Abstract
Background
Primary pigmented nodular adrenocortical disease is a rare form of adrenocorticotropic hormone–independent Cushing syndrome originating from bilateral adrenal lesions. Current guidelines do not specify a recommended strategy for determining the optimal surgery. This study evaluates the concordance between bilateral adrenal gland volume and adrenal venous sampling results and the predictive value of adrenal gland volume for postoperative outcomes in patients with primary pigmented nodular adrenocortical disease.
Method
This is a retrospective study conducted at a single center. The study cohort included 10 hospitalized patients with primary pigmented nodular adrenocortical disease from 2011 to 2023. Patients underwent thin-slice adrenal computed tomography scan. An nnU-NET–based automatic segmentation model segmented the adrenal region of interest, and adrenal gland volume were computed. The ratio of left to right adrenal gland volume were also determined. All patients underwent either unilateral or bilateral adrenalectomy and received postoperative follow-up.
Results
Adrenal gland volume enlargement was asymmetrical between the 2 sides. Larger adrenal gland volumes typically corresponded to the side of dominant cortisol production as indicated by adrenal venous sampling. Clinical and biochemical remission was achieved with left adrenalectomy when left to right adrenal gland volume exceeded 1.2, and with right adrenalectomy when left to right adrenal gland volume was below 0.9. When the left to right adrenal gland volume was approximately 1, unilateral adrenalectomy proved less effective, often necessitating bilateral adrenalectomy, either simultaneously or sequentially.
Conclusion
Measuring adrenal gland volume can aid in formulating the optimal surgical approach for patients with primary pigmented nodular adrenocortical disease.
Graphical abstract
Introduction
Primary pigmented nodular adrenocortical disease (PPNAD) is an uncommon cause of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (ACS).1 Frequently, PPNAD is associated with the Carney complex (CNC), a rare multiple endocrine neoplasia syndrome characterized by distinctive pigmented lesions on skin and mucous membranes, cardiac and extracardiac myxomas, and multiple endocrine tumors.2 Approximately 45–68.6% of patients with CNC develop PPNAD. CNC is most commonly linked to mutations in the PRKAR1A gene, which follows an autosomal-dominant inheritance pattern, although approximately 25% of cases emerge sporadically from de novo mutations.1,2
The adrenal morphology in PPNAD typically includes multiple small nodules forming a “string of beads” appearance1; however, some patients exhibit atypical features such as a normal adrenal contour, unilateral large nodules, or adenomas.3, 4, 5 In cases lacking other CNC components, these atypical features increase the risk of diagnostic errors.
To date, no universally endorsed surgical strategies exist for PPNAD. Although bilateral adrenalectomy was once the standard treatment to eliminate autonomous cortisol secretion, it leads to lifelong adrenal insufficiency, necessitating continuous glucocorticoid and mineralocorticoid replacement, and poses an ongoing risk of adrenal crisis.1 Accumulating evidence suggests that unilateral adrenalectomy can diminish cortisol levels and ameliorate metabolic disturbances associated with glucocorticoid excess, with some patients experiencing temporary adrenal insufficiency.1,6 This suggests that cortisol production may not be synchronously increased in bilateral adrenals in patients with PPNAD. Selecting the dominant cortisol-producing adrenal for resection could control the metabolic effects of autonomous cortisol production while avoiding the need for lifelong hormone replacement and the risk of an adrenal crisis.
Bilateral adrenal venous sampling (AVS), typically used to identify the dominant aldosterone-secreting side in primary aldosteronism,7 also has been employed to determine the dominant cortisol-secreting side in PPNAD, thus guiding surgical decisions.8,9 However, AVS is technically demanding, involves radiation exposure, has a notable failure rate, and is costly. Moreover, there are no standardized criteria for successful AVS or for determining the dominant side in patients with PPNAD. Therefore, exploring simpler, cost-effective, and reliable criteria for surgical decision-making is crucial.
