Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinicopathologic and Molecular Characteristics

Abstract

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

Methods: A detailed clinicopathologic review and targeted next-generation sequencing were performed on a cohort of well-differentiated thyroid carcinoma lacking gross extrathyroidal extension, extensive vascular invasion, or significant lymph node metastases but exhibiting DM.

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 (PTC), especially the encapsulated form (n = 8). The remaining patients harbored encapsulated Hürthle 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 eight 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 four 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 11/15 cases, the clinician was able to diagnose distant disease based on the clinical presentation. In 3/4 incidental cases that were genotyped, TERT promoter mutations were found.

Conclusions: When DM occur in primary thyroid carcinoma with low-risk histology, they are almost always found at presentation. The majority are encapsulated follicular variant of PTC 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.

Keywords: Hürthle cell carcinoma; RAS; TERT; distant metastasis; follicular variant; papillary thyroid carcinoma.

FIG. 1.

Workflow, methodology, and characteristics of the study cohort, which encompassed 123 patients with differentiated follicular cell–derived carcinoma and distant metastasis (either at clinical presentation or developed during follow-up). PDC, poorly differentiated carcinoma; EVI, extensive vascular invasion; GET, gross extension beyond the thyroid; LN, lymph node; DM, distant metastasis.

FIG. 2.

Microscopic pictures of encapsulated papillary thyroid carcinoma follicular variant with capsular invasion only and distant metastasis at presentation. (A) Low-power view (20 × ) showing marked intra-tumoral fibrosis (f). (B) Capsular invasion (CI) with complete penetration of tumor capsule (ca; 100 × ). (C) The tumor shows follicular growth (100 × ). (D) Nuclear features of papillary thyroid carcinoma: clear, enlarged, and irregular nuclei (arrows; 400 × ).