Determining the molecular test for indeterminate thyroid nodules best suited for our practice: A quality assurance study

Abstract

IntroductionCurrently, molecular studies are widely used as a guiding tool in further management of cytologically indeterminate thyroid nodules. At our institution, clinicians have recently expressed concern over receiving “less positive molecular results” upon switching from an extended 14 gene mutation panel (EGMP) to a 7 gene mutation panel (GMP). Our goal is to compare outcomes of these two tests in regards to the performance characteristics and clinical impact.Materials and MethodsAll thyroid fine‐needle aspiration (FNA) biopsy specimens sent for molecular studies from 2016 to 2017 were retrospectively studied. Cytopathology diagnosis, pertinent clinical findings, molecular results, and follow‐up (F/U) surgical and cytology diagnoses were recorded.ResultsOf the total 165 cases sent for molecular tests 86 (52%) were GMP and 79 (47%) EGMP. There were 21 (24%) and 40 (50%) cases with positive GMP and EGMP results, respectively. Within these positive cases (n = 61), there were a total of 33 (54%) patients who underwent surgical resection and 28 (45%) patients had no follow‐up. The molecular findings and surgical pathologic diagnoses obtained are illustrated in Figures 1 through 4 for GMP and EGMP, respectively.ConclusionsThe selection of molecular testing should be directed toward optimizing patient care and facilitate clinical management. This quality assurance study helped in understanding the complexities associated with test selection best suited for our institution and in educating clinicians.

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

“…{ Nodules from certain publications (33)(34)(35)(36)38) were tested by 7-or 14-gene panels but only reported data on a subset of genes, variants, and/or fusions. x One publication (37) analyzed nodules and reported data on two different panels.…”

“…Only 5 of 36 reported variants were reported with this frequency. a Although one study (37) specifically referred to mutation in MET, panel did not mention MET as a gene being analyzed for variants. The other study (56) did not say how MET was affected, only that it was positive.…”

“…Most publications included in our study accrued patients before the formal recognition of NIFTP, and these neoplasms would have been labeled follicular variant of PTCs and considered malignant. Of the publications in our analysis that reported NIFTP histology in their results (22,27,37,46,48,53,54,63,69), we considered them as ''malignant'' for statistical purposes, consistent with the current desire that they undergo surgical resection as opposed to in situ observation. Thus, PPVs in our study estimate the combined probably of cancer or NIFTP.…”

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

“…Some gene variants including TP53, TERT and TERT gene fusions (indicated with * in Figure 1) are rather not specific for a follicular lesion per se, and may be found in various types of thyroid lesion, so, on its own, may justify the modification of a Bethesda III to Bethesda V. GLIS gene fusions are associated with hyalinizing trabecular tumours and may modify the Bethesda class as Bethesda V. Concurrent EIF1AX and RAS variants are reported to occur in advanced thyroid carcinomas promoting tumorigenesis 51 ; however, also NIFTP cases have been described harbouring concurrent EIF1AX and RAS variants. 44,52 TERT promoter variants, concurrent TERT and RAS variants or TERT and BRAF V600E gene variants are also reported to indicate a more aggressive nature with worse prognosis. [53][54][55][56][57] In case of GLIS translocations (modification to Bethesda V), a lobectomy is the appropriate treatment, for this translocation is highly specific for hyalinizing trabecular tumour (a benign lesion).…”

“…These molecular alterations, also see Figure 1, as being mostly associated with follicular lesions and may occur in follicular adenoma/NIFTP/FVPTC/FTC, would hence suit Bethesda IV. Some gene variants including TP53 , TERT and TERT gene fusions (indicated with * in Figure 1) are rather not specific for a follicular lesion per se, and may be found in various types of thyroid lesion, so, on its own, may justify the modification of a Bethesda III to Bethesda V. GLIS gene fusions are associated with hyalinizing trabecular tumours and may modify the Bethesda class as Bethesda V. Concurrent EIF1AX and RAS variants are reported to occur in advanced thyroid carcinomas promoting tumorigenesis 51 ; however, also NIFTP cases have been described harbouring concurrent EIF1AX and RAS variants 44,52 . TERT promoter variants, concurrent TERT and RAS variants or TERT and BRAF V600E gene variants are also reported to indicate a more aggressive nature with worse prognosis 53–57 …”