Performance of multigene testing in cytologically indeterminate thyroid nodules and molecular risk stratification
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SUBMITTER: Zhou Y
PROVIDER: S-EPMC10512961 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:PurposeUltrasound (US) risk stratification systems (RSSs) are increasingly being utilized for the optimal management of thyroid nodules, including those with indeterminate cytology. The goal of this study was to evaluate the category-based diagnostic performance of US RSSs in identifying malignancy in indeterminate nodules.MethodsThis systematic review and meta-analysis was registered on PROSPERO (CRD42021266195). PubMed, EMBASE, and Web of Science were searched through December 1, 2022. Original articles reporting data on the performance of US RSSs for indeterminate nodules were included. The numbers of nodules classified as true negative, true positive, false negative, and false positive were extracted.ResultsThirty-three studies evaluating 7,225 indeterminate thyroid nodules were included. The diagnostic accuracy was quantitatively synthesized using a Bayesian bivariate model based on the integrated nested Laplace approximation in R. For the intermediate- to high-risk category, the sensitivity levels of the American College of Radiology, the American Thyroid Association, the European Thyroid Association, the Korean Thyroid Association/Korean Society of Thyroid Radiology, and Kwak et al. were found to be 0.80, 0.72, 0.76, 0.96, and 0.97, respectively. The corresponding specificity measurements were 0.36, 0.50, 0.49, 0.28, and 0.17. Furthermore, for the high-risk category, the sensitivity values were 0.40, 0.46, 0.55, 0.47, and 0.10, while the specificity levels were 0.91, 0.90, 0.71, 0.91, and 0.99, respectively.ConclusionThe overall diagnostic performance of the US RSSs was moderate in the differentiation of indeterminate nodules.
| S-EPMC10555695 | biostudies-literature
Project description:Molecular testing of indeterminate thyroid nodules informs about the presence of point mutations, insertions/deletions, copy number variants, RNA fusions, transcript alterations and miRNA expression. American Thyroid Association (ATA) guidelines suggest molecular testing of indeterminate thyroid nodules may be considered to supplement risk of malignancy (ROM). Although these recommendations have been incorporated in clinical practices in the United States, molecular testing of indeterminate thyroid nodules is not common practice in Asia. Here, we performed molecular testing of 140 indeterminate nodules from Chinese patients using a novel molecular platform composed of RNA and DNA-RNA classifiers, which is similar to Afirma GEC and ThyroSeq v3. Compared with reports from North America, the new RNA and DNA-RNA classifiers had a higher positive predictive value (p1 = 0.000 and p2 = 0.020) but a lower negative predictive value (p1 = 0.004 and p2 = 0.098), with no significant differences in sensitivity (p1 = 0.625 and p2 = 0.179) or specificity (p1 = 0.391 and p2 = 0.264). Out of 58 resected nodules, 10 were borderline and 33 malignant, indicating a 74.1% ROM, which was higher than reports in North America (10-40% ROM). Our findings emphasize molecular testing with the newly reported RNA and DNA-RNA classifiers can be used as a 'rule-in' test when ROM is high.
| S-EPMC9019878 | biostudies-literature
Project description:PurposeAs ~25% of cytologically indeterminate thyroid nodules harbour malignancy, diagnostic lobectomy is still performed in many cases. 18FDG PET/CT rules out malignancy in visually negative nodules; however, none of the currently available interpretation criteria differentiates malignant from benign 18FDG-avid nodules. We evaluated the ability of PET metrics and radiomics features (RFs) to predict final diagnosis of 18FDG-avid cytologically indeterminate thyroid nodules.MethodsSeventy-eight patients were retrospectively included. After volumetric segmentation of each thyroid lesion, 4 PET metrics and 107 RFs were extracted. A logistic regression was performed including thyroid stimulating hormone, PET metrics, and RFs to assess their predictive performance. A linear combination of the resulting parameters generated a radiomics score (RS) that was matched with cytology classes (Bethesda III and IV) and compared with final diagnosis.ResultsTwo RFs (shape_Sphericity and glcm_Autocorrelation) differentiated malignant from benign lesions. A predictive model integrating RS and cytology classes effectively stratified the risk of malignancy. The prevalence of thyroid cancer increased from 5 to 37% and 79% in accordance with the number (score 0, 1 or 2, respectively) of positive biomarkers.ConclusionsOur multiparametric model may be useful for reducing the number of diagnostic lobectomies with advantages in terms of costs and quality of life for patients.
