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.

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Annual Hazard Rate of Recurrence in Middle Eastern Papillary Thyroid Cancer over a Long-Term Follow-Up

Cancers ◽

10.3390/cancers12123624 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3624

Author(s):

Abdul K. Siraj ◽

Sandeep Kumar Parvathareddy ◽

Zeeshan Qadri ◽

Khawar Siddiqui ◽

Saif S. Al-Sobhi ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Hazard Rate ◽

Tumor Recurrence ◽

Cox Regression ◽

Middle Eastern ◽

Treatment Strategies ◽

Recurrence Risk ◽

Papillary Thyroid ◽

Cox Regression Analysis

Predicting the pattern of recurrence in papillary thyroid cancer (PTC) is necessary to establish optimal surveillance and treatment strategies. We analyzed changes in hazard rate (HR) for tumor recurrence over time in 1201 unselected Middle Eastern PTC patients. The changes in risk were further analyzed according to clinical variables predictive of early (≤5 years) and late (>5 years) recurrence using Cox regression analysis to identify patient populations that remain at risk. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 and 2 years (3.7%), with a second smaller peak between 13 and 14 years (3.2%). Patients receiving radioactive iodine (RAI) therapy had lower recurrence hazard compared to those who did not (1.5% vs. 2.7%, p = 0.0001). Importantly, this difference was significant even in intermediate-risk PTC patients (0.7% vs. 2.3%; p = 0.0001). Interestingly, patients aged ≥55 years and having lymph node metastasis were at persistent risk for late recurrence. In conclusion, we confirmed the validity of the double-peaked time-varying pattern for recurrence risk in Middle Eastern PTC patients and our findings could help in formulating individualized treatment and surveillance plans.

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Telomerase reverse transcriptase mutations are independent predictor of disease-free survival in Middle Eastern papillary thyroid cancer

International Journal of Cancer ◽

10.1002/ijc.31225 ◽

2017 ◽

Vol 142 (10) ◽

pp. 2028-2039 ◽

Cited By ~ 21

Author(s):

Rong Bu ◽

Abdul K. Siraj ◽

Sasidharan Padmaja Divya ◽

Yan Kong ◽

Sandeep Kumar Parvathareddy ◽

...

Keyword(s):

Thyroid Cancer ◽

Reverse Transcriptase ◽

Papillary Thyroid Cancer ◽

Independent Predictor ◽

Middle Eastern ◽

Disease Free Survival ◽

Telomerase Reverse Transcriptase ◽

Papillary Thyroid ◽

Free Survival ◽

Disease Free

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Loss of ZNF677 Expression Is an Independent Predictor for Distant Metastasis in Middle Eastern Papillary Thyroid Carcinoma Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22157833 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7833

Author(s):

Abdul K. Siraj ◽

Pratheesh Kumar Poyil ◽

Sandeep Kumar Parvathareddy ◽

Khadija Alobaisi ◽

Saeeda O. Ahmed ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Distant Metastasis ◽

Zinc Finger Protein ◽

Independent Predictor ◽

Middle Eastern ◽

Distant Metastases ◽

Papillary Thyroid ◽

Finger Protein

Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, the identification of targetable biomarkers in this subset of patients is of great importance. Accumulating evidence indicates that zinc finger protein 677 (ZNF677), which belongs to the zinc finger protein family, is an important effector during the progression of multiple malignancies. However, its role in Middle Eastern PTC patients has not been fully illustrated. Here, we uncovered the molecular mechanism and the clinical impact of ZNF677 expression in a large cohort of more than 1200 Middle Eastern PTC and 15 metastatic tissues. We demonstrated that ZNF677 is frequently downregulated in primary PTC (13.6%, 168/1235) and showed that complete loss of expression of ZNF677 is significantly associated with aggressive clinico-pathological markers such as extrathyroidal extension (p = 0.0008) and distant metastases (p < 0.0001). We also found a significantly higher incidence of ZNF677 loss in primary tumors with distant metastases (33.3%; p < 0.0001) as well as in distant metastatic tissues (46.7%; p = 0.0002) compared to the overall cohort (13.6%). More importantly, PTC with loss of ZNF677 expression showed significantly lower metastasis-free survival (p = 0.0090). Interestingly, on multivariate logistic regression analysis, ZNF677 loss was an independent predictor of distant metastasis in PTC (Odds ratio = 2.60, 95% Confidence interval = 1.20–5.62, p = 0.0155). In addition, we found a significant association between ZNF677 loss and phospho-AKT expression (p < 0.0001). Our functional molecular results suggest that ZNF677 acts as a tumor suppressor, mediating its effect by inhibiting AKT phosphorylation. Taken together, our results highlight the pivotal role played by ZNF677 during carcinogenesis and metastasis formation in Middle Eastern PTC patients.

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