Atypia of undetermined significance in thyroid cytology: Nuclear atypia and architectural atypia are associated with different molecular alterations and risks of malignancy

Abstract

BACKGROUND:The Bethesda System for Reporting Thyroid Cytopathology contains an atypia of undetermined significance (AUS) category with heterogeneous and distinct inclusion criteria. The purpose of this study was to investigate differences in malignancy rates and molecular alterations based on the presence of different criteria. METHODS: A laboratory information search was conducted to identify thyroid fine-needle aspiration specimens signed out as AUS. The cases were reclassified as architectural atypia (3A), cytologic atypia (3C), both architectural and cytologic atypia (3B), or Hürthle cell aspirate (3H).Surgical follow-up and concurrent molecular test results, if available, were collected. RESULTS: Five hundred ten specimens, including 258 reclassified as 3A, 40 reclassified as 3B, 119 reclassified as 3C, and 86 reclassified as 3H, were identified. The risks of malignancy for the subcategories were 13.4%, 26.3%, 44.1%, and 13.8%, respectively. Additionally, BRAF V600E mutations were more prevalent in specimens with cytologic atypia (3B/3C), whereas low-risk alterations, including KRAS, PTEN, and PAX8-PPARy2, were more prevalent in those with architectural atypia (3A). CONCLUSIONS: Subdividing AUS specimens on the basis of the type of atypia can yield categories associated with distinct molecular alterations and risks of malignancy.

Cytomorphologic features of thyroid nodules harboring thyroid adenoma‐associated fusion: A single institutional review of 11 cases

“…18 Data on the malignant fraction upon resection associated with the preoperative identification of THADA fusion across previously published studies (Table 2), including ours, ranged from 80%-100% if NIFTP is included and 32%-100% if NIFTP is excluded. 8,14,[19][20][21][22] The observed wide variation reflects the limitations shared by all of these studies: a small THADA fusion cohort size, selection bias of molecular testing on indeterminate nodules, and additionally, in our study, not all THADA fusion cases were resected, which can impact the malignant fraction estimate. Ultimately, larger studies with THADA fusion EFVPTC case that on resection demonstrated limited angioinvasion (<4 vessels).…”

“…In a recent study by Glass et al exploring thyroid lesions classified as AUS with BSRTC, two THADA::IGF2BP3 fusion cases were included in their cohort, one of which was classified as AUS with architectural atypia (with encapsulated follicular variant of PTC on histologic follow-up) and one was classified as AUS with cytologic atypia (classified as NIFTP on histologic follow-up). 14 However, the specific cytomorphologic findings seen in these cases leading to the interpretation was not discussed. Nonetheless, similar to their study, our THADA-fusion thyroid lesions demonstrated variable degrees of nuclear atypia.…”

“…In the study by Glass et al mentioned previously, their cohort included two cases harboring a PAX8::PPARgamma and four cases with PTEN alterations with all cases showing only architectural atypia. 14 Gilani et al explored the risk of malignancy of KRAS, HRAS, and NRAS alterations identified on thyroid FNAs and in their representative figures, cases demonstrated either architectural atypia in a microfollicular or crowded pattern with occasionally some nuclear atypia. 17 Similarly, in their cohort of AUS thyroid lesions, Glass et al identified 15 cases with RAS mutations that were varied with cases harboring either architectural atypia, cytologic atypia or Hurthle cell change.…”

“…17 Similarly, in their cohort of AUS thyroid lesions, Glass et al identified 15 cases with RAS mutations that were varied with cases harboring either architectural atypia, cytologic atypia or Hurthle cell change. 14 Overall, when evaluating thyroid FNAs from RAS-like lesions, it would be difficult to ascribe a particular genetic driver primarily based on cytomorphology, due to significant overlap among RAS-like tumors.…”

“…While one may suspect a DICER1 alteration in a patient of young age and with a strong family history, it would be difficult to make this determination purely on the cytomorphology alone. In the study by Glass et al mentioned previously, their cohort included two cases harboring a PAX8::PPARgamma and four cases with PTEN alterations with all cases showing only architectural atypia 14 . Gilani et al explored the risk of malignancy of KRAS , HRAS , and NRAS alterations identified on thyroid FNAs and in their representative figures, cases demonstrated either architectural atypia in a microfollicular or crowded pattern with occasionally some nuclear atypia 17 .…”