scholarly journals BRAF V600E mutation is associated with aggressive features in papillary thyroid carcinomas ≤ 1.5 cm

Author(s):  
Jennifer A. Silver ◽  
Mariya Bogatchenko ◽  
Marc Pusztaszeri ◽  
Véronique-Isabelle Forest ◽  
Michael P. Hier ◽  
...  

Abstract Background While some studies suggest that the BRAF V600E mutation correlates with a high-risk phenotype in papillary thyroid microcarcinoma (PTMC), more evidence is necessary before this mutation can be used to help guide decision making in the management of small thyroid nodules. This study investigated whether BRAF V600E mutation is associated with aggressive features in PTMC (≤ 1 cm) and small PTC (1–1.5 cm). Methods Retrospective chart review was performed on 121 patient cases. Patients who underwent thyroid surgery for PTMC (≤ 1 cm) or small PTC (1–1.5 cm) were included if molecular testing was done for BRAF V600E mutation. Two study groups were created based on tumour size: PTMC (n = 55) and small PTC (n = 66). The groups were analysed for the presence of a BRAF V600E mutation and aggressive features, including macroscopic extrathyroidal extension (ETE), lymph node metastasis (LNM), and high-risk histological features (tall cell, columnar cell, hobnail, solid/trabecular, and diffuse sclerosing). The Fischer exact test was used to calculate statistical significance. Results BRAF V600E mutations were detected in 43.6% of PTMC and 42.4% of small PTC. Of the mutated PTMC nodules, 54.1% demonstrated aggressive characteristics as compared to 19.4% of the non-mutated PTMCs (p = 0.010). Of the mutated small PTC tumours, 82.1% had aggressive features. In contrast, 28.9% of the non-mutated small PTCs showed aggressive features (p < 0.001). Conclusions Our findings demonstrate an association between a BRAF V600E mutation and aggressive features in PTMC (≤ 1 cm) and small PTC (1–1.5 cm). Therefore, determining the molecular status of these thyroid nodules for the presence of BRAF V600E can help guide patient management. Graphical Abstract

Author(s):  
Joshua R. Krasner ◽  
Nourah Alyouha ◽  
Marc Pusztaszeri ◽  
Veronique-Isabelle Forest ◽  
Michael P. Hier ◽  
...  

Abstract Background Molecular testing of thyroid nodules is a diagnostic tool used to better understand the nature of thyroid nodules. The aim of this study is to better comprehend the relationship between specific mutations and aggressive behavior of the tumour as demonstrated on postoperative pathological analysis. Methods A retrospective chart review of 103 cases was performed. Included were patients who had undergone molecular testing using a panel that tests for 9 mutations (ThyGenX®) and were found to have malignant tumours. The following gene alterations were found pre-operatively in the nodules: BRAF V600E (n = 32), BRAF K601E (n = 4), NRAS (n = 11), HRAS (n = 4), KRAS (n = 3), RET/PTC1 rearrangement (n = 1), TERT promoter (n = 2), PAX8-PPARγ rearrangement (n = 1), and 45 cases where no mutation was detected. Aggressive behavior was defined by extra-thyroidal extension (ETE), lymph node metastasis (LN+), and the following variants of papillary thyroid carcinoma: tall cell, solid, diffuse sclerosing, columnar cell and hobnail. Chi-squared testing was performed to compare groups. Results The group with BRAF V600E, RET/PTC1 rearrangement, and TERT promoter mutations was associated with ETE 37.1%, and LN+ 45.7% of the time compared to 4.3 and 13.0% in the group with other mutations, and 4.4 and 4.4% in the group with no mutations (p-value 0.02, p-value < 0.001, p-value 0.006). In addition, the BRAF V600E, RET/PTC1 rearrangement, and TERT mutations group demonstrated tall cell variants (17.1%), columnar cell variants (5.7%), and hobnail variants (3%). The other mutations group demonstrated columnar cell variants (4.3%), and the no mutations group demonstrated solid variants (2.2%). Conclusions In this study, BRAF V600E, RET/PTC1 rearrangement, and TERT mutations were associated with aggressive behaving thyroid malignancies as defined above. Molecular testing may be a useful method to anticipate aggressive tumour types and therefore assist in planning the extent and timing of surgery.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15028-e15028
Author(s):  
Yuntao Song ◽  
Jie Liu ◽  
Weiran Wang ◽  
Tonghui Ma

