9.3.1 Genetics of Differentiated Thyroid Cancer

Several genetic mutations have been associated with tumor development in differentiated thyroid cancer. The most extensively studied are the RET/PTC, BRAF V600E, RAS, and PAX8/PPARG mutations. RET/PTC rearrangements result in activation of the RET proto-oncogene and have been described in up to 43% of papillary thyroid cancers. ⁴³ Activation of the RET proto-oncogene has been associated with prior radiation exposure. Recently, RET/PTC mutations have been described in follicular adenomas and other benign thyroid pathologies, and when present are associated with an increased rate of growth. ⁴⁴

Mutation in the BRAF gene, resulting in constitutive activation of BRAF kinase, has been linked to development of PTC and poorly differentiated thyroid cancers. ⁴⁵ The BRAF mutation, which has been described in 50 to 90% of conventional PTC, is associated with older age, lymph node metastasis, distant metastasis, recurrence, and persistent disease. ^{46 , 47} However, because of its high prevalence, use of BRAF positivity has been difficult to integrate into clinical practice. Coexistent mutations in BRAF and RET/PTC have been described in up to 13% of PTC and were more common in advanced stages of disease. ⁴⁸

Mutations in the four RAS proto-oncogenes, HRAS, KRASA, KRASB, and NRAS, result in a conformational change to their active form and promote downstream growth effects. RAS mutations have been found to have a high prevalence in follicular adenomas and follicular variants of PTC. ^{49 , 50} They are associated with worse outcomes in papillary thyroid cancer and poorly differentiated thyroid cancers. ^{51 , 52}

PAX8/PPARG is a fusion gene, often the result of a t(2;3)(q13;p25) chromosomal translocation. Constitutive activation in thyroid cells leads to the overexpression of PPARG and consequent loss of the normal inhibition of cell proliferation and induction of apoptosis. The loss of these functions results in uncontrolled cell growth. ⁵³ The PAX8/PPARG fusion gene is a common genetic abnormality seen in approximately 50% of follicular adenomas and 35% of follicular carcinomas. ^{54 , 55}

9.3.2 Preoperative Evaluation

If malignancy has been confirmed by FNA, or is highly suspected, then an ultrasound of the thyroid and lateral neck should be obtained prior to any surgical intervention. Cervical lymph node involvement is estimated to occur in 20 to 50% of cases of differentiated thyroid cancer. ²⁴ Patient outcomes are highly affected by the completeness of the resection, including cervical lymph nodes, so it is important to identify patients with evidence of lymph node metastasis for optimal surgical planning. ^{56 , 57}

On ultrasound imaging, involved lymph nodes tend to have loss of the fatty hilum, a rounded shape, hypoechogenicity, cystic change, increased peripheral vascularity, and microcalcifications. ⁵⁸ The location of the lymph node is also important; lymph nodes located in the lower portion of the neck are more likely to be affected than lymph nodes in the upper portion of the neck, where they are more likely to be reactive. ⁵⁹ However, none of these criteria are sufficiently sensitive or specific to definitively identify cervical metastasis. Therefore, all abnormal-appearing lymph nodes should undergo FNA biopsy if it will change surgical management. The lymph node aspirates may also be sent for thyroglobulin to increase the diagnostic accuracy of detecting metastatic DTC. ⁶⁰ The sensitivity of other imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), for abnormal neck lymph nodes is lower than neck ultrasound and, therefore, not routinely recommended in the preoperative evaluation. ⁶¹

9.3.3 Staging

Staging for differentiated thyroid cancer is generally performed using the American Joint Committee on Cancer’s (AJCC) TNM staging system. ⁶² This is the most universally accepted staging system and is required for cancer registries. Stage is based first on patient age because older patients have a higher risk of death from thyroid cancer than younger patients. ²³ Patients under the age of 45 have stage I disease if there is no evidence of distant metastasis and stage II disease if there is evidence of distant metastasis. For patients over the age of 45, stage I disease is defined as tumor < 2 cm without lymph node or distant metastasis. Stage II disease is a tumor 2 to 4 cm without lymph node or distant metastasis. Stage III disease is a tumor that is > 4 cm or has minimal extrathyroidal extension, or the presence of metastasis to the central lymph node compartment. Stage IV is divided into three substages: IVa is a tumor that invades through the thyroid capsule or tumor with lateral compartment lymph node metastasis; IVb is a tumor that invades into the prevertebral fascia or encases the carotid artery or mediastinal vessels; IVc is a tumor with evidence of distant metastasis.

