Papillary Thyroid Cancer Disease Research Articles

Minimal residual disease assessment of papillary thyroid carcinoma through circulating tumor cell-based cytology.

The overall estimated risk of recurrence after an apparently complete thyroid cancer resection ranges from <1% to 55%, and the high-quality pathology report is crucial for proper risk stratification. The neck ultrasound (US) and serum thyroglobulin (Tg) and anti-Tg antibody (TgAb) assays are the mainstays for Differentiated Thyroid Cancer (DTC) follow-up. However, the neck US includes a high frequency of nonspecific findings and despite the serum, Tg unmasks the presence of thyrocytes, it is not discriminating between normal and malignant cells. In this study, to improve post-surgery follow-up of minimal residual disease in papillary thyroid cancer (PTC) patients, blood-derived cytology specimens were evaluated for the presence of circulating tumor cells (CTCs). The presence of CTCs of thyroid origin was confirmed by cytomorphological and tissue-specific antigens analysis (Thyroid Transcription Factor-1/TTF-1 and Tg) and proliferative profile (percentage of cells in S-phase). Our data revealed an unfavorable' prognostic risk in patients with >5% CTCs (p=0.09) and with >30% S-phase cells at baseline (p=0.0015), predicting ≤1year relapsing lesion event. These results suggest a new intriguing frontier of precision oncology forefront cytology-based liquid biopsy.

Hispanic Race Is an Independent Predictor for Increased Rates of Nodal Disease in Papillary Thyroid Cancer (PTC)

Hispanic Race Is an Independent Predictor for Increased Rates of Nodal Disease in Papillary Thyroid Cancer (PTC)

Association Between Age and Nodal Metastasis in Papillary Thyroid Carcinoma.

To determine the relationship between age and rate of lymph node metastasis, nodal burden of disease, as well as rate of lateral neck disease in papillary thyroid cancer, especially in patients aged <30 years. Population-based cross-sectional study. Population-based cancer database. Data were extracted from the SEER 18 database (Surveillance, Epidemiology, and End Results) of the National Cancer Institute. The study cohort included 59,330 patients diagnosed with papillary thyroid cancer between 1988 and 2015. Patients aged 0 to 10 years, 11 to 20 years, and 21 to 30 years old were compared with those >30 years. All analyses were adjusted for sex, race, and T classification. The overall rate of lymph node metastasis was 26.11%, which increased with decreasing age. Adjusted odds ratios of lymph node metastasis were 7.19 (95% CI, 3.76-13.75) for the 0- to 10-year-old group, 3.45 (95% CI, 3.08-3.87) for the 11- to 20-year-old group, and 2.28 (95% CI, 2.15-2.41) for the 21- to 30-year-old group, relative to the group >30 years old. Decreased age was also associated with increased total positive nodes, increased lymph node ratio, and increased risk of lateral neck disease. Pediatric and early young adult patients with papillary thyroid carcinoma have a greater risk of lymph node metastasis, greater burden of nodal disease, and a greater risk of lateral neck metastases.

Molecular imaging of platelet-derived growth factor receptor-alpha (PDGFRα) in papillary thyroid cancer using immuno-PET

IntroductionReceptor tyrosine kinase (RTK) platelet-derived growth factor receptor-alpha (PDGFRα) was recently identified as a molecular switch for dedifferentiation in thyroid cancer that predicts resistance to therapy as well as recurrence of disease in papillary thyroid cancer. Here we describe the radiolabeling and functional characterization of an imaging probe based on a PDGFRα-specific monoclonal antibody (mAb) for immuno-PET imaging of PDGFRα in papillary thyroid cancer. MethodsAntibody D13C6 (Cell Signaling) was decorated with chelator NOTA using bioconjugation reaction with 2-(p-NCS-Bz)-NOTA. Radiolabeling was carried out using 40 μg of antibody-NOTA conjugate with 143–223 MBq of [64Cu]CuCl2 in 0.25 M NaOAc (pH 5.5) at 30 °C for 1 h. The reaction mixture was purified with size-exclusion chromatography (PD-10 column). PDGFRα and mock transfected B-CPAP thyroid cancer cells lines for validation of 64Cu-labeled immuno-conjugates were generated using LVX-Tet-On technology. PET imaging was performed in NSG mice bearing bilaterally-induced PDGFRα (+/−) B-CPAP tumors. ResultsBioconjugation of NOTA chelator to monoclonal antibody D13C6 resulted in 2.8 ± 1.3 chelator molecules per antibody as determined by radiometric titration with 64Cu. [64Cu]Cu-NOTA-D13C6 was isolated in high radiochemical purity (>98%) and good radiochemical yields (19–61%). The specific activity was 0.9–5.1 MBq/μg. Cellular uptake studies revealed a specific radiotracer uptake in PDGFRα expressing cells compared to control cells. PET imaging resulted in SUVmean values of ~5.5 for PDGFRα (+) and ~2 for PDGFRα (−) tumors, after 48 h p.i.. After 1 h, radiotracer uptake was also observed in the bone marrow (SUVmean ~5) and spleen (SUVmean ~8.5). ConclusionRadiolabeled antibody [64Cu]Cu-NOTA-D13C6 represents a novel and promising radiotracer for immuno-PET imaging of PDGFRα in metastatic papillary thyroid cancer. Advances in knowledge and implications for patient careThe presented work has the potential to allow physicians to identify papillary thyroid cancer patients at risk of metastases by using the novel immuno-PET imaging assay based on PDGFRα-targeting antibody [64Cu]Cu-NOTA-D13C6.

