Bilateral follicular variant of papillary thyroid cancer with different RAS mutations detected with next‐generation sequencing: Report of an unusual case and literature review

Abstract

Multifocality in papillary thyroid carcinoma (PTC) is a common finding, but the clonal relationship between individual tumors remains uncertain. While multiple synchronous tumor foci of PTC may develop through permeation of intraglandular lymph vessels of a single malignant clone, they can also arise from independent progenitor clones sustained by different genetic events. We report the case of a 37‐year‐old man who underwent total thyroidectomy after fine‐needle aspiration of two bilateral thyroid nodules that yielded cytological findings consistent with atypia of undetermined significance/follicular lesion of undetermined significance. By next‐generation sequencing of a large panel of thyroid carcinoma related genes, we found that the larger tumor harbored a mutation of the NRAS gene, while the contralateral tumor harbored a different mutation in the HRAS gene. Final pathology of the surgical specimen showed two encapsulated follicular variant papillary thyroid carcinomas of 16 and 6 mm in the right and the left lobes, respectively. To the best of our knowledge, this is the fourth case of multifocal PTC showing different HRAS and NRAS mutations, and highlights that mutational heterogeneity is also present in non‐BRAF, non‐RET genes, supporting the hypothesis that independent progenitor clones may explain multifocality in papillary thyroid carcinoma.

Multi‐UniFocality (MUF), in contrast to multifocality, in thyroid lesions: Relation to lymphocytic thyroiditis

“…More recently, an NGS‐based approach was applied by Marín et al in their patient case involving two encapsulated FVPTC foci ( HRAS and NRAS variant, respectively) in contralateral lobes 15 ; A similar case is described in the present series. Lu et al implemented whole exome sequencing and targeted region sequencing, providing insight on tumorigenesis with extensive analyses in eight multifocal PTC cases featuring likely common clonal foci, but also likely independent clonal foci whether or not accompanied by the former 1 ; in line with findings in the present report.…”

“…14 Few studies explored clonality in multifocal PTC using BRAF analysis only, 55,56 RET/PTC-1, -2, -3 only, 57 or additional miRNA profiling. 58 Multiple mutations (BRAF, NRAS, HRAS, KRAS), and gene rearrangements (RET/PTC1, RET/PTC3) were tested for in multifocal PTC in the study by Bansal et al 14 More recently, an NGS-based approach was applied by Marín et al in their patient case involving two encapsulated FVPTC foci (HRAS and NRAS variant, respectively) in contralateral lobes 15 ; A similar case is described in the present series. Lu et al implemented whole exome sequencing and targeted region sequencing, providing insight on tumorigenesis with extensive analyses in eight multifocal PTC cases featuring likely common clonal foci, but also likely independent clonal foci whether or not accompanied by the former 1 ; in line with findings in the present report.…”

“…Also, Bansal et al characterized multifocal PTC in 60 patient cases, reporting that multiple synchronous independent primary tumors typically occurred in different lobes, showed distinct growth patterns, and no microscopic peritumoral dissemination 14 . And in their case report, Marín et al described a patient with bilateral follicular variant PTC harboring a different HRAS and NRAS variant per focus, consistent with independent clonality 15 …”

“…14 And in their case report, Marín et al described a patient with bilateral follicular variant PTC harboring a different HRAS and NRAS variant per focus, consistent with independent clonality. 15 The recognition of unifocality within multifocal thyroid lesions (Multi-UniFocality, MUF) may justify the independent clinical consideration per individual tumor focus; as a separate lesion albeit within a multifocal context. Accordingly, the recognition of MUF may potentially improve diagnosis and alter further clinical management, regarding (completing) thyroidectomy and/or subsequent radioactive iodine (RAI), in select cases.…”

Advances in targeted therapy and biomarker research in thyroid cancer

“…Molecular biomarkers are essential for thyroid cancer diagnosis, prognosis, and treatment because they offer important information on the molecular features of the illness ( 7 ). BRAF mutation ( 8 ), RAS mutation ( 9 ), RET/PTC rearrangement ( 10 ), PAX8/PPARγ rearrangement ( 11 ), and TERT promoter mutation ( 12 ), are among the major molecular indicators linked to thyroid cancer. The mutation V600E in the BRAF gene is frequently found in papillary thyroid carcinoma (PTC).…”