In particular, the management of indeterminate nodules on fine needle aspiration (with special attention to genetic and epigenetic markers of malignancy), the extent of surgery for known differentiated cancers, the role of adjuvant radioactive iodine (RAI) therapy, and novel targeted treatments with tyrosine kinase inhibitors (TKIs) represent current areas of uncertainty and opportunities for future research. remains to be seen whether preoperative knowledge of mutation status will affect operative planning and decision making (28). Regardless, the mutation is diagnostic of PTC, and can be used as an adjunct test in otherwise indeterminate thyroid FNA samples (19,20). testing is presently included in many commercially available gene-based tools for diagnosis of thyroid cancer. The second most common group of genetic mutations in DTCs involve the RAS family of proteins, specifically KRAS, NRAS, or HRAS (22). Mutations in the genes are found in less than 5% of all thyroid nodules (29), but are detectable in FNA specimens (23), and when present are nearly always associated with a follicular cytologic pattern (30) (see mutations are found in benign follicular neoplasms, and tumors with isolated mutations are usually associated with less aggressive features and a more indolent course (23). However, despite their occurrence in benign lesions, a recent meta-analysis demonstrated that mutations have a 93% specificity for malignancy (22). This has not translated to a reliable single-gene marker for malignancy, as the positive and negative predictive values (PPV and NPV) in the same analysis were only 78% and 64%, respectively (22). Still, when combined with analysis of other genetic mutations, the family of genes has become a useful data point in clarifying the risk of malignancy of indeterminate lesions. In fact, there is evidence that the risk of malignancy varies with the form of that is mutated. One group demonstrated that the specific isoform of that was mutated in follicular neoplasms determined the relative risk of malignancy, with 100% of mutant tumors being malignant, as compared Pcdha10 to 74% for (18). Table 1 Common genetic alterations in differentiated thyroid cancers and their associated characteristics and and gene, which codes for a tyrosine kinase that is normally not expressed in thyroid tissues (31,32). There are at least 13 different translocations identified in PTCs to date, and all are thought to trigger activation of the MAPK pathway leading to malignancy (33). A meta-analysis by Rodrigues in 2012 found presence of a translocation had a 87% PPV for malignancy (34). The two most common translocations, and and mutant tumors (32,33,35). Tumors with the translocation are noted to more commonly be solid variant PTC and occur more frequently in patients with a history of radiation exposure (33,36-38). Earlier studies seemed to show an association between translocations, especially translocations, and a favorable prognosis (39-41). Recently, however, several studies have noted an association between translocation and distant metastases (27,36), and patients with positive tumors have been shown to have a disease pattern similar to patients with the mutation (27). As our understanding of the prognostic impact of translocations becomes clearer, we expect that the marker will be increasingly important in the management of PTC. gene with the thyroid specific transcription factor (21). These translocations are found in up to 35% of follicular thyroid cancers, but also found in 2C13% of follicular adenomas and in 1C5% of PTCsnearly always follicular variant (15-17,42,43). In a recent retrospective analysis by Armstrong in 2012, the PPV of Afirma? testing was found to be only 38% (48). Therefore, Afirma? may be a good rule out test for malignancy when the result is negative, but a positive result can still lead many patients to undergo a potentially unnecessary operation. MicroRNA alterations MicroRNAs, or miRNAs, Istradefylline (KW-6002) are small (usually 20C30 nucleotides), non-coding, regulatory RNA molecules which downregulate expression of target messenger RNAs (52). These molecules are differentially expressed in malignancy, and numerous studies have shown that malignant and benign thyroid tissues have differential miRNA signatures (52-56). Our group identified four such miRNAs (examined 52,173 patients in the National Cancer Database that underwent either total thyroidectomy or lobectomy for PTC from 1985C1998 and found a higher risk of both recurrence and death in the lobectomy group for patients with tumors 1 cm (66). However, data were not available to determine Istradefylline (KW-6002) how many of these patients in the lobectomy group had high risk features that would have made them better candidates for total thyroidectomy. A follow-up study by Adam