Version May 2024
INTRODUCTION — A thyroid tumor develops when the growth of a single thyroid epithelial cell escapes from the normal mechanisms regulating cell division and gains a selective growth advantage. Continued growth leads, in time, to a clinically evident tumor mass. Unregulated cell division can result from mutations in both oncogenes and tumor suppressor genes.
Although thyroid epithelial tumors arise from the same cell type, they have diverse clinical characteristics. Most produce less thyroid hormone than normal thyroid tissue. Most are benign, but some are slow-growing cancers, and a few are highly aggressive cancers. Most thyroid tumors are sporadic and not familial.
An understanding of the mutations of the proto-oncogenes and tumor suppressor genes that occur in these tumors may explain the diverse clinical characteristics of thyroid tumors, provide diagnostic information, and direct therapy. The molecular profiling of thyroid neoplasms is commercially available to help distinguish benign from malignant thyroid nodules using DNA, mRNA, and microRNA from fine-needle aspiration (FNA) biopsy samples. The accuracy of this molecular testing continues to improve. Molecular profiling is now clinically indicated to direct the initial therapy of biopsy proven anaplastic thyroid cancers. Furthermore, identification of RET and TRK rearrangements can now direct therapy in aggressive differentiated thyroid cancers.
This topic review will discuss the tumorigenic gene changes found in thyroid epithelial (nonmedullary) tumors. A summary of these changes is found in the table (table 1). Medullary thyroid cancer is included in this table for comparison but is discussed elsewhere, as are the characteristics and treatment of the specific tumors. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging" and "Medullary thyroid cancer: Surgical treatment and prognosis" and "Papillary thyroid cancer: Clinical features and prognosis" and "Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)" and "Anaplastic thyroid cancer".)
AUTONOMOUSLY FUNCTIONING THYROID ADENOMAS — Autonomously functioning thyroid adenomas (or nodules) are benign tumors that produce thyroid hormone. Clinically, they present as a single nodule that is hyperfunctioning ("hot") on thyroid radionuclide scan, sometimes causing hyperthyroidism. (See "Diagnostic approach to and treatment of thyroid nodules".)
Many of these tumors are caused by somatic mutations in genes that code for two proteins of the thyroid-stimulating hormone (TSH) stimulation cascade (figure 1):
●The TSH receptor
●The alpha subunit of the guanyl nucleotide stimulatory protein (Gs)
Normally, TSH stimulates thyroid epithelial cells by binding to receptors on the plasma membrane of the cells. The signal is transduced by complexes formed between the alpha subunit of Gs and GTP in response to TSH-receptor binding. This results sequentially in stimulation of adenylyl cyclase activity, increased cyclic AMP production, and activation of protein kinases that stimulate thyroid cell division and hormone production. Adenylyl cyclase activity decreases when the GTP is hydrolyzed by the intrinsic GTPase activity of Gs-alpha. (See "Thyroid hormone synthesis and physiology".)
Activating mutations of the TSH receptor gene — Activating mutations of the TSH receptor produce constitutive activation of adenylyl cyclase in the absence of TSH [1,2]. The thyroid follicular cell with this TSH-receptor mutation divides and produces thyroid hormone without TSH stimulation, eventually becoming clinically recognized as a hot nodule. Although TSH (via the TSH receptor) also stimulates the inositol triphosphate pathway, most activating mutations of the TSH receptor do not stimulate signaling through this pathway [2-4].
Among patients with an autonomously functioning thyroid adenoma, the frequency of TSH-receptor mutations in the adenoma varies from approximately 5 to 80 percent [2-7]. The large differences in frequency may be related to the sensitivity of the methods used to screen for the mutations or interpatient differences. Since the mutations are scattered throughout the receptor, studies of the entire receptor are most likely to identify a mutation. (In rare families, germline mutations in the TSH receptor cause hereditary hyperthyroidism, initially with a diffuse goiter but ultimately with a nodular goiter with multiple hot nodules [8]).
Gs-alpha gene mutations that activate adenylyl cyclase — Gs-alpha mutations that lead to adenylyl cyclase activation have the same effects on cell division and thyroid hormone production as those in the TSH receptor (figure 1) [9,10]. These mutations code for changes in either an arginine residue at position 201 or a glutamine residue at position 227 of the molecule. The mutant Gs-alpha molecules have decreased GTPase activity; as a result, the Gs-alpha-GTP complex is more stable, leading to constitutive activation of adenylyl cyclase.
