Position paper from the Japan Thyroid Association task force on the management of low-risk papillary thyroid microcarcinoma (T1aN0M0) in adults.

Active surveillance (AS) can be considered as an alternative to immediate surgery in low-risk papillary thyroid microcarcinoma (PTMC) without clinically apparent lymph nodes, gross extrathyroidal extension (ETE), and/or distant metastasis according to American Thyroid Association. However, in the past AS has been controversial, as evidence supporting AS in the management of PTMC was scarce. The most prominent of these controversies included, the limited accuracy and utility of ultrasound (US) in the detection of ETE, malignant lymph node involvement or the advent of novel lymph node malignancy during AS, and disease progression. We summarized publications and indicated: (1) US, performer-dependent, could not accurately diagnose gross ETE or malignant lymph node involvement in PTMC. However, the combination of computed tomography and US provided more accurate diagnostic performance, especially in terms of selection sensitivity. (2) Compared to immediate surgery patients, low-risk PTMC patients had a slightly higher rate of lymph node metastases (LNM), although the overall rate for both groups remained low. (3) Recent advances in the sensitivity and specificity of imaging and incorporation of diagnostic biomarkers have significantly improved confidence in the ability to differentiate indolent vs. aggressive PTMCs. Our paper reviewed current imagings and biomarkers with initial promise to help select AS candidates more safely and effectively. These challenges and prospects are important areas for future research to promote AS in PTMC.

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.

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

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 analyze the clinical features of lymph node metastasis in papillary thyroid microcarcinoma(PTMC). Methods 198 patients with PTMC who have underwent total thyroidectomy and at least one 131I treatment were divided into two groups according to the occurrence of lymph node metastasis. The clinical features of lymph node metastasis in PTMC were retrospective analyzed, and independent risk factors of the central and lateral lymph node metastasis in PTMC patients were further analyzed. Results Clinical features of PTMC patients with cervical lymph node metastasis: (1)Most of them were<45 years old(63.4% vs 44.9%, P=0.012); (2)More patients with cancer in bilateral lobes and extrathyroidal extension in lymph node metastasis groups(56.7% vs 42.0%, P=0.043; 63.6% vs 36.4%, P=0.034); (3)The average tumor size of the patients of lymph node metastasis was larger than that of the patients without lymph node metastasis[(0.71±0.25 vs 0.64±0.24)cm, P=0.047]; (4)Preoperative thyroglobulin antibody(TgAb)level of PTMC patients with cervical lymph node metastasis was higher than the control group[(65.27±139.179 vs 36.36±95.647)IU/L, P=0.03]; (5)After the 131I treatments and by 1-6 years of follow-up, it is found no statistically significant difference in cure rate between patients with cervical lymph node metastasis after total thyroidectomy and its control group. But the frequency of 131I treatment required in patients with cervical lymph node metastasis was higher than that of the control group(1.77±0.77 vs 1.49±0.74, P=0.006). Univariate analysis revealed that central lymph node metastasis was correlated with age, tumor size and other factors. There were more patients with cancer in bilateral lobes and extrathyroidal extension in lymph node metastasis group. And lateral lymph node metastasis was correlated with Hashimoto′s thyroiditis. Multivariate analysis showed that age, tumor size, involvement of bilateral glandular lobes and extrathyroidal extension were independent risk factors for central lymph node metastasis. Conclusion The risk factors of lymph node metastasis should be fully evaluated to carry out individualized treatment for the first operation of PTMC patients. (Chin J Endocrinol Metab, 2016, 32: 900-905) Key words: Papillary thyroid microcarcinoma; Lymph node metastasis; Clinical feature; Risk factors

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.