e15028 Background: Ultrasound and ultrasound-guided fine needle aspiration (US-FNA) are a preferred method for judging benign and malignant thyroid nodules. For thyroid nodules that can’t be determined by FNA, molecular markers of thyroid cancer can be detected as assistant method. This study aim to verify the significance of molecular detection in diagnosis of benign and malignant thyroid nodules in China. Methods: We carried out a prospective study of 383 FNA samples of thyroid nodules, and performed targeted multi-gene NGS on most samples with FSZ-Thyroid NGS Panel V1, the result of which would be incorporated into the reference index for clinicians to decide whether a patient should undergo surgery. And postoperative pathology were followed up. The NGS targets were divided into three categories: high risk (BRAF V600E, TP53, PIK3CA, AKT1, CTNNB1, RET, KRAS with VAF≥30%, HRAS with VAF≥30%, NRAS with VAF≥30%, RET fusion, NTRK1 fusion, NTRK3 fusion, ALK fusion, BRAF fusion), low risk (BRAF non-V600E, EIF1AX, GNAS, TSHR, TERT, KRAS with VAF < 30%, HRAS with VAF < 30%, HRAS with VAF < 30%, PPARG fusion, THADA fusion), benign like (EZH1, SPOP, ZNF148 or no mutations). Results: Among the 383 FNA samples, 333 of them were sequenced with FSZ-Thyroid NGS Panel V1, and 211 thyroid nodules were resected. Finally, postoperative pathology showed that 180 nodules was malignant and 31 was benign. Among the 180 malignant tumors, BRAF V600E (71.1%), RET fusion (7.8%), and TERT mutation (2.8%) were the top three most mutated genes; and there were also significant differences in frequency of some mutations between malignant tumors in different BSRTC class, including more BRAF V600E (83.6%) in class VI malignant tumors, more gene fusions (26.1%) in class V malignant tumors which was significantly higher than that in class VI (7%). And, the frequency of RAS mutations (8.3%) in class III and IV malignant tumors was higher than that of class V and VI. Here a test was considered as positive if a genetic alteration was annotated with High-Risk, and negative if Low-Risk or Benign-Like, the sensitivity and specificity for detecting malignant tumors in BSRTC class III-IV were 66.7% and 100%, respectively, and the total sensitivity and specificity for BSRTC class I-VI malignant tumors were 85.6% and 100%. In addition, 21 of 383 patients underwent Re-FNA. Among these 21 patients, 11 patients detected high risk mutations and 90.9% (10/11) underwent upgrade of BSRTC class on Re-FNA. As a comparation, among the remaining 10 patients who detected low risk or benign like sites, only 30% (3/10) underwent upgrade of BSRTC class on Re-FNA which suggested that the detection of high risk sites might predict the upgrade of BSRTC class on Re-FNA. Conclusions: Molecular testing can distinguish between benign and malignant thyroid nodules and predict the upgrade of BSRTC class on Re-FNA which could provide the reference for treatment decision-making of thyroid nodules in China.


2014 ◽  
Vol 21 (6) ◽  
pp. 891-902 ◽  
Author(s):  
Min-Hee Kim ◽  
Ja Seong Bae ◽  
Dong-Jun Lim ◽  
Hyoungnam Lee ◽  
So Ra Jeon ◽  
...  

The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (≥20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (P=0.010). These results were reinforced by validation dataset (n=348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.


2020 ◽  
Vol 6 (5) ◽  
pp. e273-e278
Author(s):  
Ruey Hu ◽  
George Xu ◽  
Thomas Stricker ◽  
Bingshan Li ◽  
Vivian L. Weiss ◽  
...  

