Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinico-Pathologic and Molecular Characteristics.

BACKGROUND:

Distant metastases (DM) are a rare occurrence in well differentiatedwell-differentiated thyroid carcinoma. The aim of our study was to analyze the clinical, pathologic, and molecular features of primary thyroid carcinoma with low risk histology that develop DM.

METHODS:

Detailed clinico-pathologic review and targeted next generation sequencing were performed on a cohort of well-differentiatedwell-differentiated thyroid carcinoma lacking gross extrathyroidal extension, extensive vascular invasion or significant lymph node metastases but exhibiting distant metastases.

RESULTS:

Primary well-differentiated thyroid carcinoma with low risk histologic features and DM was a rare occurrence, accounting for only 3% of metastatic non-anaplastic thyroid carcinoma. All 15 cases meeting the inclusion criteria harbored DM at presentation. The majority (11/15) of these tumors were follicular variant of papillary thyroid carcinoma (FVPTC), especially the encapsulated form (n = 8). The remaining patients harbored encapsulated HurthleHürthle cell carcinoma (n = 2), encapsulated follicular carcinoma (n = 1), and an encapsulated papillary carcinoma classical variant (n = 1). Of the 12 encapsulated carcinomas, 10 had capsular invasion only and no vascular invasion. Ninety-two percent of the tumors exhibited extensive intra-tumoral fibrosis. Among the 8 tumors that were subjected to next generation sequencing analysis, a RAS mutation was the main driver (5/8), and TERT promoter mutation was highly prevalent (6/8). In 4 cases, TERT promoter mutations were associated with RAS or BRAF mutations. BRAF-mutated classical variant of papillary carcinoma also presented with DM but was less common (1/8). In 11 of 15 cases, the clinician was able to diagnose distant disease based on the clinical presentation. In 3 of 4 incidental cases that were genotyped, TERT promoter mutations were found.

CONCLUSIONS:

When distant metastases occur in primary thyroid carcinoma with low risk histology, they are almost always found at presentation. The majority are encapsulated FVPTC with capsular invasion only. TERT promoter mutations occur at a higher rate than that seen in PTC in general and may help explain the aggressive behavior of these histologically deceptive primary carcinomas.

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