Risk Stratification In Thyroid Cancer Research Articles

Theranostic Risk Stratification for Thyroid Cancer in the Genomic Paradigm.

Theranostics define diagnostic evaluations directing patient-specific therapeutic decisions. Molecular theranostics involves genomic, transcriptomic, proteomic, metabolomic and finally phenonic definitions thyroid cancer differentiation. It is the functional differentiation that determines the sensitivity and accuracy of RAI imaging as well as the effectiveness of RAI treatment. Total thyroidectomy is performed to empower an anticipated RAI treatment. A preoperative determination of the genomic and transcriptomic profile of the tumor is a strong predictor of response to therapeutic interventions. This article discusses the oncopathophysiologic basis of the theranostic risk stratification approach.

Mutational profiling of Chinese patients with thyroid cancer.

The incidence of thyroid cancer in China has rapidly increased in recent decades. As the genetic profiles of thyroid cancer vary dramatically between different geographical regions, a comprehensive genetic landscape of thyroid cancer in the Chinese population is urgently needed. We retrospectively included thyroid cancer patients from three Chinese medical centers between February 2015 and August 2020. To dissect the genomic profiling of these patients, we performed targeted next-generation sequencing on their tumor tissues using a 1,021-gene panel. A total of 458 Chinese patients with thyroid cancer were enrolled, including four malignant histological subtypes arising from follicular epithelial thyroid cells. BRAF driver mutations were identified in 76.0% of patients, followed by RET rearrangements (7.6%) and RAS driver mutations (4.1%). Tumors with more somatic mutations correlated with worse clinical characteristics, including older age at diagnosis, less differentiation of tumor, larger tumor size, lymph node metastasis and distal metastasis. Subclonal BRAF mutations occurred in 20% (6/30) of patients and were frequent in poorly differentiated or anaplastic tumors (33.3% [2/6] vs. 4.2% [1/24], P = 0.09) and those with distal metastasis (50.0% [2/4] vs. 8.7% [2/23], P = 0.09). Tumors with TERT promoter mutations had significantly more somatic mutations (average: 6.5 vs. 1.8, P < 0.001). Moreover, TERT promoter mutations were not associated with lymph node metastasis but significantly associated with older age at diagnosis and poorly differentiated or anaplastic tumors, regardless of their clonal architecture. Our results shed light on the molecular pathogenesis and clinical characteristics of thyroid cancer in the Chinese population. The number of somatic mutations, TERT promoter mutations, and the clonal architecture of BRAF mutations should be considered in the risk stratification of thyroid cancer.

Integrated gene profiling of fine-needle aspiration sample improves lymph node metastasis risk stratification for thyroid cancer.

Lymph node metastasis risk stratification is crucial for the surgical decision-making of thyroid cancer. This study investigated whether the integrated gene profiling (combining expression, SNV, fusion) of Fine-Needle Aspiration (FNA) samples can improve the prediction of lymph node metastasis in patients with papillary thyroid cancer. In this retrospective cohort study, patients with papillary thyroid cancer who went through thyroidectomy and central lymph node dissection were included. Multi-omics data of FNA samples were assessed by an integrated array. To predict lymph node metastasis, we built models using gene expressions or mutations (SNV and fusion) only and an Integrated Risk Stratification (IRS) model combining genetic and clinical information. Blinded histopathology served as the reference standard. ROC curve and decision curve analysis was applied to evaluate the predictive models. One hundred and thirty two patients with pathologically confirmed papillary thyroid cancer were included between 2016-2017. The IRS model demonstrated greater performance [AUC=0.87 (0.80-0.94)] than either expression classifier [AUC=0.67 (0.61-0.74)], mutation classifier [AUC=0.61 (0.55-0.67)] or TIRADS score [AUC=0.68 (0.62-0.74)] with statistical significance (p < 0.001), and the IRS model had similar predictive performance in large nodule [>1cm, AUC=0.88 (0.79-0.97)] and small nodule [≤1cm, AUC=0.84 (0.74-0.93)] subgroups. The genetic risk factor showed independent predictive value (OR=10.3, 95% CI:1.1-105.3) of lymph node metastasis in addition to the preoperative clinical information, including TIRADS grade, age, and nodule size. The integrated gene profiling of FNA samples and the IRS model developed by the machine-learning method significantly improve the risk stratification of thyroid cancer, thus helping make wise decisions and reducing unnecessary extensive surgeries.

