In the 1990s the natural history of small PTC was not clear, but it was thought that most would not grow over time or would grow very slowly. Based on this hypothesis Miyauchi et al. [21], proposed a clinical trial of observation without immediate surgery for subcentimeter PTCs at Kuma Hospital, later called “active surveillance.” Patients with subcentimeter low-risk PTC were offered active surveillance or immediate surgery as alternatives. For those who chose “active surveillance,” ultrasound was performed every 6 months after diagnosis and once a year thereafter. Surgery was recommended when tumors grew by ≥3 mm or when novel lymph node metastasis developed [21].

By 2014, they had enrolled 1,235 patients, and showed that only 8% of subcentimeter low-risk PTC had a size enlargement of >3 mm and only 3.8% were found to have novel regional nodal metastases after a 10-year observation period and none of the 1,235 patients showed distant metastasis or died from subcentimeter low-risk PTC [22,23]. They also noted that young patients (<40 years) were more likely to experience thyroid tumor enlargement and novel lymph node appearance compared with middle-age (40 to 59 years) or older patients (>60 years). Similarly, in 2010, the Tokyo Cancer Institute Hospital group reported [24] their findings on active surveillance of 300 lesions in 230 patients for a mean of 5 years (range, 1 to 17). They showed that only 7% had size enlargement during “active-surveillance” protocol, 90% had remained unchanged and 3% decreased in size. No patient developed extrathyroidal invasion or distant metastasis. Both groups data showed that rescue surgery after progression was detected was successful and no life-threatening recurrence was detected thereafter [22,24]. The results of these landmarks studies have demonstrated that active surveillance is a safe and adequate treatment for properly selected patients with subcentimeter low-risk PTC [21,25,26].

To assess if a patient with subcentimeter low-risk PTC is suitable for an “active surveillance” approach, a variety of factors should be taken into consideration. The Memorial Sloan Kettering Cancer Center (MSKCC) in collaboration with the Kuma Hospital group developed a clinical framework to assess suitability for an “active surveillance” approach. The rationale for the development of this risk-stratified clinical decision-making framework is that though the 2015 ATA guidelines endorse “active surveillance” as an alternative to immediate biopsy and surgery in subcentimeter thyroid nodules with highly suspicious ultrasonographic characteristics, as well as in cyto-confirmed very low-risk PTC; the guidelines do not specify how to properly select patients for an “active surveillance” approach. In this framework, patients are divided in distinct categories: ideal, appropriate and inappropriate candidates for “active surveillance” based on a variety of factors (inherent to the tumor, patient characteristics and medical team characteristics) (Table 3) [27]. An “ideal” candidate, would be an older patient (>60 years old), with a subcentimeter low-risk PTC (probable or proven), with regular margins, confined to the thyroid parenchyma and not adjacent to the thyroid capsule. An “appropriate” candidate, would be younger, with tumor multifocality, with potentially aggressive molecular phenotype, adjacent to thyroid capsule but not in risky-zones, or have other imaging findings that can make follow-up more problematic (e.g., thyroiditis, other benign-appearing nodules, nonspecific lymph nodes). An “inappropriate” candidate, has tumors at risky-subcapsular locations (e.g., adjacent to the trachea or recurrent laryngeal nerve), has evidence of loco-regional or distant spread, or has evidence of disease progression on serial examinations.

Patients in the “ideal” category demonstrate a <2% rate of disease progression, and should be offered active surveillance. On the other hand, patients in the “appropriate” category might demonstrate a 10% rate of disease progression, and active surveillance may be offered by an experienced management team, as delayed surgery will still be effective, with good clinical outcomes. Finally, patients in the “inappropriate” category should not be offered active surveillance given the possibility that minor disease progression could lead to significant morbidity, and because a high rate of disease progression is expected.

Despite the potential benefits of active surveillance for some patients with very low-risk thyroid cancer, this management option has not been widely adopted. One potential barrier is that clinicians may have difficulty communicating the comparative benefits and downsides of the treatment options, and understanding patients' treatment preferences. Recently, and to support decision making for patients with subcentimeter low-risk PTC, researchers from MSKCC and Mayo Clinic in the United States developed a decision aid for use in clinical encounters called Thyroid Cancer Choice (TCC). This tool includes (1) an estimate of the frequency of thyroid cancer in the population; (2) the management options, active surveillance and thyroid surgery; (3) the risk of death, metastasis, tumor growth and adverse effects with each option; (4) the planned type and frequency of follow-up; (5) the out-of-pocket costs with each choice; and (6) the interaction of pregnancy and each management option. A Korean adaption of this tool underwent pilot testing at Seoul National University Hospital and Seoul National University Bundang Hospital, and found that among the 220 patients with small PTC, patients using TCC were more likely to choose active surveillance than the patients seen in the usual care clinic (relative risk, 1.16; 95% confidence interval, 1.04 to 1.29). Although this result suggests that this tool increases acceptance of active surveillance, additional and more rigorous studies are needed to confirm this finding.

To further assess active surveillance of subcentimeter low-risk PTC in different populations, Seoul, Korea has two ongoing recruiting studies (NCT02952612 and NCT02938702; both require fine needle aspiration [FNA] diagnosis to be performed as a criteria of inclusion). And there is another study (NCT03327636) expected to start recruiting on June 2018 in Hong Kong, China, it is a randomized study comparing high intensity focus ultrasound (HIFU) versus active surveillance for the management approach of subcentimeter PTC confirmed on FNA (Bethesda V or VI).

As described above, the initial studies of active surveillance were conducted in patients with subcentimeter tumors. As the comfort with active surveillance grows, clinicians are exploring the appropriateness of active surveillance in patients with larger tumors, specifically those ≤1.5 cm.

