Pituitary adenoma is a common benign tumor, its incidence is about 1/100,000-7/100,000, it is common in people between 20 and 50 years old, there is no significant difference in incidence between men and women, it is generally high in young adults, accounting for 10% of intracranial tumors, second only to glioma and meningioma. However, in autopsy cases, suboptimal pituitary tumors are found in 20-25% of cases. With the continuous progress of medical science and technology, some new treatment methods are worth comparing with the previous ones to provide reference for choosing the appropriate treatment method in clinical practice.
I. Etiology and classification.
The pathogenesis of pituitary tumors has long been controversial, and there are mainly two different arguments: (1) pituitary gland itself is defective; (2) hypothalamic dysfunction. The former is purely due to local factors, the pituitary cells are in a hyperfunctional state and then form adenomas, therefore, early treatment of microadenomas is expected to obtain a cure. The latter is due to hypothalamic dysfunction secondary to pituitary lesions forming adenoma, therefore, pituitary adenoma is just a stage of hypothalamic endocrine dysfunction. Therefore, removal of pituitary adenoma can only treat the symptoms but not the root cause, and postoperative treatment must be supplemented by radiotherapy or medication in the hypothalamus, and is prone to recurrence [2]. In terms of gross morphology, pituitary adenomas can be classified as microadenomas (<1,0 cm in diameter), macroadenomas (>1,0 cm in diameter) and giant adenomas (>3,0 cm in diameter). According to their pathological nature, they can be classified as: prolactin (PRL) adenocytoma, growth hormone (GH) cell adenoma, adrenocorticotropic hormone (ACTH) cell adenoma, thyrotropin (TSH) cell adenoma, gonadotropin (LH) adenoma, multisecretory function cell adenoma, nonsecretory function (NFA) cell adenoma, and malignant pituitary adenoma [3].
II. Clinical presentation and diagnosis.
Pituitary tumors, especially functional hormone-secreting tumors, can have two manifestations: the dilating effect of the occupying lesion, and the abnormal secretion of hormones, or the reduction of hormone secretion due to excessive secretion or the enlargement of the tumor compressing the normal pituitary tissue, which manifests as secondary hypogonadism, adrenocortical and hypothyroidism. Through detailed history questioning and careful physical examination, it provides an important basis for the diagnosis of pituitary tumor. Currently, advanced imaging techniques such as CT and MRI and dynamic functional experiments on various pituitary hormones are mainly used to diagnose and differentially diagnose pituitary tumors, but the final diagnosis is determined by pathological examination [4].
III. Pharmacological treatment
Pharmacological treatment includes bromocriptine for PRL adenoma, GH adenoma and ACTH adenoma. Growth inhibitors or estrogens are used to treat GH adenomas. Cyproheptadine and diphenyldichloroethane (O,P`DDD), aminoglutethimide, mepyrone, etomidate, and nitrogenous phenylephrine for ACTH adenomas. Non-functioning adenomas and hypopituitarism are treated with various hormone replacement therapies. Among them, except for bromocriptine for PRL adenomas and growth inhibitor GH adenomas, which have partial efficacy, the efficacy of other drugs for tumor control is uncertain [5].
IV. Surgical treatment
1.Transcranial pituitary tumor resection
(1) Transcranial approach: Horsley used this approach to do the first case of pituitary adenoma in 1889, and it was the routine pituitary tumor resection procedure in neurosurgery before 1970s, and the indications for surgery are mainly for larger pituitary tumors with advanced stage and suprasellar development and visual dysfunction, and the tumor can be removed under direct vision, and the decompression of visual cross is more complete. However, it is more difficult for those with anterior optic cross, such as in the pterygoid saddle, and more difficult for microadenoma surgery.
(2) Transtemporal approach: Horsley adopted the transtemporal approach in 1906 to remove pituitary adenomas developing to the parsaddle, but the resection of intra-saddle tumors is not satisfactory in this operation.
(3) Transsphenoidal approach (anterolateral): Since Adson applied this approach in 1918, it is still used today. This procedure is suitable for pituitary adenomas that develop posteriorly and partially to the optic cross or invade the cavernous sinus. It can be used to explore the anterior optic cross, the pars plana, or the inferior and posterior optic cross between the optic cross and the internal carotid artery. The tumor can be easily removed with good results. This operation is complicated, and it is necessary to deal with the skull base vein and avoid damaging the optic nerve, optic cross, internal carotid artery and its posterior communicating artery, superior choroidal artery and small arteries supplying pituitary tumor and hypothalamus to avoid adverse consequences and serious complications.