Among autonomously functioning thyroid adenomas, these mutations are less common than TSH-receptor mutations, occurring in 0 to 25 percent [7,9,11]. Gs-alpha mutations are also found in other endocrine tumors such as somatotroph adenomas [11]. The occurrence of these mutations during embryogenesis causes some of the manifestations of the McCune-Albright syndrome, including hyperthyroidism (with no goiter or a diffuse or multinodular goiter) [12-15] (see "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'). Germline Gs-alpha mutations that activate adenylyl cyclase have not been reported and are probably lethal.
No autonomously functioning thyroid adenomas have been identified with mutations in both proteins, and some have no mutations in either. There are no clinical characteristics that distinguish patients with TSH-receptor mutations, Gs-alpha mutations, and no detectable mutations.
OTHER BENIGN THYROID NODULES — The most common benign thyroid tumors are the nodules of multinodular goiters (colloid nodules) and follicular adenomas. The oncogene changes accounting for these benign thyroid nodules are not well delineated.
Multinodular goiters — If a tumor arises from a single cell, it is clonal. If it arises from all or most cells in a tissue, it is polyclonal. The nodules of multinodular goiters seemed polyclonal by morphologic studies [16], but many are clonal by molecular studies [17,18]. The two types of studies, taken together, indicate that regions of phenotypic or functional heterogeneity can develop within a clonal thyroid nodule.
Multinodular goiters are occasionally familial, which means that the patient has at least one germline mutation. One familial form of nontoxic multinodular goiter has been linked to DNA markers on chromosome 14q [19], but the etiologic gene is not known.
Follicular adenomas — As anticipated from pathologic studies, follicular adenomas are clonal [20]. Point mutations in the HRAS, KRAS, and NRAS proto-oncogenes have been identified in both follicular adenomas and follicular cancers [21-25].
Approximately one-quarter of sporadic follicular adenomas have a hemizygous deletion of a chromosome region containing PTEN, the tumor suppressor gene in which germline defects cause Cowden's disease (multiple hamartomas and breast, thyroid, and other tumors). Because defects in both alleles of a tumor suppressor gene are needed for tumor formation, it remains unclear whether inactivation of PTEN itself or a different tumor suppressor gene on chromosome 10q is a cause of sporadic follicular thyroid adenomas. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)
Chromosomal translocations involving 19q13 and 2p21 are found in follicular adenomas and do not co-occur in the same neoplasm. Based upon analysis of a small number of follicular adenomas, the 19q13 rearranged gene is ZNF331 (HUGO nomenclature) [26], and the 2q21 rearranged gene is referred to as thyroid adenoma-associated gene (THADA) [27]. THADA may be a death receptor-interacting protein. Both genes may be rearranged with different partners.
PAPILLARY THYROID CANCER — The Cancer Genome Atlas summarizes the most common genetic alterations in papillary thyroid cancer [28]. The genetic alterations of papillary thyroid cancer activate the mitogen-activated protein kinase (MAPK) pathway that promotes cell division. Rearrangements of the genes coding for RET and NTRK1 tyrosine kinases, activating mutations of BRAF, and activating mutations of RAS are sequential components leading to activation of MAPK (figure 2). Additional drivers include anaplastic lymphoma kinase (ALK) rearrangements, EIF1AX mutations, and mutations of the promoter region of the telomerase reverse transcriptase gene (TERT) [28]. In general, any given papillary thyroid cancer carries only a single one of these genetic changes [29]. However, approximately 9 percent of papillary thyroid cancers harbor both a TERT promoter mutation plus either a BRAF or RAS activating mutation. These tumors are more aggressive than those papillary thyroid cancers carrying only a single driver [30].
The RAS mutations are referred to as weak drivers since they are not unique to thyroid cancer and are frequently found in benign thyroid neoplasms. In contrast, the rearrangements of RET, NTRK, and ALK, as well as mutations of BRAF, EIF1AX, and the TERT promoter are referred to as strong drivers. When strong drivers are identified in thyroid nodules, the nodule is almost always malignant. These concepts apply to the DNA analysis of thyroid nodules that are currently offered by a number of different commercial laboratories.
