Recurrence after ablation of Bethesda IV thyroid nodule: report of two cases

Introduction

The widespread implementation of high-resolution ultrasound technology has revolutionized thyroid nodule detection, revealing incidental thyroid nodules in 35–46% of the general population (1,2). While most non-palpable nodules demonstrate benign behavior (malignancy rate ~4.4%), the diagnostic challenge intensifies with ultrasound-guided fine-needle aspiration (FNA) findings categorized as Bethesda IV (follicular neoplasm or suspicious for follicular neoplasm). This diagnostic category, representing 2–25% of cytopathological evaluations (3,4), presents a critical clinical dilemma due to its histopathological spectrum encompassing follicular adenomas, carcinomas, and neoplasms of uncertain malignant potential (5).

The inherent limitations of cytological differentiation between benign and malignant follicular lesions persist despite advanced imaging modalities. Definitive diagnosis currently requires surgical histopathological evaluation to identify capsular/vascular invasion-the gold standard distinguishing follicular adenomas from carcinomas (accounting for 10–20% of thyroid malignancies) (6). This necessity subjects 70% of patients with ultimately benign lesions to potentially avoidable thyroidectomy, highlighting the need for refined management strategies.

Emerging thermal ablation (TA) modalities, including radiofrequency ablation (RFA) and microwave ablation (MWA), have demonstrated efficacy in treating benign thyroid nodules and recurrent malignancies (7,8). Recent exploratory applications have extended TA to low-risk papillary thyroid carcinomas (PTCs) and follicular neoplasms (4,9-11), sparking debate regarding its appropriateness for Bethesda IV nodules. Proponents emphasize TA’s minimally invasive nature and reduced complication risks compared to surgery, while critics cite insufficient long-term outcomes data and unresolved diagnostic uncertainties.

This controversy gains urgency from our documentation of the first reported recurrence following TA treatment of a Bethesda IV nodule. This case highlights critical knowledge gaps in patient selection criteria, ablation completeness verification, and long-term surveillance protocols for follicular neoplasms managed non-surgically. Our findings underscore the imperative for rigorous prospective studies to establish evidence-based guidelines for TA application in this diagnostically complex patient population. We present this article in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-306/rc).

Case presentation

Case 1

A 26-year-old female initially presented with a right thyroid lower pole nodule (5.1 cm × 2.7 cm × 4.1 cm) identified on ultrasound. FNA confirmed a follicular neoplasm (Bethesda IV), negative for the BRAF V600E mutation. Genetic testing further revealed no mutations in the exons of KRAS, NRAS, or HRAS genes, and no TERT promoter mutations were detected. She underwent two sessions of MWA over a 12-month period. Post-ablation imaging at 1 month demonstrated partial nodule shrinkage (3.6 cm × 2.6 cm × 3.7 cm), but subsequent follow-up evaluations showed stagnant size reduction.

Two years after the second ablation, surveillance ultrasound revealed a large mixed-echo lesion in the right thyroid lobe and abnormal cervical lymph nodes (Figure 1). Repeat FNA of the right thyroid nodule confirmed a follicular neoplasm (Bethesda IV), again negative for BRAF mutations. Biopsies of right level VI and IV lymph nodes demonstrated metastatic carcinoma with histopathological features suggestive of PTC. Lymph node puncture eluent thyroglobulin levels exceeded 500 ng/mL, and BRAF testing remained wild-type.

Figure 1 Ultrasound, CEUS, and cytopathological findings of a 26-year-old female patient with thyroid nodule. (A) Transverse view of the right thyroid lobe (ablation area): a large mixed echogenicity lesion is observed in the middle and lower regions, measuring 3.0 cm × 2.1 cm. (B) Longitudinal view of the right thyroid lobe: a heterogeneous echoic area with a maximum longitudinal diameter of 5.3 cm is noted, containing hypoechoic regions interspersed with coalesced hyperechoic areas of varying sizes. (C) CEUS of the right thyroid lobe nodule: localized hyper-enhancement and hypervascularity are demonstrated. (D) Grayscale ultrasound image of a suspicious metastatic lymph node in right cervical level VI: a mass-like hyperechoic area is visible within the lymph node. (E) Grayscale ultrasound image of a suspicious metastatic lymph node in right cervical level III. (F) CEUS image of the right cervical level III lymph node: hypervascular features are observed. (G) Cytology smear of FNA from the right thyroid lobe nodule: crowded follicular epithelial cells arranged in microfollicular structures are seen. (H,I) Cytopathological images of FNA from lymph nodes: enlarged follicular epithelial cells with pale-staining, crowded and overlapping nuclei, nuclear grooves, and irregular nuclear membranes are observed. Intranuclear inclusions are rare. Morphological findings are consistent with metastatic papillary thyroid carcinoma. Hematoxylin-eosin staining; scale bar =50 µm. CEUS, contrast-enhanced ultrasound; FNA, fine-needle aspiration.

