17 Pituitary Adenomas: Functional
Abstract
Pediatric pituitary adenomas are rare lesions, for which endoscopic surgical treatment represents a feasible and effective choice. We report our personal experience in treating these lesions, describing the surgical technique in endoscopic-extended approaches, outcome, complications, and future perspectives.
17.1 Introduction
Pituitary adenomas represent uncommon lesions in the pediatric age group, accounting for approximately 3% of intracranial supratentorial tumors, with a mean annual incidence of 0.1 per million children. 1 , 2 , 3 , 4 , 5 The age range used to define “pediatric” is an important issue, as some authors report the upper age limit varying from 16 to 20 years. Therefore, the incidence of lesions of the sellar region ascribed to the pediatric population is affected by the upper age limit used to define “pediatric.” 3 , 4 Pituitary adenoma is relatively rare in childhood, and the incidence increases from adolescence through 19 years of age. 6 , 7 Despite the rarity of these tumors, they can dramatically impact normal growth and cognitive maturation in young patients by causing changes in hormonal function and determining a significant effect on quality of life during a critical period of development. 4 , 8 This is especially true in younger children who are in periods of rapid sexual and skeletal development. Early evaluation and intervention, either medical or surgical, is necessary to avert permanent consequences of pituitary-related endocrinopathy. 9
17.1.1 General Classification and Incidence
Historically, these tumors have been classified according to their size as being micro, macro, or giant adenomas. However, this classification has been enforced by a more comprehensive system based on immunohistochemistry and electron microscopy. 1 Pituitary adenomas can be classified further as functional or nonfunctional, depending on their hormonal activity in vivo. Pituitary adenomas in the pediatric population are usually hormonally active microadenomas, manifesting with an endocrinopathy rather than with a mass effect. They cause different endocrine symptoms than in adults, with primary amenorrhea, pubertal and/or growth delay, except in growth hormone (GH) secreting adenomas. Prolactinomas are the most frequent histologic subtype in children, followed by corticotrophin-secreting tumors and somatotropinomas. 5 Thyroid-stimulating hormone (TSH) secreting adenomas are only rarely reported as unique cases. 1 , 10 Functioning gonadotroph adenomas are extremely rare. Recent review has only found two case reports of adolescent girls. Nonsecreting adenomas are very rare in children, accounting for only 3% to 6% of all pituitary tumors. This distribution is opposite to that observed in adults, where nonfunctioning adenomas predominate. 11
An increased prevalence of pituitary adenomas in female patients has been reported, which most likely reflects the relative predominance of the two main types of adenomas: prolactin (PRL) and adrenocorticotropic hormone (ACTH) secreting adenomas. 4 , 12
Childhood-onset pituitary adenomas can be associated with a variety of genetic syndromes, the most common being multiple endocrine neoplasia type 1 (MEN-1).
17.1.2 Clinical Presentation General Features
Clinical onset of pediatric pituitary tumors is generally related to endocrine dysfunction rather than mass effect. Tumors that grow rapidly, even if they are hormonally inactive, are capable of producing symptoms of an intracranial mass, such as visual field disturbances. 2 Rarely, pituitary adenomas present with pituitary apoplexy, an acute syndrome caused by infarction and hemorrhage. Small, slow-growing, hormonally inactive lesions are sometimes identified as incidental findings on radiologic or postmortem examinations, whereas small, slow-growing lesions with hormonal overproduction can manifest clinically as typical syndromes.
Pituitary Apoplexy in the Pediatric Population
Literature regarding pituitary apoplexy in the pediatric or adolescent population is restricted to case reports or individual cases; however, gaps remain in our knowledge of the differences between adults and children in the presentation, severity of symptoms, and outcomes of this disease. 13 Pituitary apoplexy is a clinical syndrome recognized by the onset of abrupt signs and symptoms that are associated with changes at the histologic level, consisting of infarction, hemorrhage, or a combination of both in pituitary tumors. 1 , 4 , 5 , 14 , 15 , 16 Some authors, like Mehrazin, reported a higher chance of pituitary apoplexy in pediatric invasive pituitary tumors. 17
Diagnosis of this entity is based on clinical and imaging features. Cornerstones of management include hormonal replacement with steroids, followed by rapid surgical decompression.
