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Objective: Tumor location in papillary thyroid microcarcinoma (PTMC) might determine tumor outgrowth from the thyroid gland. However, the clinical implications of tumor location and minimal extrathyroid extension (mETE) have not been well elucidated. We aimed to investigate the relationship between tumor location and mETE to predict the aggressiveness of PTMC. Methods: A total of 858 patients with PTMC were grouped according to tumor location on ultrasonography: central (cPTMC) and peripheral PTMC (pPTMC). PTMC without mETE (PTMC-mETE(−)) was divided further according to margin shape: encapsulated (E−) or infiltrative (I−). To understand the molecular biologic characteristics of PTMC presenting with an I-margin and mETE, transcriptome data from TCGA-THCA were analyzed using Gene Set Enrichment Analysis (GSEA). Results: pPTMC (n = 807, 94.1%) accounted for the majority of cases; mETE was identified only in pPTMC (403/807; 49.9%). pPTMC-mETE(+) showed aggressive clinical characteristics that increased the odds ratio (OR) for lymph node metastasis (LNM). Interestingly, subgroup analysis of PTMC-mETE(−) revealed that the I-margin also increased the OR for LNM, independent of other clinical factors. GSEA of TCGA-THCA data suggested coordinated upregulation of genes related to epithelial-mesenchymal transition (EMT) in PTC with mETE. Immunohistochemical staining for laminin subunit gamma 2 (LAMC2), CD59, E-cadherin and vimentin showed that these markers of EMT were associated with progressive changes in E-margin PTMC-mETE(−), I-margin PTMC-mETE(−) and pPTMC-mETE(+). Conclusion: mETE related to peripheral location of PTMC is an important predictor of tumor invasiveness, as is the I-margin, which presents with EMT features similar to mETE. I-margin PTMC-mETE(−) and pPTMC-mETE(+) might reflect the pattern of invasive PTMC. [ABSTRACT FROM AUTHOR]

Objective: The genetic mutations causing the constitutive activation of MEK/ERK have been regarded as an initiating factor in papillary thyroid carcinoma (PTC). The ERK-specific dual specificity phosphatase 6 (DUSP6) is part of the ERK-dependent transcriptional output. Therefore, the coordinated regulation of the activities of ERK kinases and DUSP6 may need to be reestablished to make new balances in PTC. Methods: To investigate the role of DUSP6 in the regulation of ERK1/2 (MAPK3/1)-dependent transcription, 42 benign neoplasms and 167 PTCs were retrospectively analyzed by immunohistochemistry with dideoxy sequencing to detect BRAFV600E mutation. Results: The expressions of total ERK1/2, DUSP6, c-Fos (FOS), c-Myc (MYC), cyclin D1, and PCNAwere markedly increased in PTC compared with those in benign neoplasms. However, phospho-ERK1/2 was detected in only eight (4.8%) cases out of 167 PTC samples. Unexpectedly, the staining intensity and nuclear localization of ERK1/2 were not affected by the presence or absence of the BRAFV600E mutation. However, the expressions of c-Fos and PCNA were elevated in BRAFV600E-positive PTC compared with those in BRAFV600E-negative PTC. Interestingly, the higher staining intensities of DUSP6 were associated with the level of total ERK1/2 expression (PZ0.04) and with high-risk biological features such as age (PZ0.05), tumor size (PZ0.01), and extrathyroidal extension (linear by linear association, PZ0.02). In addition, DUSP6 silencing significantly decreased the cell viability and migration rate of FRO cells. Conclusions: The coordinated upregulation of total ERK1/2 and its phosphatase, DUSP6, is related to bare detection of phospho-ERK1/2 in PTC regardless of BRAFV600E mutation status. A link between DUSP6 expression and high-risk features of PTC suggested that DUSP6 is an important independent factor affecting the signaling pathways in established PTC. [ABSTRACT FROM AUTHOR]