Cushing's syndrome, pheochromocytoma, or both?

CLINICAL CASE: A 45-year-old woman presented to the emergency department with weakness and was found to have a Hb level of 68 g/l. She was also tachycardic (pulse 118 x/min) and hypertensive with a BP of 210/108 mmhg. She had a history of ulcerative colitis, menorrhagia and seronegative arthritis for which she had been using 5mg prednisolone daily for several years. The patient had suffered and episode of heart failure 4 years earlier of unknown etiology, during which she was tachycardic, hypertensive and her LVEF was decreased to 35%. In 2016 the patient had undergone an abdominal CT that had shown an incidental finding of a mass in the right adrenal gland, but she did not show up for additional investigations. During the previous year, the patient had developed symptoms of decreased physical fitness, increased weight, livedo reticularis-type skin changes (Figure), agitation, hirsutism and swelling on the neck. Gastroscopy revealed esophageal candidiasis and abdominal CT-scan showed a mass in the right adrenal gland that had increased in size from 2 cm to 3.8 cm compared to the previous CT in 2016 with a density of 21 HU. The patient had clinical Cushing's syndrome, that was confirmed in the lab tests (Table). In addition, lab tests showed an excess production of catecholamines. MRI of the sellar region was performed, that showed a 3×4×3 mm size Rathke's cleft cyst/microadenoma. A CRH stimulation test with inferior petrosal sinus sampling was performed and results were consistent with ectopic ACTH production. The clinical studies were consistent with pheochromocytoma that was also producing ACTH. The patient underwent unilateral adrenalectomy after having been treated with metyrapone and phenoxybenzamine preoperatively. Histopathology was compatible with pheochromcytoma. ACTH staining was negative, but CRH staining was not available. MIB-1 proliferation index was ≤3%. Postoperatively hypercortisolism and catecholamine excess have subsided. The patient has stopped diabetic and antihypertensive medication and she also been cured of the notable livedo reticularis-type skin changes (Figure). CONCLUSION: The clinical presentation of pheochromocytoma in our patient was atypical with coexistence of ACTH-dependent Cushing's syndrome. Furthermore, the patient had a mass in the hypophysis that could have been a potential cause for ACTH-secretion. The clinical and biochemical signs were completely reversed with adrenalectomy, compatible with ectopic Cushing's syndrome due to a pheochromytoma that produced both catecholamines and most probably CRH. In summary pheochromocytomas can rarely also secrete other hormones such as interleukins, calcitonin, ACTH or CRH and this can significantly alter the clinical presentation of both Cushing's syndrome and pheochromocytoma. A recent meta-analysis (Elliott, JCEM 2021) reported 99 published cases of ACTH/CRH-producing pheochromocytomas. [Figure: see text] [Figure: see text]