Management of Sonographically Suspicious Thyroid Nodules 1 cm or Smaller and Candidacy for Active Surveillance: Experience of a Tertiary Center in China

The increasing detection of papillary thyroid microcarcinoma (PTMC) has raised concerns regarding overtreatment. For low-risk PTMC, either immediate surgery or active surveillance (AS) can be considered. To facilitate the implementation of AS, the Korean Thyroid Association convened a multidisciplinary panel and developed the first Korean guideline. AS is recommended for adults with pathologically confirmed Bethesda V-VI PTMC who have no clinical evidence of lymph node or distant metastasis, gross extrathyroidal extension, invasion of the trachea or recurrent laryngeal nerve, or aggressive histology. A baseline assessment requires high-resolution neck ultrasound performed by experienced operators to exclude extrathyroidal extension, tracheal or recurrent laryngeal nerve invasion, and lymph node metastasis; contrast-enhanced neck computed tomography is optional. Patient characteristics, including age, comorbidities, and the capacity for long-term follow-up, should be thoroughly assessed. Shared decision-making should carefully weigh the benefits and risks of surgery versus AS, considering expected oncologic outcomes, potential complications, quality of life, anxiety, medical costs, and patient preference. Follow-up involves neck ultrasound and thyroid function tests every 6 months for 2 years and annually thereafter. Disease progression, defined as significant tumor growth or newly detected nodal or distant metastasis, warrants surgery. Despite remaining uncertainties, this guideline provides a structured framework to ensure oncologic safety and supports patient-centered AS.

The clinical significance of papillary thyroid microcarcinoma (PTMC) tumors < or =1 cm is widely debated. The objective of this study was to compare conventional papillary thyroid carcinoma (PTC) (tumors >1 cm) to PTMC and assess for differences in tumor characteristics and patient outcome. A retrospective chart review of patients with PTC or PTMC who were followed for a minimum of 3 years postoperatively and managed at a single academic institute was performed. Of 202 patients in the study, 66 (32.7%) had PTMC and 136 (67.3%) had conventional PTC. Patient and tumor characteristics including tumor multifocality, extrathyroidal extension, angiolymphatic invasion, and lymph node metastasis were similar between both groups. Twenty-one percent of the PTMC tumors were discovered incidentally. Patients with conventional PTC were significantly more likely to undergo treatment with radioactive iodine therapy compared to PTMC patients (86.4% vs. 66.7%, respectively, p < 0.003). Disease recurrence was observed in 40 patients and was not statistically different between the two groups; 11 (16.7%) in PTMC and 29 (21.3%) in conventional PTC, p = 0.57. Within the PTMC group, tumors of patients that recurred were significantly larger than those who remained disease free (8.1 mm vs. 6.4 mm, p < 0.05). None of the patients with incidental PTMC had disease recurrence. Angiolymphatic invasion was the only significant prognostic indicator of recurrence on multivariate analysis (p < 0.02). Nonincidental PTMC can have aggressive tumor features and disease recurrence similar to conventional PTC. These tumors should be managed like any other papillary thyroid malignancy.

Background:Active surveillance (AS) is an alternative to thyroidectomy for the management of low-risk papillary thyroid microcarcinoma (PTMC). However, prospective AS data collected from diverse populations are needed.Methods:This multicenter prospective cohort study enrolled patients from three referral hospitals in Korea. The participants were self-assigned into two groups, AS or immediate surgery. All patients underwent neck ultrasound every 6–12 months to monitor for disease progression. Progression under AS was evaluated by a criterion of tumor size increment by 3 mm in one dimension (3 mm), 2 mm in two dimensions (2 × 2 mm), new extrathyroidal extension (ETE), or new lymph node metastasis (LNM), and a composite outcome was defined using all four criteria.Results:A total of 1177 eligible patients with PTMC (919 female, 78.1%) with a median age of 48 years (range 19–87) were enrolled; 755 (64.1%) patients chose AS and 422 (35.9%) underwent surgery. Among 755 patients under AS, 706 (female 537, 76.1%) underwent at least two ultrasound examinations and were analyzed. Over a follow-up period of 41.4 months (standard deviation, 16.0), 163 AS patients (23.1%) underwent surgery. Progression defined by the composite outcome was observed in 9.6% (68/706) of patients, and the 2- and 5-year progression estimates were 5.3% and 14.2%, respectively. The observed progression rates were 5.8% (41/706) and 5.4% (38/706) as defined by tumor size enlargement by 3 mm and 2 × 2 mm, respectively, and 1.3% (9/706) and 0.4% (3/706) for new LNM and ETE, respectively. No distant metastases developed during AS. In multivariate logistic regression analysis examining variables associated with progression under AS, age at diagnosis <30 years (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.10 − 7.45), male sex (OR, 2.48; 95% CI, 1.47 − 4.20), and tumor size ≥6 mm (OR, 1.89; 95% CI, 1.09 − 3.27) were independently significant.Conclusions:The progression of low-risk PTMC during AS in the Korean population was low, but slightly higher than previously reported in other populations. Risk factors for disease progression under AS include younger age, male sex, and larger tumor size.Clinical trial registration:Clinicaltrials.gov NCT02938702.

