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Radiofrequency Ablation of Solid, Non-Functional Thyroid Nodules

  • Michael Douek
    Correspondence
    Address reprint requests to Michael Douek, MD, MBA, Department of Radiology, David Geffen School of Medicine at UCLA, 1250 16th St, Suite 2340, Santa Monica, CA 90404.
    Affiliations
    Department of Radiology, David Geffen School of Medicine at UCLA, Santa Monica, CA
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Open AccessPublished:March 15, 2022DOI:https://doi.org/10.1016/j.tvir.2022.100821

      KEYWORDS

      Background

      Thermal ablation in the neck has been applied to several clinical conditions, but by far, the most common application is for the treatment of the benign, solid, non-functional thyroid nodule. Though relatively new to the United States, thermal ablation of these nodules has been performed internationally for nearly two decades, especially in South Korea and Italy. A number of ablative techniques - radiofrequency, laser, microwave, high-intensity focused ultrasound, and ethanol - have been studied and reported. This review will focus on the most commonly applied technology for solid non-functional nodules, RFA.
      Thyroid RFA provides a minimally invasive, low risk, efficacious therapy for the treatment of this condition. Thyroid RFA enjoys similar efficacy as surgery, results in similar degrees of patient satisfaction, but does so with a lower risk profile.
      • Guan S.H.
      • Wang H.
      • Teng D.K.
      Comparison of ultrasound-guided thermal ablation and conventional thyroidectomy for benign thyroid nodules: A systematic review and meta-analysis.
      ,
      • Tufano Ralph P.
      • Pace-Asciak P.
      • Russell Jonathon O.
      Update of radiofrequency ablation for treating benign and malignant thyroid nodules. The future is now.
      While many interventional radiologists will be familiar with thermal ablation in other organs, such as lung, liver, and kidneys, there are some important procedural modifications (namely the “moving shot” technique) which are unique to the neck. Similarly, those that perform ablations will be familiar with the potential for thermal injury to nearby structures and many will also have experience with protective maneuvers such as hydrodissection. However, in the neck, the myriad vital structures (vessels, nerves, trachea, esophagus, etc.) all coursing together in a relatively tight anatomic space, make these considerations of even greater importance and will challenge even experienced operators.

      Clinical Evaluation of the Patient

      A pre-procedural checklist is provided in Table 1.
      Table 1RFA Pre-Procedural Checklist
      Cytopathology
      Benign diagnosis on at least 2 US-guided FNA or CNB
      Benign diagnosis on at least 1 US-guided FNA or CNB if highly specific benign US features or if AFTN
      Ultrasound
      Nodule volume estimation (0.523*length*width*height)
      Nodule features (vascularity, calcifications, solid: cystic ratio, echogenicity)
      Location and proximity to critical structures
      Symptom Score
      Cosmetic Score
      Labs
      CBC, Coagulation tests
      Serum TSH, free T4, T3
      Thyroid antibodies in select circumstances
      Other Imaging
      CT or MRI for certain circumstances, such as large nodules with infraclavicular extension
      99m Tc pertechetate or 123I thyroid scan, if suspect AFTN
      Revised from Korean Society of Thyroid Radiology Societeal Guidelines.
      • Baek J.H.
      • Lee J.H.
      • Sung J.Y.
      • et al.
      Complications encountered in the treatment of benign thyroid nodules with US guided radiofrequency ablation: A multicenter study.
      AFTN, autonomously functioning thyroid nodule; CBC, complete blood count; CNB, core needle biopsy; FNA, fine needle aspiration; TSH, thyrotropin; free T4, free thyroxine; T3, triiodothyronine; US, ultrasound.

