Key points

Introduction

The sellar region is located in the central portion of the skull base, behind the posterior wall of the sphenoid sinus and between both cavernous sinuses. The pituitary gland formed by the adenohypophysis (anterior pituitary) and the neurohypophysis (posterior pituitary), lies in the sella turcica. Suprasellar growth is the main axis of extension of sellar tumors. The medial wall of the cavernous sinus that separates the pituitary fossa from the cavernous sinus is weak so that sellar tumors frequently infiltrate the cavernous sinus. Tumors of the pituitary gland and sellar region account for approximately 10% to 15% of all brain tumors and a large variety of neoplastic, inflammatory, vascular, or developmental lesions can be found in this region. Most tumors are pituitary adenomas (PAs) (9%) ( Table 1 ).

However, other diagnoses should be excluded before surgery because the optimal therapeutic strategy may vary significantly from one lesion to another.

It is crucial, in a case of a sellar lesion, to perform first a complete diagnostic workup including endocrinologic, ophthalmologic, and neurologic assessments and neuroimaging studies.

In most cases, these studies will lead to a diagnosis of near certainty, preoperatively, but in some cases, a biopsy is still necessary to define the optimum treatment strategy before a more complex surgery that may not be required.

Most often, sellar and parasellar tumors require a multidisciplinary approach including endocrinologic care, surgery, radiation therapy, or primary medical treatment. For those lesions that have a high risk of recurrence, long-term follow-up, based mainly on regular ophthalmologic and endocrinologic examinations and MRI, is required. This article provides an overview of sellar diseases with emphasis on their most useful characteristics to clinical practice.

Introduction

The sellar region is located in the central portion of the skull base, behind the posterior wall of the sphenoid sinus and between both cavernous sinuses. The pituitary gland formed by the adenohypophysis (anterior pituitary) and the neurohypophysis (posterior pituitary), lies in the sella turcica. Suprasellar growth is the main axis of extension of sellar tumors. The medial wall of the cavernous sinus that separates the pituitary fossa from the cavernous sinus is weak so that sellar tumors frequently infiltrate the cavernous sinus. Tumors of the pituitary gland and sellar region account for approximately 10% to 15% of all brain tumors and a large variety of neoplastic, inflammatory, vascular, or developmental lesions can be found in this region. Most tumors are pituitary adenomas (PAs) (9%) ( Table 1 ).

However, other diagnoses should be excluded before surgery because the optimal therapeutic strategy may vary significantly from one lesion to another.

It is crucial, in a case of a sellar lesion, to perform first a complete diagnostic workup including endocrinologic, ophthalmologic, and neurologic assessments and neuroimaging studies.

In most cases, these studies will lead to a diagnosis of near certainty, preoperatively, but in some cases, a biopsy is still necessary to define the optimum treatment strategy before a more complex surgery that may not be required.

Most often, sellar and parasellar tumors require a multidisciplinary approach including endocrinologic care, surgery, radiation therapy, or primary medical treatment. For those lesions that have a high risk of recurrence, long-term follow-up, based mainly on regular ophthalmologic and endocrinologic examinations and MRI, is required. This article provides an overview of sellar diseases with emphasis on their most useful characteristics to clinical practice.

Embryology of the pituitary gland

The pituitary gland, located in the sella turcica is composed of 2 distinct parts, the adenohypophysis (anterior pituitary) and the neurohypophysis (posterior pituitary), which differ in terms of embryologic development, anatomy, and function. The 2 lobes have entirely separate embryonic origins, which later become structurally and functionally linked. The pituitary gland has both an ectodermic and neuroectodermic origin. A small sliver of tissue, the intermediate lobe, separates both lobes.

The pituitary differentiation, under the control of a complex cascade of signaling and transcription processes, occurs during the first trimester of gestation and finally results in the juxtaposition and interaction of the oral ectoderm forming Rathke’s pouch, an upward invagination of the roof of the stomodaeum, and the neural ectoderm of the diencephalon, which bulges downward to form the infundibulum.

Once in contact, both layers will proliferate. The cells of Rathke’s pouch differentiate into the endocrine cells of the anterior pituitary. Rathke’s pouch loses its connection with the roof of the primitive mouth and comes to lie anterior to the infundibulum and wrap around the pituitary stalk. It gives rise to pars distalis, pars tuberalis, and pars intermedia. The infundibulum gives rise to the pituitary stalk and the posthypophysis.

