Active Surveillance for Papillary Thyroid Microcarcinoma: Challenges and Prospects.

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.

The incidence of thyroid carcinoma has been increasing worldwide. This is interpreted as an increase in the incidental detection of papillary thyroid microcarcinomas (PTMCs). However, mortality has not changed, suggesting overdiagnosis and overtreatment. Prospective clinical trials of active surveillance for low-risk PTMC (T1aN0M0) have been conducted in two Japanese institutions since the 1990s. Based on the favorable outcomes of these trials, active surveillance has been gradually adopted worldwide. A task force on the management of PTMC in adults organized by the Japan Thyroid Association therefore conducted a systematic review and has produced the present position paper based on the scientific evidence concerning active surveillance. This paper indicates evidence for the increased incidence of PTMC, favorable surgical outcomes for low-risk PTMC, recommended criteria for diagnosis using fine needle aspiration cytology, and evaluation of lymph node metastasis (LNM), extrathyroidal extension (ETE) and distant metastasis. Active surveillance has also been reported with a low incidence of disease progression and no subsequent recurrence or adverse events on survival if conversion surgery was performed at a slightly advanced stage. Active surveillance is a safe and valid strategy for PTMC, because it might preserve physical quality of life and reduce 10-year medical costs. However, some points should be noted when performing active surveillance. Immediate surgery is needed for PTMC showing high-risk features, such as clinical LNM, ETE or distant metastasis. Active surveillance should be performed under an appropriate medical team and should be continued for life.

Background:It has been 30 years since the initiation of active surveillance (AS) for adult patients with low-risk papillary thyroid microcarcinoma (PTMC). This study compared the long-term oncological outcomes of patients who underwent AS or immediate surgery (IS).Methods:This is a retrospective review of extended follow-up data from patients enrolled in a single-center, prospective observational study in Japan. In total, 5646 patients diagnosed with low-risk PTMC at Kuma Hospital between 1993 and 2019 were enrolled in this study. Of these, 3222 patients underwent AS (AS group), whereas 2424 underwent IS (IS group). The patients were followed up regularly, at least once per year. Descriptive outcome data were presented according to the treatment group.Results:In the AS group, 124 patients (3.8%) had tumor enlargement of ≥3 mm, and the 10- and 20-year enlargement rates were 4.7% and 6.6%, respectively. Novel lymph node metastases occurred in 27 patients (0.8%), and the 10- and 20-year nodal metastasis occurrence rates were 1.0% and 1.6%, respectively. In the IS group, 13 patients (0.5%) experienced lymph node recurrence postoperatively, and the 10- and 20-year nodal recurrence rates were 0.4% and 0.7%, respectively. Eighteen (1.4%) of the 1327 patients who underwent hemithyroidectomy experienced recurrence in the residual thyroid. The rate of lymph node metastasis was significantly higher in the AS group than in the IS group (1.1% vs. 0.4% and 1.7% vs. 0.7% at 10 and 20 years, respectively; p = 0.009), but the differences were small. However, the proportion of patients who underwent one or more and two or more surgeries was significantly higher in the IS group than in the AS group (100% vs. 12.3% and 1.07% vs. 0.09%, p < 0.01). Distant metastatic recurrence was observed in one patient after AS and conversion surgery and another after IS; however, they were alive (18.4 and 18.8 years after diagnosis, respectively). None of the patients in this study died of thyroid carcinoma.Conclusions:Long-term oncological outcomes of patients with PTMC generally did not differ clinically significantly between those undergoing AS and IS. AS is a viable initial management option for patients with low-risk PTMC.

