Bilateral inferior petrosal sinus sampling

The Neurosurgical Outcome of Pediatric Cushing’s Disease in a Single Center From China: A 20-Year Experience

Posted on September 29, 2025 by MaryO

Objective: Pediatric Cushing’s disease (CD) is exceptionally rare and poses significant diagnostic and therapeutic challenges. This study aimed to review the diagnostic features and to evaluate the long-term surgical outcomes of transsphenoidal surgery (TSS) in Pediatric CD patients at a single tertiary center in China over two decades.

Methods: A retrospective analysis included 22 pediatric CD patients (10 male, 12 female; mean age 15.8 ± 2.5 years) who underwent TSS between 2002 and 2022. Diagnosis was established through a multidisciplinary protocol involving standardized biochemical testing (LDDST, HDDST), bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin stimulation (n=19), and high-resolution pituitary MRI. Microscopic TSS (MTSS) was performed before 2016 (n=11) and endoscopic TSS (ETSS) thereafter (n=11). Surgical strategy was guided by MRI and BIPSS findings. Immediate remission was defined as a postoperative serum cortisol nadir <5 μg/dL or normal 24-h urinary free cortisol (UFC). Recurrence was defined as the reappearance of hypercortisolism after remission. Mean follow-up was 29.4 months (range 2-129).

Results: MRI identified the adenoma in 18/22 patients (81.8%; 16 microadenomas, 2 macroadenomas). BIPSS indicated lateralization in 14/19 patients (73.7%), with concordance between BIPSS and MRI lateralization in 57.9% (11/19) of cases. Immediate postoperative remission was achieved in 20 patients (90.9%). The two non-remitters (one macroadenoma, one MRI- and pathology-negative) received additional therapies. Among the 20 patients with initial remission, 2 (10.0%) developed recurrence (one microadenoma, one MRI-negative) during follow-up. The sustained long-term remission rate was 81.8% (18/22).

Conclusion: Transsphenoidal surgery represents a highly effective first-line treatment for pediatric CD, achieving high rates of immediate (90.9%) and long-term remission (81.8%) in a specialized center. A meticulous diagnostic approach incorporating BIPSS is crucial, particularly for MRI-negative cases. While recurrence occurred in a minority of patients, primarily those with microadenomas, durable disease control is attainable for the majority with appropriate surgical management. The transition to endoscopic techniques was feasible and effective.

Introduction

Cushing’s disease (CD), caused by excessive ACTH secretion from a pituitary corticotroph adenoma, is a rare disorder with an estimated prevalence of approximately 10 cases per 100,000. Its incidence is even lower in children, representing about 5% of adult cases (1). CD accounts for 75-80% of Cushing’s syndrome in pediatric patients (2, 3). Clinical manifestations include weight gain, facial rounding (“moon facies”), hypertension, fatigue, and pubertal arrest. If untreated, pediatric CD can severely impair quality of life and lead to significant morbidity and mortality.

Diagnosis of pediatric CD is frequently delayed due to atypical symptoms and remains significantly challenging for pediatricians and pediatric endocrinologists (4). It relies on standardized biochemical evaluation and neuroimaging. Transsphenoidal pituitary surgery (TSS), encompassing both microscopic and endoscopic approaches, remains the preferred treatment for pediatric CD. However, as the majority of pituitary adenomas in pediatric CD are microadenomas or radiologically occult, TSS poses significant technical challenges for neurosurgeons (5).

Here, we present a review of the diagnostic features and surgical outcomes of 22 pediatric CD patients treated at a single center in China over a 20-year period.

Patients and methods

Between 2002 and 2022, 519 patients underwent TSS for CD performed by a single neurosurgical team in the Department of Neurosurgery, Ruijin Hospital. Twenty-six patients aged 18 years or younger were initially identified as pediatric; four were excluded due to incomplete data or insufficient follow-up. Clinical features of the remaining 22 pediatric patients (10 male, 12 female) were retrospectively reviewed. Mean age at surgery was 15.8 ± 2.5 years (range 9-18), and mean symptom duration prior to diagnosis was 32.0 ± 30.8 months (range 3-108). Mean BMI was 26.4 ± 6.4 (range 18.0-39.7) (Table 1). Presenting symptoms included weight gain (18/22), acne (13/22), hirsutism (12/22), moon facies (18/22), striae (19/22), central obesity (10/22), pubertal delay or arrest (4/22), irregular menses (3/12 females), headaches (3/22), visual deficits (2/22), hypertension (7/22), and type 2 diabetes mellitus (2/22) (Table 2).

Table 1

Table 1. The demographic information of 22 patients at diagnosis of CD.

Table 2

Table 2. Clinical signs and symptoms of 22 patients at diagnosis of CD.

Diagnosis of CD was confirmed by a multidisciplinary team comprising radiologists, endocrinologists, interventional radiologists, pediatricians, and neurosurgeons. Clinical manifestations, plasma cortisol circadian rhythm, low-dose dexamethasone suppression test (LDDST, 2 mg dexamethasone), and high-dose dexamethasone suppression test (HDDST, 8 mg dexamethasone) were assessed by pediatricians or endocrinologists. Following the 2mg LDDST, the 48-hour serum cortisol level exceeded 1.8 μg/dL, indicating inadequate suppression. In contrast, after the 8mg HDDST, the 48-hour cortisol level was suppressed to <50% of baseline, demonstrating significant suppression. Bilateral inferior petrosal sinus sampling (BIPSS) with or without desmopressin (DDAVP) stimulation was performed by experienced interventional radiologists. Samples were immediately placed on ice after collection. All biochemical analyses were conducted in a College of American Pathologists-accredited laboratory (No. 7217913).

Preoperative pituitary magnetic resonance imaging (MRI) was performed at 1.5 T or 3.0 T in all patients. T1-weighted and T2-weighted spin-echo images were obtained in coronal and sagittal planes (2-mm slice thickness) before and after gadolinium injection. A dynamic coronal sequence was also acquired within 2 minutes post-injection (Table 3).

Table 3

Table 3. Preoperative endocrinological evaluation and neuroimaging results of 22 patients at diagnosis of CD.

The same surgical team performed TSS on all patients using a mononostril approach. Microscopic TSS (MTSS) was utilized in 11 patients treated before 2016, while endoscopic TSS (ETSS) was employed in the subsequent 11 patients. For patients with concordant MRI-identified adenomas and BIPSS lateralization, exploration focused on the imaging-identified region, and a rim of pituitary tissue surrounding the tumor cavity was resected. If the tumor involved the cavernous sinus (CS), the inner CS wall was also inspected/explored. If BIPSS lateralization conflicted with MRI findings, the pituitary side indicated by BIPSS was explored first. For MRI-negative tumors, exploration commenced on the side with higher ACTH levels on BIPSS (when available) and proceeded to complete gland inspection. If no adenoma was identified intraoperatively, approximately half of the gland was resected, guided by BIPSS results.

Immediate remission was defined as a postoperative serum cortisol nadir <5 μg/dL or normal 24-hour UFC. Recurrent hypercortisolism was defined as the reappearance of biochemical hypercortisolism after a period of hypocortisolism or clinical adrenal insufficiency. The concordance of BIPSS lateralization with MRI localization refers to whether the tumor side indicated by BIPSS corresponds to the tumor side identified on MRI.

Patients were followed in the outpatient clinic at regular intervals. If endocrine evaluations were performed at local hospitals, results were communicated to the authors via WeChat. Mean follow-up duration was 29.4 months (range 2–129 months).

Results

Preoperative plasma cortisol levels measured at three time points were: mean 28.10 μg/dL at 8:00 AM (range 14.70-125.62 μg/dL), 22.39 μg/dL at 4:00 PM (range 6.4-79.44 μg/dL), and 20.62 μg/dL at midnight (range 11.9-72.25 μg/dL). Mean preoperative plasma ACTH level at 8:00 AM was 95.21 pg/mL (range 12.51-272.6 pg/mL), and mean 24-hour UFC was 979.18 μg/24h (range 119.20-7669.48 μg/24h). HDDST was positive in 19/22 patients. BIPSS with DDAVP was performed in 19 patients, demonstrating lateralization in 14 patients (4/14 left, 10/14 right).

MRI localized an adenoma in 18/22 patients (81.8%), comprising 16 microadenomas and 2 macroadenomas. Tumor location on MRI was: right sellar (n=5), left sellar (n=8), and central sellar (n=5). Concordance between BIPSS lateralization and MRI localization was 57.89% (11/19).

Immediate postoperative remission was achieved in 20 patients (90.9%). The two patients without immediate remission (Case 2: macroadenoma; Case 6: MRI- and pathology-negative) received additional treatments (Case2: gamma knife radiosurgery; Case 6: ketoconazole). Among the 20 patients with initial remission, 2 (10.0%) experienced recurrence (Case 3: microadenoma; Case 10: MRI-negative). Case3 received pasireotide after recurrence; Case 10 underwent repeat TSS, which did not achieve remission. Subsequent gamma knife treatment also ultimately failed. Ketoconazole therapy was then initiated. The sustained long-term remission rate for the cohort was 81.8% (18/22).

In these cases, intraoperative bleeding was controlled in all cases, and no patient required transfusion. Case 10 experienced a CSF leak following repeat transsphenoidal surgery (TSS). All patients who achieved postoperative remission were administered cortisone replacement therapy. The requirement for levothyroxine replacement differed between groups: one child in the ETSS group (1/11) versus five patients in the MTSS group (5/11). For diabetes insipidus, oral desmopressin was administered to three patients in the ETSS group and two in the MTSS group (Table 4).

Table 4

Table 4. The neurosurgical outcome and follow-up results of 22 patients of CD.

Discussion

This 20-year single-center experience represents one of the largest reported cohorts of surgically managed pediatric Cushing’s disease patients. Our findings demonstrate that transsphenoidal surgery (TSS), whether microscopic (MTSS) or endoscopic (ETSS), is a highly effective first-line treatment for pediatric CD, achieving an immediate remission rate of 90.9% and a sustained long-term remission rate of 81.8%.

The diagnostic complexity of pediatric CD is highlighted by the significant diagnostic delay observed (mean 32.0 months) and the occurrence of MRI-negative cases (4/22, 18.2%). This aligns with established literature emphasizing the challenges of pediatric CD diagnosis stemming from its rarity, atypical presentation, and the high proportion of microadenomas or radiologically occult tumors (3, 4, 6–8). Our adherence to a rigorous multidisciplinary diagnostic protocol, incorporating standardized biochemical testing (LDDST, HDDST), BIPSS with DDAVP stimulation (performed in 19/22), and high-resolution dynamic pituitary MRI, reflects current best practices for confirming ACTH-dependent Cushing’s syndrome and tumor localization. The moderate concordance rate (57.89%) between BIPSS lateralization and MRI localization underscores their complementary roles, particularly in cases with equivocal imaging. BIPSS remains critical for guiding surgical exploration in MRI-negative or discordant cases, as evidenced by its use in our decision-making algorithm (9, 10).

Our immediate remission rate (90.9%) compares favorably with contemporary pediatric CD surgical series, which typically report rates between 70% and 98% (1–3, 8, 11–13). The two immediate surgical failures occurred in patients with a macroadenoma (Case 2) or an MRI- and pathology-negative diagnosis (Case 6), profiles consistently associated with lower remission rates. The long-term remission rate of 81.8% (18/22) is robust, although the recurrence rate of 10% (2/20 initially remitted patients) merits attention. Both recurrences arose in patients with microadenomas, one of whom was MRI-negative (Case 10). This recurrence rate falls within the reported range (5-30%) for pediatric CD and reinforces the need for lifelong endocrine surveillance (1, 14, 15). The relatively short mean follow-up (29.4 months) suggests that the true recurrence rate might be higher with extended observation, representing a limitation of this study.

Our experience reflects the evolution of surgical technique, with a transition from MTSS to ETSS after 2016. While the cohort size and follow-up duration preclude definitive conclusions regarding the comparative efficacy of MTSS versus ETSS in this specific pediatric population, both techniques yielded high success rates. In our group, no significant differences exist in remission or recurrence rates. However, regarding complications, ETSS demonstrates a lower incidence of hypopituitarism compared to MTSS, while the incidence of diabetes insipidus is similar. It should be noted, however, that this comparison remains limited by the small number of reported cases. The endoscopic approach offers theoretical advantages, such as wider panoramic visualization potentially aiding in the identification of small or laterally extending microadenomas, which are common in children. Larger, prospective studies with longer follow-up are warranted to directly compare outcomes between these surgical modalities in pediatric CD.

The spectrum of clinical manifestations observed (e.g., weight gain, moon facies, striae, hypertension, pubertal arrest/delay) demonstrates the profound multisystem impact of hypercortisolism in children. The notable prevalence of metabolic complications like hypertension (7/22) and type 2 diabetes mellitus (2/22), even in this young cohort, highlights the urgency of timely diagnosis and effective intervention to mitigate long-term morbidity (5, 16–18).

Limitations

This study shares the limitations inherent to retrospective, single-center designs. The modest sample size, though substantial for this rare condition, limits statistical power for subgroup analyses, such as rigorous comparison of MTSS vs. ETSS outcomes or identification of specific predictors of failure/recurrence. The mean follow-up period is relatively short for a disease with potential for late recurrence, long-term remission rates may be lower than reported, and the study could not capture long-term complications of TSS, particularly those affecting growth and development in pediatric patients. Detailed data on specific postoperative complications (e.g., diabetes insipidus, hypopituitarism) and pituitary function during follow-up would provide a more comprehensive assessment of treatment sequelae but were not the primary focus of this outcome report.

Conclusion

Despite the inherent diagnostic and therapeutic challenges of pediatric Cushing’s disease, transsphenoidal surgery performed in a specialized center achieves high rates of immediate and sustained remission. Our results support the efficacy of TSS as the primary treatment modality. A meticulous multidisciplinary diagnostic approach, including BIPSS when indicated, is crucial for success, particularly in MRI-negative cases. While recurrence remains a concern necessitating vigilant long-term follow-up, the majority of children with CD can attain durable disease control with appropriate surgical management. The transition to endoscopic techniques proved safe and effective, warranting further investigation in larger pediatric cohorts with extended follow-up.

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 authors.

