Macrofollicular Variant of Follicular Thyroid Carcinoma (MV-FTC) with a Somatic DICER1 Gene Mutation: Case Report and Review of the Literature

Abstract

Benign thyroid lesions such as multinodular goiter and adenomatoid nodules are well-circumscribed lesions displaying a macrofollicular growth pattern and lack of nuclear atypia. The highly unusual macrofollicular variant of follicular thyroid carcinoma (MV-FTC) mirrors these attributes and is thereby misclassified by cytological examination of fine-needle aspiration biopsies. The MV-FTC diagnosis is instead suggested following histological investigation, in which malignant attributes, most commonly capsular invasion, are noted. The bulk of MV-FTCs described in the literature arise in younger female patients and carry an excellent prognosis. A recent coupling to mutations in the DICER1 tumor suppressor gene has been proposed, possibly indicating aberrancies in micro-RNA (miRNA) patterns as responsible of the tumorigenic process. We describe the cytological, histological and molecular phenotype of a 35 mm large MV-FTC arising in the right thyroid lobe of a 33-year-old female with a family history of multinodular goiter. The tumor was encapsulated and strikingly inconspicuous in terms of cellularity and atypia, but nevertheless displayed multiple foci with capsular invasion. A next-generation molecular screening of tumor DNA revealed missense variants in DICER1 (p. D1709N) and MET (p. T1010I), but no established fusion gene events. After sequencing of germline DNA, the DICER1 mutation was confirmed as somatic, while the MET variant was constitutional. The patient is alive and well, currently awaiting radioiodine treatment. This MV-FTC mirrors previous publications, suggesting that these tumors carry a favorable prognosis and predominantly arise in younger females. Moreover, DICER1 mutations should be considered a common driver event in the development of MV-FTCs.

Macrofollicular variant follicular thyroid tumors are DICER1 mutated and exhibit distinct histological features

“…We corroborate the previously assumed association between macrofollicular variants of follicular thyroid tumours and inactivating somatic DICER1 mutations. 3,4 All cases exhibited either hot-spot missense variants in codons 1709/1810/1813, truncating mutations or a combination thereof. Moreover, we describe an MV-FTA with double somatic mutations, thereby implicating that this tumour form could also associate to aberrations in DICER1.…”

“…A single case (case 1) has been previously published as a clinical case report and was included in this extended case-series to increase the validity of our histological observations. 4…”

“…No other thyroid-related mutations or fusions were found, apart from a MET gene variant in case 1, as previously described. 4 All cases exhibited either a deleterious variant (stop codon gain or frameshift), an RNAse IIIb missense mutation or a combination of both. Codons 1709/1810/1813 are hot-spots in terms of inactivating DICER1 mutations, containing the functionally important RNAse IIIb domain implicated in miRNA processing.…”

“…Case 1 had a pT2 tumour and was treated with a completion lobectomy and 1.1 giga-Becquerel (GBq) radioiodine (RAI). 4 Cases 2 and 4 exhibited pT1b tumours, of which case 2 opted in for completion lobectomy and 1.1 GBq RAI, while case 4 was released as an outpatient without adjuvant treatment. Case 3 was not offered additional treatment, given the benign diagnosis, whereas case 5 exhibited a pT3a MV-FTC and underwent an uneventful contralateral thyroid lobectomy and is currently planned for 3.7 GBq RAI treatment.…”

“…3 Shortly thereafter, we published an additional MV-FTC case exhibiting a somatic DICER1 mutation. 4 DICER1 is involved in micro-RNA (miRNA) processing, and germline mutations in this gene causes the DICER1 syndrome, an autosomal dominant, early-onset multitumour condition. 2,5,6 Notably, DICER1 syndrome patients also display an increased risk of developing multinodular goitre and thyroid tumours, and somatic DICER1 mutations and/or gene down-regulation has been observed in PTC, FTC and poorly differentiated thyroid carcinoma, thereby establishing a possible link between dysregulation of miRNAs and the development of thyroid neoplasia.…”