The AJCC staging system addresses a patient’s risk of death due to differentiated thyroid cancer but was not developed to determine the patient’s risk of recurrence, which causes significant morbidity in patients. Thus it is suggested that risk of recurrence be classified into high, intermediate, and low risk of recurrence. ⁷ High-risk patients have macroscopic tumor invasion through the capsule, incomplete tumor resection, or distant metastatic disease. Intermediate-risk patients demonstrate microscopic tumor invasion through the capsule, cervical lymph node metastasis, aggressive histology (i.e., tall cell, insular, columnar cell), or vascular invasion. Low-risk patients have no regional or distant metastatic disease, and complete tumor resection without evidence of capsular or vascular invasion. ⁷

9.3.4 Postoperative Management

Under the influence of TSH, radioactive iodine (RAI) is taken up into thyroid cells and induces cell apoptosis. RAI has increasingly been administered in the treatment of papillary thyroid cancer, though there is variation in its use, and the indications for therapy remain a topic of debate. ⁶³ The most universally accepted indication for RAI is for the treatment of distant metastatic thyroid cancer, especially to the lungs. ^{64 , 65 , 66} In addition, RAI has been used in an adjunctive role to treat cancer cells that are suspected to be present after operative treatment but are not clinically apparent. There have been studies that show reductions in the rate of recurrence, as well as all-cause mortality. ^{23 , 67 , 68} However, other studies have not confirmed this benefit, especially in low-risk patients. ^{69 , 70 , 71 , 72} Finally, radioiodine has been used to ablate the normal remnant thyroid tissue, which facilitates postoperative surveillance of thyroglobulin levels and allows the physician to diagnose recurrence at an earlier stage. ⁷³ Radioiodine is not without side effects, most commonly salivary gland damage and obstruction of the nasolacrimal duct. ^{74 , 75} Additionally, after RAI, there appears to be a small risk of increased malignancy, especially leukemia, which is dose dependent. ^{76 , 77}

Recommendations for RAI are largely dependent on the risk of death and/or recurrence due to thyroid cancer, balanced with the increased cost and morbidity associated with treatment. For PTC, RAI is recommended for all patients with evidence of distant metastasis, gross extrathyroidal extension of the tumor, and tumors > 4 cm in size. RAI may be indicated in tumors 1 to 4 cm in size with lymph node metastasis, lymphovascular invasion, or aggressive histology, and should be considered on a case-by-case basis. RAI is not recommended in unifocal or multifocal PTC if all foci are < 1 cm and there are no other high-risk features. In contrast to PTC, follicular and Hürthle cell cancers are considered higher risk for recurrence; therefore, almost all patients with these tumors are treated with RAI (if iodine avid), with the exception of minimally invasive follicular carcinoma. ^{7 , 78}

If a patient is determined to be a candidate for RAI, there appear to be similar results using thyroid hormone withdrawal to increase the TSH versus using recombinant human TSH (rhTSH). ^{79 , 80} The treatment dose of RAI should be minimized to the greatest extent possible to prevent side effects. For thyroid remnant ablation, use of 30 mCi was found to be as effective as a higher dose of 100 mCi. ⁸¹ Treatment doses for suspected microscopic or macroscopic disease are generally higher. No randomized studies on this topic have been performed, however, so the treatment dose is largely based on physician preference.