Objective: Here we present 2 cases of papillary thyroid microcarcinomas (PMCs) that had metastasized at presentation. The 2015 American Thyroid Association and the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) criteria do not recommend biopsy of the majority of subcentimeter thyroid nodules, as PMCs are mostly indolent with excellent prognosis. However, the paradigm of active surveillance presents a conundrum on how to identify the rare patient with distant metastatic disease while avoiding unnecessary intervention in the majority. Methods: After initial discovery of incidental lesions on chest computed tomography, core or wedge biopsies of the lung lesion were performed. Thyroid nodules on ultrasound were classified by TI-RADS. Tumor DNA was sequenced, annotated, filtered on 119 known cancer genes, and filtered for variants with an exome allele frequency of <0.001. Results: A 70-year-old woman and a 29-year-old woman presented with incidental pulmonary lesions on computed tomography scan. Lung biopsy revealed lung metastases from papillary thyroid carcinoma. The thyroid nodules in both patients were TI-RADS 3 and American Thyroid Association low-suspicion. Molecular testing showed a c.1721C>G mutation (p.Thr574Ser) in the TSHR gene in patient 1 and a codon 61 mutation in the NRAS gene in patient 2. Both patients were iodine-avid, with complete structural remission in one patient and ongoing treatment with evidence of structural response in the other. Conclusion: The 2 presentations demonstrate unexpected and concerning behavior of PMCs. Both thyroid tumors were subcentimeter in diameter, meaning they would have escaped detection using traditional risk-stratification algorithms in active surveillance. Further knowledge of tumor genetics and microenvironment may assist in predicting tumor behavior in PMCs.


2020 ◽  
Vol 8 ◽  
pp. 232470962094267
Author(s):  
Gliceida Maria Galarza Fortuna ◽  
Paola Rios ◽  
Ailyn Rivero ◽  
Gabriela Zuniga ◽  
Kathrin Dvir ◽  
...  

Thyroid nodules are palpable on up to 7% of asymptomatic patients. Cancer is present in 8% to 16% of those patients with previously identified thyroid nodules. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, accounting for approximately 85% of thyroid cancers. Although most appear as solid nodules on ultrasound imaging, a subset of 2.5% to 6% has cystic components. The presence of cystic changes within thyroid nodules decreases the accuracy of fine needle aspiration (FNA) in the diagnosis of thyroid cancer, given the difficulty of obtaining appropriate cellular content. This becomes a diagnostic and therapeutic challenge. We present a case of a 31-year-old female with a 1-month history of palpitations, fatigue, and night sweats, who underwent evaluation, and was diagnosed with subclinical hyperthyroidism. She presented 4 years later with compressive symptoms leading to repeat FNA, showing Bethesda III-atypia of undetermined significance and negative molecular testing. Thyroid lobectomy revealed PTC with cystic changes. This case is a reminder that patients with hyperfunctioning thyroid nodule should have closer follow-up. It poses the diagnostic dilemma of how much is good enough in the evaluation and management of a thyroid nodule. Early detection and action should be the standard of care.


2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Tae Sook Hwang ◽  
Wook Youn Kim ◽  
Hye Seung Han ◽  
So Dug Lim ◽  
Wan-Seop Kim ◽  
...  

Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n=57), BRAF K601E (n=11), or RAS (n=64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1013-A1014
Author(s):  
Jacob Quaytman ◽  
Yuri E Nikiforov ◽  
Marina Nikiforova ◽  
Elena Morariu

