Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors

Abstract

Pituitary neuroendocrine tumors (PitNETs) arising from adenohypophyseal cells are generally accepted as benign. It is a very heterogeneous group of tumors according to their origin, biological behavior, and growth patterns. It is the third most common intracranial tumor type after meningiomas and gliomas. Transsphenoidal surgery (TSS) is the primary treatment of choice in all PitNETs except for lactotroph tumors, which are primarily treated with dopamine agonists. In this book section, surgical approaches in the treatment of PitNETs will be explained. In addition, PitNET radiosurgery will be explained in detail by using current literature information.

1. Introduction

The new classification clearly distinguishes anterior lobe (adenohypophyseal) from posterior lobe (neurohypophyseal) and hypothalamic tumors. Anterior lobe tumors include (i) well-differentiated adenohypophyseal tumors that are now classified as pituitary neuroendocrine tumors (PitNETs; formerly known as pituitary adenoma), (ii) pituitary blastoma, and (iii) the two types of craniopharyngioma.

Pituitary adenomas usually present with three types of clinical signs. The first type of clinical manifestations includes amenorrhea-galactorrhea syndrome, acromegaly or gigantism, Cushing’s disease, and secondary hyperthyroidism because of hypersecretion of prolactin, growth hormone, adrenocorticotropic hormone, and thyroid stimulating hormone (very rare). About 70% of pituitary adenomas are endocrinely active, the presence of hypersecretory endocrine status is the most common presentation.

The second type of clinical manifestations includes pituitary insufficiency and is typically associated with large tumors compressing the nontumoral pituitary gland or stalk. In general, the pituitary gland exhibits outstanding functional resistance, even in chronic compression and distortion. The tolerance of each pituitary axis to chronic compression is different. Gonadotropes are the most susceptible and the first to be affected. After that, thyrotropic, somatotropic, and corticotropic functions are affected respectively. Regardless of the size of the tumor or the degree of compression of the gland or stalk, pituitary adenomas rarely present with posterior pituitary insufficiency; the preoperative presence of this condition almost excludes the diagnosis of pituitary adenoma. The hypopituitarism associated with pituitary adenomas is usually a chronic process, but when pituitary apoplexy is present, it can be acute, unexpected, and immediately life-threatening.

The third type of clinical manifestations includes mass effect symptoms with or without endocrinopathy. Headache is usually the first finding and is attributed to stretching of the diaphragm sella innervated by the trigeminal nerve. The most common objective finding of these tumors is loss of vision, the result of the suprasellar growing tumor pressing on the anterior visual pathways. Although many patterns of visual dysfunctions are seen, asymmetrical bitemporal hemianopsia is the pathognomonic deficit. Visual field disorders decreased visual acuity, afferent pupillary defects, papilledema, optic atrophy, and total blindness can be observed.

Although the suprasellar and lateral areas are difficult to see with the microscope, the transsphenoidal microsurgical approach has yielded results as a surgical treatment for pituitary adenomas. The first transsphenoidal approach for resection of a pituitary lesion was documented by Schloffer in 1906. In 1914, Dr. Harvey Cushing developed the sublabial transseptal technique, which reduces the degree of nasal trauma associated with previous external rhinotomy incisions. The integration of the operative microscope into pituitary surgery by Hardy in the 1960s provided magnification and illumination, enabling more precise tumor resection via the transsphenoidal route, especially for pituitary microadenomas [1].

In 1987, Griffith and Veerapen reviewed the endonasal approach for microscopic pituitary surgery with the placement of a transsphenoidal retractor through the natural nasal airway into the sphenoid rostrum [2]. The first reported use of the endoscope specifically for transsphenoidal surgery was in the sublabial approach by Guiot and colleagues in 1963 [3]. Jankowski et al. performed the first full endoscopic pituitary surgery in 1992 [4]. In 1996, Jho and Carrau described their technique of a pure endoscopic approach in detail, and in 1997, they published their report of endoscopic removal of pituitary adenomas in 44 patients [5, 6]. The continuous development and improvement of endoscopic equipment and surgical instruments have greatly contributed to the advancement of endoscopic surgery as a viable procedure for transsphenoidal approaches to the sella.

2. Pituitary neuroendocrine tumors surgery

2.1 Surgical management and indications

A comprehensive preoperative evaluation is performed after the decision for surgery for resection of the pituitary tumor is made. First, the patient’s medical condition should be optimized. Hypertension, heart disease, diabetes, thyroid status, hematological problems, the presence of sleep apnea, and pituitary endocrine function should be carefully evaluated, especially in patients with Cushing’s disease or acromegaly. Common comorbid conditions in patients with pituitary tumors require special considerations regarding anesthesia [6, 7]. Prognathism and soft tissue hypertrophy (including macroglossia) in patients with acromegaly and cervico-cranial stoutness in patients with Cushing disease challenge intubation and airway management.

