Pituitary neuroendocrine tumors in patients with prior extrapituitary cancer - clinical and immunohistochemical insights into a complex association. Evidence from a retrospective series.

Pituitary neuroendocrine tumors (PitNETs), as the old pituitary adenomas are now defined, represent almost 15% of all intracranial neoplasms. Their particularity consists in considerable morphological and functional heterogeneity. Although mostly benign, PitNETs may coexist with systemic malignancies. The aim of this research was to identify possible associations between PitNETs and prior extrapituitary cancers in a series of patients in order to identify common mechanisms between pituitary and systemic pathology because such associations, although rare, are clinicopathologically significant, raising issues of differential diagnosis and therapeutic strategy. We realized a retrospective descriptive study on six patients diagnosed with PitNETs and a documented history of extrapituitary malignancy, surgically treated at Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iaşi, Romania, between January 2023 and June 2025. Clinical, imaging, and pathological data were collected. Immunohistochemical profile included synaptophysin, cytokeratins, transcription factors [pituitary-specific transcription factor-1 (Pit1), T-box transcription factor 19 (Tpit; Tbx19), steroidogenic factor-1 (SF-1), and pituitary GATA-binding protein 3 (GATA3)], hormonal markers [growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH)], as well as proliferative indices [p53 and Ki67 labeling index (LI)]. The study group comprised four women and two men (mean age 52.7 years). The most frequently associated malignancies were breast carcinoma (BC) and renal cell carcinoma (RCC) (33.3% each), followed by thyroid carcinoma (TC) and hepatocellular carcinoma (HCC) (16.6% each). PitNET subtypes included somatotroph (50%), lactotroph (16.6%), gonadotroph (16.6%), and plurihormonal (16.6%) variants, predominantly microadenomas (83.3%). The mean interval between the two diagnoses was 1632 days (≈4.6 years). GH and PRL immunopositivity predominate in cases with BC, RCC, and TC. Proliferative indices were low (Ki67 <4%), except for one lactotroph PitNET (Ki67 LI: 15%, p53: 20%) associated with HCC. This study highlights a potential bidirectional link between pituitary and systemic tumorigenesis mediated by hormonal and proliferative signaling pathways. The predominance of GH∕PRL-secreting PitNETs in patients with prior systemic malignancies supports the hypothesis of endocrine and molecular crosstalk through the GH∕insulin-like growth factor-1 (IGF-1) axis. Although causality cannot be established, these findings underscore the need for oncological surveillance and endocrine monitoring in patients with PitNETs, especially in those with a previous malignancy.