Nonfunctioning pituitary adenomas (NFPA) account for approximately 30% of all pituitary adenomas and are the most common type of benign pituitary tumor. Many incidental findings of NFPA do not cause clinical symptoms at all and therefore do not require treatment. NFPAs that require treatment are usually large and may lead to compression of the optic nerve and abnormal endocrine function of the pituitary gland. A proportion of NFPAs are aggressive and can destroy their surrounding structures, causing even more damage. The treatment of NFPA must follow the principle of individualization and standardization. Currently, the treatment of NFPA is mainly surgical, supplemented by drug therapy and radiation therapy. This article reviews the current research and clinical experience in the treatment of NFPA.
Advances in drug therapy 1. Dopamine receptors and drug therapy Pituitary adenomas mostly have dopamine 2 Receptor (D2R) on the surface, which provides a therapeutic target for dopamine agonist (DA). Currently, the main DAs are bromocriptine (BRC), carte blanche (CAB) and norgolin, which are very effective in the treatment of pituitary lactinomas (PRL). Radionuclide analysis of D2R in different pathological types of pituitary adenomas by SPECT technique showed that D2R was also present on the surface of NFPA cells, but less than in PRL. Herder et al. found a significant correlation between the number of D2R on the surface of NFPA cells and the sensitivity to norgolin by nuclear imaging analysis. pivolleno et al. found that D2R has long chain (D2L) , and short chain (D2S) isomers, and the expression rates in NFPA were 50% and 17%, respectively, and 33% of both were expressed simultaneously. Greenman et al. treated 33 patients with residual tumors after NFPA with DA and found that 11 tumors decreased in size, 5 remained the same and 7 increased in size. However, the number of cases in the above study was small, and there is a lack of strong evidence for the efficacy of DA.
2.Growth inhibitory receptor and drug treatment Somatostatin receptor (SSTR) is expressed in various pituitary adenoma cells, providing an important therapeutic target for growth inhibitory analogues such as Octreotide and Lanreotide. Octreotide and lanreotide have the highest affinity for SSTR2 and SSTR5 and the lowest affinity for SSTR3. In NFPA cells, SSTR3 and SSTR2 had the highest expression and SSTR1, SSTR4, and SSTR5 had lower expression. pawlikowski et al. found that non-selective and SSTR2/3-selective growth inhibitors were able to significantly reduce the levels of CgA and α-subunit in NFPA cells, which further increased the expression of SSTR5. Padova et al. found a positive correlation between the expression of SSTR2 and SSTR5 and cell viability in NFPA cells cultured in vitro.Pasireotide (SOM230), a growth inhibitor analogue targeting SSTR1/2/3/5, was shown by Zetalli et al. to significantly reduce the viability of NFPA cells, and this effect was achieved by inhibiting vascular endothelial growth factor (VEGF).
et al. showed that SSTR5 and D2R are able to form new receptors through heteropolymerization, which enhances their respective functions. Therefore, many studies are focusing on drug treatments that target multiple receptors simultaneously.BIM-23A760 is a drug that has a high affinity for both SSTR2 and D2R.Florio et al. used this drug on 38 NFPA cells and found that thymidine uptake was significantly inhibited in 23 of them, thereby reducing cell viability. However, there was no significant difference in the cell growth inhibition of BIM-23A760 compared with that of cabergoline (CAB).Anderson et al. administered a combination of octreotide and cabergoline at high doses to 10 NFPA patients: octreotide 200 μg/Tid and cabergoline 0.5 mg/Qd. After six months, seven patients had a >10% reduction in tumor volume and six patients had a >10% reduction in hormone levels. After six months, 7 patients had >10% reduction in tumor volume, and 6 patients had a significant decrease in hormone level. However, there is still a lack of randomized controlled and stratified trials of the combination of drugs.