Hypopituitarism is among the important endocrine conditions that require preoperative treatment, especially for hypocortisolism and hypothyroidism. For patients with preoperative vision problems or tumors affecting the optic apparatus on MRI, formal neuro-ophthalmologic evaluations are performed with preoperative follow-up eye exams. Brain MRI with pituitary focus, with and without contrast, is the best diagnostic imaging modality of choice for most pituitary adenomas (Figure 1). CT imaging with pituitary focus and dynamic contrast protocol may be an alternative for patients who cannot undergo MRI for various reasons. The basic anatomy of the paranasal sinuses and any variation of the patient can be adequately evaluated on MRI for transsphenoidal surgical planning. However, in patients with prior paranasal sinus or transsphenoidal surgery, bone window CT scans with thin-slice axial and coronal views can reveal the bony anatomy of the paranasal sinuses in detail (Figure 2).

Figure 1.

A: Sagittal and coronal preoperative MRI image in pituitary-focused contrast-enhanced brain MRI of the patient who was operated with the diagnosis of Pitnet B: Sagittal and coronal postoperative MRI image in pituitary-focused contrast-enhanced brain MRI of the patient who was operated with the diagnosis.

Figure 2.

Detailed view of the paranasal sinuses in thin section axial and coronal sections. Permission has been obtained for the figures used in the book section.

In the treatment of pituitary adenomas, it is aimed to normalize the excess of hormone secretion, if any, to preserve and even restore normal pituitary function, to eliminate the mass effect, to preserve or restore visual acuity and/or visual field, and to obtain a complete pathological diagnosis. Clinically silent pituitary tumors are primarily treated surgically because the surgical treatment modality is currently the only method that can achieve all the previously mentioned goals. Pituitary apoplexy and visual impairment due to mass effect or cranial nerve palsy can be shown as a general surgical indication for such lesions. Large invasive pituitary tumors and tumors with open cavernous sinus invasion are considered difficult to treat independently of the surgical approach, because gross complete removal of the tumor is often not achieved. Patients with hormonally inactive or dysfunctional pituitary adenomas are operated when they have symptomatic findings such as optic chiasm compression, hypopituitarism, pituitary apoplexy, or severe persistent headaches.

Prolactinoma patients are operated on only when they do not respond appropriately to dopaminergic drugs and develop intolerable side effects to drugs. In other hormone-secreting pituitary adenomas, the primary treatment is surgical, not medical.

Clear identification of anatomical landmarks is especially important for a transsphenoidal approach to the sella. The surgeon should be aware of nasal septal deviations, sphenoid septations and their relationship to the carotids, bony defects in the carotid canal, the degree of sphenoid bone pneumatization, and the extent of bone expansion or erosion from an aggressive lesion. The surgeon should try to determine the position of the normal pituitary gland and any deviations in the infundibulum prior to surgery.

2.2 Surgical approaches

2.2.1 Transcranial approaches

There are conditions that limit and sometimes contraindicate the choice of the transsphenoidal approach over the transcranial approach, regarding the anatomy of the surgical route, morphology, or consistency of the lesion. The size of the sella, the size and pneumatization of the sphenoid sinus, and the position and tortuosity of the carotid arteries can significantly increase the difficulty of the transsphenoidal procedure. When such selected indications warrant a transcranial approach, there are several options. These are pterional, subfrontal unilateral, subfrontal bilateral interhemispheric approaches.

2.2.2 Transsphenoidal approaches

Transsphenoidal resection of pituitary masses involves the operating microscope, endoscope, or a combination of both. The microsurgical transsphenoidal technique provides bimanual dexterity during dissection of the tumor from the surrounding neurovascular structures, but the viewing angle may be limited. Endoscopic techniques offer a wider field of view and flexibility to change the viewpoint all the way from the cribriform plate to the cervical junction. Transsphenoidal approaches can be divided into three main stages as nasal, sphenoidal, and sellar.

2.2.2.1 Microsurgical transsphenoidal approaches

Although many different transsphenoidal procedures and variations have been described, there are currently three mains microsurgical transsphenoidal approaches to pituitary tumors. These are the transnasal transseptal transsphenoidal approach, the sublabial transseptal transsphenoidal approach, and the endonasal trans-sphenoidal approach.

The procedure is performed with an operating microscope to visualize, illuminate, and magnify the surgical field. The three mains microscopic transsphenoidal methods differ slightly, mainly in the initial stage up to the exposure of the sphenoid sinus; they then follow the same surgical sphenoidal and sellar steps.

2.2.2.2 Endoscopic endonasal transsphenoidal approach

The main advantages of the endoscopic procedure over microsurgical procedures are the features of the endoscope itself and the absence of a nasal speculum [8, 9]. The nasal speculum forms a fixed tunnel. The endoscope allows a wider view of the surgical field with a close view inside the anatomy. Angle lens endoscopes allow the surgeon to study tumors located in the suprasellar and parasellar regions under direct visual control. The endoscopic endonasal procedure has a lower complication rate than the traditional microsurgical approach [10]. With the endoscopic procedure, microsurgery makes the procedure faster and easier compared to microsurgery, as the submucosal nasal phase of the operation is avoided.

