**4. Treatment**

The initial staging of each patient is performed post-operatively mainly on the basis of the histology report, according to the seventh edition of the TNM classification of the American Joint Committee of Cancer (AJCC), presented on **Table 2** [53]. Additionally to the TNM score, the age of the patient is also important, as young age (≤ 45 years) is considered a favorable factor upstaging the young patients with any T, any N and M0 in stage I and, respectively, young patients with distant metastases in stage II. However, some studies have questioned

**The initial risk stratification** is based on the TNM staging, as well as the type of tumor histology. ATA guidelines from 2015 proposed some additional prognostic variables as the extent of lymph node involvement presented as the number and size of lymph metastases, mutational status and degree of vascular invasion as the number of affected vessels that were not present

• Complete resection of the primary tumor (assessed macroscopically)

• The histological subtype does not belong to the aggressive ones (e.g., tall cell, columnar cell

• If 131I is administered, there are no uptake outside the thyroid bed (no metastatic foci) on the

Intrathyroidal, well differentiated follicular carcinoma with capsular invasion and no or minor (< 4

Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAFV600E mutated (if

RAI uptake outside the thyroid bed (metastatic foci) on the posttherapeutic whole-body scan (WBS) Aggressive histology (e.g., tall cell, columnar cell or hobnail cell variant, diffuse sclerosing variant)

Multifocal papillary microcarcinoma with extrathyroidal extension and BRAFV600E mutated (if

High postoperative serum thyroglobulin suggestive of distant metastases LN metastasis with any

Follicular thyroid cancer with extensive vascular invasion (> 4 foci of vascular invasion)

this "young age benefit" in the presence of lymph node metastases [54].

in previous stratification systems (**Table 3**).

Low ATA risk Papillary thyroid carcinoma (with all of the following):

or hobnail cell variant) • No vascular invasion

vessels) vascular invasion

PTC with vascular invasion

known)

known)

Distant metastases

of the LNs > 3 cm

**Table 3.** Initial risk stratification (adapted from ATA 2015 guidelines [5]).

Intermediate ATA risk

58 Thyroid Disorders

• No local (LNs) or distant metastases

• No tumor invasion of local tissues and structures

• Clinical N0 or < 5 N1 micrometastases (< 2 mm)

Intrathyroidal encapsulated follicular variant of papillary carcinoma

Microscopic invasion of tumor into the soft tissues surrounding the thyroid

High ATA risk Macroscopic invasion of tumor into the perithyroidal soft tissues Incomplete tumor resection

post-therapeutic whole-body scan (WBS)

Clinical N1 or > 5 metastatic LNs with size < 3 cm

Initial treatment of DTC includes surgery and post-operative administration of radioiodine (if indicated) and the initiation of levothyroxin therapy. In rare cases (locally aggressive thyroid cancer), external beam radiotherapy to the neck is also indicated.

### **4.1. Surgery**

#### *4.1.1. Thyroid surgery*

Thyroid surgery is an important element of the initial therapy for thyroid carcinoma. The recommended extent of thyroid surgery in patients with FNAB and cytology of malignant thyroid nodule (not medullary carcinoma) depends on the nodule size:


#### *4.1.2. Lymph node dissection*


• Thyroidectomy without prophylactic central neck lymph dissection is suitable for small (T1 or T2), noninvasive, PTC without clinically engaged LNs and for most follicular carcinomas [5].

be severe and substantially impair their quality of life [58]. Cardiovascular, respiratory, CNS and psychiatric diseases worsen, as well as renal and liver function, requiring dose adjustment of concomitant medications in comorbid patients [59]. Besides, prolonged TSH stimula-

Thyroid Cancer: Diagnosis, Treatment and Follow-Up http://dx.doi.org/10.5772/intechopen.77163 61

Alternatively, to overcome the inconvenience of this thyroid hormone withdrawal, rhTSH has been developed, and numerous studies have demonstrated its safety, noninferiority of remnant ablation efficacy and Tg secretion, a definite superiority regarding quality of life, especially in patients with significant comorbidities, and also benefits for patients unable to

Treatment with thyroid hormone is well established and its goal is (1) to correct the postoperative/post-radiation hypothyroidism and (2) to suppress the growth of neoplastic cells by reducing TSH levels [62]. Thus, thyroid hormone treatment provides replacement and

Since thyroid cell proliferation and differentiation is TSH dependent and the presence of functional TSH receptors has been documented in most DTCs, the rationale for thyroid hormone administration is to inhibit TSH secretion. According to 2015 ATA guidelines the initial TSH

