From histopathology to molecular taxonomy: predicting pituitary neuroendocrine tumors invasiveness

Pituitary neuroendocrine tumors (PitNETs) are among the most prevalent intracranial tumors in adults. Although most follow an indolent clinical course, a substantial subset exhibits local invasion, which can limit gross total resection and increase the risk of residual disease and recurrence. Importantly, anatomical invasiveness should not be equated with clinical aggressiveness. Aggressive PitNETs may also exhibit a longitudinal pattern of repeated or multiple local recurrences and frequently require multiple therapeutic interventions. The 2022 Fifth Edition of the WHO Classification formally renamed pituitary adenomas to PitNETs and established a lineage classification framework centered on core transcription factors, including PIT1, TPIT, and SF1, thereby driving the transition from traditional pathological diagnosis to molecular subtyping. Driven by recent advances in high-throughput sequencing, liquid biopsy, and single-cell omics, numerous novel molecular biomarkers have emerged, enabling the early pre- and postoperative identification of invasive subpopulations. This review systematically outlines recent progress in multidimensional biomarkers—including DNA methylation, protein markers, non-coding RNAs, liquid biopsy indicators, and tumor microenvironmental features—to provide an updated synthesis of candidate biomarkers that may support future risk stratification and individualized management of invasive PitNETs.