Giant Pituitary Adenomas
Giant pituitary adenomas (GPAs) are rare entities in the group of pituitary adenomas. A majority are functional tumors and are distinct from their adult counterparts, with prolactinomas being the most common subtype followed by GH-secreting adenomas.
Some authors have described a high invasiveness of pituitary adenomas in younger patients. GPAs present more frequently with mass effect, offering a surgical challenge, considering their close proximity to optic pathways, intracavernous carotid artery, and oculomotor nerves, therefore making a radical resection more difficult. In a study of 12 children with GPAs, it was noted that symptoms due to local mass effect were predominant, presenting with visual deterioration (73%) and headache (64%). 18 Transsphenoidal surgical removal of the adenoma is a first choice, improving vision in 44% of pediatric patients.
GPAs present a higher complication rate compared with nongiant adenomas. In the study population presented in the literature, there is a high incidence of morbidity (25%), mortality (8%), poor outcome (50%), and preoperative (18%) and postoperative (8%) pituitary apoplexy. 18 The higher rate of pituitary apoplexy in this group of tumors confirms the aggressive nature of these lesions.
17.2 Indications for Surgical Treatment
There are no consensus statements nor guidelines available for the treatment of pediatric patients with pituitary adenomas. Although medical treatment can be effective, surgery is accepted as the first-line treatment in patients with gigantism or Cushing’s disease (CD). It is also indicated when lesions cause mass effect and cranial neuropathy, mostly affecting visual function, or if the side effects of medical therapy are intolerable and endocrinologic disorders become unmanageable. The goal of surgery is radical excision of the tumor while preserving the normal pituitary gland. Tumor recurrence depends mostly on whether the patients undergo total or subtotal resection. In a retrospective review of 20 patients younger than 20 years old with pituitary adenomas, the authors describe the necessity of further surgical treatment in 5 of the 8 cases of subtotal resection; on the other hand, only 2 of the 12 patients who underwent total resection documented recurrent disease (17%). 4 Other authors like Mindermann and Wilson have described a recurrence rate of 10% in cases of subtotal resection. 3
17.3 Anatomical Peculiarities in Pediatric Population
Endoscopic transsphenoidal surgery is generally accepted as the surgical method of choice for the resection of pituitary adenomas, especially if they are large and invasive. Standard and expanded endonasal approaches (EEAs) have demonstrated their efficacy in managing sellar and parasellar skull base lesions in younger patients. Some anatomic features have to be considered when endoscopically treating sellar lesions and pituitary adenomas in the pediatric population. They are potentially limited by several bony sinonasal landmarks and critical neurovascular structures such as piriform aperture, sphenoid sinus pneumatization, and intercarotid distances.
Piriform aperture width is significantly different between patients younger than 2 years (17.2 ± 0.5 mm) and adults (22.2 ± 1.3 mm); p < 0.00003. 14 It is significantly narrower in patients up to 6 to 7 years of age compared with adults (p < 0.002); there is no significant difference among patients 9 to 10 years of age and older.
Sphenoid bone pneumatization begins after 2 years of age at the anteroinferior wall of sphenoidal bone; by 6 to 7 years of age, the anterior sphenoid wall, the anterior sellar wall (77%), and 32% of the sellar floor are pneumatized. Therefore, incomplete pneumatization of the sphenoid sinus is common in pediatric patients; this factor does not restrict resection of sellar region tumors for most of the authors via EETA (endoscopic endonasal transsphenoidal approach). The sphenoid sinus is well pneumatized in patients 10 years of age and older, and sphenoidal septations in pediatric patients older than 10 years are comparable to those in adults. Intercarotid distance is significantly narrower in patients up to 6 to 7 years old (10.2 ± 1.0 mm) compared with adults (12.6 ± 0.9), with p < 0.003 at the level of the cavernous sinus. There is no significant difference among patients 9 to 10 years of age and older (p > 0.36). At the level of superior clivus, there is no statistical difference between adults and any of the pediatric cohorts (p > 0.18). 14
These three major anatomical parameters do not represent a limitation to the use of EEAs in pediatric patients. Piriform aperture constitutes a limit only in the youngest patients (younger than 2 years); incomplete sphenoid pneumatization needs more drilling during the access; assessing the intercarotid distance during the intervention is supported by modern devices like micro-Doppler and neuronavigational systems.
