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Introduction
Pituitary neuroendocrine tumors are the third most common intracranial tumor [1], and the most frequently observed cause of sellar masses [2]. The Central Brain Tumor Registry of the United States (CBTRUS) revealed that pituitary neuroendocrine tumors accounted for 16.8% of all primary brain and central nervous system (CNS) tumors in the U.S. during 2012 to 2016 [3]. The prevalence rates of pituitary neuroendocrine tumors vary from 1/865 adults to 1/2688 adults in several European countries [4, 5, 6–7]. Pituitary neuroendocrine tumors are highly heterogeneous in growth and invasiveness. Although the majority of pituitary neuroendocrine tumors are benign, 25% to 35% of them are invasive and extremely rare cases (0.2%) are malignant pituitary carcinomas [1, 8, 9].
Pituitary neuroendocrine tumors can also be categorized in several distinct ways. Based on tumor size, pituitary neuroendocrine tumors are divided into two groups, microadenomas (< 10 mm) and macroadenomas (≥ 10 mm) [10]. According to functional status, pituitary neuroendocrine tumors are categorized as non-functioning adenomas that do not secrete hormones, or functioning adenomas with hormone hypersecretion [2, 10]. Furthermore, the Knosp classification has been developed to assess the possibility of cavernous sinus invasion by pituitary macroadenomas [11]. However, these classification systems are not exclusive of each other; an individual pituitary neuroendocrine tumor may fit into more than one subcategories. Different subcategories of pituitary neuroendocrine tumors are associated with discrete pathological and prognostic characteristics [2, 12, 13].
All pituitary neuroendocrine tumors are removed via piecemeal resection, while surgical resection of pituitary macroadenomas represents a major challenge to the neurosurgeons; the gross total resection (GTR) rate is negatively correlated with the Knosp grade of pituitary macroadenomas [14, 15, 16–17]. Furthermore, pituitary macroadenomas of greater than 30 mm in diameter may require two-stage operations, in order to remove the residual masses at the periphery that may have about 30% of preoperative volume [14, 18]. However, partial resection of pituitary neuroendocrine tumors is associated with recurrence [19], and residual tumor dramatically increases the risk of regrowth of pituitary neuroendocrine tumors [20]. Hence, it is reasonable to assume that cancer cells in the peripheral zone of pituitary macroadenomas may possess invasive properties.
A variety of molecules involved in proliferation, angiogenesis, microvessel density (MVD), and/or tumorigenesis have been proposed as potential biomarkers of invasiveness in diverse...