Ethics statement

The studies involving humans were approved by The ethics committee of Ruijin hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. 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

BW: Methodology, Writing – original draft. HZ: Conceptualization, Data curation, Formal Analysis, Writing – original draft. TS: Methodology, Project administration, Writing – review & editing. JR: Data curation, Formal Analysis, Writing – original draft. QS: Resources, Supervision, Writing – review & editing. YS: Supervision, Writing – review & editing. LB: Supervision, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

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.

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Keywords: Cushing’s disease, pediatric, transsphenoidal surgery, surgical outcome, surgical strategy

Citation: Wang B, Zhang H, Su T, Ren J, Sun Q, Sun Y and Bian L (2025) The neurosurgical outcome of pediatric Cushing’s disease in a single center from China: a 20-year experience. Front. Endocrinol. 16:1663624. doi: 10.3389/fendo.2025.1663624

Received: 10 July 2025; Accepted: 22 August 2025;
Published: 03 September 2025.

Edited by:

Sadishkumar Kamalanathan, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), India

Reviewed by:

Aleksandra Zdrojowy-Wełna, Wroclaw Medical University, Poland
Medha Bhardwaj, Mahatma Gandhi University of Medical Sciences Technology, India

Copyright © 2025 Wang, Zhang, Su, Ren, Sun, Sun and Bian. 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: Yuhao Sun, syh11897@rjh.com.cn; Liuguan Bian, Blg11118@rjh.com.cn

^†These authors have contributed equally to this work

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.

Filed under: Cushing's, pituitary, Treatments | Tagged: Bilateral inferior petrosal sinus sampling, BIPSS, pediatric, pituitary, remission, transphenoidal hyposection | Leave a comment »

Improved Noninvasive Diagnostic Evaluations in Treatment-Naïve Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s Syndrome

Posted on July 24, 2025 by MaryO

Abstract

Background

Bilateral inferior petrosal sinus sampling (BIPSS) is important in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, but BIPSS is invasive and is not reliable on tumor lateralization. Thus, we evaluated the noninvasive diagnostic evaluations, high-dose dexamethasone suppression test (HDDST) combined with different pituitary MRI scans (conventional contrast-enhanced MRI [cMRI], dynamic contrast-enhanced MRI [dMRI], and high-resolution contrast-enhanced MRI [hrMRI]), by comparison with BIPSS.

Methods

We retrospectively analyzed 95 patients with ACTH-dependent Cushing’s syndrome who underwent HDDST, preoperative MRI scans (cMRI, dMRI and hrMRI) and BIPSS in our hospital between January 2016 and December 2021. The diagnostic performance of HDDST combined with cMRI (HDDST + cMRI), HDDST + dMRI and HDDST + hrMRI, and BIPSS was evaluated, including the sensitivity of identifying pituitary adenomas and the tumor lateralization accuracy.

Results

Compared with BIPSS (AUC, 0.98; 95%CI: 0.93, 1.00), the diagnostic performance of HDDST + hrMRI was comparable in both neuroradiologist 1 (AUC, 0.95; 95%CI: 0.89, 0.99; P = 0.129) and neuroradiologist 2 (AUC, 0.98; 95%CI: 0.92, 1.00; P = 0.707). For tumor lateralization accuracy, HDDST + hrMRI (90.6-95.3%) were significantly higher than that of BIPSS (24.7%, P < 0.001).

Conclusions

In patients with ACTH-dependent Cushing’s syndrome, HDDST + hrMRI, as noninvasive diagnostic evaluations, achieves high diagnostic performance comparable with gold standard (BIPSS), and it is superior to BIPSS in terms of tumor lateralization accuracy.

Peer Review reports

Background

Cushing’s syndrome is associated with debilitating morbidity and increased mortality [1]. Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is characterized by ACTH hypersecretion. Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as the gold standard to distinguish pituitary ACTH secretion (also known as Cushing’s disease) from ectopic ACTH syndrome (EAS) [1, 2]. However, BIPSS is invasive and is not reliable on tumor lateralization [3, 4]. Thus, it is important to improve the diagnostic performance of noninvasive evaluations with high sensitivity and tumor lateralization accuracy.

Current noninvasive evaluations in the differential diagnosis of ACTH-dependent Cushing’s syndrome include high-dose dexamethasone suppression test (HDDST), the CRH stimulation test and pituitary MRI. However, due to the non-availability of CRH for testing, the sensitivities of current available noninvasive evaluations in identifying ACTH-secreting pituitary adenomas cannot satisfy the clinical needs. Conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI) with two-dimensional (2D) fast spin echo (FSE) sequence is routinely used, and only 50–66% of the ACTH-secreting pituitary adenomas can be correctly detected [5, 6]. Recently, by using 3D spoiled gradient recalled (SPGR) sequence, high-resolution contrast-enhanced MRI (hrMRI) has increased the sensitivity to up to 80% [7,8,9]. However, these noninvasive evaluations are still inferior to BIPSS, the sensitivity and specificity of which is about 90–95% [10,11,12,13]. With the development of 3D FSE sequence, superior image quality with diminished artifact has been achieved, providing a reliable alternative to detect pituitary adenomas [14]. Previous studies have shown that hrMRI using 3D FSE sequence has high diagnostic performance for identifying pituitary adenomas [15, 16]. To our knowledge, no study has investigated the diagnostic performance of HDDST combined with hrMRI using 3D FSE sequence (HDDST + hrMRI) in patients with Cushing’s syndrome, and whether it can avoid unnecessary BIPSS procedure.

The aim of this study is to evaluate the diagnostic performance of HDDST + hrMRI by comparison with BIPSS in patients with ACTH-dependent Cushing’s syndrome.

Methods

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Peking Union Medical College Hospital. Informed consent was waived in this study because it was a retrospective, non-interventional, and observational study. Clinical trial number is not applicable.

Study design and patient population

We retrospectively reviewed the medical records and imaging studies from January 2016 to December 2021, and 232 consecutive patients with ACTH-dependent Cushing’s syndrome, who underwent HDDST, cMRI, dMRI, hrMRI and BIPSS, were enrolled in the current study. A total of 137 patients were excluded from the study because of prior pituitary surgery (n = 122) or lack of histopathology due to no pituitary surgery in our hospital (n = 15). Finally, 95 patients were included in the current study (Fig. 1) and all the patients included were confirmed by histopathology or by clinical remission after surgical resection of the ACTH-secreting lesion. In the current study, all the patients with Cushing’s disease achieved clinical remission after surgical resection of the ACTH-secreting lesion. All the patients with EAS underwent contrast-enhanced thoracic and abdominal CT to identify the ACTH-secreting lesion. The clinical decision-making process was consistent with the previous study [1].

HDDST

As previously described [17], the average 24-hour urinary free cortisol (24hUFC) level of 2 days before HDDST was recorded as baseline. Then, 2 mg dexamethasone was administered orally every 6 h for 2 days, and the 24hUFC level of the second day was measured. When the ratio of 24hUFC on the second day after HDDST to 24hUFC at baseline was less than 50%, the suppression in HDDST was marked as positive in the current study.

BIPSS

BIPSS was performed according to Doppman et al. [18]. Blood samples were collected from peripheral veins and bilateral inferior petrosal sinuses (IPSs) at multiple time points (0, 3, 5 and 10 min) after the introduction of 10 µg desmopressin [19]. An IPS to peripheral ACTH ratio of ≥ 2.0 at baseline or ≥ 3.0 after desmopressin stimulation at any time point [20] was marked as positive in the current study. Furthermore, tumor lateralization was predicted by an intersinus ratio of ≥ 1.4 [20].

Imaging

All the images were acquired on a 3.0 Tesla MR scanner (Discovery MR750w, GE Healthcare) using an 8-channel head coil. Detailed acquisition parameters and sequence order before and after contrast injection (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) were as follows: coronal 2D FSE T2WI (field of view [FOV] = 20 cm × 20 cm, slice thickness = 4 mm, slice spacing = 1 mm, repetition time/echo time [TR/TE] = 4100/90 ms, number of excitation [NEX] = 1.2, matrix = 320 × 320, scan time = 49s), coronal 2D FSE T1WI (FOV = 18 cm × 16.2 cm, slice thickness = 3 mm, slice spacing = 0.6 mm, TR/TE = 400/12 ms, NEX = 2, matrix = 256 × 192, scan time = 49s), sagittal fat-saturated 3D FSE T1WI (FOV = 16.5 cm × 16.5 cm, slice thickness = 3 mm, slice spacing = 0, TR/TE = 460/16 ms, NEX = 2, matrix = 256 × 224, scan time = 60s), dynamic contrast-enhanced coronal 2D FSE T1WI (FOV = 19 cm × 17.1 cm, slice thickness = 2 mm, slice spacing = 0.5 mm, TR/TE = 375/14 ms, NEX = 1, matrix = 288 × 192, scan time = 23s/phase × 6 phases), contrast-enhanced coronal 2D FSE T1WI, contrast-enhanced sagittal fat-saturated 3D FSE T1WI, and contrast-enhanced coronal fat-saturated 3D FSE T1WI (FOV = 15.2 cm × 15.2 cm, slice thickness = 1.2 mm, slice spacing = -0.6 mm, TR/TE = 390/15 ms, NEX = 6, matrix = 256 × 256, scan time = 4 min 30s).

Images were independently evaluated by two experienced neuroradiologists (with 25 and 16 years of experience in neuroradiology, respectively). Both neuroradiologists were blinded to the clinical information of the patients. The image order of cMRI, dMRI and hrMRI was randomized. The detection of pituitary adenomas was scored using a 3-point scale (0 = poor, 1 = fair, 2 = excellent). Scores of 1 or 2 represented a successful pituitary adenoma detection. The gold standard was the histopathology, and the diameter and the location of lesions were recorded on the sequence where identified.

The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated as follows: SNR = SIadenoma / SDbackground, CNR = |SIpituitary – SIadenoma| / SDbackground. SIpituitary and SIadenoma were defined as the mean signal intensity of the pituitary gland and the pituitary adenoma, respectively. SDbackground was defined as the standard deviation of the signal intensity of the background. CNR was recorded as 0 when no pituitary adenoma was identified. Figure 2 showed the calculation of SNR and CNR using an operator defined region of interest.

Fig. 2

The calculation of SNR and CNR using an operator defined region of interest. CNR = contrast-to-noise ratio, SD = standard deviation, SI = signal intensity, SNR = signal-to-noise ratio

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Statistical analysis

The κ analysis was conducted to assess the interobserver agreements. 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 different evaluations, the receiver operating characteristic curves were plotted and the area under curves (AUCs) were compared between noninvasive and invasive evaluations for each neuroradiologist by using the DeLong test. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The Friedman’s test was used to evaluate the SNR and CNR measurements as well as conspicuity scores of pituitary adenomas between MR protocols, and the Wilcoxon signed-rank test was used for pairwise comparison. The McNemar’s test was used to evaluate the tumor lateralization accuracy. A P value of less than 0.05 was considered statistically significant. A stricter P value of less than 0.017 was considered statistically significant after Bonferroni correction. Statistical analysis was performed using MedCalc Statistical Software (version 23.0.2) and SPSS Statistics (version 22.0).

Results

Clinical characteristics

The clinical characteristics of the 95 patients with Cushing’s syndrome were shown in Table 1. There were 85 patients (median age, 38 years; interquartile range [IQR], 29–51 years; 55 females [65%]) with Cushing’s disease and 10 patients (median age, 39 years; IQR, 30–47 years; 5 females [50%]) with EAS. Of the 85 patients with Cushing’s disease, the median diameter of pituitary adenomas was 5 mm (IQR, 4–5 mm), ranging from 3 to 28 mm. Among them, 80 patients had microadenomas (less than 10 mm in size). Of the ten patients with EAS, one patient had an ovarian carcinoid tumor found by abdominal CT, others had pulmonary carcinoid tumors found by thoracic CT as the cause of Cushing’s syndrome. None of the patients with EAS had a lesion in the pituitary.

Table 1 Clinical characteristics of the patients

Full size table

Diagnostic performance noninvasive and invasive evaluations

The inter-observer agreements between two neuroradiologists were moderate on cMRI (κ = 0.597), moderate on dMRI (κ = 0.595), and almost perfect on hrMRI (κ = 0.850), respectively.

The diagnostic performance of noninvasive and invasive evaluations was shown in Table 2. Compared with BIPSS (AUC, 0.98; 95%CI: 0.93, 1.00), the diagnostic performance of HDDST + hrMRI was comparable in both neuroradiologist 1 (AUC, 0.95; 95%CI: 0.89, 0.99; P = 0.129) and neuroradiologist 2 (AUC, 0.98; 95%CI: 0.92, 1.00; P = 0.707). However, the diagnostic performance of HDDST + cMRI and HDDST + dMRI was inferior to BIPSS (P ≤ 0.001 for all). No difference was found between HDDST + cMRI and HDDST + dMRI in neuroradiologist 1 (P = 0.050) and neuroradiologist 2 (P = 0.353).

Table 2 The diagnostic performance of noninvasive and invasive evaluations

Full size table

Figures 3 and 4 showed that microadenomas were correctly diagnosed on hrMRI, but missed on cMRI or dMRI.

Fig. 3

Images in a patient 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 measuring approximately 4 mm with delayed enhancement on the left side of the pituitary gland

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Fig. 4

Images in a patient 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 measuring approximately 5 mm with delayed enhancement on the left side of the pituitary gland

Full size image

Further, subgroup analysis was conducted in 85 patients with Cushing’s disease. The conspicuity scores of pituitary adenomas on cMRI, dMRI and hrMRI were shown in Table 3. Significant differences between three MR protocols were found in neuroradiologist 1 and neuroradiologist 2 (P < 0.001 for both). Pairwise comparison showed no difference between cMRI and dMRI in neuroradiologist 1 (P = 0.732) and neuroradiologist 2 (P = 0.130). However, hrMRI had significantly higher scores than cMRI and dMRI in neuroradiologist 1 and neuroradiologist 2 (P < 0.001 for all). The SNR on cMRI, dMRI and hrMRI were 64.8 (IQR, 50.8–97.0), 42.4 (IQR, 30.2–57.0) and 65.1 (IQR, 51.9–92.4), respectively. The SNR on cMRI and hrMRI were similar (P = 0.759), but they were higher than that of dMRI (P < 0.001 for both). The CNR on cMRI, dMRI and hrMRI were27.0 (IQR, 17.8–43.8), 26.4 (IQR, 17.7–37.5), and 29.7 (IQR, 21.1–45.1), respectively. The CNR were comparable (P = 0.159).