Considering the developmental stage of the skull in children and the inconsistency of specific anatomic landmarks compared with the fully developed cranium of adults, endonasal surgical procedures in children are technically challenging and present higher surgical risk than in adults. This demonstrates the importance of smaller, dedicated instruments, together with a specific preoperative neuroimaging assessment. These anatomical peculiarities constitute an even greater limitation for the transsphenoidal microsurgical technique. The use of microdrills is impossible when working within a speculum indispensable for the microsurgical technique. In addition, several severe complications, such as skull base fractures and blindness, have been reported due to the use of a speculum.
Although the cranio-orbitozygomatic skeleton reaches 85% of adult size by 5 years of age, the size of the nasoseptal flap (NSF) area is a potential limitation in reconstructing skull base lesions. 19 Recent literature has suggested that the NSF is only a viable option in patients older than 6 to 7 years. 20 A recent retrospective review of 16 pediatric patients evaluated the viability of NSF reconstruction in endoscopic endonasal approaches (EEA) for intracranial suprasellar neoplasms. Radiographic analysis demonstrated that septal lengths even in children younger than 10 years were adequate to cover the defects created by the suprasellar resections. 20 With adequate radiographic measurements, the authors demonstrated that the flap reconstruction length is adequate for EEA reconstruction in suprasellar lesions.
17.4 Surgical Management
The EETA to the sellar region for the removal of pituitary adenomas and other neoplasms of this area has proven its efficacy in the adult population over the last 20 years. It is safe and effective thanks to its favorable peculiarities, that is, its minimal invasiveness and decreased peri- and postoperative complications, including lower rates of cerebrospinal fluid (CSF) leak, septal perforation, and lower neurovascular damage, if associated with modern intraoperative instruments as Doppler and neuronavigation.
The use of endonasal transsphenoidal endoscopic surgery is increasingly reported as the technique of choice for the treatment of sellar and suprasellar lesions in the pediatric population as well. The association with minimal surgical trauma is a recognized feature in these patients. Children report lower pain perception after endoscopic pituitary surgery compared with traditional transsphenoidal surgery. 21 , 22 They also reported a lower rate of access to ICU and lower rate of perioperative blood transfusions.
17.4.1 Endoscopic Approaches and Surgical Technique
Depending on the site of extension of the lesion, endoscopic approaches include direct paraseptal transsphenoidal approach to sellar region, usually bilateral, transethmoidal sphenoidal approach, transethmoidal-pterygoidal-sphenoidal approach (TEPSA).
The direct bilateral paraseptal transsphenoidal approach to the sellar region is the preferential approach to the sellar cavity, providing a direct access to the sphenoid sinus; it has been described as standard for space-occupying lesions in sellar and suprasellar spaces, according to specific anatomy.
A transethmoidal-sphenoidal approach is adopted for sellar lesions with extension to the medial parasellar region, the lateral recess of the sphenoid sinus, and the posterolateral ethmoid, as well as accessing the posterior ethmoid, orbital apex, lateral wall of the sphenoid sinus, and medial component of the cavernous sinus. This approach starts with an ethmoidectomy with partial resection of the middle and superior turbinates, which, in combination with resection of posterior ethmoidal cells, allows for the exposure of the anterior wall of the sphenoid sinus, orbital apex, and the base of the pterygoid. The anterior wall of the sphenoid sinus is removed, and the sphenopalatine artery (SPA) is electrocauterized. 23
TEPSA is dedicated for surgical excision of lesions extended to the lateral part of the cavernous sinus, the base of the middle cranial fossa, and the infratemporal fossa. Depending on the site of maximum lateral extension, TEPSA can be performed monolaterally with a paraseptal transsphenoidal approach contralaterally.
Surgical Steps in Paraseptal Transsphenoidal Approach
In the nasal stage, if NSF reconstruction is planned, the flap is harvested before sphenoidotomy, preserving the flap pedicle and blood supply by SPA in its septal branches (rescue flap). First described in 2006, the NSF has become the standard for adult and, more recently, pediatric skull base reconstruction. 24 Pedicled on the posterior septal branches of the SPA, this mucoperiosteal and mucoperichondrial flap is reliable for most skull base sites of reconstruction. The pedicle courses across the inferior sphenoid sinus face, and flap harvesting should occur before sphenoidotomy, as removal of the sphenoid face before this maneuver could interrupt the pedicle. 25 The maximal size of an NSF depends on nasal growth, an important consideration with the pediatric population.