A network of blood vessels, the hypophyseal portal system, functionally links the anterior lobe to the hypothalamus and posterior lobe of the pituitary.

Anatomical boundaries of the pituitary fossa

The anterior wall and the floor of pituitary fossa are formed by a bony wall that corresponds to the sellar prominence of the posterior wall of the sphenoid sinus. It is covered by a thin layer of periosteum. Superiorly, the anterior wall of the sella turcica continues with the tuberculum sellae. Laterally, the tuberculum sellae continues with the posterior edge of the optic strut. Above the tuberculum sellae is the chiasmatic sulcus. The chiasmatic sulcus is bounded posteriorly by the tuberculum sellae and anteriorly by the chiasmatic ridge, which forms the posterior border of the planum sphenoidale. The shape of the tuberculum sellae, chiasmatic sulcus, and optic strut is highly variable and correlates with the shape of the prominence and recess that are identified exocranially on the posterior wall of the sphenoid sinus.

The ceiling of the pituitary fossa is formed by the diaphragma sellae that covers the pituitary gland. It has a central opening for the pituitary stalk. The diaphragma sellae is also highly variable in terms of thickness and size of the central opening. Those variations may also influence to some extent, the superior extension of sellar lesion, especially the macroadenomas ( Fig. 1 ).

Coronal histologic section of a pituitary adenoma in an adult cadaveric specimen (hematoxylin-eosin). The black stars indicate the normal pituitary gland. The red star indicates the pituitary stalk. The red arrows indicate the extension of the pituitary adenoma toward the right cavernous sinus without a true medial wall separating the adenoma and the cavernous sinus.

The medial wall of the cavernous sinus, which separates the cavernous sinuses from the pituitary fossa, has been the subject of numerous studies and controversies. Some investigators state that there is no true medial wall and that it is only composed of a glandular capsule and of some connective tissue continuous with the supportive connective tissue of the cavernous sinus. This may account for the well-known extension of PAs and other sellar lesions in the posterior aspect of the cavernous sinus. Histologic examination of this region supports those findings indicating that the pituitary gland and PAs are separated from the lateral sellar compartment, the so-called cavernous sinus , by a thin layer of loose connective tissue ( Fig. 2 ).

Coronal histologic section of the sellar and left parasellar region of a newborn head (hematoxylin-eosin). The black arrows indicate the limit between the pituitary fossa and the cavernous sinus without clear dural medial wall.

The internal carotid artery (ICA) is in close contact with the pituitary gland. The position and the trajectory of the ICA along the lateral aspect of the pituitary gland are also highly variable and should be carefully evaluated on preoperative angiographic dedicated examinations.

The posterior wall of the pituitary fossa is formed by the dorsum sellae. The posterior clinoid processes form the superolateral margin of the dorsum sellae.

Signs and symptoms related to sellar lesions

The clinical symptomatology may be very rich and is primarily dependent on the hormones secretory active status (or nonsecretory) of the lesion, its effect on the hypothalamic-pituitary axis, its growth rate, and its upper extension toward the visual pathways and lateral extension toward the cavernous sinus.

Symptoms related to sellar regions are classified into 3 main categories: ophthalmologic, endocrine, and neurologic symptoms.

Sellar lesions may also be discovered on a routine computed tomography (CT) scan or MRI performed for another reason in a patient without any signs or symptoms of pituitary disease. The prevalence of these so-called pituitary incidentalomas estimated from autopsic series is 9.3% (range, 1.5%–26.7%). Imaging series based on MRI, however, showed a prevalence of asymptomatic pituitary macroadenomas between 0.1% and 0.3%.

Neuroimaging

Neuroradiology provides to the surgeons crucial information regarding the nature of the lesion and its relationships to neurovascular structures, its epicenter, and its extension into the surrounding tissues. MRI stands as the primary diagnostic tool for the diagnosis and assessment of sellar and parasellar lesions. However, CT scan can be a useful complement. It may show some calcifications (craniopharyngiomas [CPs], meningioma, chordoma, aneurysm) and bony erosion or destruction (floor of the sellae, clivus).

