Microscopic Extrathyroidal Extension Results in Increased Rate of Tumor Recurrence and Is an Independent Predictor of Patient’s Outcome in Middle Eastern Papillary Thyroid Carcinoma

BackgroundPapillary Thyroid Cancer (PTC) is the most common endocrine malignancy, with recurrence rate as high as 30%. A great deal of controversy surrounds the significance of microscopic extrathyroidal extension (m-ETE) as a prognostic factor. The most recent edition (8th) of American Joint Committee on Cancer (AJCC) staging system has removed m-ETE from the definition of pT3, which suggests that m-ETE may lack prognostic impact in PTC patients. Moreover, data about m-ETE prevalence and clinical impact on Middle Eastern PTC remains unknown. We therefore investigate the prevalence of m-ETE and its clinico-pathological correlation and prognostic impact in Middle Eastern PTC. We also compared the AJCC 7th and 8th staging systems and their prognostic performance.MethodsPTCs from 1430 consecutive adult (> 18 years) patients from single tertiary care hospital were included in this study. A retrospective analysis of PTC patients’ survival and recurrence were compared between AJCC 8th and AJCC 7th staging systems using Proportion of Variation Explained (PVE) and Harrell’s C-index.ResultsMedian follow up of the study cohort was 9.3 years. 31.2% (446/1430) of patients had m-ETE. In the overall cohort, m-ETE was associated with multiple adverse features such as older age (p < 0.0001), male sex (p = 0.0245), tall cell variant (p < 0.0001), bilateral tumors (p < 0.0001), multifocality (p < 0.0001), lymphovascular invasion (p < 0.0001), lymph node metastasis (p < 0.0001), distant metastasis (p = 0.0166), tumor recurrence (p < 0.0001), radioactive iodine refractoriness (p < 0.0001), BRAF mutation (p < 0.0001) and reduced recurrence-free survival (RFS; HR = 1.75; 95% CI = 1.30 – 2.35; p < 0.0001) irrespective of tumor size. Of the 611 patients with T3 disease based on AJCC 7th edition, 359 (58.8%) were down-staged in AJCC 8th edition classification. Overall, the prognostic performance of AJCC 8th edition was inferior to AJCC 7th on the basis of lower PVE (3.04% vs. 3.73%) and lower C-index (0.40 vs. 0.48).ConclusionsIn Middle Eastern PTC, m-ETE is significantly associated with compromised survival and acts as an independent predictor of RFS. Given these findings, m-ETE should be included in the thyroid cancer treatment guidelines.

The Prediction of Metastases of Lateral Cervical Lymph Node in Medullary Thyroid Carcinoma

PurposeDevelopment and validation of a nomogram for the prediction of lateral lymph node metastasis (LLNM) in medullary thyroid carcinoma (MTC).MethodsWe retrospectively reviewed the clinical features of patients with MTC in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017 and in our Department of Surgical Oncology, Hangzhou First People’s Hospital between 2009 and 2019. The log‐rank test was used to compare the difference in the Kaplan–Meier (K–M) curves in recurrence and survival. The nomogram was developed to predict the risk of LLNM in MTC patients. The prediction efficiency of the predictive model was assessed by area under the curve (AUC) and concordance index (C-index) and calibration curves. Decision curve analysis (DCA) was performed to determine the clinic value of the predictive model.ResultA total of 714 patients in the SEER database and 35 patients in our department were enrolled in our study. Patients with LLNM had worse recurrence rate and cancer-specific survival (CSS) compared with patients without LLNM. Five clinical characteristics including sex, tumor size, multifocality, extrathyroidal extension, and distant metastasis were identified to be associated with LLNM in MTC patients, which were used to develop a nomogram. Our prediction model had satisfied discrimination with a C-index of 0.825, supported by both training set and internal testing set with a C-index of 0.825, and 0.816, respectively. DCA was further made to evaluate the clinical utility of this nomogram for predicting LLNM.ConclusionsMale sex, tumor size >38mm, multifocality, extrathyroidal extension, and distant metastasis in MTC patients were significant risk factors for predicting LLNM.

Preoperative Ultrasonography in the Evaluation of Suspected Familial Non-Medullary Thyroid Cancer: Are We Able to Predict Multifocality and Extrathyroidal Extension?

