Pituitary Adenomas: Classification, Clinical Evaluation and Management

Abstract

Pituitary adenomas are one of the most common brain tumors. They represent approximately 18% of all intracranial, and around 95% of sellar neoplasms. In recent years, our understanding of the pathophysiology and the behavior of these lesions has led to better control and higher curative rates. The treatment decision is largely dependent on type of the adenoma, clinical presentation, and the size of the lesion. In addition, incidental pituitary lesions add uncertainty in the decision-making process, especially for pituitary adenomas that can be medically managed. When surgery is indicated, the endoscopic endonasal transsphenoidal approach is the technique of choice, but open standard craniotomy approaches can also be the option in selected cases. The following chapter will review the classification, clinical presentation, pathophysiology, diagnostic work-up, selection of surgical approach, and treatment complications in pituitary adenomas.

1. Introduction

Pituitary adenomas (PA) are benign tumors which account for being the second most common intracranial tumors after meningiomas [1]. The incidence of PA is 4.36 per 100,000 and can affect all age groups [1]. However, PA is uncommon in the 1st decade of life with a prevalence of 1–10% when compared to all brain tumors in that age group [2]. The overall chance of developing a pituitary adenoma increases with age, and the non-secretory type is most common after 40 years old [2, 3]. Presentation is highly dependent on the whether the tumor is capable to disrupt hormone homeostasis. Secretory adenomas, also called “functional” adenomas, tend to present early in the clinical course of disease. Conversely, non-secreting adenomas, also called non-functional” adenomas, typically present after reaching a critical size, leading to compression of surrounding neuronal and/or vascular structures.

The first step in the management of a patient with a pituitary adenoma is to distinguish the lesion between a secreting and a non-secreting one. The secreting-type subclassification is based on the specific hormone release by the tumor. Despite advancements in pharmacologic and radiotherapeutic management, surgery is still considered the main modality of treatment for most pituitary adenomas.

2. Applied anatomy and general information

The pituitary gland is located in the hypophyseal fossa, which is a depression in body of the sphenoid bone located in the middle cranial fossa. Anteriorly, this space is limited by the tuberculum sellae, posteriorly by the dorsum sellae, laterally by the medial wall of the cavernous sinus on each side which extends from the anterior clinoid process and superior orbital fissure anteriorly to the posterior clinoid process posteriorly (Figure 1A). The chiasmatic sulcus is a shallow depression running between tuberculum sellae and the limbus sphenoidale where the optic chiasm spans between two optic nerves. The anterior tip of the chiasmatic sulcus, or limbus sphenoidale, is the limit between the anterior and middle cranial fossae. The pituitary gland is an intradural extra-arachnoidal structure with an ovoid shape composed of two lobes: a larger anterior lobe and a smaller posterior one. The pituitary stalk (aka the infundibulum) provides the pathway for ascending neural connections arising from superior surface of the posterior lobe to the hypothalamus. Due to the lack of a robust blood-brain barrier, the pituitary gland exhibits intense enhancement on contrasted magnetic resonance imaging (MRI). The larger anterior pituitary gland is composed of 3 parts:

1. Pars distalis (anterior): the largest of the 3 parts, responsible for the bulk of hormone production.

2. Pars tuberalis: an upward extension of glandular cell sheaths that connects the pars distalis to the pituitary stalk.

3. Pars intermedia: epithelial cells that sheath and separate the pars distalis from the pars tuberalis.

Figure 1.

Intracranial view showing sellar and parasellar areas anatomy. A: Superior view of cranial base. Hypophyseal fossa, or sellae turcica, bounded anteriorly by tuberculum sellae, posteriorly by the dorsum sellae, laterally by the medial wall of the cavernous sinus on each side which extends form anterior clinoid process and superior orbital fissure (SOF) anteriorly to posterior clinoid process posteriorly. Anterior tip of chiasmatic sulcus called limbus sphenoidale (marked by asterisk) which is the junction between anterior and middle cranial fossa. Anterior optic strut separates optic canal superomedially from SOF inferolatearlly and maxillary strut separates SOF from foramen rotundum. Middle clinoid process (MCP), which present in 50% of population, is a projection from lateral margin of sellae turcica. It corresponds transsphenoidally to medial opticocarotid recess. B: Superior view showing the roof hypophyseal fossa and cavernous sinus. Diaphragm sellae roof the superior surface of pituitary gland with the exception of a small opening that allows the stalk to pass from the gland to the hypothalamus. It is continuous with the dura covering the planum sphenoidale anteriorly and the dorsum sellae and clivus posteriorly. The roof of cavernous sinus formed by the oculomotor triangle (blue highlighted triangle) and clinoidal triangle. Oculomotor nerve (CNIII) enter the cavernous sinus at the middle of oculomotor triangle. The roof of left cavernous sinus is opened to show the contents of the cavernous sinus. Only the ICA and abducens nerve (CN VI) are running inside the sinus. CNIII, trochlear (CNIV), ophthalmic, and maxillary nerve are running in the lateral wall of cavernous sinus. CN VI enters the cavernous sinus by passing under Gruber’s ligament (aka petrosphenoidal ligament) which spans from the petrous apex to the posterior clinoid process and form the roof of Dorello’s canal. In this specimen, Gruber’s ligament is duplicated. ACP, anterior clinoid process; CAV. ICA, cavernous segment of ICA; MCP, middle clinoid process; PCP, posterior clinoid process; ON, optic nerve; PETR. ICA, petrous segment of ICA.

Five types of endocrine cells are contained inside the anterior lobe that secrete 6 different hormones (Table 1). The secretion of hormones is under either stimulatory control from hypothalamus or inhibitory control through feed-back mechanisms. Prolactin is the only pituitary hormone that is under inhibitory control from hypothalamus by prolactin releasing inhibitory factor, mainly dopamine.

Anterior lobe
Pituitary cell	Hormone produced	Control	Staining	Target organ	Effects
Corticotrophs	ACTH	⨁CRH	Basophile	Adrenal gland	Cortisol secretion
Thyrotrophs	TSH	⨁TRH	Basophile	Thyroid gland	T3 & T4 secretion
Gonadotrophs	LH, FSH	⨁GnRH	Basophile	Gonads	♂: Testosterone; ♀: Estradiol
Somatotrophs	GH	⨁GHRH; ⊝Somatostatin	Acidophile	Epiphyses of long bones; Liver	Bones: Chondrocyte proliferation; Liver: IGF-1 release
Lactotrophs	PRL*	⊝PIF	Acidophile	Mammillary gland	Lactation
Posterior lobe
Hormone produced		Target organ		Effects
Antidiuretic hormone (ADH)		Kidneys		Fluid retention, vasoconstriction
Oxytocin		Uterine smooth muscle Mammary gland		Uterine contraction; Milk ejection into lactation ducts

Table 1.

Pituitary glandular cell types and function.

*

Prolactin is the only hormone that is under direct inhibition from hypothalamus.

ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone releasing hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone.

The roof of the sellae is formed by a structure known as the diaphragm sellae, which covers the entire superior surface of pituitary gland with the exception of a small opening that allows the stalk to pass from the gland to the hypothalamus. It is formed by a dual layer of dura that is continuous with the dura covering the planum sphenoidale anteriorly and the dorsum sellae and clivus posteriorly (Figure 1B).

