Active Surveillance Versus Immediate Surgery: Questionnaire Survey on the Current Treatment Strategy for Adult Patients with Low-Risk Papillary Thyroid Microcarcinoma in Japan

BackgroundOvertreatment of papillary thyroid microcarcinoma (PTMC) has become a common concern. This study aimed to compare clinicopathological features between PTMC and papillary thyroid carcinoma (PTC) and to explore whether surgery can confer significant survival benefits in all patients with PTC or PTMC.MethodsData of 145,951 patients with PTC registered in Surveillance, Epidemiology, and End Results (SEER) database and 8,751 patients with PTC in our institution were retrospectively collected. Patients with tumors less than 10 mm in diameter were classified as PTMC cohort and the rest as PTC cohort. Clinicopathological features between PTMC and PTC were compared on the basis of SEER cohort and validated with institutional data. Survival analysis was conducted to explore the effect of surgery on the prognosis of patients. To minimize potential confounders and selection bias, we performed propensity score matching (PSM) analysis to match more comparable cohorts.ResultsCompared with PTC, PTMC exhibited the following characteristics: more common in women and whites, older age at diagnosis, lower proportion of follicular variants, intraglandular dissemination, extraglandular and capsular invasion, higher proportion of multifocality, fewer lymph node and distant metastases, and higher cancer-specific survival (CSS) and overall survival (OS) (all p-value < 0.05). Regarding treatment, patients with PTMC received a lower proportion of radiotherapy, chemotherapy, and total thyroidectomy but a higher proportion of lobectomy and/or isthmectomy. There was no significant difference in CSS for patients with PTMC at stage T1N0M0 with or without surgery (P = 0.36).ConclusionGenerally, PTMC showed higher biological indolence than PTC, which meant a higher survival rate for patients in both OS and CSS. For patients with PTMC at staged T1N0M0, active surveillance (AS) may be a potentially feasible management strategy. However, the maintenance of good medical compliance and the management of psychological burden cannot be ignored for patients included in AS.

Objective: To investigate the rationality of management of active surveillance for papillary thyroid microcarcinoma (PTMC) and the main indications for active surveillance for PTMC. Methods: In this study, two criteria were used to evaluate patients with PTMC: low-risk PTMC conditions defined by Kuma hospital and Chinese Association of Thyroid Oncology (CATO) consensus on PTMC management of active surveillance. The patients had received surgical treatment. Clinicopathological characteristics and prognosis of the patients in different groups were compared. Results: A total of 778 patients were enrolled in the study, 565 (72.6%) of them met Kuma screening criteria and only 112 (14.4%) met CATO screening criteria. Kuma low-risk subgroup had lower incidence of cervical lymph node metastasis than Kuma high-risk PTMC subgroup(30.6% vs 47.9%, P<0.05). There were significant differences in multifocal lesions(6.3% vs 16.4%), extrathyroidal extension (1.8% vs 7.5%) and cervical lymph node metastasis(19.6% vs 38.0%) between low-risk and high-risk CATO PTMC subgroups. Patients in the CATO low-risk PTMC subgroup had lower recurrence and longer disease-free survival (DFS) than those in the CATO high-risk PTMC subgroup. But there was no significant difference in recurrence or DFS between Kuma low-risk and high-risk Kuma PTMC subgroups.The Chi-square test of Fisher's exact probabilities test was used to compare clinicopathological characteristics of patients between different groups.Rates of disease-free survival were calculated using the Kaplan-Meier method. Conclusion: CATO screening criteria is relatively strict and may be more suitable for Chinese patients with active surveillance for PTMC.

