive in DES-t, 38 patients with CD and 2 patients with EAS. Among the 40 responsive patients, 34 (85%) were also positive in BIPSS, all with a final diagnosis of CD. The 3 non-responsive patients in DES-t presented a positive response in BIPSS after desmopressin. Of the 6 patients who were positive in DES-t but negative in BIPSS, 2 were patients with EAS. Of the 4 patients with CD, 2 had normal petrosal sinus anatomy, 1 had a report of some anatomical variation, and 1 had a report of technical difficulties during BIPSS. Thus, DES-t was not able to predict response to desmopressin during BIPSS (p>0.9999). When comparing the ACTH values at baseline, 3, 5 and 10 minutes after stimulation in BIPSS, there was no significant difference between the group with positive versus negative DES-t, as well as no difference in the time to positivity between the groups, adenoma size, and number of patients with negative imaging. In addition, the clinical variables evaluated (ACTH, UFC, DST-1mg, baseline cortisol, adenoma size) were not able to significantly predict response to stimulus.

Discussion

In this study, the use of BIPSS with ACTH measurements at baseline and after stimulation with desmopressin in the differential diagnosis of the ACTH-producing source in a sample of 50 patients with ACTH-dependent CS and inconclusive non-invasive tests resulted in 85.1% baseline sensitivity, increasing to 89.6% after stimulation, maintaining 100% specificity when applying traditional IPS:P≥2 criteria at baseline and ≥3 after stimulation (29). When combined, the baseline and/or stimulated sensitivity results were 91.7%. Results of meta-analyses that combined studies performed with CRH stimulation and desmopressin indicate that the sensitivity of BIPSS ranges from 86-97% and the specificity from 89-100% (27, 30). Published studies with desmopressin are generally small, with a variable number of cases of EAS, different indications for BIPSS, and variable diagnostic criteria. In a study with a sample of 56 patients with ACTH-dependent CS and negative imaging, using the criterion of IPS:P≥2 at baseline and IPS:P≥3 after stimulation with desmopressin, the combined sensitivity was 92.1% and 100% specificity, similar to the findings of the present study (25). Smaller studies that also used desmopressin stimulation found similar (26, 31–33) or slightly higher sensitivities (34, 35). Studies performed exclusively in pediatric patients were less uniform, with one of them reporting similar results to studies that included adults (36) and another study demonstrating lower sensitivity in adult population (37).

Our institution’s optimal cut-off points, determined by analyzing the ROC curve, were IPS:P≥1.2 at baseline and ≥1.57 after stimulation. This resulted in 93.6% baseline sensitivity (it was 85.1% with IPS:P≥2), and 93.8% after stimulation (was 89.6% with IPS:P≥3), and a combined sensitivity of 97.9% (it was 91.7%), maintaining specificity at 100%. Despite the increased sensitivity, these criteria should be used with caution, since the number of cases with EAS was small. The IPS:P gradient at baseline and after stimulation achieved in patients with EAS in some studies with desmopressin would exceed the cutoffs found by us (24, 25, 27), which would incorrectly classify these patients as CD. Before adopting the new values in our institution, therefore, more patients with EAS are necessary to validate these criteria. Also using the ROC curve, Castinetti et al. evaluated 43 patients with ACTH-dependent SC (36 DC and 7 EAS) and established the criteria of IPS:P>2 at baseline or after stimulation, obtaining a sensitivity of 86% at baseline and 97% after stimulation with desmopressin, not mentioning the combined sensitivity. The study, however, showed 85% specificity at baseline, given that a patient with EAS had a 3.33 gradient (24). In addition to applying the traditional criteria, Machado et al. also used ROC curve analysis to establish cut-off points, finding an IPS:P≥1.45 at baseline (88.2% sensitivity) and ≥ 2.04 after stimulation (92.2% sensitivity) as optimal, both with 100% specificity, although the authors did not recommend the use of these new values (25). The results of these studies using the ROC curve suggest that lower cutoff points, both at baseline and after stimulation, can improve sensitivity without compromising specificity. However, a study that performed a ROC curve in patients stimulated with CRH found an optimal 2.10 baseline cut-off, slightly higher than the traditional one of 2, although the post-stimulation cut-off point was 2.15, lower than the one usually used (38). A study with desmopressin, in turn, found values in the ROC curve of 1.76 at baseline, lower than the traditional one, but ≥3.9 after stimulation, higher than the gradient of three usually used, increasing baseline sensitivity but keeping the sensitivity after stimulation unchanged (32).

The largest published study evaluating BIPSS with desmopressin stimulation evaluated 226 patients with CD and 24 with EAS (27). Applying the IPS:P>2 criteria at baseline and >3 after stimulation, the sensitivity was 87.2 and 94.2%, respectively, while maintaining 100% specificity. The combined sensitivity was 96.5%. In this series, 3 cases of EAS reached gradients greater than 2 after stimulation, which suggests that cut-off points equal to or lower than this may decrease specificity. The authors also performed an ROC curve, determining the cutoff point of >1.4 at baseline and >2.8 after stimulation. In this analysis, the sensitivity at baseline was 94.7% and 96% after stimulation, resulting in a combined 97.8% sensitivity, higher than that found with the traditional criteria. According to the authors, with these cut-off points, only 7 patients benefited from the stimulus. After this publication, no other studies have tested these new cutoffs. Our study was the first, therefore, to assess the new values. In our series, using the cutoff point of >1.4 at baseline and >2.8 after stimulation, the sensitivity was 87.2 and 89.3%, respectively, and the combined sensitivity was 91.7%, thus slightly improving the sensitivity at baseline with little change after stimulation.

In an attempt to identify predictors of need for stimulation, Chen et al. found that patients requiring stimulation had adenomas < 0.6 cm or negative imaging. In addition, patients who required stimulation had lower IPS ACTH levels and did not lateralize. These data, however, are obtained only after performing the BIPSS, which makes their use in practice unfeasible (27). In our series, among patients with microadenomas, only those with lesions <0.6 cm benefited from the stimulus. Patients with negative imaging had a small increase in sensitivity. A patient with a macroadenoma also benefited from the stimulus, although the sensitivity of the cases with macroadenoma did not change, as a positive patient at baseline became negative after the stimulus. Despite current recommendations suggesting to perform BIPSS in patients with adenomas < 0.6 cm or with negative/inconclusive imaging results (8, 39), Chen et al. identified 2 patients with EAS and adenomas > 0.6 cm who would be misdiagnosed with CD if the 0.6 cm threshold were respected. Therefore, they suggest performing BIPSS in all patients with ACTH-dependent CS (27). Given the relevance of EAS cases in this study, a discussion about the current size criteria for indicating BIPSS should be undertaken.

Of our 50 patients, 43 (41 CD and 2 EAS) underwent DES-t prior to BIPSS, and 40 were considered responsive, including the two cases of EAS. Among the responders, 34 patients also responded to the stimulus during the BIPSS, all of them with CD. The 3 patients who did not respond to the peripheral stimulus were, however, positive in the BIPSS. The lack of correlation between the DES-t results and the BIPSS may be related to the different sampling intervals in the two exams (short intervals in the BIPSS and long intervals in the peripheral test). Considering that the majority (86%) of our patients performed both tests, it is possible to conclude that the DES-t did not help in the prediction of response to the central stimulus, which makes the use of peripheral test results debatable for this purpose. Of the BIPSS studies with desmopressin, only one described the results of DES-t, although it did not perform any specific analysis of the relationship with BIPSS (36). The study differs from ours, also, as it only evaluated pediatric patients.

Although BIPSS is still considered the gold standard in the differential diagnosis of ACTH-dependent CS, some authors have suggested that the procedure should be indicated only in cases in which t-CRH was negative (40, 41). Recent studies have evaluated non-invasive strategies combining t-CRH, DES-t, TSD-8mg, and imaging to reduce the need for BIPSS. Strategies that resulted in a positive predictive value of 100%, however, included t-CRH as part of the diagnostic process (42, 43), which makes adherence to this diagnostic modality inapplicable in many countries due to the unavailability of CRH. In one of these studies, the combination of TSD-8mg with DES-t, which would be possible in Brazil, was inferior to the combination of DES-t with t-CRH or t-CRH with TSD-8mg (43). The low number of patients undergoing TSD-8mg in our study did not allow the evaluation of this strategy. Although not recommended as a test in the differential diagnosis of the etiology of ACTH-dependent SC, DES-t seems promising as a marker of long-term postoperative outcome and as an early marker of recurrence (44), which encourages further studies in these circumstances.

Despite there have been reports of thromboembolic events related to BIPSS that occurred heparin (45, 46), it is a very rare complication. The administration of desmopressin, which increases coagulation factor VIII and von Willebrand factor (47), has raised concerns about the potential for increased incidence of thromboembolic events during BIPSS. This is due to the fact that desmopressin is associated with the hypercoagulable state of CS (48) and may also interfere with VIII and von Willebrand factors. The study by Chen et al, the largest published with desmopressin to date, did not record any case of thromboembolism, even without routine anticoagulation during the procedure (27). In our study, performed without routine anticoagulation, there were also no thromboembolic events. The only desmopressin BIPSS study that recorded thromboembolic events routinely used heparin during the procedure (25). Thromboembolic events, therefore, do not appear to be an additional concern when using desmopressin, with or without the use of heparin during the procedure. The decision regarding the use or not of anticoagulants during BIPSS should be a decision of each institution and based on the usual anticoagulation recommendations.

In our study, we did not perform the concomitant dosage of prolactin in samples collected from the inferior petrosal sinuses, a procedure that potentially reduces false negatives, as advised by some authors based on studies with CRH (49–51) and a study with desmopressin (31). These findings, however, were not confirmed by all groups, both with CRH (52) and with desmopressin (32), and their applicability depends on further studies to define its role.

In our study, a total of 3 patients who were negative at baseline benefited from the stimulus, As they became positive, 2 of them with microadenomas and one with macroadenoma. The study by Chen et al. questions the use of routine stimulation in all patients to reduce the risks and the duration of the procedure, potentially reducing complications. The authors argue that, when using the IPS:P>1.4 criterion at baseline, the sensitivity was high enough to classify most patients, with the exception of 7 patients with adenoma <0.6 cm who needed stimulation (27). Our study, however, would have misclassified a case with CD and macroadenoma as EAS if the stimulus had not been performed. The assessment of the need for stimulation in cases of CS with macroadenoma is limited since most studies performed the BIPSS only in patients with lesions < 0.6 cm or negative imaging, preventing a more comprehensive assessment.

Considering that BIPSS is currently still the gold standard in the differential diagnosis of ACTH-dependent CS, even small gains in sensitivity should be considered important since incorrect classification of patients can lead to inappropriate treatments and potentially fatal delays in the resolution of hypercortisolism. Considering that BIPSS is generally well tolerated and the rate of serious complications is low (53), other strategies to reduce the risks of the procedure that do not involve avoiding the stimulus seem necessary. In this context, it is important to evaluate the time interval between the infusion of the secretagogue and the positive test result. In our study, 97.7% of the patients who tested positive after stimulation were already positive in the third minute and 100% of the patients were positive until the fifth minute, demonstrating that there seems to be no benefit in prolonging the test beyond this period. All of the few studies on BIPSS with desmopressin have directly or indirectly reported a similar time to positivity and for peak ACTH (i.e., positive up to 3-5 minutes) (26, 33, 35, 37). Stimulating patients for a maximum time of 5 minutes considerably reduces the procedure time without neglecting the sensitivity gain resulting from the stimulation and may, therefore, be a strategy to potentially reduce the risk of complications.

