2018-19 Section 7-Neoplastic and Inflammatory Diseases of the Head and Neck eBook

Molecular Testing for Thyroid Nodules/Roth et al

Figure 3. The mitogen-activated protein kinase (MAPK) pathway is the principal pathway leading to differentiated thyroid cancer. The phosphatidylinositol-4,5-bisphosphate 3-kinase–protein kinase B (PI3K-AKT) pathway is an important pathway leading to fol- licular thyroid cancer and undifferentiated thyroid cancer. a , b , and g indicate rearranged during transfection (RET) receptors a , b , and g , respectively; BRAF , v-Raf murine sarcoma viral oncogene homolog B1; ERK, extracellular signal-regulated kinase; GF, growth factor; GPT, glutamic-pyruvic transaminase; H-Ras, Harvey rat sarcoma viral oncogene homolog; K-Ras, Kirsten rat sar- coma viral oncogene homolog; MEK, mitogen activated protein extracellular signal-regulated kinase; mTOR, mammalian target of rapamycin; N, nucleus; N-Ras, neuroblastoma rat sarcoma viral oncogene homolog; Pax8/PPAR c , paired box gene 8-peroxisome proliferator-activator receptor g ; PTEN, phosphatase and tensin homolog; RAF, RAF proto-oncogene serine/threonine-protein kinase; RAS, a family of rat sarcoma (ras) small guanosine triphosphate hydrolases (GTPases); RET, rearranged during transfec- tion; Ret/PTC, rearranged during transfection/papillary thyroid cancer 1; RTK, receptor tyrosine kinase.

identify both benign and malignant thyroid cytopathol- ogy by improving sensitivity and NPV with only a mild reduction in specificity and PPV. Additional approaches to molecular testing for thyroid cytopathology include the development of micro- RNA (miRNA) testing. MiRNAs act as negative regula- tors of gene expression and may impact cellular processes that lead to carcinogenesis. Because miRNA expression may be dysregulated in thyroid cancer, this represents an additional approach to molecular test development with high sensitivity and high specificity. 19-21 The ultimate goal of all the described approaches to thyroid molecular testing is to improve the clinical man- agement of patients with thyroid nodules. Reducing the number of unnecessary diagnostic thyroid surgeries has huge implications for overall patient quality of life and cost of health care. Therefore, as the number of patients

with thyroid nodules continues to rise, the goal is to decrease potential morbidity for benign thyroid disease and to optimize initial treatment of thyroid cancer. A “Rule-In” Test: Gene Mutation Panel In the setting of a suspicious thyroid nodule with a clear gene mutation that identifies malignancy, thyroid cancer could be diagnosed before surgery and effectively decrease the number of patients who require a 2-part procedure for definitive primary treatment of thyroid cancer. The 7- gene specific mutation panel has been validated as an effective “rule-in” cytomolecular test for thyroid malig- nancy based on the high specificity and PPV (Table 1), but it has not been considered an effective “rule-out” test because of low sensitivity (Table 2). The largest prospective, single-institution study included 247 Bethesda III thyroid nodules and 214 Bethesda IV thyroid

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