Objective To study the relationship between clinicopathological features and central lymph nodes metastasis in patients with papillary thyroid microcarcinoma(PTMC). Methods From Jan. 2013 to Jun. 2013, 400 cases with PTMC in cN0 stage undergoing thyroidectomy and central neck dissection were collected. Results Univariate analysis showed that the rate of central lymph node metastasis in PTMC was 28.0%, nevertheless, the rate of central lymph node metastasis was 32.5%, 42.6%, 44.1%, 33.3%, and 37.4% respectively in patients aging below 45 years old, in male patients, in patients with extrathyroidal extension, in patients with tumor diameter larger than 5 mm and in patients with multifocality. Gender, age, extrathyroidal extension, tumor diameter, multifocality of patients had correlation with central lymph node metastasis. Multivariate binary logistic regression analysis revealed that the rate of lymph node metastasis significantly increased in cases of male, ageing below 45 years old, with extrathyroidal extension and multifocality(P<0.05). Conclusions The treatment for central lymph node metastasis of PTMC should be different considering elements including gender, age, multifocality of the tumor, and extrathyroidal extension. Prophylactic central lymphadenectomy should be performed when the primary lesion was resected. Key words: Papillary thyroid microcarcinoma; Central lymph node metastasis; Predictive factors

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.

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.

Background: Active surveillance (AS) has been considered one of the management options in patients with low-risk papillary thyroid microcarcinoma (PTMC). It is important to evaluate clinical lymph node (LN) metastasis to select appropriate candidates with low-risk disease. We investigated the predictive accuracy of computed tomography (CT) for cervical LN metastasis in patients who have PTMC with tumor characteristics appropriate for AS. Methods: This was a retrospective study. Medical records from December 2014 to the end of 2016 were reviewed. Patients who underwent thyroidectomy and who had pathologically confirmed PTMC were included. A total of 464 patients who had tumors with ultrasound (US) characteristics appropriate for AS and who underwent preoperative CT were included in the analysis. Results: CT showed higher diagnostic values especially in positive predictive value (PPV) than US. In patient-based analyses, CT showed low sensitivity and negative predictive value (NPV) (16.0% and 58.5%, respectively), but high specificity and PPV (99.6% and 97.1%, respectively) for detecting cervical LN metastasis. Similar trends were observed for the results of the central neck-level by CT (sensitivity, 14.9%; specificity, 97.4%; PPV, 82.9%; and NPV, 57.4%) in level-by-level analyses. When restricted to lateral neck levels, CT showed high diagnostic accuracy of 95.4% for detecting LN metastasis. In all analyses, CT showed better diagnostic values for cervical LN metastasis than US. Combining US and CT did not improve the diagnostic accuracy compared with CT. Conclusions: In patients with PTMC whose tumor has characteristics suitable for AS, CT had additional benefit after cervical LN assessment by US. Further studies are needed to evaluate routine initial CT scanning for patients who are candidates for AS.

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

The recent sharp increase in thyroid cancer incidence is mainly due to increased detection of small papillary thyroid microcarcinoma (PTMC). Due to the indolent nature of the disease, active surveillance (AS) of low-risk PTMCs is suggested as an alternative to immediate surgery to reduce morbidity from surgery. For appropriately selected PTMC patients, AS can be a good management option and surgical intervention can be safely delayed until progression occurs. Many considerations must be taken into account at the time of initiation of AS, including radiological tumor characteristics and clinical characteristics of the patient. A specialized medical team should be assembled to monitor patients during AS with an appropriate follow-up protocol. The fact that some patients require surgery for disease progression after long-term follow-up is a major drawback of the current AS protocol. Evaluation of tumor kinetics by three-dimensional tumor volume measurement during the initial 2–3 years of AS may be helpful for discrimination of PTMCs that need early surgical intervention. In this review, we will discuss the clinical outcomes of surgical intervention and AS, considerations during AS, and unresolved questions about AS.

Given the indolent nature and favorable outcomes of papillary thyroid microcarcinoma (PTMC), active surveillance (AS) has been adopted as an alternative management option to immediate surgery. However, the meticulous selection of patients based on individual and tumor-specific characteristics, as well as ultrasound (US) findings, is crucial in AS. Regular US monitoring is performed during AS to detect indicators of tumor progression, such as growth, the emergence of new US features suggestive of gross extrathyroidal extension, and lymph node metastasis. Thus, imaging-based evaluations play a pivotal role in guiding the decision to continue AS or proceed with surgical intervention. This review introduces the Korean Society of Thyroid Radiology (KSThR) guideline for the standardized US imaging of patients with low-risk PTMC under AS, which provide practical recommendations for tumor assessment during the initiation and follow-up phases of AS. This review compared the key features of the KSThR guideline with those of major international guidelines and identified the similarities and differences in imaging methodologies and follow-up strategies. The primary objective of this review is to support the broader implementation of AS and improve outcomes for patients with low-risk PTMC by emphasizing imaging protocols.