Our study evaluated a sample of patients whose BIPSS indication was more comprehensive since the unavailability of t-CRH and the low accuracy of TSD-8mg limited the use of non-invasive tests. The wide heterogeneity existing in the BIPSS studies regarding the characteristics of the evaluated patients (primary diagnosis or recurrence), the BIPSS technique (sampling times, anticoagulant use, material used, laboratory assays, cut-off points, type of secretagogue) makes direct comparisons difficult. Conducting multicenter prospective studies with a greater sample of EAS patients is necessary to improve our understanding of the best cut-off points and procedure duration.

The present study has some limitations, as expected in the complexity of CS investigation. Our main limitation is that the low prevalence of EAS that underwent BIPSS, resulting from the rarity of this condition, may explain the high specificity when applying the cutoff points indicated by the ROC curve, and the application of these new gradients of IPS:P depends on validation in larger samples of EAS. Lower specificity may result from poor responsiveness to the secretagogue (desmopressin or CRH), cyclic CS during periods of normal cortisol secretion or due to anomalous venous drainage (54). Retrospective data collection and analysis prevented access to complete information for all patients. There were differences over time in terms of sampling times, although at least 3 different samplings were always performed throughout the study period. We highlight that, in this study, we did not discuss the data regarding the eventual lateralization of the basal ACTH values and after stimulation with desmopressin to guide the location of the pituitary adenoma in the transsphenoidal surgery. This utility of the BIPSS has been less and less recommended in the literature due to the imprecision of the results, especially due to the existence of venous communications between the cavernous sinuses and the instability and intensity of blood aspiration for sample collection.

In conclusion, in BIPSS with ACTH dosage, the use of stimulation with desmopressin increases the sensitivity of the test from 85.1% to 89.6%, reaching 100% in the sub-analysis of microadenomas. In spite of being small, this increase is useful in the investigation of ACTH-dependent CS, a clinical situation in which gains in diagnostic sensitivity are very important. Additionally, considering the low risk of complications and the possibility to interrupt the test within 5 minutes, as demonstrated in our study, our data recommend the use of stimulation with desmopressin in the BIPSS in the differential diagnosis of ACTH-dependent CS.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving human participants were reviewed and approved by Hospital de Clínicas de Porto Alegre Ethics Committee. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Author contributions

TA, TR and MC conceived the study and designed the research. TA conducted the data collection and database management. TA performed the data analysis. LS, MF and FG performed the BIPSS procedures. TA, TR, FC and MC contributed to the interpretation of the results. TA and MC drafted the manuscript. FC critically revised the manuscript. All authors read and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the Research Incentive Fund (FIPE) of Hospital de Clínicas de Porto Alegre and the Postgraduate Program in Medical Sciences: Endocrinology (PPG ENDO) from Universidade Federal do Rio Grande do Sul.

Acknowledgments

The authors would like to acknowledge the contributions of Guilherme Alcides Flores Soares Rollin, Arthur Boschi, and Camila Viecceli to the data collection process.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

BIPSS, bilateral inferior petrosal sinus sampling; CD, Cushing Disease; CRH-t, CRH test; CS, Cushing Syndrome; DES-t, desmopressin test; DST-1 mg, 1 mg dexamethasone suppression test; DST-8 mg, 8 mg dexamethasone suppression test; EAS, Ectopic ACTH Syndrome; ECLIA, electrochemiluminescence immunoassay; F, French; IPS:P, inferior petrosal sinus to peripheral gradient; IQR, interquartile range; MRI, magnetic resonance imaging; RIA, radioimmunoassay; SD, standard deviation; UFC, urinary free cortisol; ULN, upper limit of normal.

References

 

Keywords: Cushing’s syndrome, Cushing’s disease, ectopic ACTH syndrome, bilateral inferior petrosal sinus sampling, ACTH, desmopressin

Citation: Almeida TSd, Rodrigues TdC, Costenaro F, Scaffaro LA, Farenzena M, Gastaldo F and Czepielewski MA (2023) Enhancing Cushing’s disease diagnosis: exploring the impact of desmopressin on ACTH gradient during BIPSS. Front. Endocrinol. 14:1224001. doi: 10.3389/fendo.2023.1224001

Received: 17 May 2023; Accepted: 11 July 2023;
Published: 03 August 2023.

Copyright © 2023 Almeida, Rodrigues, Costenaro, Scaffaro, Farenzena, Gastaldo and Czepielewski. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Tobias Skrebsky de Almeida, tsalmeid@gmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

 

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1224001/full

Background: Café-au-lait skin macules, Cushing syndrome (CS), hyperthyroidism, and liver and cardiac dysfunction are presenting features of neonatal McCune–Albright syndrome (MAS), CS being the rarest endocrine feature. Although spontaneous resolution of hypercortisolism has been reported, outcome is usually unfavorable. While a unified approach to diagnosis, treatment, and follow-up is lacking, herein successful treatment and long-term follow-up of a rare case is presented.

Clinical case: An 11-day-old girl born small for gestational age presented with deterioration of well-being and weight loss. Large hyperpigmented macules on the trunk, hypertension, hyponatremia, hyperglycemia, and elevated liver enzymes were noted. ACTH-independent CS due to MAS was diagnosed. Although metyrapone (300 mg/m²/day) was started on the 25th day, complete remission could not be achieved despite increasing the dose up to 1,850 mg/m²/day. At 9 months, right total and left three-quarters adrenalectomy was performed. Cortisol decreased substantially, ACTH remained suppressed, rapid tapering of hydrocortisone to physiological dose was not tolerated, and supraphysiological doses were required for 2 months. GNAS analysis from the adrenal tissue showed a pathogenic heterozygous mutation. During 34 months of follow-up, in addition to CS due to MAS, fibrous dysplasia, hypophosphatemic rickets, and peripheral precocious puberty were detected. She is still regularly screened for other endocrinopathies.

Conclusion: Neonatal CS due to MAS is extremely rare. Although there is no specific guideline for diagnosis, treatment, or follow-up, addressing side effects and identifying treatment outcomes will improve quality of life and survival.

Introduction

McCune–Albright syndrome (MAS) is a rare mosaic disorder of remarkable complexity with an estimated prevalence of 1/100,000 and 1/1,000,000 (1). Timing of postzygotic missense gain of function mutation of GNAS encoding stimulatory Gα_s determines the extent of tissue involvement, imposing a unique clinical phenotype. Although a combination of two or more classical features, such as fibrous dysplasia of bone (FD), café-au-lait skin macules, and hyperfunctioning endocrinopathies (gonadotropin-independent gonadal function, nonautoimmune hyperthyroidism, growth hormone excess, and neonatal hypercortisolism), are diagnostic, renal, hepatobiliary, and cardiac involvement have also been reported (2–4).

Adrenocorticotropic hormone (ACTH)-independent adrenal Gα_s activation results in the rarest endocrine feature of MAS, which almost invariably presents in the neonatal period: Cushing syndrome (CS). Due to greater burden of Gα_s-mutation-bearing cells, the presence of CS is correlated with increased number of accompanying features of MAS and a poorer outcome. Although there is spontaneous resolution in 33% of cases with neonatal CS, mortality occurs with a high rate of 20% (4).

A dilemma for the clinician is that most publications to date have been case reports, and there is as yet no guideline for diagnosis, treatment, or follow-up. Here, a rare case of severe CS due to MAS, underlining the unique clinical phenotype specific to the neonatal period, is presented. Our goal is to offer a practical approach based on 3 years of clinical experience of this rare disorder that will help navigate challenges during follow-up.

Case presentation

A baby girl, born small for gestational age with a birthweight of 2,340 g (−2.1 SDS) and a head circumference of 32.6 cm (−1.61 SDS) was admitted to the neonatal intensive care unit in the first day of life for respiratory distress. She was the second child of a healthy non-consanguineous Caucasian couple, born 38 weeks of gestation via cesarean section following an uneventful pregnancy. Alanine aminotransferase [ALT, 2,376 U/L (normal, 0–40)] and aspartate aminotransferase [AST, 875 U/L (normal, 0–40)] were elevated; gamma-glutamyl transferase and bilirubin were normal. Antibiotics were administered intravenously after a diagnosis of possible neonatal sepsis. Respiratory distress resolved, and liver enzymes decreased (ALT, 687 U/L; AST, 108 U/L). As soon as the antimicrobial treatment was completed, she was discharged in the seventh day of life.

She was referred to our center, 4 days later, for failure to thrive (2,315 g), difficulty in feeding, and deterioration of general health. On physical examination, round facies, elongated philtrum and retro-micrognatia, hyperpigmented macules both at the front and back of the trunk and on labia majora, which do not cross midline, and hypertrichosis on the forehead and extremities were noted (Supplementary Figure S1). Newborn reflexes were hypoactive, blood pressure was 100/70 mmHg, and second-degree cardiac murmur was also detected. Systems were normal otherwise. Laboratory findings revealed hyponatremia, impaired renal and liver function tests, tubulopathy, and proteinuria, while blood count was normal (hemoglobin, 10.4 g/dl; leukocyte, 25.0 × 10³/μl; platelet count, 449×10³/μl) (Table 1). Hyponatremia resolved with fluid treatment, while liver enzymes, blood urea nitrogen, and creatinine remained elevated. Further endocrine evaluation revealed an elevated serum basal cortisol [225.68 g/dl (N, 6.7–22.6 µg/dL)] and 24-h urinary free cortisol [1,129 μg/day (N, 1.4–20 μg/day)]. Serum cortisol was not suppressed during overnight high-dose dexamethasone suppression test (Table 2) (5). Thyroid hormones were consistent with non-thyroidal illness.

ACTH-independent CS and café-au-lait spots suggested MAS. Hypercortisolism-related complications emerged. On the 11th day, hyperglycemia (blood glucose, 250 mg/dl) was seen, and it persisted after cessation of intravenous fluids in the exclusively breastfed neonate; thus, 0.5 U subcutaneous neutral protamine Hagedorn insulin (NPH) (three times a day) was initiated on the 16th day of life when blood glucose was 340 mg/dl, and serum insulin was 18.10 μIU/ml. Hypertension (110/90 mmHg) and hypokalemia were triggered by mineralocorticoid action of excessive cortisol on 20^th day. Spironolactone (2 mg/kg/day) was started, and nifedipine (0.5 mg/kg/day) was added in order to control blood pressure (Supplementary Figure S2). Since immunosuppressive effects of excess cortisol may increase the risk for opportunistic infections, Pneumocystis jirovecii prophylaxis was started and live vaccines were postponed.

Features of MAS and accompanying hyperfunctioning endocrinopathies were screened (Table 2). On ultrasonography, adrenal glands were hypertrophic; kidneys showed increased parenchymal echogenicity, loss of separation between the cortex and medulla, and enhanced medullary echogenicity; and size and echogenicity of the liver were normal. Magnetic resonance imaging of the abdomen confirmed that adrenal glands were hypertrophic (right and left adrenal gland were 24×22×18 mm and 18×19×20 mm in size, respectively) and lobulated. Echocardiogram revealed left ventricular hypertrophy. Bone survey verified generalized decrease in bone mass and revealed areas of irregular ossification and radiolucency in radius, ulna, and distal tibia, which were interpreted as osteoporosis due to hypercortisolism (Supplementary Figure S1).

