DICER1 Mutations and Differentiated Thyroid Carcinoma: Evidence of a Direct Association

Abstract

Context: DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established.

Case description: We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings.

Conclusions: This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.

Figures

Figure 1.

Pathological features of papillary carcinoma arising in follicular nodules in three siblings with germline DICER1 mutations. A, Low-power view of a 1.3-cm encapsulated follicular nodule in patient B. Note the apparent clonal outgrowth in the left third of the photomicrograph. B, High-power view of this area shows cytological features of papillary carcinoma. C, Low-power view of a section from a 1.6-cm partially encapsulated cystic nodule from patient A. D, Medium-power view shows papillae with overlapping nuclei, nuclear clearing, grooves, and rare pseudoinclusions. E, The brother of these two siblings had two small foci of papillary carcinoma within larger encapsulated follicular nodules with cystic change and papillary hyperplasia. A low-power view of a left lobe follicular nodule with small focus of papillary carcinoma (box) is shown in panel E. F, High-power view of papillary carcinoma shown in panel E.