The role of the size in thyroid cancer risk stratification

Only a minority of cases of differentiated thyroid carcinoma (DTC) have a poor clinical outcome. Clinical outcomes and molecular aspects were assessed in: 144 DTC ≤ 40 mm without distant metastases (group 1); 50 DTC > 40 mm without distant metastases (group 2); and 46 DTC with distant metastases (group 3). Group 3 had a worse outcome than the other two groups: during the follow-up, patients more frequently had persistent disease, died, or underwent further treatment. The outcomes did not differ between groups 1 and 2. Group 3 had a higher prevalence of TERT promoter mutations than group 2 (32.6% vs 14%). Group 1 had a higher frequency of BRAF mutations than groups 2 or 3 (61.1% vs 16.0% and 26.1%, respectively), while RAS mutations were more common in group 2 than in groups 1 and 3 (16.0% vs 2.1% and 6.5%, respectively). Groups 1 and 2 shared the same outcome, but were genetically distinct. Only lymph node involvement, distant metastases, older age and (among the molecular markers) TERT promoter mutations were independent predictors of a worse outcome. Metastatic DTC had the worst outcome, while the outcome was identical for large and small non-metastatic DTC, although they showed different molecular patterns. TERT promoter mutations emerged as an independent factor pointing to a poor prognosis.

Diagnosis of Thyroid Nodule with New Ultrasound Imaging Modalities.

Introduction: B-mode ultrasound (US) technology is an integral part of diagnosing and assessing risk stratification of thyroid nodules (TNs). The addition of shear wave elastography and three-dimensional (3D) US imaging may improve risk stratification for thyroid cancer (TC).Materials and Methods: The patient was evaluated in our clinic with US imaging including B-mode, shear wave elastography, 3D-US, and fine needle aspiration biopsy (FNAB). Laboratory measurements were performed at LabCorp. The patient gave informed consent.Case: A 20-year-old female referred for hypothyroidism who was on levothyroxine 25µg daily. Her thyroid-stimulating hormone (TSH) was 3.870 (0.45–4.5 µIU/mL). Thyroid peroxidase antibody and thyroglobulin antibody were elevated, suggestive of Hashimoto's thyroiditis. Her thyroid ultrasongraph showed a heterogeneous thyroid gland with a hypoechoic TN in the right lobe measuring 9.2 × 8.9 × 9 mm. Shear wave elastography examination was suggestive of a hard TN. The shear wave velocity (SWV) measurements for the target TN was 3.9 m/s. 3D-US examination demonstrated a hypoechoic TN with irregular margins and a volume of 0.322 cm3. FNAB of right TN was performed. The cytopathology was read as malignant (Bethesa Category VI), diagnostic for papillary thyroid cancer (PTC). She underwent total thyroidectomy. Surgical pathology report showed an 8 mm PTC in the right lobe and 2 mm PTC in the left lobe with a background of Hashimoto's thyroiditis. There were 3/10 positive lymph nodes (LNs) for metastases. The largest metastatic LN measured 5 mm at level 6.Discussion: This case illustrates recent advances in US technology. For decades, clinicians relied on B-mode US to assess the risk for TC. This case illustrates important challenges and advances in US technology. Current ACR-TIRADS guideline for TN management is based on B-mode US features and TN size.1 In our experience, including additional factors such as elastography, 3D-US, and laboratory evaluation helps to improve our diagnostic accuracy. In this case, her laboratory was suggestive of autoimmune thyroid disease. This information was helpful to put this patient in a higher risk category. Recent large studies reported an association between differentiated TC and autoimmune thyroid disease and/or TSH when all Bethesda classifications were included.2–4 Shear wave elastography examination showed that this TN had a high SWV, suggestive of a hard TN, which is suspicious for malignancy. Several recent publications have reported that elastography can assess the malignant potential of TN.5–10 In our prospective study, we reported that in a single cutoff analysis for predicting malignancy in TNs, a maximum SWV of 3.54 m/s had the best sensitivity. With greater SWV values, specificity increased but sensitivity decreased.6 3D-US technology enhances our ability to visualize the target lesion because of adding a new dimension, coronal view, to the existing B-mode that consists of transverse and longitudinal views. In this case, irregular margins of the TN are seen much better with 3D-US. This is a preliminary report, and more studies need to be done.Conclusion: Adding SWE and 3D-US technology to B-mode US may enhance our ability for risk stratification for TN before FNAB. 3D-US may improve our ability to visualize the margins of TN.No competing financial interests exist.Runtime of video: 2 mins 5 secs

BRAF and TERT promoter mutations: clinical application in thyroid cancer.