Medical treatment

Metyrapone (300 mg/m²/day, per oral, in four doses) was started on the 25th day (Supplementary Figure S2) (6). Since liver function tests were impaired, metyrapone was preferred over ketoconazole. Soon after metyrapone was started, hyperglycemia and hypertension improved, enabling the discontinuation of insulin and nifedipine. Spironolactone was also gradually tapered and discontinued after 13 days of metyrapone treatment, and she was discharged.

The dose of metyrapone was adjusted frequently, according to clinical findings and serum cortisol levels during regular visits. However, even after gradually increasing metyrapone dose to 1,850 mg/m²/day over the course of 6 months, total biochemical suppression of serum cortisol could not be achieved (Supplementary Figure S3A), and the patient had progressive loss of bone mineral density, persistent left ventricular hypertrophy, and a lack of catch-up growth. In addition to that, café-au-lait macules became darker, dehydroepiandrosterone sulfate (DHEA-S) gradually increased (Table 2), and previously non-existent marked clitoromegaly was noted as a side effect of high-dose metyrapone. She was also prescribed ursodeoxycholic acid (15 mg/kg/day); however, liver enzymes remained high (Table 1).

Right total and left three-quarters adrenalectomy

Right total and left three-quarters adrenalectomy was carried out at 9 months of age in light of the patient’s continued clinical findings of hypercortisolism, the existence of unfavorable prognostic markers (high cortisol levels upon admission and heart and liver problems), and the adverse effects of high-dose metyrapone. The patient was administered 100 mg/m²/day glucocorticoids (GC) perioperatively; however, she developed symptoms of adrenal insufficiency. The required GC dose to attain euglycemia, restore general well-being, and resolve adrenal insufficiency was 300 mg/m²/day. Fludrocortisone (0.05 mg/day) was also started. Following surgery, supraphysiological doses of GC were required, as she suffered frequent symptoms of adrenal insufficiency (hypoglycemia, malaise, and loss of appetite). GC dose could be tapered very slowly, and a daily dose of 15 mg/m²/day could be attained in 2 months.

As liver function tests, serum cortisol levels and left ventricular hypertrophy all improved following adrenalectomy (Table 1). Bilateral nodular adrenal hyperplasia was observed in the pathological evaluation of surgical specimen, while the findings of liver wedge biopsy were non-specific (Supplementary Figure S4). Sequence analysis of GNAS from the surgical sample of adrenal gland revealed a heterozygous, previously described missense mutation in exon 8 (c.2530C>A, p.Arg844Ser), while the sequence analysis of the GNAS gene from peripheral blood sample was normal. Lymphocyte activation was normal 3 months post-adrenalectomy, and immunization schedule for live vaccines was established.

Other findings of MAS

She had breast development and vaginal bleeding that lasted 2 days when she was 7 months old, which repeated five more times after the adrenalectomy till 26 months of age. Breast development was Tanner stage 3, and bone age was markedly advanced (4 years and 2 months), despite severe hypercortisolism. On pelvic ultrasonography, uterus was enlarged to 34×22×24 mm; thus, letrozole (0.625 mg, per oral) was started at 26 months of age.

She also developed marked hypophosphatemia at the age of 6 months (Table 1). Radiological investigations since birth demonstrated severe osteopenia and lytic lesions, which were attributed to severe hypercortisolism; however, overt lesions of FD were not confirmed. When she was 9 months old, FGF-23 was elevated [122 pg/ml (normal <52)], which suggested hypophosphatemic rickets associated with FD. Oral phosphate (8 mg/kg) and calcitriol (18 ng/kg) were started. At the age of 23 months, bone survey revealed sclerosis of the base of the skull and maxilla and FD in the lower extremities. She has been on oral phosphate (58.7 mg/kg/day), while calcitriol was ceased.

She is now 34 months old with severe short stature [height, 81 cm (−3.5 SDS); weight, 9,580 g (−3.7SDS)] (Supplementary Figure S3B). She had been under regular clinic visits and has been on 15 mg/m²/day hydrocortisone and fludrocortisone 0.025 mg/day, letrozole (1×6.25 mg/day), phosphate (58 mg/kg), and ursodeoxycholic acid (100 mg/day) (Supplementary Figure S2). She has six words, cannot form two-word sentences, shows body parts, cannot stand up from supine position without support, and takes a few steps with support. Despite regular physiotherapy and ergotherapy, developmental delay is evident (Bayley Scales of Infant and Toddler Development III language scale, 13/79; motor scale, 2/46).

Discussion

ACTH-independent CS and café-au-lait macules suggested MAS in this case. Interestingly, this patient was admitted for hyponatremia and hyperglycemia requiring insulin treatment. Neonatal MAS and CS are rare conditions, and presentation of this case is quite unique (4).

The earlier the timing of somatic mutation, the greater the burden of G_sα-mutation-bearing cells leading to widespread tissue involvement in MAS. In the current case, adrenal, hepatic, cardiac, renal, and bone tissue involvement were evident in first weeks of life, while precocious puberty and hypophosphatemic rickets were observed later. A lifetime risk of additional tissue involvement is being acknowledged. CS is the rarest endocrine manifestation of MAS, which appears in <5%–7.1%. It presents exclusively within the first year of life (median age, 3.1 months) where features may develop as early as in utero (2–4, 7). The fact that our case was SGA and had moon facies and hirsutism with impaired linear growth, weight gain, hyperglycemia, hypertension, and nephrocalcinosis detected in the neonatal period, suggested severe, in utero onset CS. Upon suspicion, both comorbidities (hyperthyroidism, excess growth hormone, FD, and cardiac and hepatobiliary function) of MAS and complications of GC excess (hypertension, hyperglycemia, hyperlipidemia, nephrocalcinosis, decreased bone mineral density, and muscle atrophy) were assessed (1, 3).

Since the initial description of MAS, only 20 neonates with CS have been described with various initial basal serum cortisol ranging from 9.6 to 80.1 µg/dl, and data regarding long-term follow-up and outcome are still developing (1, 2, 8–11). Disease course is heterogenous, and spontaneous resolution of hypercortisolism has been reported (30%) since G_s-bearing cells are mostly located in the fetal adrenal zone, which normally undergoes apoptosis after birth. However, the outcome is mostly unfavorable in cases with extensive endocrine and extra-endocrine manifestations (1, 2, 8–15). Brown et al. reported poorer prognosis and a lower likelihood of spontaneous remission of adrenal disease in patients with cardiac (cardiomyopathy) and liver involvement (hepatocellular adenomas, inflammatory adenomas, choledochal cysts, neonatal cholestasis, and hepatoblastoma). It was hypothesized that these patients have a greater burden of G_sα mutation (3, 4).

Treatment of neonatal CS is a long and challenging path where both cortisol excess and its complications should be targeted. Marked hypercortisolism that precipitate neonatal diabetes requiring insulin treatment like our patient is rare and was previously reported only in six patients with CS (4). Until hypercortisolism is managed, hyperglycemia should be treated with insulin. Hypertension is due to mineralocorticoid effect of excess cortisol; thus, blood pressure lowering agents of choice should be aldosterone antagonists (spironolactone) or potassium-sparing diuretics.

The treatment strategy of hypercortisolism is determined by disease severity. In a mildly affected case, medical treatment with an expectation of spontaneous resolution (due to previously stated apoptosis of fetal adrenal zone) may be of choice (3, 4, 16–19). Metyrapone, ketoconazole, and mitotane are medical options for lowering cortisol (20–23). Since our patient had impaired liver function, metyrapone, a potent, rapid acting relatively selective inhibitor of 11-hydroxylase was preferred over ketoconazole for its low risk of hepatotoxicity. Reports reviewing adult data suggest an initial dose of 500–750 mg/day and achievement of biochemical control with 1,500 mg/day (23). However, the initial and maximum dose of metyrapone in neonates is unclear; some authors recommend 300 mg/m²/day in four equal doses (6). In our case, adequate biochemical and clinical suppression of cortisol with metyrapone was not achieved despite an increase in dose from 300 to 1,850 mg/m²/day.

There are important issues to be considered while using a steroidogenesis inhibitor like metyrapone. Monitoring biochemical response is essential, not only for dose titration and management of cortisol excess but also for adrenal insufficiency due to possible overtreatment. Clinical signs of adrenal insufficiency should always be questioned and assessed. The 24-h urinary free cortisol is the commonly used method; however, it may be impractical due to difficulties in the collection of urine in infants. Alternative methods may be the measurement of early morning serum cortisol and ACTH (23). Low ACTH level may indicate hypercortisolism or may be a sign of suppression due to long-term exposure to hypercortisolism. However, there are deadlocks to be considered in the evaluation of these measurements. A high cortisol level measured by immunoassays does not always indicate an actual elevation. It should be kept in mind that cortisol immunoassays exhibit significant cross-reactivity with cortisol precursors that may be elevated in patients treated with a steroidogenesis inhibitor (especially with metyrapone, which is known to increase 11-deoxycortisol). Such cross-reactivity can be a cause for overestimation of cortisol and may lead to risk of overtreatment (24, 25). It has been suggested that the patients on metyrapone should be biochemically monitored via specific methods, such as mass spectrometry (24–26).

Metyrapone is a relatively selective inhibitor of 11-hydroxylase and 18-hydroxylase. Recent in vitro studies indicate greater inhibitory action of metyrapone on aldosterone synthase, resulting in significant reversible reduction in both cortisol and aldosterone. The loss of negative feedback leads to an increase in ACTH, which causes an accumulation of cortisol and aldosterone precursors resulting in an increase in adrenal androgens (23). Although we could not serologically prove an increase in ACTH, hyperpigmentation and the increase in adrenal androgens confirm this mechanism. As far as we know, an increase in DHEA-S causing virilization was an unreported side effect of metyrapone. Clinical (clitoromegaly and hirsutism) and laboratory (DHEA-S) signs of hyperandrogenism should be monitored when higher doses of metyrapone are required.

In the severely affected case with CS, where medical treatment is inadequate and the chance of spontaneous resolution is subsiding, adrenalectomy is indicated when medically feasible. Brown et al. suggested that the presence of comorbid cardiac and liver disease like in our case should prompt consideration for early adrenalectomy (4). Although a previous correlation with initial serum cortisol level and prognosis was not established, it may be speculated that excessively high serum cortisol level is associated with increased number of G_sα-mutation-bearing adrenal cells. Thus, we suggest that in neonatal CS due to MAS, initial very high serum cortisol levels, like our case, may be a negative prognostic factor both for spontaneous resolution and clinical response to medical treatment. In infants with severe CS, bilateral adrenalectomy is generally performed. Alternatives like unilateral adrenalectomy and one-side total, other-side three-quarters adrenalectomy may be considered to avoid the requirement for lifelong GC and mineralocorticoid replacement. Unilateral adrenalectomy was reported to successfully improve clinical symptoms and endocrinological status in adult studies; nevertheless, recurrence during follow-up was 23.1%, while 17.5% required contralateral adrenalectomy (27–29). Since the causes of CS in adult series are variable and different from pediatric CS due to MAS, it should be borne in mind that reproducibility of adult data is poor. In CS due to MAS, G_sα-mutation-bearing adrenal gland cells are heterogeneously distributed, and partial adrenalectomy may carry the risk of inadequate management and recurrence. Only a few pediatric case reports addressed this issue. Unilateral adrenalectomy of the larger gland was performed in two neonates with CS due to MAS; remission was achieved for 2 years (30, 31). Itonaga et al. reported a 6-month-old neonate with MAS-associated CS treated with right-sided total adrenalectomy and left-sided half adrenalectomy with remission for 2 years (32). Although these cases were less severe [basal serum cortisol: 16.9, 18.5, and 23.4 µg/dl, respectively (N: 6.2–18.0 µg/dL)], we preferred to perform partial adrenalectomy (right total and left three-quarters adrenalectomy) and succeeded. Our patient has been in remission for more than 2 years.