Table 3 Conspicuity scores of pituitary adenomas on MRI

Full size table

The comparison of tumor lateralization accuracy was shown in Table 4. Because HDDST has no role to identify the tumor lateralization, the tumor lateralization of noninvasive evaluations was only based on MRI. The sensitivity of BIPSS was 96.5% (82/85), comparable to those of hrMRI in neuroradiologist 1 (90.6%, P = 0.227) and neuroradiologist 2 (95.3%, P > 0.99). However, for tumor lateralization accuracy, 36 patients had BIPSS lateralization predicted by an intersinus ratio of ≥ 1.4 [20], and 21 patients had BIPSS lateralization that were concordant in laterality with surgery. The tumor lateralization accuracy was 58.3% (21/36).

Table 4 Tumor lateralization accuracy comparison

Full size table

In the whole population, the tumor lateralization accuracy of BIPSS in total was 24.7% (21/85), which is significantly lower than those of hrMRI in neuroradiologist 1 (90.6%, P < 0.001) and neuroradiologist 2 (95.3%, P < 0.001).

Discussion

In patients with ACTH-dependent Cushing’s syndrome, it is crucial but challenging to distinguish pituitary secretion from ectopic ACTH secretion. In the current study, the diagnostic performance of noninvasive evaluations, HDDST + hrMRI, is comparable to BIPSS. Moreover, it is superior to BIPSS in terms of tumor lateralization.

No consensus agreement has been made that whether BIPSS should be performed in all the patients with suspected Cushing’s disease, although BIPSS is the gold standard with high sensitivity and specificity, which is about 90–95% [10,11,12,13]. On the one hand, about 10–40% of the population harbor nonfunctioning pituitary adenomas [13, 21], which may lead to false-positive results without centralizing BIPSS results. On the other hand, BIPSS is invasive and is not reliable on tumor lateralization. BIPSS will be bypassed when the tumor is greater than 6 mm in pituitary MRI and the patient has a classical presentation and dynamic biochemical results consistent with Cushing’s disease [13].

Noninvasive evaluations have comparable sensitivity to BIPSS for identifying pituitary adenomas in patients with Cushing’s disease. With the development of MRI technology, 3D FSE sequence provides a reliable alternative to detect pituitary adenomas [14]. The 3D FSE sequence overcomes the disadvantages of 3D SPGR sequence, such as bright blood and magnetic susceptibility [22, 23]. By using black blood in 3D FSE sequence, an obvious contrast between the pituitary and the cavernous sinus can be observed. By using fat saturation after enhancement, the hyperintensity of adjacent fat-containing tissue can be suppressed. All these mentioned above can facilitating the identification of pituitary adenomas. The sensitivity of hrMRI using 3D FSE sequence ranges from 87.7 to 93.8%, depending on radiologists with different experience levels [16]. Compared with traditional 2D FSE sequence acquiring images with 2- to 3-mm slice thickness, hrMRI using 3D FSE sequence acquiring images with 1.2-mm slice thickness can dramatically reduce the partial volume averaging effect, improving the identification of the microadenomas [15]. The trade-off between spatial resolution and image noise is challenging in pituitary MRI [24]. Previous studies have proved that hrMRI has high signal-to-noise ratio and contrast-to-noise ratio [15, 16], and sufficient contrast between pituitary adenomas and the pituitary gland could help to improve the identification of pituitary adenomas. In the current study, the conspicuity scores of hrMRI are significantly higher than those of cMRI and dMRI, supporting that hrMRI is reliable on identifying pituitary lesions. Besides, the diagnosis of Cushing’s disease cannot be made depending on the results of hrMRI alone. Given that there is a population with accidental adenomas when imaging, most of which are nonfunctioning pituitary adenomas, the results of HDDST will help rule out. In the current study, all the patients who underwent surgery had positive histopathology results, which means that no pituitary incidentalomas were found in this population. This might be caused by the relatively small sample size. Eighty patients with Cushing’s disease have microadenomas, and the median diameter at surgery is about 5 mm, consistent with previous studies [25, 26]. All these mentioned above makes it more difficult to identify the lesions in the current study. However, the sensitivity of HDDST + hrMRI in the current study is up to 95.3%, comparable to the gold standard.

Noninvasive evaluations have significantly higher tumor lateralization accuracy than BIPSS. According to the guideline, surgery is the first-line treatment [3]. Precise location of the pituitary adenoma before surgery can dramatically improve the postoperative remission rate [27]. However, the tumor lateralization accuracy of BIPSS, less than 80% in previous studies [19, 28, 29], cannot satisfy the clinical need. According to previous studies, the cut-off value for tumor lateralization was set as an intersinus ratio of ≥ 1.4 [20], and the accuracy of lateralization by BIPSS ranged from 48.0 to 78.7% [19, 28, 29]. In the current study, 36 patients had BIPSS lateralization and 21 patients had BIPSS lateralization that were concordant in laterality with surgery. The tumor lateralization accuracy was 58.3%, consistent with previous studies [19, 28, 29]. However, the aim of our study is to evaluate the diagnostic performance of BIPSS in all the patients underwent BIPSS, therefore, the tumor lateralization accuracy of BIPSS in total was only 24.7% (21/85). In our study, many patients have positive BIPSS results with an intersinus ratio of < 1.4, resulting in the low tumor lateralization accuracy of BIPSS. One possible reason might be that desmopressin is not so effective. Another possible reason for low tumor lateralization accuracy of BIPSS is that IPSs have considerable anatomy variations. A previous study suggests that BIPSS results are much improved when venous drainage is symmetric [30]. Patients with asymmetric IPSs have dominant venous drainage, and when the dominant side of venous drainage is discordant with the side of the lesion, BIPSS will fail in tumor lateralization [30]. Failure in tumor lateralization will result in multiple incisions into the pituitary in search of adenoma or hemi- or subtotal hypophysectomy, increasing the risk of complications and reducing the remission rate [31]. In total, only 24.7% of the patients have a BIPSS lateralization that were concordant in laterality with surgery, whereas the tumor lateralization accuracy of HDDST + hrMRI is superior to BIPSS with statistical significance.

Limitations of the study included its retrospective nature. The bias may be introduced during the patient inclusion/exclusion process. Patients lack of any of preoperative MRI scans, HDDST, or BIPSS have not been included in the current study. Some patients will bypass hrMRI as well as BIPSS when they have obvious pituitary adenomas on cMRI and dMRI. The diagnostic performance of these evaluations might be better with the inclusion of these patients. Second, the sample size in our current study is relatively small. Because this is a single institutional study and Cushing’s syndrome is a rare disease. The relatively small sample size may limit the conclusions regarding the diagnostic performance of hrMRI for differentiating ectopic from pituitary sources of ACTH. A larger population from multicenter is needed for future study. Besides, a large portion of patients with prior pituitary surgery have been excluded. The imaging findings of these patients are more complicated and hrMRI may show more advantages than routine sequences in this population.

Conclusions

In conclusion, as noninvasive diagnostic evaluations, HDDST + hrMRI achieves high diagnostic performance comparable with gold standard (BIPSS), and it is superior to BIPSS in terms of tumor lateralization accuracy in patients with ACTH-dependent Cushing’s syndrome.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

24hUFC:: 24-hour urinary free cortisol
2D:: Two-dimensional
3D:: Three-dimensional
ACTH:: Adrenocorticotropic hormone
AUC:: Area under curve
BIPSS:: Bilateral inferior petrosal sinus sampling
cMRI:: Contrast-enhanced MRI
CNR:: Contrast-to-noise ratio
dMRI:: Dynamic contrast-enhanced MRI
EAS:: Ectopic adrenocorticotropic hormone syndrome
FSE:: Fast spin echo
HDDST:: High-dose dexamethasone suppression test
hrMRI:: High-resolution contrast-enhanced MRI
IPS:: Inferior petrosal sinus
IQR:: Interquartile range
SNR:: Signal-to-noise ratio
SPGR:: Spoiled gradient recalled

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Acknowledgements

We thank Dr. Kai Sun, Medical Research Center, Peking Union Medical College Hospital, for his guidance on the statistical analysis in this study. We thank all the patients who participated in this study.

Funding

This study was supported by the National Natural Science Foundation of China (grants 82371946 and 82071899), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2021-I2M-1-025), and the National High Level Hospital Clinical Research Funding (grants 2022-PUMCH-B-067 and 2022-PUMCH-B-114). The funding played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Authors and Affiliations

Department of Radiology, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China
Zeyu Liu, Bo Hou, Hui You, Mingli Li & Feng Feng
Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China
Lin Lu, Lian Duan & Huijuan Zhu
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China
Kan Deng & Yong Yao
State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China
Yong Yao, Huijuan Zhu & Feng Feng

Contributions

All authors have participated sufficiently in this submission to take public responsibility for its content. H.Y. and F.F. proposed research ideas, revised the paper, and reviewed it academically. B.H. and Z.L. were responsible for literature review, data analysis and writing the manuscript. M.L. revised the paper. L.L., L.D. and H.Z. collected the clinical data. K.D. and Y.Y. collected the surgical and histopathology data. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Hui You or Feng Feng.

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Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Peking Union Medical College Hospital. Informed consent was waived by Institutional Review Board of Peking Union Medical College Hospital, because it was a retrospective, non-interventional, and observational study.

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Liu, Z., Hou, B., You, H. et al. Improved noninvasive diagnostic evaluations in treatment-naïve adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome. BMC Med Imaging 25, 252 (2025). https://doi.org/10.1186/s12880-025-01786-y

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Received25 January 2025
Accepted16 June 2025
Published01 July 2025
DOI https://doi.org/10.1186/s12880-025-01786-y

https://bmcmedimaging.biomedcentral.com/articles/10.1186/s12880-025-01786-y

Filed under: Cushing's, Diagnostic Testing | Tagged: ACTH, Bilateral inferior petrosal sinus sampling, BIPSS, dexamethasone suppression test, MRI, pituitary | Leave a comment »

Interpetrosal Sphingosine-1-Phosphate Ratio Predicting Cushing’s Disease Tumor Laterality and Remission After Surgery

Posted on November 20, 2023 by MaryO

Background: Cushing’s disease (CD) poses significant challenges in its treatment due to the lack of reliable biomarkers for predicting tumor localization or postoperative clinical outcomes. Sphingosine-1-phosphate (S1P) has been shown to increase cortisol biosynthesis and is regulated by adrenocorticotropic hormone (ACTH).

Methods: We employed bilateral inferior petrosal sinus sampling (BIPSS), which is considered the gold standard for diagnosing pituitary sources of CD, to obtain blood samples and explore the clinical predictive value of the S1P concentration ratio in determining tumor laterality and postoperative remission. We evaluated 50 samples from 25 patients who underwent BIPSS to measure S1P levels in the inferior petrosal sinuses bilaterally.

Results: Serum S1P levels in patients with CD were significantly higher on the adenoma side of the inferior petrosal sinus than on the nonadenoma side (397.7 ± 15.4 vs. 261.9 ± 14.88; P < 0.05). The accuracy of diagnosing tumor laterality with the interpetrosal S1P and ACTH ratios and the combination of the two was 64%, 56% and 73%, respectively. The receiver operating characteristic curve analysis revealed that the combination of interpetrosal S1P and ACTH ratios, as a predictor of tumor laterality, exhibited a sensitivity of 81.82% and a specificity of 75%, with an area under the curve value of 84.09%. Moreover, we observed that a high interpetrosal S1P ratio was associated with nonremission after surgery. Correlation analyses demonstrated that the interpetrosal S1P ratio was associated with preoperative follicle-stimulating hormone (FSH), luteinizing hormone (LH), and postoperative ACTH 8 am levels (P < 0.05).

Conclusion: Our study demonstrated a significant association between the interpetrosal S1P ratio and tumor laterality, as well as postoperative remission in CD, suggesting that the interpetrosal S1P ratio could serve as a valuable biomarker in clinical practice.

1 Introduction

Cushing’s disease (CD), also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, arises from the pituitary corticotroph cells and induces endogenous hypercortisolism by stimulating the adrenal glands to produce excessive amount of cortisol (1). Patients with CD typically exhibit symptoms of hypercortisolism, such as hypertension, diabetes, purplish skin striae, mental disturbances, hyposexuality, hirsutism, menstrual disorders, acne, fatigue, obesity, and osteoporosis (1). The overall mortality of patients with CD is twice that of the general population, and if left untreated, hypercortisolism resulting from CD increases this rate to approximately four times the expected value (2–4). Transsphenoidal surgery continues to be the primary treatment for CD (5). However, previous studies reported variable remission rates, ranging from 45% to 95% (6–8). Long-term follow-up data have revealed recurrence in 3–66% of patients who had initially achieved complete remission (9, 10). The rate of surgical remission in CD can be influenced by various factors, including the size and location of the tumor, expertise of the neurosurgeon, and criteria used for assessing remission (11). Preoperative clinical variables, such as age, gender, disease duration, and severity of clinical signs and symptoms, cannot reliably identify patients at a higher risk of nonremission (12, 13). Therefore, predicting postsurgical remission in CD remains a challenging goal.

Accumulating evidence has shown that sphingosine-1-phosphate (S1P), an intracellular pleiotropic bioactive sphingolipid metabolite synthesized by sphingosine kinase 1 (SPHK1), plays a pivotal role in diverse endocrine disorders (14–16). Overexpression of SPHK1 promotes the progression of multiple neuroendocrine tumors (17, 18). ACTH can rapidly activate sphingolipid metabolism, causing an increase in S1P secretion in the adrenal cortex (19). Furthermore, the activation of S1P signaling in H295R cells, a human adrenocortical tumor cell line, has been suggested to induce increased transcription of hormone-sensitive lipase and steroidogenic acute regulatory protein, ultimately elevating cortisol production (20). Recently, surgical removal of ACTH-secreting adenoma has been reported to cause a decline in sphingomyelin levels (21). However, whether they have a similar role in the pituitary gland remains to be investigated.

Bilateral inferior petrosal sinus sampling (BIPSS) is a highly effective procedure for diagnosing pituitary sources of ACTH in CD (22, 23). Contemporaneous differences in ACTH concentration during venous sampling between the two sides of the adenoma can predict the location of the adenoma within the pituitary (on the side of the gland with a microadenoma) and may guide surgical treatment in cases with inconclusive magnetic resonance imaging findings. Previous studies demonstrated that an ACTH gradient of ≥1.4 between the inferior petrosal sinuses can indicate microadenoma lateralization in patients with CD (24–26). However, the correct lateralization only occurs in 57–68% of all cases (27–29).

