Sellar and Suprasellar Lesions

Normal Pituitary

The pituitary resides in the sella turcica on the roof of sphenoid sinus, bounded superiorly by an encasing flap of dura (diaphragma sellae), over which rest the optic chiasm and the pituitary stalk. The cavernous sinuses, through which run the internal carotid arteries and a third of the cranial nerves, form a sheath of venous blood around the bony walls of the sella.

The main pituitary blood supply originates from the internal carotid arteries and flows first via the superior hypophyseal arteries to the median eminence of the hypothalamus, after which it forms a complex system of vascular channels, the hypophyseal portal system, that flow to the adenohypophysis. These vessels both convey the hypothalamic regulatory hormones to the adenohypophysis and distribute the pituitary hormones to the systemic circulation. Because these channels are under relatively low pressure under normotensive conditions, the anterior pituitary is prone to hypoperfusion and infarction at higher systemic pressures than other organs. The posterior lobe, or neurohypophysis, is perfused by the inferior hypophyseal arteries.

The anterior lobe, or adenohypophysis, develops from an ectodermal invagination (the Rathke pouch) of the palate during embryogenesis. The mature gland comprises three major epithelial cell populations (by hematoxylin and eosin [H&E] staining): acidophils, basophils, and chromophobes (Figure 8-1). These color classifications roughly correspond to the hormone produced by the cell, with acidophils producing growth hormone (GH), chromophobes producing prolactin, and basophils producing adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) or follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Each cell produces one hormone type, except the gonadotrophs and occasional GH- and prolactin-producing “mammosomatotrophs.” Morphologically, the only cells to show a specific identifying feature are the ACTH-secreting corticotrophs, which have a clear, spheroid, cytoplasmic vacuole called an enigmatic body (Figure 8-2) (1). Folliculostellate cells form the supporting structure for the epithelial cells and are similar to glia in that they extend numerous thin cytoplasmic processes and are positive
for S100 and GFAP (2). Some have suggested that folliculostellate cells are fundamentally similar to dendritic cells and may play a role in antigen presentation (3).

FIGURE 8-1 The normal adenohypophysis contains multiple cell types arranged in small nests, some of which contain hyaline globules.

FIGURE 8-2 Basophilic, adrenocorticotropic hormone–secreting cells usually contain an “enigmatic body,” a single clear perinuclear vacuole that is not present in adenoma cells.

The architecture of the adenohypophysis is similar to that of other endocrine organs, with nests of secretory epithelial cells trimmed with
permeable, thin-walled vascular channels, creating the “organoid” appearance of acinar architecture. Silver staining for reticulin emphasizes the borders of these nests (Figure 8-3), and can be useful in telling normal gland from adenoma, which would lack such a reticulin pattern. Many of the epithelial clusters contain a mixture of cell types, although this can be subtle in areas where one cell type makes up the majority. The cells in compressed adenohypophysis usually lose their distinctive cytoplasmic hues and become much more monotonous, making them appear more similar to adenoma cells.

FIGURE 8-3 Reticulin staining accentuates the regular nested architecture of normal adenohypophysis, which is not a characteristic of adenomas.

The anterior lobe is further compartmentalized into areas where specific epithelial cell types predominate, although a mixture of cells is seen in all areas. This concept is important to remember in certain situations, discussed later. The lateral wings of the gland contain mostly acidophils and chromophobes, whereas the central portion, the “mucoid wedge,” contains mostly basophils. At the frontier between the mucoid wedge and the neurohypophysis, basophils are normally seen wandering as groups and individuals into the posterior lobe in a phenomenon called “basophilic invasion,” an alarming behavior for cells in other organs but innocent in the pituitary (Figure 8-4).

The posterior lobe of the pituitary, or neurohypophysis, is a native resident of the central nervous system, being essentially the swollen terminus for an extension of axons from hypothalamic nuclei. The histologic appearance of the neurohypophysis confirms its neuroepithelial origin and shows several features that distinguish it from other CNS tissues and neuroepithelial neoplasms. Although fibrillar, the overall texture is loose with a degree of condensation around small blood vessels,
making the vessels appear prominent (Figure 8-5). The ends of the axons form eosinophilic, globose, granular structures called Herring bodies, which contain stores of vasopressin (ADH) and oxytocin. The supporting glial cells, or pituicytes, are conceptually similar to astrocytes and express GFAP and S100.

