Hidden diagnosis of multiple endocrine neoplasia-1 unraveled during workup of virilization caused by adrenocortical carcinoma
A 43-year-old lady presented to periphery hospital with history of amenorrhea for last 1 year, coarse hair growth over face, upper lip, trunk, arms and thighs, for which her abdominal computerized tomography (CT) scan was done which revealed adrenal mass of 4.3 × 3.4 cm. In view of this patient was referred to our tertiary care hospital as a case of hirsutism with adrenal lesion. She also complained of loss of scalp hairs, change in voice, proximal muscle weakness for last 1 year. Examination revealed hypertension (156/98 mm of Hg). She had normal body habitus (body mass index - 21.58 kg/m2, waist-hip ratio 0.72). She had temporal baldness, hirsutism (Ferriman-Gallway score – 26/36), facial plethora, acne over face and upper chest and back, and multiple bruise marks. Her systemic examination was normal except proximal muscle weakness at shoulder and hip joints (power at both joints was 4+/5). Laboratory investigations detected diabetes mellitus (Oral Glucose Tolerance Test – 156/298 mg/dl; A1C – 7.4%). Her serum sodium and potassium were in normal range. Her lipid profile was normal (triglyceride – 119; total cholesterol – 170, LDL cholesterol – 109 and HDL cholesterol – 37 mg/dl). Electrocardiogram revealed left ventricular strain pattern and echocardiography showed left ventricular hypertrophy. She had nonsuppressible cortisol levels with overnight dexamethasone (Serum cortisol – 33.2 μg/dL) and low dose dexamethasone suppression test (Serum cortisol – 22.66 μg/dL). Her ACTH level was 7.7 pg/ml (normal 10-67 pg/ml). High doses dexamethasone decreased cortisol value only by 34% of basal value (31.08 to 21.56 μg/dL). She had raised testosterone levels (6 ng/ml; normal <0.6 ng/ml), and DHEAS levels (445 μg/dl; normal 30-335). Her twenty four urinary metanephrine and normetanephrine levels were normal (80 and 40 μg/day respectively). Her dynamic MRI abdomen and pelvis revealed one 3.3 × 3.6 × 4.2 cm heterogeneously hyperintense lesion with small fat containing foci with possibility of benign adrenal adenoma. There were two well-defined space occupying lesions (SOLs) were seen in pancreas; one in body of 16 mm and other in tail was 13 mm in size. Also multiple collocated subcapsular space occupying lesions in segment V of liver were noted and there was one 18 mm aortocaval lymph node. 18F-deoxy glucose (FDG) PET-CT scan showed right adrenal mass of 4.1 cm × 3.7 × 3.5 cm (SUV - 7.3) and 1.5 cm aortocaval lymph node of 1.5 cm with SUV of 3.8 with possible diagnosis of adrenocortical carcinoma with lymph node metastasis []. In view of clinical, biochemical and imaging studies, she was diagnosed as a case of adrenocortical carcinoma with metastasis in lymphnode, liver and pancreas. She denied any history of similar illness or malignancy in her family.\nHer investigation had incidental and surprising finding of hypercalcemia, which was confirmed on repeat testing (Serum calcium – 12.7, 13.5 mg/dl) with hypophosphatemia (1.8 mg/dl) in presence of normal serum albumin (4 g/dl) and magnesium levels (1.8 mg/dl). Her 24 hour urinary calcium measurement revealed hypocalciuria (135 mg/dl in presence of hypercalcemia). Though, Cushing's syndrome particularly due to adrenal carcinoma, can cause hypercalcemia but is associated with hypercalciuria, but our patient has hypocalciuria, indicating another underlying cause. Second possibility considered was humoral hypercalcemia of malignancy, where parathyroid hormone (PTH) levels are low. Hence, a serum PTH level was measured and to our second surprise it was detected to be raised (1003.8 pg/ml; normal–15-68 pg/ml). A possibility of ectopic secretion of PTH was considered. Literature search revealed only 12 cases of ectopic PTH secretion and none was related to adrenal gland.[] She was evaluated for primary hyperparathyroidism and technetium sestamibi scan revealed left inferior parathyroid adenoma [], but her ultrasonography of neck was normal. Bone mineral density measurement by DXA showed osteoporosis with low T- and Z-score at spine L1-L4 (T score - 3.0; Z score -2.7), femur neck T score was -3.2; Z score -2.8 and radius T score was -3.6; Z score -3.0. Clinical dilemma faced was, whether it is sporadic parathyroid adenoma with adrenocortical carcinoma with metastasis, or is it that we are dealing with MEN1 with parathyroid adenoma and pancreatic tumor and associated adrenocortical carcinoma with metastasis. There were no symptoms suggestive of acid peptic disease, watery diarrhea, weight gain, and hypoglycemia. Biochemically her serum gastrin levels were raised (486 pg/ml; 13-115) strongly suggesting possibility of MEN1. Her upper gastrointestinal endoscopy was done to look for duodenal gastrinoma which was normal. MRI brain showed normal pituitary gland. She had normal baseline pituitary functions (thyroid profile (FT3 – 2.99 pg/ml; FT4 – 1.43 ng/ml; TSH – 4.76 μIU/ml) prolactin (26 ng/ml) and suppressible growth hormone (0.65 ng/ml) levels). Nuclear imaging for neuro-endocrine tumor was not done as it was unavailable at our institution.\nHer hypercalcemia was managed with saline diuresis and injection zoledronic acid. She was vaccinated with pneumococcal, meningococcal and H. Influenza vaccine in view of lesion in tail of pancreas which were to be excised, which are associated with risk of splenic injury and subsequent splenectomy. She underwent surgical excision of parathyroid adenoma with excision of all four parathyroids and half of one parathyroid gland was transplanted in left arm. In the same sitting, oncosurgeons operated her for pancreatic lesion. Her intra-operative ultrasound revealed three additional SOL in pancreas. Pancreatic lesion in head of pancreas was enucleated with resection of tail of pancreas for distal lesions along with splenectomy. Her adrenal lesion was excised in total with removal of aortocaval lymph node. Her postoperative recovery was uneventful.\nHistopathology revealed parathyroid hyperplasia in all four parathyroid glands with left inferior parathyroid adenoma and neuroendocrine tumor in pancreas and liver. Immunohistochemistry (IHC) [] showed similar pattern of positivity in pancreatic tumor and liver metastasis - cytokeratin, synaptophysin and chromogranin A. Adrenal lesion was seen as adrenocortical carcinoma which expressed vimentin, synaptophysin, S-100 and inhibin; all of these were shared by aortocaval lesion []. Finally, patient had parathyroid hyperplasia with pancreatic neuroendocrine tumor with liver metastasis and adrenocortical carcinoma with lymphnode metastasis confirming the diagnosis of sporadic form of MEN1 with adrenocortical carcinoma. Her postoperative PTH ratio in transplanted arm to non transplanted arm was ~ 3 (27.35/9.74). Her testosterone value got (0.33 ng/ml) normalized post operatively. She developed primary adrenal insufficiency as evidenced by her low basal cortisol on fifth post operative day (0.9 μg/dl). She has been started on replacement doses of hydrocortisone and she is planned for chemotherapy and regular follow up for periodic assessment of recovery of hypothalamic adrenal axis.\nThus, this case presented with rapidly progressive virilization with adrenal mass which during workup was detected to have parathyroid adenoma and asymptomatic pancreatic neuroendocrine lesions with liver metastasis leading to final diagnosis of clinical MEN1 syndrome with adrenocortical carcinoma.