A study of craniofacial CT scans suggests that although the width of the NSF is likely sufficient at any age, the length may be insufficient for a transsellar/transplanum defect until age 6 to 7 years, a transcribriform defect until age 9 to 10 years, and insufficient for a clival defect at all pediatric ages. 16
During the procedure, many important anatomical landmarks should be taken into account in order to be preserved. Identification of the choanal margin, the superior turbinate, and the sphenoid ostium, the latter of which is visible in the region medial to the tail of superior or supreme turbinate, represents the first step to safely accessing the sphenoid sinus. The secure site to access the sphenoid sinus is located at the junction of two lines: the first vertical and parallel to the interchoanal septum and the second horizontal (parallel to the tail of the superior turbinate). 23 Access to sphenoidal sinus is gained by drilling medially to this secure anatomical site. On the contrary, in widening and opening inferiorly, attention must be paid to septal branches of SPA, which need to be electrocoagulated in case of damage.
If trimming/drilling of the superior turbinate is needed to enlarge access, attention must be paid to preserve the superolateral attachment and the tail of superior turbinate (axilla), preventing iatrogenic injury to the olfactory neuroepithelium, causing hyposmia.
After bilateral sphenoidotomy and drilling of the sphenoidal rostrum and intrasphenoidal septum, the next step is represented by identification of intrasphenoidal key landmarks. Enlarging the sphenoid sinus facilitates locating the intracavitary position of the internal carotid artery (ICA) and optic nerves bilaterally. Complete bilateral sphenoidotomy allows complete removal of the entire anterior wall of the sphenoid sinus, joining the two ostia, removing the intersphenoidal septum, and exposing the sellar floor. Once the entire sphenoid sinus cavity is exposed, the sellar floor must be opened. 23 Removal of the sellar floor involves prior anatomical localization of specific landmarks to avoid major iatrogenic injuries. Varying according to the type of sphenoid anatomy, the surgeon must identify the bony prominence covering both paraclival ICAs, depression of the wall of the clivus, the bony prominence of the cavernous tract of the ICAs, chiasmatic protrusions, and interoptic carotid recesses. Anatomical landmarks are checked during the intervention using Doppler sound and neuronavigation systems. When the central bony part of the sellar floor has been removed, the periosteal dural layer is incised to gain access to the lesion.
The intrasellar surgical technique consists of classical curettage for tumor excision in sellar cavity. The use of different graded scopes is essential to check a 360-degree tumor extension in the sellar, parasellar, and suprasellar spaces.
In the sellar stage, care must be taken to enlarge the approach laterally. Control with a micro-Doppler is important in order not to injure vital neurovascular structures.
Depending on the consistency of the lesion, hydrodissection can be sufficient to complete tumor excision in very soft tumors. In fibrous lesions or hard consistency tumors, microsurgical sharp dissection is needed, and fibrous or calcific components could require Sonopet® or cavitron® ultrasonic aspirator (CUSA) use.
Lesion removal is completed by planned endoscopic “diving” exploration of the sellar and parasellar spaces; this technique is useful to complete and evaluate the radical removal of sellar lesions, providing a faster and safer removal of sellar and suprasellar lesions. We described this technique in view of our experience in neuroendoscopic transcranial approaches to the ventricular system in the early 1990s. 26 Diving technique optimizes vision using the dynamic fluid film lens principle, becoming useful to go beyond mere visualization of the surgical field, to complete the removal of the lesion, improving hemostasis, CSF leakage, and lesion removal detection. The diving technique is particularly useful to detect small infiltrations to the cavernous sinus and in checking the integrity of the pituitary stalk when instruments are introduced into the sella.
Hemostasis is conducted during the whole procedure with warm water irrigation, the use of cottonoids, and the attempt to preserve normal mucosa. In the presence of abundant bleeding, sealants and hemostatic matrices such as thrombin-derived products can improve bleeding control and can be placed in the surgical site.