      History and Physical

      The pre-procedural workup begins with a thorough history and physical. Typical symptoms will include dysphagia, a sensation of a lump in the throat, discomfort, cough, difficulty breathing, and cosmetic issues. Typical motivations for pursuing RFA in lieu of surgery include a fear of surgery and its complications, the desire to avoid hypothyroidism (and the need for lifelong thyroid medications), the desire to preserve normal, non-nodal thyroid tissue, and avoiding the surgical scar.
      While no patient is “typical” there are some trends worth mentioning. First, a good many patients in our practice (as is likely the case with any relatively new procedure and the “early adopter” patients that consider these procedures) are self-referred, knowledgeable about the procedure, and have often already considered and excused surgery as an option. Second, there are a minority of patients who, in spite of being biochemically euthyroid, ascribe a host of symptoms (fatigue, insomnia, anxiety, etc.) as attributable to their nonfunctional nodule. In all patients, but especially these, a thorough discussion of motivations and expectations is important.
      There are two standardized scoring systems used to evaluate symptomatic thyroid nodules (both on initial visit and as post-procedural follow-up): the symptom score, which is a visual analog scale from 0 to 10 to rank the patient's subjective severity of discomfort, and the cosmetic score, which is the physician's assessment of the nodule's conspicuity on physical exam (ranging from 1 for no visible or palpable mass, to 4, for a readily detectable cosmetic issue), see Table 2 and Figure 1.
      Table 2Cosmetic Score
      ScoreExamination
      1No palpable mass
      2Palpable without cosmetic issues
      3Cosmetic issue with swallowing only
      4Readily detectable cosmetic issue
      Figure 1
      Figure 1An example of a patient with a readily detectable cosmetic issue caused by a large right thyroid nodule. This nodule would be assigned a cosmetic score of 4. (Color version of figure is available online.)
      Figure 2
      Figure 2An example of an appropriate candidate nodule for thyroid RFA. Transverse (A) and longitudinal (B) ultrasound images of a right thyroid lobe, demonstrate a solid, isoechoic, thyroid nodule (between *) with an estimated volume of 6 cc in a patient with complaints of cough and a “lump” in her throat.
      Laboratory evaluation: should at least include a complete blood count (CBC), coagulation profile, and thyroid function tests, including thyrotropin (TSH), free thyroxine, and triiodothyronine (T3). In certain circumstances, thyroid antibody tests, such as thyroid peroxidase antibody and thyroglobulin antibody, can be helpful. Patients with elevated autoantibody levels are more prone to developing hypothyroidism following RFA and should be counseled as such.
      • Baek J.H.
      • Lee J.H.
      • Sung J.Y.
      • et al.
      Complications encountered in the treatment of benign thyroid nodules with US guided radiofrequency ablation: A multicenter study.

      Cytopathology

      Current recommendations call for at least two benign (Bethesda II) fine-needle aspirations (FNAs) or core needle biopsies of any nodule targeted for ablation unless: (1) the nodule has specifically benign sonographic features; or (2) is an autonomously functioning nodule. In both of these latter cases, a single benign result will usually suffice.
      • Kim J.H.
      • Baek J.H.
      • Lim H.K.
      • et al.
      Guideline committee for the Korean society of thyroid radiology (KSThR) and korean society of radiology. 2017 thyroid radiofrequency ablation guideline: Korean society of thyroid radiology.
      ,
      • Papinia E.
      • Monpeyssenb H.
      • Frasoldatic A.
      • et al.
      2020 European thyroid association clinical practice guideline for the use of image-guided ablation in benign thyroid nodules.
      The risk of malignancy in the context of two benign cytopathologic diagnoses is extremely low, nonetheless, caution should be exercised in any nodule with suspicious sonographic features.
      • Oertel Y.C.
      • Miyahara-Felipe L.
      • Mendoza M.G.
      • et al.
      Value of repeated fine needle aspirations of the thyroid: An analysis of over ten thousand FNAs.
      Given recent trends, cytologically indeterminate thyroid nodules are worth some discussion. FNA reliably classifies sampled nodules as benign or malignant in the majority of cases by the Bethesda System for Reporting Thyroid Cytopathology (Table 3).

      Cibas ES, Ali SZ: The 2017 Bethesda system for reporting thyroid cytopathologythyroid. 2017. 1341-1346. https://doi.org/10.1089/thy.2017.0500.

