*DOI: http://dx.doi.org/10.5772/intechopen.108481 Aspects Considered in Differentiated Thyroid Cancer for Radioiodine Therapy*

provides the tumor with a more aggressive growth initiative. Alternatively, the cancer phenotype may be dictated by the differential nature of the stem cells capable of initiating PTC, FTC, and ATC [24]. The most common thyroid cancer mutations originate from follicular or parafollicular cells [25]. These mutations are the basis for the design of molecular markers and molecular approaches to thyroid cancer.

In some populations, malignant DTC might only occasionally lead to death, including cases of PTC in children and young adults presenting with lymph node metastases (LNMs). Some TC types were recently reclassified from malignant to benign, such as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) [21]. Based on clinical evidence, it is associated with no reports of cancer-related deaths and estimated risk of recurrence of <1% [26]. PTC accounts for 80% of TC with molecular characteristics predominant consisting of BRAF mutation, RAS mutation, and RET rearrangements, nearly 70% as shown in **Table 1** [28]. These mutations are


*Uncertain Malignant Potential (UMP)*

*Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features (NIFT-P). References: [10, 22, 32].*

#### **Table 1.**

*Classification of thyroid cancer based on World Health Organization (WHO) 2017.*

associated with radioiodine refractory (RAIR) [10]. BRAF V600E mutations are frequently reported in a subgroup of PTCs with more aggressive behavior [23, 26, 28–30]. The fatal forms of non-anaplastic cancer are generally PTC variants harboring BRAF or RAS mutations plus other genomic alterations such as mutations involving the TERT promoter, POLE, TP53, PI3K/AKT/mTOR pathway, SWI/SNF subunits, and/or histone methyltransferases [10, 30, 31]. BRAF mutations are present in 30%–67% of PTCs and are associated with locoregional metastases and extra-thyroidal extension [32]. A positive test for BRAF mutations means a close to 100% probability of malignancy [27]. This is likely helpful to guide the extent of thyroidectomy.

Follicular thyroid, accounting for 2%–5% of TC cancer, is considered minimally invasive when capsular penetration is present without vascular involvement (a condition associated with an excellent prognosis) by WHO [10, 11]. The angioinvasive and widely invasive term is when neoplastic emboli involve < 4 or ≥ 4 blood vessels, respectively [11]. FTC type is frequently linked to activation of the PI3K and MAPK pathways through loss of PTEN expression, NRAS mutations, rearrangements such as PPARγ/PAX8, and other events [27, 28, 30]. Hurthle cell carcinomas are no longer classified as follicular tumors. They are generally much less aggressive and less likely to present with lymph node metastases [11]. Hurthle cell carcinomas associated with extensive vascular and/or capsular invasion should be managed like other high-risk carcinomas [11].

Furthermore, once thyroid cancer is highly suspected or diagnosed, a decision must be made regarding the extent of surgery. Risk factors must be considered, such as clinical risk factors associated with aggressive tumor behavior, the patient's age and sex, the initial tumor size and location, the presence of lymph nodes and/or distant metastases, cytologic and mutational data, and patient preferences. Most DTC can be identified through cytology, and when the result is indeterminate, assessment with malignancy markers (HBME1 or galectin-3) and molecular alterations (BRAF mutations, RET fusions, other novel gene alterations) are reportedly helpful for identifying malignancy [11].
