Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases (summary by Vriens et al., 2009). The remaining cancers originate from parafollicular cells (medullary thyroid cancer, ... Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases (summary by Vriens et al., 2009). The remaining cancers originate from parafollicular cells (medullary thyroid cancer, MTC; 155240). NMTC is classified into 4 groups: papillary (188550), follicular, Hurthle cell (607464), and anaplastic. Approximately 5% of NMTC is hereditary, occurring as a minor component of a familial cancer syndrome (e.g., familial adenomatous polyposis 175100, Carney complex 160980) or as a primary feature (familial NMTC or FNMTC). Papillary thyroid cancer (PTC) is the most common histologic subtype of FNMTC, accounting for approximately 85% of cases. Follicular thyroid cancer (FTC) accounts for approximately 15% of NMTC and is defined by invasive features that result in infiltration of blood vessels and/or full penetration of the tumor capsule, in the absence of the nuclear alterations that characterize papillary carcinoma (summary by Bonora et al., 2010). FTC is rarely multifocal and usually does not metastasize to the regional lymph nodes but tends to spread via the bloodstream to the lung and bones. An important histologic variant of FTC is the oncocytic (Hurthle cell, oxyphilic) follicular carcinoma composed of eosinophilic cells replete with mitochondria.
In all of 6 examples of follicular thyroid carcinoma (FTC), Herrmann et al. (1991) found loss of heterozygosity (LOH) for RFLP markers on the short arm of chromosome 3. Such was not found ... - Somatic Mutation In all of 6 examples of follicular thyroid carcinoma (FTC), Herrmann et al. (1991) found loss of heterozygosity (LOH) for RFLP markers on the short arm of chromosome 3. Such was not found in any of 3 follicular adenomas (FA) or 12 papillary thyroid carcinomas (PTC; 188550). Herrmann et al. (1991) suggested that a tumor suppressor gene on 3p is important for the development or progression of FTC. Trovato et al. (1999) tested the hypothesis that both FTC and anaplastic thyroid cancer (ATC), but not PTC, could harbor LOH in segments of 7q encompassing the protooncogenes HGF (142409) and MET (164860). They screened 6 normal thyroids, 10 colloid nodules, 10 follicular hyperplasias, 10 oncocytic adenomas, 10 FAs, 10 FTCs, 6 ATCs, and 12 PTCs using 2 microsatellite markers for HGF and 2 for MET. LOH for all 4 markers was found in 100% of FTCs, 100% of ATCs, and (for only 1 or 2 markers) in 10% to 29% of FAs. The authors concluded that loss of genetic material explains why FTC and ATC, but not PTC, fail to express both HGF and MET. Kitamura et al. (2001) carried out a genomewide allelotyping study of 66 follicular thyroid carcinomas using 39 microsatellite markers representing all nonacrocentric autosomal arms. The mean frequency of loss of heterozygosity was 9.2%, and the mean fractional allelic loss was 0.09. The most frequent allelic losses were detected in 7q (28%), 11p (28%), and 22q (41%). Frequent allelic losses of markers on chromosome 7q, 11p, and 22q suggested locations to examine for the presence of suppressor genes associated with the development of follicular thyroid carcinoma. Nikiforova et al. (2003) identified a somatic mutation in the NRAS gene (Q61R; 164790.0002) in 70% (12) of follicular carcinomas and 55% (6) of follicular adenomas studied. Garcia-Rostan et al. (2005) analyzed 13 thyroid cancer cell lines, 80 well-differentiated follicular (WDFTC) and papillary (WDPTC) thyroid carcinomas, and 70 anaplastic thyroid carcinomas (ATC) for activating PIK3CA (171834) mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 (23%) ATC cases, 2 (8%) WDFTC cases, and 1 (2%) WDPTC case. In 18 of 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component. Garcia-Rostan et al. (2005) concluded that mutant PIK3CA is likely to function as an oncogene in anaplastic thyroid carcinoma but less frequently in well-differentiated thyroid carcinomas. Liu et al. (2008) explored a wide-range genetic basis for the involvement of genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in anaplastic thyroid cancer (ATC) and FTC. They found frequent copy gains of RTK genes including EGFR (131550) and VEGFR1 (165070), and PIK3CA and PIK3CB (602925) in the P13K/Akt pathway. RTK gene copy gains were preferentially associated with phosphorylation of Akt, suggesting their dominant role in activating the P13K/Akt pathway. Liu et al. (2008) concluded that genetic alterations in the RTKs and P13K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former. - LOH of Imprinted Regions Sarquis et al. (2006) investigated the hypothesis that in thyroid neoplasias loss of imprinted loci becomes enriched during oncogenesis. They studied thyroid tissue from 72 patients with thyroid neoplasias comprising 34 follicular thyroid carcinomas and 38 follicular adenomas. Overall LOH frequencies for the imprinted region (IR) markers were 26% for the adenomas and 38% for the carcinomas. In the nonimprinted regions (NIR), the overall LOH frequency was 23% and 26% for FAs and FTCs, respectively. The difference in LOH frequencies between IRs and NIRs was statistically significant only for the carcinomas (p = 0.001), although there was a similar trend for the atypical adenomas (p = 0.06). Sarquis et al. (2006) concluded that IRs are more prone to genomic instability in FTCs. Weber et al. (2005) studied the frequency and mechanism of ARHI (605193) silencing in benign and malignant thyroid neoplasia. They demonstrated that underexpression of ARHI occurs principally in FTC (P = 0.0018), including its oncocytic variant (11 of 13), even at minimally invasive stage, but not classic PTCs (2 of 7) or follicular adenoma (FA) (3 of 14). FTC showed strong allelic imbalance with reduction in copy number/LOH in 69%, compared with less than 10% for FA. In combination with LOH data, bisulfite sequencing in a subset of samples revealed a symmetric methylation pattern for FA, likely representing 1 unmethylated allele and 1 presumptively imprinted allele, whereas FTC showed a virtually complete methylation pattern, representing LOH of the nonimprinted allele with only the hypermethylated allele remaining. Weber et al. (2005) showed that pharmacologic inhibition of histone deacetylation, but not demethylation, could reactivate ARHI expression in the FTC133 FTC cell line. Weber et al. (2005) concluded that silencing of the putative maternally imprinted tumor suppressor gene ARHI, primarily by large genomic deletion in conjunction with hypermethylation of the genomically imprinted allele, serves as a key early event in follicular thyroid carcinogenesis. - Malignant Transformation of Congenital Goiter Alzahrani et al. (2006) reported 2 brothers, born of consanguineous parents, who had recurrent large goiters due to a homozygous mutation in the thyroglobulin gene (188450.0018), 1 of whom developed metastatic follicular thyroid carcinoma. Alzahrani et al. (2006) screened for RAS oncogene mutations by direct sequencing of thyroid tumor DNA, but identified no mutation in codons 12, 13, and 61 of the HRAS (190020), KRAS (190070), and NRAS (164790) oncogenes. The authors concluded that the malignant transformation of the congenital goiter was likely the result of prolonged TSH stimulation, probably in combination with mutations of oncogenes and/or tumor suppressor genes other than RAS.