In preparation for surgery, it is also useful to study the bony anatomy and its relationship with the tumor and important structures, such as the internal carotid artery. CT angiography helps to rule out life-threatening diagnoses, such as sellar aneurysm, preoperatively and to study more precisely the shape and trajectory of the paracavernous segment of the ICA. Cerebral angiography and extracranial imaging studies must be considered for specific etiologies (aneurysm, hypophysitis, malignant tumor, metastasis).

Biological workup

In all patients with sellar tumors, the pituitary function should be evaluated with a complete biochemical workup (gonadal, adrenal, and thyroid function and PRL and GH secretion). Specific stimulation and suppression tests for pituitary hormones are required in selected cases to evaluate some pituitary hypersecretion or pituitary deficiency.

Neoplastic lesions

Pituitary Lesions

Anterior pituitary lesions

Benign lesions

Hyperplasia

Hyperplasia is defined as a cell proliferation of one or more specific anterior pituitary cell types induced by a known stimulus. It is a process that stops when the stimulus is removed. Pituitary hyperplasia is classified as primary (idiopathic) or secondary hyperplasia in the case of absent or negative feedback stimulation accompanying end-organ failure (particularly primary hypothyroidism). Hyperplasia can be physiologic, for example, when lactotroph cells proliferate during pregnancy, or pathologic, as when induced by an excess of hypophysiotropic hormones. It may cause clinical endocrine syndrome, such as acromegaly or Cushing disease. Hyperplasia appears as a pituitary enlargement on MRI and can be clinically indistinguishable from adenomas. A complete endocrinologic evaluation should be performed. The suppression of the promoting factors is usually sufficient. Close follow-up is required.

Adenomas

PAs are the most common intracranial neoplasm with a population prevalence of 0.1% and autopsy prevalence of around 15%. Most PAs are sporadic. Rare hereditary conditions, such as multiple endocrine neoplasia type 1, are associated with the development of PAs. PAs are composed of adenohypophyseal cells. Any kind of cell types encountered in the adenohypophysis may be found in PAs.

According to their size, PAs are classified into microadenomas (<1 cm in diameter), macroadenomas (>1 cm), and giant adenomas (>4 cm) ( Fig. 3 ). Clinically, PAs are classified as functioning adenomas and nonfunctioning adenomas. Approximately 65% of adenomas secrete hormones (PRL, 48%; GH, 10%; ACTH, 6%; thyrotropin-releasing hormone, 1%) causing hypersecretory syndromes. In addition to the hypersecretion syndromes, large tumor with compression of the surrounding normal pituitary tissue can alter the production of other hormones.

Giant macroadenoma in a patient presenting with blindness on the left side (optic atrophy), intracranial hypertension, and cognitive deficit. ( A ) Coronal T2-WI. ( B ) Axial T1 gadolinium-enhanced WIs. Note the impressive mass effect on the temporal lobe.

Functioning adenomas

Prolactinomas are the most frequent functioning PAs. Most of the microprolactinomas are diagnosed in women during the reproductive period and present with oligomenorrhea or amenorrhea, galactorrhea, and infertility. In men and elderly women, prolactinomas are mostly macroadenomas and present with visual symptoms. Impotence and decreased libido are common in men but are usually not the revealing complaint. Most patients presenting with prolactinomas are usually given medical treatment. Therefore, surgery for prolactinomas is considerably reduced, and the candidates for surgery are those patients who did not respond to medical treatment, experienced major adverse effects induced by all of the available dopaminergic agonists, or have persistent masse effects requiring surgery. Prolactinomas resistant to dopaminergic agonists are good candidates for surgery and if complete resection is not achievable, hormonal control helps with surgical debulking. It has also been reported that patients undergoing surgery for a prolactinomas that have been exposed to bromocriptine are more likely to be fibrous during surgery than those in an untreated patient. This was not observed for patients previously exposed to cabergoline. Curative surgical resection as a primary mode of treatment for small lesions when complete resection can be easily achieved has recently gained attention as an alternative to lifelong dopamine agonist treatment.

