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6.1 How Often Will I Find an Adrenocortical Carcinoma with Associated Endocrine Syndromes in My Practice?

Interestingly, 50–60% of adrenocortical carcinoma (ACC) patients present with steroid hypersecretion at diagnosis, which may result in overt endocrine syndromes, which cause additional challenges to the management [1, 2]. In a large and well-characterized series of patients with ACC from 12 expert centers in Italy, steroid hypersecretion was reported in more than half of cases and hypercortisolism was the most common hormonal excess in both sexes [3]. In women with ACC, the second most common isolated hypersecretion was androgen excess, while ACC secreting aldosterone or estrogens in men were uncommon [3]. Secretion of multiple steroids (usually cortisol plus androgens, or cortisol and other steroids) is a frequent condition, which can be considered a hallmark of ACC [1].

6.2 What Is the Clinical Presentation of Adrenocortical Carcinoma with Associated Endocrine Syndromes?

Hypercortisolism can occur with a large spectrum of clinical manifestations, from subclinical to overt Cushing’s syndrome (CS), depending on the severity and the duration of glucocorticoid excess.

In patients with overt CS, physical examination can reveal central obesity with muscle hypotrophy of the upper and lower limbs, round face (the so-called “moon-like face”), a hump on the back of the neck (“buffalo hump”), thin skin with purple striae and widespread ecchymoses. When faced with this full-blown picture, often associated with severe metabolic alterations (hypokalemia, hyperglycemia, metabolic alkalosis), the diagnosis of CS is fairly obvious [4]. However, other patients could present with subtle cortisol secretion, without overt stigmata. Even patients with subclinical CS can show detrimental consequences such as hypertension, insulin resistance with glucose intolerance or type 2 diabetes mellitus, hirsutism and menstrual irregularities (in women), neuropsychological symptoms (including depression, insomnia, irritability and memory loss), proximal myopathy and osteoporosis with an increased risk of bone fractures. A high frequency of thromboembolic events has also been reported. This is due to a hypercoagulability status that contributes, in addition to the abovementioned cardiometabolic comorbidities, to produce an increased risk of cardiovascular events. Finally, the chronic exposure to hypercortisolism causes immunodepression with a consequent increased risk of bacterial, viral and fungal infections [5]. Therefore, patients with cortisol-secreting ACC are complex and fragile, and they need a multidisciplinary approach for optimal management.

Androgen excess in women can cause hirsutism, acne and signs of virilization, such as deepening of voice and temporal balding, which only occur in females with severely high levels of serum androgens. Estrogen excess can cause testicular atrophy and gynecomastia in men through the induction of hypogonadism. The excess of mineralocorticoids is characterized by severe hypokalemia and hypertension [6].

6.3 How to Diagnose the Endocrine Syndrome Associated with Adrenocortical Carcinoma?

As recommended by the European Society of Endocrinology (ESE) and European Network for the Study of Adrenal Tumors (ENSAT) guidelines, in all patients with a suspected ACC a careful physical examination aiming to identify suggestive clinical features of steroid excess and a hormonal work-up should be performed before surgery [2]. The key points to assess the hormonal activity of adrenal masses are reported in the chapter on adrenal incidentaloma (see Ch. 8).

In the case of a suspected ACC, the hormonal work-up should also include assessment of serum dehydroepiandrosterone sulfate (DHEAS), 17-OH progesterone, androstenedione, 17β-estradiol (only in men and postmenopausal women), and testosterone (only in women).

The identification of hormonal hypersecretions is a key step in the management of patients with ACC, particularly in the case of hypercortisolism. Severe cortisol excess can cause life-threating complications (hypokalemia, infections, thromboembolic events) that should be recognized and treated as soon as possible, requiring a medical treatment which could impact the chances of patient survival. Moreover, patients with cortisol-secreting ACC who underwent surgery could develop postoperative adrenal insufficiency. Finally, monitoring of the steroid profile during follow-up after radical resection may be useful to detect ACC recurrence.

6.4 Does Hypercortisolism Affect Patient Outcome?

Cortisol excess is a well-known negative prognostic factor in patients with ACC, in addition to tumor stage, resection status and Ki67 index [7,8,9,10].

In recent decades, retrospective studies [11,12,13,14] and a meta-analysis [15] showed that hypercortisolism was a strong independent factor associated with shorter overall and recurrence-free survival. Conversely, no association between androgen excess and survival has been found (relative risk 0.82, 95% CI 0.60–1.12) [15].

Interestingly, a recent multicenter study demonstrated that at multivariate analysis hypercortisolism was associated with a higher risk of recurrence (hazard ratio [HR] 2.17; 95% CI 1.50–3.12; p < 0.001] in patients with localized ACC, and with a high risk of mortality both in patients with localized (HR 2.15; 95% CI 1.34–3.46; p = 0.002) and metastatic (HR 2.05; 95% CI 1.06–3.98; p < 0.05) disease at diagnosis [3].

