Adrenocortical carcinoma (ACC) consists of a malignant neoplasm arising from the adrenal cortex that typically has a poor prognosis [1]. It is a very rare endocrinopathy, with an estimated incidence of 0.7 to 2 cases per million per year [1, 2]. The age of diagnosis during adulthood typically ranges around the fifth to sixth decade of life, but another peak may be seen in childhood during the first decade of life [1].

This neoplasm may present with symptoms and signs of hormone excess (40 to 60% of patients) or nonspecific symptoms due to tumor growth (about a third of patients) [3]. More rarely, ACC may be incidentally diagnosed through imaging procedures for unrelated health issues [4]. Biochemical evidence of excess adrenocortical hormone secretion is present in up to 70% of the cases, with hypercortisolism being the most common [1]. If hypercortisolism occurs, patients may present with rapidly progressive Cushing’s syndrome―manifestations may include facial plethora, violaceous abdominal striae, easy bruising, proximal muscle weakness, new-onset diabetes mellitus, osteoporosis, hirsutism (in female patients), hypertension, and hypokalemia [1, 5]. The Cushing’s syndrome associated with ACC is characteristically classified as ACTH-independent, as most patients with cortisol-secreting tumors will have a morning level of ACTH of less than 10 pg/mL [1, 6].

On the other hand, ectopic Cushing’s syndrome (ECS) is an infrequent form of ACTH-dependent Cushing’s syndrome that is typically associated with severe hypercortisolism due to adrenal cortex stimulation by ectopic ACTH secretion [7]. ECS characteristically derives from neuroendocrine tumors, which may vary in clinical aggressiveness and location. The most common causes of ECS are bronchial carcinoids, small-cell lung carcinomas, gut neuroendocrine tumors, thymic carcinoids, medullary thyroid carcinomas, and pheochromocytomas/paragangliomas [7]. Other well-established, albeit rare, possible etiologies include breast [8], ovaries [9] and prostate cancers [10], uterine tumors [11], parotid tumors [12], olfactory bulb neuroblastomas [13], sarcomas, and peritoneal [14] and pleural [15] mesotheliomas. Interestingly, other tumoral sites have been exceptionally described, namely the ileum, mesentery [16], liver [17], and the sphenoid sinus [18].

A previously healthy 26-year-old woman was referred to our department due to a history of weight gain, peripheral edema, hair loss, hirsutism, and acne that had been evolving for the past 8 months. In the last month, she also reported new-onset arterial hypertension and vinous abdominal striae. Her family physician had already asked for an abdominal computed tomography scan that showed a bulky tumor mass arising from the right adrenal gland with areas of necrosis, invaded the ipsilateral kidney and the liver, and had an estimated size of 16.2 × 14.6x20.2cm. On physical examination at the first endocrinology appointment, the patient had an arterial blood pressure of 160/100 mmHg, facial plethora, dorsocervical fat pad (buffalo hump), large vinous striae on the abdomen and thighs, proximal muscle atrophy, and axillary acanthosis nigricans.

Laboratory studies were ordered, and all of the hypercortisolism screening tests were positive: serum cortisol of 36.2 μg/dL after the 1 mg overnight dexamethasone suppression test, 24-h free urinary cortisol of 1260.0 μg (reference range (RR): 4.3–176.0 μg), and late-night salivary cortisol of 4.070,μg/dL (RR: 0–0.208 μg/dL). Unexpectedly, her morning-ACTH serum level was elevated: 351 pg/mL (RR: 9–52 pg/mL; chemiluminescent immunoassay testing by IMMULITE® 2000); we repeated this dosing and the result was consistent: 556pg/mL (electrochemiluminescent immunoassay testing by Roche Cobas® E601). She had a mild hypokalemia of 3.28 mmol/L (RR: 3.50–5.00 mmol/L) and an elevation of all serum androgens, including dehydroepiandrosterone sulfate (916 μg/dL, RR: 35–430 μg/dL). There was no biochemical evidence of primary hyperaldosteronism or elevation of serum or urinary metanephrines. The most relevant lab results are displayed in Table 1.

Functional imaging studies were also performed. A 18F-FDG PET/CT scan confirmed an adrenal voluminous hypermetabolic mass (maximum standardized uptake value (SUVmax) of 30.4), compatible with a high-grade malignant neoplasm with invasion of the right lobe of the liver and the right kidney; secondary hypermetabolic liver lesions, suggesting metastasis, were also documented. A 68Ga-DOTATOC PET/CT scan further confirmed the aforementioned adrenal mass and liver metastasis (Fig. 1).

68Ga-DOTATOC PET/CT scan showing a bulky adrenal mass and liver metastasis

Based on these clinical, analytical, and imaging studies, we were able to conclude that the patient probably had a functional ACC causing both hypercortisolism and hyperandrogenism. We could not explain the high levels of ACTH as the PET scans showed no other synchronous tumors that could potentially be associated with ectopic ACTH production.

The patient was then proposed for surgical debulking, but unfortunately during the procedure, the tumor mass was deemed unresectable due to direct invasion of the right kidney and retroperitoneum and the presence of multiple metastatic liver nodules. Additionally, the tumor was subjected to spontaneous rupture during surgery, resulting in the release of tumor tissue into the abdomen. During the procedure, a biopsy from one of hepatic nodules was taken, and histopathological examination revealed infiltration of the liver parenchyma by nodules of large cells with abundant eosinophilic cytoplasm. The neoplastic cells exhibited intranuclear inclusion, brisk mitotic figures (> 20 per 10 high power fields (HPF) visible in the small sample, which is > 20 per 50 HPF according to Weiss score), atypical mitoses, and tumor necrosis (Fig. 2). These findings confirmed the clinical suspicion of metastatic adrenocortical carcinoma to the liver. Immunohistochemical analysis was performed on the liver biopsy, and the tumor cells were found to be positive for synaptophysin, inhibin, and ACTH and were negative for chromogranin (Fig. 3), thus proving the adrenocortical origin of the neoplasm and the ability to synthesize ACTH.

Biopsy from liver metastasis showing infiltration of the liver parenchyma by large nodules of cells with eosinophilic cytoplasm (H&E × 40). Higher power view showing the neoplastic cells have abundant eosinophilic cytoplasm and numerous mitotic figures (H&E × 200)

A Tumor cells showing positive cytoplasmic staining for synaptophysin (100x). B Positive cytoplasmic staining for α-inhibin (100x). C Focal positive cytoplasmic for ACTH (100x). D Negative staining for chromogranin A (40x)

Palliative chemotherapy with a combined regimen of etoposide, doxorubicin, cisplatin, and mitotane was then offered to the patient. She was also started on metyrapone and spironolactone to control both the hypercortisolism and hyperandrogenism symptoms. Unfortunately, the patient ended up suffering from a sudden death event less than a month after her first chemotherapy cycle. The family refused autopsy examination.