Therefore, we analyzed the clinical behavior of a well-characterized cohort of patients with CD who underwent BIPSS before surgery. We measured the difference in the concentration of S1P in bilateral petrosal sinus blood samples and explored the clinical predictive value of the S1P concentration ratio in determining tumor laterality and postoperative remission.

2 Materials and methods

2.1 Patients and study design

This study was conducted at a tertiary center, involving a cohort of 25 patients diagnosed with CD who had undergone BIPSS and surgery, with a minimum follow-up duration of 2 years. Comprehensive chart reviews were conducted to collect data on demographics, clinical characteristics, pituitary imaging findings, tumor pathology, and biochemical tests.

The criteria used for diagnosing CD encompassed the presence of characteristic signs and symptoms of hypercortisolism, along with biochemical evaluation of two urinary free cortisol measurements exceeding the normal range for the respective assay, serum cortisol level >1.8 μg/dL (50 nmol/L) after an overnight 1-mg dexamethasone suppression test, and two late-night salivary cortisol measurements exceeding the normal range for the respective assay (30). A diagnosis of Cushing’s syndrome was established if the patient had positive test results for at least two of the three aforementioned tests. Adrenal insufficiency was diagnosed if patients exhibited symptoms or signs of adrenal insufficiency or if serum cortisol levels were ≤3 μg/dL, even in the absence of clinical signs or symptoms. Remission was defined as normalization of the levels of 24-h urinary free cortisol, late-night salivary cortisol, and overnight 1-mg dexamethasone suppression test in patients without concurrent central adrenal insufficiency after surgery (31).

2.2 Patients and tissue/serum samples

Surgical specimens of CD-affected tissues were collected from Xiangya Hospital, Central South University. Three normal pituitary tissues were obtained from cadaveric organ donors without any history of endocrine disease (Central South University). A total of 25 CD tissue samples were obtained for immunohistochemistry analysis. This study was conducted in compliance with the Helsinki Declaration and was ethically approved by the Xiangya Hospital Ethics Committee, Xiangya Hospital (Changsha, China). Tumor samples and corresponding clinical materials were obtained with written consent from all patients.

2.3 BIPSS

After obtaining informed consent, BIPSS was performed using standard techniques described in previous studies (32, 33). Briefly, the patient’s head was immobilized to ensure midline positioning and prevent any potential bias towards asymmetric pituitary drainage by the petrosal sinuses. After placing peripheral catheters and cannulating both inferior petrosal sinuses, blood samples were collected at baseline and at 3, 5, 10, and 15 min following intravenous administration of DDAVP, which stimulates pituitary production of ACTH. Additional samples for experimental purposes were collected immediately following the 15-min sample collection to avoid interference with the patient’s diagnostic study.

2.4 Measurement of baseline plasma S1P concentration

Blood samples were obtained from both petrosal sinuses and were centrifuged to remove cellular components. Samples that exhibited hemolysis or coagulation were excluded from the study. Plasma samples were stored at −80°C. The S1P levels in plasma were analyzed using a S1P competitive ELISA kit (Echelon Biosciences, Salt Lake City, UT) according to the manufacturer’s instructions (34).

2.5 Immunofluorescence staining

The pituitary tissues were post-fixed and dehydrated with alcohol as follows: 70% for 24 h, 80% for 3 h, 90% for 4 h, 95% for 3 h, and finally in absolute alcohol for 2 h. Tissue slices with a 5-μm thickness were cut using a microtome (Thermo Fisher Scientific), blocked with 3% BSA, and then treated with primary antibodies to SPHK1 (CST, #3297) and ACTH (Proteintech, CL488-66358). Subsequently, the tissue slides were incubated with Alexa Fluor 488-conjugated anti-rabbit (Invitrogen, A21206, 1:200) or Alexa Fluor 555-conjugated anti-rabbit (Invitrogen, A21428, 1:200) secondary antibodies. Specimens were visualized and imaged using a fluorescence microscope.

2.6 Statistical analysis

The Mann–Whitney U test was used to assess the clinical–molecular associations in adenoma samples, whereas the chi-square test was used to compare categorical data. The Kruskal–Wallis analysis and ANOVA were conducted for multiple comparisons. Statistical analyses were conducted using SPSS v20 and GraphPad Prism version 7. All results were presented in graphs and tables as median ± interquartile range. The distribution of each parameter was presented as the minimum–maximum range. Parametric or nonparametric statistical tests were applied, as appropriate, after testing for normality. The receiver operating characteristic curve was used to determine the cut-off value for predicting tumor laterality. Pearson correlation analyses was used to examine the correlations between variables. Proportions were expressed as percentages, and significance was defined as P < 0.05.

3 Results

3.1 Clinical characteristics of remission and nonremission in patients with CD

This study included 25 patients with CD who underwent BIPSS before surgery (Figure 1). Among them, 12 patients had microadenomas, whereas the remaining 13 had inconclusive magnetic resonance imaging findings; clinicopathological data are summarized in Supplementary Table 1. Table 1 displays the demographics of patients who achieved remission (n = 16) and those who did not (n = 9). No significant differences were observed in terms of sex, age at diagnosis, or radiological variables between patients who achieved and those who did not achieve remission (P > 0.05). Patients who achieved remission exhibited a higher prevalence of emotional lability (P < 0.05). However, no significant differences were observed in other parameters (P > 0.05).

Figure 1

Figure 1 Flowchart of the screening process employed to select eligible participants for the study.

Table 1

Table 1 Baseline clinical features of patients with pituitary tumors secreting adrenocorticotropin.

Several recent studies have established morning cortisol level measured on postoperative day 1 (POD1) as a predictive biomarker for long-term remission of CD (35, 36). For biochemical features, patients who did not achieve remission exhibited higher serum cortisol (19.16 ± 5.55 vs. 5.95 ± 1.42; P = 0.014) and median serum (8 am) ACTH (10.26 ± 8.24 vs. 5.15 ± 3.68; P = 0.042) levels on POD1. No significant differences were observed in the preoperative baseline 4 pm serum cortisol levels, preoperative baseline 0 am serum cortisol levels, preoperative 8 pm ACTH levels, 4 pm ACTH levels, and 0 am ACTH levels (P > 0.05) (Table 2). In addition preoperative FT3, FT4, TSH, GH, FSH, LH, and PRL levels were comparable in patients with and without remission.

Table 2

Table 2 Baseline clinical and biochemical features of patients with pituitary tumors secreting adrenocorticotropin.

3.2 Overexpression of SPHK1 and higher concentrations of serum S1P on the tumor side in patients with CD

Prior studies have demonstrated that ACTH acutely activates SPHK1 to increase S1P concentrations (19). Upregulation of SPHK1 is associated with poor prognosis in endocrine-related cancer (17, 18, 21). To investigate the role of SPHK1 in CD, we performed a heatmap analysis of key genes involved in phospholipid metabolism and signaling pathways in CD adenomas and surrounding normal tissues using the GEO dataset (GEO208107). This analysis revealed the activation of crucial genes involved in phospholipid metabolism and signaling pathways in ACTH-secreting pituitary adenomas (Supplementary Figure 1). Subsequently, we compared the association between pituitary SPHK1 expression and proopiomelanocortin, corticotropin-releasing hormone, corticotropin releasing hormone receptor 1, and corticotropin releasing hormone receptor 2 in pituitary tumor tissues and identified a positive correlation between SPHK1 and ACTH tumor-related genes in the TNM plot database (Supplementary Figure 2). To investigate the potential role of SPHK1 in CD, we compared the expression values of SPHK1 in the normal pituitary tissues and those obtained from patients with CD in the remission/nonremission groups. Immunofluorescence staining (Figures 2A, B; Supplementary Figure 3) revealed an increased number of double-positive cells for SPHK1 and ACTH in CD-affected pituitary tissues than those in the normal pituitary tissues. Furthermore, the proportion of double-positive cells for SPHK1 and ACTH was significantly higher in the nonremission CD adenomas tissues than that in the remission CD adenomas. Furthermore, we investigated the concentration of S1P in bilateral petrosal sinus blood samples and observed that the concentration was significantly higher on the adenoma side than that on the nonadenoma side (397.7 ± 15.4 vs. 261.9 ± 14.88; P < 0.05, Figure 2C). Thus, these findings suggested a close association between S1P concentration and the development of ACTH-secreting tumor.

Figure 2

Figure 2 (A) Representative images of immunofluorescence double staining for SPHK1 (green) and ACTH (pink) in normal pituitary glands and ACTH-secreting pituitary adenomas from the remission and nonremission groups (Normal: n = 3, ACTH pituitary adenoma: remission vs. nonremission: n = 16 vs. 9); scale bars: 100-μm upper and 50-μm lower. (B) Quantitative analysis; white arrows indicate double-positive cells for ACTH and SPHK1. (C) The concentration of S1P in the plasma obtained from the inferior petrosal sinus of the adenoma side and nonadenoma side. ***P < 0.001. Bar represents mean ± SD.

3.3 Combination of interpetrosal S1P and ACTH ratios improved the diagnostic performance for adenoma laterality

The pathology of patients with CD was classified based on adenomatous tissue with ACTH-positive immunostaining into adenoma or nonadenoma sides. To evaluate the correlation between the interpetrosal S1P ratio lateralization and tumor location, we compared the accuracy of predicting tumor laterality using the interpetrosal S1P ratio (>1) and interpetrosal ACTH ratio (>1.4) (the interpetrosal ACTH ratio >1.4 is acknowledged for its positive role in predicting tumor laterality), as well as their combination. Our results indicated that using the interpetrosal S1P or ACTH ratios alone yielded accuracies of 64% and 56% respectively. Notably, the combination of both demonstrated a significantly improved accuracy of 73% (Figure 3A).

Figure 3

Figure 3 (A) Bar graph illustrating the accuracy of predicting tumor laterality. (B) Receiver operating characteristic (ROC) curve analysis of interpetrosal ACTH ratio to predict tumor location. (C) ROC curve analysis of the interpetrosal S1P ratio to predict tumor location. (D) ROC curve analysis of the combination of the interpetrosal S1P and ACTH ratios to predict tumor location.

Thereafter, the receiver operating characteristic analysis was performed to determine the role of predicting tumor laterality. In particular, the interpetrosal ACTH ratio with an AUC of 75.32% (95% CI: 60.06–97.46%, P < 0.05) and the interpetrosal S1P ratio demonstrated a clinically significant diagnostic accuracy for lateralization, with an AUC of 79.17% (95% CI: 44.40–85.84%, P < 0.05). Furthermore, combining the interpetrosal S1P and ACTH ratios generated an receiver operating characteristic curve with an AUC of 84.09% (95% CI: 52.3–96.77%, P < 0.05) for predicting lateralization with tumor location (cutoff value: interpetrosal S1P ratio ≥1.06, interpetrosal ACTH ratio ≥2.8, 81.82% sensitivity, and 75% specificity) (Figures 3B–D).

3.4 Interpetrosal S1P ratio serves as a predictive factor for early remission in CD

To investigate whether the interpetrosal S1P ratio is associated with early postoperative remission in CD, we compared the baseline interpetrosal S1P ratio between patients with CD in the remission and nonremission groups. Interestingly, we observed that the nonremission group exhibited higher interpetrosal S1P ratios than those of the remission group (median, 1.28 ± 0.25 vs. 1.10 ± 0.09, P = 0.012) (Figure 4).

Figure 4

Figure 4 Left picture: Scatter plot of bilateral S1P concentrations in the remission and nonremission groups; the slope represents the interpetrosal S1P ratio, blue dots represent the remission group, and red dots represent the nonremission group. Right picture: The interpetrosal S1P ratio in the remission and nonremission groups. *P < 0.05. Bar represents mean ± SD.

To investigate potential factors affecting the interpetrosal S1P ratio, we compared the correlation between interpetrosal S1P ratio and various clinical indicators. This analysis revealed that the interpetrosal S1P ratio positively correlated with preoperative FSH and LH levels, as well as with postoperative 8 am ACTH levels. No significant difference was observed between the interpetrosal S1P ratio and other indicators (Supplementary Figure 4).

4 Discussion

The use of BIPSS involves collection of samples from each inferior petrosal sinus simultaneously, enabling a direct comparison of ACTH concentrations between the left and right petrosal sinuses. BIPSS is used for two purposes: 1) to assist in the differential diagnosis of Cushing’s syndrome; and 2) to determine which side of the pituitary gland contains an adenoma in patients with CD. The interpetrosal ACTH ratio is also useful in determining the location/lateralization of pituitary microadenomas (24, 30, 37), thereby providing guidance to the neurosurgeon during surgery.

To our knowledge, this is the first study to demonstrate that serum S1P levels in patients with CD are significantly higher on the adenoma side of the inferior petrosal sinus than on the nonadenoma side. The interpetrosal S1P ratio exhibited a positive significance in predicting tumor laterality, and the predictive performance was improved when S1P was combined with the interpetrosal ACTH ratio. Notably, the interpetrosal S1P ratio exhibited a positive significance in predicting remission after surgery. Furthermore, the interpetrosal S1P ratio demonstrated a positive and significant correlation with preoperative FSH and LH levels, as well as 8 am ACTH levels on POD1.

ACTH is recognized for its role in controlling the expression of genes involved in steroid production and cortisol synthesis in the human adrenal cortex through sphingolipid metabolism (19). Specifically, ACTH rapidly stimulates SPHK1 activity, leading to an increased in S1P levels, which in turn, increases the expression of multiple steroidogenic proteins (20). Our study demonstrated that higher S1P concentrations were present on the tumor side than on the nontumor side in patients with CD, indicating that the regulatory relationship between ACTH and S1P also exists in ACTH-secreting pituitary adenomas. Several pieces of evidence have supported the potential relationship between S1P and the occurrence of CD. Interestingly, SPHK1 and S1P are known to be integral to the regulation of epidermal growth factor receptor (EGFR) (38), which is highly expressed in human corticotropinomas, where it triggers proopiomelanocortin (the precursor of ACTH) transcription and ACTH synthesis (39). Blocking EGFR activity with an EGFR inhibitor can attenuate corticotroph tumor cell proliferation (40). Furthermore, SPHK1 and proopiomelanocortin share a common transcriptional coactivator, P300 (41, 42). Notably, S1P also directly binds to and inhibits histone deacetylase 2, thereby regulating histone acetylation and gene expression (43). Notably, histone deacetylase 2 expression is deficient in ACTH-pituitary adenomas in CD, contributing to glucocorticoid insensitivity (44), which is a hallmark of CD and a feature associated with nonremission. These studies further demonstrated an association between high S1P ratio and nonremission of CD. Our study, for the first time, established an association between SPHK1/S1P and ACTH adenoma. Nevertheless, further experimental verification is required to confirm the existence of common pathways linking SPHK1 and ACTH. Thus, these findings indicated that the S1P ratio can, to some extent, reflect the differences in ACTH levels and may serve as a surrogate marker for detecting ACTH-secreting pituitary adenomas.