Building on the experience from the two cohorts in Japan, Tuttle et al. [28] developed an active surveillance cohort at MSKCC. The cohort consisted of 291 patients with low-risk PTC (≤1.5 cm) followed by a median of 25 months (range, 6 to 166). Consistent with previous reports, growth in tumor diameter ≥3 mm was observed in 11 of 291 (3.8%), with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during “active surveillance.” They also noticed that the tumor growth follows an exponential pattern with a median doubling time of 2.2 years (range, 0.5 to 4.8) indicating the change in tumor size could be modeled and predicted (Table 4). Other studies assessing the possibility of active surveillance for larger low-risk PTC tumors are currently active at different locations. There is a study (NCT03271892) recruiting patients 18 years of age or older with newly diagnosed previously untreated PTC (FNA biopsy positive for PTC or suspicious for PTC) and a tumor size <2 cm in maximal diameter on thyroid ultrasound, with no evidence of lymph node and/or distant metastatic disease. The study, based in Toronto, started in May 2016 and the estimated completion date of the study is May 2026. Another study (NCT02609685), being conducted in Los Angeles, is recruiting adult patients with pathologically confirmed Bethesda V or VI thyroid nodules with PTC and ≤1.5 cm, the study started in December 2015 and the estimated primary completion date is December 2030.

As the role of active surveillance has expanded, so has the role of lobectomy as a treatment option for low-risk tumors. Previously, lobectomy was only indicated for unifocal tumors <1 cm in size without preoperative evidence of extrathyroid extension or lymph node metastases (cN0). More recent evidence however, suggests that lobectomy can be safely performed in patients with larger tumors [29,30]. Lobectomy is most commonly performed using a transcervical approach (collar incision) under general anesthesia. However, a variety of minimally invasive techniques have been developed which are appropriate for low-risk tumors. These approaches often leave no obvious scar, a patient important outcome, and include techniques such as: endoscopic thyroidectomy using transaxillary approach, anterior chest, breast, “facelift” or even transoral endoscopic thyroidectomy via a vestibular approach (TOETVA). TOETVA is a novel, scar-free procedure that has no visible incisions [31].

For low-risk PTC, the decision to perform a total thyroidectomy or a lobectomy must be based on accurate and complete preoperative assessment as to the extent of the disease and after properly assessing patient's preferences. Thyroid surgery should be performed by high-volume surgeons (>25 thyroid surgeries yearly) at high-volume centers to avoid higher rates of surgical complications [32,33,34]. Furthermore, thyroidectomy without prophylactic central neck dissection is appropriate for low-risk thyroid cancer.

It is important to properly assess the benefits and harms of each particular therapy and to set expectations clear upfront to patients, so they engage fully in a conversation around what is the best therapy for them. The advantages of near total or total thyroidectomy is the ease of follow-up and the capability of administering RAI though, RAI has very limited role in the treatment of low-risk PTC; patients treated without RAI have similar survival rates. The disadvantages of total or near total thyroidectomy are that it is associated with higher surgical risks (e.g., transient or permanent post-surgical hypoparathyroidism, recurrent laryngeal nerve injury unilateral or bilateral, hematoma formation, infection and even chyle leak with unexperienced surgeons when thyroidectomy is combined with prophylactic node dissection) and the necessity of thyroid hormone replacement in all. The lobectomy has the advantages of lower surgical risks (e.g., unilateral recurrent laryngeal nerve injury, transient hypoparathyroidism, hematoma, infection) and only around 50% of patients will require thyroid hormone replacement after surgery [35]. The disadvantages are that biochemical follow-up is not as straightforward; therefore, the follow-up should rely more on structural serial-imaging assessment and some patients might require a second surgery to remove the contralateral lobe in the future.

Radioactive remnant ablation (RRA) is the process by which the administration of RAI is given to treat any possible remnant of “normal” thyroid tissue, while RAI for therapeutic adjuvant purposes is used when we know there is disease left, like due to incomplete tumor resection with “gross residual disease” [36]. The doses vary for RRA and therapeutic RAI, with 30 mCi now considered appropriate to ablate the remnants in selected patients and higher doses administered in the setting of adjuvant therapeutic doses [7].

The goal of RAI is to reduce risk of recurrence and mortality, and to facilitate follow-up. When deciding if a patient is candidate for RAI, using validated scoring systems to determine the risks of recurrence and mortality, as well as to having a thorough conversation with the endocrine surgeon as to determine if there was any disease left is imperative [9,37,38]. Patients with low-risk PTC have an excellent survival, with rates at 30 postoperative years of only 1% cause-specific-mortality and <15% tumor recurrence at any site [39]. Patients with high-risk for recurrence or mortality are good candidates for RAI because of the absolute benefit of this therapy is higher (higher risk and higher benefit from the intervention). For patients with low and intermediate risk, the decision to treat with RAI should be an individualized one. Most recent systematic reviews and meta-analysis suggest that overwhelming evidence shows that RAI has no role in improving survival or recurrent rates of low-risk PTC [40,41]. This body of evidence suggests that the only role for RAI in low-risk patients is to facilitate follow-up. Though, low-risk PTC patients treated with total thyroidectomy and without RAI can be safely and easily followed by ultrasound assessment and thyroglobulin (TG) trend overtime. Furthermore, they tend to have low TG levels and the levels tend to spontaneously drop over time [42].

For low-risk PTC, thyroid stimulating hormone (TSH) suppression is generally not recommended. The goal of L-thyroxine treatment among low-risk patients is to restore euthyroidism, and to avoid iatrogenic hyperthyroidism, with a TSH goal of 0.5 to 2.0 mU/L [7].