L. Yang
Department of Neurology
The Second Xiangya Hospital of Central South University
Changsha, China

H. Tang
Department of Radiology
The First Xiangya Hospital of Central South University
Changsha, China

A.M. Lee
Department of Radiology
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania

Y. Zou, X. Huang and X. Tang
Department of Neurology
The Second Xiangya Hospital of Central South University
Changsha, China

H.X. Bai
Department of Radiology
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania

We read with great interest the recent article by Che et al.¹ In this article, the authors compared the efficacy, safety, and cost-effectiveness of surgery versus radiofrequency ablation (RFA) for the treatment of benign thyroid nodules. Two hundred patients were retrospectively selected for each group. The authors assessed procedure-related complications, the length of hospitalization, and cost. In addition, nodule volume, incidence of hypothyroidism, and the rate of residual nodules were assessed at 1-year follow-up. All of these outcomes uniformly favored RFA over surgery; the cost between the 2 procedures was not significantly different. Consequently, the authors advocated RFA as the first-line treatment for benign thyroid nodules.

We commend the authors for conducting the largest retrospective cohort study comparing these 2 treatment options for benign thyroid nodules. However, the result could be significantly confounded by patient-selection bias. The authors used different criterion standards to define benign thyroid nodules in the surgery-versus-RFA groups (surgery pathology and cytology from fine-needle aspiration, respectively). This patient-selection method excluded patients whose nodules were benign by cytology but malignant by surgical pathology in the surgery group. In fact, the potential of mistreating malignant nodules as benign ones is the strongest argument against RFA as the first-line treatment for symptomatic nodular goiter.²

Two studies in the literature compared surgery and RFA as a treatment for benign thyroid nodules. One is the current study.¹ In the other study, the authors found that 8% of their patients (6 of 74) in the surgical arm were misdiagnosed as having benign nodules.³ Surgical pathologies in these patients later revealed malignant cells in their nodules.³ RFA did not allow any pathologic analysis of the nodules. On the basis of these results, the authors concluded that RFA was not a safe alternative to surgery for the treatment of hyperfunctioning nodules.

In a related study, Negro et al⁴ assessed the risk of undiagnosed malignancy in patients with multinodular goiter presumed to have benign thyroid disease and eligible for nonsurgical treatments. They found that 84 of 970 (8.6%) patients who underwent thyroidectomy had malignancy by histologic examination (5% incidental thyroid cancer and 3.6% false-negative fine-needle aspiration cytology).⁴ Although 67 of these malignant thyroid nodules (79.8%) were stage I disease by the American Joint Committee on Cancer criteria, the authors concluded that the risk of malignancy in presumably benign thyroid disease cannot be overlooked.

In another related study of 1161 patients who underwent total thyroidectomy for diffuse multinodular goiter, 252 (21.7%) were cases of thyroid cancer.⁵ In this study, the sensitivity of thyroid sonography and fine-needle aspiration cytology for cancer detection was only 30.3% and 64.1%, respectively. By preselecting patients who have benign disease on surgical pathology to compare with the RFA group, the current article effectively bypassed the most important question facing clinicians who need to discuss the pros and cons of the 2 approaches with their patients: What is the risk of a missed malignancy if I choose RFA over surgery? The consequence of such missed malignancy is currently unclear.

In conclusion, a randomized controlled trial is needed to compare the safety and efficacy of surgery versus RFA for the treatment of “benign” nodular goiter. If this is not feasible, long-term follow-up of patients treated with RFA is required before it can be recommended as first-line therapy.

Acknowledgements

This work was supported by the Natural Science Foundation of China (grant number 81301988) to Li Yang, and China Ministry of Education Doctoral Program Spot Foundation (grant number 20130162120061) to Li Yang.

References

1. Che Y, Jin S, Shi C, et al. Treatment of benign thyroid nodules: comparison of surgery with radiofrequency ablation. AJNR Am J Neuroradiol 2015;36:1321–25 » Abstract/FREE Full Text
2. Arora N, Scognamiglio T, Zhu B, et al. Do benign thyroid nodules have malignant potential? An evidence-based review. World J Surg 2008;32:1237–46 » CrossRef » Medline
3. Bernardi S, Dobrinja C, Fabris B, et al. Radiofrequency ablation compared to surgery for the treatment of benign thyroid nodules. Int J Endocrinol 2014;2014:934595 » CrossRef » Medline
4. Negro R, Piana S, Ferrari M, et al. Assessing the risk of false-negative fine-needle aspiration cytology and of incidental cancer in nodular goiter. Endocr Pract 2013;19:444–50 » CrossRef » Medline
5. Lasithiotakis K, Grisbolaki E, Koutsomanolis D, et al. Indications for surgery and significance of unrecognized cancer in endemic multinodular goiter. World J Surg 2012;36:1286–92 » CrossRef » Medline

