Molecular Pathological Characteristics of Thyroid Follicular-Patterned Tumors Showing Nodule-in-Nodule Appearance with Poorly Differentiated Component

SIMPLE SUMMARY: Poorly differentiated thyroid carcinoma (PDTC) is aggressive and is reportedly evoked by well-differentiated thyroid follicular-patterned tumors (TFTs). TFTs showing nodule-in-nodule (NN) appearance with PD component (PDc) but neither invasion nor metastasis are uncommon and are regarded as benign nodules despite their high-grade histological features. Our study aimed to preliminarily assess the potential role of PDc in NN in PDTC carcinogenesis using dual-color immunofluorescence of 53BP1 as a DNA damage response (DDR) molecule and the Ki-67, NRAS codon 61, and TERT-promoter (TERT-p) mutations. The prevalence of abnormal type 53BP1 expression and NRAS and TERT-p mutations in PDc was comparable to that of carcinomas. Because co-expression of 53BP1 and Ki-67 can be an indicator of altered DDR, the development of PDc in NN may be associated with DDR impairments after harboring NRAS and TERT-p mutations. Therefore, PDc in NN is potentially a precursor lesion associated with PDTC. ABSTRACT: Thyroid follicular-patterned tumors (TFTs) showing nodule-in-nodule (NN) appearance with poorly differentiated component (PDc) but neither invasion nor metastasis are diagnosed as benign nodules. Although PDc exhibits histologically aggressive features relative to the outer nodule (Out-N), its pathological significance remains unclear. TP53 binding protein-1 (53BP1) is a DNA damage response (DDR) molecule that rapidly localizes at DNA double-strand breaks. Using dual-color immunofluorescence with Ki-67, the profile of 53BP1 expression is shown to be significantly altered during diverse tumorigenesis. In this study, we aimed to elucidate the malignant potential of PDc at the molecular level. We analyzed the profile of 53BP1 expression and NRAS codon 61 and TERT-promoter (TERT-p) mutations in 16 cases of TFTs showing NN with PDc compared to 30 adenomatous goiters, 31 follicular adenomas, 15 minimally invasive follicular carcinomas (FCs), and 11 widely invasive FC cases. Our results revealed that the expression level of abnormal type 53BP1 and incidence of NRAS and TERT-p mutations in PDc were comparable to FCs, suggesting a malignant potential. Because co-expression of 53BP1 and Ki-67 can be an indicator of altered DDR, the development of PDc in NN may be associated with DDR impairments after harboring NRAS and TERT-p mutations.