Nonsurgical Thermal Ablation of Thyroid Nodules: Not if,but Why,When,and How?

The last decade has seen increasing interest in minimalistic diagnostic and therapeutic management options for thyroid nodules and low-risk papillary thyroid cancer (1,2). These recommendations are based on the observations that most thyroid nodules are benign and asymptomatic, with 10% or less demonstrating clinically significant growth over time (3,4). Furthermore, in properly selected low-risk papillary thyroid cancer patients, minimalistic management options, including thyroid lobectomy or active surveillance, have proven to be safe and effective (5).

The increasing availability of thermal ablation (TA) technologies (such as laser ablation [LA], radiofrequency ablation [RFA], microwave ablation, and high-intensity focused ultrasound), that are being successfully used in a variety of benign and malignant medical conditions has led to the exploration of potential applications of these technologies to patients with symptomatic benign nodules, recurrent cervical lymph node metastases, distant metastatic foci, and more recently, primary low-risk papillary microcarcinoma. In the present issue of Thyroid, three articles highlight 5-year follow-up data in patients treated with TA for benign thyroid nodules (6) or thyroid papillary microcarcinomas (7,8) and provide very reassuring data on safety and efficacy.

In terms of nonsurgical therapeutic options, ethanol sclerotherapy for recurring benign thyroid cysts has been accepted as part of routine clinical care with excellent outcomes for many years (1,2,9). The American Thyroid Association 2015 guidelines provide recommendations for the use of TA in selected patients with metastatic disease with no recommendation given regarding TA in benign nodules (1). In 2017, the guidelines from the Korean Society of Thyroid Radiology endorsed RFA as a first line therapy option for benign nodules causing symptoms or cosmetic problems, and as an alternative to surgery in patients at high surgical risk or refusing surgery in the setting of primary thyroid cancers and recurrent thyroid cancer in the thyroid bed or cervical lymph nodes (10). More recently, a German multisociety working group (German Society for Endocrinology, German Society for Nuclear Medicine, German Association of Endocrine Surgeons, and the German Society of General and Visceral Surgery) endorsed TA techniques as a first line alternative for surgical intervention for benign nodules that were symptomatic or had a cosmetic indication for intervention (11).

Interestingly, despite compelling evidence for more than two decades that TA is a safe and effective therapy for symptomatic benign nodules (12), a recent survey of European Thyroid Association (ETA) members found that only 5% of ETA members personally performed TA, and that only 13% of respondents referred potentially eligible patients (“often or always”) to centers with specific expertise in this field (13). The survey identified inequality of access, lack of experience with TA, and the absence of societal guidelines as the primary factors cited for not using TA technologies for benign nodules, papillary microcarcinoma, or recurrent papillary thyroid cancer cervical lymph node metastasis (13).

Anecdotally, many of these same reasons appear to be responsible for the lack of routine use of TA therapies for symptomatic benign thyroid nodules in the United States and Japan as well. The recently published ETA guidelines for use of TA in benign thyroid nodules (primarily focused on LA and RFA, since these are the techniques with the highest levels of evidence) are the first international endocrine society guidelines in this field, and offer critical insights into technical aspects of the procedure, indications for use, patient preparation recommendations, as well as an assessment of efficacy, side effects, and cost comparisons (12).

To date, most patients selected for TA, for either benign nodules or thyroid cancer, were eligible for these therapies because of concurrent medical conditions that rendered them high risk for surgical intervention or because they declined surgical intervention. While some patients are undoubtedly ineligible for thyroid surgery, this likely constitutes a small minority compared with the many who decline surgery for a wide variety of reasons. Therefore, the fact that a large number of nonsurgical thyroid options are being investigated is most probably due to the following: (i) availability of a number of ultrasound-guided TA techniques; (ii) increasing prevalence of thyroid nodules either previously undiagnosed or not offered treatment due to few or no symptoms; and (iii) patients' demand for nonsurgical therapy options.