      However, approximately 15% of the time, cytologic results are indeterminate, classified as Bethesda III (atypia of undetermined significance, follicular lesion of undetermined significance), and Bethesda IV (follicular neoplasm, suspicious for follicular neoplasm).
      • Gortakowski M.
      • Feghali K.
      • Osakwe I.
      Single institution experience with afirma and thyroseq testing in indeterminate thyroid nodules.
      Historically, diagnostic thyroidectomy has been performed for most of these indeterminate thyroid nodules, with the majority eventually found to be benign on final pathology.
      Table 3The 2017 Bethesda System for Reporting Thyroid Cytopathology
      Diagnostic CategoryRisk of malignancyIf NIFTP ≠ CA (%)Risk of MalignancyIf NIFTP = CA (%)
      1Nondiagnostic or unsatisfactory5-105-10
      2Benign0-30-3
      3Atypia of undetermined significance or follicular lesion of undetermined significance6-1810-30
      4Follicular neoplasm or suspicious for follicular neoplasm10-4025-40
      5Suspicious for malignancy45-6050-75
      6Malignant94-9697-99
      Adapted with permission from Cibas and Ali.

      Cibas ES, Ali SZ: The 2017 Bethesda system for reporting thyroid cytopathologythyroid. 2017. 1341-1346. https://doi.org/10.1089/thy.2017.0500.

      CA, carcinoma; NIFTP, non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
      Increasingly, molecular testing is being utilized to help risk-stratify these indeterminate nodules and to assist in clinical decision-making. Several molecular tests are currently commercially available in the United States, the most common being Afirma, Gene Sequencing Classifier and Xpression Atlas (GSC & XA; Veracyte, South San Francisco, CA) and ThyroSeq version 3 (TSv3; CBLPath, Rye Brook, NY), which predict benignity or malignancy-based DNA, RNA analysis, or a combination of the two.
      • Patel S.G.
      • Carty S.E.
      • Lee A.J.
      Molecular testing for thyroid nodules including its interpretation and use in clinical practice.
      In a meta-analysis investigating the diagnostic performance of available molecular tests, Silaghi et al. found Thyroseq v3 to have an overall sensitivity of 0.99, specificity of 0.64, positive predictive value of 0.78, and negative predictive value of 0.96 in detecting malignancy.
      • Silaghi C.A.
      • Lozovanu V.
      • Georgescu C.E.
      • et al.
      Thyroseq v3, Afirma GSC, and microRNA panels versus previous molecular tests in the preoperative diagnosis of indeterminate thyroid nodules: A systematic review and meta-analysis.
      Afirma GSC was found to have an SE of 0.95, specificity of 0.51, positive predictive value of 0.6 and negative predictive value of 0.91. Owing to the high sensitivity and negative predictive value of both of these molecular tests, these can be regarded as good “rule out” tests, accurately excluding malignancy when negative. It thus stands to reason that nodule with cytologically indeterminate FNA results (Bethesda III and IV) and subsequent negative molecular markers, can be considered as having had a benign FNA with regards to the pre-RFA workup, though this is an area of study that requires warrants investigation.
      Ultrasound of the thyroid gland plays an important role during the pre-procedural evaluation. Nodule location and accessibility, calculation of nodule volume (using the formula 0.523 x abc, where a is the maximal nodule diameter and b and c are orthogonal diameters), presence of calcifications, proximity to nearby structures, degree solid vs cystic, and nodule vascularity should all be assessed.
      We strive to approach each patient in a multidisciplinary fashion, with our team comprised of interventional radiologists, endocrinologists, and surgeons who are familiar with RFA. For patients who have not already spoken to a surgeon, we encourage this consultation, so that the patients can make a fair assessment of their best option.
      All patients should be counseled on expected treatment outcomes, the number of anticipated treatment sessions, the post-procedural follow-up schedule, the possibility of regrowth over time with the need for further intervention, the alternatives to the procedures, including surgery and watchful waiting, and the potential complications of thermal ablation.

