ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2016) 40 P8 | DOI: 10.1530/endoabs.40.P8

Medullary thyroid cancer in a RET-negative patient with a germline SDHB mutation

J Simões-Pereira & V Leite

Endocrinology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, Lisboa, Portugal.

Introduction: Medullary thyroid cancer (MTC), in its familial forms, is usually associated with pheochromocytoma and primary hyperparathyroidism, related to an underlying germline RET mutation. SDHx germline mutations associated with MTC have not yet been reported.

Case report: We report the case of a 60-years-old woman, who was submitted, elsewhere, in November/2013, to a total thyroidectomy+right lymph-node dissection due to a nodule suspicious of MTC on fine-needle biopsy. Histology confirmed a MTC with blood vessel invasion (pT3N1bMx). Serum calcitonin was 264 pg/ml before surgery and <2 pg/ml 3 months after surgery (NR<2). Surgery induced a bilateral vocal cord paralysis and hipoparathyroidism. A pre-operatory CT scan revealed a 17 mm left adrenal nodule. She was normotensive and urinary metanephrines were normal. Her daughter had been previously diagnosed with a carotid body paraganglioma and multinodular goiter. Gene testing revealed a deletion on SDHB gene (p.Ser198AlafsX22 (c.591delC), exon 6) in both the patient and daughter; no germline mutations were found on RET, VHL, TMEM127 or other SDH genes.

Nine months after surgery, the patient was diagnosed with a biochemical (calcitonin 6.2 pg/ml (N<2.0)) and neck recurrence and she was re-operated. There were metastases in 3/29 lymph-nodes resected. Serum calcitonin increased after surgery to 27.9 pg/ml and a PET-CT showed neck and bone disease (skull, mandible, dorsal vertebrae, ribs and hip). She was submitted to radiotherapy of the mandible and dorsal spine in September/2015.

Bone disease has been progressing and the pain difficult to control. Her last PET-CT revealed new neck lesions and extensive bone disease: skull, mandible, scapula, sternum, ribs, cervico-dorso-lombar column, hip, humerus and femur. Serum CT and CEA levels were 362 pg/ml and 53.1 ng/ml, respectively. Recently, she developed high blood pressure, slight face rounding and hypokalemia. ACTH level of 58 pg/ml (NR<46) confirmed ectopic Cushing syndrome. Given the progressive and symptomatic disease she started sunitib on December 17th 2015.

Conclusion: To our knowledge, no germline mutations have been found on SDHx genes in MTC patients, turning our case the first demonstrating this association. An increased frequency of some SDHx polymorphisms in patients with sporadic and familial MTC has been reported.

Other interesting point is that our patient exhibits an extensive plurimetastatic disease with a relatively modest serum calcitonin elevation. Some authors believe that, in contrast with RET and NF-1 mutations, pheochromocytomas/paragangliomas with SDHB/D and VHL mutations are characterized by low tissue levels of epinephrine with corresponding usually normal levels of plasmatic and urinary metanephrines. Our hypothesis is that the modest elevation of serum calcitonin may be related to a poorly differentiated phenotype in patients with SDHB mutations.

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