Two layers of dura cover the sellar anterior wall and the floor, namely: the inner (meningeal) layer, and the outer (periosteal) layer. These dural layers run adherent to each other on the anterior and floor of the hypophyseal fossa. Laterally, these 2 dural layers split, as the outer layer continues laterally and form the anterior wall of the cavernous sinus, and the inner layer adheres to lateral wall of pituitary gland to form the medial wall of cavernous sinus (Figure 2). Inferior and superior intercavernous sinuses are venous channels that connect the bilateral cavernous sinuses to each other. These venous channels run in the space between the two dural layers in superior and inferior aspects of the hypophyseal fossa (Figure 2). In extended transsphenoidal approaches, it is important to coagulate those venous channels before dural opening to avoid significant venous bleeding.

Figure 2.

Transsphenoidal endoscopic stepwise dissection of sellar floor. (A) Sellar floor bone over the right side anterior wall of cavernous sinus and pituitary gland has been removed and kept intact on the left side. Important landmarks can be appreciated on the sellar floor. Optic nerve, cavernous and paraclival ICA segments prominences can be seen. Lateral opticocarotid recess (LOR) seen superolateral to carotid prominence and inferior to optic nerve prominence (ON Prom.), and it corresponds to optic strut. Limbus sphenoidale spans between optic chiasm/chiasmatic sulcus and planum sphenoidale. (B) Bone over sellar floor removed completely. Periosteal layer of dura (PoL) has been peeled from the meningeal layer (MenL) on the right half of the gland and kept on the left. The anterior wall of cavernous sinus formed by PoL after separating form MenL on the lateral aspect of the pituitary gland and MenL remains stuck to the gland forming the medial wall of cavernous sinus. Note the ligament (marked by “*”) that anchor the medial wall of cavernous sinus. Also, those 2 layers separate at superior and inferior aspects of pituitary gland to form superior intercavernous sinus (Sup. InterCavS.) and inferior intercavernous sinus (Inf. InterCavS.), respectively, which are venous channels connecting the bilateral cavernous sinuses. Inferior hypophyseal artery (IHA) is a branch from meningohypophyseal trunk in majority of cases and supply the pituitary gland with blood. (C) Dura over sellae and suprasellar area has been removed to show the superior hypophyseal artery (SHA) which is a direct branch from supraclinoidal segment of ICA to supply the stalk and gland in addition to optic chiasm and nerves. The arrow heads pointing to diaphragma sellae. Note the opening in the diaphragm through which the stalk ascends from the gland to hypothalamus.

The floor of the sellae forms the posterior wall of sphenoidal sinus, which offers a shortcut in approaching the sellar region. The sphenoidal sinus can be classified based on the degree of pneumatization: conchal, presellar, and sellar. The sellar type is the most common and it is found in 80% of population, representing of a fully pneumatized sphenoid sinus. The conchal type is present in 3% of the population, and it represents a non-pneumatized form. It is common to see this type in the pediatric age population as aeration begins at 10 months of age and rapidly progresses between ages 3 and 6 years—eventually achieving final pneumatization around the 3rd decade of life. The presellar type is an intermediate classification between the conchal and sellar types in which partial pneumatization is observed.

During the endonasal transsphenoidal approach to the sellar and suprasellar regions important structures can be identified as bony prominences on the posterior wall of sphenoidal sinus depending on the degree of aeration. These include the cavernous carotid artery prominences, optic nerves prominences, pituitary gland prominence, and paraclival carotids segments prominences. The lateral optic carotid recess is a depression seen between internal carotid artery (ICA) and the optic nerve prominences. This structure correlates with the optic strut/anterior clinoid process when viewed transcranially (Figure 2).

2.1 Blood supply of pituitary gland

The pituitary gland receives its blood supply from bilateral superior and inferior hypophyseal arteries. Superior hypophyseal artery (SHA) is a direct branch from the supraclinoidal segment of the ICA. In addition to supplying the pituitary gland and stalk, the SHA also supplies the optic nerve and chiasm. The inferior hypophyseal artery (IHA) branches from the cavernous segment of the ICA, but can also branch from the meningohypophyseal trunk. The IHA supplies the pituitary gland and to some extent the stalk (Figure 2). Truong et al. [4] found that the bilateral coagulation of IHA has minimal effect on adenohypophysis and neurohypophysis functions due to presence of rich intraarterial anastomosis between SHAs. However, injury to SHA branches supplying the visual apparatus may result in visual field defects or vision loss due to paucity of anastomosis in the optic nerves or chiasm.

3. Classification of pituitary adenomas

Multiple classification systems have been adopted to classify pituitary adenomas. They can be classified either based on functioning status (i.e. secretory and non- secretory) or on the size of the adenoma (i.e. >1 cm in diameter macroadenoma, <1 cm diameter microadenoma). Other classification systems include pathological findings under light microscopy with hematoxylin and eosin stains (basophilic, acidophilic, or chromophobic), or growth characteristics found on imaging studies (e.g. modified Hardy’s classification for suprasellar extension and Knosp classification for parasellar/cavernous sinus extension).

The functional classification is the most widely used. It classifies pituitary adenomas on the hormone secretion status and the resultant endocrinologic manifestation. Functioning adenomas may secrete PRL, GH, ACTH, TSH, or FSH/LH, and patients usually present with endocrinologic manifestations of endogenous effect of the hyper-secreted hormone. Non-functioning adenomas usually present with mass effect on surrounding neuronal or vascular structures or with pituitary dysfunction due to compression on normal glandular tissue.

4. Clinical presentation

Pituitary adenomas may present with multiple different manifestations. These include: hormonal hypersecretory signs and symptoms, pituitary dysfunction, mass effect on surrounding neuronal structures, or may present acutely with headache and altered mental status due to pituitary apoplexy. However, asymptomatic pituitary adenomas discovered incidentally on brain MRI are not uncommon. It was found that 10% of general adult population may have asymptomatic pituitary adenoma (pituitary incidentalomas) [5].

4.1 Hormonal manifestations

One of the most common clinical presentation of pituitary adenomas is hormonal disturbances. Hypersecretion of one of the pituitary hormones will result in distinctive clinical syndrome that is related to endogenous effect of the hormone (Table 2).

Adenoma type	Incidence*	Hormone in excess	Clinical manifestation
Prolactinoma	40–57%	PRL	Male: decrease libido, impotence.; Female: amenorrhea-galactorrhea syndrome; Either sex: infertility, osteoporosis, headache, visual changes
GH cell (somatotroph) adenoma	11%	GH	Acromegaly
Corticotroph adenoma	2%	ACTH	Cushing’s disease
Thyrotroph adenoma	Rare	TSH	Hyperthyroidism
Gonadotroph adenoma	Rare	LH, FSH	Mostly present as non-secretory adenoma; rarely may cause menstrual abnormalities, ovarian hyperstimulation syndrome, and in males may cause testicular enlargement, hypogonadism

Table 2.

Functional pituitary adenomas clinical presentation.

*

Incidence of all pituitary adenomas [41].