Family history of thyroid cancer increases the risk of harboring thyroid malignancies that end up having extrathyroidal extension (ETE) and multifocality on histology; some authors suggest a more aggressive surgical approach. Their pre-operative identification could allow more conservative surgical procedures if none of these features are suspected. Our aim was to assess if neck ultrasonography could identify or exclude multifocality or ETE in these patients to tailor the extent of surgery. This retrospective study included patients with previous thyroid surgery, ≥1 first-grade relative with thyroid cancer, and who had undergone pre-surgical ultrasound. ETE was suspected in the case of thyroid border interruption or gross invasion of perithyroidal tissues. Multiple suspicious nodules were defined as suspicion of multifocal cancer. The cohort consisted of 45 patients (median age 49 years, 40 with thyroid cancer, 30 females). The positive predictive value of ultrasonography in predicting multifocality and ETE was 57.14% (25.25–84.03) and 41.67% (21.5–65.1%), respectively, while the negative predictive values were 63.2% (56.4–69.4%) and 72.7% (63.3–80.5%). Pre-operative ultrasound examination is unable to reliably identify or exclude multifocal disease or extrathyroidal extension. In patients scheduled for surgery and with a first-degree relative affected by DTC, a “negative” pre-operative US report does not exclude the potential finding of multifocality and ETE at final histopathology.

High Incidence of Distant Metastasis Is Associated With Histopathological Subtype of Pediatric Papillary Thyroid Cancer - a Retrospective Analysis Based on SEER

ObjectiveChildren with papillary thyroid cancer (PTC) have a higher invasive rate and distant metastasis rate, but the mortality rate is lower with unknown reasons. The majority of PTC cases comprise classical papillary thyroid carcinoma (CPTC) and follicular variant papillary thyroid carcinoma (FVPTC). This study aimed to determine the relationship between histopathological subtype and rate of distant metastasis and investigate factors influencing distant metastasis in pediatric PTC.MethodsA total of 102,981 PTC patients were recruited from SEER registry, 2004-2015. Proportion of distant metastasis between children (≤18 years) and adults with different histopathological subtypes was compared by propensity score matching. The cut-off age for distant metastasis in children was calculated by receiver operating characteristic (ROC) curve, and the risk factors for distant metastasis in pediatric patients were analyzed by logistic regression models.ResultsAmong the 1,484 children and 101,497 adults included in the study, the incidence of CPTC patients with distant metastasis in children was higher than that in adults (p<0.001). The ROC curve was calculated, which yielded a cut-off age for distant metastasis in CPTC children as 16 years old. In CPTC, the proportion of young children (2-16 years) with distant metastasis was higher than that of adolescents (17-18 years) and adults (>18 years) (both p<0.001). While there was no such trend in FVPTC. In young children (2-16 years), the incidence of CPTC with distant metastasis was higher than FVPTC (p=0.006). There was no difference between the proportion of CPTC and FVPTC with distant metastasis in adolescents (17-18 years) and adults. Logistic regression models revealed that extrathyroidal extension, lymph node metastasis and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2 -16 years.ConclusionsIn CPTC, the incidence of distant metastasis in young children (2-16 years) was significantly higher than that in adolescents (17-18 years) and adults (>18 years). In patients with distant metastasis aged 2-16 years, the proportion of CPTC was higer than that of FVPTC. Extrathyroidal extension, lymph node metastasis, and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2-16 years.

Extranodal Extension Is an Independent Prognostic Factor in Papillary Thyroid Cancer: A Propensity Score Matching Analysis

PurposeTo investigate the prognostic significance of extranodal extension (ENE) in papillary thyroid cancer (PTC).MethodsSeven hundred forty-three PTC patients were enrolled in the study from January 2014 to December 2017. The patients were dichotomized according to the presence of ENE. Logistic analysis was used to compare differences between the two groups. Kaplan–Meier (K-M) curve and propensity score matching (PSM) analyses were used for recurrence-free survival (RFS) comparisons. Cox regression was performed to analyze the effects of ENE on RFS in PTC.ResultsThirty-four patients (4.58%) had ENE. Univariate analysis showed that age, tumor size, extrathyroidal extension, and nodal stage were associated with ENE. Further logistic regression analysis showed that age, extrathyroidal extension, and nodal stage remained statistically significant. Evaluation of K-M curves showed a statistically significant difference between the two groups before and after PSM. Cox regression showed that tumor size and ENE were independent risk factors for RFS.ConclusionsAge ≥55 years, extrathyroidal extension, and lateral cervical lymph node metastasis were identified as independent risk factors for ENE. ENE is an independent prognostic factor in PTC.