| S-EPMC8763930 | biostudies-literature
Project description:Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAFV600E (98%, 95% confidence interval [CI 96-99%]), PAX8/PPARG (55% [CI 34-78%]), HRASQ61R (45% [CI 22-72%]), BRAFK601E (42% [CI 19-68%]), and NRASQ61R (38% [CI 23-55%]). Excluding BRAFV600E, the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in ∼1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAFV600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.
| S-EPMC6864764 | biostudies-literature
Project description:ImportanceUse of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic surgery.ObjectiveTo measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules.Design, setting, and participantsA blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017.ExposuresThyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data.Main outcomes and measuresThe primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules.ResultsOf the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58).Conclusions and relevanceThe genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.
| S-EPMC6583881 | biostudies-literature
Project description:BackgroundApproximately 25% of thyroid nodule fine-needle aspirates (FNAs) have cytology that is indeterminate for malignant disease. Accurate risk stratification of these FNAs with ancillary testing would reduce unnecessary thyroid surgery.MethodsWe evaluated the performance of an ancillary multiplatform test (MPTX) that has three diagnostic categories (negative, moderate, and positive). MPTX includes the combination of a mutation panel (ThyGeNEXT®) and a microRNA risk classifier (ThyraMIR®). A blinded, multicenter study was performed using consensus histopathology diagnosis among three pathologists to validate test performance.ResultsUnanimous consensus diagnosis was reached in 197 subjects with indeterminate thyroid nodules; 36% had disease. MPTX had 95% sensitivity (95% CI,86%-99%) and 90% specificity (95% CI,84%-95%) for disease in prevalence adjusted nodules with Bethesda III and IV cytology. Negative MPTX results ruledout disease with 97% negative predictive value (NPV; 95% CI,91%-99%) at a 30% disease prevalence, while positive MPTX results ruledin high risk disease with 75% positive predictive value (PPV; 95% CI,60%-86%). Such results are expected in four out of five Bethesda III and IV nodules tested, including RAS positive nodules in which the microRNA classifier was useful in rulingin disease. 90% of mutation panel false positives were due to analytically verified RAS mutations detected in benign adenomas. Moderate MPTX results had a moderate rate of disease (39%, 95% CI,23%-54%), primarily due to RAS mutations, wherein the possibility of disease could not be excluded.ConclusionsOur results emphasize that decisions for surgery should not solely be based on RAS or RAS-like mutations. MPTX informs management decisions while accounting for these challenges.
| S-EPMC7754490 | biostudies-literature
Project description:BackgroundFine-needle aspiration cytology (FNAC) is a basic diagnostic tool for thyroid nodules. However, 15-30% of nodules are cytologically indeterminate. Midkine (MK), a pleiotropic growth factor, is often upregulated in patients with cancers. This study aimed to evaluate the role of MK and its ratios in fine-needle aspirates (FNA) for predicting thyroid malignancy.MethodsThis retrospective study included patients with thyroid nodules who underwent preoperative FNA and/or thyroidectomy between April 2017 and September 2017. MK levels in FNA washout were measured by enzyme-linked immunosorbent assay, and thyroglobulin (TG) and free thyroxine (FT4) levels in FNA washout were measured by chemiluminescent immunometric assays.ResultsA total of 217 patients with 242 nodules were included in this study. The concentrations of TG, FT4, MK/TG, MK/FT4, and FT4/MK were significantly different between papillary thyroid carcinomas and benign thyroid nodules. Both MK/TG and MK/FT4 ratios were positively correlated with maximum tumor diameter, extrathyroidal extension, and T and N stages. The area under the curve for MK/TG was 0.719 with a cutoff value of 55.57 ng/mg, while the area under the curve for MK/FT4 was 0.677 with a cutoff value of 0.11 μg/pmol. FNAC in combination with MK/FT4 had a higher sensitivity (95% vs. 91%) and accuracy (96% vs. 92%) than FNAC alone for cytologically indeterminate specimens, those of unknown significance, or those suspected of malignancy.ConclusionsMK/FT4 and MK/TG may have diagnostic utility for evaluation of papillary thyroid carcinomas, particularly for cytologically indeterminate thyroid nodules.