In the largest case–control analysis of CS in patients with MAS, overall mortality was 20% (six cases) where four of them were deceased following bilateral adrenalectomy (66.7% of all deaths) (4). Anaphylaxis (or adrenal insufficiency), sudden cardiac arrest, sepsis, and sudden death were listed as causes of mortality in those four cases where GC dose and process of GC tapering were not clearly described. The fact that our patient required high-dose GC during peri- and postoperative period to restore well-being, tapering to maintenance dose was very slow, and she is still on maintenance dose GC, suggests that rapid tapering of GCs should be avoided and, although being speculative, may explain sudden death following adrenalectomy.

Gross motor developmental delay may be caused by prenatal exposure to excess GCs. Prenatal GC treatment for possible congenital adrenal hyperplasia or risk of premature birth have been shown to result in cognitive deficits after birth. Furthermore, children who develop CS later in life may experience a decline in cognitive and school performance where the younger the age of onset, the greater the deterioration in IQ scores (3, 4, 33, 34). Since transgenic mice with G_sα mutation was shown to have short- and long-term memory deficits and impaired associative and spatial learning, it may also be speculated that G_sα mutation may also be present in the central nervous system (35, 36).

The establishment of diagnosis of FD follows a characteristic and predictable time course. Although GNAS mutations are acquired early in embryogenesis, skeletal development appears to be relatively normal in utero, without frank clinical signs of FD at birth. Boyce et al. affirmed that FD lesions become apparent over the first several years of life and expand during childhood and adolescence, like our case. Previous case reports have also stated severe osteoporosis, rickets, polyostotic irregular lucencies, pathological fractures, and biopsy-proven FD during infancy (1, 2, 8–15). The exact pathophysiological mechanism is unclear, and G_sα activation in abnormally differentiated osteocytes is accused. FGF-23 overproduction is an inherent feature of FD, and most patients have elevated circulating levels of FGF-23, but frank hypophosphatemia is rare. The increase in FGF-23 is linked to substantial skeletal involvement. Although FGF-23 levels may wax and wane over time, an increase in FGF-23 usually occurs during periods of rapid growth like infancy and adolescence. Concurrent hyperfunctioning endocrinopathies like hyperthyroidism or CS may also adversely affect bone health.

Peripheral precocious puberty (PP) is the most frequent presenting feature in female patients with MAS (85%) (6). To date, a safe, effective, and long-term treatment for PP in girls with MAS has not been established. The benefits of current interventions on the ultimate outcome of interest, adult height, have not been well-established due to the rarity of the condition and heterogeneous nature of the disease. Despite the small sample size, studies have concluded that letrozole resulted in a statistically significant decrease in the bone age/chronological age ratio, growth velocity, hence increasing predicted adult height (37). Growth outcome in MAS is not only dependent on timing of pubertal onset but on several other disease components (skeletal involvement and endocrinopathies) as well. Hyperthyroidism and growth hormone excess may accelerate growth, while CS may decelerate it (37, 38).

Lack of consensus on both medical and surgical treatment strategies were major obstacles while navigating this case of severe neonatal MAS. The eminence of this report is that it presents current literature with clinical experience on this rare case of neonatal CS due to MAS. High index of suspicion for MAS in a neonate with extensive café-au-lait macules and symptoms of hypercortisolism is the key for early recognition and intervention. Initial excessive cortisol in neonatal CS may be a negative prognostic factor for spontaneous resolution and response to medical treatment, indicating early right total and left three-quarters adrenalectomy. Post-adrenalectomy survival may be related to close supervision during GC tapering.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

Ethics statement

Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author contributions

YU collected and analyzed data, drafted the initial manuscript, and reviewed and revised the manuscript. OG collected data. İU, HH, BG, SE, and TK collected data and reviewed and revised the manuscript. ZO and EG analyzed data, conceptualized the work, and revised and critically reviewed the manuscript for important intellectual and medical content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgments

We thank our patient’s family for providing consent for publication of this work.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1209189/full#supplementary-material

Supplementary Figure 1 | (A) The findings of physical and radiologic examination. Notice cushingoid facies, hyperpigmented macules that does not cross the midline at the front of the trunk. (B) Anteroposterior radiographs reveal irregularities in radius, ulna and femur. Although generalized osteopenia improves at 34 months, FD lesions become prominent over months.

Supplementary Figure 2 | Timeline of the course of symptoms in neonatal McCune Albright Syndrome noting adjustments made in treatment. Grey box denotes age in days for the first month of life then in months. NPH: Neutral Protamine Hagedorn insulin, CS: Cushing syndrome, PP: precocious puberty.

Supplementary Figure 3 | (A) Change in serum cortisol with increased metyrapone (methyrapone was initiated on day 25). (B) Growth chart, the arrow represents right total and left three quarters adrenalectomy.

Supplementary Figure 4 | Representative histological features of nodular adrenal hyperplasia. (A,  show low-power while (C) Show high-power views.

References

 

Keywords: McCune Albright syndrome, neonatal Cushing syndrome, metyrapone, adrenalectomy, follow-up

Citation: Unsal Y, Gozmen O, User İR, Hızarcıoglu H, Gulhan B, Ekinci S, Karagoz T, Ozon ZA and Gonc EN (2023) Case Report: Severe McCune–Albright syndrome presenting with neonatal Cushing syndrome: navigating through clinical obstacles. Front. Endocrinol. 14:1209189. doi: 10.3389/fendo.2023.1209189

Received: 20 April 2023; Accepted: 04 July 2023;
Published: 25 July 2023.

Copyright © 2023 Unsal, Gozmen, User, Hızarcıoglu, Gulhan, Ekinci, Karagoz, Ozon and Gonc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yagmur Unsal, yagmurunsal@yahoo.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1209189/full

Abbreviations

CT

computed tomography

MRI

Magnetic resonance imaging

USG

Ultrasonography

¹³¹I-MIBG

iodine 131 labeled meta-iodobenzylganidine

RAAS

Renin-angiotensin-aldosterone system

Conflict of interest statement

N/A.

 

 

From https://www.sciencedirect.com/science/article/pii/S2210261223005370

Cushing's syndrome (CS) is a rare disease with multiple somatic signs and a high prevalence of co-occurring depression. However, the characteristics of depression secondary to CS and the differences from major depression have not been described in detail. In this case, we report a 17-year-old girl with treatment-resistant depression with a series of atypical features and acute psychotic episodes, which is a rare condition secondary to CS. This case showed a more detailed profile of depression secondary to CS and highlighted the differences with major depression in clinical features, and it will improve insight into the differential diagnosis especially when the symptoms are not typical.

Introduction

Depression is a chronic medical problem with typical features, including sadness, decreased interest and cognitive impairments. In clinical practice, depression can occur in other medical conditions, especially endocrinopathies, making it a more complex problem and exhibiting a challenge in diagnosis, especially in first-contact patients or when the clinical presentations are atypical. It is generally accepted that patients who failed to respond to two or more adequate trials of first-line antidepressants for treatment of major depressive episode are considered to have treatment-resistant depression (TRD) (1). For patients with TRD, a throughout evaluation should be performed to investigate the underlying organic causes.

Cushing's syndrome is a rare but serious endocrine disease due to chronic exposure to excess circulating glucocorticoids with multisystem effects (2). The etiology of CS can be divided into adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent. It is characterized by a series of clinical features suggesting hypercortisolism, for example, metabolic abnormalities, hypertension and bone damages (3). A variety of neuropsychiatric symptoms, such as mood disturbance, cognitive impairment and psychosis, also occur in more than 70% CS patients (4). CS is life-threating if not timely diagnosed and treated, however, correct diagnosis can be delayed due to the wide range of phenotypes, especially when they are not classical (5).

Previous studies suggested that major depression was the most common co-morbid complication in CS patients, with a prevalence of 50–81% (6). Haskett's study confirmed that 80% of subjects meet the criteria for major depression with melancholic features (7). As reported in most recent investigations, depression in CS was not qualitatively different from non-endocrine major depression and the similarity was even striking (3, 8). However, some studies showed different conclusions and suggested a high prevalence of atypical depressive features other than melancholic features in CS (9). TRD and anxious depression has also been reported in CS patients (10, 11). All of the above conclusions suggest the complexity of depression with CS, and no distinct features have been found pertaining to hypercortisolism (12, 13). Although the intensity of depression secondary to CS is severe, suicidal depression is still an unusual condition (14).

Psychosis is a rare manifestation of CS, and the literature is limited. Only a few cases have been reported so far, especially combined with depression episode. In this case report, we presented a girl with CS, who experienced suicidal depression with a series of atypical features and acute psychotic symptoms, which was rarely reported in previous studies.

Case description

A 17-year-old girl with major depression for 3 years was involuntarily admitted for severe depressed mood with suicide attempts (neck cutting; tranquilizer overdose) and paranoid state in the last 2 weeks without any precipitating factors.

She experienced depressed and irritable mood in the last 3 years, and her condition had not improved although several adequate trials of antidepressants were used with satisfactory compliance (sertraline 200 mg/d; escitalopram oxalate 20 mg/d). Over the 2 weeks prior to admission, her depression continued to worsen with increasing irritability, she committed several suicide attempts, and once stated that she was unsafe at home. On admission, her heart rate was 116 bpm with blood pressure 139/81 mmHg and normal temperature; physical examination showed a cushingoid and virilising appearance (central obesity, swollen and hirsute face with acne, purple striae on the abdomen and bruises on the arms). No other abnormal signs were noted. She seemed drowsy but arousable, and she walked slowly, with bent shoulders and an inclined head. Mental state examination was hard to continue because she was passive and reluctant to answer our questions. Venlafaxine 150 mg/d has been used for more than 3 months with poor effects at that time.

Besides, weight gain (25 kg), irregular menstrual cycles and numbness of the hands and feet in the last half year were reported by her parents. Otherwise, No episodes of elevated mood and hyperactivity were found during the history taking. She does not have remarkable family history of serious physical or psychiatric illness; she was healthy, had an extroverted personality and had never used substances. Her premorbid social function and academic performance were good.

Several clinical characteristics found during the following mental state examinations were listed as follows:

• Prominent cognitive impairment without clouding of consciousness: Forgetfulness was frequently noted; she easily forgot important personal information such as her school and grade; she could not recall the suicide attempt committed recently and perfunctorily ascribed it to a casual event; and it was hard for her to recall her medical history (as it is for other depressive patients). The serial seven subtraction task could not be finished, and the interpretation of the proverb was superficial. Difficulty was found in attention maintenance; an effective conversation was hard to perform because she was mind-wandering (we needed to call her name to get her immediate attention) and often interrupted our conversations by introducing irrelevant topics or leaving without apparent reasons.

• Decreased language function that did not match her educational background: The patient could not find the proper words to articulate her feelings; instead, many simple, obscure and contradictory words were used, which made her response seem perfunctory. For example, she responded with “I do not know,” “I forgot,” or kept silent in response to our questions, which made the conversations hard to perform.

• Psychotic outbursts: Once she left the psychological therapy group, ranted about being persecuted and shook in fearfulness, stated “call the police” repeatedly, negative of explanations and comforts from others, but she cannot give any explanation about her behavior when calmed down. Sometimes she worried about being killed by the doctors but the worries were transient and fleeting.

