circumstances Leading to the Initial Diagnosis Symptoms leading to the diagnosis of ACC can be due to steroid excess and/ or tumour mass and metastases. Although ACC is not the most frequent diagnosis of incidentalomas, nowadays the diagnosis of ACC is more often made during the diagnostic work- up of an adrenal incidentaloma. This circumstance is important since it might be a way to diagnose an ACC at an earlier stage and to improve the prognosis by an early complete surgical removal. This underlines the need for careful investigations of adrenal incidentalomas in order to decide on timely surgery if malignancy is suspected. Other specific features may be associated with rare genetic diseases such as the Li– Fraumeni and Beckwith– Wiedemann syndromes where ACC is part of a more complex syndrome as just discussed.
Less than a third of ACC are really ‘non- hypersecreting’ after careful hormonal investigations. In these cases, one should be cautious not to overdiagnose a tumour of the adrenal area as an ACC. These non- hypersecreting ACC can be diagnosed after investigation of adrenal incidentalomas or discovered by the manifestations of the tumour growth or extension: local symptoms (pain, palpation of a tumour, venous thrombosis), or distant metastases (liver, lung, bones). Fever may occur in some after tumour necrosis. However, in non- functional ACC, the general wellbeing of the patient is usually preserved until at a very late stage when the tumour causes signs and symptoms due to tumour expansion, which likely explains that non- hypersecreting ACC are typically diagnosed at a late stage.
Steroid excess
Most patients will present with signs of steroid excess. Cushing’s syndrome associated with signs of androgen excess with rapid onset and progression of clinical symptoms is the most characteristic presentation (Figure 1). Signs of mineralocorticoids or oestrogen excess are less frequent but highly suggestive of the diagnosis of ACC in a patient with an adrenal mass above 3 cm.
Fig1. Steroid secretion. The figure shows the frequency of each steroid secretion profile (expressed as percentage) according to hormonal investigations in secreting ACC (Cochin endocrinology department series, investigated as reported in Abiven et al. 2006 [22]). Note that almost half of the secreting tumours are associated with mixed secretion of cortisol and androgens.
More than three- quarters of ACC are secreting tumours when assessed by careful hormonal investigations with current plasma and urine assays. In the absence of steroid excess, one should be cautious before diagnosing a mass of the adrenal area with suspicious imaging findings as an ACC. Hormonal investigations also provide important information for patient management and can serve as a tumour marker for follow- up. In 2018, the ACC guideline of the European Society of Endocrinology (ESE) and ENSAT has recommended a minimal hormonal work- up in patient with ACC [24] (Box 1).
Box1. Hormonal investigations in patients with ACC
In contrast to benign adrenocortical tumours, which usually oversecrete a single steroid, usually either cortisol or aldosterone, ACC can secrete various types of steroids. Cosecretion of androgens and cortisol is the most frequent and is highly suggestive of a malignant adrenocortical tumour. Cortisol oversecretion will in duce centripetal obesity, protein wasting with skin thinning and striae, muscle atrophy (myopathy), and osteoporosis. Cortisol excess can also cause increased infections, diabetes, hypertension, psychiatric disturbances, and gonadal dysfunction in men and women. Androgen oversecretion may induce various manifestations in women: hirsutism, menstrual abnormalities, infertility, and eventually frank virilization (alopecia, deepening of the voice, clitoris hypertrophy). ACC can also secrete mineralocorticoids and steroid precursors. Oversecretion of oestrogens can be observed in rare cases and is very suggestive of ACC in a male patient with an adrenal tumour. Oestrogen excess is responsible for gynaecomastia in male.
Adrenocorticotrophic hormone (ACTH)- independent cortisol oversecretion is easily demonstrable: increased urinary cortisol excretion that is not suppressible with high doses of dexamethasone, and associated with undetectable ACTH plasma levels. Plasma 17- hydroxyprogesterone is often elevated at baseline and/ or after ACTH stimulation, as well as the adrenal androgen precursor dehydroepiandrosterone sulphate (DHEA-S), which can lead to testosterone excess in females. Secretion of aldosterone by ACC is not frequent and can be detected by plasma aldosterone and renin assays.
Recently, mass spectrometry approaches have allowed detailed steroid profiling including precursor steroids usually not captured with routine assays, revealing a pattern of predominantly immature, early- stage steroidogenesis in ACC versus ACA and healthy controls. Interestingly, urinary steroid metabolite profiling detected abnormal steroid precursor excretion even in ACC that were considered as non- hypersecreting using routine biochemical work- up. Thus, urine steroid metabolomics can be used as a biomarker tool for detecting malignancy in adrenal tumours.
