Clinicopathologic and Molecular Characteristics of Pituitary Neuroendocrine Tumors (PitNETs) Treated with Extra-Pseudocapsule Resection and Their Clinical Implications: A Single-Center Experience with 274 Cases

Purpose To evaluate associations between transcription factor (TF)–defined molecular lineage and the clinical characteristics of pituitary neuroendocrine tumors (PitNETs). Methods A retrospective cohort analysis was performed in 274 patients undergoing extra-pseudocapsular transsphenoidal resection, tumors were classified by TF-defined lineage and invasiveness (0–3) and Knosp score. Group differences were tested with appropriate parametric/nonparametric and χ²/Fisher’s exact methods. Predictors of GTR were examined using prespecified hierarchical multivariable logistic regression, and model discrimination compared using ROC/AUC with LRT and DeLong testing. Results TF-defined lineage classification improved diagnostic precision. Among tumors previously classified as nonfunctioning adenomas, 74.7% received a definitive lineage assignment. TF-negative and multilineage tumors showed higher invasiveness rates and higher invasiveness grades than single-lineage tumors. The PIT1–GH/PRL subgroup had the highest prevalence and grade of invasiveness; SOX2 positivity was most frequent in this subgroup (41.7%), which also exhibited the lowest GTR rate (58.3%). SOX2-positive tumors were associated with higher preoperative ACTH and GH levels. SOX2 positivity was more common in multilineage tumors (20.5%) and recurrent cases (20.0%). Compared with Trouillas grading alone, incorporation of invasiveness grade and intraoperative features (capsule status and vascularity) improved discrimination for predicting GTR (AUC, 0.866 vs 0.795; ΔAUC = 0.071; DeLong 95% CI, 0.022–0.120; P = 0.0047). Conclusions The 2022 WHO TF-defined lineage system improves diagnostic precision and facilitates interpretation of PitNET differentiation and molecular pathology. Tumors in the PIT1–GH/PRL subgroup demonstrate more aggressive invasive features. SOX2 positivity has the highest proportion in multilineage tumors and in recurrent surgical patients, and close follow-up is needed.