Genetic origin of multifocal sporadic medullary thyroid cancer and C-cell hyperplasia

Objective: Sporadic medullary thyroid cancer (sMTC) mostly presents as a single lesion, but additional tumor foci may be present. The present study aimed to analyze the mutation profile of different tumor foci of multifocal sMTC to verify whether they represent an intra-organ metastatic dissemination or if they are independent tumors. Moreover, the genetics of C-cell hyperplasia (CCH) associated with sMTC was studied to verify whether CCH could be considered preneoplastic or reactive lesions. Methods: Thirty-eight multifocal sMTCs and 15 sMTCs with associated CCH were included: A total of 106 tumor foci and 25 different CCH areas were studied. The mutational status was analyzed by Next-Generation Sequencing and/or droplet-digital PCR. Results: Thirty-one/38 (81.6%) sMTCs had a somatic mutation in the main tumor, while 7/38 (18.4%) cases were negative. Thirty/31 (96.8%) mutated sMTCs had a single mutation, while 3 different mutations were detected in 1 case (3.2%). Twenty-eight/31 (90%) mutated sMTCs showed the same mutation profile in the main tumors and in all secondary foci, while 3 cases were discordant. Eleven/15 (73.4%) sMTC with CCH showed a somatic mutation in the main tumor, while 4 (26.6%) were negative. Only 1/11 (9%) mutated cases showed the same mutation in the main tumor and in the CCH. Conclusions: Our data demonstrate that multiple foci of sMTC share the same driver mutation as the main tumor and support the hypothesis that they are intrathyroidal metastases. Most of the CCH associated with sMTC should not be considered a preneoplastic lesion as they are negative for the mutation of the main sMTC.