GH-secreting adenomas account for about 20% of PAs. Acromegaly affects both sexes similarly, and the mean age at diagnosis is 40 to 45 years. Because the symptoms are slowly progressive, the dysmorphic syndrome is usually recognized quite late by the patient and his relatives (swelling of the hands and feet is often an early feature, protrusion of the brow and lower jaw, enlarged nose and inferior lip, wide spacing of the teeth). Therefore, most patients have a macroadenoma at the time of diagnosis, and visual symptoms may also be present. The biochemical workup shows high serum GH and insulinlike growth factor levels. In about 30% to 50% of patients, there is a cosecretion of PRL resulting in associated symptoms of hyperprolactinemia. Surgery is considered the first-line treatment when the tumor is resectable, especially in cases of well-circumscribed adenomas. Severe associated comorbidities associated with severe acromegaly (hypertension, diabetes mellitus, cardiovascular disease, severe sleep apnea) should be ruled out carefully preoperatively, as they may increase the surgical risk. Preoperative treatment with somatostatin receptor ligands may be considered to reduce this risk. When total resection is unlikely, the best treatment strategy is significant debulking if possible followed by medical treatment. Medical treatment options include somatostatin receptor ligands, dopamine agonist, and GH receptor antagonist. Radiation therapy is indicated in case of residual mass after surgery and if the medical treatment is unsuccessful or not tolerated.

ACTH-secreting adenomas associated with Cushing disease represent approximately 10% to 15% of all adenomas. Cushing disease has a peak incidence between the ages of 30 and 40 years and tends to be more frequent in women. Most ACTH-secreting adenomas are microadenomas, and approximately 15% are invasive at the time of surgery. Ectopic PA tissue causing Cushing’s disease is rare but a potential cause for surgical failure. Microadenomas and ectopic adenomas may be extremely difficult to locate on MRI. On the other hand, any lesion that harbors the radiologic features of a microadenoma is not necessarily endocrinologically active. Indeed, as previously mentioned, the prevalence of incidentalomas is high. In complex cases, bilateral inferior petrosal sinus sampling is sometimes required. High-resolution functional imaging along with with high-resolution morphologic MRI improve the detection of intrasellar or ectopic microadenomas.

TSH-secreting adenomas are the least frequent PAs. Clinically, they may present with hyperthyroidism, but they can also arise in the setting of hypothyroidism or in clinically euthyroid patients. Most TSH-secreting adenomas are invasive macroadenomas.

Nonfunctioning adenomas

Approximately one-third of PAs are not associated with clinical evidence of hormone hypersecretion. However, most nonfunctioning PAs are actually gonadotropin-secreting adenomas. They present rarely with clinical evidence of hormone excess and are considered silent adenomas. In 10% of nonfunctioning PAs, immunostaining is negative. Exceptionally, nonfunctioning PAs may be positive for GH, PRL, TSH, or ACTH despite no secretion being identified clinically; such cases are known as silent somatotroph , lactotroph , thyrotroph , or corticotroph adenomas.

Nonfunctioning PAs, because they have usually reached a significant size at the time of diagnosis, most often present with visual symptoms and signs of hypopituitarism ( Fig. 4 ). Hypopituitarism is related to the compression caused by the adenoma on the normal pituitary the function of which is secondarily impaired. At time of diagnosis, 60% to 85% of patients present at least 1 pituitary deficiency. They also sometimes present with mild hyperprolactinemia caused by pituitary stalk compression.

Large nonfunctional intra- and suprasellar macroadenoma. Patient has a light perception on the left side and an optic atrophy. ( A ) Coronal T1-WI without gadolinium. ( B ) Coronal T1-WI shows homogenous enhancement after gadolinium. The pituitary stalk is deviated ( white arrow ). ( C ) Coronal T2-WI shows more clearly the compression of the chiasma and optic nerve on the left side ( white arrow ). ( D ) Coronal T2-WI at the level of the orbital apex shows atrophy and hypersignal of the Optic Nerve ( white arrow ).

Surgery is required in cases of visual disorders. Hypopituitarism may be an indication for surgery, but recovery is uncertain (30%) and surgery by itself carries a risk of hypopituitarism of 5% to 10 %. Careful follow-up is advocated for incidentalomas.

To evaluate the risk of recurrence or progression, it is advocated to test 3 proliferation markers: proliferation index assessed on Ki-67 antibody, mitotic activity, and p53 expression. Recent studies have found that a Ki-67 greater than 3% predicts recurrence/progression with high specificity (89%). However, even in cases of recurrent tumors, the Ki-67 may be low so it is recommended to test the 3 proliferative markers.

