Extensive lymphatic spread of papillary thyroid microcarcinoma is associated with an increase in expression of genes involved in epithelial-mesenchymal transition and cancer stem cell-like properties.
ABSTRACT: BACKGROUND:Active surveillance is an alternative management for patents with low-risk papillary thyroid microcarcinoma (PTMC); however, there is an absence of specific molecular markers that predict its progression. We compared gene expression patterns between PTMC with lateral neck-node metastasis (N1b) and PTMC-lacking nodal metastasis (N0). METHODS:We performed oligonucleotide microarray analysis in three PTMCs without cervical lymph-node metastases (N0), and five PTMCs with lateral neck-node metastasis (N1b) at initial diagnosis, using an Illumina HumanHT-12 v4.0 Expression BeadChip. Quantitative real-time PCR (qPCR) and western blot analysis confirmed microarray data. We performed immunohistochemistry (IHC) to confirm protein overexpression in samples from 20 N0 and 24 N1b PTMC patients who underwent thyroidectomy. RESULTS:Microarray analyses identified 52 probes corresponding to 45 genes. Expression of these genes differed significantly between the two PTMC groups. Forty genes were significantly upregulated and five genes were downregulated in N1b PTMC compared to N0. Four genes related to epithelial-to-mesenchymal transition (EMT) and stem cell markers, including ALDH1A3, TM4SF1, PROM1, and CAV1 were significantly upregulated in N1b PTMCs. Real-time qPCR confirmed this expression and western blot analysis confirmed higher expression of ALDH1A3, TM4SF1, PROM1, and CAV1 in N1b than in N0 PTMCs. IHC indicated overexpression of ALDH1A3 and CAV1 in N1b compared to N0 PTMCs. CONCLUSIONS:Genes related to EMT and thyroid cancer stem cell-like properties are upregulated in early extensive lymphatic spread of PTMC.
Project description:We performed oligonucleotide microarray analysis to assess the genetic expression alteration wich affected on lateral neck node metastasis of thyroid papillary microcarcinoma(PTMC). We performed microarray analysis in three PTMCs without cervical lymph-node metastases (N0), and five PTMCs with lateral neck-node metastasis (N1b) at initial diagnosis, using an Illumina HumanHT-12 v4.0 Expression BeadChip. Overall design: Total 16 samples (3 T1aN0 PTMC and 5 T1aN1b or T3N1b PTMC(papillary thyroid microcarcinoma) and its paired normal thyroid tissue) were used. We obtained thyroid tissues from eight PTMC patients who underwent thyroidectomy. We also obtained eight normal thyroid tissue specimens from the thyroid lobes of the same patients for pairwise analysis. Of eight PTMC, three did not have nodal involvement and extrathyroidal extension (T1aN0). The remaining patients had lateral neck-node metastasis at initial diagnosis (T1aN1b or T3N1b) and underwent modified radical neck dissection combined with thyroidectomy. Immediately after thyroidectomy, we obtained the three pairs of 0.2 × 0.2 × 0.2-cm cubes of both cancer and normal thyroid tissue from the surgeon; the samples were snap-frozen in liquid nitrogen at the operation theater and then stored at ˗80°C.
Project description:Background: Lateral lymph node metastasis (LLNM) is associated with distant metastasis, locoregional recurrence and cancer-specific mortality, although the prevalence of LLNM among patients with papillary thyroid microcarcinoma (PTMC) is relatively low. The potential benefits and risks of routine lateral level V dissection (LVD) for PTMC with LLNM have not been previously investigated. Methods: A total of 6,880 consecutive PTMC patients who underwent initial surgery at the First Hospital of Jilin University from January 2009 to July 2017 were retrospectively analyzed. A total of 252 N1b PTMC patients were enrolled in our study. Results: The overall and occult metastasis rates in level V lymph nodes were 21.4 and 6.4%, respectively. Patients with N1b PTMC who received LVD did not show a significantly lower disease-free survival (DFS) than that of patients who did not receive LVD [hazard ratio = 1.11 (CI 0.38-3.21); p = 0.85]. Meanwhile, LVD simultaneously increased the hospital stay and cost (p = 0.03; 0.02). Multivariate logistic regression analysis revealed that 3-level simultaneous metastasis in the lateral neck was an independent risk factor for level V metastasis [odds ratio = 8.6 (CI 1.42-51.72); p = 0.02]. Conclusions: Because of the low metastasis rate in level V lymph nodes, the lack of benefit for recurrence, the longer hospital stay and the higher cost associated with LVD, N1b PTMC patients without clinical level V metastasis may not need to undergo routine dissection. Prophylactic LVD may be recommended only for patients with N1b PTMC with 3-level simultaneous metastasis.