Given the long-term survival of most patients with thyroid cancer, it is very important to distinguish patients who need aggressive treatment from those who do not. Conventional clinicopathological prognostic parameters could not completely predict the final outcome of each patient. Recently, molecular marker-based risk stratification of thyroid cancer has been proposed to better estimate the cancer risk. Although BRAF mutation has drawn much attention based on its high prevalence, its association with recurrence or mortality is not clear. Recently, telomerase reverse transcriptase (TERT) promoter mutation has been identified in thyroid cancer. It increases telomerase activity, which allows cancer cells to immortalize. It was found in 10 to 20% of differentiated thyroid carcinoma and 40% of dedifferentiated thyroid carcinoma. It is highly prevalent in old age, large tumor, aggressive histology, advanced stages, and distant metastasis. It is associated with increased recurrence and mortality. Concomitant BRAF and TERT promoter mutations worsen the survival rate. Inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

Molecular testing approaches in thyroid cancer diagnosis

Thyroid cancer (TC) is the most common endocrine malignancy worldwide, with an annual incidence of around 300,000 cases. In recent decades, the incidence of TC in many countries, including Saudi Arabia, has increased significantly. Genomics has allowed multiple mutations to be examined simultaneously across multiple genes, providing a detailed genomic profile for a given tumor. It is understood from a molecular perspective that different signaling pathways may have genetic abnormalities as the primary factors in thyroid tumorigenesis. While there is still early progress in the usage and standardization of targeted next-generation sequencing (NGS) in TC, a major ongoing study to distinguish malignant from benign thyroid nodules from fine-needle aspiration (FNA) has shown promising results that can prevent unnecessary surgery, based on NGS analyses of mutations and gene fusions associated with most TC. The differential diagnosis and malignancy risk stratification of TC require multidisciplinary skills and experience of both ultrasound and the FNA and molecular analysis. The most common TC mutations are point mutations in the BRAF and the chromosome rearrangements of RET/papillary TCs. The transition mechanisms tend to be linked to specific etiological features, which are very crucial while deciding the treatment protocol. On the other hand, FNA cytology has an intrinsic drawback. The findings of infinite cytology cannot differentiate some types of TC, such as follicular adenomas, thyroid follicular carcinomas, or papillary thyroid follicular. Nevertheless, accumulating evidence indicates that molecular diagnostic approaches can overcome these limitations. In this review, we present an updated summary, which focuses primarily on molecular alterations in the tumorigenesis and biomarker investigations of TC.

Impact of Mutation Density and Heterogeneity on Papillary Thyroid Cancer Clinical Features and Remission Probability.

The need to integrate the classification of cancer with information on the genetic pattern has emerged in recent years for several tumors. The genomic background of a large series of 208 papillary thyroid cancers (PTC) followed at a single center was analyzed by a custom MassARRAY genotyping platform, which allows the simultaneous detection of 19 common genetic alterations, including point mutations and fusions. Of the PTCs investigated, 71% were found to have pathognomonic genetic findings, with BRAFV600E and TERT promoter mutations being the most frequent monoallelic alterations (42% and 23.5%, respectively), followed by RET/PTC fusions. In 19.2% of cases, two or more point mutations were found, and the co-occurrence of a fusion with one or more point mutation(s) was also observed. Coexisting BRAFV600E and TERT promoter mutations were detected in a subgroup of aggressive PTCs (12%). A correlation between several aggressive features and mutation density was found, regardless of the type of association (i.e., only point mutations, or point mutations and fusions). Importantly, Kaplan-Meier curves demonstrated that mutation density significantly correlated with a higher risk of persistent disease. In most cases, the evaluation of the allelic frequencies normalized for the cancer cell content indicated the presence of the monoallelic mutation in virtually all tumor cells. A minority of cases was found to harbor low allelic frequencies, consistent with the presence of the mutations in a small subset of cancer cells, thus indicating tumor heterogeneity. Consistently, the presence of coexisting genetic alterations with different allelic frequencies in some tumors suggests that PTC can be formed by clones/subclones with different mutational profiles. A large mono-institutional series of PTCs was fully genotyped by means of a cost- and time-effective customized panel, revealing a strong impact of mutation density and genetic heterogeneity on the clinical features and on disease outcomes, indicating that an accurate risk stratification of thyroid cancer cannot rely on the analysis of a single genetic event. Finally, the heterogeneity found in some tumors warrants attention, since the occurrence of this phenomenon is likely to affect response to targeted therapies.

