Pituitary neuroendocrine tumors (PitNETs) are usually benign intracranial neoplasms that may exhibit invasion of the cavernous sinus, complicating surgery and increasing the risk of recurrence. This study aimed to investigate membranous E-cadherin (mE-cad) expression across PitNET subtypes and transcription factor (TF) lineages, including Pit-1 (pituitary-specific positive transcription factor 1), SF-1 (Steroidogenic Factor 1), and TPIT (T-box pituitary transcription factor), and its association with tumor invasiveness in sixty-nine patients. mE-cad expression was evaluated as the percentage of positive cells (0%, 1–10%, >10%) and by immunoreactive score (IRS). Staining intensity was scored as: 0, no staining; 1, weak; 2, moderate; 3, strong. The proportion of positive cells was scored as: 0, none; 1, <10%; 2, 10–50%; 3, 51–80%; 4, >80%. Mean mE-cad expression was 5.2% in gonadotroph, 3.2% in corticotroph, 0.5% in lactotroph, and 17.5% in plurihormonal PitNETs. By TF lineage, the mean expression was 5.3% for Pit-1, 3.2% for TPIT, and 5.1% for SF-1. Low mE-cad expression (IRS 1–2) was associated with higher odds of cavernous sinus invasion compared with IRS 3–6 (adjusted OR = 6.0, 95% CI 1.08–33.4, p = 0.04), independent of tumor volume (adjusted OR = 4.0, 95% CI 1.50–10.7, p = 0.01). After restricting the analysis to the gonadotroph PitNET group, tumors with an IRS of 1–2 showed significantly higher invasiveness compared with those with an IRS of 3–6 (p = 0.012). These findings suggest that mE-cad may serve as a biomarker of PitNET invasiveness, with expression varying according to TF lineage and tumor subtype.