Yield and costs of molecular diagnostics on thyroid cytology slides in the Netherlands, adapting the Bethesda classification

Aydemirli, Mehtap Derya; Snel, Marieke; Wezel, Tom van; Ruano, Dina; Obbink, Christianne M. H.; Hout, Wilbert B. van den; Schepers, Abbey; Morreau, Hans

doi:10.1002/edm2.293

Cited by 8 publications

(6 citation statements)

References 69 publications

(143 reference statements)

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“… 36 This may guide treatment decisions, for example, in the context of de-escalation strategies or directing toward initial total thyroidectomy when a high-risk alteration is found (e.g., ALK , PIK3CA , NTRK fusion, TP53 + RAS , or BRAF V600E + TERT ). 4 , 31 , 36 , 37 A minority of the alterations observed in this study were high risk, confining this benefit as well as the PPV of MD in Bethesda III/IV populations. Other therapeutic advantages, such as those regarding targeted therapies for advanced-stage thyroid carcinoma, are likely more confined for preoperative MD as they only apply to the limited number of patients that develop iodine-refractory disease.…”

Section: Discussionmentioning

confidence: 57%

“…As previously described, the custom Ampliseq™ Cancer Hotspot v6 panel (Thermo Fisher Scientific, Waltham, MA), which targets 87 genes that are relevant for the characterization of thyroid neoplasms, and the Archer ® FusionPlex CTL v2 panel (ArcherDX Inc., Boulder, CO), which assesses 19 relevant genes, were used for somatic mutation and gene fusion analysis, respectively (details provided in the Supplementary Data ). 4 , 25–27 …”

Section: Methodsmentioning

confidence: 99%

“… 1–3 The interpretation and use of finding different molecular alterations including DNA variants, gene fusions, and chromosomal copy number alterations (CNA) is based on many contributions in the literature. 4–7 In oncocytic neoplasms, CNA with near-whole genome haploidization (GH) with or without subsequent genome doubling is considered to be an important genomic driver. 8–14 …”

Section: Introductionmentioning

confidence: 99%

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Molecular Diagnostics and [¹⁸F]FDG-PET/CT in Indeterminate Thyroid Nodules: Complementing Techniques or Waste of Valuable Resources?

de Koster,

Morreau,

Bleumink

et al. 2024

Thyroid®

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Background: An accurate preoperative workup of cytologically indeterminate thyroid nodules (ITN) may rule out malignancy and avoid diagnostic surgery for benign nodules. This study assessed the performance of molecular diagnostics (MD) and 2-[ 18 F]fluoro-2-deoxy- d -glucose ([ 18 F]FDG)-positron emission tomography/computed tomography (PET/CT) in ITN, including their combined use, and explored whether molecular alterations drive the differences in [ 18 F]FDG uptake among benign nodules. Methods: Adult, euthyroid patients with a Bethesda III or IV thyroid nodule were prospectively included in this multicenter study. They all underwent MD and an [ 18 F]FDG-PET/CT scan of the neck. MD was performed using custom next-generation sequencing panels for somatic mutations, gene fusions, and copy number alterations and loss of heterozygosity. Sensitivity, specificity, negative and positive predictive value (NPV, PPV), and benign call rate (BCR) were assessed for MD and [ 18 F]FDG-PET/CT separately and for a combined approach using both techniques. Results: In 115 of the 132 (87%) included patients, MD yielded a diagnostic result on cytology. Sensitivity, specificity, NPV, PPV, and BCR were 80%, 69%, 91%, 48%, and 57% for MD, and 93%, 41%, 95%, 36%, and 32% for [ 18 F]FDG-PET/CT, respectively. When combined, sensitivity and specificity were 95% and 44% for a double-negative test (i.e., negative MD plus negative [ 18 F]FDG-PET/CT) and 68% and 86% for a double-positive test, respectively. Concordance was 63% (82/130) between MD and [ 18 F]FDG-PET/CT. There were more MD-positive nodules among the [ 18 F]FDG-positive benign nodules (25/59, 42%, including 11 (44%) isolated RAS mutations) than among the [ 18 F]FDG-negative benign nodules (7/30, 19%, p = 0.02). In oncocytic ITN, the BCR of [ 18 F]FDG-PET/CT was mere 3% and MD was the superior technique. Conclusions: MD and [ 18 F]FDG-PET/CT are both accurate rule-out tests when unresected nodules that remain unchanged on ultrasound follow-up are considered benign. It may vary worldwide which test is considered most suitable, depending on local availability of diagnostics, expertise, and cost-effectiveness considerations. Although complementary, the benefits of their combined use may be confined when therapeutic consequences are considered, and should therefore not routinely be recommended. In nononcocytic ITN, sequential testing may be considered in case of a first-step MD negative test to confirm that withholding diagnostic surgery is oncologically safe. In oncocytic ITN, after further validation studies,...