Disadvantages of the endoscopic approach include the unusual anatomy of the nasal cavities and the learning curve to rely on specific endoscopic dexterity. However, after sufficient experience, especially in the case of relapse, the operative time becomes the same or shorter than the time required for transsphenoidal microsurgery. The endoscope offers only two-dimensional vision on the video monitor. The sense of depth can be gained by the surgeon’s experience, allowing the endoscope to move in and out. To achieve surgical targets, especially those that angled endoscopes can show special microsurgical endoscopic instruments with secure grip, flat and non-bayonet-shaped, equipped with different and variable-angle tips are required.

In general, endoscopic instruments are long, rotating instruments with a single straight shaft equipped with angled tips. Angled tips on the working ends of many surgical instruments allow for a greater range of motion than standard instruments. The use of straight shaft instruments is preferred in endoscopy compared with the microsurgical technique, which typically uses bayonet instruments to avoid interference with the light source. The endoscope can be inserted into the nostrils with a sheath attached to an irrigation system that allows cleaning the lens without repeatedly removing and reentering the telescope. An endoscope holder can be used during the sellar phase of the procedure to stabilize the view of the surgical field, but its use limits dynamic movement that helps compensate for the loss of depth perception. The use of neuronavigational systems, although not essential, may be helpful in patients with recurrent lesions or abnormal sellar or paranasal sinus anatomy.

Key components of the endoscopic setup include a rigid lens endoscope, a high-resolution camera, a fiberoptic cable and light source, a large high-definition video monitor, and a video recording system. The most used endoscope is 4 mm in diameter and 18 or 30 cm in length. Differences in lens angle exist for certain steps of the operation, including 0-degree binoculars, 30-degree binoculars, and 45-degree binoculars. Wider-angle binoculars, ranging from 70 to 120 degrees, are available, but are rarely required for most endoscopic skull base operations.

2.2.2.2.1 Operational setup in surgery

The video monitor is placed behind the patient’s head and, in most cases, in the direct line of sight of the surgeon standing on the right side of the patient. The anesthesiologist is on the left side of the patient. The head of the bed is turned approximately 120 degrees away from the anesthesiologist, and the patient is placed in a semi-recumbent position with the thorax elevated to 15 degrees to optimize venous flow. The head is positioned with a slight degree of rotation toward the surgeon, approximately 10 degrees, with the midline of the patient’s head parallel to the side walls of the operating room and the patient’s nose bridge parallel to the floor. The degree of flexion/extension of the patient’s head depends on the location of the lesion. Lesions located primarily in the clivus, or sphenoid sinus, often require slight flexion of the head to allow working space for the endoscope. More anteriorly located lesions, such as the planum sphenoidale, require the head to be neutral or slightly hyperextended.

2.2.2.2.2 Patient preparation

Nasal decongestion facilitates pituitary procedures in most patients, except for patients with a history of hypertension and coronary artery disease. Before and immediately after induction of anesthesia, patients are given a 0.05% spray solution of oxymetazoline (Afrin) intranasally. During positioning, bayonet forceps are used to insert cotton pads soaked in oxymetazoline, followed by pads soaked in 1:200,000 epinephrine and 1% lidocaine between the middle turbinates and septum. The pads are allowed to remain in contact with the nasal mucosa for 5–10 minutes. The nostrils are then wiped with an aqueous solution of antibiotics such as chlorhexidine. A broad-spectrum antibiotic is given perioperatively with a nasal packing attached. If the results of the preoperative adrenal axis test suggest adrenal insufficiency, intravenous hydrocortisone is given before induction of anesthesia. Steroids are avoided in patients with Cushing’s disease to allow postoperative evaluation of successful resection. Leg fascia lata area or lower quadrant abdominal area is prepared in all patients to allow potential fat grafting in case of encountering cerebrospinal fluid (CSF).

2.2.2.2.3 Nasal stage

The aim of the nasal phase is to reach the sphenoid sinus through the sphenoid ostium and posterior nasal septectomy, which can be achieved with different strategies for manipulation of the mucosa and nasal septum. The endoscopic endonasal transsphenoidal technique begins with the insertion of a 0-degree endoscope into one nostril to identify the nasal cavity floor for orientation, the inferior turbinate laterally, the nasal septum medially, and the choana posteroinferiorly. The inferior and middle turbinates, which are the main barriers to the sphenoid ostium, should be carefully lateralized with blunt pressure to avoid excessive mucosal damage. Some surgeons choose to remove part of the middle or upper turbinate, but this is not usually necessary for resection of most pituitary tumors. After creating an appropriately wide working corridor, the sphenoid ostium is defined 1.5 cm above the choana.