Abstract Somatic and germline mutations of PTEN tumor suppressor gene are associated with follicular-pattern thyroid tumors and PTEN Hamartoma Tumor Syndrome (PHTS). The incidence of cancer in thyroid nodules positive for PTEN mutations on fine-needle aspiration (FNA) is not well defined. The aim of this study was to characterize diagnostic and phenotypic features of thyroid nodules with preoperatively detected PTEN mutations and their impact on management. Thyroid nodules with PTEN mutations on ThyroSeq v3 GC testing of FNA and core needle biopsy specimens from November 2017 to July 2020 were identified from the ThyroSeq Molecular Database. Demographic and clinicopathologic data were obtained through retrospective chart review. We identified 49 PTEN mutation-positive nodules from 48 patients. Patients were 57 years old on average (range 14-88) and 80% female. Cytology was predominantly indeterminate (73% atypia of undermined significance, 18% follicular neoplasm). There were 18 (29%) frameshift, 6 (10%) splice site, and 39 (62%) single nucleotide variant PTEN mutations. Fourteen (29%) nodules had two PTEN mutations, 5 (10%) had copy number alterations, and single cases had concurrent BRAF K601N, EZH1, and NRAS mutations. Surveillance was pursued for 27 (56%) and surgery for 21 (44%) patients (16 lobectomies, 5 total thyroidectomies). There were 14 follicular adenomas (FA), 4 oncocytic FA’s, 1 oncocytic hyperplastic nodule, and 1 encapsulated follicular variant papillary thyroid carcinoma (EFVPTC). The EFVPTC had two low-frequency PTEN mutations, PTEN locus loss, an NRAS mutation, and was a low-risk tumor with capsular but no angiolymphatic invasion. Four (8.3%) patients had confirmed or suspected PHTS, all with multiple nodules. Two had surgery finding no malignancies (2 FA). One PHTS patient had a prior thyroidectomy for a MET mutation-positive nodule that was follicular carcinoma. On US, the mean nodule size of patients who had surgery was larger than the surveillance group (3.2 cm vs. 2.3 cm, p=0.02) but there was no difference in TI-RADS level (p=0.54). There was no difference in mean nodule size (3.5 cm vs. 2.6 cm, p=0.35) or TI-RADS level (p=0.81) between PHTS and non-PHTS patients. Among surveillance patients, follow-up US was done at 1 year in 13/19 (68%) and 2 years in 3/6 (50%) of eligible cases. Only 1/19 (5%) underwent repeat FNA for increased nodule size. No thyroid malignancy was found with a mean of 1.75 years of follow-up (range 1.00-2.78). The EFVPTC patient had no recurrence after 1.05 years of follow-up. In summary, thyroid nodules with isolated somatic PTEN mutations are primarily benign and can be safely followed with serial imaging. Nodules with multiple PTEN mutations were only associated with malignancy when accompanied by an additional NRAS mutation. About 8% of patients with PTEN mutations may be PHTS patients who may be at greater risk for malignancy.


2011 ◽  
pp. 430-437 ◽  
Author(s):  
Luis Eduardo Carmona ◽  
Niradiz Reyes ◽  
Farith González

Objectives: To detect the presence of Streptococcus mutans and Streptococcus sobrinus in dental plaque of children from Cartagena and correlate it to dental caries precavity stages, applying a standardized PCR-based technique for epidemiological purposes. Methods: Descriptive study using a non-probabilistic sample of 50 children between 3 and 5 years of age, preschoolers from a Caribbean population in Colombia. Criteria for selection were that children should exhibit plaque accumulations on the surface of the cervical margins of the rearmost molars, and placed in one of two study groups: carious lesions and sound surfaces. Dental plaque samples from both groups were subjected to molecular analysis and statistical analysis was applied to determine the difference between the two groups using the frequencies of presence of S. mutans, S. sobrinus or both in the two groups applying Fisher’s exact test for association between the presence of microorganisms and the state of the tooth surface from where the dental plaque was taken. Results: The frequency of S. mutans in carious lesions was 76% and 24% in healthy surfaces. The frequency of S. sobrinus in carious lesions was 81.9% and 18.1% in caries-free surfaces. There was statistical significance between the presence of S. mutans and the presence of caries (p=0.001) and between the presence of S. sobrinus (p=0.02) and the presence of caries. There was no statistical significance between the presence of caries and the simultaneous presence of both microorganisms (p=0.08). Conclusions: The presence of S. mutans and S. sobrinus in dental plaque samples is highly prevalent and associated to non cavitated carious lesions, being the molecular identification of these microorganisms by PCR a sensitive, fast, and easy to use detection method for the mutans group of oral bacteria.


2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 410-410
Author(s):  
Ulyana Dashkevych ◽  
Eric Brucks ◽  
Kathylynn Saboda ◽  
Juan Chipollini ◽  
Hani M. Babiker ◽  
...  