Active surveillance has emerged as an initial management strategy for patients with low-risk papillary thyroid microcarcinoma (PTMC). The main objective of this research was to investigate the frequency of risk pathological characteristics among patients with clinically low-risk PTMC who are suitable for Active Surveillance. A retrospective review was conducted on patients who underwent lobectomy for PTMC between January 2013 and December 2018. Patients with bilateral tumors, macroscopic multifocal tumors, macroscopic extrathyroidal extension (ETE), clinical lymph node metastases, macroscopic extranodal extension (ENE), distant metastases, a history of neck radiation or familial thyroid cancer were excluded. Pathological characteristics were collected from the postoperative pathological results. Aggressive variants, multifocality, ETE, lymphovascular invasion (LVI), perineural invasion (PNI), metastatic lymph nodes (LNs) ≥ 5, and ENE were defined as risk characteristics. The study included 4923 patients, of whom 1229 (25.0%) were male. The mean age was 43years. A total of 2250 patients (45.7%) exhibited risk characteristics. Among them, 15 patients presented with aggressive variants, and 1813 patients (36.8%) had ETE. Multifocality, LVI, and PNI were observed in 551 (11.2%), 21 (0.4%), and 40 (0.8%) patients, respectively. A total of 139 patients (2.8%) had five or more metastatic LNs, and ENE was identified in 140 patients. Notably, 172 patients (3.5%) fulfilled the criteria for completion thyroidectomy, as they had aggressive variants, LVI, or five or more metastatic LNs. Nearly half of the patients diagnosed with clinically low-risk PTMC exhibited risk pathological characteristics, and a small proportion of patients met the criteria for completion thyroidectomy.

Background: Papillary thyroid carcinoma (PTC) is treatable, with favorable prognosis and very low disease-specific mortality. However, PTC recurrence is relatively common in loco-regional and distant sites. Although multifocality is a common occurrence in PTC, its prognostic impact remains controversial. In addition, data on prevalence and prognostic significance of multifocality in PTC from Middle Eastern ethnicity is unknown. Therefore, the aim of this study was to investigate the prognostic value of multifocality in PTC larger than 1cm and papillary thyroid microcarcinoma (PTMC) in our center. Methods: A cohort of 1515 patients who underwent total thyroidectomy were retrospectively reviewed. Aggressive histopathologic variants of PTC were excluded to avoid their potential confounding effect on clinical outcomes. We identified 1087 patients who had PTC with primary tumor exceeding 1cm and 150 patients with PTMC, with medium follow up of 9.2 years. In each group, we compared patients with unifocal and multifocal disease. Clinico-pathological and molecular correlations were analyzed. Logistic regression analysis was used to assess the relation between multifocal tumors and lymph node metastasis. Results: The incidence of multifocality in PTC larger than 1cm was 48.3% (525/1087), whereas it was 38.7% (58/150) in PTMCs. In patients with PTC &amp;gt; 1cm, multifocality was significantly associated with aggressive markers such as extrathyroidal extension (p &amp;lt; 0.0001), lymphovascular invasion (p = 0.0047), lymph node (LN) metastasis (p = 0.0006), distant metastasis (p = 0.0305) and BRAF mutation (p = 0.0113). In analogous analysis of patients with PTMC, multifocality was significantly associated with extrathyroidal extension (p &amp;lt; 0.0001), LN metastasis (p = 0.0005) and BRAF mutation (p = 0.0006). In both sub-groups, disease recurrence and overall survival did not differ between unifocal and multifocal group. Multivariate analysis showed that multifocality was an independent predictor of LN metastasis (Odds ratio (OR) = 1.31; 95% confidence interval (CI) = 1.00 - 1.71; p = 0.0472 for PTC &amp;gt; 1cm and OR = 1.88; 95% CI = 1.00 - 3.54; p = 0.0491 for PTMC). Conclusions: Tumor multifocality is frequently observed in Middle Eastern PTC and PTMC and is a predictive factor for LN metastasis in PTC. Given the predictive value of multifocality in Middle Eastern ethnicity, aggressive therapy and intensive follow-up should be considered for both PTC and PTMC with multifocality. Regional LN metastasis should be closely monitored and prophylactic central lymph node dissection could be considered in these patients. Citation Format: Pratheeshkumar Poyil, Abdul K Siraj, Sandeep Kumar Parvathareddy, Divya Padmaja, Saravanan Thangavel, Rafia Begum, Roxanne Diaz, Khadija Al-Obaisi, Khawla S. Al-Kuraya. Multifocality is an independent predictor of regional lymph node metastasis in Middle Eastern papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5178.

