Radiofrequency Ablation of Papillary Thyroid Microcarcinoma: A 10-Year Follow-Up Study.

Purpose: To investigate the efficacy and safety of radiofrequency ablation (RFA) for papillary thyroid microcarcinoma (PTMC) after > 10 years of follow-up. Materials and
Methods: This study included five patients who underwent RFA to treat PTMCs (five lesions, mean diameter 0.5 cm, range 0.4-0.7 cm) between November 2006 and December 2009. The inclusion criteria were histopathologically confirmed PTMCs, a single PTMC lesion without extrathyroidal extension, no metastasis, and ineligibility or refusal to undergo surgery. RFA was performed by a single radiologist using a radiofrequency generator and an internally cooled electrode. We retrospectively analyzed the procedure-induced complications, serial changes in ablated tumors, recurrence, and local as well as lymph node metastasis based on data obtained from medical records and radiological images.
Results: The mean follow-up period was 130.6 months (range 121-159 months). Three patients underwent a single RFA session, and two patients underwent two RFA sessions. We observed no procedure-induced complications. Three tumors completely disappeared after ablation, and ablation of the other two tumors resulted in the formation of a small scar that showed long-term stability (mean duration 16.8 months, range 12-27 months). At the last follow-up, no patient showed recurrence or lymph node metastasis, and serum thyroglobulin levels were within normal limits in all patients.
Conclusion: RFA may be effective and safe to treat low-risk PTMC in patients who refuse or are ineligible for surgery. Copyrights

INTRODUCTION

The incidence of thyroid carcinomas is rapidly increasing (123), mainly due to enhanced early diagnosis of small cancers that are mostly known to be indolent (45678). Among them, low-risk papillary thyroid microcarcinomas (PTMCs) with a maximum diameter of ≤ 1 cm, without gross extra-thyroidal extension, lymph node (LN) metastasis, distant metastasis, or aggressive histopathological features are the subject of active discussion for treatment options (3891011). The current trend of treatment options for low-risk PTMC is becoming more conservative considering the indolence of the tumor and the long life expectancy of patients (412131415). For example, reducing the extent of surgical excision from total thyroidectomy to thyroidectomy is suggested (131415). Furthermore, active surveillance without immediate surgery is considered one of the main options for managing low-risk PTMC (16). Based on this trend, attempts have been made to treat low-risk PTMC by thermal ablation, which can preserve most of the thyroid parenchyma (171819).

According to a recent meta-analysis, the results of thermal ablation for PTMC were favorable, reporting less than 0.5% LN metastasis, no distant metastasis, and a 1.5% proportion of delayed surgery (202122). However, the mean follow-up period was only 39 – 25 months. The study with the longest follow-up was retrospective and only evaluated for a mean of 49.2 – 4.5 months of follow-up (2021222324). In addition, the follow-up periods for thermal ablation studies were still insufficient compared to the studies of active surveillance as an option for treating low-risk PTMC. Therefore, studies reporting results for more than 10 years of follow-up for radiofrequency ablation (RFA) treatment of PTMC are needed.

MATERIALS AND METHODS

This retrospective study was approved by the Institutional Review Boards of Kangwon National University Hospital (IRB No. KNUH-2020-06-004), and written informed consent was obtained from all patients prior to RFA.

STUDY POPULATION

Between November 2006 and December 2009, five patients with PTMC were treated with RFA. The inclusion criteria for RFA were: 1) cytologically or pathologically proven papillary thyroid carcinoma confirmed by fine needle aspiration or core needle biopsy under ultrasonographic guidance, 2) maximum tumor diameter of ≤ 1 cm, 3) no evidence of gross extrathyroidal extension, 4) no evidence of LN or distal metastasis, 5) unifocal carcinoma, and 6) ineligibility or refusal for general anesthesia and/or surgery. The characteristics of the patients in this study are shown in Table 1.

Table 1

Basic Characteristics of Enrolled Patients

Patient	1	2	3	4	5
Age at time of initial ablation	47	29	36	39	51
Sex	Female	Female	Female	Female	Female
Reason for RFA instead of surgery	Refusal	Ineligible (cardiac)	Refusal	Refusal	Refusal
Tumor diameter (mm)	7	4	5	5	4
Tumor location	Mid-left	Mid-right	Mid-right	Mid-right	Mid-left
Tumor distance from nearest capsule (mm)	2	4	1	1	0
Method of diagnosis	FNA	FNA	FNA	CNB	CNB
Follow-up period (months)	159	125	125	124	121

CNB = core needle biopsy, FNA = fine needle aspiration, RFA = radiofrequency ablation

PRE-RFA EVALUATION

Ultrasonographic scans were performed for all patients using real-time ultrasonographic systems with linear probes of 5–13 MHz (Accuvix XG and Accuvix V10, Samsung Medison Co. LTD., Seoul, Korea) and 5–12 MHz (Envisor, Philips Healthcare, Andover, MA, USA). The maximum tumor diameter, tumor location (including the distance between nodule margin and nearest capsule), total number of thyroid carcinomas, and LN metastasis were evaluated using ultrasonographic evaluation.