EEA to skull base lesions requires correct reconstruction of skull base defect in case of CSF leakage, and if there is intraoperative evidence of cisternal opening into the sphenoid, in case of extended surgical approach. The technique requires multilayer reconstruction strategy using different kinds of materials. The choice of material depends on the type of surgical approach and the patient’s anatomy. The authors prefer autologous materials such as temporal fascia, septal or turbinate mucoperiosteum, quadrangular cartilage, and turbinate bone. If, during access, the middle turbinate has to be removed (as in TEPSA), it can be used as a free graft. Reconstruction techniques require placement of the intrasellar layer of connective fascia, a second layer of bone or cartilage (underlay), and a third extracranial layer of mucoperiosteum on the sellar floor (overlay); these layers can be reduced to two (underlay and overlay), and the fascia may also be used alone.
The authors believe that in standard direct paraseptal approach, reconstruction is not mandatory.
Final placement of hemostatic material and Merocel packing are useful to complete closure, together with bilateral paraseptal Silastic sheets to help re-epithelialization and avoid synechiae.
17.4.2 Intraoperative and Postoperative Complications
Possible complications are related to sinonasal function, neurovascular injury, CSF leak, central nervous system (CNS) infection (meningitis, abscess), and damage to CNS tissue (endocrinopathy, motor, or sensory dysfunction). Neurovascular complications include intraoperative acute bleeding (hemorrhage from ICA and its branches, SPA bleeding), stroke, and cranial nerve damage, especially the sixth cranial nerve, causing diplopia.
An important consideration in pediatric patients is the potential impact of skull base surgery on craniofacial growth. Endoscopic skull base surgery is safe in well-trained skull base teams with little impact on craniofacial growth.
CSF leakage is one of the most adverse complications described for EETA. Published CSF leak rates in adults range from 1.3% to 15% and in the pediatric age from 8% to 10.5%. 27 Higher rates in adults may be associated with extended procedures, with greater subarachnoid dissection required to access the lesions. Many techniques have been described to prevent CSF leakage after endoscopic transsphenoidal approaches, but we prefer multilayer reconstruction with autologous material and pedicled NSF as described in the previous section. 20 Its efficacy in preventing postoperative CSF leaks in adult population has already been proven and described in the literature. Less is known about reconstruction in the pediatric population.
Mucocele represents another possible complication in this kind of surgery. The basic etiologic problem is the compromised ventilation of sinuses. Children may be particularly at risk for mucocele formation because of the pediatric anatomical features with incomplete sinus development. A recent study in traumatic cases has described the importance of proper positioning of the graft in endoscopic repair of frontal recess fractures. 28 Pediatric cases of mucocele are also described decades after the initial trauma. Endoscopic sinonasal procedures such as functional endonasal endoscopic surgery have been proven to raise the risk of nasofrontal duct stenosis and mucocele formation. This type of approach, in particular transethmoidal approach, might play a role in mucocele pathogenesis. Avoiding trauma of the healthy mucosa, especially in the middle meatus region, as well as meticulous postoperative cleaning and debridement of the ethmoid cavity might decrease the risk for middle meatus adhesion and mucocele formation. 28 When the middle turbinate is used for the repair, care must be taken to strip off both the mucosa surrounding the defect and the skull base facing turbinate mucosa, to avoid any mucosal inclusion, as it may generate a future mucocele. 29
Other endonasal complications include local crusting (treated with softening medications), scarring, and synechiae, prevented with placement of Silastic sheets at the end of surgical procedure. Short-term sinonasal dysfunction requiring debridement and saline irrigation is expected, but long-term issues are possible and include synechiae, nasal obstruction, chronic sinusitis, septal perforation, and altered olfaction.
Transient diabetes insipidus (DI) is a described complication after EETA, ranging from 0.4% to 48.8% for transient DI. Permanent DI rates range from 2.3% to 8.1%. DI is neurogenic from injury to the magnocellular neurons in the hypothalamus where arginine-vasopressin is produced and transported to the posterior pituitary gland. Factors including lesion size, adherence to surrounding structures, and histopathology, and surgical approach can result in DI. Care should be taken during surgery to preserve neurovascular structures in close proximity to the lesion.
Hypopituitarism occurred in 1.4% to 19.8% of cases reported in the literature. It can be associated with dysfunction of the anterior pituitary gland, requiring hormonal replacement therapy. 15 , 19 , 30
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