However, the exact mechanisms responsible for this detrimental impact of hypercortisolism on prognosis are largely unknown. Many factors can be considered. First, severe hypercortisolism causes several potentially life-threating complications, as previously discussed. Moreover, cortisol excess has an immunosuppressive effect which may favor tumor progression. Another reasonable hypothesis is that functional tumors are more aggressive. This concept is supported by retrospective studies reporting higher Ki67 index in this subset of tumors compared to non-secreting ACC [3, 9] and by genomic studies demonstrating a transcriptome signature in cortisol-secreting tumors linked to a more aggressive behavior [16].

6.5 Which Treatment for Endocrine Syndromes?

When addressing hypercortisolism in patients with ACC, it is important to implement two parallel strategies: on one hand, a prompt control of cortisol excess and, on the other hand, treatment and prevention of the complications of CS.

Adrenalectomy is the mainstay treatment of ACC and aims to achieve complete resection in patients with localized disease or debulking in metastatic patients. Nonetheless, it is sometimes necessary to control hypercortisolism with medical treatment before surgery to reduce the risk of perioperative and postoperative complications. Presurgical control of cortisol excess is mandatory when the operative risk is presumed to be elevated because of poor general condition and/or severe hypercortisolism. A nationwide analysis including 276 patients with functional ACC (86% cortisol, 16% aldosterone, and 4% androgen excess) showed a significantly increased risk of wound issues, adrenocortical insufficiency and acute kidney injury in the postoperative period and a longer hospital stay compared with 1923 patients with non-functional ACC [17]. Similarly, a retrospective study, analyzing perioperative complications and mortality within 30 days from adrenalectomy, reported longer hospital stay and increased frequency and severity of complications in patients with cortisol-secreting compared with non-cortisol-secreting ACC [14].

The other cornerstone of treatment in ACC is mitotane, a cytotoxic drug that is also able to inhibit several enzymes of adrenal steroidogenesis. Therefore, mitotane reduces cortisol secretion, but it has a slow onset of action and it could require months before reaching full efficacy which is linked to therapeutic plasma concentrations [18]. To promptly control severe hypercortisolism, steroidogenesis inhibitors with rapid onset of action can be used. Ketoconazole, metyrapone and osilodrostat are administered orally, while etomidate is administered intravenously.

Moreover, in patients with severe hypercortisolism, a combined therapy could be useful. The combination of metyrapone and ketoconazole with mitotane was reported to rapidly control severe hypercortisolism in eight patients with ACC, leading to a dramatic reduction of cortisol secretion during the first week of treatment and a rapid clinical improvement of diabetes and hypertension [19]. In a case series of three patients with advanced ACC, the addition of metyrapone to EDP-M (etoposide, doxorubicin and cisplatin plus mitotane) regimen was effective and well tolerated [20]. This last study shows another possible indication for anti-cortisol treatment, in preparation for chemotherapy to reduce the risk of infections.

When mitotane reaches therapeutic plasma concentrations, the dose of other steroidogenesis inhibitors can be reduced, according to clinical response and cortisol levels. Later, glucocorticoid replacement therapy with cortisone acetate should be administered throughout treatment with mitotane.

Osilodrostat is the most recently introduced drug for the treatment of hypercortisolism, so the evidence in patients with ACC is limited. One study demonstrated the efficacy and safety of osilodrostat in patients with CS due to ACC [21]. The study showed that osilodrostat had quick action while sensitivity to the drug varied among the patients; for this reason, a wide range of doses was used and monitoring of serum and urinary cortisol 2–5 days after the beginning of treatment is recommended to adjust dosing. A block-and-replace therapy is suggested to enable the use of larger doses with the aim of ensuring more rapid efficacy while avoiding adrenal insufficiency [21].

The management of comorbidities of hypercortisolism is key for patients with ACC and CS. The monitoring of blood pressure and glycemic levels is necessary to optimize the treatment of hypertension and diabetes. After adrenalectomy or start of steroidogenesis inhibitors, serum cortisol should decrease, allowing the dose of antihypertensive and antidiabetic medications to be reduced.

As hypercortisolism induces immunosuppression, to prevent the occurrence of opportunistic infections, trimethoprim-sulfamethoxazole should be administered in patients with very high 24-h urinary free cortisol levels and/or additional risk factors (hyperglycemia, obesity) [22] since pneumonia due to Pneumocystis jirovecii in patients with moderate-severe hypercortisolism is associated with high mortality rate [23]. In the case of infections a prompt treatment is mandatory.

Thromboembolic events must be treated with anticoagulant therapy, and they can be prevented with pharmacologic (i.e., low-molecular-weight heparin) or non-pharmacologic (i.e., elastic compression stockings and intermittent pneumatic leg compression) prophylaxis, according to the individual risk of bleeding [22].