The sphenoid ostium is sometimes hidden by mucous membranes or a thin layer of bone, in which case it may be helpful to first try to identify the ostium on the opposite side. Use of neuronavigational can also be helpful in confirming the pathway to the sphenoid sinus, then a small dissector instrument can be used to gently probe for the ostium and enter the sinus. If a pedicled nasoseptal flap is being prepared, it should be done at this stage. Once the ostium has been identified, its mucosal edges are coagulated using light monopolar cautery, which can be extended toward the medial and inferior surfaces of the sphenoid cusp. Avoiding inferolateral cauterization and dissection helps prevent arterial bleeding from septal branches of the sphenopalatine artery. Local anesthesia (epinephrine 1:100,000 to 1% lidocaine) is then injected medially into the posterior nasal septum using a spinal needle with a 20-degree bend.

Placement of the mucosal incision is dependent on expected closure needs and whether a nasoseptal flap is required to close the skull base. An incision can be made at the junction of the bony and cartilage septum and moved inferiorly and posteriorly in a standard transsphenoidal approach for an intrasellar lesion. Extended transsphenoidal approaches for complex sellar, parasellar, and suprasellar lesions often result in high-flow CSF leaks. In this situation, a vascularized nasoseptal flap closure is important to take advantage of natural wound healing mechanisms. While preparing the nasoseptal flap, parallel incisions can be made along the maxillary crest, inferiorly and superiorly caudal to the olfactory epithelium, with an anteriorly connected vertical incision [11]. The size of the flap can be adjusted according to the size of the expected defect. The flap remaining at the base of the sphenopalatine artery is compressed into the nasopharynx or, in some extended approaches, into the maxillary sinus for protection during the operation.

A posterior bite instrument can be used to extend the posterior septectomy further forward as needed to improve communication between both sides of the nasal cavity, improve visualization and instrument mobility, and minimize the possibility of instrument collision. The lateral and superior soft tissue and bony prominence of the sphenoid rostrum and sinus may be resected to provide sufficient space to position the endoscope superolateral at the 10 o’clock position. The bony rostrum is raised to the level of the floor of the sphenoid sinus to create a working area for the endoscope and two instruments.

2.2.2.2.4 Sphenoid stage

The sphenoid surface of the pneumatized sinus can be entered after dilation of the ostium or resection of the vertical plate. In a presellar or conchal sphenoid sinus, the bone is removed with a chisel or drill. Care must be taken to avoid injury to the sphenopalatine artery as it arises near the inferolateral vomer. This is particularly important when a pedicled nasoseptal flap is envisioned for reconstruction at the end of the procedure, called the salvage flap. The mucosa within the sphenoid sinus is often removed to reduce the risk of postoperative mucocele. Septations within the sphenoid sinus are also removed. The surgical view at this point should encompass the sellar floor at the center, the rostral clivus inferiorly, the planum sphenoidale superiorly, the bulge of the internal carotid siphon immediately juxtaposed to the sella, the wings of the optic nerves coursing superolaterally with respect to the sella, and the opticocarotid recess in between the optic nerve canal and the carotid protuberance.

2.2.2.2.5 Sellar stage

To safely perform bimanual microdissection for the sellar phase of the operation, two surgeons switch to the “four-handed” technique. Alternatively, the endoscope can be secured with the endoscope holder so that a single surgeon can operate with both hands. When the base of the sella is enlarged and thinned by an intrasellar lesion, it can usually be fractured using a pituitary rongeur or blunt microdissector. In some cases, a thicker sellar floor prevents this maneuver and requires the use of an osteotome, drill, or ultrasonic bony curette. A sellar bone defect is then performed, typically extending from one cavernous sinus to the other. In addition to defining the cavernous sinuses laterally, the anterior intercavernous sinus is often defined in the rostral aspect of exposure. A micro-Doppler probe and neuro-navigation can be routinely used to check the location of the internal carotid arteries and to confirm the location of the planned dural opening. The carotid artery may be ectatic within the sella, especially in acromegalic patients. Macroadenomas often compress the venous plexus between the two leaves of the dura, allowing a relatively bloodless opening. In contrast, intact venous channels between the dura and intercavernous sinuses may surround smaller tumors and should be thoroughly investigated prior to tumor resection.

Dural clearance differs according to surgeon preference; A rectangular opening allows dural pathology to be obtained for pathological examination when dural invasion is suspected. If the gland needs to be separated from an underlying lesion, the first vertical incision preserves blood flow. Care should be taken to remove as many tumors as possible for pathology and/or tissue banking. After sufficient specimen has been collected, curettes and aspiration can be used to remove the remainder of the tumor. The arachnoid may descend into the field of view at this point and should be carefully manipulated and protected with a cotton swab to avoid direct aspiration. Venous cavernous sinus bleeding may be encountered following tumor removal and temporary gelatin foam filling and/or injection may be given. A 30- or 45-degree endoscope may be inserted to look laterally and superiorly into the cavernous sinuses to assess the remaining tumor. In cases of macroadenoma with large suprasellar extension, the tumor will often subside spontaneously with mild curettage given sufficient time. Intrasellar and cavernous sinus hemostasis can be achieved, typically by temporary packing with a gelatin sponge followed by coating the tumor cavity with oxidized cellulose (Surgicel).