4.2 Pituitary dysfunction

Pituitary dysfunction is generally caused by the adenoma compression over normal secretory glandular tissue or the pituitary stalk. Usually, significant tumor growth (size >1 cm) and pituitary compression is needed to cause pituitary dysfunction. GH is the first hormone to be affected, followed by LH and FSH, then TSH and lastly ACTH. Single hormonal dysfunction due to pituitary compression is extremely rare. Pituitary stalk compression may result in hyperprolactinemia due to the loss of inhibitory control from hypothalamus which manifest as a moderate elevation in prolactin level (usually <150 μg/l).

4.3 Mass effect

Pituitary macroadenomas may extend to the suprasellar region causing compression to the optic nerves and chiasm. Visual impairment is seen in about 40–60% of patients upon presentation and the classical presentation is bitemporal hemianopsia. In addition, suprasellar mass growth may result in hypothalamic compression with subsequent disturbances in eating, emotion or sleep pattern. Rarely, 3rd ventricle extension may result in obstructive hydrocephalus. Parasellar extension into cavernous sinus is usually asymptomatic, however, oculomotor, abducens and trigeminal nerves compressive symptoms may occur. Additional parasellar extension may compress the mesial temporal lobe which can result in seizures.

4.4 Pituitary apoplexy

Pituitary apoplexy is defined as sudden onset of intense headache associated with visual field defects, ophthalmoplegia, and/or altered mental status [6]. Pituitary apoplexy is clinically observed in 1–7% of pituitary adenomas [6, 7]. The accepted pathophysiology is tumor outgrowth of the vascular blood supply resulting in hemorrhagic infarction of the tumor mass [8]. Headache is the most common symptom which is usually felt over frontal or retro-orbital areas. However, visual field defects, cranial nerves palsy, and meningeal irritation signs and symptoms are not uncommon. Approximately 80% of patients have anterior pituitary hormonal dysfunction with ACTH deficiency being the most critical one.

There is evidence suggesting that the risk of pituitary apoplexy is higher in functional pituitary adenomas (e.g. GH-secreting adenomas and prolactinomas). However, there is contradicting data demonstrating a higher risk in non-functional ones [7]. Multiple risk factors for pituitary apoplexy have been identified including; sudden changes in blood pressure, (e.g. major surgeries), coagulative disorders and anticoagulation usage, radiotherapy, estrogen-based oral contraceptive pills, and head trauma [6, 7, 9].

5. Prolactinoma

Prolactinoma is the most common type in secretary pituitary adenoma with an incidence of 50% of all pituitary adenomas. It is typically commonly seen in women aged 20–50 years old. As stated previously, prolactin is under continuous inhibition from dopamine, a PIF, secreted from hypothalamus through the pituitary stalk. Stalk dysfunction, either by compression or hypothalamic lesion, will result in loss of prolactin inhibition with subsequent prolactin elevation. Prolactinomas arise from monoclonal expansion of pituitary lactotrophs, however, 5–10% of prolactinomas can co-secrete GH resulting in superimposed gigantism/acromegaly [10]. As the disruption of hormone homeostasis causes subtle symptoms in some prolactinoma patients, it is the most likely tumor to become large enough to cause clinical manifestations of mass effect compared to other secreting tumors.

5.1 Signs and symptoms

Hyperprolactinemia symptoms in males include decreased libido, sexual dysfunction and oligozoospermia (due to secondary hypogonadism). In perimenopause females, amenorrhea-galactorrhea syndrome is usually seen, which is a triad of galactorrhea, amenorrhea and infertility. In children and adolescents, growth arrest, pubertal delay and primary amenorrhea are frequently seen. Symptoms may also be due to mass effect which may cause headache, vision field deficits, cranial nerve palsy, seizure, and hydrocephalus.

5.2 Evaluation

Diagnosis of prolactinoma requires both: radiological evidence of adenoma and sustained hyperprolactinemia. Normal PRL levels in women are <25 μg/l and in men are <20 μg/l. Single random measurement of PRL at any time of the day is adequate for evaluation of hyperprolactinemia. The differential diagnosis of hyperprolactinemia is wide (Table 3), but PRL level is seldom >100 μg/l in these conditions. Pituitary stalk compression (Stalk Effect) can also cause hyperprolactinemia (e.g. PRL level up to 150 μg/l) [11, 12].

Head trauma

Convulsions

Medication (antipsychotics, antiemetics, verapamil)

Chest wall stimulation, strenuous exercises, heavy meals.

Craniopharyngioma, granulomatous disease of the hypothalamus, acromegaly

Primary hypothyroidism

Pregnancy and breast feeding

Table 3.

Differential diagnosis of hyperprolactinemia.

In PRL-secreting adenomas, PRL level usually correlates with tumor size as levels above 250 μg/l are commonly seen in macroadenomas [12]. In the setting of low PRL level in patients with clinical presentation strongly suggestive of a prolactinoma, “hook effect” should be suspected. Hook effect occurs due to the impairment of immune-complex formation in the presence of high levels of PRL. To overcome this phenomenon, serial dilution of the sample with repetition of the immunoassay is needed.

After ruling-out other causes of hyperprolactinemia, diagnosis confirmation of prolactinoma is made by gadolinium-enhanced brain MRI.

5.3 Management

Management of prolactinomas depends on several factors: tumor size, patient symptoms and preferences, and PRL level. All patients with macroadenoma require treatment, however, mildly symptomatic microadenoma patients (e.g. premenopausal woman with normal menstrual cycles and galactorrhea, or postmenopausal woman with tolerable galactorrhea) can be followed-up with serial PRL level measurement and brain MRI. Since only 5–10% of microadenomas will enlarge in size [13], management of microadenomas should not be based on size control alone. Prolactinomas respond very well to medical therapy, and dopamine agonists are the first line of management (e.g. bromocriptine or cabergoline) (Table 4).

Dopamine agonist	Bromocriptine	Cabergoline
Mode of action	Ergot-derivate D1 and D2 receptors agonist	Non-ergot-derivate Selective D2 agonist
starting dosage	1.25 mg/day	0.5 mg/week
Desired dosage	1.25 mg increment weekly until 2.5 mg × 3/day is reached	0.5 mg increment monthly until maximum dose of 3 mg/week is reached
Side effects	Gastrointestinal (GI) upset, postural hypotension, peripheral vasodilation, mood disturbances	GI upset, headache, dizziness, hypotension, cardiac valve fibrosis (mitral valve most commonly affected)
Response rate [14]	Microadenoma: normalize PRL in 82%, gonadal function restoration in 90%; Macroadenoma: 80% will reduce in size	Microadenoma: 70% effective in bromocriptine resistant patients with fewer side effects rate; Macroadenoma: higher tumor size control compared to bromocriptine

Table 4.

Bromocriptine and cabergoline specifications.

Bromocriptine is a non-selective dopamine receptor agonist. It is the first line of management for microadenoma patients seeking fertility restoration and it is effective in 90% of patients and PRL level normalization can be achieved in 82% of patients [14]. If pregnancy has been achieved, bromocriptine can be stopped safely without a risk of abortion or congenital malformation. In child-bearing age women with microadenomas, risk of microadenoma progression is low and prolactin level monitoring is not necessary [15].