Risk Factors for Large-Volume Lymph Node Metastasis in Papillary Thyroid Carcinoma: A Meta-Analysis

Background We defined large-volume lymph node metastasis (L-VLNM) as more than five lymph node metastases (LNMs) or any lymph node with a diameter of 2 mm or greater in any case of papillary thyroid cancer (PTC). This study investigated risk factors for the development of L-VLNM in PTC with meta-analysis.Methods Articles published until July 2021 on clinicopathological factors of L-VLNM in PTC were searched in electronic databases (PubMed, Web of Science (WOS), Embase, Cochrane, Wanfang Data and Chinese National Knowledge Infrastructure (CNKI)) to identify studies based on predefined criteria. Statistical analysis was performed using STATA 14.0. The outcomes were clinical and pathologic factors for L-VLNM, and the individual and pooled odds ratios (ORs) with 95% confidence intervals (CIs) of each outcome were analysed by fixed-/random-effects models. Egger’s test was used to assess publication bias in the publications. This study is registered with PROSPERO (CRD 42020213831).Results Twelve studies included 10806 patients in total. Meta-analysis revealed that an increased risk of L-VLNM was associated with male sex (OR=2.20, 95% CI=1.63–2.97, P<0.001), age<45 years (OR=2.34, 95% CI=1.36–4.02, P<0.001), tumour diameter>1 cm (OR=3.99, 95% CI=3.45–4.62, P<0.001), extrathyroidal extension (OR=2.42, 95% CI=1.90–2.82, P<0.001), capsule invasion (OR=3.62, 95% CI=1.44–9.06, P<0.001) and multifocality (OR=2.02, 95% CI=1.47–2.77, P<0.001). Hashimoto’s thyroiditis (HT; OR=0.82, 95% CI=0.60–1.11, P=0.03) was not associated with L-VLNM.Conclusions Male sex, age <45 years, tumour diameter >1 cm, extrathyroidal extension, capsule invasion and multifocality were risk factors for L-VLNM, HT was not a risk factor.

Preoperative serum inflammation-based scores in medullary thyroid cancer

Introduction: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) are prognostic factors in several tumours, however little is known in medullary thyroid cancer (MTC). Objective: To evaluate the association between preoperative NLR, PLR and SII with MTC clinicopathological and molecular features, and their predictive value for lymph-node and distant metastasis. Methods: We retrospectively analysed 75 patients with MTC who underwent surgery at our institution. Results: In our cohort, 56% were females, the median age at diagnosis was 57 years (44–69), the median tumour diameter was 25mm (15–50); 21.3% were multifocal and 34.7% had extrathyroidal extension. Fibrosis was present in 30 of the 37 analysed samples; RET somatic status was assessed in 35 cases and 21 harboured a mutation. Lymph-node and distant metastasis were observed in 36 (48.0%) and 8 (10.7%), respectively. Higher NLR was associated with preoperative calcitonin, angioinvasion, extrathyroidal extension, moderate/severe fibrosis; higher PLR was associated to extrathyroidal extension and advanced T stages; lower SII and NLR were associated with biochemical cure after surgery. Increased PLR, NLR and SII were associated with advanced MTC stages. In the univariate analysis, only NLR was associated with lymph-node metastasis (odds ratio (OR) = 2.69, 95% confidence interval (CI): 1.50–5.84; p = 0.004); however, in the multivariate model, NLR was no longer a predictive factor for lymph-node metastasis. Conclusion: None of these serum inflammatory markers predicted the occurrence of distant metastasis. In conclusion, NLR, PLR and SII may indicate aggressive MTC disease, but do not predict lymph-node or distant metastasis.