Risk of malignancy in PTEN-altered thyroid nodules detected on preoperative FNA molecular testing: a systematic review and meta-analysis.

AIMS: Phosphatase and tensin homolog (PTEN) alterations are increasingly encountered on molecular testing of thyroid fine-needle aspiration (FNA) specimens in Bethesda III/IV nodules. Unlike high-specificity alterations (e.g., BRAF V600E), PTEN alterations can map to a broad morphologic spectrum and are influenced by the diagnostic pathway determining which nodules proceed to surgery. We performed a systematic review and meta-analysis to define risk of malignancy (ROM) for PTEN-altered thyroid nodules detected preoperatively.

METHODS

Studies (2020-2025) reporting PTEN alterations detected preoperatively on FNA-based testing with surgical histopathology were reviewed. The primary meta-analysis included Bethesda III/IV-predominant cohorts with PTEN-altered nodules undergoing surgery. We pooled invasive malignancy ROM using random-effects meta-analysis and performed a sensitivity analysis counting noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) as an event.

RESULTS

Three cohorts comprised 87 resected PTEN-altered nodules with 28 invasive malignancies. Pooled ROM for invasive malignancy was 32.4% (95% confidence interval (CI) 23.4-42.9; I2 = 0%). Malignant outcomes included follicular thyroid carcinoma, papillary thyroid carcinoma (including variants), and rare poorly differentiated or anaplastic thyroid carcinoma. Counting NIFTP as an event increased pooled ROM to 37.7% (95% CI 23.9-53.9).

CONCLUSIONS

PTEN alterations detected preoperatively confer an intermediate ROM (∼32%) in surgically followed cohorts, but ROM is modulated by pathway-related selection for surgery and by how PTEN alteration is operationalized (sequence variant vs protein loss). A PTEN-altered preoperative result should be communicated as a moderate-risk molecular finding that frequently maps to follicular/oncocytic neoplasia yet includes differentiated carcinomas and rare high-grade disease, supporting integrated pathology-radiology-molecular decision-making.