Macroadenomas always need management. Bromocriptine should be the drug of choice for patients who need fertility restoration. Pregnant women with macroadenoma without extrasellar extension can be followed similarly as microadenoma patients. However, if the suprasellar extension was detected before pregnancy, tumor debulking is advisable as the risk of macroadenoma growth during pregnancy is up to 35% [15, 16]. In these patients, it is also prudent to have a visual field assessment every 3 months till delivery.

Surgical management of prolactinoma is indicated in patients who are non-responders to dopaminergic therapy, with intolerable adverse effects from medical therapy (e.g. bromocriptine), CSF fistulas under DA, cystic tumors with intramural hemorrhage, or progressive neurological deficits [11, 17]. Stable visual field defect is not considered an indication for surgery as most patients will have tumor shrinkage on medical therapy with improvement on visual symptoms.

When to consider a prolactinoma as being medication resistant?

1. Failure to normalize serum prolactin levels after having received a daily dose of 15 mg of Bromocriptine for 3 months (25% of patients).

2. Failure to normalize serum prolactin levels after having received a weekly dose of 1.5–3.0 mg of Cabergoline for 3 months (10–15% of patients).

Seventy-percent of bromocriptine resistant patients will respond on cabergoline. Around 10–16% of prolactinoma patients will need surgical management [11]. Most patients will have a reduction of PRL levels 2–3 weeks after dopamine agonist initiation, which generally precedes the tumor size reduction. Periodic PRL measurements and pituitary MRI every 6–12 months is advised. After 2 years of continuous therapy, if prolactin levels have been normalized and >50% reduction of tumor size has been achieved, medication dose can be reduced. Typically, a low-dose of dopamine agonist after 2 years of tumor control will usually keep prolactin within normal range and prevent tumor recurrence [18].

6. Acromegaly and gigantism

Acromegaly is a rare disorder resulting from exposure to high levels of GH which is associated with significant morbidity and mortality. The most common cause of acromegaly is pituitary adenomas which may be either pure-GH secreting adenoma (60%) or mixed cell adenoma. In children before epiphyseal plate closure, GH secreting adenoma results in gigantism. It has an annual prevalence of 4 new cases per million inhabitants, with male and female being equally affected [19]. Other rare causes of acromegaly include growth hormone releasing hormone (GHRH) secretion from hypothalamus (e.g. hamartoma or glioma) or ectopic GHRH secreting tumors (e.g. primary bronchial carcinoid or pancreatic cancers).

6.1 Clinical presentation

The majority of acromegaly cases are due to GH-secreting pituitary adenomas. Similar to other subtypes of pituitary adenomas, GH-secreting adenomas may present with mass effect symptoms and/or with signs and symptoms of the endogenous effect of the over secreted hormone (i.e. GH).

Acromegaly dysmorphic features include enlarged hands and feet, facial bone enlargement that results in frontal bossing, prognathism, maxillary widening with the resultant of teeth separation and jaw malocclusion. The pathophysiology of bone changes is due to GH/IGF-1 effects on the periosteum of bones that results in new bone formation and bone remodeling. In the extremities, these effects will result in osteophyte formation over the digits with cartilage hypertrophy. Radiological hand findings include joint spaces widening, enthesopathy, diaphysis broadening and soft tissue hypertrophy. Due to these changes, two-thirds of patients will have degenerative arthropathy with large joints more commonly affected. In fact, arthropathy is the most common symptom referred by patients with acromegaly on presentation and the leading cause of morbidity. The axial skeleton can be affected by the same mechanism resulting in excessive kyphotic angulation of the thoracic spine with a compensatory hyperlordotic angulation of lumber vertebrae. These factors contribute to the fact that approximately half of these patients have low back pain. Neurogenic claudication is not uncommon due to ligamentum flavum hypertrophy with the resultant spinal canal stenosis. Patients with pure somatotroph pituitary adenoma usually have normal bone mineral density, however, acromegaly patients showed a higher incidence of vertebral compression fractures with high IGF-1 being a significant risk factor [20].

Growth Hormone and insulin like growth factor 1 can also affect visceral organs. Up to 50% of acromegaly patients have hypertension [21, 22]. The underlying cause is multifactorial. Endothelial dysfunction can be caused by GH-induced hyper-reactivity of the sympathetic nervous system [23]. In addition, high levels of GH/IGF-1 increase sodium reabsorption in renal distal tubules which results in chronic water retention/hypervolemia and increased plasma volume (up to 40%) when compared with normal individuals. Another important cause is chronic-sleep-apnea-induced hypertension as 80% of acromegaly patients have obstructive-sleep apnea induced by soft tissue hypertrophy. In addition, hypertrophic cardiomyopathy is commonly found in long standing acromegaly with diastolic dysfunction being the most common cardiac manifestation. Moreover, premature ventricular contractions can be detected in up to 50% of patients. The most common cause of mortality in acromegaly patients is due to cardiac arrhythmias or dysfunction [19].

Acromegaly has deleterious effects on both the upper and lower respiratory systems. Costal bone and subsequently chest wall changes (e.g. barrel chest) are common. Intercostal muscles also are affected by segmental degenerative fibrotic changes resulting weak inspiratory and expiratory efforts [24]. In the upper respiratory tract, acromegaly patients develop macroglossia, narrowing of pharyngeal airway space and thickening of vocal cords. These changes contribute largely to the pathogenesis of obstructive sleep apnea. One third of acromegalic patients with sleep apnea have neurogenic causes due to the effect of GH/IGF-1 on the respiratory center in the brain stem. Total lung capacity is increased in the majority of acromegalic patients due to increased alveolar volume. Narrowing of bronchi and bronchioles lead to obstructive patterns found in approximately 30% of patients, but they rarely have hypoxia due to the absence of ventilation-perfusion mismatch.

In the intestine, increased GH results in an incidence of colon polyps and cancer. Delhougne et al. [25] found in a prospective study that 45% of acromegalic patients had colonic polyps, 24% of them were of the adenomatous type. IGF-1 is unique in that it induces cellular growth and proliferation while also possessing an anti-apoptogenic effect. In 2010, The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) advised to start screening of acromegaly patients at the age of 40 with colonoscopy, 10 years earlier than the general population. Patients who were found to have adenoma at first screening or an increased serum IGF1 level above the maximum of the age-corrected normal range needed to be screened every 3 years. Patients with normal colonoscopy or non-adenomatous polyp, or normal growth hormone/IGF1 level, should be screened every 5–10 years [26].

6.2 Evaluation

Due to its pulsatile nature of secretion, random GH measurement is not preferred. Clinical diagnosis starts by observing the typical manifestations of GH hypersecretion (Figure 3). Once it is suspected, early morning GH level and IGF-1 level are measured. It is highly advised to use sex and age adjusted levels of IGF-1 as variations in the levels may result in false negative results. The gold standard test for acromegaly diagnosis confirmation is oral-glucose tolerance test (OGTT).

Figure 3.

Acromegaly diagnosis algorithm.