• Depressed mood and negative thoughts (self-blame, worthlessness, and hopelessness) that were not persistent and profound: During most of her hospitalization, the patient seemed confused and apathetic, with intermittent anxiety, but she could not clearly express what made her anxious. Her crying and sadness happened suddenly, without obvious reasons, and she even denied low mood sometimes and said she had come to the hospital for cardiac disease treatment (she did not have any cardiac disease). Her description of her depressed mood was uncertain when specifically questioned, and she rarely reported her depressed feeling spontaneously as other depressed patients would. She did not even have the desire to get rid of her “depression”. Her suicidal ideation was transient and impulsive, and she could not provide a comprehensive explanation for her suicide attempts, such as emptiness, worthlessness or guilt. She was impatient and restless when interacting with others or when a more in-depth conversation was performed. She seemed apathetic, gave little response to emotional support from others and did not care about relevant important issues, such as hospital discharge or future plans. Elevated mood and motor activity were not found during the admission period.

• Social withdrawal and inappropriate behaviors: The patient often walked or stayed alone for long periods of time before speaking to other patients suddenly, which seemed improper or even odd in normal social interactions. During most hospitalization periods, lethargy and withdrawal were obvious.

Diagnostic assessment and therapeutic interventions

Basic laboratory tests reported abnormal results (Table 1), and the circulating cortisol level was far beyond the upper limit of normal, with a loss of circadian rhythm (Table 2); 24-h urinary free cortisol : >2897 nmol/24 h↑(69–345 nmol/24 h); serum ACTH (8 AM, 4 PM, 12 PM): 1.2 pg/ml, 1.3 pg/ml, <1 pg/ml (normal range: 1–46 pg/ml); low-dose dexamethasone suppression test (1 mg) (cortisol value): 1010.1 nmol/l (not suppressed; normal range: <50 nmol/L); high dose dexamethasone inhibition test (cortisol value): 879.0 nmol/l (not suppressed); OGTT and glycosylated hemoglobin; both normal. Other results used to rule out hyperaldosteronism and pheochromocytoma, such as the aldosterone/renin rate (ARR) and the vanillylmandelic acid, dopamine, norepinephrine and epinephrine levels, were reported to be within normal limits; ECG suggested sinus tachycardia; dual-energy X-ray bone density screening values were lower than the normal range; B-mode ultrasound showed a right adrenal tumor and fatty liver. The abdominal CT scan showed a tumor in her right adrenal gland. Brain MRI showed no abnormalities. Psychometric tests including HAMD (Hamilton depression scale), MADRS (Montgomery-Asberg Depression Rating Scale), WAIS (Wechsler Intelligence Scale) and MMSE (Mini-mental State Examination) were hard to perform due to her poor attention and non-cooperation presentation.

The patient had little response to adequate antidepressants in our hospital, including fluoxetine 20–60 mg/d and aripiprazole 5–30 mg/d combined with 3 sessions of MECT (modified electroconvulsive therapy), which was stopped because of her poor cognitive function and poor response.

Her last diagnosis was right adrenal adenoma and non-ACTH-dependent Cushing's syndrome. The adrenal adenoma was excised through laparoscopic resection in a general hospital. Hydrocortisone, amlodipine besylate, potassium chloride, metoprolol and escitalopram were used for treatment. Escitalopram 10 mg/d has been used until 2 weeks after her discharge. At the follow-up visit about 1 month after the surgery, her depressive mood had significantly improved, with no self-injury behaviors or psychiatric symptoms found. The patient was calm but still reacted slowly, and cognitive impairment was still found at the last visit.

Discussion

Previous studies have reported a close association between CS and depression (15). However, suicidal depression with atypical features and acute psychosis have rarely been reported, and the characteristics of depression secondary to CS and the differences from major depression have not been described in detail.

This case did not show a full-blown presentation of major depression according to the DSM-5. She presented with a series of features that were not typical as major depression, however, it should be emphasized that the atypical features were not identical to those noted in DSM5, especially regarding increased appetite and hypersomnia. The features suggesting difference from major depression were listed as follows: (a) depressed mood is not constant, it does not exist in most of the day; it is episodic without regular cyclicity, can happen or exacerbate suddenly; (b) the ability to describe anhedonia is poor, she can't report her feeling voluntarily like other patients with major depression, which might be partially related with the decreased language function; (c) depressive thoughts such as self-accusation and feelings of guilt, the classical symptoms of major depression, were rarely found; (d) more exaggerated cognitive impairment and decrease language function; € partial or little useful effect of SSRIs (selective serotonin reuptake inhibitors). The above characteristics were similar to those reported in Starkman's research (13, 16, 17), in which increasing irritability was also regarded as one of the important features for depression in CS.

The literature about depression combined with psychosis episode in CS is rare. This patient showed acute episodes of persecutory delusion with disturbed behaviors; her psychotic symptoms occurred suddenly and were fragmentary, with poor sensitivity to antipsychotics; the content was not constant (she never referred to and even denied the unsafe feeling at home before admission), it changed with the environment and was not consistent with the mood state. However, we cannot reach an effective conclusion because the evidence was small; thus, these findings should be evaluated in combination with other clinical presentations.

Conclusion

Most reviews have concluded that mood disturbances in CS indicate “major depression”, but the detailed description of clinical features are lack, making clinicians uncertain about the presentation and confused about the diagnosis, especially when the somatic signs are indiscriminate. The clinical presentation in this case highlighted the fact that there is a wide range of phenotypes of depression in CS, for some CS patients, the depressive features are not highly consistent with the criteria of major depression regardless of the melancholic or atypical features in the DSM-5. Thus, a thorough and periodic evaluation is necessary to detect the underlying organic and psychosocial causes if the clinical symptoms are not typical (10).

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethics statement

Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author contributions

XY, SC, XJ, and XH were responsible for clinical care. XY did literature search and drafted the manuscript. XH revised the manuscript. All authors contributed to the article and have approved the final manuscript.

Acknowledgments

We want to thank Juping Fu, Ying Zhang, and all other medical staff who gave careful nursing to the patient.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

 

Keywords: Cushing's syndrome (CS), treatment-resistant depression, acute psychosis, adrenal adenoma (AA), adolescent girl

Citation: Yin X, Chen S, Ju X and Hu X (2023) Case report: Treatment-resistant depression with acute psychosis in an adolescent girl with Cushing's syndrome. Front. Psychiatry 14:1170890. doi: 10.3389/fpsyt.2023.1170890

 

From https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1170890/full

 

Introduction

Cushing’s disease (CD) is the most common cause of endogenous glucocorticoid excess due to uncontrolled adrenocorticotropic hormone (ACTH) secretion from a pituitary adenoma, for the most part a microadenoma [1]. A rare condition with an estimated incidence of 0.6—2.6 cases per million per year, it is burdened by high morbidity and mortality, for the most part linked to cardiovascular (CV) events. This is particularly true for active CD which is characterized by hypertension, diabetes mellitus, obesity and dyslipidaemia. The severity of the clinical picture seems to depend more on the duration of the disease rather than on the degree of cortisol elevation, although other confounding factors may affect the clinical phenotype [2]. Prompt diagnosis and resolution of hypercortisolemia are paramount to revert cortisol-related comorbidities and to improve life expectancy. Although new individualized medical treatment options for CD continue to evolve, transsphenoidal surgery (TSS) remains the first line treatment for potentially operable patients as it is the only treatment that seems to provide a rapid, long-lasting remission. Persistent and recurrent cases are nevertheless major concerns, since up to 50% of cases might require other treatment modalities to achieve disease control and those patients are once again exposed to cortisol excess that can negatively impact their survival [3]. An increased mortality has been noted in patients with active CD, while patients in remission show a markedly lower one. It is still unclear if mortality in these patients is higher than that in the general population. Some studies report a normal life expectancy [4,5,6,7,8] while others describe a persistently higher mortality [9,10,11]. One study reported finding a higher mortality as long as 10 years after remission, and only patients cured by a single TSS showed a normal life expectancy [12].

In view of these considerations, this study was designed to assess the prevalence of cortisol-related comorbidities/complications and mortality in a large group of CD patients attending a tertiary referral centre over the past 20 years. Other study aims were to evaluate the predictors of long-term outcomes and the impact of different treatments on life expectancy in CD patients.

Materials and Methods

One hundred twenty-six CD patients diagnosed between December 2001 and December 2021 were eligible for this monocentric, retrospective, observational study. Hypercortisolism was suspected on the basis of the patient’s clinical features and it was confirmed by appropriate hormonal testing [low dose dexamethasone suppression test (LDDST), 24-h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC)] after excluding the possibility of exogenous glucocorticoid intake from any route [13]. UFC and LNSC were assessed at least in two different samples as recommended [14, 15].

The diagnosis of ACTH-dependent syndrome was confirmed on the strength of detectable ACTH levels (> 10 ng/L) and appropriate responses to a high dose dexamethasone suppression test (HDDST), corticotrophin releasing hormone (CRH) and/or desmopressin (DDAVP) tests [16]. All the patients underwent a pituitary magnetic resonance imaging (MRI); they also underwent bilateral inferior petrosal sinus sampling (BIPSS) when the results of hormonal tests were ambiguous. The pituitary origin of ACTH secretion was confirmed by biochemical remission after TSS, histology and/or post-operative hypoadrenalism.

The results of clinical, biochemical and radiological tests as well as the treatments performed to control cortisol secretion (surgery, radiotherapy and/or medical therapy), any comorbidities (i.e., arterial hypertension, impaired glucose homeostasis, dyslipidaemia, overweight), any hormone deficiencies, any complications (i.e., CD-related events such as infective, CV and thromboembolic events) and any deaths recorded in the medical charts were collected.

The disease severity at baseline was defined on the basis of the patient’s UFC values as mild (up to two-fold the upper limit of normal – ULN), moderate (between 2 and 5 times the ULN) or severe (over five-fold the ULN).

Patient’s classification on the basis of disease activity are indicated in Supplementary material and methods sections.

The presence of hypertension, glucose metabolism impairment, obesity, dyslipidaemia and hypopituitarism were defined as by specific Guidelines, Supplementary [19,20,21,22,23,24].

The current study was designed in accordance with the principles of the Declaration of Helsinki and approved by the Ethical Committee of the province of Padova (protocol code 236n/AO/22, date of approval 29 April 2022).

The types of CD complications characterizing the patient were classified into three categories: CV, thromboembolic (TE), or infective (IN) events. Depending on the timing of its presentation, an event was classified as occurring: “prior” to diagnosis, “during” active CD or “after” CD remission. Events requiring hospitalization or iv antibiotic administration were registered as IN events. The causes of death were classified under the following headings: CV, infections, cancer, psychiatric complications leading to suicide, TE events or other (the last when none of the previous causes was applicable).

Statistical analysis

Categorical variables were reported as counts or percentages, and quantitative variables as median and interquartile ranges [IQR]. The comparisons between groups were performed with a Mann–Whitney sum rank test for independent quantitative variables; a Wilcoxon signed-rank test was run for dependent quantitative variables. As far as categorical variables were concerned, the McNemar test or a chi-square test were used for paired and unpaired data, respectively.