Reply

Y. Che
Department of Ultrasound
First Affiliated Hospital of Dalian Medical University
Liaoning, China

Radiofrequency ablation (RFA) has been used for more than 20 years as a minimally invasive treatment of tumor. It has been widely recognized by scholars.^1,2 In the past 10 years, RFA of thyroid nodules has developed rapidly because of the application of moving-shot technique, solving the problem of the important structures around the thyroid. A number of studies have shown that among the current treatment methods for benign thyroid nodules, RFA has many prominent advantages over the others, such as being minimally invasive, effective, relatively safe, cosmetically satisfactory, and having lower recurrence and so forth.^3,4

Obviously, however, how to select the RFA cases, not only to treat but also to identify them, was a key issue that concerned Bai et al. Based on a comprehensive analysis of the literature, the results of multicenter studies, and expert consensus, an RFA recommendation was published in 2012 by Korean Society of Thyroid Radiology (KSThR).⁵ In this publication, the indications for RFA of benign thyroid nodules included patients with nodule-related clinical problems: 1) symptoms of neck pain, dysphasia, foreign body sensation, discomfort, and cough; 2) cosmetic problems; and 3) autonomously functioning thyroid nodules causing problems related to thyrotoxicosis. Patients with nodules with a maximum diameter of >2 cm that continue to grow may be considered for thyroid RFA on the basis of symptoms and clinical concerns. The KSThR did not recommend thyroid RFA for follicular neoplasms or primary thyroid cancers because there is no evidence of treatment benefit. Before treatment, thyroid nodules should be confirmed as benign on at least 2 separate sonography-guided fine-needle aspirations and/or core needle biopsies.

At present, the concerning issue is the risk of malignancy in symptomatic nodular goiter. Ucler et al⁶ and Lee et al⁷ showed that the accuracy of fine-needle aspiration biopsy (FNAB) was 64.1%–99.6%. The diagnosis of false-negative findings was mainly due to groups of small cancer cells in the nodules and small cancers invisible under sonography. The results of the 2 punctures of the nodules in different places at different times should be benign, to avoid the risk of malignancy.⁸ Furthermore, with combined elastography or contrast-enhanced sonography, the puncture point and results are more accurate. The operation for benign thyroid nodules is thyroidectomy, and the identification standard is intraoperative frozen pathology. Prades et al⁹ reported that the accuracy of frozen pathology was 90% and maybe the potential malignancy was emerged in “benign” nodules. Negro et al¹⁰ reported that postoperative pathology of symptomatic nodular goiter accidentally confirmed microcarcinoma in 5%; papillary thyroid microcarcinoma (PTMC) was 96%, and there was the possibility of recurrence. With no difference from pathology, which determined the operation mode, FNAB was used for preoperative diagnosis in all minimally invasive treatments. Ito et al¹¹ reported that there was no obvious growth and metastasis in the 8-year follow-up without treatment of 732 cases of PTMC. Yue et al¹² reported that during the 3-month follow-up period, ablation appears to be a safe and effective technique for solitary T1N0M0 PTMC.

Genetic testing had been used in the diagnosis of benign nodules undetermined by FNAB. Several molecular assays have been developed to detect the B-Raf proto-oncogene (BRAF) V600E mutation in fine-needle aspirates for the diagnosis of papillary thyroid cancer (PTC).¹³ Musholt et al¹⁴ considered that mutations ofRET/PTC, RAS, and PAX8/peroxisome proliferator-activated receptor γ (PPARγ) were predominantly associated with thyroid malignancy with varying frequency and had less impact on the clinical management. However, in the study of Song et al,¹⁵ BRAFmutations were the most common ones observed in PTCs, followed by RET/PTCrearrangements and RAS mutations, while follicular thyroid cancers were more likely to have RAS mutations or PAX8/PPARγ rearrangements.¹⁵ Therefore, more extensive research is needed in genetic testing.

In conclusion, we suggested that RFA would be used as the first-line treatment of benign thyroid nodules with strict indications chosen. Elastography, contrast-enhanced sonography, and genetic testing would be used to differentiate the benign and malignant lesions.

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