RET and NTRK — Papillary thyroid cancers are associated with rearrangements of three different transmembrane tyrosine kinase genes: RET, NTRK1, and NTRK3. These rearrangements result in the production of chimeric proteins with constitutive tyrosine kinase activity that contributes to the development of the malignant phenotype (figure 3). The chimeric genes resulting from RET rearrangements are referred to as RET/PTC and those resulting from NTRK1 rearrangements as TRK (table 2).
●RET codes for a glial cell line-derived neurotrophic factor receptor with tyrosine kinase activity. Germline RET mutations cause the multiple endocrine neoplasia type 2 (MEN2) syndromes. (See "Classification and genetics of multiple endocrine neoplasia type 2".)
●NTRK1 and NTRK3 code for a nerve growth factor receptor that also has tyrosine kinase activity [31].
Neither of these genes is expressed in normal thyroid epithelial cells. As a result, patients with MEN2 syndromes do not have an increased incidence of papillary thyroid cancer.
In somatic rearrangements of the RET or NTRK genes, the attachment of new genetic material to the 5' end of the tyrosine kinase domain of the gene leads to a constitutive increase in tyrosine kinase activity that activates growth pathways and may be sufficient to cause the papillary cancer phenotype (figure 3). This etiologic role has been confirmed in transgenic mice, in which an activated RET gene in thyroid epithelial cells causes papillary cancer [32,33].
The frequency of gene rearrangements involving RET and NTRK1 in papillary thyroid cancers has varied in different studies. In adults, approximately 40 percent of sporadic papillary cancers have these rearrangements, with those involving RET being approximately three times more common [34]. The incidence of RET rearrangements in papillary cancers is higher in children (approximately 60 percent) [35,36] and is approximately 80 percent in the papillary cancers of children exposed to external x-irradiation and those exposed to radiation after the Chernobyl nuclear accident in 1986 [35,37].
Over 20 chimeric RET and TRK genes have been identified in papillary thyroid cancer. Six of the more common rearrangements are summarized in the table (table 2). Their clinical importance seems to be similar [34,35,37-43]. For those few patients with these rearrangements and aggressive disease, directed tyrosine kinase inhibitors are now available [44-46]. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Mutation-specific kinase inhibitor' and "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Treatment with TRK inhibitors'.)
BRAF mutations — The BRAF isoform of RAF has been implicated in the pathogenesis of papillary thyroid cancer, but not of benign or follicular neoplasms [29]. The RAF proteins are serine-threonine kinases that activate the RAF/MEK/MAPK signaling pathway. The T1799A mutation of the BRAF gene, which was originally found in over 50 percent of malignant melanomas and a smaller percentage of colon cancers, occurs in 29 to 69 percent of papillary thyroid cancers [29,47-49]. The predicted protein product BRAF V600E has increased basal kinase activity and transforms NIH3T3 cells with a higher efficiency than does the wild-type BRAF. Transgenic mice expressing this mutation develop papillary thyroid cancer [50].
In one report, BRAF mutations were found in 219 of 500 patients with papillary thyroid cancer (44 percent) [51]. BRAF V600E, the most prevalent mutation, was associated with invasive tumor growth and the follicular variant of papillary cancer.
BRAF mutations may confer a worse clinical prognosis than for papillary thyroid cancer without the BRAF mutation [52-54]. Recurrence occurs more frequently when BRAF mutations are present [55]. In addition, BRAF mutations are associated with extrathyroidal invasion, lymph node metastases, and advanced tumor stage at initial surgery, although for these findings, conventional histologic evaluation was as effective in predicting outcome as was the presence of the BRAF mutation [53,56]. Interestingly, some lymph node metastases may acquire additional BRAF mutations [57,58].
BRAF point mutations appear to be much less common in childhood thyroid cancers, including those that developed after the Chernobyl accident [59,60]. However, an oncogene (AKAP9-BRAF) that derives from a paracentric inversion of the long arm of chromosome 7 has been identified in radiation-associated papillary thyroid cancers developing after a short latency [61].
Because BRAF mutations are not found in follicular carcinomas and benign thyroid nodules, identification of a BRAF mutation may aid in the diagnosis and management of papillary thyroid cancer. In a preliminary report, BRAF mutations were detected in blood samples from patients with papillary thyroid cancer [62]. BRAF positivity correlated with the presence of residual or metastatic disease. In addition, the detection of BRAF gene mutations in fine-needle aspiration biopsy specimens may prove useful in the assessment of follicular lesions. This topic is discussed in detail elsewhere.
