Anaplastic thyroid carcinoma: an epidemiologic, histologic, immunohistochemical, and molecular single-institution study

Highlights

• The frequency of anaplastic thyroid carcinoma was 0.5%.

• Anaplastic thyroid carcinoma closely simulated a large variety of nonepithelial neoplasms.

• Extensive p53 expression was present in all anaplastic thyroid carcinomas.

• BRAF G469A mutation was identified in anaplastic thyroid carcinoma with follicular carcinoma component.

Summary

Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of thyroid cancer. A single-institution thyroid cancer cohort of ATC was identified within the last 10 years at our institution. Retrospective analysis revealed that the frequency of ATC was 0.5% (11/2106 thyroid carcinomas). The average age at diagnosis of ATC was 74 years, and the female-to-male ratio was 1.2:1. ATC presented as a rapidly enlarging neck mass involving predominantly the left thyroid lobe (7/11; 64%). Cervical adenopathy was present in 7 (64%) of 11 cases. Fifty-five percent (6/11) of patients had distant metastases at the time of diagnosis. Histologically, ATC closely simulated a large variety of soft tissue sarcomas; osteoclast-like giant cell–rich tumors; squamous cell, spindle cell, and small cell carcinomas; and anaplastic/large cell lymphomas. Four tumors (4/11; 36%) showed heterologous elements, including rhabdoid and chondroid differentiation. Immunohistochemical studies showed that all ATCs lost TTF-1 and thyroglobulin expression, whereas PAX-8 expression was identified in 36% (4/11) of tumors. Intense and extensive nuclear staining of p53 (>50%) and high Ki-67 proliferative rate (>30%) were seen in all ATCs (11/11; 100%). Next-generation sequencing revealed recurrent BRAF V600E and TP53 gene mutations. Individual examples of a BRAF G469A mutation in ATC with follicular carcinoma component, EGFR, PTEN, PIK3CA, and FGFR3 mutations, were also identified, whereas 1 case of ATC showed wild-type sequencing with no identifiable alterations.

Introduction

Anaplastic thyroid carcinoma (ATC) is defined by the World Health Organization classification of tumors of endocrine organs as a highly aggressive thyroid malignancy composed of undifferentiated follicular thyroid cells [1]. It usually affects elderly people, with a mean age in the mid-60s, and shows a female predominance [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. Accumulated clinical, pathologic, and experimental evidence has led to acceptance of the hypothesis that ATC transforms or evolves from preexisting differentiated thyroid carcinoma [1], [2], [5]. No precipitating events have been identified, and the mechanisms leading to anaplastic transformation of differentiated carcinomas are uncertain. More than 80% of patients with ATC have a history of goiter [5]. ATC represents the most aggressive extreme of the clinical spectrum of thyroid carcinomas, with a median survival on the order of 3 to 5 months after diagnosis and mortality rate of greater than 90% [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. Because of the aggressive nature of the disease, prompt diagnosis is critical to determining appropriate treatment options. ATC is typically diagnosed based on clinical symptoms, unlike differentiated thyroid carcinoma, which is typically diagnosed after fine-needle aspiration on a suspicious thyroid nodule. The discovery of somatic mutations integral in ATC will increase our understanding of tumor pathogenesis and should facilitate identification of mutations relevant to clinical treatment decisions and targeted therapy for this disease.

This study aims to (1) analyze the incidence of ATC based on the past 10 years of a large thyroid cancer cohort classified on current histologic criteria, (2) evaluate the morphologic features and establish an efficient diagnostic immunohistochemical panel to distinguish ATC from its mimickers, and (3) evaluate ATC for recurrent genetic mutations by sequencing.