Risk stratification of thyroid cancer using thyroid nodule ultrasound classification systems – A review paper

Risk stratification of thyroid cancer using thyroid nodule ultrasound classification systems – A review paper

Mutational Markers and Risk Stratification in Thyroid Cancer—The Art of War Refined

Mutational Markers and Risk Stratification in Thyroid Cancer—The Art of War Refined

Subgrouping of N1a Stage Papillary Thyroid Carcinoma with Positive Node Ratio

Background : The 2015 American thyroid association (ATA) guidelines greatly expanded section on risk strat-ification of thyroid cancer. Definition of "Low risk of recurrence" has expanded, by inclusion of small volume lymph node involvement, such as less than 5 lymph node metastases each smaller than 2mm in central compartment. Purpose : We evaluated the number of positive nodes, Positive node ratio (PNR), recurrence, and radioablation therapy. Also, evaluated the safety of omitting strategy of radioablation after total thyroidectomy with PTC, espe-cially on low-PNR N1a patients compared with high-PNR N1a patients. Methods : Consecutive 147 N1a and 216 N0 patients who underwent total thyroidectomy with central neck dissection between 2003 and 2004 were enrolled. We divided 147 N1a patients into two groups, such as 96 high-PNR versus 51 low-PNR group according to 50% of PNR, and compared these two groups with N0 group. Results: 7.2% (26/363) recurrences were occurred, and 21/147 (14.3 %) recurrences were on N1a patients, and 5/216 (2.3 %) were on N0 patients. Of these 21 recurrences in N1a stage patients, 20 (95.2 %) recurrences were occurred in high-PNR N1a group and only 1 (4.8 %) recurrence was in low-PNR N1a group. The recurrence of low-PNR N1a group was significantly lower than high-PNR N1a group (Log-rank p value = 0.003), but sig-nificantly not different from N0 group (Log-rank p value = 0.889). Although this study was a retrospective non-randomized trial with small number of patients, the 10-year recurrence of omitting RAI in low-PNR N1a patients with less than 50% of PNR were shown to be comparable with 216 N0 low risk patients. Conclusion : Positive node ratio could be a useful predictor of recurrence and useful guidance postoperative management -rather than absolute number of positive node.

The Impact of Metastatic Lymph Nodes on Risk Stratification in Differentiated Thyroid Cancer: Have We Reached a Higher Level of Understanding?

The revised American Thyroid Association (ATA) management guidelines for differentiated thyroid cancer emphasize a variety of clinicopathologic features of metastatic lymph nodes in determining the risk of recurrence. The mere presence of a positive node is not sufficient to confer reliable prognostic significance. The number and size of lymph nodes, as well as the presence of extranodal extension (ENE), impact risk stratification. Moreover, the presence of clinically evident lymph nodes is important for determining risk of recurrence. A patient's place on the risk spectrum has ramifications for the management of differentiated thyroid cancer. However, there are inherent inconsistencies in the identification and characterization of metastatic lymph nodes. Moreover, the significance of ENE must be clarified. There are many obstacles to the consistent reporting of metastatic lymph nodes. What constitutes a "clinically evident" lymph node has not been well defined, lacks precision, and varies depending on clinical context, as well as the experience of the surgeon and the ultrasonographer. The number of lymph nodes sampled by surgeons and reported by pathologists may vary from institution to institution. The literature on ENE has been limited by the fact that the definition of ENE has not been standardized. Nevertheless, 17/19 manuscripts reviewed herein suggest that ENE confers a worse prognosis. The ATA risk stratification for metastatic lymph nodes published in the 2015 guidelines combines clinicopathological features that are variably identified and reported across institutions. This review brings into question the significance of the number of nodes with ENE, a factor that is used as an important stratifying variable in the latest guidelines. Metastatic lymph nodes do not all carry the same prognostic significance, but a risk assignment based on the ATA guidelines is limited by a lack of standardization in clinical and pathologic definitions, lymph node sampling, and reporting. This study reviews the limitations of prior studies on ENE and concludes that the body of the evidence reported in those studies suggests that ENE increases the risk of recurrence. The impact of ENE in lymph nodes in thyroid cancer risk stratification should be reconsidered.

A new computational model for human thyroid cancer enhances the preoperative diagnostic efficacy.

