Paediatric ectopic ACTH syndrome aetiology differs to that of adults

medwireNews: Children and adolescents with ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) show a different aetiological profile to that of adults, suggests a systematic review of the literature.

The findings based on a total of 161 children and adolescents aged 20 years or younger with the condition showed that, akin to adults, EAS, was mainly caused by bronchial neuroendocrine tumours (NETs), followed by thymic NETs.

However, Tushar Bandgar (King Edward Memorial Hospital, Mumbai, India) and fellow researchers highlight in the European Journal of Endocrinology that while this was the case for youth aged 10–20 years, primitive cell-derived tumours (PCDTs) were the predominant cause in children up to 10 years of age.

This “indicates a unique etiological profile of pediatric and adolescent EAS”, they say.

Specifically, more than half (53.4%) of the 45 participants aged up to 10 years had PCDTs, while 36.2% of 116 aged 10 to 20 years had bronchial NETs and 27.5% had thymic NETs.

The researchers also note that between the ages of 10 and 20 years, there was a “conspicuous absence” of the small-cell lung cancer cases found in older patients and the presence of nested stromal epithelial tumours, which are not typically seen in adults with EAS.

Most of the participants were identified from a literature review conducted between 1970 and 2022, with an additional three patients who presented to the researchers’ centre between 1997 and 2021. They all had biochemically proven ACTH-dependent Cushing’s syndrome with an ectopic source confirmed by either hypercortisolism resolution after surgery or positive immunostaining for ACTH or corticotropin-releasing hormone.

The average age of symptom onset was 11.9 years and EAS was diagnosed at an average age of 13.1 years. Just over half (53.5%) of the participants were girls.

The underlying causes of EAS were bronchial NETs (28.5%), thymic NETs (22.9%), PCDTs (18.6%), gastro-entero-pancreatic NETs (13.7%) and miscellaneous tumours (16.1%).

In addition to being the most common cause of EAS in the first decade of life, the team reports that PCDTs were also the largest tumour type, at a median maximum tumour diameter of 82 mm, compared with bronchial NETs, which were the smallest, at 15 mm.

This may explain the higher sensitivity of computed tomography (CT) to diagnose EAS in this paediatric population compared with adults, say Bandgar et al. CT was used in 127 patients and showed positive localisation of tumours in 92.9% of cases, including 100% of 30 PCDTs and 85.7% of 42 bronchial NETs. This compares with a previously reported rate of 81.1% for adults with EAS, they note.

Given that Cushing’s disease is rare in children younger than 5 years old, the researchers suggest that EAS is likely to be the most common cause of ACTH-dependent Cushing’s syndrome and therefore recommend that “whole body thin-slice CT should be the first-line imaging” choice in this age group.

Weight gain and round facies were the most common features of paediatric EAS, observed in 90.0% and 97.4% of patients, respectively. Weight gain is unusual in adult EAS, which can even present with weight loss in up to 22% of cases, say the investigators, adding that “the reasons for this difference are not clear.”

Like in adults, however, paediatric EAS patients in this review were more likely to have catabolic and metabolic features than 97 children with Cushing’s syndrome without EAS, at the same centre and had higher median morning serum cortisol (1296.6 vs 766.8 nmol/L) and plasma ACTH (37.4 vs 17.2 pmol/L) levels.

Among 113 patients who underwent surgery, 77.9% went into remission immediately afterwards, which is similar to the rate for adult EAS, while 30.4% of 79 patients relapsed after a median of 13 months. Both the remission and relapse rates were similar across the various tumour types.

Based on this finding, Bandgar et al say that “if a localized source of ACTH excess is identified, a curative surgery should be offered not only to attain rapid control of hypercortisolism but also to achieve long-term remission.”

Over a median follow-up of 2 years, 31.4% of patients died within a median of 1 year. This is comparable to rates in adults, the team notes. And like adult EAS, the lowest rate of death was seen among individuals with bronchial NETs, at 6.3%, compared with 30.0–45.7% among those with other causes. The median duration of survival of bronchial NET patients was between 2 and 6 years longer than that of patients with other NETs.

Distant metastasis was an independent predictor of death, as it is in adults with EAS, with a significant hazard ratio (HR) of 7.38. Increased tumour size was also an independent predictor, at a significant HR of 1.01, whereas, unlike in adults, NET surgery was not found to be a predictor.

“[T]his is the first systematic review to describe in detail the aetiology, clinical characteristics, outcomes, and prognostic factors of paediatric and adolescent EAS”, Bandgar and co-authors conclude.

They believe that “[l]arge, multicentric, prospective studies are warranted to better characterize pediatric EAS.”

By Lucy Piper

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

Eur J Endocrinol 2023; 189: S75–S87
Martin Savage
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