Progression of Papillary Thyroid Carcinoma to Anaplastic Carcinoma in Metastatic Lymph Nodes: Solid/Insular Growth and Hobnail Cell Change in Lymph Nodes Are Predictors of Subsequent Anaplastic Transformation

Abstract

Most anaplastic thyroid carcinomas (ATCs) arise from papillary thyroid carcinoma (PTC). This process is also called anaplastic transformation, and the morphological harbingers of this phenomenon in nodal recurrence have not been assessed systematically. For this reason, the current study focused on features of 10 PTCs with regional lymph node recurrence that was accompanied with disease progression due to anaplastic transformation in at least one of the nodal recurrences. The findings of additional 19 PTCs which recurred without anaplastic transformation after ≥ 10 years of follow-up served as the control group. There were no clinicopathological differences between the two groups at initial surgery including age, gender, tumor size, lymph node metastasis, distant metastasis, extrathyroidal extension, histologic subtype, and treatment. The median time from the initial thyroid surgery to anaplastic transformation in the nodal recurrence was 106 months (range 6 to 437 months). Mutational analyses showed recurrent PTCs with anaplastic transformation had a high prevalence of BRAF^V600E mutation (8/9) and TERT promoter mutation (9/9), both of which were detected in primary tumors. PIK3CA^H1047R mutation was detected in one case. No case had RAS mutation. Nineteen recurrent PTCs without anaplastic transformation harbored BRAF^V600E mutation and seventeen of these had TERT promoter mutation. Unlike primary tumors with subsequent nodal anaplastic transformation, TERT promoter mutation was only present in the metastatic nodal recurrence from 4 patients without transformation. No patients had neither high-grade features (necrosis and increased mitotic activity) nor solid/insular growth or hobnail cell features in their primary tumors. In the group of patients with transformation, 3 had solid/insular growth in the lymph node metastasis at the time of primary tumor resection (one displaying nuclear features of PTC and solid growth with increased mitotic activity, one with insular component consistent with poorly differentiated carcinoma component, and one displaying nuclear features of PTC and solid growth), and additional 2 patients had solid/insular growth with no high-grade features or poorly differentiated carcinoma component at the time of subsequent nodal recurrence prior to anaplastic transformation. Hobnail cell features were exclusively seen in subsequent metastatic lymph nodes prior to anaplastic transformation. The control group lacked solid/insular growth and hobnail cell features in the metastatic nodal disease. Aberrant p53 expression and loss of TTF-1 featured tumor components with anaplastic transformation. This series identified a subset of recurrent PTCs with TERT promoter mutation was prone to undergo anaplastic transformation, and that solid/insular growth and hobnail cell features were morphological predictors of anaplastic transformation in the nodal recurrence.

Keywords: Anaplastic thyroid carcinoma; Anaplastic transformation; BRAF; Papillary thyroid carcinoma; TERT.

Fig. 1

Representative histopathology of anaplastic thyroid carcinomas including sarcomatoid (a), giant cell (b), and epithelioid (c) variants

Fig. 2

Graphical representation of molecular and histologic findings of recurrent papillary thyroid carcinoma (PTC) with transformation to anaplastic thyroid carcinoma (ATC) (a) and recurrent PTC without ATC transformation (b). P indicates primary site. PL indicates lymph node involvement at the time of thyroidectomy; L with a number indicates the number of lymph node recurrences. Lymph node recurrence in which PTC transforms into ATC is grey colored

Fig. 3

Representative histology of solid/insular growth and hobnail cell change in the group of patients with subsequent nodal recurrence with anaplastic transformation. Solid pattern in case 1 (a, b) and case 6 (c, d). Hobnail cell change in case 8 (e, f). Insular pattern in case 10 (g, h)

Fig. 4

Immunohistochemistry of papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs). p53 expression is weak in PTC component (a) but diffuse and strong in ATC component (b). Hobnail cell change in a recurrent lymph node metastasis (case 3) shows diffuse and strong p53 positivity (c). Nuclear expression of TTF-1 is retained in the PTC component (d) but lost in the ATC component (e) within the same tumor. Nuclear positivity of β-catenin is absent from all study samples (f)

Fig. 5

Schematic representation of putative pathway of anaplastic transformation in recurrent papillary thyroid carcinoma