Quality of Life in Patients with Low-Risk Papillary Thyroid Microcarcinoma: Active Surveillance Versus Immediate Surgery

Background: Active surveillance (AS) of papillary thyroid microcarcinomas (PTMC) is emerging as an alternative to immediate surgery. While thermal ablation has also shown promise for low-risk PTMC, it has not been prospectively studied in patients appropriate for AS. This study aimed to evaluate the efficacy and safety of ultrasound (US)-guided radiofrequency ablation (RFA) for tumor control and quality of life (QoL) management in patients with PTMC who favored AS over immediate surgery. Methods: This prospective clinical trial was conducted at a single tertiary referral hospital from 2018 to 2021. Of 227 adult patients aged ≤60 years with low-risk unifocal PTMC favoring AS over immediate surgery, 100 patients underwent RFA for their management. The primary endpoint was the disease progression rate, and secondary endpoints were technical success, volume reduction rate (VRR), complication rates, and QoL. Results: The median age of the study population was 42 years (range, 27-59 years), and 83% (83/100, [CI: 66.1-100]) were female. The median follow-up was 30 months (range, 12-56 months). All 100 patients underwent RFA with technical success. Most of the ablation zones showed continuous volume reduction, and 95.9% (94/98, [CI: 77.5-100.0]) showed complete disappearance at the last follow-up. The median VRR was 100.0% at 1-year follow-up and persisted throughout the last follow-up. The cumulative disease progression rate among 98 patients who underwent at least 1-year follow-up was 3.1% (3/98, [CI: 0.6-9.0]); one patient had lymph node metastasis (treated with surgery), and two patients had new PTMC (1 treated with RFA, 1 ongoing AS). Major complications were not observed. Psychological (baseline vs. last follow-up, 7.3 vs. 8.0, p = 0.002) and social (8.0 vs. 8.7, p = 0.005) QoL scores significantly improved during follow-up without compromising physical QoL (8.6 vs. 8.5, p = 0.99). Conclusions: RFA can be a reasonable strategy for effectively and safely controlling tumors and improving QoL in non-elderly patients with low-risk PTMC appropriate for AS. Clinical Trial registration: This trial is registered with ClinicalTrials.gov: NCT03432299.

Papillary thyroid carcinoma is the most common endocrine malignancy. Papillary thyroid microcarcinomas (PTMCs) are tumors with a size of ≤1 cm. The biological behavior of these tumors differs due to the presence of their aggressive features. The prognosis of PTMCs with high-risk features, such as clinical node metastasis, distant metastasis, and significant extrathyroidal extension to the tracheal or recurrent laryngeal nerve invasion, is poor, even if a sufficient immediate surgery is performed at diagnosis. However, PTMCs without these aggressive features are low-risk tumors because of their indolent and slow growth behaviors. The increase in thyroid cancer incidence is mostly a result of overdiagnosis of small low-risk PTMCs with indolent clinical course. Despite the sudden increase in thyroid cancer incidence worldwide, cancer mortality did not increase. Although the traditional treatment strategy for PTMC is immediate surgery at diagnosis, because of the rather low disease-specific mortality rate, low recurrence rate, and potential risk for postoperative complications, active surveillance has been proposed recently as an alternative option for PTMCs without invasion, metastasis, or cytological or molecular characteristics. The recent data support that active surveillance of low-risk PTMC should be the initial treatment modality, because only a small percentage of low-risk PTMCs show signs of progression, and delayed surgery has not caused significant recurrence. However, recent management guidelines are shifting toward more conservative treatments, such as active surveillance. Although there is an increase in the number of studies related to active surveillance, prospective studies have been mostly from academic referral centers in Japan. The world still needs class 1 evidence extended prospective studies originating from different geographic regions. Active surveillance may be a good alternative to immediate surgery for appropriately selected patients with PTMC.

Although the outcomes of active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) are generally excellent, some patients undergo conversion surgery for various reasons, including disease progression. We studied the outcomes of PTMC patients who underwent AS, who underwent conversion surgery after AS, and who underwent immediate surgery. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk cT1aN0M0 PTMC at Kuma Hospital: 2,896 opted for AS (AS group) and 1,739 underwent immediate surgery (Surgery group). In the AS group, 242 patients underwent conversion surgery (Conversion group): 72 owing to disease progression (Conversion-prog group) and 170 for other reasons (Conversion-non-prog group). Of the 1,739 patients in the Surgery group, 1,625 had no high-risk features (Surgery-low-risk group). Locoregional recurrence (LRR) occurred in 9, 1, 1, and 0 patient in the Surgery-low-risk group, the Conversion-prog group, the AS group, and the Conversion-non-prog group, respectively. The LRR rate of the AS group was significantly lower than that of the Surgery-low-risk group (0.1% vs. 0.7% at 10 years, p = 0.006). Additionally, the LRR rate of the Conversion group (0.6% at 10 years, p = 0.741) and that of the Conversion-prog group (3.3% at 10 years, p = 0.103) did not significantly differ from the LRR of the Surgery-low-risk group. As the postoperative prognosis of patients with progressive PTMC who underwent conversion surgery did not significantly differ from that of patients who underwent immediate surgery, we think that AS may have resulted in efficient identification of the small proportion of patients with progressive PTMC that require surgical treatment.

Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC), which was initiated at Kuma Hospital (Kobe, Japan) in 1993 and Cancer Institute Hospital (Tokyo) in 1995, is now gradually being adopted worldwide, and several prospective studies have described the favorable outcomes of PTMC patients who underwent AS. The most important factor predicting PTMC growth is young age, and PTMC enlargement in young patients may be affected by high serum levels of thyroid-stimulating hormone. This review notes that one patient showed lung metastasis after conversion surgery (CS) following AS, but there are no reports of patients dying of thyroid carcinoma during or after AS. Some PTMCs enlarge or show newly appeared metastatic nodes requiring CS, and findings on the postoperative prognosis and incidence of significant surgical complications (e.g., permanent vocal cord paralysis, hypoparathyroidism) do not differ significantly between patients who underwent CS after AS and those who underwent immediate surgery (IS). IS has been associated with significantly higher incidences of these complications compared to AS as the initial management. Several studies have examined the quality of life (QoL) of patients who underwent AS versus IS, and reported discrepant findings regarding various psychological conditions (including anxiety). Medical costs for AS and IS vary regionally, and in Japan, the 10-year total cost of IS was 4.1 times greater than that of AS in 2017. Taken together, the existing findings demonstrate that AS can be appropriate for the initial management of patients with PTMC.

Background:Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and has gradually spread worldwide. We previously demonstrated that AS is associated with a much lower incidence of unfavorable events than immediate surgery (IS). However, conversion surgery (CS) raises concerns about increased surgical complications due to advanced disease. In this study, we conducted a comparative analysis of unfavorable events after IS and CS.Methods:Between 2005 and 2019, 4635 patients clinically diagnosed with low-risk PTMC at Kuma Hospital were enrolled. Of these, 2896 underwent AS (AS group), and the remaining 1739 underwent IS (IS group). To date, 242 patients (8.4%) in the AS group have undergone CS for various reasons (CS group).Results:The incidence of unfavorable events, such as levothyroxine administration after surgery, postoperative hematoma, transient/persistent hypoparathyroidism, and transient/persistent vocal cord paralysis, did not differ between the CS and IS groups. None of the patients in the CS group had permanent vocal cord paralysis; however, this occurred in 15 patients (0.9%) in the IS group and was caused by accidental injury in 4 patients and carcinoma invasion in 11 patients. The incidence of surgery, levothyroxine administration, postoperative hematoma, transient/permanent hypoparathyroidism, and vocal cord paralysis was significantly higher (p < 0.001) in the IS group than in the AS group. There were no differences in the incidence of lymph node recurrence and overall mortality between the AS and IS groups. None of the patients in the AS and IS groups showed distant metastasis or died from thyroid carcinoma.Conclusions:There were no differences in the incidence of unfavorable events between the CS group and the IS group. Although none of the CS and AS groups had permanent vocal cord paralysis, accidental injury of the recurrent laryngeal nerve occurred in four patients (0.2%) in the IS group. The IS group had a significantly higher incidence of unfavorable events than the AS group. The prognoses of patients in both the AS and IS groups were excellent. Therefore, we recommend AS as the first-line management for low-risk PTMC.Correction added on February 20, 2023 after first online publication of November 9, 2022: In the Methods section of the abstract, 242 patients (0.8%) has been corrected to 242 patients (8.4%).