A Cox regression analysis was performed to evaluate possible predictors for events and mortality based on the assumption of constant hazards over time. As time-dependent variables (e.g., achieving remission) did not meet this assumption, their survival analysis was performed using Kaplan–Meier analysis. Regarding complications, as there is usually a delay in CD diagnosis [25], Kaplan Meier curves for event free probability were calculated beginning 24 months prior to the diagnosis in order to include “prior” events possibly related to cortisol excess in our analysis. Vice versa, survival analysis for mortality was calculated beginning with the CD diagnosis date. Standardized mortality ratio (SMR) was calculated based on indirect age standardization in order to compare the observed deaths in our CD population with the expected number of deaths in the general population [26, 27]. A Fisher exact test was carried out to assess significant differences with respect to the general population and calculating the 95% confidence interval (95% CI) for SMR.

The threshold for statistical significance was set at p-value < 0.05. Statistical analyses were performed with R: R-4.2.0 for Windows 10 (32/64 bit) released in April 2022 and R studio desktop version 4.2.0 (2022-04-22) for Windows 10 64 bit (R Foundation for Statistical Computing, Vienna, Austria, URL https://www.R-project.org/). An open-source calculator was also used to perform the Fisher exact test (http://www.openepi.com).

Results

Baseline

The data of 167 CD patients attending the Centre between December 2001 and December 2021 were collected. The information regarding 41 patients were not included in the analysis because of insufficient follow-up data (i.e. patients referred for second opinion or for diagnostic workup or those with follow-up < 1 year from first line treatment). The remaining 126 patients presented a median age at diagnosis of 39 [31–50 years]; the female: male ratio was 3:1. The median follow-up was 130.5 months [72.5–201.5]. The patients’ clinical features at the time of diagnosis are outlined in Table 1.

Full size table

The median UFC levels were 3.2 times the ULN [2–5.6]. Almost half of the cohort presented moderate cortisol excess (45/98, 45.9%), with lower proportions of the patients presenting mild (26/98, 26.5%) and severe disease (22/98, 27.6%).

Most of the patients (91/113, 80.5%) had a microadenoma, including 29/91(31.9%) with negative imaging. The remaining 22 patients (19.5%) had a macroadenoma.

Treatments

Most of the patients underwent TSS as the first line treatment (113/126), only one patient underwent craniotomy. Eight patients received primary medical treatment, three received first-line radiotherapy and one underwent BA soon after diagnosis. Overall, 115 patients underwent pituitary surgery (one patient with a previous unsuccessful pituitary irradiation) and the remission rate was 60.9%. Relapses were observed in 46.7% of the cases after a median time of 56 [29–83] months. The second surgery proved less successful with respect to the first one; the remission rate was 43.2% (16/37); of these, 25% developed recurrence during the follow-up period. The median time to relapse was 66.5 [36–120] months. Only two patients underwent a third surgery; in both cases it was not curative (Supplementary Fig. 1) [27]. A 4th and a 5th TSS were performed in one of these for debulking purposes due to an aggressive pituitary lesion. Surgical remission was not affected by pre-treatment with cortisol-lowering medications neither before the first (p = 1.0) nor the second TSS (p = 0.88). Moreover, hormone control did not improve the surgical outcomes, although a tendency towards a higher remission rate was observed in those patients who showed good disease control before undergoing the second surgery (Supplementary Fig. 2) [27].

Overall, 34 patients received radiotherapy, either the conventional (18.5%) or the stereotactic type (81.5%). Remission was noted in 36.7% (11/30) of the patients with at least a 12-month post-radiotherapy follow-up. As expected, the longer the follow-up, the higher the remission rate; it was 41.67% (10/24) and 46.7% (7/15) at 5 and 10 years, respectively.

Thirteen patients underwent BA and achieved complete remission. Excluding the patients with less than 12 months of follow-up, 4 out of 11 (36.4%) of the patients developed CTP-BADX/NS over a mean follow-up period of 110 [106 -329] months. Three patients out of the 11 were previously irradiated at pituitary level to control cortisol secretion. Four CD patients underwent unilateral adrenalectomy due to a dominant adrenal lesion consistent with chronic ACTH stimulation. Two (50%), harbouring unilateral adenomas larger than 5 cm, achieved remission after surgery; both cases were previously irradiated at the pituitary level.

All but one of the 48 patients with persistent hypercortisolism at the last follow-up were on cortisol lowering medications. The untreated patient had a residual mild cortisol excess after TSS and medical therapy was discontinued because of multiple drug intolerance. At the last follow-up 28 patients were receiving monotherapy, and 19 were receiving combination treatment; 25 patients were receiving steroidogenesis inhibitors, 9 pituitary-target drugs and 13 a combination of the two compounds (Supplementary Table 1) [27]. Most of our patients achieved UFC normalization (complete control in 67.4%, partial control in 22.7%, uncontrolled in 10.9%). Data pertaining to a single patient with renal function impairment who presented falsely low UFC were not included in this analysis. When available, LNSC was restored in 14/41 cases (34.2%). No differences in the patients’ outcomes linked to the type of treatment prescribed (monotherapy vs combination treatment) or its target (adrenal vs pituitary) were found (data not shown).

We also evaluated the extent of cortisol excess throughout the active phase of CD both for the patients presenting persistence at the last available follow-up (n = 48) and for those in remission after multiple therapies (i.e., late remission) (n = 33). As described in the material and methods section, disease activity for each year of active disease was defined on the basis of patients’ UFC levels. A minimum of three UFC measurements were registered every year and the median value was calculated. When data were missing, the patients were considered uncontrolled during that period. The results are reported in Supplementary Table 2 [27]; both the persistence and late remission groups showed UFC levels < 2xULN over more than 50% of the time span evaluated (58.8% and 73.6%, respectively). There was a progressive increase in the proportion of controlled patients over the observation period (Fig. 1).

Percentage of patients controlled during active CD

Full size image

Comorbidities

The principal CD features at baseline and at the last follow-up examination were evaluated, (Supplementary Table 2). At time of diagnosis, no differences were observed as regards comorbidities between patients who achieved remission and those with persistent disease at baseline, (Supplementary Table 3). The patients in remission at the last examination showed a significant improvement in all the parameters considered; those with persistent CD did not (Table 2).

Full size table

As far as hormone deficiencies were concerned, 42/126 (33.3%) of the patients developed at least one deficit due to previous treatments (Supplementary table 4) [27], including hypocortisolism due to BA. Neither the second surgery nor radiotherapy led to an increase in hypopituitarism (Supplementary Fig. 3) [27].

Complications and mortality

As far as CD complications were concerned, 18.3% of the patients had a TE event, 17.5% presented an IN event and 7.1% presented a CV one. Most of the events occurred during an active phase of CD (Table 3). Other concomitant thrombotic risk factors were present in 10/19 (52.6%) of the patients experiencing TE events. TE events were related to surgery (pituitary, adrenal or others) in 5 cases, to post-traumatic fractures in 2, to prolonged immobilization in 2, and to a symptomatic SARS CoV2 infection in one case. IN events affected the respiratory system in 9 cases, the gastro-intestinal tract in 5 cases, the soft tissues in three cases, the central nervous system in 2 cases, the musculoskeletal system in 2 cases and the genitourinary tract in one case.

Full size table

Overall, 11 deaths were recorded during the follow-up period (130.5 [72.5–201.5] months). The causes of death were classified as: cardiovascular events (n = 4), infections (n = 2), cancer (n = 2), suicide (n = 1), thromboembolic events (n = 0), others (n = 2; a cerebral haemorrhage in one case and an unknown cause in the other).

Cox regression was performed to evaluate the predictors of events (CV, IN, TE) and mortality (Fig. 2). The older patients presented an increased risk of mortality (HR 9.41, 95%CI [1.97; 44.90], p = 0.005), of CV events (HR 4.84, 95%CI [1.13; 20.75], p = 0.003) and of TE events (HR 2.41, 95%CI [1.02; 5.65], p = 0.04). Similarly, the presence of a macroadenoma at the time of the first MRI was associated with reduced survival (HR 9.29, 95%CI [2.30; 37.53], p = 0.002). Smoking was correlated to CV events (HR 5.33, 95%CI [1.33; 21.37], p = 0.02). Hypercortisolism severity at baseline did not affect the risk of complications or survival. No gender related differences were observed, although a tendency toward more CV events was noted in the males (p = 0.08).

 

Cox regression analysis for predictors of mortality and cardiovascular, infective or thromboembolic events; only significant results are shown. HR: Hazard ratio; CI: confidence interval; n: number, CV: cardiovascular; TE: thromboembolic. *p < 0.05

Full size image

 

Kaplan Meier curves for cardiovascular events based on: A) comorbidities at the last follow-up examination; disease status at the last follow-up examination; C) control during active disease for patients presenting persistence at the last follow-up. Kaplan Meier curves for survival plotting: D) comorbidities at the last follow-up examination; E) disease status at the last follow-up examination. Kaplan Meier curves for infective events based on: F) hormone control during active disease of patients presenting persistence at the last follow-up examination. FU: follow-up; CV: cardiovascular; IN: infective. *p < 0.05

Full size image

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Copyright © 2023 Wanwan Sun et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

From https://www.hindawi.com/journals/ije/2023/3334982/

 

Introduction

Cushing’s syndrome, caused by excessive exposure to glucocorticoids, is associated with considerable morbidity and increased mortality [1]. Cushing’s syndrome has diverse manifestations, including central obesity, moon facies, purple striae, and hypertension [2]. Cushing’s disease, due to adrenocorticotropic hormone (ACTH) hypersecretion from pituitary adenomas, is the most common etiology of ACTH-dependent Cushing’s syndrome [1, 2]. According to the Endocrine Society Clinical Practice Guideline, transsphenoidal surgery is the first-line treatment for Cushing’s disease [3]. The identification of pituitary adenomas on preoperative MRI can significantly increase the postoperative remission rate from 50 to 98% [4]. Therefore, it is critical to identify pituitary adenomas on MRI before surgery.

However, there are considerable challenges in identifying ACTH-secreting pituitary adenomas. This is because about 90% of the tumors are microadenomas (less than 10 mm in size) and the median diameter at surgery is about 5 mm [5, 6]. Conventional contrast-enhanced MRI (cMRI) using a two-dimensional (2D) fast spin echo (FSE) sequence has been routinely used to acquire images with 2- to 3-mm slice thickness, but some microadenomas are difficult to be identified on cMRI, resulting in false negatives reported in up to 50% of patients with Cushing’s disease [7]. Dynamic contrast-enhanced MRI (dMRI) increases the sensitivity of identifying pituitary adenomas to 66% [8], but it also increases false positives at the same time [9, 10]. The 3D spoiled gradient recalled (SPGR) sequence has been introduced in high-resolution contrast-enhanced MRI (hrMRI) to acquire images with 1- to 1.2-mm slice thickness. It is reported that the 3D SPGR sequence is superior to the 2D FSE sequence in the identification of pituitary adenomas with a sensitivity of up to 80% [11,12,13], but it cannot satisfy the clinical needs that about 20% of the lesions are still missed. Therefore, techniques are needed that can help better identify pituitary adenomas, particularly microadenomas. Previously, the 3D FSE sequence was recommended in patients with hyperprolactinemia [14]. Recently, the 3D FSE sequence has developed rapidly and can provide superior image quality with diminished artifacts [15]. Sartoretti et al demonstrated in a very effective fashion that the 3D FSE sequence is a reliable alternative for pituitary imaging in terms of image quality [16]. However, to our knowledge, few studies have investigated the diagnostic performance of 3D FSE sequences for identifying ACTH-secreting pituitary adenomas, particularly microadenomas.