In thyroid cancer cell lines harboring activated BRAF, the addition of selective inhibitors of BRAF inhibited proliferation of BRAF mutant cell lines, suggesting a possible role of such inhibitors in the treatment of patients with papillary thyroid cancer and BRAF mutations [63,64].
RAS mutations — Although activating RAS mutations are found in follicular adenomas, they have also been reported in follicular variant of papillary thyroid cancers [65]. NRAS mutations are more common than HRAS mutations [66].
TERT promoter mutations — Two promoter region mutations of the TERT have been reported in many malignancies. The chr5:1,295,228C>T (C228T) mutation was found in approximately 10 percent of sporadic papillary thyroid cancers, and the chr5:1,295250C>T (C250T) was found in approximately 2 percent of sporadic papillary thyroid cancers [28]. When TERT promoter mutations coexist with either the V600E BRAF mutation or with a RAS mutation, the thyroid cancers are more aggressive [67].
Other genetic abnormalities — MicroRNAs (miRNAs) modify gene expression by binding to specific targets in the 3' untranslated region and are being implicated in tumorigenesis of a variety of tissues. Several miRNAs (miR-221, miR-222, miR-146, and others) are upregulated in papillary thyroid cancer and may contribute to tumorigenesis [68]. The expression profiles in the TCGA database confirmed the upregulation of these miRNAs as well as miR-181a/b/d, miR-34a, and miR-424 [28]. It also identified downregulation of miR-363, miR-138, mir-363, miR-20b, miR-195, and miR-152 [69]. In addition, mutations were identified in PPM1D and CHEK2, both DNA repair genes [28].
Common germline sequence variants — Large population studies have identified multiple different single nucleotide polymorphisms (SNPs) that are associated with a clinically modest, but statistically significant, increased risk of well-differentiated thyroid carcinoma, including the following:
●A G/C heterozygosity within the precursor of miRNA-146a predisposes to papillary thyroid cancer (odds ratio [OR] 1.62) [70]. This polymorphism alters the miRNA sequence and induces miRNA overexpression with new miRNA forms that alter target gene expression [71].
●SNPs at 9q22.33 that are close to FOXE1 (TTF2) and at 14q13.3 that are close to NKX2-1 (TTF1) [72]. Both FOXE1 and NKX2-1 are known to regulate gene transcription within the thyroid cells.
●SNPs found in CHEK2, NBS1, XRCC3, and the promoter of RAD51 have all been associated with an increased risk of differentiated thyroid cancer, which are mostly papillary thyroid cancers [73-76].
Methylation often decreases gene expression and may contribute to tumorigenesis. Increased methylation of several tumor suppressor genes (TIMP3, SLC5A8, DAPK, and RARbeta2) is associated with features of papillary thyroid cancer aggressiveness [77,78].
There may be an increased incidence of papillary cancer in patients with familial adenomatous polyposis [79]. This disorder is caused by germline mutations of the APC gene, a tumor suppressor gene of unknown function (see "Epidemiology and risk factors for colorectal cancer"). In comparison, somatic mutations of this gene are uncommon in sporadic papillary cancers [80]. The papillary thyroid cancers of patients with familial adenomatous polyposis may have rearrangements of RET [81].
Papillary thyroid cancers are usually sporadic, but approximately 5 percent have a familial predisposition [82-85]. Surprisingly, powerful genetic linkage methodologies have been relatively ineffective in identifying the predisposing gene abnormalities. A single kindred has a mutation in a long-term enhancer element in 4Q32 that predisposes to thyroid cancer [86]. An increased incidence of papillary thyroid cancer is found in patients with congenital hypothyroidism with huge goiters caused by thyroglobulin gene mutations [87]. Other potential regions of linkage include chromosome regions 1q21 [88], 8q24 [89], and 19p13.2.
FOLLICULAR THYROID CANCER — Follicular thyroid cancers tend to be caused by mutations that signal through the AKT pathway (figure 4) [90]. Since activating RAS mutations occur in both follicular and papillary thyroid cancer and participate in both the MAPK and AKT pathways, this is an oversimplification.