In this study, we included previously diagnosed patients with PPNAD to apply machine-learning algorithms for segmenting adrenal region of interest (ROI) and analyze the relationship between adrenal morphologic changes and clinical outcomes, thereby providing guidance for surgical planning.
Access through your organization
Check access to the full text by signing in through your organization.
Section snippets
Patients and diagnoses
From December 2011 to August 2024, 321 patients with ACS were diagnosed and treated in the Department of Endocrinology and Metabolism at West China Hospital of Sichuan University. Among them, 12 patients with PPNAD were identified, and 10 of them with preoperative adrenal computed tomography (CT) imaging, comprising 2 male and 8 female patients, were included in this study. Among them, 8 patients were found to carry PRKAR1A gene mutations, as identified by next-generation sequencing of DNA
Patient clinical characteristics
The study analyzed data from 10 patients, comprising 8 women and 2 men, with a mean age of 30.5 years (range, 15–55 years). Eight patients were diagnosed with arterial hypertension, 4 exhibited impaired glucose regulation, and 2 had normal glucose levels and arterial blood pressure. Nine patients displayed typical features of Cushing syndrome, with the exception of 1 individual who presented solely with hypertension and central obesity. In addition, all female participants experienced menstrual
Discussion
This retrospective study examined the relationships among AGV, AVS, and surgical outcomes in 10 patients diagnosed with PPNAD. We observed that AGVs in patients with PPNAD were not uniformly enlarged. Variability in enlargement was noted, with some patients developing larger left adrenal lesions, others larger right adrenal lesions, and some exhibiting equivalently sized bilateral adrenal lesions. Generally, larger AGVs correlated with the dominant side of cortisol production as indicated by
Funding/Support
The study was supported by a grant from the Science &Technology Department of Sichuan Province (2023YFS0262) and a grant from the Ministry of Science and Technology of the People’s Republic of China (2022YFC2505303).
CRediT authorship contribution statement
Tao Chen: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Sikui Shen: Resources, Project administration, Investigation. Yeyi Tang: Resources. Wei Xie: Resources. Huaiqiang Sun: Software, Methodology, Data curation. Yuchun Zhu: Resources. Mingxi Zou: Resources. Ying Chen: Resources. Haoming Tian: Supervision. Xiaomu Li:
Conflict of Interest/Disclosure
The authors have no relevant financial disclosures.
References (18)
- K.L. Hackman et al.
Cushing syndrome in a young woman due to primary pigmented nodular adrenal disease
Endocr Pract
(2010) - G. Luo et al.
An optimized two-stage cascaded deep neural network for adrenal segmentation on CT images
Comput Biol Med
(2021) - A.C. Powell et al.
Operative management of Cushing syndrome secondary to micronodular adrenal hyperplasia
Surgery
(2008) - L. Bouys et al.
Bilateral adrenocortical nodular disease and Cushing’s syndrome
J Clin Endocrinol Metab
(2024) - L. Bouys et al.
Management of endocrine disease: carney complex: clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) gene
Eur J Endocrinol
(2021) - L. Groussin et al.
Mutations of the PRKAR1A gene in Cushing’s syndrome due to sporadic primary pigmented nodular adrenocortical disease
J Clin Endocrinol Metab
(2002) - K.M. Lowe et al.
Cushing syndrome in carney complex: clinical, pathologic, and molecular genetic findings in the 17 affected mayo clinic patients
Am J Surg Pathol
(2017) - D. Vezzosi et al.
Hormonal, radiological, NP-59 scintigraphy, and pathological correlations in patients with Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD)
J Clin Endocrinol Metab
(2015) - Y. Zhu et al.
Primary pigmented nodular adrenocortical disease: report of 5 cases
Chin Med J (Engl)
(2006)
There are more references available in the full text version of this article.
Filed under: Cushing's | Tagged: ACTH, Carney Complex, Cushing's Syndrome, PPNAD, Primary pigmented nodular adrenocortical disease |
CushieBlog 
Leave a comment