All patients with confirmed acromegaly should be screened for associated comorbidities which include hypertension, diabetes, cardiomyopathy and ECG, sleep apnea, and colonoscopy if the age above >40 years old. Patients who have acromegaly related comorbidities have two-fold increase in mortality [24]. While clinical manifestation is extremely indicative of the type of pituitary adenoma—lab values for other pituitary hormones are important screening factors for mixed adenomas (e.g. PRL co-secretion is found in 30% of patients). Standard visual field assessment should be offered to all patients who have macroadenomas abutting the visual apparatus on imaging studies.

Pituitary MRI is needed for evaluation of acromegaly of pituitary source. Because of its insidious onset, GH secreting pituitary adenomas present around 4–7 years after onset. At the time of diagnosis, around 75% of acromegaly patients have macroadenoma on MRI. It is important to note the extent of invasion to suprasellar and cavernous sinus compartments (Figure 4).

Figure 4.

Modified Hardy’s classification for sphenoidal sinus and extrasellar extension (A), and Knosp classification of cavernous sinus invasion (B).

6.3 Management

The goal of management in GH-secreting adenomas is to normalize GH/IGF-1 levels, remove the mass effect of adenoma from surrounding neurovascular structure, and reverse or control comorbidities that are related to high GH levels. Most of biochemical and structural changes caused by high GH status are reversible (Table 5). Treated acromegaly patients with postoperative GH <1 ng/mL have mortality rate that is similar to age-matched general population [27].

Cardiovascular changes	Outcome	Notes
Hypertrophic cardiomyopathy	Reversable	Better prognosis in patients <40 years and shorter duration of GH exposure (<5 years duration)
Arrhythmias	Reversable
Hypertension	Possible reversable	Unsolid data showed possible reversibility
Valvular hear disease	Irreversible	Mitral and aortic valves are most commonly affected
Metabolic changes	Outcome	Notes
Insulin resistance/diabetes	Reversable	Depends on the status of beta-cells function. Octreotide associated with deleterious effect on glucose metabolism especially at the beginning of treatment
Hyperlipidemia	Reversable
Respiratory changes	Outcome	Notes
Sleep apnea	Reversible (unless significant remodeling of upper airways due to long-standing acromegaly)	Nocturnal PEEP-ventilation assisted device ma needed in treated patients with irreversible upper airway changes
Lung volume and elasticity	Reversible
Musculoskeletal changes	Outcome	Notes
Arthropathy	Irreversible	Treated patients may have improvement on pain and range of motion, but not on the structural joints changes.
Carpal tunnel syndrome	Reversible

Table 5.

Reversible and irreversible biochemical and structural changes in treated acromegaly patients [22].

Surgical excision through a trans-sphenoidal route is the gold standard. Unless it is contraindicated, all patients should be offered surgical excision of the adenoma. In older reports before the year of 2000, GH normalization rate after surgical management was between 40 and 70% [28]. The most common cause of incomplete tumor excision and failure of GH normalization after surgery is extra-sellar tumor growth, specifically invasion into the cavernous sinus. Adenoma total resection will result in a biochemical cure which is defined as IGF-1 within normal range for age and gender, and suppression of GH to <1 ng/mL following OGTT [29].

Recent studies have found that the rate of medial wall invasion in GH-secreting adenomas between 70 and 89% and resection of the medial wall of the cavernous sinus resulted in higher post-operative GH normalization rate which in recent reports was found to be 67–92% [29, 30, 31, 32]. Detection of suprasellar extension or cavernous sinus invasion can be evaluated and graded on pre-operative MRI scans by using Hardy’s and Knops’ classification systems (Figure 4), This system uses CISS and VIPE sequences to evaluate cavernous sinus invasion and optic canal tumor extension [33, 34].

Treatment algorithm is summarized in (Figure 5) which is adopted from The Endocrine Society Guidelines released in 2014 [35].

Figure 5.

Acromegaly management algorithm. SRL, somatostatin receptors ligands. *Repeat surgery is recommended for residual and resectable disease. **SRL are the first line of management in patients who are poor surgical candidates, have extensive parasellar invasion, or who had only tumor debulking.

Important points regarding the management of GH-secreting adenomas:

• Surgical debulking should be offered to patients who harbor large adenomas with significant extra-sellar extension as that would increase the response to medical therapy.

• All patients who had total resection of the adenoma and achieved biochemical cure should be followed-up with IGF-1 level annually.

• All patients who did not achieve biochemical cure should be treated with octreotide (SRL). Pegvisomant is added to medical regimen if the response on octreotide is suboptimal.

• Radiotherapy is offered for patients who had recurrent adenoma or in suboptimal response on medical therapy. All patient who received radiotherapy should be monitored for hypopituitarism as 80–100% of patients will develop it about 10 years after radiotherapy [28]. It is particularly helpful in adenoma growth control in 90% of patients and can achieve normal IGF-1 level in up to 70% of patients, however, full response takes 10 to 15 years to be seen [28, 36].

• On early morning of post-operative day 1, GH level < 2 ng/ml is highly predictive of surgical biochemical cure [37].

• Octreotide may result in gastrointestinal hypomotility and increase the risk of gallbladder stones, however, regular monitoring with ultrasound is not needed.

• Pegvisomant reversibly elevates liver enzymes. Patients should have liver enzymes monitored every month for first 6 months and every 6 months thereafter. If liver enzymes become elevated three-times above the baseline level, Pegvisomant should be stopped.

• Patients may experience excessive diuresis after surgery with immediate improvement in soft tissue edema which should be differentiated from postoperative diabetes insipidus. This phenomenon occurs due to fluid mobilization from soft tissue as GH cause significant fluid retention and plasma volume expansion. Zada et al. found that patients with a negative cumulative fluid balance at 48 hours after surgery were more than twice as likely to have a GH level of <1.5 ng/ml (55 vs. 25%, p = 0.023) [38].

7. Cushing disease

Cushing disease (CD) is a clinical syndrome caused by exposure to supraphysiological levels of cortisol due to adrenocorticotropic hormone (ACTH) hypersecretion from pituitary gland. Cushing disease has an annual incidence of about 2.4 cases/million and a prevalence of 39.1 cases/million [39, 40]. The cause of 70% of endogenous CD is by pituitary adenomas. 20–30% of endogenous CD are due to ectopic-ACTH secreting tumors, 50% of them are from lung cancer.

In normal physiological conditions, ACTH secretion from the anterior pituitary gland is under stimulatory effect by corticotropin-releasing hormone (CRH) released from the paraventricular hypothalamic nucleus. CRH is delivered to pituitary corticotroph cells through hypophyseal portal venous system. ACTH release will stimulate cortisol secretion from adrenal glands. Cortisol will exert an inhibitory effect on ACTH and CRH release from pituitary gland and the hypothalamic nucleus, respectively, in a negative feedback-mechanism. Adenoma cells are not sensitive to high levels of cortisol, however, CRH levels will be suppressed.

ACTH-secreting adenomas are rare, they constitute around 6% of pituitary adenomas [41]. On diagnosis, the majority are microadenomas and only 4–10% are macroadenomas [40]. Unlike acromegaly, CD has female predominance (3:1). Unlike prolactinomas and GH-secreting adenomas, ACTH-secreting adenomas have no relationship between the size of the adenoma and the extent of hypersecretion. Mathioudakis et al. found that patients with microadenomas had more clinical signs and symptoms overall when compared to patients with macroadenomas [42].