BRAF V600E status may facilitate decision-making on active surveillance of low-risk papillary thyroid microcarcinoma

Background/Objectives: MicroRNAs are emerging as valuable diagnostic markers for various diseases, including papillary thyroid carcinoma (PTC). However, there is limited research on circulating miRNA expression in papillary thyroid microcarcinoma (PTMC). Therefore, we conducted a study to explore whether plasma-derived miRNAs can distinguish PTMC from benign nodules or predict aggressiveness. Methods: A total of 150 patients who underwent thyroidectomy from January 2013 to July 2021 were enrolled in this study. Patients were divided into three groups: benign, low-risk PTMC, and advanced PTMC. Nine patients from each group were selected for microarray analysis for plasma miRNAs. Six miRNAs were selected for comparison of expression levels using TaqMan assay. The ROC curve was utilized to evaluate the diagnostic and aggressiveness value of the miRNAs. Results: From the microarray analysis, miR-455-3p and miR-548ac were identified as miRNAs that can significantly differentiate between benign nodules and PTMC. A combination of six miRNAs (miR-455-3p, miR-548ac., miR-221, miR-222, miR-146a. miR-146b) rather than individual miRNAs had the highest AUC (0.857), sensitivity (0.867), and specificity (0.800) in differentiating benign and PTMC. In microarray analysis, no significant miRNAs were observed to distinguish between low-risk group and aggressive PTMC. However, in the six-miRNA combination, it was possible to distinguish low-risk PTMC from aggressive PTMC with an AUC of 0.763, sensitivity of 0.739, and the specificity of 0.727. Conclusions: A combination of six miRNAs presents the possibility of distinguishing between benign and PTMC and low-risk and aggressive PTMC with an acceptable AUC, sensitivity, and specificity.

Papillary thyroid microcarcinoma (PTMC) management has evolved, with active surveillance (AS) gaining prominence as a management option. However, a key concern for both clinicians and patients is the potential for patient loss to follow-up during AS. This study aimed to determine adherence and loss-to-follow-up rates in low-risk PTMC patients undergoing AS versus surgical intervention, in order to gain insights into clinical pathways and safety profiles. This cohort study analyzed the 2016 data from a single registered institution of Japan's public National Cancer Registry. We identified and retrospectively analyzed the cases of 327 patients diagnosed with low-risk PTMC; 227 patients chose to undergo AS while the other 100 underwent PTMC surgery. Main outcomes were the adherence rate and loss-to-follow-up rate of each group, factors influencing discontinuation, and safety considerations. The rate of AS adoption was substantial in the complete series of 327 low-risk PTMC patients (69.4%). There was a significantly higher loss-to-follow-up rate at 5 years in the AS group (28.6%) compared to the Surgery group (17.8%) (HR 1.62, 95% CI: 1.01-2.61; p = 0.046). Both univariate and multivariate analyses confirmed the significantly higher loss-to-follow-up rate in the AS group as well as in older patients. No deaths due to PTMC progression were observed in the cases lost to follow-up. Despite concerns about loss to follow-up, active surveillance remains a safe option for low-risk PTMCs. Consistent follow-up strategies are crucial, and further research is needed to enhance patient counseling and care for the management of patients with PTMC.

Papillary thyroid microcarcinoma(PTMC)of the thyroid is defined as papillary thyroid carcinoma measuring<1 cm. The incidence of differentiated thyroid cancer is increasing greatly. However, roughly half of this increase is attributable to the identification of PTMC. Serum thyroid stimulating hormone, thyroid ultrasound and ultrasound guided thyroid fine needle aspiration cytology(FNAC)are still the cornerstone for its diagnosis. The active surveillance approach in which active treatment is delayed until the cancer shows signs of substantial progression could be considered in selected patients with low-risk PTMC. Active surgery is still the first line treatment for other PTMC patients, although thermal ablation may be an alternative option for low-risk patients with PTMC. (Chin J Endocrinol Metab, 2018, 34: 353-358) Key words: Papillary thyroid microcarcinoma; Active surveillance; Thermal ablation