The aim of our study was to assess the diagnostic performance of hrMRI with 3D FSE sequence by comparison with cMRI and dMRI with 2D FSE sequence for identifying ACTH-secreting pituitary microadenomas in patients with Cushing’s syndrome.

Materials and methods

This single-institutional retrospective study was approved by the Institutional Review Board of our hospital. The study was conducted in accordance with the Helsinki Declaration. The informed consent was waived due to the retrospective nature of the study.

Study participants

We retrospectively reviewed the medical records and imaging studies of 186 consecutive patients with ACTH-dependent Cushing’s syndrome, who underwent a combined protocol of cMRI, dMRI, and hrMRI from January 2016 to December 2020. Postoperative patients with Cushing’s disease (n = 97), patients with ectopic ACTH syndrome who underwent pituitary exploration (n = 2), and patients with macroadenomas (n = 5) or lack of pathology (n = 13) were excluded from the study. Finally, 69 patients with ACTH-dependent Cushing’s syndrome were included in the current study (Fig. 1) and the patients included were all surgically confirmed.

Flowchart of patient inclusion/exclusion process and image analysis. ACTH adrenocorticotropic hormone, CD Cushing’s disease, EAS ectopic ACTH syndrome, T1WI T1-weighted imaging, T2WI T2-weighted imaging

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MRI protocol

All the patients were imaged on a 3.0 Tesla MR scanner (Discovery MR750w, GE Healthcare) using an 8-channel head coil. The MRI protocol included coronal T2-weighted imaging, coronal T1-weighted imaging, and sagittal T1-weighted imaging before contrast injection. After contrast injection of gadopentetate dimeglumine (Gd-DTPA) at 0.05 mmol/kg (0.1 mL/kg) with a flow rate of 2 mL/s followed by a 10-mL saline solution flush, dMRI and cMRI with 2D FSE sequence were obtained first, and hrMRI with 3D FSE sequence using variable flip angle technique was performed immediately afterward. Detailed acquisition parameters are presented in Table S1.

Image analysis: diagnostic performance

Image interpretation was independently conducted by two experienced neuroradiologists (F.F. and H.Y. with 25 and 16 years of experience in neuroradiology, respectively), who were blinded to patient information. The evaluation order of cMRI, dMRI, and hrMRI sequences was randomized. The identification of pituitary microadenomas on images was scored based on a three-point scale (0 = poor; 1 = fair; 2 = excellent). Scores of 1 or 2 represented the identification of the lesion. Reference standards were established by using all available imaging, clinical, surgical, and pathological resources, with a multidisciplinary team approach.

Image analysis: image quality

Two readers (Z.L. and B.H. with 4 years of experience in radiology, respectively) were asked to assess the image quality of cMRI, dMRI, and hrMRI. Before exposure to images used in the current study, these readers underwent a training session to make sure that they were comparable to the experienced neuroradiologists in terms of image quality assessment. Images were presented in a random order. Image quality was assessed by using a 5-point Likert scale [17], including overall image quality (1 = non-diagnostic; 2 = poor; 3 = fair; 4 = good; 5 = excellent), sharpness (1 = non-diagnostic; 2 = not sharp; 3 = a little sharp; 4 = moderately sharp; 5 = satisfyingly sharp), and structural conspicuity (1 = non-diagnostic; 2 = poor; 3 = fair; 4 = good; 5 = excellent). An example of image quality assessment is shown in Table S2. Final decision was made through a consensus agreement.

The mean signal intensity of pituitary microadenomas, pituitary gland, and noise on cMRI, dMRI, and hrMRI was measured using an operator-defined region of interest. For noise, a 10-mm² region of interest was placed in the background, and noise was defined as the standard deviation of the signal intensity of the background [17]. For pituitary microadenomas and pituitary gland, the region of interest should include a representative portion of the structure. The mean signal intensity of the pituitary microadenoma was replaced with that of the pituitary gland when no microadenoma was identified. A signal-to-noise ratio (SNR) was defined as the mean signal intensity of the pituitary microadenoma divided by noise. A contrast-to-noise ratio (CNR) was defined as the absolute difference of the mean signal intensity between the normal pituitary gland and pituitary microadenomas divided by noise [17]. Supplementary Fig. 1 shows how to measure the SNR and CNR with the region of interest in a contrast-enhanced pituitary MRI. Supplementary Fig. 2 shows the selection of images for the SNR and CNR calculation.

Statistical analysis

The κ analysis was conducted to assess the inter-observer agreement for identifying pituitary microadenomas. The κ value was interpreted as follows: below 0.20, slight agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; greater than 0.80, almost perfect agreement.

To assess the diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas, the receiver operating characteristic curves were plotted and the area under curves (AUCs) were compared between MR protocols for each reader by using the DeLong test. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The Mann–Whitney U test was used to evaluate the difference in image quality scores and the Wilcoxon signed-rank test was used to evaluate SNR and CNR measurements between MR protocols. A p value of less than 0.05 was considered statistically significant. Statistical analysis was performed using MedCalc Statistical Software (version 20.0.15; MedCalc Software) and SPSS Statistics (version 22.0; IBM).

Results

Clinical characteristics

A total of 69 patients (median age, 39 years; interquartile range [IQR], 29–54 years; 38 women [55%]) with ACTH-dependent Cushing’s syndrome were included in the study and their clinical characteristics are shown in Table 1. Among the 69 patients, 60 (87%) patients were diagnosed with Cushing’s disease and 9 (13%) were ectopic ACTH syndrome. The median disease course was 36 months (IQR, 12–78 months). The median serum cortisol, ACTH, and 24-h urine free cortisol level before surgery were 33.0 μg/dL (IQR, 25.1–40.1 μg/dL; normal range 4.0–22.3 μg/dL), 77.2 ng/L (IQR, 55.0–124.0 ng/L; normal range 0–46 ng/L), and 422.0 μg (IQR, 325.8–984.6 μg; normal range 12.3–103.5 μg), respectively. The median serum cortisol and 24-h urine free cortisol level after surgery were 3.0 μg/dL (IQR, 1.8–18.4 μg/dL) and 195.6 μg (IQR, 63.5–1240.3 μg), respectively. The median diameter of pituitary microadenomas was 5 mm (IQR, 4–5 mm), ranging from 3 to 9 mm.

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Diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas

The inter-observer agreement for identifying pituitary microadenomas by κ statistic between two readers was moderate on cMRI (κ = 0.50), moderate on dMRI (κ = 0.57), and almost perfect on hrMRI (κ = 0.91), respectively.

The diagnostic performance for identifying pituitary microadenomas on cMRI, dMRI, hrMRI, and combined cMRI and dMRI is summarized in Table 2. For reader 1, the diagnostic performance of hrMRI (AUC, 0.95; 95%CI: 0.87, 0.99) was higher than that of cMRI (AUC, 0.75; 95%CI: 0.63, 0.85; p = 0.002), dMRI (AUC, 0.59; 95%CI: 0.47, 0.71; p < 0.001), and combined cMRI and dMRI (AUC, 0.65; 95%CI: 0.53, 0.76; p = 0.001). For reader 2, the diagnostic performance of hrMRI (AUC, 0.97; 95%CI: 0.89, 1.00) was higher than that of cMRI (AUC, 0.74; 95%CI: 0.63, 0.84; p = 0.001), dMRI (AUC, 0.68; 95%CI: 0.56, 0.79; p = 0.001), and combined cMRI and dMRI (AUC, 0.70; 95%CI: 0.58, 0.80; p = 0.003).

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For reader 1, 23 of the 69 patients (33%) were misdiagnosed on both cMRI and dMRI, but 18 of the 23 misdiagnosed patients (78%) were correctly diagnosed on hrMRI. For reader 2, 17 of the 69 patients (25%) were misdiagnosed on both cMRI and dMRI, but 14 of the 17 misdiagnosed patients (82%) were correctly diagnosed on hrMRI.

Figure 2 shows that a 5-mm pituitary microadenoma was identified on preoperative pituitary MRI. The margin of the lesion was fully delineated on hrMRI, but not on cMRI and dMRI. Figure 3 shows that a 3-mm pituitary microadenoma was missed on cMRI, but identified on dMRI and hrMRI. Figure 4 shows that a 5-mm pituitary microadenoma was correctly diagnosed on hrMRI, but missed on cMRI or dMRI. Figure 5 shows that a 4-mm pituitary microadenoma was evident on coronal images as well as reconstructed axial and reconstructed sagittal images on hrMRI.

 

Images in a 56-year-old man with Cushing’s disease. The 5-mm pituitary microadenoma (arrow) can be identified on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence, but the margin is not fully delineated. The lesion (arrow) is well delineated on (c) coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence. d Intraoperative endoscopic photograph during transsphenoidal surgery after exposure of the sellar floor shows a round pituitary microadenoma (arrow)

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Images in a 34-year-old woman with Cushing’s disease. No tumor is identified on (a) coronal contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. The 3-mm pituitary microadenoma (arrow) with delayed enhancement is identified on the left side of the pituitary gland on (b) coronal dynamic contrast-enhanced T1-weighted image obtained with 2D FSE sequence and (c) coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence. d Intraoperative endoscopic photograph during transsphenoidal surgery shows a 3-mm pituitary microadenoma (arrow)

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Images in a 43-year-old man with Cushing’s disease. The lesion is missed on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. c Coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence shows a round pituitary microadenoma (arrow) measuring approximately 5 mm with delayed enhancement on the left side of the pituitary gland. d Intraoperative endoscopic photograph for microsurgical resection of the 5-mm pituitary microadenoma (arrow)

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Images in a 48-year-old woman with Cushing’s disease. Preoperative high-resolution contrast-enhanced MRI using three-dimensional fast spin echo sequence shows a 4-mm pituitary microadenoma (arrow) with delayed enhancement is well delineated on the left side of the pituitary gland on (a) coronal, (b) reconstructed axial, and (c) reconstructed sagittal contrast-enhanced T1-weighted images. d Intraoperative endoscopic photograph during transsphenoidal surgery after exposure of the sellar floor shows a round pituitary microadenoma (arrow)

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From https://jamanetwork.com/journals/jama/article-abstract/2807073

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From https://www.selectscience.net/application-articles/minimizing-the-number-of-false-positives-in-dexamethasone-suppression-testing-for-the-diagnosis-of-cushings-syndrome?artID=59632

1. Introduction

Pituitary adenoma arises from the anterior pituitary cells and is the commonest tumor of the sellar region.^[1] It makes up approximately 10% to 15% of all intracranial tumors.^[2] Ectopic pituitary adenoma (EPA) is defined as a pituitary adenoma that occurs outside the sellar area and has no direct connection to normal pituitary tissue.^[3] The most frequent sites of EPA are the sphenoid sinus and suprasellar region, and much less frequent sites including the clivus region, cavernous sinus, and nasopharynx.^[4]

Hypercortisolism and the series of symptoms it leads to is termed Cushing syndrome (CS).^[5] CS is classified into adrenocorticotropin (ACTH)-dependent and ACTH-independent CS depending on the cause, accounting for 80% to 85% and 15% to 20% of cases, respectively.^[6] Pituitary adenoma accounts for ACTH-dependent CS 75% to 80%, while ectopic ACTH secretion accounts for the remaining 15% to 20%.^[7] Ectopic CS is a very rare disorder of CS caused by an ACTH-secreting tumor outside the pituitary or adrenal gland.^[8] It has been reported that ectopic ACTH-producing pituitary adenoma (EAPA) can occur in the sphenoid sinus, cavernous sinus, clivus, and suprasellar region,^[9] with EAPA in the clivus region being extremely rare, and merely 6 cases have been reported in the English literature (Table 1).^[10–15] Furthermore, as summarized in the Table 1, EAPA in the clivus area has unique symptoms, which may lead to misdiagnosis as well as delay in treatment. Therefore, we herein described a case of CS from an EAPA of the clivus region and reviewed relevant literature for the purpose of further understanding this extraordinarily unusual condition.

