Aggressive metastatic follicular thyroid carcinoma with anaplastic transformation arising from a long-standing goiter in a patient with Pendred's syndrome

In this article we describe detailed pathological and molecular genetics st udies in a consanguineous kindred with Pendred's syndrome. The index patien t was a 53-year-old female patient with congenital deafness and goiter. Her parents were first-degree cousins. She had a large goiter (150 g) that had been present since childhood. One of her sisters and a niece are also deaf and have goiter as well. The presence of Pendred's syndrome was confirmed by a positive perchlorate test and the demonstration of a Mondini malformat ion. Thyroid function tests (under levothyroxine [LT4] therapy) were in the euthyroid range with a thyrotropin [TSH] level of 2.8 muU/mL (0.2-3.2), a serum total thyroxine (T-4) of 90 nmol/L (54-142), and a serum total triiod othyronine (T-3) of 2.7 nmol/L (0.8-2.4). Total thyroidectomy was performed , and the mass in the right lobe was found to have invaded adjacent tissues . The histopathological findings were consistent with a follicular carcinom a with areas of anaplastic transformation and lung metastasis. The patient was treated twice with 100 mCi (131)iodine (3,700 MBq) and received suppres sive doses of LT4. Postoperatively, the serum thyroglobulin (Tg) levels rem ained markedly elevated (2,352 to 41,336 ng/mL). The patient died of a sudd en severe episode of hemoptysis. Sequence analysis of the PDS gene performe d with DNA from the two relatives with Pendred's syndrome revealed the pres ence of a deletion of thymidine 279 in exon 3, a point mutation that result s in a frameshift and a premature stop codon at codon 96 in the pendrin mol ecule. We concluded that prolonged TSH stimulation because of iodine defici ency or dyshormonogenesis in combination with mutations of oncogenes and/or tumor suppressor genes, may result in the development of follicular thyroi d carcinomas that undergo transformation into anaplastic cancers. It is lik ely that these pathogenetic mechanisms have been involved in the developmen t of aggressive metastatic thyroid cancer in this unusual patient with Pend red's syndrome.