RAS mutations — Approximately 30 percent of follicular thyroid cancers have RAS mutations with the NRAS mutations being more common than HRAS and KRAS [66]. Overexpression of normal c-myc and c-fos genes, as well as mutations of HRAS, NRAS, and KRAS proto-oncogenes, are found in follicular adenomas, follicular cancers, and occasionally papillary cancers [21-23,25,91]. These abnormalities may confer a growth-promoting effect that is not specific for tumor type.
PAX8 fusion — A chromosomal translocation has been identified in some follicular cancers that distinguishes them from papillary cancers and follicular adenomas [92]. The translocation (t(2;3)[q13;p25]) results in fusion of part of the DNA-binding segment of the PAX8 gene and the peroxisome proliferator-activated receptor gamma 1 (PPAR-gamma-1) gene; PAX8 is a thyroid transcription factor, and PPAR-gamma-1 is a transcription factor that stimulates cell differentiation and inhibits cell growth.
The product of the fusion gene blocks the action of the PPAR-gamma-1, an effect that might inhibit cell differentiation and stimulate cell growth. In one study, the translocation was found in 5 of 8 follicular cancers and 0 of 20 follicular adenomas [92], and in another study, it was found in 5 of 9 cancers and 2 of 16 adenomas, suggesting that it may be useful for distinguishing between follicular cancers and follicular adenomas [93].
TERT promoter mutations — The two telomerase reverse transcriptase (TERT) promoter mutations described above in the discussion of papillary thyroid cancer have also been described in follicular thyroid cancer [28,67]. The chr5:1,295,228C>T (C228T) mutation was found in approximately 30 percent of follicular thyroid cancers, and the chr5:1,295250C>T (C250T) was found in approximately 5 percent of follicular thyroid cancers. Thyroid cancers harboring both a TERT promoter mutation and a RAS mutation are more aggressive [30].
PTEN — Germline mutations in PTEN, a tumor suppressor gene, have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumor syndromes (PHTS). Cowden syndrome is the best described syndrome within PHTS. In addition to benign follicular adenomas, individuals with Cowden syndrome have an approximately 70-fold increased incidence of thyroid cancer relative to the general population [94]. Both follicular and papillary neoplasms may occur. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Thyroid'.)
RASSF1A — Hypermethylation of RASSF1A, a known tumor suppressor gene, has been described in 75 percent of follicular thyroid cancers (9 of 12) as well as in a smaller percentage of benign adenomas (44 percent), and papillary thyroid cancers (20 percent) [95]. This may be an early step in thyroid epithelial tumorigenesis.
HÜRTHLE CELL TUMORS — Some benign and malignant thyroid tumors are found to have an increased number of mitochondria and are referred to as oxyphil or Hürthle cell tumors. Hürthle cell carcinomas were once thought to be a variant of follicular thyroid carcinomas, but more recent analyses demonstrate that these are much more complex tumors with both nuclear and mitochondrial DNA alterations. Multiple driver mutations have been identified and include mutations of EIF1AX, MADCAM1, OR4L1, and ATXN1 in addition to multiple others. Whole chromosome duplication of chromosomes 5 and 7 occurs as well as widespread loss of heterozygosity. In the mitochondrial genome, there are a large number of disruptive mutations of the protein-coding and tRNAs encoding regions [96].
NONINVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY-LIKE NUCLEAR FEATURES (NIFTP) — An indolent variant of a follicular cell-derived neoplasm has been identified, termed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) [97]. Preliminary studies suggest that the most frequent gene mutations are activating RAS mutations [98,99]. (See "Papillary thyroid cancer: Clinical features and prognosis", section on 'Variant forms'.)
ANAPLASTIC AND POORLY DIFFERENTIATED THYROID CANCER — Anaplastic and poorly differentiated thyroid cancers are the most aggressive thyroid cancers. Combined pathology/molecular studies have identified regions within the anaplastic thyroid cancer that are well differentiated and contain the same BRAF or RAS mutation as the regions of anaplastic thyroid cancer [100]. More recent genetic analyses suggest that these tumors arise from well-differentiated thyroid cancers with BRAF V600E or RAS mutations that have accumulated a greater mutational burden [101]. The differentiated thyroid cancers [100-102] with RET, NTRK [101,103], or PAX8-PPAR-gamma-1 rearrangements do not appear to progress to these aggressive malignancies [101,103].