410 Background: MB is a serious complication in patients with CAVTE receiving treatment with DOAC or LMWH. The most recent meta-analysis of the four major RCT showed that MB events rate were similar among the DOAC and LMWH group, however, it was noted that MB occurred at GU site 4.9 times more in DOAC than LMWH patients. While GUCA (e.g. bladder and testicular) are considered to be high-risk based on the Khorana Score, they were underrepresented among the RCT ( < 12%). We present a Real-World retrospective cohort study analyzing the MB rates in patients presenting with GU-CAVTE treated either by a DOAC or LMWH compared to those of the RTC. Methods: We performed a retrospective chart review of patients with a diagnosed GUCA and VTE who presented to The University of Arizona Cancer Center (UACC) and were subsequently placed on anticoagulant therapy with either a DOAC or LMWH from 11/2013-4/2020. MB outcome was defined as documented Hgb drop of ≥2 g/dL, ≥2 units of PRBC, MB in a critical site, or contributing to death. MB was extracted and compared from the SELECT D, ADAM VTE, and Caravaggio for DOAC and Hokusai for the LMWH control arm with the GUCA subgroup. Recurrent VTE was collected. In situations where there was insufficient data to categorize individuals, those individuals were excluded from the analysis. The proportion of MB reported in each study were compared using a binomial test. Results: Our review included 56 patients with similar baseline characteristics to the RCT, who were prescribed enoxaparin (n = 13), apixaban (n = 27) and rivaroxaban (n = 16). Our UACC data was compared to the RCT reported MB outcomes with rivaroxaban (12% vs 8%, [p = 0.63]), apixaban (11% vs 6%, [p = 0.40]), and LMWH (both 0 vs 1% [p = 0.67]). No statistical difference among DOAC selection [p = 0.90]. Our UACC rate of MB in patients with GUCA for both DOAC combined versus LWMH were 11.6% (5/43) and 0% [p = 0.1910], compared to the RCT GU subgroup was 5.7% (6/104) [p = 0.02] and 0.6% (1/175) [p = 1.0], respectively. Furthermore, our data found no statistical significance difference among the recurrent VTE rate among DOAC, LMWH, UACC Retrospective or RCT events. Conclusions: In agreement with the four major RCT, our study demonstrated that patients with high-risk GUCA and underlying VTE treated with a DOAC had a non-significant higher incidence of MB compared to those treated with LMWH. Further, our Real-World experience showed that GUCA DOAC had a significantly higher MB event rate compared to the RCT subgroup population. We acknowledge there are inherent biases in all retrospective studies and RCT. These data support the idea that DOAC should be further studied and used with caution in patients with a high risk of bleeding. We recommend LMWH being the safest anticoagulation modality for High-Risk Bleeding GU malignancy.


Author(s):  
C. Griggs ◽  
M. Schmaedick ◽  
C. Gerall ◽  
W. Fan ◽  
C. Orlas ◽  
...  

BACKGROUND: A congenital lung malformation (CLM) that is diagnosed on prenatal ultrasound exam may subsequently become undetectable on later scans, a “vanishing” CLM. OBJECTIVE: The purpose of our study is to characterize the prenatal natural history and postnatal outcomes of “vanishing” lesions treated at our institution. METHODS: We performed a retrospective chart review of 107 patients diagnosed prenatally with CLM at our institution. Comparisons were made using Kruskal-Wallis or t-test for continuous variables and Fisher’s exact test or Chi-Square test for categorical variables. Multivariable analysis using logistic regression was performed. RESULTS: Of the 104 patients, 59 (56.7%) had lesions that became sonographically undetectable on serial ultrasound scans. Patients with lesions that vanished prenatally tended to need less Neonatal Intensive Care Unit (NICU) admission at birth (persistent CLM: 54.8%vs vanished CLM: 28.8%), decreased need for supplemental O2 at birth (persistent CLM: 31.0%vs vanished CLM: 11.9%), and decreased delay in feeds (persistent CLM: 26.2%vs vanished CLM: 8.5%) compared to those with persistent CLM. After multivariate analysis controlling for maternal steroid administration and sex, admission to NICU maintained a slight statistical significance, with patients in the vanishing CLM group 2.5 times less likely to be admitted to the NICU. None of our patients whose lesions vanished prenatally required mechanical ventilation. Eighty-six patients underwent postnatal computed tomography (CT) chest. Only 2 patients had lesions that regressed on postnatal CT. CONCLUSION: Lesions that vanish on prenatal imaging may be associated with improved clinical outcomes. The rate of true regression at our institution was as low as 2.3%.


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