7.1 Clinical presentation

High cortisol levels have deleterious effects on almost every organ or system in the body. The most common signs and symptoms are glucose intolerance, hypertension, plethoric rounded facies, decreased libido in both sexes, and menstrual irregularities in females [43]. Other manifestations include osteoporosis, skin thinning and easy bruising, buffalo hump, acne, and proximal muscle weakness. In the pediatric age group, CD should be suspected in children who present with rapid weight gain, growth retardation and dorsocervical fat pad. Uncontrolled CD is associated with high mortality with estimated 5 years’ survival of 50% [44]. The main causes of morbidity and mortality in untreated patient are myocardial infarction, strokes, diabetes mellitus, and infection. However, even after successful management, patients are at higher risk for lethal cardiovascular incidents up to 5 years after treatment [45].

7.2 Evaluation

Early recognition of CD is vital for mitigation of long-term consequences from high cortisol exposure. The first step in diagnosis relies on clinical suspicion. Exogenous corticosteroid source should be first ruled-out by a detailed history. The diagnostic work-up is summarized by 3 broad steps: detection of high cortisol level, ACTH level status, and localization of the disease origin (Figure 6). After biochemical confirmation of Cushing syndrome, ACTH level should be measured.

Figure 6.

Diagnosis algorithm for Cushing disease.

Low-ACTH levels mean that pituitary cells are suppressed and there is no extra-pituitary ACTH secretion. In this setting, it is prudent to rule-out adrenal adenomas. If ACTH level is high, CD is confirmed and the localization of the source of ACTH secretion should be evaluated. Unlike cancer cells that secret ACTH, adenomas affecting corticotrophic pituitary cells are usually suppressed by exogenous high corticosteroids doses. High-dose dexamethasone test (e.g. 8 mg given at 9 p.m. and cortisol levels measured at 8 a.m. the next morning) will suppress ACTH secreted from pituitary adenoma but not from ectopic sources. MRI pituitary need to be ordered if high-dose dexamethasone test localize the source to pituitary gland. As mentioned earlier, 70–75% of ACTH-secreting adenomas are microadenomas. However, up to 60% of these adenomas are not detected on MRI [43, 45, 46]. To increase detection rate of the adenoma, volumetric interpolated breath-hold examination (VIBE) sequences should be added [47]. If the brain MRI is negative or high-dose dexamethasone test is unequivocal and a pituitary source is still highly suspected, inferior petrosal sinus (IPS) sampling would confirm the pituitary source and also localize the tumor within the pituitary gland to the left or right side. IPS sampling has an accuracy rate of up to 95%, however, it is an invasive procedure and requires highly experienced operators. To enhance the detection rate, bilateral simultaneous IPS sampling after CRH or desmopressin stimulation is highly recommended (Figure 7) [48, 49].

Figure 7.

Bilateral internal jugular vein catheterization (A) and selective contrast injection and sampling of bilateral inferior petrosal sinuses (B).

It is important to mention that IPS sampling is not recommended for adenoma localization in previous surgically treated patients because the venous drainage of the pituitary gland lateralizes unpredictably after initial surgery [50].

7.3 Management

The only current treatment is surgery, and the aim should be total adenomectomy. Surgical cure and recurrence rate depends on surgeon experience, adenoma size, extra-sellar extension, and adenoma detection on preoperative MRI. The definition of postoperative biochemical remission varies in the literature but cortisol levels in the early morning after surgery <5 μg/dl within 2–7 days of adenomectomy is widely considered to have high positive predictive value of remission [51].

Remission rate in surgically treated CD is 69–93% [52, 53, 54]. Recurrence rate after successful management is between 3 and 22% of patients after 3 years [50]. However, in patients whose preoperative MRI failed to show the adenoma, remission rate drops to 50–70% [54]. Adenomectomy resection using pseudocapsule technique in which the tumor is resected with its surrounding adherent pituitary cells is associated with higher success rate, longer remission rate, and higher rate of cortisol decline in the post-operative period (Figure 8) [45, 55].

Figure 8.

A 30-year-old female patient presented with typical features of Cushing disease. Preoperative workup revealed high cortisol level. She was investigated with MRI pituitary with contrast which showed microadenoma involving the left half of the pituitary gland (A). The patient underwent endoscopic transsphenoidal total resection by utilizing pseudocapsular technique (B). She went to complete remission 36 hours after surgery.

In cases where the adenoma is small or not visualized on MRI, several options are available which will aid in intraoperative tumor localization. Waston et al. could localize ACTH-secreting adenomas by using intraoperative ultrasound in 69% of their patients with negative preoperative MRI [56]. If intraoperative ultrasound is not available or inconclusive, sellar exploration with making multiple cuts within the pituitary gland looking for the adenoma may be warranted. However, in such cases it is very important to expose the whole pituitary gland by wide removal of sellar floor bone and wide dural opening. Additionally, it is crucial to expose the anterior and medial walls of cavernous sinuses bilaterally for adequate visualization. If the exploration was not fruitful, then a partial hypophysectomy of the side that was lateralized by IPS sampling should be considered. Total hypophysectomy (i.e. removal of the anterior pituitary gland while leaving the posterior gland attached to the stalk) may be considered in cases where IPS sampling was unable to lateralize the adenoma, or in cases where intraoperative localization of the adenoma failed.

But the question is when to consider that patient has failed the surgical management and did not achieve remission?

Determining when to consider a patient has failed surgical management is difficult. As stated, all patients should have their cortisol levels evaluated the morning after surgery. Immediate postoperative cortisol levels may fluctuate. Generally after 72 h, cortisol level is stabilized, and therefore can be a better determinant of whether that the patient did not reach the remission state [57]. However, it was found that cortisol level ≤2 μg/dl within first 24 h after surgery there is a 100% sensitivity for durable remission [58]. A serum cortisol value >5 μg/dl up to 6 weeks post-surgery is considered to have persistent disease and should be considered for repeat surgery. Ten percent of patients who had durable remission after adenomectomy will develop recurrence of the disease, therefore, all patients need regular long follow-up for recurrence monitoring [59].

Then, what if the patient failed first surgery and remission did not achieved?

If a patient failed to achieve remission after their first surgery, it is always advisable to do an exploration of the pituitary gland and resect any remnant of the adenoma. Firstly, a pituitary MRI should be repeated; if MRI shows remnant adenoma, resection is needed as soon as possible. If MRI failed to show the remnant disease, surgical exploration of the resected cavity and possible partial or total hypophysectomy should be considered.

But, what if partial or total hypophysectomy have been done in first operation?

In such cases, patient should receive medical therapy, radiotherapy, or other adjuvant therapy.

The aforementioned plan can also be adopted for recurrent disease after an initial biochemical cure. In terms of radiotherapy, stereotactic radiosurgery has the highest incidence of CD remission with rate of 70–75% according to recent reports [60, 61].

