Progress in molecular-based management of differentiated thyroid cancer

Abstract

Substantial developments have occurred in the past 5-10 years in clinical translational research of thyroid cancer. Diagnostic molecular markers, such as RET-PTC, RAS, and BRAF(V600E) mutations; galectin 3; and a new gene expression classifier, are outstanding examples that have improved diagnosis of thyroid nodules. BRAF mutation is a prognostic genetic marker that has improved risk stratification and hence tailored management of patients with thyroid cancer, including those with conventionally low risks. Novel molecular-targeted treatments hold great promise for radioiodine-refractory and surgically inoperable thyroid cancers as shown in clinical trials; such treatments are likely to become a component of the standard treatment regimen for patients with thyroid cancer in the near future. These novel molecular-based management strategies for thyroid nodules and thyroid cancer are the most exciting developments in this unprecedented era of molecular thyroid-cancer medicine.

Figure 1. MAPK and PI3K-AKT-MTOR pathways—genetic alterations and therapeutic targets in thyroid cancer

Right side shows the MAPK pathway; left side shows the PI3K-AKT-MTOR pathway. The two classic signalling pathways are coupled to the receptor thyrosine kinase (RTK) at the cell membrane which transduces extracellular growth signals into intracellular signalling downstream of the two pathways. RAS can couple the signalling from RTK to both pathways. PTEN terminates the PI3K signalling. Genetic RTK amplifications are common. Common activating mutations in the MAPK pathway include RET-PTC rearrangement, RAS mutation, and BRAF mutation. Common genetic alterations in the PI3K pathway include RAS mutation, PTEN mutation or deletion, PIK3CA mutation or amplification, and AKT1 mutation. The two pathways, driven by these genetic alterations, have a fundamental role in thyroid tumorigenesis. Amplifications of RTK genes are also common. *Denotes therapeutic targets in the two pathways that are currently being actively tested clinically.

Figure 2. Sensitivity, specificity, PPV, and NPV

Histopathology diagnosis is the reference (ie, gold standard). PPV=positive predictive value. NPV=negative predictive value.

Figure 3. Algorithm for management of thyroid nodules on the basis of FNAB and molecular marker tests

Depending on the cytology categories, molecular tests with high sensitivity and NPV (eg, gene expression classifier) or high specificity and PPV (eg, BRAF mutation) are chosen. Extent of surgery should be decided on the basis of the combined assessment of clinical, imaging, cytological, and molecular marker data. FNAB=fine needle aspiration biopsy. AUS/FLUS=atypia of undetermined significance/follicular lesion of undetermined significance. FN/SFN=follicular neoplasm/suspicious for follicular neoplasm. PTC=papillary thyroid cancer. NPV=negative predictive value. PPV=positive predictive value. Tx=total/near total thyroidectomy. LND=lymph node dissection.