 

Table 1 - Literature review of cases of primary clival ectopic ACTH-producing pituitary adenoma (including the current case).

 

 

Reference	Age (yr)/sex	Symptoms	Imaging findings	Maximum tumor diameter (mm)	Preoperative elevated hormone	IHC	Surgery	RT	Follow-up (mo)	Outcome
Ortiz et al 1975[10]	15/F	NA	NA	NA	NA	NA	Right transfrontal craniotomy, NA	Yes	NA	Symptomatic relief
Anand et al 1993[11]	58/F	Anosphrasia, blurred vision, occasional left frontal headache,	Routine radiographic evaluation revealed a clival tumor and nasopharyngeal mass with bone erosion. MRI demonstrated a Midline homogeneous mass.	30	ACTH	ACTH in a few isolated cells	Maxillotomy approach, GTR	Yes	12	Symptomatic relief
Pluta et al 1999[12]	20/F	Cushing syndrome	MRI revealed a hypodense contrast-enhancing lesion.	NA	ACTH	ACTH	Transsphenoidal surgery, GTR	No	18	Symptomatic relief
Shah et al 2011[13]	64/M	Facial paresthesias, myalgias, decreased muscle strength, and fatigue	CT imaging showed a clival mass.	21	ACTH	ACTH	NA, GTR	No	7	Symptomatic relief
Aftab et al 2021[14]	62/F	Transient unilateral visual loss	MRI showed a T2 heterogeneously enhancing hyperintense lesion.	21	No	ACTH	Transsphenoidal resection, GTR	NO	6	Symptomatic relief
Li et al 2023[15]	47/F	Bloody nasal discharge, dizziness and headache	CT revealed an ill-defined mass eroding the adjacent bone. MRI T1 showed a heterogeneous mass with hypointensity, hyperintensity on T2-weighted images and isointensity on diffusion-weighted images.	58	NA	ACTH	Transsphenoidal endoscopy, STR	Yes	2	Symptomatic relief
Current case	53/F	Headache, and dizziness, Cushing syndrome	CT demonstrated bone destruction and a soft tissue mass. MRI T1 revealed irregular isointense signal, and MRI T2 showed isointense signal/slightly high signal.	46	ACTH	ACTH	Transsphenoidal endoscopy, GTR	NO	6	Symptomatic relief

ACTH = adrenocorticotropin, CT = computed tomography, GTR = gross total resection, IHC = immunohistochemistry, MRI = magnetic resonance imaging, NA = not available, RT = radiotherapy, STR = subtotal resection.

 

2. Case presentation

A 53-year-old female presented to endocrinology clinic of our hospital with headache and dizziness for 2 years and aggravated for 1 week. Her past medical history was hypertension, with blood pressure as high as 180/100 mm Hg. Her antihypertensive medications included amlodipine besylate, benazepril hydrochloride, and metoprolol tartrate, and she felt her blood pressure was well controlled. In addition, she suffered a fracture of the thoracic vertebrae 3 month ago; and bilateral rib fractures 1 month ago. Physical examination revealed that the patient presented classical Cushing-like appearances, including moon face and supraclavicular and back fat pads, and centripetal obesity (body mass index, 25.54 kg/m²) with hypertension (blood pressure, 160/85 mm Hg).

Laboratory studies revealed high urinary free cortisol levels at 962.16 µg/24 hours (reference range, 50–437 µg/24 hours) and absence of circadian cortisol rhythm (F _[0am] 33.14 µg/dL, F _[8am] 33.52 µg/dL, F _[4pm] 33.3 µg/dL). ACTH levels were elevated at 90.8 pg/mL (reference range, <46 pg/mL). The patient low-dose dexamethasone suppression test demonstrated the existence of endogenous hypercortisolism. High-dose dexamethasone suppression test results revealed that serum cortisol levels were suppressed by <50%, suggesting the possibility of ectopic ACTH-dependent CS. Serum luteinizing hormone and serum follicle stimulating hormone were at low levels, <0.07 IU/L (reference range, 15.9–54.0 IU/L) and 2.57 IU/L (reference range, 23.0–116.3 IU/L), respectively. Insulin-like growth factor-1, growth hormone (GH), prolactin (PRL), thyroid stimulating hormone, testosterone, progesterone and estradiol test results are all normal. Oral glucose tolerance test showed fasting glucose of 6.3 mmol/L and 2-hour glucose of 18.72 mmol/L; glycosylated hemoglobin (HbA1c) was 7.1%. Serum potassium fluctuated in the range of 3.14 to 3.38 mmol/L (reference range, 3.5–5.5 mmol/L), indicating mild hypokalemia.

High-resolution computed tomography (CT) scan of the sinuses revealed osteolytic bone destruction of the occipital clivus and a soft tissue mass measuring 20 mm × 30 mm × 46 mm (Fig. 1A). The mass filled the bilateral sphenoid sinuses and involved the cavernous sinuses, but the pituitary was normal. Cranial MR scan showed the T1W1 isointense signal and the T2W1 isointense signal/slightly high signal in the sphenoid sinus and saddle area (Fig. 1B–D). Bone density test indicated osteoporosis.

Subsequently, the patient underwent gross total clivus tumor resection via transsphenoidal endoscopy. During surgery, the tumor was found to be light red in color with a medium texture, and the tumor tissue protruded into the sphenoidal sinus cavity and eroded the clival area. Histologically, the tumor cells were nested, with interstitially rich blood sinuses and organoid arrangement (Fig. 2A). The tumor cells were relatively uniform in size, with light red cytoplasm, delicate pepper salt-like chromatin, and visible nucleoli (Fig. 2B). In addition, mitosis of tumor cells was extremely rare. Immunohistochemically, the neoplasm cells were diffuse positive for CK (Fig. 2C), CgA (Fig. 2D), ACTH (Fig. 2E), Syn and CAM5.2, with low Ki-67 labeling index (<1%) (Fig. 2F). Simultaneously, all other pituitary hormone markers like GH, thyroid stimulating hormone, PRL, luteinizing hormone, as well as follicle stimulating hormone were negatively expressed. On the basis of these medically historical, clinical, laboratorial, morphologic, and immunohistochemical findings, the final pathological diagnosis of an EAPA was established.

When evaluated 2 months after surgery, her Cushing-like characteristics had well improved, and her blood pressure was normal. Furthermore, her serum cortisol and ACTH returned to the normal levels. Six-month postoperative follow-up revealed that serum cortisol and ACTH were stable at normal levels, and no signs of tumor recurrence were detected on imaging.

3. Discussion

EAPA is defined as an ACTH-secreting ectopic adenoma located outside the ventricles, and has no continuity with the normal intrasellar pituitary gland.^[9] ACTH promotes cortisol secretion by stimulating the adrenal cortical fasciculus. The clinical manifestations of hypercortisolism are diverse, and the severity is partly related to the duration of the cortisol increase.^[8] Clival tumors are typically uncommon, accounting for 1% of all intracranial tumors. There are many differential diagnoses for clival lesions, including the most common chordoma (40%), meningioma, chondrosarcoma, astrocytoma, craniopharyngioma, germ cell tumors, non-Hodgkin lymphoma, melanoma, metastatic carcinoma, and rarely pituitary adenoma.^[16] The commonest clival EPA is a PRL adenoma, followed by null cell adenoma, and the least common are ACTH adenoma and GH adenoma.^[2] The clival EAPA is extremely unwonted, and only 6 other cases apart from ours have been reported in literature so far (Table 1).

The average age of the patients with these tumors was 48 years (range, 15–64 years). There was a obvious female predominance with a female-to-male prevalence ratio of 6:1. Only 2 patients (2/6, 33.3%) with reported clinical symptoms, including our patients, presented with overt clinical manifestations of CS. Compression of the mass on adjacent structures (e.g., nerves) may result in anosphrasia, visual impairment, headache, myalgias, decreased muscle strength, dizziness and facial sensory abnormalities. The diagnosis and localization of these tumors relied heavily on radiological imaging. Head MRI was the most basic method used for them detection, for localization adenomas and their invasion of surrounding structures to guide the choice of treatment and surgical options methods. Radiographic characteristics had been reported in 6 patients with EAPA in the clivus region. All of these patients (6/6, 100%) had initial positive findings of sellar MRI (or CT) identifying an ectopic adenoma before surgery. MR T1 was usually a low-intensity or isointense signal, while MR T2 was usually an isointense or slightly higher signal. The maximum diameter of the tumor was reported in 5 cases, with the mean maximum diameter was 35.2 mm (range, 21–55 mm) according to preoperative MRI and intraoperative observations. As summarized in Table 1, 4/5 clival EAPA cases secreted ACTH. Histologically, all cases (6/6, 100%) expressed ACTH scatteredly or diffusely.

The gold standard for the treatment of CS caused by EAPA was the surgical removal of EPA, which was essential to achieve remission and histological confirmation of the disease.^[9] The most common method of EAPA resection in the clivus region was transsphenoidal sinus resection (4/6, 66.67%), followed by craniotomy (1/6, 16.67%) and maxillary osteotomy (1/6, 16.67%). Transsphenoidal endoscopic surgery allowed resection of the EAPA and manipulation of neurovascular structures and avoidance of cerebral atrophy, whereas craniotomy allowed full exposure of the suprasellar region, direct visualization or manipulation of the adenoma, and reduced the risk of postoperative CSF leak.^[9] Both approaches had their advantages, and there was no consensus on which surgical approach was best for the treatment of EAPA in the slope area.^[9] The choice of the best surgical approach was believed to be based on the condition of the adenoma, as well as the general condition of the patient and the experience of the surgeon.^[9] As summarized in Table 1, most complete tumor resections were achieved regardless of the method chosen. A minority of patients underwent postoperative radiotherapy (3/7, 42.86%), and most of them had invasion of the surrounding bone tissue. All patients experienced effective postoperative relief of symptoms.

In summary, due to the rarity of this disorder, an accurate preoperative diagnosis of EAPA in the slope area is extremely challenging for the clinician or radiologist. The final precise diagnosis relies on a combination of clinical symptoms, imaging findings, histology and immunohistochemical markers. For this type of tumor, surgery is an effective treatment to relieve the clinical manifestations caused by tumor compression or hormonal secretion. The choice of postoperative adjuvant radiotherapy is mainly based on the presence of invasion of the surrounding bone tissue. Further cases may be necessary to summarize the clinical features of such lesions and to develop optimal treatment strategies.

Acknowledgments

We would like to thank the patient and her family.

Author contributions

Conceptualization: Yutao He.

Data curation: Ziyi Tang.

Formal analysis: Na Tang.

Methodology: Yu Lu, Fangfang Niu, Jiao Ye, Zheng Zhang, Chenghong Fang.

Writing – original draft: Yutao He.

Writing – review & editing: Yutao He, Lei Yao.

^{Abbreviations:}

ACTH

 

adrenocorticotropin

 

CS

 

cushing syndrome

 

CT

 

computed tomography

 

EAPA

 

ectopic ACTH-producing pituitary adenoma

 

EPA

 

ectopic pituitary adenoma

 

GH

 

growth hormone

 

PRL

 

prolactin

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