      Nodule Selection

      Ideal nodules for thyroid ablation are solid or predominately solid, well visualized sonographically in their entirety, with a “reasonable” volume (see Fig. 1). What determines a “reasonable” volume is not well defined. Currently there are no firmly established nodule size guidelines for RFA.
      • Kim J.H.
      • Baek J.H.
      • Lim H.K.
      • et al.
      Guideline committee for the Korean society of thyroid radiology (KSThR) and korean society of radiology. 2017 thyroid radiofrequency ablation guideline: Korean society of thyroid radiology.
      This is in part because of variable patient anatomy. Small isthmic nodules in slender patients may cause significant symptoms whereas large lobar nodules in patients with thicker necks may go undetected (Fig. 3). While there is great variability between patients as well as between nodules of different composition and vascularity, we have found a good rule of thumb is that roughly 20 to 30 cc of solid nodular tissue can be ablated in a single session. Larger than that may require multiple ablation sessions as larger nodules will require longer ablation times, which can impact the ability of patients to tolerate the procedure, may result in increased post-procedure pain and swelling, and may increase complication rates.
      Figure 3 (
      Figure 3.(A) An ultrasound image of a right paramedian isthmic nodule with an estimated volume of 5 cc (depicted by calipers). (B) A photograph from the same patient demonstrates, that, though relatively small, given the isthmic location, this nodule creates a readily detectable lump in the patient's neck. (Color version of figure is available online.)
      Nodules which should be avoided include those which are very large (where volume control would not be expected with a reasonable number of ablation sessions), heavily calcified nodules (which limit sonographic visualization and monitoring during the procedure and which will be difficult or impossible to penetrate with the electrode), nodules with significant infraclavicular components (such that sonographic monitoring during the procedure would be compromised), and thyroid glands which are diffusely involved by nodules where no discrete target nodules accounting for the patient's symptoms can be found (Fig. 4). Entirely or predominately (>90%) cystic nodules may respond better to ETOH ablation reference.
      • Baek J.H.
      • Ha E.J.
      • Choi Y.J.
      • et al.
      Radiofrequency versus ethanol ablation for treating predominantly cystic thyroid nodules: A randomized clinical trial.
      ,
      • Sung J.Y.
      • Baek J.H.
      • Kim K.S.
      • et al.
      Single-session treatment of benign cystic thyroid nodules with ethanol versus radiofrequency ablation: A prospective randomized study.
      Figure 4 (
      Figure 4.(A) Photographs of a patient with a very large, symptomatic goiter. (B) CT scan demonstrates a diffuse, bilateral, multinodular goiter (+), with mass effect on the trachea (*). Owing to the very large size and diffuse nature of this process, this is a non-ideal candidate for RFA. (Color version of figure is available online.)
      Occasionally asymptomatic patients with benign nonfunctional nodules will seek treatment. In general, only nodules causing cosmetic or referable pressure symptoms should be treated. Some advocate treatment for continuously growing nodules which are expected to eventually cause symptoms, as treatment at a smaller size is easier and safer, though this is an area which requires further investigation.
      • Lee M.
      • Baek J.H.
      • Suh C.H.
      • et al.
      Clinical practice guidelines for radiofrequency ablation of benign thyroid nodules: A systematic review.

