Case Reports: Follicular Carcinoma Presenting as Autonomous Functioning Thyroid Nodule and Containing an Activating Mutation of theTSH Receptor(T620I) and a Mutation of TheKi-RAS(G12C) Genes

Abstract

Most autonomous functioning thyroid nodules (AFTN) are benign thyroid follicular neoplasms. There are rare reports of malignant hot nodules, in which activating mutations of the TSH receptor (TSHR) were found. We report a case of follicular carcinoma presenting as an AFTN causing subclinical hyperthyroidism in a 64-year-old woman who had a 6-cm hot nodule in the left thyroid lobe. Genomic DNA was extracted from paraffin-embedded tissues from the tumor and extratumoral thyroid tissue. Sequence analyses revealed point mutations in two different genes: the normal ACC sequence at codon 620 of the TSHR gene was replaced by ATC, changing the threonine by isoleucine (T620I); and the wild-type GGT at codon 12 of Ki-RAS mutated to TGT, replacing glycine by cysteine (G12C). In transfection experiments the T620I mutant showed constitutive activity in terms of cyclic adenosine monophosphate (cAMP) production when permanently transfected in 3T3 cells. Here, we describe for the first time an activating mutation in 3codon 620 of the TSHR. In addition, the cancerous AFTN also contained a G12C Ki-RAS mutation. We hypothesize that the combination of these two mutations might have played an important role in both the hyperfunction of the tumor and the carcinogenetic process.

Identification of a paired box gene 8–peroxisome proliferator-activated receptor gamma (PAX8–PPARγ) rearrangement mosaicism in a patient with an autonomous functioning follicular thyroid carcinoma bearing an activating mutation in the TSH receptor

“…Concurrent mutations in RAS and TSHR or GNAS1 genes have been found in some cases of nonfunctioning differentiated thyroid carcinomas and high adenyl cyclase activity (Russo et al 1995, Suarez 2000. However, we are aware only of one case of an autonomously hyperfunctioning thyroid follicular carcinoma with concurrent mutations in TSHR and RAS genes having been reported to date (Niepomniszcze et al 2006).…”

“…Nevertheless, some cases of thyroid carcinoma presenting as 'hot' thyroid nodules have been described (Russo et al 1997, Camacho et al 2000, Mircescu et al 2000, Gozu et al 2004, Majima et al 2005, Niepomniszcze et al 2006.…”

“…As in benign autonomously functioning thyroid nodules, mutations in either the TSH receptor (TSHR) gene, or the adenylate cyclasestimulating G alpha protein (GNAS1) gene that activates the cAMP cascade, have been detected in a small number of thyroid carcinomas (Russo et al 1995, Spambalg et al 1996, Collins et al 2003, with a handful of those being autonomously hyperfunctioning thyroid carcinomas (Russo et al 1997, Camacho et al 2000, Mircescu et al 2000, Collins et al 2003, Fuhrer et al 2003, Gozu et al 2004, Niepomniszcze et al 2006. Chronic cAMP stimulation may contribute, under certain conditions, to tumor progression (Ludgate et al 1999), although it does not seem sufficient for malignant transformation of thyroid follicular cells, and other genetic alterations are probably required to achieve cancer development (Matsuo et al 1993, Russo et al 1995, Spambalg et al 1996, Ludgate et al 1999, Collins et al 2003, Sobrinho-Simões et al 2008.…”

Hot and malignant – a case of invasive papillary carcinoma in hyperthyroid patient with hot nodules

“…Most of these malignancies were of the papillary carcinoma type [6]. While the exact pathophysiological mechanism has not been elucidated, mutations in TSH receptors and Ki-RAS play an important role in the hyper-functioning of the thyroid tumor and its carcinogenetic process [13,14]. …”

Uncommon Causes of Thyrotoxicosis

“…In the case described by Pont et al, the cancer weighed 900 g and produced only T 3 (67). It is clear that such a primary cancer must be functioning, and this notion argues against the dogma that hot nodules are not thyroid cancers (68,69). Therefore, when a hot nodule has certain clinical characteristics, we recommend fine-needle aspiration, and when cytologic results are positive, thyroidectomy is recommended.…”