2.2.2.2.6 Closure

After tumor resection is complete and hemostasis is achieved, the closure phase begins with the goal of reconstructing the skull base defect and repairing any possible CSF leak. Many methods are available to perform reconstruction, including conventional repairs with autologous or artificial grafts, vascularized pedicled nasoseptal flap formation and rotation, and multilayer closure techniques using dural and bone substitutes.

CSF leaks may result from tumor removal from a thinned or inadequate diaphragm, from traction applied during dissection, or from deliberate opening of the diaphragm to access suprasellar lesions. High-flow CSF leakage is expected, especially in tumors that extend into the suprasellar compartment or the third ventricle. In the absence of significant CSF leakage, the Valsalva maneuver can be performed to detect minimal CSF leakage. A drip of dark liquid against the background of venous bleeding indicates a hidden leak.

For smaller defects, the sellar base can be reconstructed with allograft bone, cartilage, or ideally a biosynthetic substitute placed in the sellar extradural space. Alternative reconstruction techniques include the gasket-seal method and the use of synthetic grafts reinforced with fascia lata or fibrin sealant [12, 13]. For large CSF leaks, in addition to the maneuvers mentioned above, a vascularized flap provides the most effective closure.

2.2.2.3 Extended endoscopic endonasal transsphenoidal approach

Medial cavernous sinus tumor surgery can be performed with an extended transsphenoidal transsellar approach. This approach involves puncturing the bone over the carotid siphon and removing the medial opticocarotid recess. However, this only provides limited access to the medial cavernous sinus wall. The ethmoids need to be opened using the transethmoidal corridor to gain better access to the cavernous sinus. Additional lateral access can be achieved using the transmaxillary corridor. This approach can be used for cavernous sinus tumors or lateral sphenoid pathology.

The extended endoscopic endonasal approach does not require brain and optic nerve manipulation compared with transcranial approaches. It provides a direct view of the suprasellar region. Because of this advantage, the risk of worsening postoperative vision is much less than with transcranial approaches. However, the extended endoscopic endonasal approach is technically much more difficult and can be performed by experienced surgeons.

2.3 Complications

Despite the minimally invasive nature of transsphenoidal approaches to sella turcica, complications can occur. Complications encountered in the nasal cavity during the approach include anosmia, nasal septal perforation, crusting, saddle nose deformity, orbital fracture, cribriform plate injury with CSF leakage, and epistaxis. Complications occurring within the sphenoid sinus include sinusitis, mucocele formation, and optic nerve or carotid artery injury resulting from sphenoid body fracture. Potential complications associated with tumor resection and the sellar phase include CSF leakage, hypopituitarism, diabetes mellitus, meningitis, postoperative hematoma, carotid artery or other vascular injury, optic nerve injury, ophthalmoplegia, subarachnoid hemorrhage, vasospasm, and tension pneumocephalus. The most common non-endocrine complications for both microscopic and endoscopic transsphenoidal surgery are CSF leakage, meningitis, and sinusitis [14, 15].

2.4 Postoperative care and follow-up

Patients should be observed very closely following endoscopic transsphenoidal pituitary surgery. Most patients are discharged home on the second or third day after surgery. In most patients, serum sodium levels and urine output are monitored every 6–8 hours for the first 48 hours. Patients with any new evidence of hypocortisolemia should receive adequate replacement therapy. Patients with functional pituitary adenomas typically undergo basic non-stimulation hormonal testing (e.g., serum prolactin, cortisol, or growth hormone) on the first and second postoperative days. If nasal packing is used, it is usually removed on the first postoperative day. The patient is usually discharged from the hospital on the second or third postoperative day and is expected to see an endocrinologist for hormonal follow-up. The patient will be evaluated in the outpatient clinic 3 months later with sellar contrast MRI postoperatively.

3. Pituitary neuroendocrine tumors radiosurgery

Especially in macroadenomas and tumors invading the cavernous sinus, total resection is not always possible. Total resection rate in pituitary adenomas remains below 70% [15]. Tumor control rates with microsurgery between 50 and 80% vary [16]. Another factor limiting the effectiveness of surgical treatment in pituitary adenomas is recurrence in 11.5% of radiologically resected pituitary adenomas [17].

Pituitary adenomas are very suitable lesions for radiosurgery if suprasellar and parasellar neural tissues can be preserved because they are in a well-circumscribed environment. For this reason, radiosurgery has been applied as an adjuvant treatment method for many years to provide hormonal normalization and control of tumor growth. It has been proven that a single dose of stereotactic radiosurgery can effectively provide tumor control and hormonal normalization as adjuvant therapy [18]. It can even be applied as a primary treatment method in cases where surgical and medical treatment cannot be applied.

