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

Abstract

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 BRAF V600E (98%, 95% confidence interval [CI 96-99%]), PAX8/ PPARG (55% [CI 34-78%]), HRAS Q61R (45% [CI 22-72%]), BRAF K601E (42% [CI 19-68%]), and NRAS Q61R (38% [CI 23-55%]). Excluding BRAF V600E , 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; BRAF V600E 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.

ThyroSeq v3 for Bethesda III and IV: An institutional experience

“…For cases with gene fusions, the ROM was 91% (10 of 11 cases) for the THADA/IGF2BP3 fusion, similar to the report by Goldner and colleagues (positive predictive value, 100%) 9 . Although, only 2 of our cases contained the PAX/PPARγ fusion, both were malignant, consistent with ATA classification as a high‐risk mutation (95%) 5 .…”

“…Our study demonstrated a 100% ROM when any of these were present. As reported by previous studies, solo mutations in the PTEN , DICER1 , E1F1AX , TSHR , and TP53 genes were associated with benign pathologic follow‐up 9 …”

“…The ROM was 64% (23 of 36) in cases with RAS mutations alone; however, it rose to 100% when it was associated with CNA or other mutations (10 of 10 cases). A recent publication by Goldner et al reported an increased ROM when combinations of genetic alterations were present in the same nodule 9 . In our study, the histopathologic follow‐up of most nodules that had RAS mutations (21 of 33 nodules; 64%) was either NIFTP or PTC‐FV.…”

The Afirma Xpression Atlas for thyroid nodules and thyroid cancer metastases: Insights to inform clinical decision‐making from a fine‐needle aspiration sample

“…For Afirma XA, PPV is reported either for the specific alteration identified or for alterations of that gene. These values were derived from validation data, 3,15,16 a systematic review of the published literature 17 and its periodic update, or real-world experience among consecutively identified patients with available surgical histopathology. 18 These PPVs are reported to their nearest quartile (eg, PPV 50% or 75%), except for those >95% (BRAFV600E, NTRK fusions, and RET fusions) and >99% (medullary thyroid cancer classifier positive).…”

DNA repair proteins may differentiate papillary thyroid cancer from chronic lymphocytic thyroiditis and nodular colloidal goiter

“…The prediction of malignancy of thyroid nodules continues to improve. Sonographic features of thyroid nodules alone are not sufficient to predict malignancy risk 3 . Each year, as many as 50,000 patients in the United States undergo unnecessary thyroidectomy because of the difficulty in distinguishing benign thyroid nodules from thyroid cancers preoperatively.…”