• For intermediate-risk DTC patients, initial TSH suppression of 0.1–0.5 mU/L is recom-

• Low-risk patients who have undergone remnant ablation should maintain TSH at the lower end of the reference range (0.5–2 mU/L) if Tg is undetectable or TSH at or slightly below the lower limit of normal (0.1–0.5 mU/L) if Tg is low but detectable. For low-risk patients who have undergone lobectomy, TSH may be maintained in the mid-to-lower reference

In the very rare cases of RAI refractory DTC patients with metastatic, rapidly progressive and symptomatic disease, kinase inhibitors may be considered after a careful evaluation of the

Most differentiated thyroid cancers are characterized by an indolent course with low morbidity and mortality. The methods used in the long-term follow up of patients with DTC are clinical examination, US (with special focus on the thyroid bed and lymph node status of the

• High-risk DTC patients require initial TSH suppression to below 0.1 mU/L [4, 5].

range (0.5–2 mU/L) while surveillance for recurrence is continued [5, 61].

tion may be associated with increased growth of metastatic tissue [16].

mount an endogenous TSH rise [60, 61].

suppressive therapy at the same time.

suppression is considered as the following:

potential risks and benefits of such therapies [5].

**5. Follow-up of patients with DTC**

**4.3. Hormonal therapy**

mended [5, 61].

**4.4. Other therapies**

• Therapeutic lateral-compartment lymph node dissection is recommended for patients with biopsy-proven metastatic lateral lymph nodes [55].

#### *4.1.3. Completion thyroidectomy*

Completion thyroidectomy is a reoperation to completely remove residual thyroid parenchyma and should be offered to patients for whom total thyroidectomy would have been indicated if the diagnosis was known prior to the initial surgery. This underlines the importance of routine referral of patients with nodular goiter to FNAB, since malignant or suspicions for malignancy cytology suggests a one-step operation (total or near-total thyroidectomy) in contrast to a suboptimal operation (lobectomy) for preoperatively unspecified carcinoma which could require a second operation (completion thyroidectomy), the latter being often difficult to perform due to adhesions and neck changes after the previous operation [4, 5].

#### **4.2. Post-operative radioiodine (RAI) treatment**

Post-operative administration of 131I aims to destroy the remnant in the thyroid bed, as well as microscopic tumor foci, thus reducing the likelihood of recurrence [56, 57]. The ablation of residual normal thyroid tissue allows adequate long-term follow-up and early detection of recurrence based on serum Tg and whole-body scintigraphy (WBS). The high activity 131I, given as a therapeutic dose (from 30 to 100 mCi), can also be used for diagnostic purposes by conducting a WBS from 2 to 5 days after the iodine administration, thus detecting small invisible with diagnostic doses (from 1 to 3 mCi) foci [57].

However, RAI remnant ablation is not routinely recommended after thyroidectomy for all DTC patients. For patients with low ATA risk and tumor ≤1 cm, there is no evidence that RAI improves disease-related survival and is not recommended [5, 56, 57]. For patients with low ATA risk and tumor size between 1 and 4 cm, RAI is not routinely recommended, but it can be considered in aggressive histology and vascular invasion. Moreover, for low-risk patients, preference is given to the use of lower activities (30 mCi). For intermediate risk patients, the data on the survival benefits of RAI is controversial, and RAI is recommended for larger tumor size (> 4 cm) and age above 45 years [5]. In high-risk patients (with LN metastases, extrathyroidal spreading and distant metastases), RAI is generally indicated and in doses of 100 mCi [5].

If RAI therapy or diagnostic testing (WBS, stimulated thyroglobulin measurement) is planned, a TSH stimulation should be achieved before these procedures. TSH level may rise through two methods: thyroid hormone withdrawal or application of recombinant human TSH (rhTSH, Thyrogen). Levothyroxine (LT4) should be withdrawn for 4–6 weeks to induce transient hypothyroidism with TSH > 30 mU/l that can stimulate iodine uptake (diagnostic or therapeutic) and Tg release. Liothyronine (LT3) may be substituted for LT4 in the initial weeks, but LT3 should be withdrawn for at least 2 weeks before testing/therapy. During the withdrawal period, patients experience signs and symptoms of hypothyroidism which may be severe and substantially impair their quality of life [58]. Cardiovascular, respiratory, CNS and psychiatric diseases worsen, as well as renal and liver function, requiring dose adjustment of concomitant medications in comorbid patients [59]. Besides, prolonged TSH stimulation may be associated with increased growth of metastatic tissue [16].