Dipeptidyl Peptidase IV as a Prognostic Marker and Therapeutic Target in Papillary Thyroid Carcinoma

Dipeptidyl peptidase IV (DPP4) is overexpressed in thyroid cancer and certain malignancies. Furthermore, DPP4 has been identified as a discriminatory marker for thyroid cancer. However, it remains unclear whether DPP4 expression plays a prognostic role. The aim of this study was to investigate the expression and function of DPP4 in thyroid cancer and the mechanisms involved. We determined the expression of DPP4 by immunohistochemistry in tissue microarrays of thyroid tumors. In vitro functional studies were performed after genetic and pharmacological inhibition of DPP4. Gene expression and pathway analyses were used to identify downstream targets. The therapeutic potential of DPP4 inhibition was evaluated in a mouse xenograft model. High DPP4 expression was associated with extrathyroidal extension (P < 0.001), BRAF mutation (P < 0.001), and advanced tumor stage (P = 0.007) in papillary thyroid cancer. Patients in the high-DPP4 expression group were less likely to be classified as having no evidence of disease at final follow-up (P = 0.042). DPP4 silencing or treatment with DPP4 inhibitors significantly suppressed colony formation, cell migration, and invasion. Analysis of differentially expressed genes after DPP4 knockdown suggested that the transforming growth factor-β signaling pathway is involved. In vivo experiments revealed that sitagliptin treatment reduced tumor growth and xenograft transforming growth factor-β receptor I expression. Increased DPP4 expression is associated with cellular invasion and more aggressive disease in papillary thyroid cancer. Targeting DPP4 may be a therapeutic strategy for DPP4-expressing thyroid cancer.

Role of RAI in the management of incidental N1a disease in papillary thyroid cancer.

Following total thyroidectomy (TT) for papillary thyroid cancer (PTC), pathological assessment can occasionally reveal incidental perithyroidal lymph nodes (LNs) with occult metastases. These cN0pN1a patients often receive radioactive iodine (RAI) therapy for this indication alone. The aim of this study was to determine the central compartment nodal recurrence-free survival in patients treated without RAI compared to those who received RAI treatment. An institutional database of 3664 previously untreated patients with differentiated thyroid cancer operated between 1986 and 2010 was reviewed. A total of 232 pT1-3 patients managed with TT and no neck dissection were subsequently found to have incidental level 6 LNs on pathology. Patients with other indications for RAI, such as extrathyroidal extension and close or positive margins, were excluded. One hundred and four patients remained for analysis. Kaplan-Meier method was used to determine central neck LN recurrence-free survival (RFS). The median age of the cohort was 40years (range 17-83). The median follow-up was 53months (range 1-211). The median number of positive LNs removed and maximum LN diameter were 1 (range 1-8) and 5mm (range 1-16mm), respectively. A total of 67 (64%) patients had adjuvant RAI and 37 (36%) did not. Patients with vascular invasion (P=0·01), LNs>2mm (P=0·07) and >2 positive nodes (P=0·06) were more likely to be selected for adjuvant RAI therapy. Patients without RAI therapy had similar 5-year central neck LN RFS compared to those treated with RAI: 96·2% vs 94·6%, respectively (P=0·92). There is no difference in the 5-year central compartment nodal recurrence-free survival in patients treated without RAI compared to those who received RAI treatment.

Papillary thyroid cancer: factors involved in restaging N1 disease after total thyroidectomy and radioactive iodine treatment.

The presence of cervical lymph node metastases is a strong predictor of persistent disease in papillary thyroid cancer (PTC). The objective of the study was to investigate factors associated with improved outcome in patients with PTC and lymph node metastases. Retrospective Cohort Setting: The study was conducted at a tertiary university-affiliated medical center. PATIENTS treated for PTC and N1 disease since 1995 participated in the study. Partial thyroidectomy, distant metastases, and poor differentiation were the exclusion criteria. The intervention was a data search of the Thyroid Registry. Significant association of clinical and disease-related factors with persistent disease was measured. Of 800 patients treated for PTC during the study period, 182 (69% female; mean age at diagnosis 46.5 ± 15 y) had N1 disease (47% N1a, 53% N1b). Most (93.4%) had a classical/follicular variant; 65% had T1-2 disease; and 42.6% had extrathyroid extension. All patients were treated with total thyroidectomy and radioactive iodine (mean first dose 147 ± 26 mCi). Lateral neck dissection was performed in 53% patients. Mean follow-up was 9.2 ± 4.5 years. On regression analysis, factors significantly and independently associated with persistent disease at 1 year (94 of 182, 52%; 40% of N1a group, 59% of N1b group) were primary tumor size, focality, and extrathyroid extension and at the last follow-up (62 of 182, 34%; 27% of N1a group, 33% of N1b group), primary tumor size, 1-year stimulated thyroglobulin level, and cumulative I(131) dose. Stimulated thyroglobin less than 2.1 ng/mL at 1 year predicts the absence of disease at the last follow-up with an 86% negative predictive value. PATIENTS with PTC and N1 disease treated with total thyroidectomy and radioactive iodine have a significant risk of persistent disease at early and late follow-up. The extension of the primary tumor at diagnosis appears to be the only significant predictor of persistency in these patients.