All included tumors were diagnosed as papillary carcinoma by fine needle aspiration cytology or core-needle biopsy. All patients underwent blood testing for thyroid function and coagulation profiles.

RFA PROCEDURE

A single radiologist performed the RFA procedure using generators (RF 300, Apro-Korea, Gunpo, Korea; SSP-2000, Taewoong Medical, Gimpo, Korea) and straight-type modified internally cooled electrodes with active tip lengths of 5 mm and 7 mm (Well-Point RF Electrode, STARmed, Goyang, Korea; CoATherm electrode, Apro-Korea). The RFA experience of this radiologist was 4 years at that time. Grounding pads were attached to the hips or thighs depending on the patient. We used the following standard techniques suggested by the Korean Society of Thyroid Radiology (25). Patients were placed in a supine position with the necks fully extended. Under local anesthesia with 2% lidocaine, we used a trans-isthmic approach and moving-shot technique. We made every effort to avoid blood vessel injury by ultrasonography with Doppler imaging. Tumors near the nerves and capsule were ablated using the hydrodissection technique (26). The procedure was initiated with an output radiofrequency power of 20 W. If no evaporation was observed from the tip of the electrode for 10 s, the output power was increased by 5 W. The highest output power was 50 W. As the procedures were performed to treat the malignant tumors, we ablated the entire tumor volume and surrounding thyroid parenchyma as much as possible without injury to nearby critical tissues or organs. During the procedure, we frequently checked the patients' voices and blinking. All procedures were performed on an outpatient basis, and patients were offered a resting time of 1 to 6 hours to recover after the procedure. None of the patients required overnight observation following the procedure. The RFA parameters are described in detail in Table 2.

Table 2

Data from the Radiofrequency Ablation Procedures

Patient	1		2	3	4		5
Session	1	2	1	1	1	2	1
Active electrode tip length (mm)	7	5	5	7	5	7	5
Maximum energy strength (watts)	20	30	20	50	35	50	30
Total energy delivery (kJ)	0.73	0.24	1.27	0.69	0.52	1.07	1.83
Ablation time (seconds)	107	27	202	33	53	47	207
Hospitalization time (hours)	2	1	5	4	4	4	6

POST-RFA FOLLOW-UP

RFA was tolerable in all five patients. All patients underwent post-RFA ultrasonography to check for immediate complications before discharge. The first follow-up evaluation was performed 1 month after the procedure. The patients were then followed up for intervals of 3–6 months for 1 year and an average of once per year thereafter. Follow-up evaluations included ultrasonography, depending on the clinical status, to evaluate the maximum diameter of nodules, recurrence, LN metastasis, early (within 30 days) and late (later than 30 days) complications, and thyroid function (2027). Ten years after the initial RFA procedure, all patients underwent ultrasonography, thyroid function tests, serum thyroglobulin level, and neck CT to evaluate recurrence and/or metastasis.

RESULTS

The mean maximum diameter was 0.5 cm (range, 0.4–0.7 cm) of the five PTMCs from the enrolled five patients. Three of the PTMCs were located in the right thyroid lobe and the other two were located in the left thyroid lobe. The mean distance from the nearest thyroid capsule was 1.6 mm (range, 0–4 mm). Despite a tumor (in patient 5) showing a protrusion from the lateral capsule of the left lobe, the tumor was totally ablated using the hydrodissection technique (26). There were no procedure-related complications in any patient. All patients were followed up for > 10 years. The mean follow-up period was 130.6 months (range, 121–159 months).

Treatment was completed after a single RFA session in three patients, while two patients (patients 1 and 4) underwent two sessions. The second RFA sessions of patients 1 and 4 were performed 23 and 51 months, respectively, after the first session was performed. Three tumors completely disappeared, whereas two tumors showed small irregular hypoechoic lesions with tiny spots at the site of RFA (Fig. 1A, B). Despite confirmation of tumor absence by fine needle aspiration, the two tumors were additionally ablated with the patients' agreement to avoid recurrence. Final evaluation showed minimal residual scar-like changes (Fig. 1C). The mean time to reach final tumor status (i.e., complete disappearance or minimal and long-term stable scar formation) was 16.8 months (range, 12–27 months).

Fig. 1

Ultrasonographic images of patient 4.

A–C. Pre-RFA (A), 46 months after the first RFA session (B), and 34 months after the second RFA session (C). Arrow in (A) shows the papillary thyroid microcarcinoma before ablation. Arrows in (B) and (C) show tiny remnant hypoechoic spots near the site of RFA. Histopathological evaluation of a fine-needle aspiration biopsy specimen after obtaining image (B) shows no malignant cells.