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Section: Discussionmentioning

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Diagnostics and [¹⁸F]FDG-PET/CT in Indeterminate Thyroid Nodules: Complementing Techniques or Waste of Valuable Resources?

de Koster,

Morreau,

Bleumink

et al. 2024

Thyroid®

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“…[2][3][4] The utility of comprehensive next-generation sequencing analysis in the context of equivocal Bethesda category III (B-III) lesions has been validated and a recent report suggested that the use of molecular testing may prevent repeat cytology testing and unnecessary surgery. 5 Many pathology laboratories have not implemented these multi-gene platforms in their daily clinical work-up of thyroid nodules yet due to logistical challenges and/or affordability. In this aspect, single-gene analyses of cytology material have proven a cost-effective substitute that increases the diagnostic accuracy of thyroid lesions, including BRAF V600E and TERT promoter mutations.…”

Section: Introductionmentioning

confidence: 99%

“…Combining FNAC with molecular analyses has proven particularly useful for subsets of challenging cases in which standard reporting is not always sufficient to pinpoint malignant cases preoperatively 2–4 . The utility of comprehensive next‐generation sequencing analysis in the context of equivocal Bethesda category III (B‐III) lesions has been validated and a recent report suggested that the use of molecular testing may prevent repeat cytology testing and unnecessary surgery 5 . Many pathology laboratories have not implemented these multi‐gene platforms in their daily clinical work‐up of thyroid nodules yet due to logistical challenges and/or affordability.…”

Section: Introductionmentioning

confidence: 99%

Digital droplet PCRTERT promoter mutational screening in fine needle aspiration cytology of thyroid lesions: A highly specific technique for pre‐operative identification of high‐risk cases

Hysek

Hellgren

Stenman

et al. 2023

Diagnostic Cytopathology

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Background Despite the advent of comprehensive molecular testing in surgical pathology, most centers still rely on the morphological assessment of fine‐needle aspiration cytology (FNAC) to triage patients with thyroid nodules for surgery. Subsets of patients could benefit from the inclusion of molecular testing to increase the diagnostic and/or prognostic properties of the cytology analysis, including the assessment of TERT promoter mutations, an event coupled with thyroid malignancy, and poor prognosis. Methods In this prospective study, preoperative FNAC material from 65 cases was assessed for TERT promoter hotspot mutations C228T and C250T using the digital droplet PCR (ddPCR) technique on frozen pellets and re‐evaluated postoperatively. Results Our cohort consisted of 15 B‐III (23%), 26 B‐IV (40%), 1 B‐V (2%), and 23 (35%) B‐VI lesions according to the Bethesda System for Reporting Thyroid Cytopathology. TERT promoter mutations were detected in 7 cases; 4 papillary thyroid carcinomas (all with preoperative B‐VI status), two follicular thyroid carcinomas (one B‐IV and one B‐V status), and one poorly differentiated thyroid carcinoma (with B‐VI status). All mutated cases were verified by mutational analysis of tumor tissue derived from postoperative formalin‐fixed paraffin‐embedded tissue, while all cases identified as wild‐type on FNAC remained wild‐type postoperatively. Moreover, the occurrence of a TERT promoter mutation was significantly associated with malignant disease and higher Ki‐67 proliferation indices. Conclusion In the present cohort, we found that ddPCR is a highly specific method for detecting high‐risk TERT promoter mutations on thyroid FNAC material that could guide different surgical approaches in subsets of indeterminate lesions if reproduced in larger materials.

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