Alternatively, to overcome the inconvenience of this thyroid hormone withdrawal, rhTSH has been developed, and numerous studies have demonstrated its safety, noninferiority of remnant ablation efficacy and Tg secretion, a definite superiority regarding quality of life, especially in patients with significant comorbidities, and also benefits for patients unable to mount an endogenous TSH rise [60, 61].

#### **4.3. Hormonal therapy**

• Thyroidectomy without prophylactic central neck lymph dissection is suitable for small (T1 or T2), noninvasive, PTC without clinically engaged LNs and for most follicular carci-

• Therapeutic lateral-compartment lymph node dissection is recommended for patients with

Completion thyroidectomy is a reoperation to completely remove residual thyroid parenchyma and should be offered to patients for whom total thyroidectomy would have been indicated if the diagnosis was known prior to the initial surgery. This underlines the importance of routine referral of patients with nodular goiter to FNAB, since malignant or suspicions for malignancy cytology suggests a one-step operation (total or near-total thyroidectomy) in contrast to a suboptimal operation (lobectomy) for preoperatively unspecified carcinoma which could require a second operation (completion thyroidectomy), the latter being often difficult

Post-operative administration of 131I aims to destroy the remnant in the thyroid bed, as well as microscopic tumor foci, thus reducing the likelihood of recurrence [56, 57]. The ablation of residual normal thyroid tissue allows adequate long-term follow-up and early detection of recurrence based on serum Tg and whole-body scintigraphy (WBS). The high activity 131I, given as a therapeutic dose (from 30 to 100 mCi), can also be used for diagnostic purposes by conducting a WBS from 2 to 5 days after the iodine administration, thus detecting small invis-

However, RAI remnant ablation is not routinely recommended after thyroidectomy for all DTC patients. For patients with low ATA risk and tumor ≤1 cm, there is no evidence that RAI improves disease-related survival and is not recommended [5, 56, 57]. For patients with low ATA risk and tumor size between 1 and 4 cm, RAI is not routinely recommended, but it can be considered in aggressive histology and vascular invasion. Moreover, for low-risk patients, preference is given to the use of lower activities (30 mCi). For intermediate risk patients, the data on the survival benefits of RAI is controversial, and RAI is recommended for larger tumor size (> 4 cm) and age above 45 years [5]. In high-risk patients (with LN metastases, extrathyroidal spreading and distant metastases), RAI is generally indicated and in doses of 100 mCi [5]. If RAI therapy or diagnostic testing (WBS, stimulated thyroglobulin measurement) is planned, a TSH stimulation should be achieved before these procedures. TSH level may rise through two methods: thyroid hormone withdrawal or application of recombinant human TSH (rhTSH, Thyrogen). Levothyroxine (LT4) should be withdrawn for 4–6 weeks to induce transient hypothyroidism with TSH > 30 mU/l that can stimulate iodine uptake (diagnostic or therapeutic) and Tg release. Liothyronine (LT3) may be substituted for LT4 in the initial weeks, but LT3 should be withdrawn for at least 2 weeks before testing/therapy. During the withdrawal period, patients experience signs and symptoms of hypothyroidism which may

to perform due to adhesions and neck changes after the previous operation [4, 5].

biopsy-proven metastatic lateral lymph nodes [55].

**4.2. Post-operative radioiodine (RAI) treatment**

ible with diagnostic doses (from 1 to 3 mCi) foci [57].

nomas [5].

60 Thyroid Disorders

*4.1.3. Completion thyroidectomy*

Treatment with thyroid hormone is well established and its goal is (1) to correct the postoperative/post-radiation hypothyroidism and (2) to suppress the growth of neoplastic cells by reducing TSH levels [62]. Thus, thyroid hormone treatment provides replacement and suppressive therapy at the same time.

Since thyroid cell proliferation and differentiation is TSH dependent and the presence of functional TSH receptors has been documented in most DTCs, the rationale for thyroid hormone administration is to inhibit TSH secretion. According to 2015 ATA guidelines the initial TSH suppression is considered as the following:


#### **4.4. Other therapies**

In the very rare cases of RAI refractory DTC patients with metastatic, rapidly progressive and symptomatic disease, kinase inhibitors may be considered after a careful evaluation of the potential risks and benefits of such therapies [5].