While we have improved our ability to evaluate the quality of life following therapeutic interventions using validated disease-specific instruments such as the ThyPRO (14), we rarely use these instruments in a routine clinical setting, and if we do, the specific thresholds that should guide us in offering or refraining from treatment remain to be defined.

As a group, patients offered TA for benign nodules or papillary microcarcinoma differ from those offered surgery, typically by having much smaller thyroid nodules, and a large proportion would never have been candidates for surgery because of choice or medical comorbidities. Therefore, a fair comparison between surgery and TA—without access to data from randomized studies—is not possible and cannot be our aim. It follows that TA should, currently, be considered an alternative in properly selected patients with benign nodules and papillary thyroid microcarcinomas, which, with time, once compared head-to-head with surgery, will allow improved individualization of treatment.

In benign nodules that cause pressure symptoms and/or cosmetic concerns, when balancing efficacy, side effects, and cost, both LA and RFA are considered to be alternative options to surgical treatment or observation alone for (i) solid nodules, (ii) purely or predominantly cystic nodules that recur after aspiration and ethanol ablation, and (iii) those that have a residual solid component after such therapy (12).

Mounting evidence links TA with a 12-month volume reduction rate of 50–90% (6,10,15,16). In the recent study by Bernardi et al. this translated into acceptable efficacy (≥50% post-therapy volume reduction) in 85% of RFA-treated and 63% of LA-treated individuals (6). The superior effect on nodule shrinkage also meant that only 20% in the RFA group versus 38% in the LA group had significant regrowth in the long-term (7), and that fewer RFA than LA treated required retreatment (12% and 24%, respectively). Young age, large pretreatment volume, small volume reduction at 1-year follow-up, delivery of low energy per milliliter of nodule tissue, and nonspongiform nodules were associated with regrowth and need of retreatment (6,17). In experienced hands, serious side effects are very rare as is post-therapy hypothyroidism. For functioning thyroid nodules, the efficacy of any TA technique is at present considered inferior to that of radioactive iodine (11,12,18).

The application of TA to malignant thyroid nodules has largely been restricted to very small (usually ≈5 mm maximal diameter), intrathyroidal low-risk papillary microcarcinomas in patients who had significant medical contraindications to surgery, or in patients who refused surgery and active surveillance (7,8,10). In addition, RFA has been used successfully to treat cervical recurrences in patients at high surgical risk and in those patients that refused surgery (10,19). Unlike TA of symptomatic benign nodules where significant decrease in nodule volume is an appropriate objective, the goal of TA in primary malignant nodules must be to destroy the entire nodule with a surrounding rim of normal thyroid tissue (usually 2–5 mm in other tumor types).

While very few studies have histologically confirmed complete ablation of the tumor after TA, the studies by Cho and Teng in this edition of Thyroid provide data demonstrating that after 5 years of follow-up, ultrasonographic evaluation of the ablation site reliably and consistently demonstrates no evidence of viable tumor (8,9). Although very reassuring, given the indolent nature of papillary microcarcinoma, we cannot be certain that all tumor cells have been destroyed. Furthermore, the published studies documenting that TA of these small intrathyroidal papillary thyroid cancers can be done safely, with minimal complications, and with excellent local control rates, arise from specialized centers where experienced management teams have developed considerable technical expertise and use strict eligibility criteria for patient selection (7,8,20). The authors of both studies argue that anxiety and the psychological stress of living with a diagnosed papillary thyroid cancer make many of their patients unwilling to follow with active surveillance but open to a more limited treatment option such as TA (7,8).

From an oncologic perspective, we need to be careful that a more widespread access to a safe and effective localized TA therapy option does not inadvertently lead to a renewed interest in the detection and diagnosis of these small papillary microcarcinomas simply because we have a treatment option perceived to be less aggressive than thyroid surgery. It is important to note that these small, highly suspicious thyroid nodules would have been candidates for active surveillance management (either with or without cytological confirmation by fine needle aspiration), indicating that immediate diagnostic and therapeutic interventions for these small papillary microcarcinomas were not mandatory.

