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

Objective To determine the prevalence of lymph node (LN) metastasis and extrathyroidal extension (ETE) in patients with papillary thyroid microcarcinoma (PTMC) in Cyprus and to evaluate the role of preoperative ultrasound (U/S) examination. Methods A retrospective study of 102 patients who underwent thyroidectomy for PTMC in a 2-year period. Preoperatively, all patients had a thyroid and neck U/S examination with LN mapping. Tumor size according to the largest diameter, number of foci, LN metastasis, and ETE data was collected from the histopathological report and was compared to the preoperative U/S reports. Results LN metastasis was present in 23.5% of patients. 15.7% had central, 3.9% had lateral, and 3.9% had both central and lateral LN metastasis. ETE was present in 27.5% of patients. 21.6% had multifocal disease, and in this group, 40.9% had LN metastasis and 36.4% had ETE. Multifocality (p = 0.03), size of tumor (p = 0.05), and ETE (p ≤ 0.001) were significantly associated with LN metastasis. The prevalence of LN metastasis in multifocal PTMC ≤5 mm was the same with multifocal PTMC >5 mm. The preoperative U/S sensitivity for the suspicious lateral neck and central LN was 100%, and the specificity was 100%. The preoperative U/S sensitivity for nodules suspicious for ETE was 53.6%, and the specificity was 100%. Conclusion The presence of LN metastasis and ETE in our PTMC patients in Cyprus is frequent. Neck U/S mapping is a highly reliable and accurate tool in identifying metastatic nodes. LN metastasis is associated with ETE and multifocality. Suspicious subcentimeter nodules should undergo FNA irrespective of size when multifocality is suspected.

Papillary thyroid microcarcinomas that metastasize to lymph nodes

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

Can ratio of the biggest tumor diameter to total tumor diameter be a new parameter in the differential diagnosis of agressive and favorable multifocal papillary thyroid microcarcinoma?

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.

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.

SEVERE MAJOR ORGAN INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS: Diagnosis and Management

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.

Active surveillance (AS) is an alternative treatment approach for small, low-risk papillary thyroid microcarcinoma (PTMC). This study aimed to assess the clinical outcomes of small, highly suspicious nodules lacking initial cytological confirmation. This study included 112 patients with highly suspicious nodules measuring ≤ 10 mm who underwent serial ultrasound at Asan Medical Center, Korea, between 2010 and 2023. The median participant age was 51.9 years, and 74.1% were female. The median maximal tumor diameter and tumor volume (TV) were 4.5 (interquartile range [IQR] 3.7-5.2, range 2.2-9.3) mm and 25.2 (IQR 13.1-49.2) mm3, respectively. During a median follow-up period of 4.8 years, four (3.6%) patients showed a ≥ 3 mm increase in maximal diameter, and two (1.8%) developed new lymph node (LN) metastasis. Disease progression was associated with a TV doubling time (TVDT) of < 5 years and a ≥ 75% increase in TV (p = 0.017 and p < 0.005, respectively). Furthermore, 34.8% of patients underwent fine needle aspiration (FNA), primarily at their own request, yielding 46.2%, 5.1%, 41.0%, and 12.8 % malignant, benign, indeterminate, and non-diagnostic results, respectively. Of 18 patients with PTMC, 8 (44.4%) underwent surgery and 10 continued AS, with no LN metastasis during AS and no postoperative recurrence. Small, highly suspicious nodules had a low disease progression rate during AS without FNA. Disease progression was associated with a TVDT of < 5 years and a ≥ 75% increase in TV. FNA can be performed more conservatively than it currently is in patients with highly suspicious nodules measuring ≤ 10 mm.