In 1993, active surveillance of low-risk papillary thyroid microcarcinomas (PTMCs) started in Kuma Hospital, Kobe, Japan. It has spread globally after the publishing of American Thyroid Association (ATA) guidelines. During our hospital's active surveillance program, few patients (8.0%) showed tumor size enlargement ≥3 mm or the new appearance of node metastasis (3.8%) at 10-year follow-up. Conversion surgery was recommended for patients with disease progression. To date, no patients showed significant recurrence or metastasis or died with thyroid carcinoma when patients underwent active surveillance or after surgery due to PTMC progression. Unlike clinical papillary thyroid carcinoma (PTC), elderly patients' PTMCs were less progressive compared to those of young and middle-aged patients, indicating that elderly patients are strong candidates for the active surveillance of their PTMC. Although young patients' PTMCs are the most progressive, >50% and >75% of patients in their 20s and 30s would avoid conversion surgical treatment in their lifetime, respectively (according to estimated lifetime probability), indicating that such young patients are still candidates for active surveillance. It can thus be concluded that active surveillance is appropriate to be first management for PTMCs, based on the accumulation of favorable outcomes of PTMC patients who have undergone active surveillance, as well as the lower incidences of unfavorable events and lower medical cost than immediate surgery.

Background: The Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) started in June 2016. As a follow-up study of comparing the quality of life (QoL) of the active surveillance (AS) and immediate surgery (OP) groups at 8 months (9.3±4.8 and 7.1±4.2 months, respectively), here we aimed to compare the QoL between the AS and OP groups after 18 months (22.8±4.0 and 22.3±4.3 months, respectively) of follow-up.Methods: QoL of 108 participants who chose AS, 101 who underwent OP, twelve who changed from AS to OP was evaluated using a thyroid‐specific QoL questionnaire at diagnosis and during follow‐up (median 23 months).Results: The mean ages of the participants in the AS and OP groups were 47.7±11.0 and 45.1±10.0 years (p=0.075), respectively. At baseline, better physical (8.2±1.4 vs. 7.6±1.8, p=0.032), psychological (7.4±1.2 vs. 6.7±1.6, p=0.010), and total health (7.4±1.0 vs. 6.7±1.3, p=0.005) were observed in the AS group than in the OP group. After a mean follow up of 22.7±4.2 months, better physical (8.1±1.5 vs. 7.4±1.7, p=0.008), psychological (7.7±1.3 vs. 7.0±1.5, p=0.002), and total health (7.5±1.2 vs. 6.8±1.3, p=0.001) were observed in the AS group than in the OP group, whereas spiritual health was comparable between the two groups: compared with the AS group, the OP group experienced more alterations in appetite, sleep, menstrual cycle, voice, motor skill, weight, appearance, cold or heat tolerance, and body swelling. Furthermore, better QOL scores were observed in the AS group in self-concept, personal relationships, sexual life, work motivation, productivity and quality of work, feeling of isolation, driving, doing household chores, preparing meals and doing leisure activities after long term follow up.Conclusion: Patients who underwent AS had better QOL even after long term follow up. Low risk papillary thyroid microcarcinomas do not influence survival, however surgery related deterioration of QOL lasted long and did not improve even in late post-operative stages when patients were fully recovered from surgery.Keywords: Quality of life; papillary thyroid microcarcinoma; active surveillance; immediate surgery

BackgroundDistant metastasis is extremely rare for papillary thyroid microcarcinoma (PTMC) without lymph node metastasis or extrathyroidal extension, for which active surveillance (AS) is indicated. The evaluation of distant metastases in low-risk PTMC is controversial. A case of PTMC in which AS would have been performed if chest CT and lung surgery had not been performed is reported.Case presentationThe patient was a 71-year-old woman undergoing follow-up in the Department of Thoracic Surgery at our hospital for multiple frosted glass shadows in both lung fields for one and a half years. To make a definitive diagnosis, thoracoscopic right middle lobectomy and left upper partial lobectomy were performed 4 and 6 months earlier, respectively. In both resected specimens, lung adenocarcinoma and small metastasis of papillary thyroid carcinoma (PTC) were found. The patient was transferred to our department for a thorough examination for PTC. Ultrasonography was performed to search for the primary lesion, and it showed an irregular hypoechoic mass of 4 mm and 6 mm in the middle of the right lobe of the thyroid gland. The patient was diagnosed with PTC. Its clinical stage was T1a (m) N0 M1 (stage IVC). Total thyroidectomy and prophylactic central node dissection were performed. The pathological diagnosis was PTC (typical type) pT1a (m) N0. Postoperatively, she received radioactive iodine therapy.ConclusionsWe experienced an extremely rare case and struggled to determine a treatment plan. We might be aware that lung metastases could develop in low-risk PTMC.