The aim of radiosurgery of pituitary adenomas is to normalize abnormal levels of hormone, reduce the size of the tumor, or at least control its growth, without damaging neural tissues, especially the optic apparatus, and without causing pituitary insufficiency.

The marginal dose should be at least 12 Gray (gy) to achieve tumor control. Otherwise, even if growth control is achieved, hormonal recovery may not be possible. It has been reported that small lesions at some distance from optic nerves marginal doses about up to 30–35 Gy. Although it is recommended to avoid doses of more than 8–10 Gy to protect the optic nerve, there are series in which the median maximum dose of the optic apparatus is increased up to 12 Gy [19, 20].

Hormone-suppressing drugs should be quitted 1–2 months ago because of the possibility of affecting tumor cell cycle and metabolism and reducing sensitivity to radiation. There is no consensus on the time of initiation after radiosurgery [21].

The effectiveness of conventional radiotherapy in pituitary adenomas is well known. Although different results have been reported between series, it generally provides approximately 90% tumor control and 40–70% hormonal control [22]. However, in addition to this efficacy, it has disadvantages such as toxicity in temporomesial and hypothalamic structures, high pituitary insufficiency rate, optic neuropathy, long treatment time, and long time required for the effect to occur [16].

3.1 Tumor growth and hormonal control

Pituitary adenomas are already very slow growing tumors. For this reason, long-term follow-ups should be made after radiosurgery to decide that the growth is under control. This rate has been reported as 83–100% in series with a follow-up period of 4 years or more. This rate includes not only patients with reduced tumor volume, but also patients with growth arrest. For growth control of hormone-active tumors compared with nonfunctional adenomas, higher doses are needed.

Volumetric shrinkage may vary depending on the pathology of the tumor. Growth hormone-secreting adenomas tend to shrink more than prolactinomas and nonfunctional adenomas [23].

In the series published by Park et al. in 2011, in which they applied radiosurgery to 125 cases of nonfunctional adenoma, the 1-year control rates were 99%, while this rate decreased to 94% in 5 follow-ups and to 76% at the end of 10-year follow-up [24].

The onset of hormonal recovery after radiosurgery takes an average of 2 years (3 months–8 years). Hormone remission rate varies according to which hormone the adenoma secretes, how much maximum and marginal dose is applied, and whether antisecretory drugs are used during radiosurgery. If infundibulum damage develops during surgery and/or radiosurgery due to the compression of the tumor, it should be kept in mind that a decrease in prolactin level can be observed regardless of the adenoma [25].

The hormone remission rate after radiosurgery is the lowest in prolactinomas (25–30%). The most important factor here is thought to be the long-term dopaminergic treatment of the patients. Therefore, it is recommended to quitting antisecretory therapy at least 1–2 months before radiosurgery.

In tumors that secrete growth hormone, the hormonal response is obtained after an average of 2 years. The aim of radiosurgery is to reduce the GH level below 1 ng/ml. In big series with long follow-up, it has been reported that the hormonal cure rate between 20 and 96% varies. Also, it is thought that using somatostatin analogue reduces the response radiosurgery by changing the cell cycle. For this reason, it is recommended to stop or reduce the treatment at least 1 month before the radiosurgery.

Although hormone remission starts a little earlier in Cushing’s disease (14–18 months), they reported remission rates varying between 17 and 83% in big series.

3.2 Non-functional adenomas and stereotactic radiosurgery

Since non-functional adenomas are usually asymptomatic until signs of compression appear, they are found to be larger than functional adenomas at the time of diagnosis, and surgical resection is the first choice. However, the development of residual or recurrent tumors after surgery is substantial. For these cases, radiosurgery has become a comfortable and very effective treatment option, protecting patients from the risks of revision surgery. In non-functional microadenomas or macroadenomas that do not create optic pressure, follow-up is the strategy that should be considered first, and treatment should be planned in case of tumor growth.

There are many studies in the literature showing the efficacy of radiosurgery in non-functional adenomas. When the data of 512 patients with non-functional adenomas from nine Gamma Knife centers were analyzed, 94% had a history of previous surgical treatment, 6% had a history of prior radiotherapy. In the series, where the mean dose was 16 Gy and the mean follow-up was 36 months, the tumor control rate was 98, 95, 91, and 85% at the 3rd, 5th, 8th, and 10th years, respectively. The rate of pituitary insufficiency after radiosurgery was 21%, new or progressive cranial nerve deficit was 9%, and new or progressive optic nerve dysfunction was 6.6%. When the factors associated with cranial nerve deficit were examined, it was revealed that young age, increased volume, and the presence of previous radiation therapy increased the risk [26].