RFA = radiofrequency ablation

There were no early or delayed complications during the follow-up period. At the last > 10-year follow-up evaluation, there was no tumor recurrence or LN metastasis in any patient. No patient underwent delayed surgery. Furthermore, the serum thyroglobulin levels remained within the normal range in all patients (Table 3).

Table 3

Follow-Up Results

	1	2	3	4	5
Total follow-up period (months)	159	125	125	123	121
Number of RFA sessions	2	1	1	2	1
Timing of second RFA (months)	23	Not performed	Not performed	51	Not performed
Final result	Minimal and stable scar	Complete disappearance	Complete disappearance	Minimal and stable scar	Complete disappearance
Time to reach final status (months)	14	12	12	27	19
Local recurrence at last follow-up	None	None	None	None	None
LN metastasis at last follow-up	None	None	None	None	None
Tg level at last follow-up (ng/mL)	5.6	NA	21.0	NA	16.4

LN = lymph node, NA = not available, RFA = radiofrequency ablation, Tg = thyroglobulin

DISCUSSION

This study is the first to present follow-up results of more than 10 years for five PTMCs treated by RFA. No patients experienced local tumor recurrence, LN metastasis, or distant metastasis. There were no early or delayed complications and no delayed surgery during the 10-year follow-up period. Therefore, RFA is safe and effective for 10-year control of low-risk PTMC.

The prognosis for papillary thyroid carcinoma is excellent, and the recent treatment trend is gradually changing from total thyroidectomy to lobectomy (12). However, due to the intrinsic disadvantages of the operation itself (9), active surveillance has been proposed as the firstline treatment for low-risk PTMC (2829). However, patient anxiety due to the presence of a mass limits active surveillance. In a systematic review and meta-analysis by Cho et al. (20), 8.7% to 32% of patients elected for surgery during active surveillance, whereas only 1.1% of the patients underwent surgery after RFA. Active surveillance of low-risk PTMC after thermal ablation has been considered effective and safe in several published reports (132930). Zhang et al. (30) reported a prospective 1-year follow-up study after treatment with RFA for papillary thyroid cancer. They found that the malignant lesions disappeared or decreased in volume in 96% of patients, and there was no local recurrence or neck LN metastasis (130). Kim et al. (25) and Jeong et al. (29) reported excellent and safe outcomes after a follow-up of 4 years in six patients and 19.3 months in nine patients, respectively, after RFA for thyroid cancer.

Recently, thermal ablation has been found to be an effective and safe treatment for patients with low-risk PTMC in studies with extended follow-up periods. Lim et al. (21) performed RFA for 152 biopsy-proven PTMC and followed up for an average of 39 – 25 months. All nodules were treated, and there were no recurrences or complications. Cho et al. (17) collected 84 PTMC cases in the same cohort that were followed for > 5 years and reported that RFA treatment remained effective and safe. Li et al. (31) reported a retrospective review of patients with PTMC treated with microwave ablation (n = 168) and surgery (n = 143) after a follow-up of 824 – 452 days. A prospective study was conducted by Zhang et al. (32) in patients treated with RFA (n = 94) and surgery (n = 80) after > 5 years of follow-up. In all these meaningful comparative studies, thermal ablation was not inferior to surgery in any respect, such as treatment effects and complications.

However, some researchers disagree with the use of RFA for patients with PTMC. Ma et al. (33) reported that 12 patients showed incomplete treatment after thermal ablation of papillary thyroid carcinoma. They claimed that thermal ablation was insufficient and the risk of recurrence and metastasis was high. After careful review of the details of the 12 patients, we found that none of the 12 incompletely treated patients met the inclusion criteria of our and other well-designed studies (203031). All 12 patients had multifocal lesions and/or lesions > 1 cm in size (33). On the contrary, we included patients using the strict criteria of maximum diameter ≤ 1 cm, no evidence of gross extra-thyroidal extension, no evidence of LN or distal metastasis, or unifocal carcinoma. Therefore, strict inclusion criteria should be secured to obtain favorable long-term results of RFA after treatment of PTMC (343536).

Residual hypoechoic scar-like lesions were observed in two cases. Both cases were examined by cytology, and only benign cells were detected. No changes in the shapes of the hypoechoic lesions were seen one year after the second RFA session, and there were no changes in the ultrasonographic findings for > 5 years in both cases. We now think that these findings were post-ablation scars. Kim et al. (25) reported similar findings after RFA for PTMC (one of six cases), with benign findings on histological examination and no ultrasonographic changes for > 2 years (14). Lim et al. (21) also reported a small scar-like lesion on follow-up ultrasonographic imaging after RFA for recurrent thyroid cancer (18).

The small sample size of 5 patients is the major limitation of this study. The results of long-term studies with more than 10 years of follow-up are expected to prove the effectiveness and safety of RFA treatment for low-risk PTMC.

In conclusion, we suggest that RFA may be an alternative to surgery for patients with lowrisk PTMC.