Subsequent mutational burden leading to aggressive behavior and found in both poorly differentiated thyroid cancer and anaplastic thyroid cancer occur in the TERT promoter, P53, EIF1AX, PI3K/AKT/MTOR pathway effectors, the SWI/SNF subunits, histone methyltransferases, exon 3 of the beta-catenin gene, and the anaplastic lymphoma kinase gene (ALK) [101,104-106]. Mutations of the p53 tumor suppressor gene that lead to production of an inactive p53 protein occur in many anaplastic thyroid cancers, but not well-differentiated thyroid cancers [101,107]. The protein product of p53 is a transcription factor that regulates both apoptosis and the cell cycle.
Therapies targeted at specific gene mutations have emerged, so that molecular profiling of anaplastic thyroid cancer is recommended by the American Thyroid Association at the time of diagnosis [108]. (See "Anaplastic thyroid cancer", section on 'Molecular testing' and "Anaplastic thyroid cancer", section on 'BRAF V600E mutation identified'.)
SUMMARY
●General principles – Our knowledge of the molecular pathogenesis of benign and malignant thyroid neoplasia is evolving. The molecular profiling of thyroid neoplasms is commercially available to help distinguish benign from malignant thyroid nodules using DNA, mRNA, and microRNA from fine-needle aspiration (FNA) biopsy samples. The accuracy of this molecular testing continues to improve. Molecular profiling is now clinically indicated to direct the initial therapy of biopsy-proven anaplastic thyroid cancers. Furthermore, identification of RET and TRK rearrangements can now direct therapy in aggressive differentiated thyroid cancers. (See 'Introduction' above.)
●Autonomously functioning adenomas – Autonomously functioning thyroid nodules are benign tumors that produce thyroid hormone. Many of these tumors are caused by somatic mutations in genes that code for the thyroid-stimulating hormone (TSH) receptor or the alpha subunit of the guanyl nucleotide stimulatory protein (Gs). (See 'Autonomously functioning thyroid adenomas' above.)
●Other benign nodules – The most common benign thyroid tumors are the nodules of multinodular goiters (colloid nodules) and follicular adenomas. The oncogene changes accounting for these benign thyroid nodules are not well delineated. (See 'Other benign thyroid nodules' above.)
●Papillary thyroid cancer – Papillary thyroid cancers frequently carry gene mutations and rearrangements that lead to activation of the mitogen-activated protein kinase (MAPK) that promotes cell division. Rearrangements of RET and NTRK1, activating mutations of BRAF, and activating mutations of RAS are sequential components leading to activation of MAPK (figure 2). Any given papillary thyroid cancer carries only a single one of these genetic changes. Approximately 9 percent of papillary thyroid cancers harbor both a TERT promoter mutation and one of the driver mutations and are more aggressive. Molecular profiling of aggressive papillary thyroid cancer not responsive to conventional therapies is indicated, since directed therapies are available for those with rearrangements of RET or NTRK1. (See 'Papillary thyroid cancer' above and "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Mutation-specific kinase inhibitor'.)
●Follicular thyroid cancer – Follicular thyroid cancers frequently carry gene mutations that lead to activation of the AKT pathway (figure 4). PAX8/PPAR-gamma-1 rearrangements and mutations of HRAS, NRAS, and KRAS proto-oncogenes are found in follicular thyroid cancers and occasionally papillary cancers. (See 'Follicular thyroid cancer' above.)
●Hürthle cell thyroid cancers – Once thought to be a variant of follicular thyroid cancer, Hürthle cell thyroid cancers are now recognized to be a distinct tumor type with complex alterations in both the nuclear and mitochondrial DNA. (See 'Hürthle cell tumors' above.)
●NIFTP – RAS mutations are common in noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), an indolent thyroid neoplasm. (See 'Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)' above and "Papillary thyroid cancer: Clinical features and prognosis", section on 'Variant forms'.)
●Anaplastic thyroid cancer – Anaplastic thyroid cancers and poorly differentiated thyroid cancers are the most aggressive of the thyroid cancers. Many of these arise from well-differentiated thyroid carcinomas that originally contained BRAF or RAS driver mutations and subsequently acquired mutations conferring increased aggressiveness. Additional mutations include those in the TERT promoter region, p53, and PIK3CA. Molecular profiling is clinically indicated at the time of diagnosis to assist in directing therapy. (See 'Anaplastic and poorly differentiated thyroid cancer' above.)
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