A 75-year-old female was referred from a local hospital under the suspicion of Cushing syndrome. She had a 7-month history of hypertension, low potassium, uncontrollable type 2 diabetes mellitus (T2DM) and osteoporosis. She presented with a typical Cushingoid phenotype. The biochemical investigations are noted in table 1.
Q What are the clinical features of Cushing’s syndrome which have high discriminatory value ?
- Facial flushing
- >1 cm purple pink striae
- Proximal muscle weakness
- Children- Short stature
The initial biochemistry results suggested ACTH-dependent Cushing syndrome with grossly elevated plasma (P)-ACTH, P-cortisol and 24-h urinary free cortisol (Table 1). Cerebral magnetic resonance imaging (MRI) did not reveal a pituitary adenoma. At referral, she was treated by 4 different antihypertensive drugs, 90 mmol potassium daily, metformin, and insulin. A dexamethasone suppression test was performed (24 h without dexamethasone, 0.5 mg dexamethasone every 6 h for 48 h and 2 mg every 6 h for another 48 h). Urinary free cortisol levels were not suppressed after 48 hours with low-dose dexamethasone, confirming the diagnosis of Cushing syndrome. During high-dose dexamethasone exposure, a paradoxic increase in urinary free cortisol was observed (7,031 nmol/24 h at baseline vs. 8,159 nmol/24 h) supporting ACTH secretion by an ectopic source.
Q What are the conditions associated with paradoxical increase in Cortisol on low dose dexamethasone suppression test ?
- Primary pigmented nodular adrenal disease (PPNAD)
- Ectopic ACTH dependent Cushing’s
- Rarely in Pituitary macroadenoma (few case report)
Combined abdominal positron emission tomography-computed tomography (PET-CT) imaging showed a 3 × 2.5 × 2-cm heterogeneous cystic mass at the left adrenal gland with high 18F-fluorodexyglucose (FDG) uptake; therefore either a primary malignant adrenal tumor or metastasis could not be excluded. There were no other visible tumors or pathological FDG uptake.
Q Can FDG PET distinguish Benign from malignant adrenal mass ?
Yes FDG PET CT has good sensitivity and specificity for distinguish benign from malignant adrenal lesions. If SUV 3.1 is used for cut off , PET CT can reliable distinguish benign from malignant adrenal mass.
Preoperative ketoconazole treatment was initiated but had to be stopped due to a significant increase in liver enzymes. Adrenal venous sampling and bilateral inferior petrosal sinus sampling was performed in an attempt to identify the source of ACTH and cortisol secretion. However, the patient rapidly deteriorated before the results were available, and left adrenalectomy was performed to reduce tumor burden and obtain a histologic diagnosis. The histopathologic examination of the surgical specimen revealed a small rim of preserved normal adrenocortical tissue with minimal adrenocortical hypertrophy and a pheochromocytoma, sized 2.5 × 1.5 × 1.5 cm, confined to the adrenal gland without vascular invasion, necrosis, or mitoses. Sixty percent of the tumor cells stained positive for ACTH (Fig. 1, case 1). The venous samplings confirmed ACTH secretion from the left adrenal gland (ACTH: 96 pmol/L in left adrenal vein vs. 22 pmol/L in a peripheral vein, Cortisol: 4,390 nmol/L in left adrenal vein vs. 1,248 nmol/L in a peripheral vein) and excluded pituitary source by an inferior petrosal sinus/peripheral ACTH ratio of 1 after stimulation with corticotrophin-releasing hormone.
After adrenalectomy, hydrocortisone replacement therapy was initiated, and the patient recovered quickly without any features of cortisol excess 6 months post surgery.
Insulin treatment was no longer necessary, and she only required 2 antihypertensive drugs. Five years after the operation she remains on hydrocortisone replacement therapy. Prior to adrenalectomy there were no symptoms or signs of adrenergic hyperactivity, but P-metanephrines and urinary catecholamines were not measured. Postoperatively, no excess of catecholamines could be detected in plasma or urine, and no pathological uptake was seen on 123I-metaiodobenzylguanidine (MIBG) scintigraphy.
A 60-year-old female was referred from a local hospital with a history of uncontrolled T2DM, low potassium, and 10-kg weight loss. Thorax-abdominal CT imaging showed a solitary 6 × 5 × 4.5-cm cystic tumor in the right adrenal gland.
Q What would be your evaluation of this adrenal mass ?
- Overnight dexamethasone suppression test
- Aldosterone / Renin ration
- 24 hr urinary metanephrine
Considering the size of the tumor , surgery would be considered in any case.
P-ACTH and 24-hour urinary free cortisol levels were highly elevated. She was referred for further workup of the adrenal mass and due to rapid decrease in renal function over a period of 2 months. Despite weight loss, she presented with a typical Cushingoid phenotype with facial erythema, moon face, and ecchymosis. At referral she was treated with insulin, 2 antihypertensive drugs, and 100 mmol potassium daily. A diagnosis of ACTH-dependent Cushing syndrome was confirmed by grossly elevated P-ACTH and P-cortisol that did not suppress during an overnight 1-mg dexamethasone suppression test.
