Rapid development of thymic neuroendocrine carcinoma despite transcervical thymectomy in a patient with multiple endocrine neoplasia type 1
A 56-year-old non-smoker male presented with generalized bodyaches, low back pain, and proximal myopathy of 1-year duration without any fragility fractures. Examination revealed bony tenderness over the sternum and proximal muscle weakness of the lower limbs. Laboratory evaluation revealed hypercalcemia (serum total calcium 12.8 mg/dl, normal 8.5-10.5 mg/dl), hypophosphatemia (serum phosphorus 2.1 mg/dl, normal 2.5-4.5 mg/dl), normal serum albumin (3.8 g/dl), normal serum alkaline phosphatase (136 IU/L, normal 50-150 IU/L), vitamin D sufficiency (serum 25OH vitamin D 31 ng/ml), and normal renal function (serum creatinine 1.2 mg/dl). Hypercalcemia was PTH dependent (serum calcium 12.8 mg/dl with high serum intact PTH 215 pg/ml, normal 15-70 pg/ml). His hemogram and ESR were unremarkable (Hb 13.4 g/dl, TLC 6700/mm3, platelet count 2.8 lakhs/mm3, and peripheral smear showed normocytic, normochromic RBCs, ESR 20 mm at end of the first hour). A diagnosis of sporadic PHPT was made. Bone mineral density by dual energy X-ray absorptiometry showed osteoporosis (T-score −2.7 at lumbar spine, −2.0 at total hip, and −3.4 at distal forearm). Ultrasound neck revealed multiglandular parathyroid enlargement, while a 99mTc tetrofosmin parathyroid scan showed a right inferior parathyroid tumor. The patient was advised surgery as he had serum calcium >12 mg/dl and osteoporosis. The patient was subjected to bilateral neck exploration, where asymmetrical parathyroid hyperplasia was found. Subtotal parathyroidectomy (3.5 gland) with TCT was performed. TCT was performed to identify any supernumerary parathyroid glands. No supernumerary parathyroid glands were identified, and the excised thymus was unremarkable. The patient had an uneventful postoperative recovery. Histopathology showed multiglandular parathyroid hyperplasia and a normal thymus.\nOn follow-up, 8 months after parathyroidectomy, he presented with heaviness in the left side of the chest, dry cough, and exertional dyspnea of 3 months duration. Chest radiograph revealed mediastinal widening with an oval well-circumscribed homogenous opacity (-dark arrow) in left hemi-thorax. Contrast-enhanced computed tomography (CT) of thorax showed a 10 × 6.7 cm inhomogenously enhancing anterior mediastinal soft tissue mass in the prevascular space on the left side, in close proximity to the ascending aorta and arch of aorta []. Chest radiograph done 9 months earlier [] did not show any mediastinal widening.\n99mTc Methylene diphosphonate (MDP) whole-body skeletal scan showed increased tracer uptake at thoraco-lumbar vertebrae and multiple ribs suggestive of skeletal metastases. A CT-guided biopsy from D11 and L3 vertebrae showed metastatic NE carcinoma.\nThe anterior mediastinal mass was excised in toto via trans-sternal approach. On surgery, the tumor was not found to invade any of the adjacent structures. The excised tumor measured 12 × 7 × 5 cm and weighed 264 g []. On microscopy [ and ], the tumor was partially encapsulated, and was composed of rosettes of tumor cells traversed by thin fibro-vascular septae. The tumor cells displayed round to oval nuclei, granular chromatin, occasional nucleoli, and moderate amount of granular to pale cytoplasm with areas of punctate necrosis and lympho-vascular emboli suggestive of thymic NE carcinoma. Immuno-histochemical studies were suggestive of positive staining for chromogranin and synaptophysin, but absence of staining for NSE and vimentin [ and ], consistent with thymic NE carcinoma.\nWith strong suspicion of sporadic MEN-1, in view of coexistence of PHPT with metastatic thymic NE carcinoma, work up for MEN-1 was done, which revealed raised fasting serum gastrin (18,000 pg/ml, normal <200) suggestive of gastrinoma. His serum prolactin (12 ng/ml, normal 2.1-17.7 ng/ml) and serum IGF-1 (131 ng/ml) were within normal range, thereby ruling out any functioning pituitary tumors. There was no family history of disorders suggestive of MEN-1 (family pedigree chart, ). Biochemical screening of family members for MEN-1 was also negative. Somatostatin-receptor scintigraphy with 68Ga-DOTANOC PET/CT revealed somatostatin receptor expressing tumors involving second part of duodenum, head, body, and tail of pancreas, suggestive of gastrinomas. There was no evidence of somatostatin receptor expression in the mediastinum or vertebrae, suggesting that the vertebral metastasis were from the thymic NE carcinoma and not from the gastrinomas.\nThe diagnosis of sporadic MEN-1, with two major endocrine gland involvement (PHPT due to parathyroid hyperplasia and gastrinomas) along with a rare occurrence of thymic NE carcinoma was apparent. The thymic NE carcinoma had evolved rapidly within a span of 8 months after parathyroidectomy and TCT, and presented with bony metastases. With wide-spread metastatic disease, the patient was managed palliatively (pantoprazole, zoledronic acid 4 mg intravenous infusion 4 weekly and Lanreotide 20 mg intramuscular 4 weekly). The patient has been followed up with serum alkaline phosphatase, calcium, chromogranin and gastrin estimations; and 68Ga-DOTANOC PET/CT and 99mTc MDP bone scans at 6 monthly intervals, and other appropriate imaging such as abdomnal and thoracic CE-CT scans. He has been treated with external beam radiotherapy as well as 153Sm Samarium therapy for palliation of painful spinal lesions. Thirty months in follow-up, biological therapy in form of Tab. Sunitinib maleate- a multi-target tyrosine kinase inhibitor- 37.5 mg per orally, once daily was initiated in view of progressive metastatic disease, including liver, lungs and skeletal metastases, which he has received for 18 months with effective symptom palliation, and manageable toxicity. He suffered osteo-necrosis of the jaw- a known complication of long-term zoledronic acid usage, which has been managed by discontinuation of Inj Zoledronic acid and other supportive care. Four years since being operated upon for the thymic N-E carcinoma, the patient is alive, ambulatory, is reasonably symptom free with good quality of life, and is normocalcemic, with no loco-regional recurrence of the thymic tumor.