| S-EPMC8543763 | biostudies-literature
Project description:Background: Fine needle aspiration (FNA) cytology, a diagnostic test central to thyroid nodule management, may yield indeterminate results in up to 30% of cases. The Afirma® Genomic Sequencing Classifier (GSC) was developed and clinically validated to utilize genomic material obtained during the FNA to accurately identify benign nodules among those deemed cytologically indeterminate so that diagnostic surgery can be avoided. A key question for diagnostic tests is their robustness under different perturbations that may occur in the lab. Herein, we describe the analytical performance of the Afirma GSC. Results: We examined the analytical sensitivity of the Afirma GSC to varied input RNA amounts and the limit of detection of malignant signals with heterogenous samples mixed with adjacent normal or benign tissues. We also evaluated the analytical specificity from potential interfering substances such as blood and genomic DNA. Further, the inter-laboratory, intra-run, and inter-run reproducibility of the assay were examined. Analytical sensitivity analysis showed that Afirma GSC calls are tolerant to variation in RNA input amount (5-30 ng), and up to 75% dilution of malignant FNA material. Analytical specificity studies demonstrated Afirma GSC remains accurate in presence of up to 75% blood or 30% genomic DNA. The Afirma GSC results are highly reproducible across different operators, runs, reagent lots, and laboratories. Conclusion: The analytical robustness and reproducibility of the Afirma GSC test support its routine clinical use among thyroid nodules with indeterminant FNA cytology.
| S-EPMC6620518 | biostudies-literature
Project description:BackgroundManagement recommendations for thyroid nodules rely primarily on the cytological diagnosis. However, 25% of biopsies render an indeterminate cytology for which management decision is more challenging due to heterogeneity of the specimens. This study aimed to stratify the cancer risk through subcategorization of indeterminate cytology.MethodsThe indeterminate cytological specimens (Bethesda-III or IV) of 518 thyroid nodules consecutively evaluated at our academic cancer center between October 2008 and September 2015, blinded to the histological outcome, were retrospectively reviewed. Cytological specimens were subclassified into four groups: aspirates exhibiting nuclear atypia (n?=?158; 31%); architectural atypia (n?=?222; 43%); oncocytic features (n?=?120; 23%); or other types of atypia (n?=?18; 3%). The prevalence of malignancy and odds ratio for malignancy were calculated in 323 nodules with histological confirmation.ResultsThe prevalence of malignancy was 26% overall (20% in Bethesda-III and 29% in Bethesda-IV; p?=?0.07), and 47%, 12%, 24%, and 25% for aspirates with nuclear atypia, architectural atypia, oncocytic features, or other types of atypia, respectively. The OR of nuclear atypia over architectural atypia was 6.4 (3.4-12.2; p?<?0.001), and 2.7 over oncocytic features (1.4-5.1; p?=?0.01), whereas the OR of architectural atypia over oncocytic features was 0.4 (0.2-0.9; p?=?0.03). Results were similar for Bethesda-III and IV aspirates when analyzed independently. Furthermore, cytological subcategories improved cytology-histology correlation, as they were associated with distinct profiles of histological diagnoses (p?<?0.001).ConclusionsCytological subcategories can effectively stratify the risk of malignancy of thyroid nodules with indeterminate cytology and improve cytology-histology correlation.
| S-EPMC6112164 | biostudies-literature
Project description:BackgroundThe impact of oncogene panel results on the surgical management of indeterminate thyroid nodules (ITNs) is currently unknown.MethodsSurgical management of 649 patients consecutively evaluated from October 2008 to April 2016 with a single nodule biopsied and indeterminate cytology (193 evaluated with and 456 without oncogene panels) was assessed and compared. Histological features of 629 consecutively resected ITNs (164 evaluated with and 465 without oncogene panels) were also characterized and compared.ResultsOncogene panel evaluation was associated with higher rates of total thyroidectomy (45% vs 28%; P = .006), and central lymph node dissection (19% vs 12%; P = .03) without increasing the yield of malignancy or decreasing the rate of completion thyroidectomy. Most malignancies (64%), including 83% of those with driver mutation identified, were low-risk cancers for which a lobectomy could have been sufficient initial treatment.ConclusionCurrent oncogene panel results seem insufficient to guide the surgical extent of solitary ITNs.
| S-EPMC7771319 | biostudies-literature