Most patients who had successful resection of the adenoma will develop hypocortisolism. This is happens due to longstanding suppression of normal corticotroph cells by high cortisol levels and it takes more than 6 months for those cells to recover. In our practice, we do the first cortisol level measurement 6 h after the surgery and we repeat it every 6 h for the first 3 days. We give replacement therapy (hydrocortisone 8 mg/m² on early morning and 4 mg/m² on evening) only if cortisol level < 1.8 ug/dl. Hypopituitarism occurs after adenoma resection in <5% of cases, therefore, pituitary function assessment should be usually done 2 weeks after surgery by measuring prolactin and T4 levels [45].

Lastly, Cushing’s disease patients have an increased risk of venous thromboembolism (VTE). The incidence of postoperative VTE was found to be 3.4% in one study. Excess circulating corticosteroids cause inhibition of fibrinolysis and accelerated activation of coagulation factors. Even after correction of high cortisol level, Hypercoagulability state persist for extended period and the exact time of hemostatic parameters normalization is not well studied [62]. One proposed plan is to keep the VTE chemoprophylaxis up to 30 days after surgery [62].

8. Nonfunctional pituitary adenoma

Non-functional, or non-secretory, adenomas constitute about 10–20% of all intracranial tumors and 15–30% of all pituitary adenomas [63]. They are the second most common pituitary adenoma after prolactinoma. However, if only macroadenomas are considered, NFPA is the most common one [64]. NFPA is unique compared to functional pituitary adenomas in different aspects. First, NFPA are usually seen in old age groups compared to functional adenomas. Second, patients present mainly with signs and symptoms of mass effect. Third, large number of patients have hypopituitarism in one or more of pituitary axes. On the other side, many of NFPA patients are detected incidentally (pituitary incidentalomas). The incidence of asymptomatic NFPA varies in the literature, but one large meta-analysis-autopsy study found the mean prevalence of pituitary incidentalomas was 10.7% [65].

The natural history of incidentally discovered NFPA remains relatively unknown. However, the risk of tumor expansion is related closely to tumor size on presentation and, to lesser extent, tumor relation to optic apparatus [66]. Microadenomas have a low chance of expansion (19%) compared to macroadenomas (25–50% of macroadenoma patients show tumor expansion on follow-up imaging) [66].

8.1 Clinical presentation

The most common presentation of NFPA is headache. It may be caused by intrasellar pressure increment and dural lining compression which are innervated by trigeminal nerve branches. Visual field defect is the second most common clinical presentation that may be seen in up to 61% of cases [64, 67]. Visual field defects are asymmetrical in 2/3 of the patients. They occur due to optic nerves and/or chiasm displacement and compression, which also may result in permanent deficit in long-standing compressions.

Tumor extension to cavernous sinus may result in ophthalmoplegia due to compression of CNIII, CNIV, and CNVI. CNIII is most commonly affected followed by CNVI and then CNIV.

Adenomas greater than >4 cm of diameter may obstruct foramen of Monro and cause obstructive hydrocephalus.

Pituitary apoplexy is another common presentation for these lesions. Pituitary apoplexy is most commonly seen in NFPA, accounting for 45–82% of pituitary apoplexy cases, and 7–9.5% of asymptomatic NFPA present initially with pituitary apoplexy [64].

Hypopituitarism is another common sequela of NFPA. 70–85% patients will have deficiency in at least one axis of pituitary cells secretion [68]. Hypopituitarism occurs in an expected sequence of hormonal loss which usually affect GH, then LF/FSH, then TSH, and lastly ACTH. Diabetes insipidus is rare in non-surgically-NFPA-treated patients, and if it is found in a patient with pituitary lesion, other lesions should be considered (e.g. craniopharyngioma, aneurysms, metastasis).

Lastly, as stated previously, NFPA may be discovered incidentally on brain MRI that was done for other causes. In one large single-center prospective study, 49% of NFPA presented incidentally and 85% of them harbored macroadenomas. Interestingly, in the same cohort, they found that half of the patients in the asymptomatic group reported some mass effects symptoms like headache and/or visual symptoms and only 35% of the incidentally discovered group (in which brain imaging done for unrelated reasons) has no symptoms at all [69].

8.2 Evaluation

All patients who their imaging studies showed pituitary adenoma, whether symptomatic or asymptomatic, should go thorough hormonal evaluation as recommended by The Clinical Guidelines Subcommittee of The Endocrine Society [70]. These include IGF-1 and GH, ACTH, prolactin, FSH/LH, and TSH. If ACTH and IGF-1 test are equivocal, stimulatory tests are recommended. Hypopituitarism is not uncommon and hormonal replacement therapy should be initiated in patients with hormonal deficiency. Panhypopituitarism can be seen in up to 30% of patients. Prolactin level could be elevated in 25–65% caused by pituitary stalk compression (stalk effect) [71]. Therefore, it is important to differentiate between hyperprolactinemia caused by a prolactinoma or NFPA. Prolactin level > 200 μg/L is unlikely to be caused by stalk effect.

The diagnostic approach and follow-up are different between symptomatic and asymptomatic NFPA. In symptomatic NFPA, and after doing the hormonal laboratory tests, all patients need to have ophthalmic evaluation for assessing optic apparatus function. Also, it is important to have a detailed history and physical examination to assess the patient symptoms. In asymptomatic NFPA, patients need to have complete hormonal evaluation as mentioned previously to rule-out hyper-or-hypopituitarism. Asymptomatic microadenomas can be followed-up after 1 year of diagnosis by repeating the brain imaging only. In asymptomatic macroadenomas, follow-up is after 6 months with brain MRI and hormone levels, then every year if the follow-up images and laboratories did not show tumor progression or pituitary dysfunction (Figure 9).

Figure 9.

Simplified scheme of NFPA diagnosis and management.

8.3 Management

Treatment of patients with NFPA starts with hormonal replacement therapy in case of hypopituitarism. It is vital to recognize and treat cortisol deficiency efficiently. The same is true for secondary hypothyroidism as patients should receive thyroxine immediately after confirming its deficiency. Both cortisol and thyroxine should be initiated before surgery, and in non-emergency surgery, it is better to replace thyroxine and wait until hypothyroidism is adequately treated.

Surgical indications for NFPA are symptomatic optic nerve or chiasm compression, cranial nerves dysfunction, and pituitary apoplexy with visual impairment (Figure 9). However, surgery is also advised in asymptomatic growing adenomas that are close to or progressively abutting optic nerves and/or chiasm on follow-up imaging studies [70].

What about patients who have hypopituitarism or headache only?

Surgery in patients with hypopituitarism alone without visual symptoms is not recommended as only 30% of patients will have improvement over pituitary function. Also, headache is a common symptom in NFPA patients, but as headache has multiple causes, there is a high chance of headache persistence after adenoma resection. Therefore, only intractable headache that is affecting patient’s daily activities should be an indication of surgery and the patient should be aware that headache relief cannot be guaranteed [71].

After surgery, patients should be evaluated for hypopituitarism 6 weeks after surgery. Also, pituitary MRI should be done 3 months after surgery to have it as a baseline for future follow-up. Gross-total resection of NFPA has a recurrence rate of 7–24%, and 47–64% of cases in partially resected ones [72].

