Letter to the Editor from Lamas: “Personalized Noninvasive Diagnostic Algorithms based on Urinary Free Cortisol in ACTH-Dependent Cushing Syndrome”

The differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing syndrome remains challenging. Current guidelines of the Pituitary Society have proposed an imaging-based algorithm, starting with a pituitary magnetic resonance imaging (MRI), followed by a whole-body computed tomography (CT) scan and functional tests when the MRI is normal or shows a microadenoma of less than 6 to 9 mm. However, the high frequency of incidental pituitary microincidentalomas can hinder this diagnostic strategy.

Lavoillotte et al (1) published the results of an interesting study in which they propose an alternative diagnostic algorithm that begins with urinary free cortisol (UFC), a test that is available in virtually all patients being evaluated for suspected Cushing syndrome. Their strategy would lead to a prompt treatment of patients with life-threatening hypercortisolism due to ectopic ACTH secretion and would spare many inferior petrosal sinus sampling.

While we find the approach very attractive, we do not fully agree with the management proposed for patients in the lowest UFC group. This is because it is precisely in these patients, with milder hypercortisolism, that it is difficult to differentiate ectopic ACTH secretion from the much more common pituitary-derived Cushing disease, since both clinical presentation and response to functional tests often overlap in these two entities. In the study by Lavoillotte and colleagues (1), none of the 36 patients with ectopic ACTH secretion from whom the model was generated, nor any of the 15 patients in the external validation cohort, fell into the mildest hypercortisolism group. But this is not the case for many other published series of ectopic ACTH secretion, where patients with UFC below 3 times the upper limit of normal have been reported. Although it is difficult to extract from the literature what percentage they represent among all ectopic cases, as the data are presented in aggregate, the analysis of ranges and interquartile ranges allows us to observe that there is an indeterminate number of patients (at least one) below this range in most published series (2-7). It is in these patients, who usually have small, benign bronchial carcinoid tumors, where it is easy to mistakenly indicate an inappropriate pituitary surgery, especially considering that they can present with incidental pituitary microadenomas with the same frequency as the general population (up to 20%). Performing a neck-to-pelvis CT scan, as the authors propose as an optional complement, would not always resolve the error, as up to 20% of cases of ectopic ACTH secretion do not locate the responsible tumor in initial imaging tests (8), and again, these smaller and benign tumors (mainly bronchial carcinoids) are the most frequently implicated.

For all these reasons, in this author’s opinion, the differential diagnosis between Cushing disease and mild ectopic ACTH secretion remains an unsolved issue. Therefore, studies on the differential diagnosis of ACTH-dependent Cushing syndrome focusing on patients with mild to moderate UFC elevations are needed. Given the low incidence of cases with ectopic ACTH production that meet this requirement, we should pool our efforts and address the issue through multicenter studies.

Disclosures

The author has nothing to disclose.

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