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

Abstract

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.

A critical analysis of the current TNM classification for differentiated thyroid carcinoma in young patients: Time for a change?

“…Gross ETE was recognized as a variable that negatively affects prognosis in DTC, and whether microscopic ETE significantly increases the risk of recurrence and overall mortality remains controversial ( 33 – 35 ). A recent study has reported that microscopic ETE was an independent predictor of recurrence-free survival and significantly associated with poor survival ( 36 ). Another study reached the opposite conclusion that microscopic ETE had no effect on the risk of death or recurrence ( 37 ).…”

Prognostic Impact of Microscopic Extra-Thyroidal Extension (mETE) on Disease Free Survival in Patients with Papillary Thyroid Carcinoma (PTC)

“…Jingzhe Xiang et al found that mETE was significantly associated with poorer outcome on cancer-specific survival [ 14 ]. Parvathareddy et al analyzed a cohort of 1430 patients and suggested that m-ETE is an independent marker for poor recurrence-free-survival (RFS) [ 15 ]. On the contrary, Nixon et al [ 16 ] studied 984 patients and found no significant difference in 10-year disease-specific survival or RFS between the two groups.…”

“…Indeed, other factors than mETE can affect DFS and especially the presence of LNI, which is a recognized factor of recurrence [ 19 ]. In his recent study, Parvathareddy et al found that mETE was associated with LNI at the beginning of the disease, but also with distant metastasis [ 15 ]. However, despite the difference in the rate of patients with LNI between the two groups, mETE kept its own prognostic impact on DFS after adjustment on the other prognostic variables, as well as in our study.…”

“…Prospective studies should be realized to bring a definite answer to this problem and should address the question of the optimal treatment of these patients, especially regarding the post-operative radioiodine administration. It could be interesting to proceed to other studies taking molecular markers into account, in order to estimate if mETE remains associated with prognosis in models including molecular markers, such as BRAF V600E or TERT promoter mutations [ 15 , 31 ]. In such situations, oncogenic alterations may help in tailoring treatment decision making.…”

Development of a Risk Predictive Model for Evaluating Immune Infiltration Status in Invasive Thyroid Carcinoma

“…Extrathyroidal extension of thyroid carcinoma has been demonstrated to show an adverse impact on the prognosis of patients [25]. In this study, we first investigated the genes and pathways that dysregulated in invasive thyroid carcinoma based on the data in the TCGA database (thyroid carcinoma samples with extrathyroid carcinoma present extension status ≥ T3).…”