Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic options. As a promising therapeutic approach, cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The purpose of this review is to report the progress of immunotherapy in pituitary tumors, including refractory PAs and PCs. The tumor immune microenvironment has been recognized as a key contributor to tumorigenesis, progression, and prognosis. One study indicated that the number of CD68+ macrophages was positively correlated with tumor size and Knosp classification grade for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but pituitary growth hormone (GH) adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in pituitary tumor size and invasiveness. Another study suggested that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogs in acromegaly patients, highlighting a potential role of the tumor immune microenvironment in determining the prognosis of somatotroph pituitary tumors. Preclinical studies have indicated that widely varying degrees of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are found among different subtypes. Functional PAs and aggressive PAs express significantly higher levels of PD-L1 and TILs than other subtypes, indicating that PD-1 blockade might be a promising alternative therapy for patients with aggressive PAs. PD-L1 transcript and protein levels were found to be significantly increased in functioning (GH and prolactin-expressing) pituitary tumors compared to nonfunctioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary tumors harbored higher levels of PD-L1 mRNA than recurrent tumors. These findings suggest the possibility of considering checkpoint blockade immunotherapy for functioning pituitary tumors refractory to conventional management. Animal models of Cushing’s disease also demonstrated PD-L1 and TIL expression in cultured tumors and murine models, as well as the effectiveness of checkpoint blockade therapy in reducing the tumor mass, decreasing hormone secretion, and increasing the survival rate. Clinical studies show that immunotherapy may be an effective treatment in patients with pituitary tumors. One corticotroph carcinoma patient showed a significant reduction in hormone levels and shrinkage of the tumor size of primary and metastatic lesions immediately after investigational treatment with ipilimumab and nivolumab. However, another patient with corticotroph adenoma progressed rapidly after four cycles of anti-PD-1 (pembrolizumab) treatment. To date, there are two registered clinical trials of immunotherapy for pituitary tumors. One of them is the phase II clinical trial of nivolumab combined with ipilimumab for patients with aggressive pituitary tumors (NCT04042753). The other one is also a phase II clinical trial of the combination of nivolumab and ipilimumab for rare tumors, including pituitary tumors (NCT02834013). Both clinical trials are in the stage of recruiting patients and have not been completed. In summary, the results from preclinical research and clinical studies indicated that immunotherapy might be a promising alternative therapy for PCs and refractory PAs resistant to conventional treatments. The combination of immunotherapy and radiotherapy or temozolomide may have synergistic effects compared to a single treatment. More preclinical and clinical studies are needed to further indicate the exact efficacy of immunotherapy in pituitary tumors.

Pituitary adenomas (PAs) are a group of tumors with complex and heterogeneous clinical manifestations. Early accurate diagnosis, individualized management, and precise prediction of the treatment response and prognosis of patients with PA are urgently needed. Artificial intelligence (AI) and machine learning (ML) have garnered increasing attention to quantitatively analyze complex medical data to improve individualized care for patients with PAs. Therefore, we critically examined the current use of AI and ML in the management of patients with PAs, and we propose improvements for future uses of AI and ML in patients with PAs. AI and ML can automatically extract many quantitative features based on massive medical data; moreover, related diagnosis and prediction models can be developed through quantitative analysis. Previous studies have suggested that AI and ML have wide applications in early accurate diagnosis; individualized treatment; predicting the response to treatments, including surgery, medications, and radiotherapy; and predicting the outcomes of patients with PAs. In addition, facial imaging-based AI and ML, pathological picture-based AI and ML, and surgical microscopic video-based AI and ML have also been reported to be useful in assisting the management of patients with PAs. In conclusion, the current use of AI and ML models has the potential to assist doctors and patients in making crucial surgical decisions by providing an accurate diagnosis, response to treatment, and prognosis of PAs. These AI and ML models can improve the quality and safety of medical services for patients with PAs and reduce the complication rates of neurosurgery. Further work is needed to obtain more reliable algorithms with high accuracy, sensitivity, and specificity for the management of PA patients.

Most pituitary tumors are considered benign adenomas, and only 0.1%–0.2% of them present metastasis and are defined as pituitary carcinomas (PCs). Refractory pituitary adenomas (PAs) lie between benign adenomas and true malignant PCs and are defined as aggressive-invasive PAs, characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments. Refractory PAs and PCs are notoriously difficult to manage because of limited therapeutic options. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis not only during development but also during pathological processes in pituitary tumors. Recently, increasing numbers of preclinical studies and clinical research have demonstrated that anti-VEGF therapy plays an important role in pituitary tumors. The purpose of this review is to report the role of VEGF in the development and pathology of pituitary tumors and the progress of anti-VEGF therapy in pituitary tumors, including refractory PAs and PCs. Previous preclinical studies indicated that cyclin-dependent kinase 5 (CDK5)-mediated VEGF expression might play a crucial role in the development of PAs. Vascular endothelial growth inhibitors have been reported as independent predictors of invasion in human PAs and have been indicated as markers for poor outcome. Furthermore, several studies have reported that angiogenesis decreases tumor sizes in experimental animal models of pituitary tumors. The expression of VEGF is relatively high in PAs; therefore, anti-VEGF therapy has been used in some refractory PAs and PCs. To date, anti-VEGF has been reported as monotherapy, in combination with temozolomide (TMZ), TMZ and radiotherapy, and with pasireotide, which might be a promising alternative therapy for refractory PAs and PCs resistant to conventional treatments. However, the role of anti-VEGF therapy in pituitary tumors is still controversial due to a lack of large-scale clinical trials. In summary, the results from preclinical studies and clinical trials indicated that anti-VEGF therapy monotherapy or in combination with other treatments may be a promising alternative therapy for refractory PAs and PCs resistant to conventional treatments. More preclinical studies and clinical trials are needed to further evaluate the exact efficacy of anti-VEGF in refractory PAs and PCs.

Background: This study analyzed the clinical features, imaging manifestations, histopathology, immunohistochemistry, and surgical approaches of the orbital solitary fibrous tumor (OSFT), as well as the factors for postoperative recurrence of such disease. Methods: The clinical data of 16 patients with OSFT treated in our center from 2003 to 2020 were analyzed retrospectively, and the clinical symptoms, treatment methods, and follow-up results were recorded. Results: Of the 16 patients, 8 were females (50.0 %) and 8 were males (50.0 %); the average age of treatment was 37 ± 7 years and the median follow-up time was 74 (8, 228) months. Sixteen patients with OSFT underwent a total of 29 operations, of which 12 were transorbital approach operations and 17 were transfronto-orbital approach operations. Ten patients (10/16, 62.5 %) had recurrence. The recurrence rate of transorbital approach operations was 83.3 % (10/12), and the recurrence rate of transfronto-orbital approach operations was 17.6 % (3/17). No patients had treatment-related complications. Conclusions: The main pathological feature of OSFT is a benign tumor. OSFT has a tendency to grow toward the cranio-orbital junction. The postoperative recurrence rate of OSFT is relatively high, so complete tumor resection is very important for prognosis. Inappropriate surgical approaches can lead to incomplete removal of the tumor and cause recurrence. Choosing the correct operation approach according to the position of the OSFT in the orbit and complete removal of the dura mater and bone affected by the tumor is crucial for the prognosis. Nevertheless, regular long-term follow-up after complete resection is necessary.