Levothyroxine must be used to replace physiological thyroid hormone levels after total thyroidectomy, but it is also often employed as a therapeutic agent. TSH receptor proteins are present on the membranes of DTC, and these cells respond with accelerated cell growth in the presence of TSH. For that reason, larger doses of levothyroxine have been used following primary treatment for DTC to suppress the TSH, preventing growth of tumor cells. This practice, which has been shown to reduce both mortality and recurrence, is supported by most studies in the literature, including a previous meta-analysis. ⁸² Like RAI, these benefits are not as clear in low-risk patients. ⁷² TSH suppression is also not without side effects; it may contribute to increased cardiovascular mortality in elderly patients and fractures in postmenopausal women. ^{83 , 84 , 85}

The physician must balance the risks and benefits of TSH suppression therapy in each patient. With the increasing incidence of low-risk DTC, controversy remains over the degree and duration of TSH suppression. Patients at intermediate and high risk for recurrence should generally undergo TSH suppression to < 0.1 mU/L, whereas those at low risk for recurrence should have a TSH in the 0.1 to 0.5 mU/L range. ⁷ Long-term TSH goals may be more relaxed, with a target of 0.5 to 2 mU/L in those at low risk for recurrence. However, those at high risk should continue to have a TSH suppressed below 0.1 mU/L in the absence of significant risk of side effects. ^{86 , 87}

Although the risk of death from thyroid cancer is low, persistent and recurrent disease remains a significant source of morbidity. Several techniques are employed to detect recurrent disease in patients after treatment of DTC. Thyroglobulin (Tg) is a protein produced only by thyroid cells, so its presence in blood suggests that there are residual thyroid cells (either normal thyroid or DTC). It can be measured while the patient has a suppressed TSH on levothyroxine therapy (suppressed Tg) or under levothyroxine withdrawal (stimulated Tg). Alternatively, rhTSH has also been employed to obtain stimulated Tg levels. ⁸⁸ In a patient who has undergone thyroid remnant ablation, Tg should be undetectable. Stimulated Tg < 1 ng/mL is indicative of remission, whereas a suppressed Tg > 1 ng/mL suggests the presence of disease. ⁸⁹ Tg levels are more difficult to interpret in a patient who has not undergone remnant ablation. Additionally, some patients develop Tg antibodies, which can result in a falsely low level in a patient with recurrent disease.

The most common area for DTC recurrence is in the neck. ⁶⁸ Therefore, an ultrasound is generally obtained 6 to 12 months after therapy to determine if there are any suspicious-appearing lymph nodes. Concerning lymph nodes should undergo FNA biopsy. An iodine-131 (I-131) diagnostic scan can also be performed, especially in patients with mildly elevated Tg levels (suppressed Tg > 1 ng/mL or stimulated Tg > 2 ng/mL) and a normal neck ultrasound; however, it is of little utility in patients with undetectable thyroglobulin levels. ⁹⁰ In patients with a negative I-131 scan and significantly elevated stimulated Tg (> 5–10 ng/mL), a PET scan may be useful to detect noniodine avid disease. ^{91 , 92}

Tumor characteristics can be used to estimate the risk of recurrence, discussed earlier in this chapter. Additionally, patient response to initial therapy is predictive of the likelihood of recurrence and can therefore be used to “restage” patients. ⁹³ In one study, patients at low risk for recurrence had a 3% rate of recurrent disease in the 2 years after treatment, whereas those at intermediate risk had a 21% rate and those at high risk had a 68% rate. In the cohort who demonstrated an excellent response to therapy (stimulated Tg < 1 ng/mL, negative neck ultrasound), the risk of recurrence was 2% in the low-risk group, 2% in the intermediate-risk group, and 14% in the high-risk group. Alternatively, the cohort who had an incomplete response to therapy (suppressed Tg > 1 ng/mL, stimulated Tg > 10 ng/mL, rising Tg level or evidence of structural disease on imaging) had a 13% recurrence rate in the low-risk group, 41% in the intermediate group, and 79% in the high-risk group.