Predictive value of the Delphian and level VI nodes in papillary thyroid cancer

Recent published data has shown that metastatic involvement of the prelaryngeal or Delphian lymph node (DLN), the highest of the central (level VI) cervical lymph nodes, is highly predictive of advanced nodal disease in papillary thyroid cancer (PTC). The aims of this study were to determine the diagnostic accuracy of all the level VI cervical nodes in PTC and to determine which node group, if any, is the most accurate in predicting lateral node (N1b) disease. This was a retrospective cohort study. Data were obtained from the University of Sydney Endocrine Surgical Unit Database and through a review of the histopathology records. The study cohort was composed of 177 consecutive patients with a final diagnosis of PTC who underwent total thyroidectomy and lymph node dissection, spanning the period from May 2001 to December 2006. Of the 177 patients with PTC, 86 had the DLN removed, 51 had a pretracheal node removed and 76 had the paratracheal group removed. DLN, paratracheal and pretracheal node disease was present in 21%, 39% and 46%, respectively. Lateral node (N1b) disease was present in 35%. Paratracheal node involvement was mildly predictive of further disease with patients 1.7 times more likely to have lateral node involvement (sensitivity=55%, specificity=68%). Pretracheal node involvement was moderately predictive of further disease with patients three times more likely to have lateral node involvement (sensitivity=72%, specificity=74%). DLN involvement was highly predictive of further node involvement with patients nine times more likely to have lateral node disease (sensitivity=53%, specificity=94%) and 40 times more likely to have any nodal disease (sensitivity=41%, specificity=100%). This is the first study to examine the diagnostic accuracy of all level VI lymph nodes in PTC. While, metastatic involvement of all central nodal groups is indicative of further disease, the DLN is the most accurate predictor.

ES02 SIGNIFICANCE OF LYMPH NODE MICROMETASTASES IN PAPILLARY THYROID CARCINOMA

Purpose Management of nodal disease in papillary thyroid cancer (PTC) varies. The significance of micrometastases and their relationship to locoregional recurrence has not been well described. We set out to compare patients with micrometastatic nodal disease to those with macrometastases and those with no metastases. Our service follows a policy of routine central/recurrent nerve dissection and ipsilateral jugulocarotid node sampling for cases of PTC.Methodology One hundred and seventy patients who had surgery for PTC between January 1995 and December 2000 were included and split into three groups. Micrometastases (only micrometastatic disease), Macrometastases (any macrometastaic nodal involvement) and No metastases (absence of any nodal involvement). These three groups were compared for rates of locoregional disease recurrence and distant metastases.Results Contingency analysis showed that the Macrometastases group had a significantly higher rate of locoregional recurrence compared with both No metastases(Odds ratio 7.67, p &lt; 0.0001) and Micrometastases groups (Odds ratio 9.212, p 0.0154). There was no difference between the No metastases and micrometastases groups (p 1.000), the p value suggesting the two groups were likely to be equivalent. Analysis revealed that distant disease was significantly more common in the Macrometastases group when compared to the No metastases group, (Odds ratio 25.09, p 0.0032)Conclusions Micrometastatic nodal disease associated with PTC does not lead to higher rates of locoregional recurrence or distant disease. These patients do not need completion neck dissection and have a low risk of locoregional recurrence.

Multicentricity in papillary thyroid carcinoma: analysis of predictive factors.

Multicentricity has been cited as a rationale for total thyroidectomy in patients with papillary thyroid carcinoma (PTC) confined to one lobe. The purpose of this study was to examine the incidence of multicentricity of PTC in a cohort of 165 patients with PTC confined to one lobe and to examine clinical and pathologic features that may help predict for the presence of contralateral disease. Retrospective review. Tertiary care hospital. A retrospective review of 165 patients with PTC confined to one lobe treated at the Toronto General Hospital from 1992 to 1997 was performed. The predictive factors affecting the presence of multicentricity of PTC were analyzed. The incidence of PTC present in the contralateral lobe was 56.3%. We were unable to find any correlation of multicentricity with age, sex, tumour size, extrathyroidal spread, thyroiditis, or tall cell variant of PTC. There were trends toward higher incidence of contralateral disease in those patients with a prior history of irradiation and those with lymphatic metastases, but these trends did not reach statistical significance. The incidence of contralateral disease in papillary thyroid cancer treated at the Toronto Hospital was 56.3%. There was a higher incidence of contralaterality in those patients with a previous history of irradiation and in those with lymphatogenous metastases, but this did not reach statistical significance.