in 2014 analyzed 61,775 patients from the same database undergoing thyroidectomy or lobectomy from 1998 to 2006. When adjusted for high risk features such as extrathyroidal.Earlier studies seemed to show an association between translocations, especially translocations, and a favorable prognosis (39-41). some of the questions that remain. and mutations, and rearranged during transfection (and mutation and a more aggressive phenotype; a recent meta-analysis demonstrated that the mutation was associated with an increased rate of lymph node metastasis, extrathyroidal extension, resistance to RAI therapy, and even decreased overall survival (26). Other studies have shown a decreased disease-free survival (27). However, it remains to be seen whether preoperative knowledge of mutation status will affect operative planning and decision making (28). Regardless, the mutation is diagnostic of PTC, and can be used as an adjunct test in otherwise indeterminate thyroid FNA samples (19,20). testing is presently included in many commercially available gene-based tools for diagnosis of thyroid cancer. The second most common group of genetic mutations in DTCs involve the RAS family of proteins, specifically KRAS, NRAS, or HRAS (22). Mutations in the genes are found in less than 5% of all thyroid nodules (29), but are detectable in FNA specimens (23), and when present are nearly always associated with a follicular cytologic pattern (30) (see mutations are found in benign follicular neoplasms, and tumors with isolated mutations are usually associated with less aggressive features and a more indolent course (23). However, despite their occurrence in benign lesions, a recent meta-analysis demonstrated that mutations have a 93% specificity for malignancy (22). This has not translated to a reliable single-gene marker for malignancy, as the positive and negative predictive values (PPV and NPV) in the same analysis were only 78% and 64%, respectively (22). Still, when combined with analysis of other genetic mutations, the family of genes has become a useful data point in clarifying the risk of malignancy of indeterminate lesions. In fact, there is evidence that the risk of malignancy varies with the form of that is mutated. One group demonstrated that the specific isoform of that was mutated in follicular neoplasms determined the relative risk of malignancy, with 100% of mutant tumors being malignant, as compared to 74% for (18). Table 1 Common genetic alterations in differentiated thyroid cancers and their associated characteristics and and gene, which codes for a tyrosine kinase that is normally not expressed in thyroid tissues (31,32). There are at least 13 different translocations identified in PTCs to date, and all are thought to trigger activation of the MAPK pathway leading to malignancy (33). A meta-analysis by Rodrigues in 2012 found presence of a translocation experienced a 87% PPV for Istradefylline (KW-6002) malignancy (34). The two most common translocations, and and mutant tumors (32,33,35). Tumors with the translocation are mentioned to more commonly become solid variant PTC and happen more frequently in individuals with a history of radiation exposure (33,36-38). Earlier studies seemed to show an association between translocations, especially translocations, and a favorable prognosis (39-41). Recently, however, several studies have mentioned an association between translocation and distant metastases (27,36), and individuals with positive tumors have been Istradefylline (KW-6002) shown to possess a disease pattern similar to individuals with the mutation (27). As our understanding of the prognostic effect of translocations becomes clearer, we expect the marker will become increasingly important in the management of PTC. gene with the thyroid specific transcription element (21). These translocations are found in up to 35% of follicular thyroid cancers, but also found in 2C13% of follicular adenomas and in 1C5% of PTCsnearly constantly follicular variant (15-17,42,43). In a recent retrospective analysis by Armstrong in 2012, the PPV of Afirma? screening was found to be only 38% (48). Consequently, Afirma? may be an excellent rule out test for malignancy when the result is negative, but a positive result can still lead many individuals to undergo a potentially unneeded operation. MicroRNA alterations MicroRNAs, or miRNAs, are small (usually 20C30 nucleotides), non-coding, regulatory RNA molecules which downregulate manifestation of target messenger RNAs (52). These molecules are differentially indicated in malignancy, and several studies have shown that malignant and benign thyroid tissues possess differential miRNA signatures (52-56). Our group recognized four such miRNAs (examined 52,173 individuals in the National Cancer Database that underwent either total thyroidectomy or.