Project description:Lymph node metastases at the time of diagnosis have a major impact on both therapeutic strategy and tumor recurrence for patients with papillary thyroid microcarcinoma (PTMC). Our objective was to evaluate the usefulness of PTMC characteristics on ultrasonography for predicting central compartment lymph node metastases (CCLNM) of PTMC. One hundred twenty seven patients who underwent surgery for PTMC were enrolled in this study. The relationship between the CCLNM and the characteristics on conventional US, elastographic, and contrast enhanced ultrasound (CEUS) were investigated. Univariate analysis indicated that PTMCs with CCLNM were more often nodule irregular shape, microcalcifications, hyperenhancing or isoenhancing parametric maps, and peak index ≥1 at preoperative US and CEUS than those without CCLNM (P< 0.01, 0.05, 0.01 and 0.05 respectively). Multivariate analysis showed that microcalcification (OR:2.378, 95% CI: 1.096-5.158) and hyperenhancement or isoenhancement (OR:2.8, 95% CI: 1.287-6.094) were predictive for the presence of CCLNM. Elastography score was not significantly different between the groups. Our study indicated that preoperative thyroid nodule characteristics on conventional US and CEUS may serve as a useful tool to predict central compartment lymph node metastases in PTMC.
Project description:It is controversial as to whether papillary thyroid microcarcinoma (PTMC) has some genomic and transcriptomic characteristics that differentiate between an early-stage lesion that would eventually evolve into the larger papillary thyroid cancer (PTC), and an occult indolent cancer in itself. To investigate this, we comprehensively elucidated the genomic and transcriptomic landscapes of PTMCs of different sizes, using a large-scaled database. This study included 3435 PTCs, 1985 of which were PTMCs. We performed targeted next-generation sequencing for 221 PTCs and integrated these data with the data including The Cancer Genome Atlas (TCGA) project. The frequency of v-raf murine sarcoma viral oncogene homolog B (BRAF)V600E mutation was higher in PTMCs >0.5 cm than that in very small PTMCs (?0.5 cm) and decreased again in PTCs >2 cm. Among PTMCs, the prevalence of mutations in rat sarcoma (RAS) and telomerase reverse transcriptase (TERT) promoter was not significantly different according to their size, but lower than in large PTCs. There was no change in the tumor mutational burden, the number of driver mutations, and transcriptomic profiles with tumor size, among PTMCs and all PTCs. Although a few genes with differential expression and TERT promoter mutations were found in a few PTMCs, our findings showed that there were no useful genomic or transcriptomic characteristics for the prediction of the future progression of PTMC.
Project description: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.
Project description:The definitive diagnosis of minimal extrathyroid extension (ETE) is subjective because a well-defined true capsule is absent in the thyroid gland. We subclassified the extent of minimal ETE and investigated the clinicopathological significance of the presence of minimal ETE in patients with solitary papillary thyroid carcinomas (PTCs) and solitary papillary thyroid microcarcinomas (PTMCs).A series of 546 patients with solitary PTCs, including 144 patients with solitary PTMCs, were retrospectively analyzed. Whether the presence of minimal ETE had an effect on recurrence-free survival (RFS) along with other clinicopathological parameters was investigated.The only independent prognostic factor found to be associated with recurrence was the presence of LN metastasis in solitary PTC (p = 0.002) but not in solitary PTMC groups (p = 0.073). The presence of minimal ETE had no effect on RFS in both solitary PTC (p = 0.053) and solitary PTMC (p = 0.816).The presence of minimal ETE has no significant influence on RFS in solitary PTC and PTMC. There is a risk of overrepresenting the T3 category in solitary PTC and PTMC patients with minimal ETE.