      The RFA Procedure

      Radiofrequency ablation of benign, nonfunctional thyroid nodules, follows the same technique principles as for any thyroid RFA, including the trans-isthmic approach and moving-shot techniques. The goal of treatment is to ablate nodular tissue as completely as possible, both to achieve better volume reductions as well as to reduce the incidence of later marginal recurrences.
      • Sim J.S.
      • Baek J.H.
      Long-term outcomes following thermal ablation of benign thyroid nodules as an alternative to surgery: The importance of controlling regrowth.
      Of course, this requires a balancing act between achieving as complete an ablation as possible while avoiding injury to structures at the nodule margin.
      “Large” thyroid nodules are typically defined in the literature as those greater than 20-30 cc.
      • Cesareo R.
      • Pasqualini V.
      • Siimeoni C.
      • et al.
      Prospective study of effectiveness of ultrasound-guided radiofrequency ablation versus control group in patients affected by benign thyroid nodules.
      • Lin W.C.
      • Kan N.N.
      • Chen H.L.
      • et al.
      Efficacy and safety of single-session radiofrequency ablation for benign thyroid nodules of different sizes: A retrospective study.
      • Lim H.K.
      • Lee J.H.
      • Ha E.J.
      • et al.
      Radiofrequency ablation of benign non-functioning thyroid nodules: 4-year follow-up results for 111 patients.
      As above, while there are no established nodule size limits for RFA, large nodules may require more than one session to achieve adequate volume control. In certain circumstances, for large nodules, we have found it helpful to treat nodules in a planned, “staged” approach, whereby a geographic region of the nodule (for example the upper half) is systematically ablated during a first session, and remaining portions are targeted during a separate session (or sessions), spaced several weeks or months apart. This has proven especially helpful in patients with nodules that partially extend infraclavicular, whereby the superior portion is treated first and with its volume regression, the inferior portion ascends in the neck, making it more accessible for the subsequent second “stage” of ablation. (Fig. 5). Staged procedures may also be appropriate in patients with bilateral nodules, as posttreatment inflammation and swelling theoretically pose greater risk to the patient if RFA is performed in both lobes at the same time, not to mention the potential for bilateral vocal cord paralysis.
      Figure 5
      Figure 5“Staged ablation”5A. Ultrasound images of a multi-component thyroid nodule with right, superior, medial components (estimated volume = 5 cc, measured nodule), and a larger, inferior isthmic component (estimated volume approximately 26 cc, between “+” s). (B) Staged ablation of this nodule was performed whereby right superior components (red) were targeted initially, followed by inferior right lateral (purple) and inferior left lateral (blue) components subsequently. (C) Follow-up ultrasound 2 y after ablation demonstrates decreased size of all components with volume reduction ration (VRR) of 96% for the superior component and 92% for the inferior components (residual nodules depicted by calipers). (Color version of figure is available online.)
      The isthmic nodule presents some unique challenges. Owing to the interposition of the anteriorly situated thyroid isthmus between the trachea and skin, care must be taken to prevent thermal injury to both of these areas during treatment of these nodules. Hydrodisplacement maneuvers, to separate skin from anterior nodule surface can be helpful. Cold packs on the skin may also be helpful. 5% Dextrose in water (D5W) injection between the trachea and posterior aspect of the thyroid isthmus may help to displace the nodule from the trachea, thus avoiding tracheal thermal injury (Fig. 6). It should be noted that local anesthetic should not be used in this latter scenario as this may mask symptoms related to tracheal thermal injury (such as cough and pain).
      Figure 6
      Figure 6Hydrodissection in an isthmic nodule. A needle is introduced via a transthismic approach, with the needle tip (arrow) positioned between nodule and trachea (arrowheads). D5W is subsequently infused to “lift” the nodule away from the trachea prior to RFA. (Color version of figure is available online.)
      The hypervascular nodule is harder to treat, owing largely to the heat sink effect, and may require higher wattages and more total energy deposition.
      • Lim H.K.
      • Lee J.H.
      • Ha E.J.
      • et al.
      Radiofrequency ablation of benign non-functioning thyroid nodules: 4-year follow-up results for 111 patients.
      In these circumstances, advanced techniques such as “artery first” and “marginal vein” ablation, may be considered.