2. Transsphenoidal pituitary tumor resection
Since Schloffer used transnasal pterygoid sinus for pituitary tumor resection in 1907, there have been many variations of the transsphenoidal approach, such as transoral nasal pterygoid approach, transnasal pterygoid (unilateral or bilateral) approach, transseptal pterygoid approach and maxillary sinus pterygoid approach. protect the pituitary function. In China, Yin Zhaoyan [7] was the first to carry out this modern transoral nasopalatine sinus microsurgery in 1979 to treat microscopic tumors in the pituitary region. In recent years, with the development of microsurgery, various conventional open transsphenoidal pituitary tumor surgeries have been used for endoscopic operations. jankowski [8] et al. first reported the successful treatment of three pituitary tumors by endoscopic transsphenoidal surgery in 1992, and this procedure has gained more and more attention since then. Zhou Bo [9] et al. reported 32 cases of endoscopically assisted transsphenoidal sinus resection of pituitary adenomas, 26 cases of complete tumor resection and 6 cases of near-total resection, all of which had restored visual field compared with the preoperative period. Currently Cappabianca [10] et al. have designed an updated set of endoscopic transsphenoidal-pituitary adenoma resection instruments, which have a great impact on the surgical outcome. Liu Yansheng [11] et al. reported that the tumor parenchyma, intra-saddle and supra-saddle tumor walls were surgically excised by using a locked-hole approach (transbrow incision or trans-pterygoid point approach incision), and the surgical total resection rate reached 86,1%, and postoperative MRI and CT confirmed the total resection of the tumor without postoperative radiation therapy, with a recurrence rate of less than 7%. Guo Yongchuan [12] concluded that although the transsphenoidal sinus approach to remove pituitary adenoma as a conventional procedure has the advantages of small trauma and quick recovery, there are still some blind areas in the microscopic saddle area, parasternal area and suprasaddle area, and intraoperative tumor residual, saddle septal perforation and even internal carotid artery injury may occur. The results were 7 cases of total resection, 14 cases of submicroscopic total resection, and 2 cases of partial resection without death or serious complications. For huge pituitary adenomas in the midline of the skull base, especially those invading the nasal, pterygoid, septal sinus and slope areas, Derme [13] used the anterior skull base epidural approach to remove the tumor in this area, which is more difficult to remove the tumor and skull base reconstruction because of the deep location and small clearance. In China, Liangfu Zhou [14] improved the Derome approach to an expanded inferior frontal epidural approach and achieved satisfactory results. In China, there are also reports of combined transfrontal and transsphenoidal approaches and combined expanded inferior frontal dural and extradural approaches [15]. Tong [16] reported 10 cases of giant pituitary tumor resection by using the enlarged anterior skull base approach and combined trans-platform pterygoid sinus and trans-longitudinal fissure simultaneously, with 8 cases of total microscopic sarcoma and 2 cases of subtotal resection. Based on the traditional transsphenoidal approach, Kitano [17] invented an extended submucosal posterior septal osteotomy with a transsphenoidal approach for resection of cavernous sinus tumors or suprasellar region tumors that could not be resected by the traditional transsphenoidal approach. This procedure was performed on 14 patients with large pituitary adenomas, 3 patients with craniopharyngioma, and 1 patient with pterygoid nodal cerebrospinal meningioma. The traditional submucosal dissection of the nasal septum via the pterygoid approach was extended to the superior lateral wall of the nasal cavity, thus exposing the bony surface of the superior turbinate bone located under the nasal mucosa. The submucosal septal sinus excision widens the view of the upper and lateral parts of the nasal cavity exposed through the traditional transsphenoidal approach. This procedure provides a safer and less invasive approach to the cavernous sinus or suprasellar region through the pterygoid sinus. Using this approach the authors have not encountered postoperative complications such as olfactory disturbances, cranial nerve palsy or arterial injury. In recent years, due to the establishment of the microinvasive concept and the maturation of microneurosurgical techniques, more and more pituitary adenomas are being resected by different modalities of transsphenoidal surgery. However, the experience and lessons learned about the lethal complications that occur with transsphenoidal surgery [18] and the protection of the normal pituitary gland during transsphenoidal surgery have also raised concerns. Endoscopic assistance can improve visualization within the saddle area and enhance safety, but it is still difficult to manage lesions in some hard and tough pituitary adenomas or when some giant pituitary adenomas are beyond the endoscopic visualization range. The principle should be to facilitate normal pituitary function. Therefore, the following indications are recommended: ①minor pituitary adenoma with well-developed pterygoid sinus. ②Tumor is confined to the saddle. ③Pituitary adenoma with obvious invasion of the pterygoid sinus and no suprasellar growth or mild suprasellar growth. ④Tumor with soft texture of macroadenoma or giant adenoma (size <4cm, blunt and round shape, without obvious saddle opening narrowing and pre-saddle, para-saddle and post-saddle extension). In contrast, those with hard and tough tumors, narrow saddle opening and giant pituitary adenoma (>4cm) with obvious pre-saddle, para-saddle and post-saddle extensions should be operated transcranially. Except for those who mainly invade the pterygoid sinus, the aggressiveness of pituitary adenoma is not the main basis for the selection of this operation.
