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.