Another point to consider is that in all of the published active surveillance studies, it was the change in size of the index papillary microcarcinoma that served as the primary biomarker to signal that surgical intervention was warranted (21,22). If that index lesion is destroyed with TA, it will be identification of other papillary thyroid cancer foci either within the gland or in surrounding cervical lymph nodes that will be the primary biomarker of disease progression. Given the indolent nature of papillary microcarcinoma, it is likely that active surveillance in the absence of observation of the primary papillary microcarcinoma will be safe and effective, but this remains unproven at the current time.

As described above, most patients included in these publications of TA of papillary microcarcinomas would be classified as ideal candidates for observation, based on tumor/imaging characteristics and medical team characteristics. We agree that many patients with papillary microcarcinoma do have a variety of patient characteristics that may make them less than ideal for an observational management approach (5,23). However, with proper communication, shared decision-making, trust and support, levels of cancer worry decrease over time in patients on active surveillance (24,25). Furthermore, we do not see TA as the only option to address the anxiety, worry, and psychological stress that are common in this patient population nor do we accept that successful ablation of a small primary tumor will completely alleviate all of the patient concerns for future detection of disease in the thyroid or surrounding lymph nodes (26 –28).

The above evidence of efficacy for properly selected patients with benign or malignant thyroid conditions has not translated into widespread use of these technologies. While the fact that only 5% of ETA members personally performed TA does not necessarily reflect whether TA is offered for the needy, the fact that only 13% of respondents referred such patients (“often or always”) to centers with specific expertise in this field highlights the enormous inequality in access to alternatives to thyroid surgery (13). The ETA questionnaire data, obtained from individuals with thyroid expertise, suggest that the figures overestimate overall availability of TA to thyroid patients. The reasons offered for this reluctance of TA use include absence of dedicated guidelines, uncertainty about clinical long-term outcome, concerns of side effects, and fear of overlooking malignancy (13). Some of these concerns no longer seem valid, while others demand further studies and action.

Most importantly, we are of the opinion that the international thyroid community needs to contemplate multisocietal guidelines, and offer dedicated teaching that emphasizes not only the technical aspects of TA but also proper identification of patients deemed most likely to benefit from these localized therapies and those who are very unlikely to have a clinical benefit from destruction of an asymptomatic benign thyroid nodule or very low-risk thyroid cancer. A good example of a note of caution in patient selection comes from the German multisociety working group that specifically recommended against any therapeutic intervention (TA or surgery) for “sonographically visible nodules per se without symptoms or hyperfunction and without suspicion or evidence of malignancy. (11)” If this important message is not given urgent priority, there is a considerable risk of overutilization of TA technologies not based on an unmet need but rather on the availability of a safe and effective therapy applied to nodules that require no therapy at all. If we fall into the trap of overutilization of TA technologies (just as we did with overutilization of diagnostic fine needle aspiration when applied indiscriminately to all thyroid nodules), we risk years of debate and research into when not to use TA, at enormous cost to society as well as to our credibility.

In conclusion, TA techniques have repeatedly shown efficacy in the treatment of a spectrum of benign thyroid nodules. Furthermore, preliminary evidence now indicates that TA can also play an important role in thyroid cancer, particularly in patients with significant comorbidities that increase the risk of surgical interventions and in patients who decline a surgical or active surveillance option. Additional studies are required before we consider TA a first line alternative to surgical therapy in papillary microcarcinomas in patients who would otherwise be good candidates for, and willing to accept, either active surveillance or surgical intervention. Additional studies are needed to address which specific TA treatment modality is optimal for the individual patient in relation to thyroid disease phenotype, long-term efficacy, quality of life, cost, and when compared with observation alone or the current gold standard, surgery.

While waiting for such clarification, we encourage appropriate discussion and incorporation of TA therapeutic alternatives in medical societal clinical guidelines and formalized educational activities to ensure that these technologies are being applied appropriately as new evidence continues to emerge. We view appropriate use of TA technologies as the next logical approach to minimalistic management options but caution that we must use these technologies judiciously to avoid overtreatment of indolent benign or malignant thyroid nodules in which the risk of any therapeutic intervention may outweigh any potential benefit.