Papillary Thyroid Cancer and a Promotor Mutation-positive Paraganglioma in a Patient With a Germline Mutation.

PURPOSE

About 40% of paragangliomas (PGL) are due to germline mutations in one of several susceptibility genes. These genes rarely predispose to other non-PGL tumors. Here, we describe and functionally characterize a germline mutation in a patient who developed a mutation-positive papillary thyroid cancer (PTC) and a promotor mutation-positive PGL.

EXPERIMENTAL DESIGN

A 28-year-old asymptomatic man was discovered incidentally to have a large left-sided mid-abdominal PGL and PTC. He underwent resection of the PGL and total thyroidectomy and neck dissection followed by I-131 adjuvant therapy for PTC. The histopathology revealed a high-grade PGL and a tall cell-variant PTC with lymph node metastases (T1b N1b M0). He soon developed PGL spinal metastases that have been rapidly progressing and is currently being treated with Lu-dotatate therapy. Family screening revealed a positive mutation in the mother, a son, and a brother.

RESULTS

In addition to the heterozygous germline mutation (c.688C>T, p.Arg230Cys), molecular analysis revealed a somatic promotor mutation (C228T) in PGL (negative in PTC) and a somatic mutation in PTC (negative in PGL). Functional studies showed a higher proliferation rate in the mutant compared with the wild-type SDHB.

CONCLUSION

Germline mutations rarely occur in patients with PTC and may contribute to its aggressiveness. Somatic promotor mutations rarely occur in PGL and contribute to its aggressiveness and metastatic potential.