Frequency of Cushing’s syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center

A 50-year-old woman presented to the emergency department (ED) due to gastroenteritis followed by palpitations, headache, and anxiety. She had a previous history of headaches, tremor, chest pain, palpitations, anxiety, and perspiration for at least 3 years and had had both a Coronary Care Unit admission and a neurology out-patient review for these symptoms. There was no family history of Cushing’s syndrome or pheochromocytoma. An increased blood pressure of 160/105 was found with slightly low plasma potassium (3.2 mmol/L). Bisoprolol 2.5 mg was initiated, but as the patient did not feel well on this medication a change to amlodipine 5 mg daily was made with a plan of follow-up with the general practitioner. She presented again to ED a month later with decreased appetite, weight loss of 12 kg during the last month (from 65 to 53 kg), fatigue, muscle weakness, anxiety, hirsutism, increased urine output, blurry vision, and increased palpitation and tremor. Increased plasma glucose levels and severely low potassium were found together with a metabolic alkalosis (Table 2). She was admitted with potassium replacement and insulin treatment. Following days serum cortisol was measured at different times and they were all >2000 nmol/L and urinary cortisol level was very high. Urinary steroid profile demonstrated increased secretion of cortisol metabolites and also androgens consistent with Cushing’s syndrome but no precursor steroids that could indicate an adrenocortical cancer. Her appearance was not typical for Cushing’s syndrome but she looked unhealthy with muscle wasting and rapid weight loss (Fig. 1, upper panel). A computed tomography (CT) scan identified a 3.5-cm large mass on the left adrenal and radiological bilateral adrenal hyperplasia (Fig. 2, upper panel), while the abdomen, thorax, and MRI of the pituitary were normal. Subsequent plasma ACTH was high, plasma metanephrine was almost three times upper reference limit, while plasma normetanephrine was just above the upper reference limit (Table 2). Alfa blocker and spironolactone were added and she underwent an uncomplicated left adrenalectomy 3 weeks after the admission under the cover of hydrocortisone infusion and later oral hydrocortisone. After surgery, the doses of insulin and potassium were decreased dramatically and she was discharged 4 weeks after the admission much improved. Histology showed a radically extirpated 3.5 × 2.2 × 1.5 cm large pheochromocytoma displaying multifocal evidence vascular invasion. The majority (75–100 %) of tumor cells expressed ACTH and the Ki67-index was 7 %. The surrounding adrenocortical tissue was hyperplastic and negative for ACTH immunoreactivity (Fig. 3, upper panel). Since the current WHO criteria for malignancy (presence of metastases) could not be fulfilled, the tumor was considered benign with potential of malignant behavior and so close follow-up was recommended. Two months post surgery she was in a good shape, had regained her previous weight, and all her symptoms had disappeared (Fig. 1, lower panel). During the next 4 months all medications were weaned off and she had started doing exercise on a regular basis. She claimed feeling better than she had done in many years. Three years later, there was still no biochemical or radiologic signs of recurrence.

A 44-year-old woman with levothyroxin-treated hypothyroidism was referred to the out-patient clinic from her general practitioner with the question of Cushing’s syndrome. The last few years she had suffered from depression, fatigue, insomnia, concentration difficulties, easy bruising, proximal muscle weakness, and muscle and joint pain, as well as amenorrhea. Her face had got slightly round and red. Fat deposition at the supraclavicular fossa, between the shoulders and abdomen was noted. Acne and perspiration were present but no hirsutism. Physical fitness had decreased but she was still jogging or cycling a few times a week to keep her weight stable. She had acquired stress fractures to her foot in connection with running. The symptoms had aggravated significantly during the last 3 months before referral. The patient had been on sick leave intermittently during the last years. There was no family history of Cushing’s syndrome or pheochromocytoma. Blood pressure was 130/85. Serum and urine cortisol were increased, while plasma ACTH was only marginally elevated (Table 2). MRI of the pituitary was normal and sinus petrosus sampling could not show an increase in ACTH after corticotropin-releasing hormone (CRH) stimulation. Low-dose and high-dose dexamethasone suppression test did not suppress cortisol levels, but instead paradoxical increases were seen. CT of the neck, thorax, and abdomen revealed a heterogeneous 5-cm large left adrenal mass (Fig. 2, lower panel). Plasma metanephrine, normetanephrine, and chromogranin A were all normal. Urine steroid profile demonstrated increased cortisol metabolites, low androgens, and no precursor steroids. During surgery when the left adrenal was mobilized, blood pressure increased to 250/120 and i.v. alpha blockade and adenosine were administered due to suspicion of a pheochromocytoma. After surgery the patient needed norepinephrine infusion on top of the hydrocortisone infusion. Histology revealed a radically extirpated adrenal mass presenting as nodular adrenocortical hyperplasia together with adrenal medullar hyperplasia, in which 10 % of the adrenal medullary cells expressed ACTH but the Ki67-index was low (<1 %) (Fig. 3, lower panel). In contrast, there was no ACTH expression in the nodular adrenocortical hyperplasia tissue. After surgery the patient felt better and the hydrocortisone supplementation was slowly lowered. However, at the last follow-up 2.5 years later serum cortisol and plasma ACTH were still suppressed and she still needed hydrocortisone replacement, felt tired, and was working only 50 %.