Folate receptor and drug therapy The folate receptor (FR), also known as folate-binding proteins (FBP), is not expressed or very low in normal tissues and is specifically highly expressed in some epithelial-derived tumor tissues. It includes at least four isoforms: α, β, γ/γ’ and δ. Evans et al. found by gene microarray, immunohistochemical staining and Western hybridization that FRα is differentially expressed in different pathological types of pituitary adenomas, with high expression in NFPA and low or no expression in secretory function pituitary adenomas (PRL, ACTH, GH). In a subsequent experiment, Evans et al. found that the expression of FRα was positively correlated with the growth rate and mitotic rate of murine alphaT3-1 cells (NFPA) and that transfection of this cell line with the FRα variant gene could have a significantly opposite effect. These results suggest that overexpression of FRα plays an important role in the proliferation of NFPA cells. The folate receptor on the surface of tumor cells has become an important target, providing new ideas for targeted chemotherapy and nuclear imaging studies of certain tumors (e.g., ovarian, lung, and breast cancers). The treatment of NFPA with folic acid analogues also has a very promising future.
4. Temozolomide Temozolomide (TMZ) is a cytotoxic alkylating agent that can methylate the O-6 site of DNA guanine and inhibit angiogenesis in tumor tissues. Hagen et al. used TMZ treatment (150-250 mg/M2 body surface area, 5 days each time with 23 days interval) in one case of pituitary cancer and two cases of invasive pituitary adenoma (PRL and NFPA, respectively). The results showed that all three patients had significant tumor shrinkage and normalization of hormone levels. Moreover, all three patients had MGMT that was not expressed or was lowly expressed. Widhalm et al. analyzed 24 cases of aggressive, recurrent NFPA and found that the percentage of MGMT (-) was 50%, which was higher than that of the general population (24%). This study suggests that aggressive, recurrent NFPA may be suitable for treatment with TMZ. Kovacs et al. analyzed 2 cases of highly aggressive lactinomas and ACTH tumors and found that tumors not expressing MGMT responded more satisfactorily to TMZ. In addition, there are many case reports of treatment with TMZ in various pathological types of aggressive pituitary adenomas, all showing that TMZ significantly controls tumor growth and stabilizes hormone levels, and that this effect is dependent on the absence or low expression of MGMT.
Surgical innovations (endoscopic techniques in pituitary adenoma surgery) The most common treatment for pituitary non-functioning adenomas is currently microscopic transsphenoidal adenomectomy. In recent years, endoscopic transnasal butterfly surgery has received increasing attention and its efficacy has been widely affirmed. In China, Ling Feng et al. summarized 66 cases of endoscopic transnasal butterfly pituitary adenoma surgery and found that the procedure was safer and less complicated, especially for microscopic adenomas and pituitary adenomas confined to the saddle and butterfly sinus. Haisheng Liu and Yazhuo Zhang summarized 100 and 678 cases of endoscopic pituitary tumor surgery, respectively, and obtained similar conclusions. 20 cases of endoscopic pituitary tumor surgery were compared with traditional pituitary surgery cases by Rudnik et al. and found that endoscopic surgery has the advantages of shorter operative time, clearer visual field and less postoperative pain, which is especially suitable for the treatment of recurrent and residual pituitary adenomas. With the continuous improvement of endoscopic technology, it is believed that endoscopic transsphenoidal adenomectomy will be more frequently used in clinical practice.
Radiation therapy for pituitary non-functional adenoma Gamma knife is widely used in the treatment of pituitary non-functional adenoma, especially for postoperative residual adenoma and recurrent adenoma. Wang Meihua et al. followed up 255 patients with NFPA after gamma knife treatment and affirmed the safety and effectiveness of gamma knife in the treatment of NFPA, and found that for patients with residual and recurrent tumors after craniotomy, gamma knife had fewer complications and was superior to conventional radiotherapy. By summarizing 82 cases of NFPA involving the optic pathway, Liu A-li et al. found three cases of tumor enlargement after treatment, suggesting that gamma knife treatment should be carefully chosen for NFPA with significant pressure on the optic pathway. Hoybye et al. summarized 109 cases of pituitary microadenoma treated with gamma knife and obtained satisfactory results. 23 patients with postoperative residual or recurrent NFPA were treated with gamma knife by Hoybye et al. and found significant efficacy and almost no side effects, and GH replacement therapy did not weaken the tumor-killing effect of gamma knife.
With the progress of scientific research and clinical experience, many new options for the treatment of pituitary non-functional adenoma will emerge. The principles of individualization and standardization will be important criteria for measuring these options.