In the review of Kim et al., tumor marginal dose ranges between 13 and 24 Gy and 83–100% tumor control are reported in Gamma Knife series. The authors, who did not detect a significant relationship between tumor control and dose, reported a decrease in these rates as the follow-up period increased. Tumor shrinkage ranged from 42–89% [27].

In a large series evaluating Gamma Knife radiosurgery results in non-functional adenomas, visual side effects were found to be 0.8%, and cranial nerve deficit rate was 1.6%. This series shows that tumor control rates decrease as the tumor volume grows, the follow-up period increases, and the treatment dose decreases. In addition, there was no difference in outcome between operated and unoperated cases [24].

In the long-term follow-up (80.5 months mean) series of Gopalan et al. 48 cases, the tumor control rate was 83% and the new hormone deficit was 39%. Hormone deficits were found to be 8% for corticotropin deficiency, and as 4.2% for thyroid hormone deficiency with 20.8% gonadotropin deficiency, respectively. A decrease in tumor control rate and an increase in complications were found to be associated with the size of the irradiated tumor volume [28].

It has been shown that Gamma Knife radiosurgery at doses ranging from 10 to 25 Gy provides tumor control at a rate of 94–95% in 5–7 years of follow-up, and these rates decrease to 76% at the end of 10-year follow-ups [20, 29].

Effective tumoral control can be achieved with 12–15 Gy in non-functional adenomas. Therefore, in non-functional adenomas, radiosurgery can be applied even in some cases where the tumor meets the optic apparatus. Another option for large tumors is hypo-fractionated radiosurgery, and it is possible to better protect the optic structures by dividing the total dose 3–4 times.

As can be seen, radiosurgery provides more than 90% tumor control in non-functional adenomas. Since hormonal remission is not targeted, the fact that lower doses are frequently administered ensures that the rates of pituitary insufficiency and visual complications are lower than in the functional adenomas. In cases where it is thought that complete removal cannot be achieved due to cavernous sinus invasion or other reasons, surgical strategies that will reduce the tumor below 3 cm and remove it from the optic structures can make patients suitable for radiosurgery and provide an effective and safe treatment.

3.3 Functional adenomas and radiosurgery

Despite advances in surgical techniques and medical agents, endocrine remission, or recurrences are observed in a significant proportion of pituitary adenomas. In such difficult cases, the option of radiosurgery is often on the agenda. The literature clearly reveals hormonal remission rates with radiosurgery, endocrine cure is between 20 and 30% in prolactinomas, 50% in growth hormone adenomas, and 40–65% in ACTH-secreting adenomas.

The ideal dose for functional adenomas has not been determined, yet. However, the chance of achieving hormonal normalization at doses below 16 Gy is low. The chance of success increases with doses up to 30 Gy. Doses between 20 and 25 Gy are frequently preferred [16]. The possibility of pituitary insufficiency increases, especially at doses above 24 Gy [30].

The major disadvantage in radiation therapy of pituitary adenomas is the length of time required for biochemical remission. Sheehan et al.’s study of 418 cases found the mean time required for remission to be 48.9 months. They reported that this time was inversely proportional to the dose received by the tumor and directly proportional to the tumor volume [21].

3.3.1 Cushing’s disease

The first and most effective treatment for Cushing’s disease is surgery. However, there is a significant group of patients who cannot be cured by surgery, and radiosurgery has become an effective option for these patients. Recurrence develops in 30% of patients after successful surgery in Cushing’s disease [31]. In these patients, radiosurgery is one of the treatment options.

Jaganathan et al. evaluated the results of 49 Cushing’s patients who applied Gamma Knife and followed up for an average of 45 months and reported that the tumor shrank 80%. The average dose in this series is 23 Gy. In this study, in which the criterion of successful endocrinological response was determined as the normal level of free cortisol in 24-hour urine, successful endocrinological results were obtained in 54% of the patients in 13 months average. In 27 months, average, 20% of the patients relapsed and new hormonal deficits occurred in 22% of the patients. In this study, no relationship was found between tumor volume and endocrine response to radiosurgery. Hormonal normalization after radiosurgery varies between 7.5 and 58 months [13, 20]. In series where the marginal dose ranged from 15 to 30 Gy, it was reported that an average of 20 Gy accelerated the clinical and endocrine cure response. Cushing’s disease’s radiosurgery response develops more rapidly than other functional tumors. Although hormonal normalization has been reported between 10 and 87%, the success rate in most series is between 40 and 65%. Tumor control is reported in 80–100%, and shrinkage is reported in 10–70% of cases [16]. As with other adenomas, the response to radiosurgery is higher in ACTH-secreting microadenomas [32].

3.3.2 Prolactinomas

Surgery and radiosurgery options should be considered in a group of patients who are resistant or intolerant to medical treatment.