9. Surgical approaches to pituitary adenomas

Currently, pituitary adenomas are approached almost exclusively through transsphenoidal route because it offers a direct access to sellar and suprasellar region by removing of posterior wall of sphenoidal sinus. Also, it is associated with lower morbidity and it is considered a less invasive approach than the transcranial route. Either endoscopic and microscopic, transsphenoidal approach is adequate to remove intrasellar lesions with satisfactory outcomes. Recent advancements in surgical endoscopy have improved our ability to visualize and dissect normal anatomical structures from the adherent pathologies in a way that is nearly similar to microneurosurgery. However, in selected cases, transcranial approaches are still needed for resecting tumors extending to suprasellar or parasellar regions that could not be addressed by transsphenoidal approaches.

9.1 Transsphenoidal approach

It is an extra-arachnoidal direct route to pituitary gland. It has the advantage of avoiding brain retraction, early optic nerves decompression with minimal manipulation, and wide operative view. Posterior wall of sphenoidal sinus, or sellar floor, can be accessed via a transnasal or translabial route. Usually, it involves the usage of microscope, endoscope, or both. Whether endoscope or microscope is used, the procedure has three-stages that are needed to reach the intrasellar space: nasal stage, sphenoidal stage, and sellar stage.

It is important to utilize an operative setup that is comfortable for whole team. Patient is typically positioned supine with 20-degrees head elevation and is positioned straight or slightly extended and fixed using Mayfield head clamp. The surgeon usually operates on the right and facing of the patient. We prefer to have the scrub nurse on the right side of the surgeon and the assistant on the left side. The screen and the navigation are positioned on the left side of the patient facing the surgeon (Figure 10). Neuronavigation is essential for dealing with tumors that extended to supra- or para-sellar regions, and recurrent tumors.

Figure 10.

Patient positioned supine, with head slightly extended, monitors are placed to left of the patient (A). The surgeon standing on the right of the patient and the assistant on the surgeon’s left side (B).

9.1.1 Nasal stage

Using 0-degree endoscopy, inferior, middle and superior turbinates are identified. Middle turbinate usually obstructs the access to sphenoidal sinus. To have unobstructed route, middle turbinate is typically displaced laterally, or resected if a wider view is needed, using a blunt dissector to create enough working space. After that, the choana is found on the inferomedial aspect of the view. Sphenoethmoidal recess is identified and sphenoid ostium is seen on the roof of the recess and the choana. Nasal septum the best landmark for midline identification.

9.1.2 Sphenoidal stage

It starts with enlarging the sphenoidal ostium lateral and inferiorly. This step is usually undertaken by using chisel or high-speed drill. Care is taken to avoid injury to sphenopalatine artery the lies in the inferolateral direction. Posterior nasal septum is coagulated and detached from the sphenoidal rostrum. Anterior wall of the sphenoidal sinus now is exposed, circumferentially with bony removal using high-speed drill and sphenoidal rostrum is removed in fragments. It is important to perform a wide removal of anterior wall of sphenoidal sinus to avoid a narrow working space. Multiple sphenoidal septa can be seen inside the sinus and may need to be drilled. Care is taken septa drilling as one or more of the septa may be attached to carotid prominences.

9.1.3 Sellar stage

After a wide removal of anterior wall of sphenoidal sinus and drilling of sphenoidal septa, sellar floor will be seen. Important anatomical landmarks at sellar floor include carotids, optic nerves, pituitary prominences, and lateral opticocarotid recesses bilaterally (Figure 2). Progressive thinning of sellar floor using diamond drill and Kerrison rongeur till the dura over the pituitary gland is exposed. Lateral and superior exposure depends on the extent of the tumor. We prefer not to expose the intracavernous carotids unless the anterior wall of cavernous sinus is needed to be opened for medial wall resection or when dealing with functional adenomas.

9.1.4 Complications

Transsphenoidal approach is usually safe and associated with low morbidity rate [73]. The most feared intraoperative complication is ICA injury, which has a very low incidence rate. However, it is associated with significant morbidity and mortality. Consequences of a such injury include pseudoaneurysm formation and carotid cavernous fistula.

Postoperative complications include the ones related to the nose (nasal septum perforation, insomnia, epistaxis from injury to sphenopalatine artery or its branches), sphenoid sinus complications (mucocele formation, sinusitis or sphenoid bone fractures), or related to intrasellar (hemorrhage, cerebrospinal fluid (CSF) leak and tension pneumocephalus).

CSF leak incidence has decreased in recent years due to the advancements and newer techniques in harvesting vascularized nasoseptal flaps [74]. CSF leak incidence in recently published series falls between 1% and 4% [75].

9.2 Transcranial approaches

The majority of patients can be treated using transsphenoidal route. However, a few of pituitary adenomas may require transcranial approaches for resecting adenoma extensions that cannot be reached by transsphenoidal route.

Common indications for transcranial surgery in pituitary adenomas include:

1. Lateral and significant suprasellar adenoma extensions to critical neurovascular structures.

2. Anatomical challenges like conchal-type sphenoidal sinus, kissing carotids, sinuses infection.

3. Unsuccessful previous transsphenoidal surgery.

Other uncommon indications include patients with obstructive sleep apnea who could not be weaned off CPAP or concomitant aneurysm that is in proximity to the sellar area.

Recurrent adenomas are no longer an indication for transcranial surgery [76, 77]. Also, giant adenomas (>4 cm) used to be an indication for transcranial surgery, but due to recent advancements in endoscopic approaches, large size adenomas can be effectively treated through transsphenoidal route [78].

In dealing with giant pituitary adenomas that encasing nearby neurovascular structures, both transsphenoidal and transcranial may be needed, especially when the goal of surgery is gross total excision in functional-adenoma cases.

But what approach should be the first choice, the transsphenoidal or the transcranial surgery?

The answer of this question relies on the understanding of the blood supply of pituitary adenomas. These tumors share the same blood supply of normal pituitary gland which comes from inferior and superior hypophyseal arteries. In general, pituitary adenomas have low vascular density which may explain their slow growth [77]. Attacking the adenoma through transsphenoidal route will result in acute devascularization of the remaining unresected adenoma which result in intratumoral necrosis and subsequently hemorrhage (Figure 11). Therefore, it is preferred to go transcranially first then to operate transsphenoidal [79, 80].

Figure 11.

Preoperative MRI (A and B) and postoperative CT scan (C and D) for a senior male patient who was complaining form headache and progressive visual dysfunction. The patient was operated in outside hospital through transsphenoidal approach. Incomplete excision was done. However, the patient developed decrease in the level of consciousness and oculomotor nerve dysfunction after surgery. Brain CT scan showed excessive hemorrhage in the unresected intracranial part of the adenoma.

Transcranial approaches that commonly utilized to deal with pituitary adenomas include pterional, orbitozygomatic, bifrontal, and supraorbital approaches. The choice of the approach depends on tumor extension and the neurovascular structures that are needed to be addressed intraoperatively.

10. Conclusion

Pituitary adenomas associated with significant morbidity and require multiple modalities of treatment. Management is usually surgical except for prolactinomas. The therapeutic decision should be adjusted to adenomas type, center expertise, and patient desire. Thorough understanding of the pathophysiology and management options of PA different types is essential to achieve the therapeutic goals, which can be summarized in pituitary and neurological function restoration.