The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central/lateral lymph node dissection, remains controversial. This study investigated the clinicopathologic factors predictive of lymph node metastasis (LNM) in patients diagnosed with PTMC. Multivariate logistic regression analysis was used for PTMC patients identified from the Surveillance, Epidemiology, and End Results database who were treated by surgery between 2002 and 2012, to determine the association of clinicopathologic factors with LNM. According to the results, a total of 31,017 patients met the inclusion criteria of the study. Final histology confirmed 2,135 (6.9%) cases of N1a disease and 1,684 cases (5.4%) of N1b disease. Our multivariate logistic regression analysis identified variables associated with both central LNM and lateral lymph node metastasis (LLNM), including a younger age (<45 years), male sex, non-Hispanic white and other race, classical papillary histology, larger tumor size, multifocality, and extrathyroidal extension; distant metastasis was also significantly associated with LLNM. The significant predictors identified from multivariable logistic regression were integrated into a statistical model that showed that extrathyroidal extension had maximum weight in the predictive role for LNM. LLNM was validated to be a significant risk factor for cancer-specific death in Cox regression analyses, whereas central LNM failed to predict a worse cancer-specific survival according to our data. Therefore, we suggested that central lymph node dissection could be performed in certain patients with risk factors. Given the prevalence of LLNM in PTMC, a thorough inspection of the lateral compartment is recommended in PTMC patients with risk factors for precise staging; from the viewpoint of a radical treatment for tumors, prophylactic lateral lymph node dissection that aims to remove the occult lateral lymph nodes may be an option for PTMC with risk factors. Multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for cervical nodes in PTMC.

Ultrasound-Guided Radiofrequency Ablation of Low-Risk Papillary Thyroid Microcarcinoma: a Prospective Study

Background: The question of how to manage patients with low-risk papillary thyroid microcarcinoma (PTMC; T1aN0M0) has recently become an important clinical issue. Two Japanese centers have conducted prospective clinical trials of active surveillance (AS) for low-risk PTMC since the 1990s, reporting favorable outcomes. This policy has thus seen gradual adoption worldwide to avoid overtreatment. Not all PTMCs are suitable for AS, however, and many physicians still hesitate to apply the management policy in daily clinical practice. A task force on management for PTMC created by the Japan Association of Endocrine Surgery collected and analyzed bibliographic evidence and has produced the present consensus statements regarding indications and concrete strategies for AS to facilitate the management of adult patients diagnosed with low-risk PTMC.Summary: These statements provide indications for AS in adult patients with T1aN0M0 low-risk PTMC. PTMCs with clinical lymph node metastasis, distant metastasis, recurrent laryngeal nerve (RLN) paralysis due to carcinoma invasion, or protrusion into the tracheal lumen warrant immediate surgery. Tumors suspected of aggressive subtypes on cytology are recommended for immediate surgery. Immediate surgery is also recommended for tumors adherent to the trachea or located along the course of the RLN. Practical strategies include diagnosis, decision-making, follow-up, and monitoring related to the implementation of AS. The rate of low-risk PTMC progression is lower in older patients. However, we recommend continuing AS as long as circumstances permit. Future tasks in optimizing management for low-risk PTMC are also described, including molecular markers and patient-reported outcomes.Conclusions: An appropriate multidisciplinary team is necessary to accurately evaluate primary tumors and lymph nodes at the beginning of and during AS, and to adequately reach a shared-decision with individual patients. If appropriately applied, AS of low-risk PTMC is a safe management strategy offering favorable outcomes and preserves quality of life at low cost.