In the study of Jezkova et al. examining the role of radiosurgery in prolactinomas with 35 cases with an average follow-up of 75 months, normoprolactinemia was achieved in 37%, and dopamine agonist use was discontinued in 43% of cases. The time required for hormone normalization has been reported as 96 months. The tumor control rate was found to be 97% [33].

In the series of 38 cases with 22 years of follow-up, published by Sheehan et al. in 2015, it was reported that 55% of the patients used dopamine agonists before radiosurgery. In this series with an average follow-up of 43 months, endocrine remission was reported as 50% without using dopamine agonists. Pituitary insufficiency secondary to radiosurgery was found to be 30%. In this study, it is reported that medical treatment before radiosurgery worsens hormone normalization results [34].

Although a higher dose (mean marginal dose of 25Gy) is applied in the radiosurgical treatment of prolactinomas compared with other functional adenomas, the endocrine remission rate is lower. In addition, 80% of the patients have a decrease in prolactin level [16].

3.3.3 Growth-hormone-secreting adenomas

In the study by Franzin et al., in which they examined the Gamma Knife radiosurgery results in 103 patients with acromegaly, 58.3% of the 63 patients who were followed up for an average of 71 months achieved remission in 58.3%, while 14.6% of the patients achieved remission with somatostatin analogues. The rate of hormonal deficit was found 7.8% [6]. It has been determined that the most important factor affecting the success of radiosurgery is low GH and/or IGF-I levels during treatment. IGF-1 lower than 2.25 times normal is a positive prognostic factor [16].

In the series of Jagannathan et al.’s 95 cases, which were followed up 57 months average and underwent radiosurgery after unsuccessful surgery, a successful result was accepted as IGF-I normalization, and a successful result was obtained in 53% of the patients after an average of 30 months after radiosurgery. In this study, where the mean treatment dose was 22Gy, reduction in tumor volume was found in 92% of patients, and new endocrinological deficits occurred in 34% of patients. This study also shows that the duration of hormonal remission is faster in radiosurgery than radiotherapy. Researchers recommended that hormone-suppressing therapy should be discontinued 2 months before radiosurgery and not used for 6 weeks afterwards [35].

3.4 Radiosurgery in cavernous sinus invasive adenomas

Cavernous sinus invasion is observed in 7–42% of the cases in pituitary adenomas. Post-surgical residual tumor in pituitary adenomas is most frequently observed in tumors that have spread to the cavernous sinus. Neurovascular complex and venous hemorrhage in this region reduce the chance of surgeons to intervene in this area, and morbidity may be 27–50% because of intervention in this area. For this reason, radiosurgery is frequently the option for residual tumors in this region.

In 89 patients with recurrent or residual pituitary adenomas located in the cavernous sinus, who underwent radiosurgery by Hayashi et al., 97% tumor control was achieved at a mean 36-month follow-ups. Tumor shrinkage was detected in 64% of them. 18.2 Gy average was applied in non-functional adenomas, and 25.2 Gy average was applied in functional adenomas, and transient cranial nerve dysfunction was observed in 2% of cases. In this series, hormonal normalization was found in 39% of cases. Radiosurgery-related morbidity is less than 1% in lesions invading the cavernous sinus [36].

3.5 Complications

The main problems that may arise in radiosurgery of pituitary adenomas are pituitary insufficiency, optic neuropathy, and other cranial nerve paralysis.

The most important risk factors in the development of optic neuropathy are the contact of the tumor with the optic nerve, the size of the tumor, and the inability to clearly evaluate the relationship between the tumor and the optic apparatus in operated cases. After radiosurgery, a decrease in visual acuity and/or narrowing of the visual field may occur due to the proximity of the residual mass to the optic nerve. This rate is 1–6% and decreases further with advanced MRI. It is known that the cranial nerves in the cavernous sinus are more radioresistant than the optic nerve. In big series, damage to other cranial nerves (CN III, IV, V, VI, VII) is 2–3%.

Diabetes insipidus development due to neurohypophysis or infundibulum damage is approximately 1–2% in big series [19, 28]. Very rarely, narrowing of the carotid artery has been observed after radiosurgery, but it is even rarer to cause symptoms [26].

Stereotactic radiosurgery is an effective and safe alternative or supportive treatment to conventional treatments in the treatment of pituitary adenomas. Due to the risks of radiation, it should be applied in the right indications, considering the appropriate dose-volume relationship, and protecting critical structures. While the short duration of the treatment is advantageous, the most important risks that may develop after the procedure are pituitary insufficiency and vision problems due to optic nerve damage. Neurosurgeons, endocrinologists, and ophthalmologists should take a multidisciplinary approach together both in the evaluation of the efficacy of the treatment and in the management of its complications.

After radiosurgery, patient follow-up should continue for a long time, both to evaluate the effectiveness of the treatment and to develop complications after a long time.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations

PitNET	Pituitary Neuroendocrine Tumors
CSF	Cerebrospinal fluid
Surgicel	oxidized cellulose
Gy	Gray