The patient underwent total thyroidectomy with bilateral central (level VI) and right lateral (levels IIa, III, IV, V) lymph node dissection. Intraoperatively, the right thyroid mass was found to adhere to the sternothyroid muscle. Histopathological examination of the surgical specimen confirmed post-ablation treatment changes in the right thyroid lobe. Metastatic PTC was identified in level VI and IV cervical lymph nodes.

This case highlights the challenges of managing follicular neoplasms with indeterminate genetics and underscores the importance of long-term surveillance following ablation therapy. Postoperative evaluation showed suppressed thyroglobulin (Tg: 2.36 ng/mL) and elevated thyroid-stimulating hormone (TSH) (>150 µU/mL). Diagnostic whole-body scintigraphy (DxWBS) identified residual iodine-avid tissue at the thyroid bed, but no distant metastases. The patient received TSH suppression therapy (levothyroxine) without adjuvant radioiodine (¹³¹I) treatment.

Case 2

A 12-year-old female presented with a palpable neck mass. Ultrasound evaluation identified a well-circumscribed thyroid nodule in the left lobe, measuring 2.6 cm × 2.5 cm × 1.4 cm, featuring a peripheral halo and marked vascularity on color Doppler flow imaging (CDFI). FNA cytopathology classified the lesion as Bethesda category IV (follicular neoplasm). The patient subsequently underwent ultrasound-guided MWI.

At the 9-month follow-up, post-ablation surveillance ultrasound demonstrated a significant reduction in the treated lesion (1.1 cm × 1.2 cm × 0.6 cm). However, a newly identified complex cystic-solid nodule (1.8 cm × 1.5 cm × 0.8 cm) with intranodular vascularity was observed adjacent to the ablation zone, raising concern for follicular tumor recurrence (Figure 2). Repeat FNA and histopathological analysis at our institution confirmed the diagnosis of follicular thyroid neoplasm. Further surgical intervention is under multidisciplinary discussion.

Figure 2 Post-ablation follow-up ultrasound findings of a 12-year-old girl with thyroid nodule. (A) Transverse grayscale ultrasound image during post-ablation follow-up of the thyroid nodule. (B) Longitudinal grayscale ultrasound image during post-ablation follow-up of the thyroid nodule. (C) Post-ablation color Doppler ultrasound image of the thyroid nodule, demonstrating linear vascular signals within the ablation zone.

Ethical statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patients/patients’ parents for publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

In the present case report, both patients were preoperatively classified as Bethesda IV (follicular neoplasm or suspicious for follicular neoplasm) on FNA and experienced tumor recurrence following TA. Both cases involved off-label use of MWA for Bethesda IV nodules, which is not recommended by major thyroid societies. The procedures were conducted externally, and it is unclear whether they were part of a research protocol. This highlights the need for rigorous patient selection and institutional oversight when considering ablation for indeterminate nodules.

This outcome underscores the critical need to reevaluate the safety boundaries of ablation therapy for follicular thyroid neoplasms. International guidelines have not explicitly included follicular tumors in the indications for ablation, primarily due to the fact that FNA has inherent limitations in distinguishing between benign and malignant follicular lesions. Specifically, cytology is unable to evaluate capsular or vascular invasion, which are considered the gold standard for diagnosing follicular carcinoma (12). Before performing ablation of a benign thyroid nodule, it is generally recommended to confirm a benign cytological diagnosis through dual ultrasound-guided FNA or CNB, as outlined in previous guidelines (13-16). It is important to note that both patients underwent ablation at external institutions, and therefore detailed pre-procedural diagnostic records-including whether dual FNA or CNB was performed-were not available. CNB has been proposed as a valuable tool in cases of indeterminate cytology, providing better architectural assessment (13-16). The absence of these adjuncts may have contributed to the diagnostic uncertainty in these cases.