BIPSS is a highly effective procedure for diagnosing pituitary sources of ACTH in CD and remains the gold standard diagnostic method. However, some findings indicated certain limitations associated with the use of the inferior petrosal sinus sampling (IPSS) method in predicting tumor lateralization. The possible causes of error include asymmetrical or underdeveloped petrosal sinus anatomy and placement of the catheter (27). The present study revealed a notable increase in the interpetrosal ACTH ratio among patients with accurate predictions of tumor laterality than among those with inaccurate predictions, although the positive predictive value remained low. These findings suggested that other mechanisms may exist that contribute to false-positive results. The limitations on lateralization highlighted the need for further research to understand the underlying mechanisms contributing to the accuracy of IPSS in predicting tumor lateralization. Further investigation is required to understand these potential mechanisms and improve the accuracy of IPSS in predicting tumor lateralization.

We observed that the interpetrosal S1P ratio was slightly more effective than the ACTH ratio in predicting tumor laterality. However, combining both methods significantly improved the diagnostic sensitivity and specificity. These results have important implications for clinical practice as accurate tumor lateralization is essential for the correct management and treatment of pituitary adenomas. Overall, these findings highlighted the importance of using multiple measures in predicting tumor lateralization and suggested that combining measures may be more effective than relying on any single measure alone. Future research should investigate additional measures to improve the accuracy of tumor lateralization and optimize the use of existing measures for making clinical decisions.

The initial treatment recommendation for CD is surgery. However, long-term surveillance is necessary because of the high recurrence rate (12). Therefore, identifying patients who are at a greater recurrence risk would be helpful in establishing an effective surveillance strategy. Our study revealed that the expression of SPHK1 in pituitary tissue was higher in postoperative nonremission group than in postoperative remission group. Moreover, patients in the nonremission group exhibited significantly higher interpetrosal S1P ratios than those of patients in the remission group. SPHK1 catalyzes the direct phosphorylation synthesis of S1P, and the S1P ratio can thus reflect the expression level of SPHK1 in ACTH tumors. Since S1P can increase the expression of multiple steroidogenic proteins, including steroidogenic acute regulatory protein, 18-kDa translocator protein, low-density lipoprotein receptor, and scavenger receptor class B type I (20), the interpetrosal S1P ratios may be indicative of disease prognosis. This finding is consistent with previous findings indicating the overexpression of SPHK1 is associated with poor prognosis in various neuroendocrine tumors, as factors associated with tumor proliferation, S1P and SPHK1, may play a key role in the proliferation and survival of ACTH pituitary adenomas. The high proportions of SPHK1/ACTH double-positive cells are likely associated with greater phenotypic severity, and CD tumors with this phenotype may have a poor prognosis. These findings hold clinically significance for predicting early postoperative remission in patients with CD. As aforementioned, the interpetrosal S1P ratios have been suggested as a useful diagnostic tool for determining adenoma lateralization in CD, which can also serve as a prognostic indicator for postoperative remission.

Pearson correlation analysis indicated that ACTH 8 am on POD1 and FSH/LH levels were significantly associated with the interpetrosal S1P ratio, suggesting that these pituitary dysfunctions may have a role in the early remission of CD. However, the sample size in this study was relatively small, and further studies with larger sample sizes are needed to confirm these findings. Additionally, other factors affecting surgical outcomes, such as the experience of the surgeon, extent of surgical resection, and use of adjuvant therapy, should be considered when predicting postoperative remission in patients with CD.

This study has some limitations. First, the study was retrospective in design, which limited the control of confounding factors. Additionally, because of the limited sample size, we did not specifically investigate cases where the ACTH ratio failed to accurately identify the correct tumor location. Finally, we did not explore the functional evidence of a common pathway between SPHK1 and ACTH. Despite these limitations, the study contributes to our understanding of the potential utility of the interpetrosal S1P ratio as a biomarker for CD and provides a basis for future research in this area.

In conclusion, our study demonstrated a significant association between the interpetrosal S1P ratio and tumor laterality, as well as in early remission in CD. These findings suggested that the interpetrosal S1P ratio could serve as a useful biomarker in clinical practice. Moreover, targeting genes and drugs related to SPHK1/S1P could provide novel therapeutic strategies for treating CD.

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

The studies involving humans were approved by The Xiangya Hospital Ethics Committee, Xiangya Hospital (Changsha, China). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

HS: conceptualization, methodology, software, visualization, and investigation. CW and BH: software. YX: writing – review & editing. All authors contributed to the article and approved the submitted version.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

The authors gratefully acknowledge contributions from the GEO databases and TNMplot database (https://www.tnmplot.com/).

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

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1238573/full#supplementary-material

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Keywords: ipss, sphingosine-1-phosphate, Cushing’s disease, remission, tumor laterality

Citation: Sun H, Wu C, Hu B and Xiao Y (2023) Interpetrosal sphingosine-1-phosphate ratio predicting Cushing’s disease tumor laterality and remission after surgery. Front. Endocrinol. 14:1238573. doi: 10.3389/fendo.2023.1238573

Received: 12 June 2023; Accepted: 17 October 2023;
Published: 31 October 2023.

Edited by:

Anton Luger, Medical University of Vienna, Austria

Reviewed by:

Guangwei Wang, Hunan University of Medicine, China
Marie Helene Schernthaner-Reiter, Medical University of Vienna, Austria

Copyright © 2023 Sun, Wu, Hu and Xiao. 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: Yuan Xiao, xiaoyuan2021@csu.edu.cn

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1238573/full

Filed under: Cushing's, Diagnostic Testing, pituitary, symptoms | Tagged: ACTH, Bilateral inferior petrosal sinus sampling, BIPSS, pituitary | Leave a comment »

Bilateral Inferior Petrosal Sinus Sampling: Validity, Diagnostic Accuracy in Lateralization of Pituitary Microadenoma, and Treatment In Eleven Patients with Cushing’s Syndrome – a Single-Center Retrospective Cohort Study

Posted on November 17, 2023 by MaryO

Abstract

Background

This single-center retrospective cohort study aimed to describe the findings and validity of Bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of patients with ACTH-dependent Cushing’s syndrome (CS).

Methods

Eleven patients underwent BIPSS due to equivocal biochemical tests and imaging results. Blood samples were taken from the right inferior petrosal sinus (IPS), left IPS, and a peripheral vein before and after stimulation with desmopressin (DDAVP). ACTH and prolactin levels were measured. The diagnosis was based on the ACTH ratio between the IPS and the peripheral vein. Also, lateralization of pituitary adenoma in patients with Cushing’s disease (CD) was predicted. No significant complications were observed with BIPSS.

Results

Based on the pathology report, eight patients had CD, and three had ectopic ACTH syndrome (EAS). Unstimulated BIPSS resulted in a sensitivity of 87.5%, specificity of 100%, PPV of 100%, NPV of 75%, and accuracy of 91%. Stimulated BIPSS resulted in a sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and accuracy of 100%. However, pituitary magnetic resonance imaging (MRI) had a lower diagnostic accuracy (sensitivity:62.5%, specificity:33%, PPV:71%, NPV:25%, accuracy:54%). BIPSS accurately demonstrated pituitary adenoma lateralization in 75% of patients with CD.

Conclusions

This study suggests that BIPSS may be a reliable and low-complication technique in evaluating patients with ACTH-dependent CS who had inconclusive imaging and biochemical test results. The diagnostic accuracy is improved by DDAVP stimulation. Pituitary adenoma lateralization can be predicted with the aid of BIPSS.

Peer Review reports

Introduction

All disorders with manifestations associated with glucocorticoid excess are called Cushing’s syndrome. Exogenous corticosteroids cause most CS cases, and endogenous CS cases are rare [1, 2].

The diagnosis of Cushing’s syndrome may be complicated, particularly in cases with ambiguous clinical findings, atypical presentations, and cyclic hypercortisolemia [3,4,5]. The initial laboratory tests for diagnosis of CS include 24-hour urinary free cortisol (UFC), late-night salivary cortisol, and low-dose dexamethasone suppression test (DST). These tests only represent hypercortisolemia [1, 2].

Once CS is diagnosed, further evaluations are needed to identify the etiology. The first step is to measure the plasma ACTH level. A low plasma ACTH level indicates ACTH-independent CS and a high level suggests ACTH-dependent CS. Normal ACTH can also occur in ACTH-dependent CS. Almost all cases of ACTH-dependent are due to pituitary adenoma (Cushing’s disease) or EAS [1, 2, 6].

Some ectopic sources include neuroendocrine tumors, bronchial carcinoma, and pancreatic carcinoma [7, 8]. Because of the high mortality in tumors associated with EAS, it is essential to differentiate CD from EAS.

To distinguish CD from EAS, a high-dose dexamethasone suppression test (HDDST), corticotropin-releasing hormone (CRH), or DDAVP stimulation tests, or pituitary MRI is recommended [1, 2, 6, 9,10,11,12]. MRI can be equivocal in half of the patients, and only relatively large lesions (> 6 mm) detected on MRI reliably confirm the diagnosis of CD with biochemical confirmation and expected clinical symptoms [9].

Considering the relatively low sensitivity and specificity of non-invasive tests [13, 14] and the high complications of the surgery, it seems reasonable to use a test with high sensitivity and specificity and few complications before resection. BIPSS with CRH or DDAVP stimulation can be helpful for further evaluation [1, 2, 10, 15, 16]. The BIPSS procedure is the same in both stimulation methods. Due to its lower cost, availability, and comparable diagnostic accuracy, using DDAVP instead of CRH for BIPSS is an alternative [17, 18]. BIPSS has been reported to have high sensitivity and specificity and is a safe procedure when performed by experienced interventional radiologists [15, 16, 19, 20].

This case series describes the experience with BIPSS and examines the validity of BIPSS for differentiating CD from EAS in patients with ACTH-dependent CS who had ambiguous or equivocal results in non-invasive tests.

Materials and methods

Patients

This retrospective cohort study included 11 patients with ACTH-dependent CS who underwent BIPSS between 2018 and 2020 in a tertiary care hospital.

Data collection

Well-trained nurses conducted anthropometric measurements, including height and weight. Standing height was measured with a portable stadiometer (rounded to the nearest 0.1 cm). Using a calibrated balance beam scale, this study measured weight in the upright position (rounded to the nearest 0.1 kg). Body mass index (BMI) was calculated by dividing weight (kg) by height squared (m2). Well-trained examiners measured blood pressure (systolic and diastolic) at the left arm in the sitting position after 5 min of rest using a calibrated mercury sphygmomanometer. The blood sample was taken, and fasting blood sugar (FBS), hemoglobin (Hb), potassium (K), and creatinine (Cr) were measured. All research was performed in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants or their legal guardians.

Biochemical tests and imaging

Patients with signs and symptoms of CS underwent screening evaluations, and confirmatory tests were performed using serum cortisol and 24-hour UFC. After confirmation of CS, ACTH was measured using an immunoradiometric assay to categorize patients into ACTH-dependent or independent groups. ACTH test was performed with SIEMENS IMMULITE 2000 device with an analytical sensitivity of 5 pg/ml (1.1 pmol/l) and CV ∼7.5%. HDDST was conducted by administering 2 mg dexamethasone every 6 h for 48 h to all patients, and then serum cortisol and 24-hour UFC were rechecked. A pituitary MRI was performed with sagittal and coronal T1- and T2-weighted images before and after the gadolinium injection.

BIPSS procedure

After biochemical tests and imaging, an experienced interventional radiologist performed bilateral and simultaneous catheterization of the inferior petrosal sinuses. Venography was obtained to evaluate venous anatomy and catheter placement. The retrograde flow of contrast dye into the contralateral cavernous sinuses was used as a marker of adequate sampling. After the correct placement of catheters, blood samples were obtained from each of three ports (peripheral (P), left inferior petrosal sinus (IPS), and right IPS) at -15, -10, -5, and 0 min. The current study used DDAVP for stimulation. After peripheral injection of 10 micrograms of DDAVP, blood samples from these three sites were obtained at + 3, +5, + 10, and + 15 min. Three samples from these sites were also obtained to measure prolactin. Upon collection, BIPSS samples were placed in an ice-water bath. At the end of the procedure, samples were taken to the laboratory, where the plasma was separated and used for immediate measurement of ACTH. Specimens were refrigerated, centrifuged, frozen, and assayed within 24 h.

After the samples were obtained, both femoral sheaths were removed, and manual compression was used to obtain hemostasis before transferring patients to the recovery room. The whole procedure took 1–2 h. Patients underwent strict bed rest for 4 h before discharge on the same day. All BIPSS were performed without significant complications, and only hematoma at the catheterization site was observed in some patients.

BIPSS interpretation

The ratio of IPS ACTH to peripheral ACTH level (IPS/P ACTH) for each side was calculated. Baseline sampling at minute 0 with IPS/P ≥ 2 or stimulated sampling at minute 3 with 1PS/P ≥ 3 is confirmatory for CD [1, 8]. Also, the IPS/P ratio was checked for prolactin level after DDAVP stimulation (stimulated IPS/P prolactin). A stimulated IPS/P prolactin ≥ 1.8 indicates successful catheterization, meaning the catheter is correctly placed in the IPS [21]. For further evaluation, the current study normalized the ACTH to the prolactin level by dividing stimulated IPS/P ACTH into stimulated IPS/P prolactin for each side. A normalized ACTH/prolactin IPS/P ratio ≥ 1.3 supports a pituitary ACTH source (Cushing’s disease), and a normalized ratio ≤ 0.7 an ectopic source (EAS) [22]. The values between 0.7 and 1.3 are equivocal. The inter-sinus ratio was defined as the ratio of the IPS/P ACTH level of one side with the higher level divided by the IPS/P ACTH level of the other side with the lower level, either before or after stimulation. An inter-sinus ratio ≥ 1.4 indicates lateralization to the side with a higher IPS/P ACTH level [23].

