The clonal origin of multifocal papillary thyroid cancer: intrathyroidal spread or independent tumors?

Multifocality is a common finding in papillary thyroid cancer but the molecular pathogenesis, prognosis and management of multifocal papillary thyroid cancer are debated. The clonal origin of multifocal papillary thyroid cancer represents a controversial aspect, as two opposite viewpoints have been proposed: independent origin or intraglandular spread. Different approaches have been used for inferring the clonality of multifocal papillary thyroid cancer, including X-chromosome inactivation, mutational analysis, determination of loss of heterozygosity and, more recently, next-generation sequencing. Next-generation sequencing, able to provide information on genetic heterogeneity and phylogenetic evolution in multifocal tumors, represents the most reliable approach. While most evidences indicated an independent origin of multifocal papillary thyroid cancer, a minority of studies suggested that multifocal papillary thyroid tumors might be monoclonally derived. This discrepancy may reflect technical limitations; nevertheless, studies based on next-generation sequencing indicated that both independent and clonal origins are possible. The co-existence of multiple tumors implies a high degree of genetic heterogeneity, which may influence the best and targeted therapeutic strategy. On the other hand, intrathyroidal dissemination may indicate metastatic potential of the dominant tumor, thereby prompting more aggressive treatments. In conclusion, data available in the literature indicated that multifocal papillary thyroid cancer may derived from both intraglandular spread and independent tumor foci. The understanding of the clonal origin of multifocal papillary thyroid tumors might represent an important issue in patient treatment.