V. Radiotherapy.
1.Conventional radiotherapy: conventional radiotherapy is suitable for pituitary adenoma cases with incomplete surgery or possible recurrence. Generally speaking, conventional radiotherapy has certain effects, among which substantial ones are more sensitive than those with cystic changes. It can control the tumor development, sometimes shrink the tumor and make the visual field improve, but it cannot cure fundamentally. However, the incidence of complications such as alopecia, optic nerve damage and pituitary hypoplasia is high.
2.Stereotactic radiosurgery: Using stereotactic technology, high-energy rays are converged on the intracranial target foci to destroy the target tissues once or more, and the surrounding tissues are protected from damage due to the sharp reduction of radiation dose. Among them, γ-knife is increasingly valued for its advantages of precise positioning, high precision, and very low complications [21]. For primary as well as residual and recurrent tumors after surgery, tumors >0,3 mm away from the visual path and <4 cm in diameter can be directly treated with γ-knife. In recent years, literature [22] reported that γ-knife radiosurgery for pituitary adenoma controlled tumor growth rate of 92%~100%, decreased hormone secretion and improved endocrine symptoms rate of 77,1%~93%. ), complications are minimal, and NFA and microinvasive growth of pituitary adenoma can be the preferred treatment for gamma-knife radiosurgery. For well-defined functional adenomas (FA), γ-knife radiosurgery is allowed to give high doses to treat the tumor, but the rate of hormonal decline after γ-knife treatment is slow, and microsurgery should be chosen for the treatment of rapidly progressing Cushing`s disease. The establishment of its long-term effect needs to be followed up in clinical practice in the future for a longer period of time.
3.Stereo-structural ortho-projective radiotherapy: Stereo-structural ortho-projective radiotherapy is a highly accurate technique for the treatment of pituitary adenoma patients who require radiotherapy. Preliminary results indicate that it is effective in controlling tumors with low toxicity, which is within the range expected from conventional external beam radiotherapy. While this technique has the potential advantage of reducing the volume of normal brain tissue irradiated, long-term studies are needed to prove that it can maintain tumor control and reduce toxicity more than conventional radiotherapy.
4.Heavy particle radiotherapy: The heavy particle therapy carried out by foreign applications of cyclotron includes alpha particle beam, proton beam, negative meson, fast neutron and so on. The efficacy is up to 80%.
5, radionuclide implantation irradiation: through craniotomy or puncture route to implant radionuclides (gold 198, yttrium 92) in the cranium, but the dose is difficult to grasp, the efficacy is poor, many complications, now less used.
Sixth, gene therapy:
With the increasing research on pituitary molecular and cell biology, gene therapy of pituitary tumors by applying vectors such as adenovirus [24] has attracted great interest, and the feasibility of in vivo specific pituitary cell type gene expression has been observed using brain stereotaxic injection of adenoviral vectors with pituitary-specific initiation. The approach was to incorporate a human growth hormone promoter (AdGHGal) or a human glycoprotein hormone alpha subunit promoter (AdαGal) into the recombinant adenovirus as a means of driving β-galactosidase gene expression. The expression activity of pituitary β-galactosidase was analyzed by injecting recombinant adenovirus into the murine pituitary via peripheral vein or carotid artery or using brain stereotaxics. The results showed that transvascular injection of AdGHGal or AdαGal failed to successfully deliver the marker gene to the pituitary gland. However, direct stereotactic injection of recombinant adenoviral vectors into the pituitary gland showed high expression of the higher gene. In addition, immunohistochemical staining also showed that pituitary cells selectively expressed AdGHGal or AdαGAL light genes. These findings suggest that adenoviral vectors with pituitary-specific promoters may be useful for targeted gene therapy of somatic diseases. However, the yield of peripherally administered transgenes is low [25]. Therefore, stereotactic injection or local administration of the virus during pituitary surgery should be used and will probably improve the efficiency of gene expression Although it will take a long time for pituitary tumor gene therapy to reach the clinical trial stage, the process is accelerating.