Despite the increased incidence of papillary thyroid microcarcinoma (PTMC), clinical importance is still controversial. Although risk factors for PTMCs have been identified previously, prognostic factors have not been established clearly. In this study, we aimed to review the presentation features and outcomes of the patients with PTMC. Our study included 144 patients that underwent thyroidectomy and were diagnosed with PTMC according to the postoperative pathology report. All data included age, gender, mode of diagnosis, preoperative ultrasonography and fine needle aspiration cytology (FNAC) results, tumor features (diameter, unilobar localization, multifocality, and stage), the presence of residual thyroid tissue, postoperative serum thyroglobulin (Tg) levels, and radioactive iodine (RAI) ablation were retrospectively reviewed. Only 29 patients (20%) with PTMC could be diagnosed preoperatively with FNAC which was performed in 67% of the patients. The diameter and the number of thyroid nodules were significantly related to the mode of diagnosis. The average size of the tumor diameter was 5 mm ± 2.87. An extrathyroidal extension (ETE) was observed in 10 patients (7%). Lymph node metastasis (LNM) was diagnosed in 6 patients (16%). There was a significant correlation between ETE and tumor diameter with LNM (p = 0.008 and p < 0.001, respectively). Residual tissue was noted in 110 patients (76%). The presence of residual thyroid tissue was significantly related to the extent of surgery, unilobar location, and multifocality. Mode of diagnosis (incidental or non-incidental), tumor diameter, the number of thyroid nodules, unilobar location, and multifocality seem to be related to unfavorable outcomes of patients with PTMC.

The incidence of thyroid cancer has been rapidly increasing in recent years largely due to improved diagnostic methods. There is evidence to suggest that in papillary thyroid microcarcinoma (PTMC), active surveillance (AS) is comparable in effectiveness compared to immediate surgery (IM). We conducted a survey of Clinicians and Surgeons from Australia and New Zealand to assess the role of AS in the management of PTMC. A short electronic survey was created on the platform Survey Monkey, separate links containing the survey were sent to various medical societies to be distributed to its members. The list of medical societies included: General Surgeons Australia, Endocrine Society of Australia, Australian and New Zealand Endocrine Surgeons, Australian and New Zealand Head and Neck Cancer Society and New Zealand Association of General Surgery. We received 110 complete responses, which demonstrated that 63% of clinicians will discuss AS with patients diagnosed with PTMC. Surgeons are more likely to discuss AS compared to endocrinologists (P=0.03). Forty-eight percent of respondents report managing patients with AS in the past year, those who are able to perform thyroid ultrasounds are more likely to utilise AS (P=0.03). Common perceived barriers to AS include patient anxiety, lack of access to regular follow-up and lack of patient compliance. Our survey shows that Australian and New Zealand clinicians are generally aware of AS as a treatment option for PTMC, but there remain considerable barriers for common implementation.

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.