Background: Active surveillance (AS) is offered as a choice to patients with low-risk papillary thyroid microcarcinoma (PTMC). This study aimed to identify patient and physician factors associated with the choice of AS. Methods: We conducted a cross-sectional survey of patients with low-risk PTMC who were enrolled in a prospective study comparing outcomes following AS and surgery. Patients completed a questionnaire to assess their prior knowledge of the disease, considerations in the decision-making process, and reasons for choosing the treatment. We also surveyed 19 physician investigators about their disease management preferences. Variables affecting the patients' choice of AS, including patients' characteristics and their decision-making process, were analyzed in a multivariable analysis. Results: The response rate of the patient survey was 72.8% (857/1177). Among the patients who responded to the survey, 554 patients (128 male; mean age 49.4 ± 11.6 years; response rate 73.4%) with low-risk PTMC chose AS (AS group), whereas 303 patients (55 male; 46.6 ± 10.7 years; 71.8%) chose immediate surgery (iOP group). In the AS group, 424 patients (76.5%) used a decision aid, and 144 (47.5%) used it in the iOP group. The choice of AS was associated with the following variables: patient age >50 years (odds ratio 1.713 [confidence interval, CI 1.090-2.690], p = 0.020), primary tumor size ≤5 mm (odds ratio 1.960 [CI 1.137-3.379], p = 0.015), and consulting an endocrinologist (odds ratio 114.960 [CI 48.756-271.057], p < 0.001), and use of a decision aid (odds ratio 2.469 [CI 1.320-4.616], p = 0.005). The proportion of patients who were aware of AS before their initial consultation for treatment decision was higher in the AS group than in the iOP group (64.6% vs. 56.8%). Family members were reported to have influenced the treatment decisions more in the iOP group (p = 0.025), whereas the AS group was more influenced by information from the media (p = 0.017). Physicians' attitudes regarding AS of low-risk PTMC tended to be more favorable among endocrinologists than surgeons and all became more favorable as the study progressed. Conclusions: Emerging evidence suggests that physicians' attitudes and communication tools influence the treatment decision of low-risk PTMC patients. Support is needed for patient-centered decision making. (Clinical trial No: NCT02938702).

BackgroundLow-risk papillary thyroid microcarcinoma (PTMC) without clinically evident lymph nodes, extrathyroidal expansions, and distant metastases may be candidates for active monitoring.ObjectiveThe purpose of this research is to identify risk factors for papillary thyroid microcarcinoma (PTMC) metastasis to central cervical lymph nodes (CLNM) and to discuss the viability of an active surveillance strategy to minimize unnecessary therapy for patients.MethodsThis single-center retrospective study was conducted on the data and medical records of the patients who were diagnosed with PTMC and underwent surgery at the Baotou Cancer Hospital, China, between January 1, 2018, and December 31, 2019. Both lobectomy and complete thyroid resections were performed, and central lymph node dissections (CLND) were used in all patients. Comparisons and analyses were conducted on the preoperative ultrasound (US) characteristics, the post-operation pathological results, and lymph node metastasis.ResultsWe analyzed 172 patients with PTMC with average age 48.32 ± 10.59 years old, with 31 males and 142 females. US testing showed 74 (43.0%) patients had suspicious lymph nodes; 31 (41.9%) had capsular invasion and 52 (30.2%) patients were confirmed to have CLNM. Based on logistic regression analysis, central lymph node metastasis was shown to be more common in individuals with PTMC who were older than 45 years old, male, and had tumors that lacked micro-calcification on US imaging. Postoperative pathology assessments suggested that 58 cases (33.7%) were more suitable candidates for active surveillance cohorts.ConclusionsWhile active surveillance might benefit many PTMC patients, treatments for the patients should also encompass occult lymph node metastasis, especially in patients with over 45 years old, male, tumor without micro-calcification in the US imaging. Furthermore, the prediction of lymph nodes in the central cervical via the preoperative US and the PTMC risk stratification accuracy need to be improved. Our findings showed about 30% of the patients with PTMC had no active surveillance high-risk factors but required surgical treatment. Fear of cancer in the PTMC patients, although informed of the details, is still the main reason for choosing surgical treatment over active surveillance.