Statistical analysis

This analysis used SPSS software version 18 (SPSS, Inc.) to perform analyses. Data were expressed as numbers and percentages. Continuous variables were presented as means (± SD). This study reported the median or range when the data did not follow a normal distribution. The Shapiro-Wilk test was used to test for normality. The nonparametric Mann-Whitney U Test was utilized to compare variables. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the tests were calculated based on standard statistical equations.

Results

Baseline characteristics and clinical manifestations

This retrospective research studied 11 patients with ACTH-dependent CS, including eight females (72.7%) and three (27.3%) males. The median (Q1-Q3) age was 32.0 (22–45) years. The median (Q1-Q3) of BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), FBS, Hb, K, and Cr were 29.2 (24.8–33.3), 130.0 (125–140), 80.0 (80–95), 98.0 (88–103), 13.5 (12.4–13.9), 4.2 (3.9–4.5), and 1.0 (0.9–1.1), respectively. The demographic characteristics of patients are presented in Table 1. The Hb levels were not different in women and men (median 13.35 vs. 13.70, p-value = 0.776). In addition, no statistical difference between patients with a final diagnosis of CD and EAS was detected for Hb levels (Total: median 13.60 vs. 13.2, p-value > 0.05) (Women: median 13.5 vs. 13.2, p-value > 0.05) (Men: median 13.7 vs. 13.25, p-value > 0.05).

Table 1 Demographic characteristics of the studied patients

Full size table

90% of patients had at least one skin manifestation, such as striae, easy bruising, acne, hyperpigmentation, hirsutism, hair loss, edema, and hypertrichosis. Other symptoms were hypertension (HTN) (81%), reproductive dysfunction (81%), including infertility, oligomenorrhea, loss of libido, weight gain (72%), proximal muscle weakness (45%), and headache (27%) (Table 2).

Table 2 Clinical manifestations of the studied patients

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Results of biochemical tests

Biochemical tests results, including basal serum cortisol (median:26 mcg/dl, range:15-54.5 mcg/dl), basal 24-hour UFC (median:670 mcg/dl, range:422–1545 mcg/dl), ACTH (median:58.8 pg/ml, range:25–155 pg/ml), serum cortisol after HDDST (median:14.2 mcg/dl, range:2.63-36.0 mcg/dl), 24-hour UFC after HDDST (median:292 mcg/dl, range:29.5–581 mcg/dl) are presented in Table 3. According to the basal serum cortisol results, eight patients (Cases 1, 3, 5, 7, 8, 9, 10, and 11) had basal serum cortisol levels > 22 mcg/dl, which indicates hypercortisolemia. Other patients (Cases 2, 4, and 6) had basal serum cortisol in the normal range (5–25 mcg/dl) and were considered as false negative results of this test.

Table 3 The results of biochemical tests in the studied patients

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All patients had elevated basal 24-hour UFC levels (422–1545 mcg/dl), indicative of hypercortisolemia (Table 3).

There were six patients with elevated peripheral ACTH levels (> 58 pg/ml) (cases 5, 6, 8, 9, 10, and 11). Other patients had ACTH within the normal range (6–58 pg/ml) (cases 1, 2, 3, 4, 7) (Table 3).

None of the patients showed suppression after 1 mg DST. After HDDST, cases 2, 3, 8, and 10 had more than 50% suppression of serum cortisol. In the other six patients, serum cortisol was not suppressed or suppressed by less than 50%. In one patient, serum cortisol levels were not measured (case 1) because the sample was not stored under standard test conditions.

Also, eight patients had more than 50% 24-hour UFC suppression after HDDST (cases 1, 2, 3, 4, 6, 7, 9, and 10). In two patients, 24-hour UFC was suppressed less than 50% (cases 5 and 11), and in one patient (case 8), the 24-hour UFC sample was not tested due to the non-standard condition of the sample.

BIPSS results

BIPSS results before and after stimulation are shown in Table 4. The baseline value (sampling at minute 0) of IPS/P ACTH ≥ 2 confirms CD. According to this ratio, cases 1,3,4,5,6,7, and 8 were diagnosed as CD. The unilateral source for CD was confirmed in cases 1, 3, 7, and 8. BIPPS didn’t demonstrate lateralization in cases 4, 5, and 6.

Table 4 Baseline and stimulated IPS/P ratio for ACTH and Prolactin in the studied patients

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The highest IPS/P ACTH ratio was 3 min after the DDAVP injection. A sampling at minute 3 with stimulated IPS/P ACTH ≥ 3 confirms CD. This ratio confirmed CD in cases 1–8 and showed a unilateral source for CD in cases 1, 2, 3, and 7. The ratio didn’t demonstrate lateralization in cases 4, 5, 6, and 8. The stimulated IPS/P prolactin was ≥ 1.8 in all cases.

The variability in the IPS/P ACTH ratio in patients with CD is shown in Fig. 1. The peak of this ratio was 3 min after the DDAVP injection. In patients with EAS, there were no changes before or after the DDAVP stimulation.

Fig. 1

Comparison of mean values of IPS/P ACTH in CD (Lt.) and EAS (Rt.). IPS; inferior petrosal sinus; P: peripheral; ACTH: adrenocorticotropic hormone; CD: Cushing’s disease; EAS: ectopic ACTH syndrome; Lt: left; Rt: right

Full size image

According to the Prolactin-normalized ACTH IPS/P ratios, eight patients (cases 1–8) were diagnosed as CD and three as EAS (cases 9–11). In cases 1, 2, 3, 7, and 8, unilateral sources of CD were confirmed, but in cases 4,5 and 6, bilateral sources were detected (Table 4).

According to the inter-sinus ratio, BIPSS could lateralize the source of ACTH in all patients with CD. The inter-sinus ratio in patients with EAS could not lateralize any pituitary source for ACTH (Table 4).

In five patients with CD and one with EAS, the highest peripheral ACTH level was observed 15 min after stimulation. Two patients with CD and one with EAS had the highest peripheral ACTH level 10 min after stimulation. Only one patient with CD and one with EAS had the highest peripheral ACTH level 5 min after stimulation. No patient had maximum peripheral ACTH levels in the first post-stimulation sample (minute 3).

The larger numerator or smaller denominator produces a higher value in a ratio. In the samples obtained immediately after stimulation, the highest concentration of ACTH was in the IPS, and the lowest was in the peripheral blood. Therefore, as mentioned, the highest post-stimulation value of the IPS/P ACTH ratio was obtained at minute 3.

MRI results

MRI results showed pituitary adenoma in five patients, enhancement in one patient, pituitary mass and lesion in two patients, empty sella in two patients, and possible pituitary adenoma and adrenal mass in one patient (Table 5).

Table 5 Final diagnosis, lateralization, MRI results, and management

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Immunohistochemistry (IHC) results

According to the pathology report, eight patients were confirmed as CD (Table 5). The other two patients were EAS (one carcinoid tumor of the lung and one pheochromocytoma). One patient had no documented pathologic source of hypercortisolemia because the patient did not consent to surgery, and the diagnosis of EAS was made based on the results of biochemical tests.

BIPSS vs. MRI results

MRI results showed pituitary adenoma in five patients with CD. MRI and BIPSS showed the adenoma on a similar side in two of them. In the other three patients, MRI showed bilateral adenoma, but BIPSS lateralized the adenoma to one side. One of the other three patients had only left-sided enhancement but no overt adenoma on MRI, whereas BIPSS lateralized the adenoma to the right side. One patient had a low-signal pituitary mass on the right side on MRI, and BIPSS also lateralized to the right. Another patient with a history of transsphenoidal surgery (TSS), diagnosed as recurrent CD, had a partially empty sella. MRI was equivocal, but BIPSS lateralized to the left side.

Among patients with EAS, one with an equivocal BIPSS result had an empty sella on MRI. Two other patients had pituitary lesions on MRI, but BIPSS results were equivocal.

Comparison between BIPSS, MRI, and surgery

Among patients with CD, the final diagnosis based on surgery in three patients was consistent with MRI and BIPSS results and lateralized the adenoma on the same side. In one patient, the surgery result was similar to the MRI findings and showed bilateral adenoma, but BIPSS showed adenoma on the left side. In the patient with equivocal MRI findings and a history of TSS, IHC could not identify ACTH +, although BIPSS lateralized to the left side. In three other patients, surgery results were concordant with BIPSS and lateralized the adenoma on the same side, although MRI showed discordant results.

Validity of BIPSS

Baseline IPS/P ACTH resulted in a sensitivity of 87.5%, specificity of 100%, PPV of 100%, NPV of 75%, and accuracy of 91%. Stimulation with DDAVP improved validity. Both stimulated IPS/P ACTH and normalized ACTH/prolactin IPS/P ratio resulted in a sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and accuracy of 100%. BIPSS, either unstimulated or stimulated, had higher validity than MRI, with a sensitivity of 62.5%, specificity of 33%, PPV of 71%, NPV of 25%, and accuracy of 54%. BIPSS accurately predicted pituitary adenoma lateralization in 75% of patients with CD.

Discussion

In this study, BIPSS before stimulation showed a sensitivity of 87.5% and a specificity of 100%. However, BIPSS after stimulation showed a sensitivity of 100% and specificity of 100%. It has been demonstrated that the sensitivity of BIPSS can vary from 88 to 100%, and its specificity from 67 to 100% in the diagnosis of CD [24]. Previous studies have reported sensitivity and specificity of more than 80% and 90% for BIPSS, and the combination of BIPSS with stimulation by CRH or DDAVP improves the sensitivity and specificity to more than 95 and 100%, respectively [15, 19, 25]. Chen et al. suggested the optimal IPS:P cutoff value of 1.4 before and 2.8 after stimulation [20]. Considering these cutoffs, the only patient in this study who was negative for CD before stimulation becomes positive, and the sensitivity before stimulation increases from 87.5 to 100%. The diagnostic accuracy after stimulation remains unchanged. Results of the current study showed that BIPSS is highly valued in final diagnosis, even without stimulation.

In this investigation, the utilization of Prolactin-normalized ACTH IPS/P ratios exhibited a sensitivity and specificity of 100% for the CD diagnosis. This finding aligns with research conducted by Detomas et al., which reported a sensitivity of 96% and specificity of 100% for the normalized ACTH: Prolactin IPS/P ratio [26]. It seems that concurrently assessing prolactin levels may potentially enhance the diagnostic accuracy of BIPSS. However, the current literature is inconsistent. Some studies do not support the use of prolactin to diagnose CD [27].

In all patients, the IPS/P ACTH ratio at minute 15 did not show a considerable difference from this ratio at minute 0. Previous studies have shown that sampling at minute 15 is not helpful for diagnosis [1, 15, 20, 28]. Unlike the IPS/P ACTH ratio, six patients had the highest peripheral ACTH level at minute 15 after stimulation, but no patient had it at minute 3 after stimulation. However, more studies are needed to obtain more precise results, and this study’s sample size was limited.

BIPSS accurately lateralized the adenoma in six patients with CD, but MRI was able to lateralize the adenoma in two patients correctly. BIPSS had higher validity than MRI in differentiating CD from EAS, both with and without stimulation. The current literature is controversial. Colao et al. reported that adenoma could be accurately localized in 65% of patients using IPSS [23]. However, Lefournier et al. showed that the diagnostic accuracy of IPSS in identifying the side of the pituitary adenoma was 57% [28]. Wind et al. showed that the PPV for IPSS to identify the tumor side correctly was 69%. Additionally, MRI was more accurate than IPSS in tumor lateralization [29]. Earlier studies have shown that MRI may show a pituitary lesion, and BIPSS indicates a pituitary adenoma. However, the lesion observed on the MRI is not related to the pituitary adenoma [1, 15, 19, 25, 28]. Also, MRI may show pituitary lesions, while BIPSS indicates EAS.

In the current study, the concordance of IHC results with BIPSS and MRI findings was inconclusive, possibly due to the limited number of patients. However, there is disagreement about the role of pathological study in diagnosis [19, 28].

Eight patients had elevated basal serum cortisol levels in this study (Sensitivity:73%). Instead, all patients had hypercortisolemia according to basal 24-hour UFC results, and no false-negative results were observed (Sensitivity:100%). This study’s findings were consistent with previous studies regarding low sensitivity for basal serum cortisol and high sensitivity for 24-hour UFC as screening tests for hypercortisolemia [6, 30, 31].

After HDDST, basal serum cortisol suppression was observed in three patients with CD (cases 2, 3, and 8) but not in the others with CD. Also, serum cortisol levels were suppressed after HDDST in a patient with EAS who had a lung carcinoid tumor. Arnaldi et al. showed that some carcinoid tumors might be sensitive to HDDST, and suppression of serum cortisol may be observed after this test [1, 32]. After HDDST, six patients with CD had suppressed 24-hour UFC, but one did not show more than 50% suppression. Two patients with EAS had more than 50% 24-hour UFC suppression.

According to the final pathology report, the sensitivity of serum and urine cortisol level tests after HDDST was 43% and 86%, and the specificity was 67% and 33%, respectively. PPV in both was 75%, NPV was 33% and 50%, and accuracy was 50% and 70%, respectively, which shows that these preliminary tests cannot be a good guide for the final diagnosis and subsequent treatment planning. Previous studies showed that more than one biochemical test could improve the accuracy for differentiating between CD and EAS [1, 5, 6, 9, 31]. The current study confirms the importance of using more than one biochemical test for diagnosing hypercortisolemia and diagnosing CD from EAS.

Detomas et al. reported that Hb levels were high in females with CS while they were low in males with CS. Furthermore, there were lower levels of Hb in EAS than in CD in females [33]. In the current study, the Hb levels were not different in women and men. Furthermore, no statistical difference was observed for Hb levels between patients with a final diagnosis of CD and EAS. Hb levels did not contribute to diagnosing ACTH-dependent CS in this analysis.

There were some limitations in this study. First, the sample size was relatively small. Second, it was a retrospective study. Further studies could investigate the BIPSS in a larger sample size and determine the validity of this method in patients with CS.