Considering the high rate of missed diagnosis and delayed treatments for thyroid cancer, an effective systematic model for the differential diagnosis is highly needed. Thus we analyzed the data on the clinicopathological characteristics, routine laboratory tests and imaging examinations in a cohort of 13,980 patients with thyroid cancer to establish a new diagnostic model for differentiating thyroid cancer in clinical practice. Here, we randomly selected two-thirds of the population to develop the thyroid malignancy risk scoring system (TMRS) for preoperative differentiation between thyroid cancer and benignant thyroid diseases, and then validated its differential diagnostic power in the rest one-third population. The 18 predictors finally enrolled in the TMRS included male gender, clinical manifestations (fever, neck sore, neck lump, palpitations or sweating), laboratory findings (TSH>1.56mIU/L, FT3>5.85pmol/L, TPOAb>14.97IU/ml, TgAb>48.00IU/ml, Tg>34.59μg/L, Ct>64.00ng/L, and CEA>0.41μg/L), and ultrasound features (tumor number≤ 23mm, site, size, echo texture, margins, and shape of neck lymphnodes). The TMRS is validated to be well-calibrated (P = 0.437) and excellently discriminated (AUC = 0.93, 95% CI [0.92, 0.94]), with an accuracy of 83.2%, a sensitivity of 89.3%, a specificity of 81.5%, positive and negative predictive values of 56.8% and 96.6%, positive and negative likelihood ratios of 4.83 and 0.13 in the development cohort, respectively. The TMRS highlights that this differential diagnostic system could help provide accurate preoperative risk stratification for thyroid cancer, and avoid unnecessary over- and under-treatment for such patients.

Using diffusion-weighted MRI to predict aggressive histological features in papillary thyroid carcinoma: a novel tool for pre-operative risk stratification in thyroid cancer.

Initial management recommendations of papillary thyroid carcinoma (PTC) are very dependent on preoperative studies designed to evaluate the presence of PTC with aggressive features. The purpose of this study was to evaluate whether diffusion-weighted magnetic resonance imaging (DW-MRI) before surgery can be used as a tool to stratify tumor aggressiveness in patients with PTC. In this prospective study, 28 patients with PTC underwent DW-MRI studies on a three Tesla MR scanner prior to thyroidectomy. Due to image quality, 21 patients were finally suitable for further analysis. Apparent diffusion coefficients (ADCs) of normal thyroid tissues and PTCs for 21 patients were calculated. Tumor aggressiveness was defined by surgical histopathology. The Mann-Whitney U test was used to compare the difference in ADCs among groups of normal thyroid tissues and PTCs with and without features of tumor aggressiveness. Receiver operating characteristic (ROC) analysis was performed to assess the discriminative specificity, sensitivity, and accuracy of and determine the cutoff value for the ADC in stratifying PTCs with tumor aggressiveness. There was no significant difference in ADC values between normal thyroid tissues and PTCs. However, ADC values of PTCs with extrathyroidal extension (ETE; 1.53±0.25×10(-3) mm2/s) were significantly lower than corresponding values from PTCs without ETE (2.37±0.67×10(-3) mm2/s; p<0.005). ADC values identified 3 papillary carcinoma patients with extrathyroidal extension that would have otherwise been candidates for observation based on ultrasound evaluations. The cutoff value of ADC to discriminate PTCs with and without ETE was determined at 1.85×10(-3) mm2/s with a sensitivity of 85%, specificity of 85%, and ROC curve area of 0.85. ADC value derived from DW-MRI before surgery has the potential to stratify ETE in patients with PTCs.

Diagnostic and prognostic TERT promoter mutations in thyroid fine-needle aspiration biopsy.

Two promoter mutations, chr5:1 295 228C>T and chr5:1 295 250C>T, in the gene for telomerase reverse transcriptase (TERT) have been recently identified in thyroid cancers and shown to be important in thyroid tumor pathogenesis. The diagnostic and prognostic potentials of testing for these mutations on thyroid fine-needle aspiration biopsy (FNAB) have not been investigated. Herein, we examined the two TERT promoter mutations along with the BRAF V600E mutation by direct DNA sequencing on 308 FNAB specimens preoperatively obtained from thyroid nodules with postoperatively confirmed pathological diagnoses. We found TERT promoter mutations in 0.0% (0/179) of benign thyroid nodules and 7.0% (9/129) of thyroid nodules of differentiated thyroid cancer, representing a 100% diagnostic specificity and 7.0% sensitivity, with the latter rising to 38.0% (49/129) when combined with BRAF V600E testing. Several TERT-promoter-mutation-positive thyroid nodules were cytologically indeterminate on FNAB. Approximately 80% of the TERT promoter mutation-positive thyroid nodules were thyroid cancers with aggressive clinicopathological behaviors, such as extrathyroidal invasion, lymph node metastases, distant metastases, disease recurrence or patient death. Thus, a positive TERT promoter mutation test not only definitively diagnoses a thyroid nodule as cancerous but also preoperatively identifies a cancer with aggressive potential. This is the first study, to our knowledge, of TERT promoter mutations on thyroid FNAB, demonstrating the value of this novel molecular testing in the diagnosis of thyroid nodules and preoperative risk stratification of thyroid cancer. Thus, testing of TERT promoter mutations on FNAB will enhance and improve the current molecular-based approaches to the management of thyroid nodules and thyroid cancer.