*2.5.1 Various sentinel lymph node techniques*

Various SLNB techniques have been studied in PTC. The use of vital dye was the earliest described technique, but it is growing out of popularity due to its disadvantages that (1) lateral compartment SLN cannot be visualized during thyroidectomy; (2) parathyroid glands may have uptake; and (3) the risks of anaphylaxis [71]. The use of radioisotope as an alternative technique allows identification of SLN located outside the central compartment without parathyroid gland uptake. Furthermore, the addition of SPECT/CT imaging can improve preoperative anatomical localization of the SLN. In a meta-analysis including 45 retrospective studies, the SLN detection rates for vital dye technique, radiolabelled lymphoscintigraphy, vital dye plus lymphoscintigraphy, and lymphoscintigraphy plus SPECT/CT were 83, 96, 87, and 93% respectively, while the reported respective false negative rates were 38, 40, 17, and 8% [72].

#### *2.5.2 Using sentinel lymph node biopsy to guide neck dissection*

SLNB has been applied in the management of PTC where SLNB-positive patients can undergo dissection of the involved compartments, and negative patients can be spared the risks and added costs of unnecessary procedure. The negative predictive value of each SLNB technique is the most important parameter to determine whether neck dissection should be performed, and it is dependent on the SLN detection rate and the false negative rate of each technique. Relevant literature data was diversified, firstly due to the difficulty to interpret SLN at frozen section; secondly due to variable definition of the SLN resulting in non-sampling of non-dominant nodes; thirdly due to the occasional skip metastasis; and finally due to the learning curve [73, 74]. Therefore, despite promising initial results from SLNB, further high-quality prospective evidence is necessary. Furthermore, the cost-effectiveness of SLNB strategy also remains ambiguous. A retrospective study reported that the cost of implementing SLNB outweighed the potential cost saving from avoided procedures and morbidities [75]. As such, the current use of SLNB remains within clinical trial settings.

## **3. Management of recurrent nodal disease**

DTC recurs in up to 30% of patients. Three quarters of these recurrences are at the cervical and mediastinal lymph nodes, 20% are in the thyroid remnant and 21% are distant with the lungs being the most common [76]. Although recurrences are common, resultant cancer related deaths are not [77].

#### **3.1 Management of resectable nodal recurrence**

When patients develop isolated nodal recurrence after previous surgery, further curative surgery, if technically feasible, confers the advantages of avoiding future local complications arising from the recurrent tumor, improving serum thyroglobulin level, and facilitating RAI treatments.

#### *3.1.1 Low volume recurrences*

Although surgical removal of recurrence confers advantages, low volume recurrence does not necessarily require surgery. Several observational studies have suggested that low-volume recurrent nodal disease can be indolent and can be managed with active surveillance. In a retrospective cohort of 166 patients with suspicious lateral compartment lymph node of a median size of 1.3 cm, less than 10% of the patients had interval progression by >5 mm, and 14% had complete resolution [78]. Thyroid stimulating hormone suppression therapy should be continued during active surveillance.

#### *3.1.2 Macroscopic resectable recurrence*

Larger volume recurrent nodal disease has been associated with poorer cancerspecific survival and is best treated with revision surgery [79]. In the cases where the recurrence occurs in a previously un-operated neck region, a formal neck dissection should be considered. Revision surgery achieves biochemical remission rates of 21−66%. While most modern series suggest that revision surgery can achieve a high clearance rate of structural disease in over 80% of patients [80].

However, in the cases where recurrence occurs in a previously operated area, the risk of re-operative surgery should be balanced against oncological disease clearance. Re-operative surgery for recurrent nodal disease has higher risk of major complications due to the increased technical demand for dissecting scarred tissue and altered anatomy. The morbidity from re-operative surgery is related to the region undergoing dissection, the experience of surgeons, and the degree of scarring from initial surgery. In general, the incidence of permanent and transient hypoparathyroidism was 0–9.5%, and 0–46.3% respectively. While the rate of transient and permanent unexpected RLN palsy was an average of 3.6 and 1.2%, respectively [81].

#### *3.1.3 Decision-making for re-operative neck dissection*

The ATA recommends that radiologically localized, cytology confirmed, recurrent central neck nodes ≥8mm and lateral neck nodes ≥10mm in the smallest dimension should be considered for surgery. The exact size threshold for re-operative neck

#### *Lymph Node Metastasis in Differentiated Thyroid Cancers DOI: http://dx.doi.org/10.5772/intechopen.106696*

dissection is anecdotal by consensus, and available supporting evidence are scarce. The relationship between the size of recurrent structural disease, morbidity from surgery, and response to therapy had been assessed by Lang et al. in their cohort of 130 patients [82]. Lesion >15 mm was an independent risk factor for incomplete biochemical response. The rates of incomplete surgical resection, unexpected vocal cord palsy, and overall morbidity were also significantly higher in patients with lesions >15 mm than those with lesions <15 mm. Hence, the authors propose that the threshold for continued active surveillance can be less stringent and extended to larger lesions.