Conclusions

The current study suggests that BIPSS can be a reliable and low-complication method in evaluating patients with ACTH-dependent CS who had equivocal results in imaging and biochemical tests, even before stimulation. Stimulation with DDAVP increases diagnostic accuracy. BIPSS can be used to predict the lateralization of the pituitary adenoma.

Data Availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

BIPSS:: Bilateral inferior petrosal sinus sampling
ACTH:: Adrenocorticotropic hormone
CS:: Cushing’s syndrome
IPS:: Inferior petrosal sinus
DDAVP:: Desmopressin
CD:: Cushing’s disease
EAS:: Ectopic ACTH syndrome
MRI:: Magnetic resonance imaging
UFC:: Urinary free cortisol
DST:: Dexamethasone suppression test
HDDST:: High-dose dexamethasone suppression test
CRH:: Corticotropin-releasing hormone
BMI:: Body mass index
FBS:: Fasting blood glucose
Hb:: Hemoglobin
Cr:: Creatinine
PPV:: Positive predictive value
NPV:: Negative predictive value
SBP:: Systolic blood pressure
DBP:: Diastolic blood pressure
K:: Potassium
HTN:: Hypertension
IHC:: Immunohistochemistry
TSS:: Transsphenoidal surgery

References

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Acknowledgements

The authors wish to thank the patients for their participation and kind cooperation.

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Authors and Affiliations

Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
Mohammadali Tavakoli Ardakani, Soghra Rabizadeh, Amirhossein Yadegar, Fatemeh Mohammadi, Sahar Karimpour Reyhan, Reihane Qahremani, Alireza Esteghamati & Manouchehr Nakhjavani
Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran
Hossein Ghanaati

Contributions

MN and MTA and SR: Conception and design of the study. AY and FM and HG: Acquisition of data. MTA and AY and SR: Analysis and interpretation of data. FM and RQ and SK: Drafting the article. MN and AE and AY: Critical revision of the article. All authors read and approved the final manuscript.

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Correspondence to Manouchehr Nakhjavani.

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Ardakani, M.T., Rabizadeh, S., Yadegar, A. et al. Bilateral inferior petrosal sinus sampling: validity, diagnostic accuracy in lateralization of pituitary microadenoma, and treatment in eleven patients with Cushing’s syndrome – a single-center retrospective cohort study. BMC Endocr Disord 23, 232 (2023). https://doi.org/10.1186/s12902-023-01495-z

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Received05 July 2023
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DOIhttps://doi.org/10.1186/s12902-023-01495-z

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Dynamic And Invasive Testing in Cushing’s Disease

Posted on December 2, 2021 by MaryO

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Abstract

Purpose

Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing’s syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing’s syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing’s disease (CD).

Methods

Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome.

Results

Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6–10 mm lesion (Group and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78).

Conclusions

CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

Introduction

Cushing’s syndrome (CS) is a rare and potentially fatal condition due to chronic exposure to cortisol. After excluding exogenous glucococorticoid assumption from any route, the diagnosis is based on clinical suspicion and further confirmed with appropriate testing as suggested by Endocrine Society Guidelines [urinary free cortisol (UFC), late night serum/salivary cortisol and 1 mg dexamethasone suppression test] [1]. Once the diagnosis of endogenous hypercortisolism is confirmed, the measurement of morning ACTH levels allows to discriminate ACTH-dependent from ACTH-independent CS that originates from primary adrenal disorders. Among ACTH-dependent CS, the most common form is caused by an ACTH-secreting pituitary tumor, a condition named Cushing’s disease (CD), accounting for about 80% of all cases, whereas the rest is due to an ectopic source (EAS); even though ACTH levels are usually higher in EAS than in CD, there is a significant overlap between these two conditions, thus further diagnostic procedures are needed [1]. Desmopressin (DDAVP) stimulatory test is helpful in suggesting risk of recurrence in the post-neurosurgical follow-up, but it seems to have a limited diagnostic utility in the differential diagnosis of ACTH-dependent CS due to the expression of vasopressin receptors in both CD and EAS [2]. Conversely, high-dose dexamethasone suppression test (HDDST) and corticotropin-releasing hormone (CRH) test have been widely used for this purpose and represent the mainstay in the differential diagnosis of ACTH-dependent CS forms [3,4,5,6]. Despite their satisfactory accuracy, there is no consensus on how to interpret their results [7]. Previous studies found that the presence of concordant clear-cut response to both HDDST and CRH test is able to exclude the diagnosis of EAS, irrespective of magnetic resonance imaging (MRI) finding [8, 9]. Even though MRI with intravenous gadolinium administration is certainly useful for individuation of the pituitary tumor, it results in little help in about 30% of cases due to tiny dimensions, localization and characteristics of the ACTH-secreting pituitary adenomas [10]. Conversely, radiological studies may sometimes disclose abnormalities with no functional significance, the so-called “pituitary incidentalomas”, that have been found in about 10% of healthy individuals [11], as in up to 38% of patients with EAS [12]. However, it is noteworthy that the finding of a pituitary incidentalomas larger than 6 mm in patients with EAS is usually very rare [13]. The presence of a microadenoma is therefore not enough for hypercortisolism to be labeled as pituitary-dependent and the role of hormonal tests is crucial for a correct diagnosis. When discordant results to dynamic tests and/or when pituitary MRI shows a lesion < 6 mm, bilateral inferior petrosal sinus sampling (BIPSS) is still recommended as the gold-standard procedure to achieve correct differential diagnosis due to its high sensitivity and specificity [7]. However, even BIPSS is not always fully reliable; false negative results are indeed possible in case of anatomical variations of the venous drainage from the cavernous sinuses to the jugular veins or when BIPSS is performed in a low-normal cortisolemic phase, as might happen in cyclic CS or during treatment with cortisol-lowering medications [14]. Furthermore, BIPSS requires hospitalization, is time- and cost-consuming and in few instances might lead to severe complications [15, 16]. Given the fact that BIPSS is not 100% accurate, has poor reliability to suggest intrapituitary localization/lateralization and has some drawbacks [17], we collected clinical, biochemical and neuroradiological data of a large series of CD patients as well as biochemical and neuroradiological data of a group of EAS patients with the following aims: (i) to describe the responsiveness to dynamic testing (CRH test, DDAVP test and HDDST) and its performance in the differential diagnosis of ACTH-dependent Cushing’s syndrome in possible different scenarios given by MRI finding; (ii) to assess whether the decision of BIPSS execution can affect surgical outcome of patients affected by Cushing’s disease.

Patients and methods

We performed a retrospective analysis on 148 patients (F/M 113/35, mean age 42.4 ± 14.2 years) affected by CD followed at 2 tertiary care centers in Italy between 2000 and 2017 [Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (62 patients); Endocrinology Unit, Department of Medicine-DIMED, University of Padova (86 patients)].

The diagnosis of hypercortisolism was performed on the basis of typical clinical features in the presence of at least two of the following abnormal tests: high 24-h UFC levels, loss of circadian rhythm in plasma/salivary cortisol and lack of cortisol suppression after 1 mg of dexamethasone overnight [1]. The diagnosis of ACTH-dependent hypercortisolism was confirmed in case of detectable baseline ACTH plasma levels (> 20 ng/L) [18]. Pituitary MRI (magnet strength ranging from 1.5 to 3.0 TESLA over the study period) with gadolinium was performed in all patients and reviewed by experienced neuroradiologists. Differential diagnosis of ACTH-dependent hypercortisolism was established through: (i) CRH test (positive response: ACTH and/or cortisol plasma levels increase by more than 50% and/or 20%, respectively) [12, 18,19,20]; (ii) high-dose dexamethasone suppression test (HDDST) (positive response: serum cortisol levels reduction to a value of < 50% of the basal level) [19]; (iii) DDAVP test (positive response: increase of both ACTH and cortisol greater than 30% and 20%, respectively) [21, 22].

For CRH and DDAVP tests, all patients were evaluated after an overnight fast; blood samples for ACTH and cortisol measurements were collected − 15, 0, 15, 30, 45, 60, 90 and 120 min after intravenous bolus injection of human CRH 100 µg or DDAVP 10 µg, respectively.

For HDDST, dexamethasone 8 mg was administered orally at 23.00 h and serum cortisol levels were measured between 8.00 and 9.00 a.m. on the next morning.

The decision whether to perform bilateral inferior petrosal sinus sampling (BIPSS) was guided by clinical judgement considering neuroradiological and biochemical findings. After catheter placement, ACTH was measured simultaneously in a blood sample obtained from each petrosal sinus and from a peripheral vein before and 1, 3, 5, and 10 min after the injection of 1 µg/Kg of CRH.

An inferior petrosal sinus to periphery ratio (IPS:P) ≥ 2 at baseline or ≥ 3 after CRH administration was considered as positive response [23]. All patients included in this study underwent transsphenoidal surgery (TSS) performed by neurosurgeons with recognized expertise in the management of pituitary diseases.

The pituitary origin of ACTH secretion was then confirmed by immediate (serum cortisol < 138 nmol/L within 7 days following TSS) and/or sustained biochemical remission [hypoadrenalism (morning serum cortisol < 138 nmol/L or lack of cortisol response to Synacthen stimulation test considering a cut-off of 500 nmol/L) for at least 6 months] after TSS and/or histological examination (defined as positive immunostaining for ACTH on the adenomatous tissue).

Finally, data describing biochemical responses to CRH test, DDAVP test and HDDST and pituitary MRI in a group of 26 patients (14 of which were presented in a previous publication) [9] with histologically confirmed ectopic ACTH syndrome (EAS) were also collected.

Statistical analysis

Data are shown using mean ± standard deviation for normally distributed continuous variables or median and interquartile range (IQR) for non-Gaussian data and proportion for categorical parameters. Categorical data were analyzed using the χ² test or the Fisher exact test if the expected value was < 5. Continuous parameters with normal distribution were compared using the t test and non-Gaussian data using the non-parametric test of Mann Whitney. The relation between two or more variable was assessed through logistic regression in case of binary dependent variable and linear regression in case of continuous dependent variable. Sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) were calculated with 95% confidence intervals (CI) using the exact binomial method. All statistical analyses were performed using SPSS, version 25 (IBM, Cary, NC, USA).

Results

Neuroradiological findings

Patients with CD were divided into three groups on the basis of MRI results; group A included 97 patients (65.5%) with negative imaging (n = 40, 27% of total) or with a pituitary lesion < 6 mm (n = 57 patients, 38.5%); group B those with visible pituitary adenoma sized between 6 and 10 mm (29 subjects, 19.6%), while group C accounted for patients with macroadenoma (22 patients, 14.9%) (Fig. 1).

Fig. 1

Different groups of patients according to MRI findings

Full size image

Among patients with EAS, seven had a microadenoma < 6 mm, while pituitary imaging was negative in 19.

Biochemical characteristics at baseline

Demographic, basal and dynamic biochemical characteristics and remission rates of three groups of patients affected by CD are summarised in Table 1.

Table 1 Demographic, basal and dynamic biochemical characteristics and remission rates of three groups of patients

Full size table

Basal levels of cortisol, ACTH and UFC were evaluated for each group. Because of different assay methods performed during time, we preferred to use relative UFC (UFC/upper normal limit ratio). Patients of Group C showed higher basal ACTH levels compared to patients with negative MRI imaging or microadenomas (Group A + B) [90(54.5–113.5) vs 44.6(33.7–65.6), p < 0.001), without difference between Group A and Group B. No difference in basal cortisol and relative UFC levels was found between groups.

Late night salivary cortisol levels were evaluated in 73 patients (47 of Group A, 13 of Group B and C) without any difference between groups.

Suppression test

Overall, a positive response to HDDST was observed in 91.4% of cases of CD. The rate of responders to HDDST was similar between negative MRI/microadenomas (Group A + B) and macroadenomas (respectively 92.6% vs 83.3%, p = 0.18) and no differences were found in cortisol levels and percentage of cortisol reduction after HDDST among the three different groups of patients (Table 1).

Six out of 26 patients affected by EAS were responsive to HDDST (23.1%). HDDST had a 91% SE, 77% SP, 95% PPV and 62% NPV to diagnose Cushing’s disease (Table 2).

Table 2 Diagnostic performance of positive response to CRH test, HDDST and their combination for the correct identification of Cushing’s disease

Full size table

Dynamic tests

Overall, CRH test was positive in 89.4% of CD subjects. The response rate was significantly higher in patients with negative MRI/microadenomas (Group A + B) with respect to those with macroadenomas (91.7% vs 75%, p = 0.04), without difference between Group A and Group B. Likewise, negative MRI/microadenomas showed a higher response in terms of ACTH [140.5 (71.9–284.9) vs 82 (26.4–190.9) p = 0.02] and cortisol percentage increase [61.8 (30.7–92.8) vs 36.8 (15.6–63.1), p = 0.03].

As far as DDAVP is concerned, a positive response was recorded in 70.1% of the whole cohort. In this case, unlike CRH test, the response rate was significantly higher in patients with macroadenomas than in those with negative MRI/microadenomas (90% vs 66.3%, p = 0.03). However, no differences between negative MRI/microadenomas and macroadenomas in terms of percentage increase of ACTH and cortisol were found.

Concordance of positive responses between CRH test and HDDST was observed in 81.5% of all patients (82.4% in Group A, 88.4% in Group B and 66.6% of Group C) without any difference between groups. In four cases, a negative response to both tests was recorded; all these patients had a macroadenoma with a minimum diameter of 20 mm.

Concordant positive responses to CRH and DDAVP tests were observed in 62.6% of patients (62.9% in Group A, 56.5% in Group B and 68.4% in Group C, p = NS between groups). In Group A, the concordance rate between CRH and DDAVP was significantly lower than that observed between CRH test and HDDST (62.9% vs 81.5%, p = 0.035). Additionally, six patients (four of Group A, one of Group B and one of Group C) showed a negative response to both tests.

With regards to EAS, one patient had a positive response to CRH test and six patients to HDDST, respectively. Data regarding DDAVP test were available in 22 out of 26 patients: in this subgroup, a false positive response was observed in 11 patients. However, no patient showed a concordant positive response to CRH test and HDDST or to CRH test and DDAVP test. Conversely, two patients responded to both HDDST and DDAVP test. Although it is beyond the aim of this paper, our data confirm previous studies reporting a higher sensitivity of CRH in respect to HDDST and DDAVP test in this setting [24,25,26].