Surgical resection (lobectomy or total thyroidectomy) remains the gold standard for managing follicular neoplasms, as it enables definitive histopathological diagnosis through comprehensive specimen evaluation. This approach not only permits intraoperative frozen section analysis to optimize resection margins but also ensures oncological safety while preserving functional anatomy, aligning with current guideline recommendations (17). The inherent diagnostic limitations of follicular neoplasia-particularly the inability of preoperative FNA or CNB to reliably exclude malignancy due to sampling constraints and a high false-positive rate (22.2–35%)-further reinforce the necessity of surgical intervention (18). The histologic discrepancy between the primary lesion (follicular neoplasm) and nodal metastasis (PTC) suggests the original tumor may have been a follicular variant of papillary thyroid carcinoma (FVPTC), a known diagnostic challenge on cytology. This further underscores the risk of ablation in Bethesda IV lesions without definitive histology.

Tumor size (>2 cm) serves as a critical predictor of malignancy in follicular lesions (18,19), though histopathological analysis reveals that even larger nodules may mimic benign entities such as thyroiditis or nodular goiter. This diagnostic ambiguity is exacerbated by the high false-positive rate (22.2–35%) of preoperative FNA in follicular neoplasia (18), underscoring the challenges in reliably excluding malignancy. Moreover, the technical details of the ablation procedures—including device type, energy delivery, and use of hydrodissection—were not available to us, as treatments were conducted in other hospital. This precludes a detailed analysis of ablation completeness. It is well recognized that nodules larger than 3 cm pose a greater risk of incomplete ablation due to technical limitations (19), which may have been a factor in these recurrences. Consequently, while surgical resection remains the definitive management strategy, there is growing interest in developing conservative therapeutic alternatives for high-surgical-risk patients.

Emerging evidence reveals divergent outcomes for TA in managing Bethesda III/IV follicular neoplasms, contingent upon lesion size and diagnostic certainty. A 5-year longitudinal study demonstrated RFA efficacy for sub-2 cm follicular neoplasms (Bethesda III/IV), with no recurrences or metastases observed (9). However, this promising result contrasts sharply with findings from a trial involving larger lesions (>2 cm), where RFA-treated Bethesda III nodules showed post-ablation regression but were ultimately diagnosed as minimally invasive follicular carcinoma and neoplasms of undetermined malignant potential (20). Notably, this study cautioned against RFA’s first-line use for indeterminate nodules, emphasizing two critical risks: (I) potential underestimation of malignancy in lesions with inherent diagnostic ambiguity, and (II) delayed definitive surgery due to ablation-induced tissue remodeling (20). Particular caution is warranted in pediatric patients, as highlighted in Case 2. Ablation for Bethesda IV nodules in children is not recommended by current guidelines due to the higher risk of malignancy and lack of safety data. This case underscores the importance of adhering to surgical standards in young patients.

These paradoxical outcomes underscore a fundamental challenge across Bethesda III/IV categories: tumor biology heterogeneity compounded by cytological limitations. While smaller lesions (<2 cm) may represent lower-risk candidates for ablation, the absence of reliable preoperative markers for capsular/vascular invasion—particularly critical in Bethesda IV cases—creates an unacceptable diagnostic blind spot. This concern is supported by reports of local recurrence following incomplete TA in thyroid nodules and other organs, such as the liver (21). Current consensus guidelines therefore maintain a conservative stance, explicitly excluding both Bethesda III and IV follicular neoplasms from ablation indications until robust risk-stratification protocols emerge (7,8,20,22).

Conclusions

TA for Bethesda IV follicular neoplasms carries substantial diagnostic uncertainty and recurrence risk. Strict adherence to guideline-based preoperative confirmation and surgical management remains essential until robust selection criteria emerge.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-306/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-306/prf

Funding: This study was supported by the China-Japan Friendship Hospital Talent Recruitment Project (No. 2019-RC-2).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-306/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patients/patients’ parents for publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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