Besides the size of recurrence, several other factors are also important to be considered during discussion for revision surgery. These include patient's factors (symptoms arising from recurrent disease, vocal cord status, previous neck irradiation/ surgery, motivation for surgery), surgeon's experience, and disease factors (lesion's location in relation to vital structures, factors reflecting tumor aggressiveness such as serum thyroglobulin doubling time, speed of radiological growth, iodine avidity, and the presence of adverse molecular markers) [81]. Hence, such a decision is best discussed with a dedicated multidisciplinary team including surgeons, endocrinologists, nuclear medicine physicians, pathologists, and oncologists [83].

#### **3.2 Nonoperative local treatment for nodal recurrence**

Radioactive iodine ablation (RAI) may be employed in patients with 131I-avid low-volume disease detected on WBS or as adjuvant treatment following surgery. To date, no randomized controlled trials had demonstrated superior outcomes with RAI alone or as adjuvant treatment in the setting of locoregional recurrent disease [59]. However, 131I non-avid lesions are unlikely to respond and empirical RAI is not recommended [84].

With a larger volume of nodal recurrences, percutaneous ethanol injection (PEI) for metastatic cervical lymph node was first reported in the early 1990s−2000s [85]. Studies have reported sonographic successful ablation in up to 84% of treated lymph nodes after repeated sessions of treatment [86]. Most ablated lymph nodes decreased in size and 46% completely disappeared [87]. Radiofrequency ablation (RFA) for metastatic cervical lymph node is another newer modality of nonoperative treatment for recurrent nodal disease. It has been associated with a greater mean volume reduction of 55–95% and complete resolution of the structural lesion in 40–60% [88]. The limitation of these ablative modalities is that only limited small studies are available. They are considered a nonoperative form of lymph node picking and, as such, are best considered in patients with high surgical risks or those who declined surgery.

#### **3.3 Management of extensive/unresectable nodal recurrence**

Advanced nodal recurrence may involve extensive soft-tissues with potential laryngeal, tracheal, esophageal, or carotid sheath invasion. While there is no strict description to define unresectable diseases, extensive organ resections such as hemior total laryngectomies, circumferential tracheal resection, and esophagectomies have been described [89]. The related morbidity and the anticipated functional impairment must be accepted by the patient. Even in patients with distant metastases and concomitant loco-regional recurrent disease compromising the aerodigestive tract, palliative re-operative surgery may be considered on a case-by-case basis, followed by adjuvant RAI treatment [90].

In extensive unresectable nodal recurrences, RAI alone is unlikely able to eradicate the disease as the absorbed radiation dose is generally inadequate. External beam radiotherapy (EBRT) can be considered for locoregional control in such patients. However, acute treatment-related morbidities, including dermatitis, mucositis, and dysphagia, are not uncommon and efficacy has only been reported in retrospective cohorts [91]. To date, there are no randomized trials that address specific indications for EBRT in patients with recurrent DTC. Hence, individual practice is variable.

#### *3.3.1 Other systemic treatment for extensive/unresectable recurrent diseases*

Patients with gross symptomatic recurrent disease that cannot be alleviated with surgery or EBRT or had become RAI refractory, are candidates for systemic therapy. Inhibition of protein kinases that function in key signaling pathways can regulate tumor proliferation, angiogenesis, metastasis, and apoptosis. Furthermore, inhibition of kinases involved in the mitogen-activated protein kinase pathway has been shown to re-express genes of iodine metabolism and thus allow restoration of RAI uptake in RAI refractory DTC [92]. Somatic mutation testing can be performed to identify oncogenic targets such as gene rearrangements in NTRK, RET, or BRAF. This may guide the use of mutation-specific kinase inhibitor such as TRK inhibitors (e.g. Larotrectinib, Entrectinib) and RET inhibitors (e.g. Selpercatinib, Pralsetinib). However, BRAF inhibitors (e.g. Vemurafenib, Dabrafenib) are currently nonapproved in thyroid cancers and have been used off-labeled.

Given the high cost of performing mutation analysis and the limited participation in clinical trials, anti-angiogenic multi-kinase inhibitors (aaMKI) such as Lenvatinib or Sorafenib are alternative agents. No head-to-head comparisons of aaMKI are available. Most of these aaMKI target vascular endothelial growth factor receptors (VEGFR) in angiogenic pathways. Of note, patients with risks of bleeding e.g. recent major surgery, haemorrhagic brain metastasis, or recent thromboembolic events are relatively contraindicated for MKI. Furthermore, tracheoesophageal fistulation have been reported in patients with prior EBRT and MKI treatment.

If a patient is intolerant to, or the disease is refractory to kinase inhibitors, conventional cytotoxic agents (e.g. Doxorubicin) may be alternative options but experience is sparse.