Cerebral MRI did not show any pituitary adenomas. During admission, her kidney function further decreased, and haemodialysis was initiated. The patient’s clinical condition was complicated by intracerebral bleeding (neurosurgery was not required), epileptic attacks, sepsis, a duodenal ulcer, and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome mandating daily plasma exchange in the intensive care unit.
A very labile blood pressure and tachycardia were observed during admission, and she reported symptoms before admission that were consistent with pheochromocytoma with attacks of dizziness, rapid heart beat, and sweating.
Q What are the classical triad of Pheochromocytoma ?
Headache, palpitation and sweating.
Therefore a diagnosis of ACTH-secreting pheochromocytoma was suspected, and P-metanephrines were measured. At the time of blood sampling, the patient was not on catecholamine therapy or other medications that could interfere with the interpretation of P-metanephrines levels.
Q What are the drugs that you need to stop before checking for catecholamines ?
- Alpha and beta blockers
Before the results were available, a right adrenalectomy was performed on vital indication. Histopathologic examination revealed a 7.5 × 5.5 × 3-cm pheochromocytoma confined to the adrenal gland. Only a small rim of normal adrenocortical tissue was preserved and was without adrenocortical hypertrophy. There were necrosis and bleeding within the tumor, but in ACTH staining in areas with vital tumor cells was positive in approximately 10% of the tumor cells
P-metanephrines taken preoperatively showed highly increased levels which normalized after surgery, and P-ACTH levels became undetectable (<1 pmol/L). Hemodialysis, plasma exchange, and insulin treatment could be stopped immediately after adrenalectomy. She recovered completely within 3 months after surgery. The patient is still supplemented with hydrocortisone 3 years later.
A 64-year-old male with a 20 years history of hypertension and T2DM was admitted to a local hospital with tachycardia, severe hypertension, and angina pectoris. He was treated with 2 antihypertensive drugs. The patient’s T2DM was well controlled by metformin and a glucagon-like peptide-1 agonist (glycated hemoglobin [HbA1c] 7.3%). He was referred to our hospital for a coronary arteriography that did not show any stenosis, and a CT scan was performed to exclude aortic dissection.
A 9 × 8 × 5-cm large irregular heterogeneous adrenal tumor was incidentally discovered. The patient had a 2-year history of sweating, tachycardia, and dyspnea, suggesting pheochromocytoma as a likely diagnosis. Levels of P-metanephrines and free urine catecholamines were highly elevated
A 123I-MIBG scintigraphy scan showed increased uptake at the adrenal mass. α-Receptor blocker treatment with phenoxybenzamine was initiated, and the patient was scheduled for adrenalectomy.
Q Discuss the preoperative management of Pheochromocytoma ?
- Start Phenoxybenzamine in dose of 10 mg twice a day 2 weeks before surgery
- Increase by 10 mg every 3rd day till target BP achieved
- Target BP
- Sitting <130/90 mm Hg
- Standing , Systolic BP >90 mm Hg
- Liberal salt intake 2-3 days before surgery with liberal IV fluids
- If Preoperative Heart rate is high, add beta blocker 2-3 days before surgery
He had no clinical signs of cortisol excess, but as part of the routine biochemical work-up we measured circulating levels of ACTH, cortisol, and 24-hour urinary cortisol, which all were markedly elevated suggesting Cushing syndrome due to ectopic ACTH production. During admission, there was a rapid deterioration of his clinical condition including atrial and ventricular tachyarrhythmias, pneumonia, and gastrointestinal bleeding. He was highly insulin resistant, requiring more than 100 units of insulin/day. A left adrenalectomy was performed without complications 3 weeks after the initial admission. Histopathologic examination revealed an 8 × 5.5 × 4-cm pheochromocytoma in areas with extra-adrenal extension and vascular invasion but without necrosis or mitoses. A small portion of the normal adrenocortical tissue was preserved with minimal adrenocortical hypertrophy. Immunohistochemical staining for ACTH revealed approximately 10% positive tumor cells
The patient recovered quickly after surgery. Hydrocortisone replacement therapy was stopped just 5 weeks after adrenalectomy due to normal levels of endogenous cortisol and no signs of adrenal failure when hydrocortisone treatment was paused. All antidiabetic and antihypertensive drugs were also stopped 1 month after surgery. Three months postoperatively, 24-hour urinary excretion of catecholamines and cortisol (58 nmol/24 h) were within normal ranges. Dual-energy x-ray absorptiometry showed normal mineral bone density with a positive T-score in both the hip and vertebrae.
Pre- and postoperative imaging did not show extra-adrenal disease in any of the 3 patients, with no local spread or distant metastases.
Learning points from this case
- Ectopic ACTH secreting tumors can have paradoxical increased Cortisol production on Dexamethasone suppression test
- Dual ACTH and Cathecholamine secreting adrenal tumors have more severe clinical presentations.