      Expected Outcomes

      A number of studies, predominately from South Korea, China, and Italy, have reported on the efficacy of RFA in improving patient cosmetic and compressive symptoms and in achieving nodule volume reductions (the latter typically reported as a volume reduction ratio, or “VRR”, calculated as VRR = [initial volume-final volume] x 100/initial volume). Most of this data reports on short-term results, but studies reporting long-term results are beginning to emerge.
      A recent, multi-institution study demonstrated mean volume reductions at 1, 6, 12, 24, 36, 48 and 60 months at 44%, 69%, 80%, 84%, 89%, 92%, and 95%.
      • Jung S.L.
      • Baek J.H.
      • Lee J.H.
      • et al.
      Efficacy and safety of radiofrequency ablation for benign thyroid nodules: A prospective multicenter study.
      The mean number of RF sessions in this study was 1.3, with additional treatment allowed if the follow-up ultrasound showed remaining viable portions of the nodule and if the patient complained of ongoing symptomatic or cosmetic problems. Overall theapeutic success rate (defined as >50% volume reduction) was 97.8%. Mean symptom and cosmetic scares were 2.5 and 3.7 respectively prior to ablation, 1.3 and 2.9 at 1 months, and 0.4 and 1.9 at 12 months. Volume data is summarized in Figure 7.
      Figure 7
      Figure 7Nodule size change over time. Depicts residual nodule volume (as a percent from baseline) over time. (Adapted with permission from Jung SL.
      • Jung S.L.
      • Baek J.H.
      • Lee J.H.
      • et al.
      Efficacy and safety of radiofrequency ablation for benign thyroid nodules: A prospective multicenter study.
      ). (Color version of figure is available online.)
      Denadrea, et al. reported on the long-term efficacy of a single RFA session for benign thyroid nodules, reporting overall volume reductions of 67% at 5 years.
      • Deandrea M.
      • Trimboli P.
      • Garino F.
      • et al.
      Long-term efficacy of a single session of RFA for benign thyroid nodules: A longitudinal 5-year observational study.
      Notably, better results were achieved with smaller nodules; those with initial volumes <10 mL, averaged 82% volume reduction, those between 10 mL and 20 mL, 75% volume reduction, and those 20 mL or larger, reaching 65% volume reductions at 5 years.
      Several additional studies have demonstrated similar long-term results.
      • Park H.S.
      • Baek J.H.
      • Park A.W.
      • et al.
      Thyroid radiofrequency ablation: Updates on innovative devices and techniques.
      • Trimboli P.
      • Castellana M.
      • Sconfienza L.M.
      • et al.
      Efficacy of thermal ablation in benign non-functioning solid thyroid nodule: A systematic review and meta-analysis.
      • Cho S.J.
      • Baek J.H.
      • Chung S.R.
      • et al.
      Long-term results of thermal ablation of benign thyroid nodules: A systematic review and meta-analysis.
      The majority of nodule shrinkage (typically in excess of 65%) occurs by 6 months, with slower, progressive shrinkage in the months afterwards; cosmetic and local symptom improvement accompany this size reduction. For most of these studies more ablation sessions were required for larger nodules than for smaller nodules.
      It has been estimated that nodule recurrence (that is regrowth after initial successful treatment) occurs in anywhere from 5.6 to 24% of cases, usually several years after initial treatment (see Fig. 8).
      • Sim J.S.
      • Baek J.H.
      • Lee J.
      • et al.
      Radiofrequency ablation of benign thyroid nodules: Depicting early sign of regrowth by calculating vital volume.
      ,
      • Sim J.S.
      • Baek J.H.
      Long-term outcomes following thermal ablation of benign thyroid nodules as an alternative to surgery: The importance of controlling regrowth.
      This is thought to be due to growth of incompletely ablated tissue at the nodule margin. Several authors thus emphasize the importance of treating the nodule margin as completely as possible, as well as marginal assessment by ultrasound on follow-up visits, as early marginal regrowth may herald the need for repeat ablation.
      • Sim J.S.
      • Baek J.H.
      Long-term outcomes following thermal ablation of benign thyroid nodules as an alternative to surgery: The importance of controlling regrowth.
      Figure 8
      Figure 8Nodule recurrence (A). Initial gray scale and color Doppler sonographic images demonstrate a highly vascular nodule, prior to RFA, with an estimated volume of 13 ml (depicted by calipers). (B) Images 12 mo after ablation demonstrate decreased size, with an estimated volume of 6 cc and VRR of 54%, but some persistent, vascularized tissue at the nodule margin. (C) Images 18 mo after ablation show an interval increase in size with estimated volume of 8.6 cc, with increased growth and vascularity of marginal tissue. Overall VRR is 34% compared to baseline, but 43% increase from the nadir value of 6, with a return of symptoms. The patient was subsequently retreated. (Color version of figure is available online.)
      While there is a paucity of North American literature, initial reports show similar results in the United States. Hamidi performed a retrospective review of 14 patients treated in the United States with RFA, achieving a median VRR of 53% at 24 months.
      • Hamidi O.
      • Callstrom M.R.
      • Lee R.A.
      • et al.
      Outcomes of radiofrequency ablation therapy for large benign thyroid nodules: A mayo clinic case series.
      Hussain reported on 58 nodules in 53 patients, achieving a VRR of 71% after a median follow-up of 109 days.
      • Hussain I.
      • Zulfiqar F.
      • Li W.
      • et al.
      Safety and efficacy of radiofrequency ablation of thyroid nodules—Expanding treatment options in the United States.

      Conclusions

      Thyroid RFA, following trends in Asia and Europe, is emerging in the United States as a minimally invasive treatment for certain thyroid conditions. While more long-term data are needed, initial results suggest that thyroid RFA is a safe and highly effective treatment for the non-surgical treatment of the symptomatic, benign, nonfunctional thyroid nodules.

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