The elevation for lateral lymph node metastasis (LLNM) plays an important role in therapeutic decision-making for thyroid carcinoma. A reliable forecasting model for LLNM in patients with papillary thyroid micro-carcinoma (PTMC) is needed, using clinicopathological characteristics. A total of 576 PTMC patients with suspicious lateral cervical lymph node (II, III, IV or V region) metastasis and known clinicopathological variables were randomly collected at Shenzhen Second People's Hospital. Cervical lymph node status of every patient was assessed by ultrasonography (US). The patients in this cohort study underwent thyroidectomy and lateral neck lymph node dissection. Univariate analysis and logistic regression analysis were performed to screen out the predictive variables associated with LLNM, and a nomogram was constructed by integrating clinicopathological features collected in our study. The overall LLNM rate was 23.0% (133/576). After statistical analysis, central lymph node metastasis (CLNM), prelaryngeal lymph node metastasis (PLNM), bilateral lesions, tumor location in thyroid (upper or lower), and gross extrathyroidal extension (ETE) were found to be independent predictive factors for LLNM (P < 0.01). The nomogram built to predict LLNM in PTMC patients passed the calibration step and the area under the receiver operating characteristic curve was 0.967, which showed that the nomogram we used had a good predictive effect. The nomogram constructed in this study has a good predictive value for LLNM, which will help thyroid surgeons to make a more accurate surgical plan for patients with PTMC. A strict preoperative evaluation and total thyroidectomy and lateral neck dissection may be indicated when patients with PTMC have a high score.

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.

Papillary thyroid microcarcinoma (PTMC) typically has an indolent course and excellent prognosis. Nonetheless, a subset of PTMC carries a risk of lymph node metastasis (LNM) and local recurrence. PTC from the Middle Eastern population is unique with respect to demographic and clinico-pathological characteristics as compared to other ethnicities of the world. The risk factors of LNM in PTMC patients of Middle Eastern ethnicity have not been fully explored. The present study aims to investigate the influencing factors of LNM in Middle Eastern PTMC patients and its predictive impact on patient’s outcome. A total of 226 confirmed PTMC cases were selected in this retrospective study. The correlation between clinico-pathological, as well as molecular, characteristics and LNM was evaluated. Multivariate analysis was performed by logistic regression and Cox proportional hazards models. Among the 226 patients, the rate of LNM was 43.8% (99/226). Bilaterality, multifocality, gross extrathyroidal extension (ETE), and intermediate-to-high American Thyroid Association (ATA) risk tumors were significantly associated with LNM in PTMC. Multivariate logistic regression analysis showed that bilaterality and gross ETE were independent predictive factors for LNM in PTMC. The recurrence-free survival (RFS) was shorter in PTMC with LNM compared to those without LNM (p = 0.0051) and was significant on multivariate analysis. In conclusion, our study showed that bilaterality and gross ETE were independent influencing factors of LNM in Saudi patients with PTMC. LNM was also associated with shorter RFS. The identification of risk factors for LNM in patients of Middle Eastern ethnicity could help the individualization of clinical management for PTMC patients.

Purpose: Despite the overall excellent prognosis for patients with papillary thyroid microcarcinoma (PTMC), these tumors are also associated with a 5% relatively high lymph node (LN) recurrence rate and the optimal surgical extent of papillary thyroid microcarcinoma has been controversial. Cervical LN metastases (LNMs) are found in about 40∼65% of patients with PTMC. The aim of this study is to identify the factors affecting lymph node metastases (LNMs) in patients with PTMC. Methods: We performed a retrospective study of 335 patients with PTMC who underwent total thyroidectomy or lobectomy with elective central lymph node dissection (CLND) at Kangnam St. Mary’s Hospital between Jan. 2006 and Dec. 2008. We investigated the association of LNMs and clinicopathologic factors such as sex, age, multiplicity, extrathyroidal extension, and tumor size. Results: LNMs were present in 88 patients (26.3%). Univariate analysis showed that less than 45 years of age, male, multiplicity, a tumor size of greater than 5 mm, thyroid capsular invasion and extrathyroidal extension were predictive factors for LNMs (P＜0.05). Of these, the age, male, tumor size and extrathyroidal extension were independent predictive factors for LNMs on multivariate analysis. Conclusion: A tumor size (＞5 ㎜), male, age (＜45) and extrathyroidal extension were determined as the predictive factors for LNMs, which occurred in about one fourth of the patients with PTMC. Therefore, elective CLND should be considered in patients with PTMC who have these factors through a thorough investigation before surgery.

Clinical and pathologic predictors of lymph node metastasis in papillary thyroid microcarcinomas