Pituitary apoplexy

Pituitary apoplexy is a serious acute complication of PAs, most often nonfunctioning. They usually present with acute symptoms characterized by a sudden onset of headache. It is frequently associated with nausea and vomiting. Visual symptoms such as diplopia, ptosis, visual acuity, and visual field impairment are also common manifestations of pituitary apoplexy. Decreased consciousness may also occur.

The incidence of pituitary apoplexy is probably around 2% of all surgically treated patients with pituitary adenoma. The etiology is an infarct in a pre-existing lesion, usually a macroadenoma, followed by hemorrhage or necrosis. Promoting factors may be low blood pressure (cardiac surgery, myocardial infarction, trauma with shock) with an increased demand of the lesion or treatments (anticoagulants, dopamine agonists), and it has been described as the consequence of stimulation test of pituitary hormones.

MRI is highly sensitive for the detection of acute or old hemorrhage ( Fig. 5 ). Subarachnoid hemorrhage may also be seen. Angiographic MRI should be performed to rule out any associated aneurysm (differential diagnosis) or vasospasm of the anterior communicating complex.

Pituitary apoplexy in a patient followed up for PAs and presenting in the emergency room with acute headache. ( A ) CT scan before hemorrhage. ( B ) CT scan shows hyperdensity caused by hemorrhage.

Pituitary apoplexy is frequently associated with hypopituitarism, and hydrocortisone replacement should be initiated immediately after diagnosis. Although surgery was historically advocated by most neurosurgeons, conservative treatment is becoming more popular and is now advocated in cases of mild stable or long-standing visual symptoms or isolated occulomotor palsy, together with adequate endocrinologic management and close clinical and ophthalmologic follow-up. Early surgical decompression should be considered in cases of visual status worsening.

Atypical adenomas

Tumors that show histologic features suggestive of aggressive clinical behavior, a Ki-67 labeling index (LI) greater than 3%, and extensive nuclear p53 positivity on immunohistochemial staining are considered atypical adenomas. In such cases, a close follow-up after surgery is highly recommended. The proliferative marker Ki-67 (MIB-1) has been used to distinguish aggressive tumors but some controversies remain about its real prognosis value. Several studies have shown a correlation between the Ki-67 LI and the invasiveness of pituitary carcinomas, and it seems that some of the controversies come from the various criteria used to defined invasiveness. In a study of 159 patients from Pizarro and colleagues, the Ki-67 index was not significantly different in adenomas infiltrating the cavernous sinus, which supports the hypothesis that the medial wall of the cavernous sinus is a weak barrier. Although the Ki-67 LI does not seem to provide independent information to predict tumor recurrence, it does seem to provide valuable prognostic information, and in the case of high Ki-67 labeling index, a closer follow-up is advocated. However, new markers are certainly needed to help clinicians.

Malignant lesions: primary pituitary carcinomas

Pituitary carcinomas are rare, accounting for less than 1% of all pituitary neoplasms. The diagnosis of pituitary carcinoma requires the demonstration of distant metastasis ( Fig. 6 ). Most of them are functionally active and most produce ACTH and PRL. Usually the initial course cannot be distinguishable from the one of a benign pituitary adenoma. Multiple local recurrences and finally metastatic dissemination usually occur later in the course of the condition. Only rarely do patients present with metastases concurrent with the initial sellar tumor. On the contrary to metastatic pituitary carcinoma, primary pituitary carcinomas generally do not impair pituitary endocrine function. The latency between the diagnosis of a PA and the diagnosis of metastasis ranges from a few months to almost 20 years. It seems to be shorter for PRL-producing tumors than for ACTH-producing lesions. Once the diagnosis is made, the survival is poor, and 66% of patients die within 1 year. Standard morphologic features associated with malignancy (hypercellularity, nuclear and cellular pleomorphism, increased mitotic activity, necrosis, and dural/osseous invasion) are commonly present but are not necessarily diagnostic of carcinoma. Ki-67 labeling indices are quite variable and show considerable overlap with common PAs; however, they are often higher, and it may help to alert the clinicians about the possibility of a pituitary carcinomas. Treatment strategies include dopamine agonists for PRL-secreting tumors, radiation therapy, and chemotherapy (Temozolomide) but are only palliative.

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