Project description:To investigate the value of the annual follow-up neck ultrasonography (US) for postoperative surveillance in patients with papillary thyroid microcarcinoma (PTMC). This retrospective study has been approved by our institutional review board (IRB) with waiver for informed consent. A total of 375 patients diagnosed as PTMCs, who underwent total thyroidectomy with radioiodine remnant ablation were included, to identify the recurrence rate and the false-positive rate of annual ultrasound. The number, interval, and the results of follow-up US or fine needle aspiration were obtained from electronic medical records. Four (1.1%, 4/375) recurrences were found 3 years after the initial treatment, and only 1 patient (0.3%, 1/375) had a metastatic lymph node larger than 8 mm in the shortest diameter on US found 7.6 years after initial treatment with biochemical abnormalities. Cumulative risk of having at least 1 false-positive exam was 8.3% by the 8th US, and 8.1% by the 8-9 year follow-up. Cox multivariate regression showed shorter interval of follow-up US and presence of lymph node metastasis at initial surgery are independent predictors affecting the cumulative false-positive results (hazard ratio [HR], 0.60; 95% confidence interval [CI]: 0.49-0.73; P < 0.001 and HR, 2.19; 95% CI: 1.01-4.75; P = 0.048, respectively). Short-term follow-up US can result in higher cumulative false-positive results without detection of meaningful recurrences in patients with PTMCs who do not have biochemical abnormalities.
Project description:Active surveillance (AS) can be considered as a treatment strategy for low risk papillary thyroid microcarcinoma (PTMC), with the absence of clinically apparent lymph nodes, extrathyroidal extensions, and distant metastasis. After reviewing the reports on AS of low risk PTMCs worldwide, we introduced AS, and discussed the selection criteria for active surveillance candidates based on different guidelines and the follow-up schedules. Moreover, the requirement of cytological diagnosis, progression evaluation methods, necessity of thyrotropin suppression, and medical costs were issues that both clinicians and patients considered. The usefulness of AS for low risk PTMC patients depended on accurate and confidential evaluation of patient risk. Clinicians may adopt measures like dynamic monitoring, risk stratification, and making personal follow-up schedules to minimize these potential risks. By appropriately selecting PTMC patients, AS can be an effective alternative treatment to immediate surgery.
Project description:Background:To evaluate the efficacy of the nodal descriptors and subgroups proposed by International Association for the Study of Lung Cancer (IASLC) in the 8th edition of the TNM classification system and to provide references for future editions. Methods:A total of 3,177 patients with non-small cell lung cancer at the Beijing Cancer Hospital were classified based on the following three methods: (I) the N descriptors in the 8th edition of the TNM classification system: N0, N1, N2, and N3; (II) the IASLC-proposed N subgroups: N1a, N1b, N2a1, N2a2, and N2b; (III) our more extensive division method: N1a, N1b, N1c, N2a1, N2a2, N2b1, N2b2, N2c, N3a, and N3b. Five-year survival analysis was performed using the Kaplan-Meier method, and differences between subgroups were evaluated using the log-rank test. Results:(I) A significant survival difference was found between each adjacent N descriptor; (II) the difference between each adjacent subgroup N descriptor was significant, but the difference between N1b and N2a1 was not; (III) in our proposed method, a significant difference was found between all the subgroups apart from N2a2 and N2b1, N2b1 and N2b2, N2c and N3a, and N3a and N3b. Conclusions:The N descriptors in the 8th edition of the tumor, node, and metastasis (TNM) classification system are consistent with our data. Although our more extensive division method could distinguish between patients at different stages, its implementation is complicated; thus, we recommend the implementation of the IASLC-proposed subgroups with the addition of the N1b and N2a1 groups.
Project description:BACKGROUND:To identify the sonographic features that help to differentiate medullary thyroid microcarcinomas (MTMCs) from papillary thyroid microcarcinomas (PTMCs). METHODS:A total of 46 MTMCs in 41 patients and 136 PTMCs in 104 patients that were proven by surgery and pathology were included in the study. Patient age and nodule size were analyzed by independent sample t-tests, and sex, multiplicity and cervical lymph node metastases were analyzed by ?2 or Fisher's exact tests. Univariate analysis and multivariate logistic regression analysis were performed on the sonographic features of thyroid nodules, including location, shape, boundary, margin, peripheral halo ring, echogenicity, composition, calcifications and vascularization. RESULTS:Compared with the corresponding number of patients with PTMCs, more MTMC patients had cervical lymph node metastases (P?=?0.040). There were no significant differences in age, sex, nodule size, multiplicity, location, boundary, margin, peripheral halo ring, echogenicity or microcalcifications between MTMCs and PTMCs (P?>?0.05 for all). However, significant differences were found in shape (P?=?0.000), composition (P?=?0.032), macrocalcifications (P?=?0.004) and vascularity (P?=?0.000) between the two groups. CONCLUSIONS:There were some overlapping sonographic features between MTMCs and PTMCs. However, MTMCs tended to have a?>?50% solid composition, be ovoid to round nodules with macrocalcifications and be hypervascular. Cervical lymph node metastases were more common in MTMC patients.