CRH test showed a SE of 89%, SP of 96%, PPV of 99% and NPV of 62% for the diagnosis of CD (Table 2). The combination of the concordant positive responses to CRH test and HDDST performed better than single tests, reaching a 100% SP and PPV irrespective of pituitary MRI.

Considering only the patients with negative imaging or a pituitary lesion < 6 mm, the SE, SP, PPV and NPV of combined positive responses were 82%, 100%, 100% and 62%, respectively (Table 2). On the other hand, combined negative responses in this subgroup of patients showed a SP and PPV of 100% for the diagnosis of EAS.

Similarly, a positive response to both CRH test and DDAVP test reached a SP and PPV of 100% for the diagnosis of CD (Table 3).

Table 3 Diagnostic performance of positive response to DDAVP test or to the combination DDAVP/CRH and DDAVP/HDDST for the correct identification of Cushing’s disease

Full size table

Bilateral inferior petrosal sinus sampling in CD

BIPSS was performed in 29/97 patients of Group A and 1/29 patient of Group B. In particular, 20 of 29 patients of Group A had a negative MRI. In four out of these patients, CRH and HDDST were discordant (two negative results for each test) and BIPSS confirmed a pituitary origin of CS. In the other 16 cases, a positive response to both tests was observed: in 15 cases BIPSS confirmed the diagnosis of CD, while a central/periphery ratio of 2.91 after CRH administration was recorded in one case. The latter patient underwent TSS and CD was then confirmed by immediate and long-term remission of disease. Notably, no patient of Group A presented a negative response to both CRH test and HDDST, while four patients presented a combined negative response to CRH and DDAVP tests.

In the remaining nine patients of Group A, MRI showed a visible microadenoma < 6 mm and BIPSS confirmed the diagnosis of CD both in concordant (n = 6) and discordant (n = 3) patients.

BIPSS was not consistent with a pituitary origin in a patient of Group B with discordant tests. However, as her pretest probability of having CD was high (she was a young female without any suggestive features of ectopic CS and no lesion at thoracoabdominal computed tomography), also in this case the patient underwent TSS and both short and long-term remission confirmed the diagnosis of CD.

No complications were observed in 29/30 patients after BIPSS. One patient died about 24 h after the procedure because of cardiac rupture. Since autopsy revealed a left ventricular free-wall rupture after asymptomatic acute myocardial infarction and cortisol related myopathy, this event was considered as unlikely related to BIPSS.

Remission rates after surgery and role of BIPSS in CD patients with inconclusive neuroradiological imaging

Overall, surgical remission was achieved in 107/148 (72.3%) patients. No difference between groups was found, also considering all patients with negative MRI or microadenomas (Group A + B) with respect to those with macroadenomas (Group C) (73.8% vs 63.6%, p = 0.31).

Finally, when considering patients of Group A with concordant positive responses to HDDST and CRH test (n = 75), no difference in surgical outcome was found between patients who performed BIPSS and those who did not [respectively, 14/21 (66.6%) vs 38/54 (70.4%), p = 0.78] (Fig. 2).

Fig. 2

Remission rate in patients of Group A with concordant positive tests

Full size image

Discussion

Differential diagnosis of ACTH-dependent CS is challenging and to date a single best approach in the diagnostic work-up of these patients does not exist.

Whereas the usefulness of stimulatory and suppression tests is widely accepted, their role to the light of positive MRI (pituitary adenoma < or > 6 mm) or negative findings is still a matter of debate. In the latter case, although BIPSS still represents the gold-standard procedure for differential diagnosis regardless the results of dynamic tests [7, 18], different clinical approaches and opinions are reported in the literature.

In a recent opinion statement by members of the Italian Society of Endocrinology, Italian Society of Neurosurgery and Italian Society of Neuroradiology that summarizes different strategies adopted in the prescription of BIPSS [27], the authors report two studies in which BIPSS did not show any influence on neurosurgical remission rates. In the first one, Bochicchio and coll. retrospectively analyzed data from 668 patients affected by CD and described that in 98 subjects who underwent BIPSS, surgical failure was similar to patients who did not [28]; however, in this cohort CRH and TRH tests but not HDDST, were performed and selection criteria for BIPSS were not clearly reported. In the second one, Jehle and coll. performed a retrospective analysis of 193 patients with ACTH-dependent CS [29]; also in this case, BIPSS did not affect remission rate after TSS as far as recurrence and long-term remission rates. The procedure was reserved to patients with equivocal scan and/or biochemical tests; however, biochemical evaluation consisted of ACTH and UFC levels, while CRH test was not performed and data about HDDST were lacking in all but six patients.

In a subsequent review about the role of BIPSS in CS, Zampetti et al. [30] suggested that, on the basis of authors’ experience, BIPSS should not be performed in patients with positive response to CRH test (defined as increase > 50% in ACTH and > 30% in cortisol), particularly if a consistent suppression to HDDST is present, independently of MRI findings. This opinion was finally remarked by Losa et al. [14] which pointed out CRH test as the main factor in providing indication to BIPSS.

In this area of controversy, we performed a retrospective analysis on 148 patients with CD and 26 patients with EAS aiming to evaluate the role non-invasive tests in the diagnostic work-up, with secondary focus on the need of BIPSS in CD patients with inconclusive neuroradiological examination. In all 148 patients of our cohort, the diagnosis of CD was confirmed by biochemical remission after TSS, histology and/or > 6 months post-surgical hypoadrenalism.

In agreement with previous data, our results confirm that CRH test and HDDST have high accuracy in differential diagnosis of ACTH-dependent CS [8, 9, 27]. As a whole, a positive response was observed in 89.4% and 91.4% of patients with CD, and in 3.8% and 23.1% of patients with EAS, respectively. More importantly, the combination of concordant positive responses to CRH test and HDDST reaches 100% specificity and PPV, thus allowing the diagnosis of CD irrespective of MRI findings. Otherwise, a single-test approach is not able to reach a specificity of 100%. The same performance is maintained in the subgroup of patients with negative MRI or with a microadenoma < 6 mm. Furthermore, in this subgroup, a negative response to both CRH test and HDDST is sufficient to make the diagnosis of EAS.

Interestingly, in CD patients, the response rate to CRH test, as far as ACTH and cortisol percentage increase, were significantly higher in patients with microadenomas or negative imaging in respect to those with macroadenomas. A similar observation was recently reported in a group of 149 CD patients where macroadenomas tended to show a lower increase of ACTH after CRH compared to microadenomas [9]. As a negative correlation between baseline secretion and ACTH and cortisol responses to CRH in CD patients has been described [31], suggesting in this context a different degree of negative feedback impairment at the pituitary level, the finding of higher baseline ACTH levels in our patients may represent the most likely explanation for this observation.

Accordingly, the highest rate of false negative responses to dynamic tests were observed in patients with macroadenomas, in which a false negative result to both CRH and HDDST was recorded in four cases; nevertheless, in this condition BIPSS is already overlooked due to the low pretest probability of the co-existence of a pituitary macroadenoma and an ectopic CS.

The role of DDAVP test in differential diagnosis of ACTH-dependent CS is still controversial and a high frequency of false positive results in patients with EAS has been reported [2]. However, in a recent work including 167 patients with CD and 27 patients with EAS, the positive response to both CRH and DDAVP test showed a positive predictive value of 100% for CD in patients with negative MRI and negative computed tomography scan [32]. In our study, similarly to CRH test and HDDST, also the combination of positive responses to both CRH and DDAVP tests reaches a specificity and PPV of 100% for the diagnosis of CD. However, DDAVP test presents low sensitivity and specificity, thus resulting in a high prevalence of false negative and false positive results as well as a concordance rate significantly lower than that observed for CRH test and HDDST in patients with negative MRI or with a microadenoma < 6 mm. In addition, in four of these patients we recorded a concordant negative response to CRH and DDAVP tests that might have resulted in misdiagnosis. Therefore, our data indicate that DDAVP test may represent a valid alternative, in particular when discordant results arise from other dynamic tests, but CRH test, HDDST and their combination perform better and reduce the need to perform BIPSS.

On the other hand, it is well recognized that DDAVP may have an important role in the post-surgical follow-up of CD patients, as the persistence or reappearance of a positive response may precede the clinical recurrence of disease [21, 22, 33,34,35,36,37,38].

In our series, BIPSS confirmed the diagnosis of CD in 28 out of 30 patients who underwent this procedure. Two negative cases included one patient with a pituitary adenoma sized between 6 and 10 mm but discordant CRH test and HDDST and another one with negative imaging and concordant tests. Notably, in the latter case, a borderline central/periphery ratio of 2.91 was recorded. Nevertheless, diagnosis of CD was subsequently proven by remission after neurosurgery, suggesting that BIPSS returned a false negative result in both patients. The proportion of false negative we observed is in line with previous literature data reporting a prevalence of 3–19%, possibly related to anatomical or biochemical variations of disease [14, 17, 27, 30, 39, 40]. Furthermore, BIPSS is burdened by possible complications. In particular, minor adverse events (i.e., groin hematoma, tinnitus, otalgia) have been reported in about 4% of patients, while severe complications (i.e., brainstem infarction, subarachnoid haemorrhage, pulmonary and deep venous thrombosis) are expected in less than 1% of cases [27, 30]. As reported above, in our series one patient died 24 h after BIPSS due to cardiac rupture, while no complications in the other subjects were recorded. Although our fatal event was unlikely related to the procedure and complications are rare, all these observations point out the need for an accurate selection of patients referred to BIPSS.

Following the results of diagnostic performance analysis, in those patients with concordant positive responses to CRH test and HDDST but inconclusive neuroradiological findings (i.e., negative imaging or pituitary adenoma < 6 mm), the execution of BIPSS did not improve surgical outcome. Then, our data do not support the routine use of BIPSS in this subgroup of CD patients, in whom BIPSS could have been avoided in 22 out of 29 subjects. In this setting, contrarily to what the current guidelines propose [7, 13, 18, 19], CRH test and HDDST seems to be sufficient to confirm the diagnosis of CD and to provide indication to pituitary surgery. Similarly, a negative response to both tests pointed toward EAS diagnosis; in this circumstance BIPSS can be avoided too. Indeed, the present study does not propose to remove BIPSS from the diagnostic work-up of ACTH-dependent CS diagnosis, but to restrict its use when really necessary.

Our study has some limitations: first, its retrospective nature, leading in particular to an inhomogeneous selection of patients referred to BIPSS. Second, our data do not allow to draw conclusions about patients with intermediate pituitary lesion between 6 and 10 mm. Although our approach was to avoid BIPSS even in case of discordant results, except in the presence of clinical features suggestive for ectopic CS (rapid onset, hypokalemia, advanced age), these cases can still represent matter of debate.

On the other side, the strength is represented by the comprehensive and punctual biochemical and diagnostic characterization of patients which in our view makes our results very reliable.

In conclusion, our study confirms that CRH test, DDAVP test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In particular, the combination of CRH test and HDDST allows to achieve the best performance in terms of sensitivity and specificity. In patients with negative MRI or with a microadenoma < 6 mm, the presence of concordant positive response to CRH test and HDDST or to CRH test and DDAVP test seems to be sufficient to establish the diagnosis of CD. In this subgroup of patients, BIPSS should be therefore reserved for those cases with discordant tests.

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Funding

This work was supported by AIRC (Associazione Italiana Ricerca Cancro) grant to GM (IG 2017-20594), Italian Ministry of Health grant to GM (PE-2016-02361797) and by Ricerca Corrente Funds from the Italian Ministry of Health.

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E. Ferrante and M. Barbot have equally contributed to this work.

Affiliations

Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Via Francesco Sforza, 35, 20122, Milan, ItalyE. Ferrante, A. L. Serban, G. Carosi, E. Sala, R. Indirli, M. Arosio & G. Mantovani
Endocrinology Unit, Department of Medicine DIMED, University of Padova, Padua, ItalyM. Barbot, F. Ceccato, L. Lizzul, A. Daniele, M. Cuman, M. Boscaro & C. Scaroni
Department of Experimental Medicine, Sapienza University of Rome, Rome, ItalyA. L. Serban
Department of Clinical Sciences and Community Health, University of Milan, Milan, ItalyG. Carosi, R. Indirli, M. Arosio & G. Mantovani
Neurosurgery Department, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, ItalyM. Locatelli
Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyM. Locatelli
Department of Neurosciences, University of Padua, Padua, ItalyR. Manara

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Correspondence to G. Mantovani.

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The study was approved by the Ethics Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (Comitato Etico Milano Area 2, number 651_2019).

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Ferrante, E., Barbot, M., Serban, A.L. et al. Indication to dynamic and invasive testing in Cushing’s disease according to different neuroradiological findings. J Endocrinol Invest (2021). https://doi.org/10.1007/s40618-021-01695-1

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Received13 October 2020
Accepted18 October 2021
Published26 October 2021
DOIhttps://doi.org/10.1007/s40618-021-01695-1

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Keywords

Cushing’s disease
ACTH-dependent Cushing’s syndrome
Differential diagnosis
Bilateral inferior petrosal sinus sampling

Filed under: Cushing's, Diagnostic Testing | Tagged: ACTH, Bilateral inferior petrosal sinus sampling, dexamethasone suppression test, PET scan | Leave a comment »

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The Neurosurgical Outcome of Pediatric Cushing’s Disease in a Single Center From China: A 20-Year Experience

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Improved Noninvasive Diagnostic Evaluations in Treatment-Naïve Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s Syndrome

Abstract

Background

Methods

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Background

Methods

Study design and patient population

HDDST

BIPSS

Imaging

Statistical analysis

Results

Clinical characteristics

Diagnostic performance noninvasive and invasive evaluations

Discussion

Conclusions

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Interpetrosal Sphingosine-1-Phosphate Ratio Predicting Cushing’s Disease Tumor Laterality and Remission After Surgery

1 Introduction

2 Materials and methods

2.1 Patients and study design

2.2 Patients and tissue/serum samples

2.3 BIPSS

2.4 Measurement of baseline plasma S1P concentration

2.5 Immunofluorescence staining

2.6 Statistical analysis

3 Results

3.1 Clinical characteristics of remission and nonremission in patients with CD

3.2 Overexpression of SPHK1 and higher concentrations of serum S1P on the tumor side in patients with CD

3.3 Combination of interpetrosal S1P and ACTH ratios improved the diagnostic performance for adenoma laterality

3.4 Interpetrosal S1P ratio serves as a predictive factor for early remission in CD

4 Discussion

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