FIGURE 8-4 Basophilic invasion of normal, nonneoplastic corticotrophs into the neurohypophysis, a physiologic finding.

FIGURE 8-5 The neurohypophysis is fibrillar neuroglial tissue with round granular anucleate storage structures called Herring bodies (arrows) and subtle condensation of cellular processes around capillaries.

Nonneoplastic Conditions of the Pituitary and Parasellar Area

Pituitary Hyperplasia

This condition is a numerical increase in anterior lobe epithelial cells of one or more types. The vast majority of pituitary hyperplasias are secondary, with vanishingly rare examples of primary hyperplasias reported (4). Biopsy of hyperplastic pituitary gland is rare and typically the result of mass effects.

The most common hyperplasia is that of lactotrophs during pregnancy and lactation, where these cells can make up almost three-quarters of the cells in the adenohypophysis and increase the mass of the gland. A mild hyperplasia also occurs due to “stalk effect” in situations where portal blood flow to the adenohypophysis is decreased due to compression of the infundibulum, releasing the lactotrophs from the inhibitory effects of dopamine from the hypothalamus. Dopamine antagonist medications, usually antipsychotics, also elicit this effect.

Hyperplasias of several other cell types are due to lack of feedback inhibition by the products of their target organs. The most common of these is thyrotroph hyperplasia, which occurs in the setting of primary hypothyroidism due to low thyroxine levels and is reversed after institution of hormone replacement therapy (5). Similar phenomena can be seen in corticotrophs among patients with adrenal insufficiency due to Addison disease or adrenalectomy, and in gonadotrophs among patients with primary hypogonadism. Somatotroph hyperplasia is extremely rare and has occurred in cases of ectopic growth-hormone–releasing hormone (GHRH) production by peripheral neuroendocrine neoplasms (6).

Histopathology

Hyperplasias retain the nested, cytologically and immunohistochemically heterogeneous appearance of normal adenohypophysis, making the distinction from normal gland difficult. Reticulin staining may show expanded acini, but this finding is subjective and should be interpreted in the context of clinical and laboratory data.

Lymphocytic Hypophysitis

Clinical Context

This uncommon autoimmune illness occurs most often in women, although male cases are now thought to account for about 20% to 30% of cases (7). Although the third trimester and postpartum period were initially strongly associated with lymphocytic hypophysitis, a recent large series showed only about 10% of cases were associated with pregnancy (8). Children are rarely affected, and the disease is most common in the fourth decade. Patients present with symptoms similar to those of nonfunctioning pituitary macroadenomas, including headache, visual disturbances, and hypopituitarism. In a majority of cases, the hypopituitarism is hormone restricted, most often affecting ACTH, but reductions in other hormones occur with disease progression. Diabetes insipidus accompanies
cases with posterior lobe damage. The inflammation extends into the posterior lobe in about 25% of cases but is limited to the neurohypophysis in only 10% (9).

Because of swelling and mass effects, this lesion is sometimes clinically mistaken for pituitary adenoma, especially when the gland bulges from the sella like a mass. Even when adenoma is not suspected, biopsy and/or decompressive surgery is attempted to confirm the diagnosis and to relieve pressure and prevent infarction, ameliorating headache and visual symptoms but not affecting the endocrine deficits. High-dose glucocorticoids have a dual role in relieving cortisol insufficiency and reducing inflammation. Almost three-quarters of reported cases require long-term hormone replacement (10).

Histopathology

The characteristic appearance is lymphocytic infiltration of the pituitary, often so floridly as to distort the architecture of the gland and obscure native cells (Figure 8-6). This is in striking contrast to the normal gland, where scattered lymphocytes can be seen in the pars intermedia but do not populate the anterior or posterior lobes. Lymphoid follicles are present in a minority of cases. The lymphocytes are predominantly T cells, evenly split between CD4⁺ and CD8⁺ (11). Plasma cells, macrophages, eosinophils, and neutrophils may all appear in smaller numbers. Necrosis is seen in only about 5% of cases (10).

Granulomatous Hypophysitis

FIGURE 8-6 Lymphocytic hypophysitis can obscure native glandular structures with lymphocytes and plasma cells.

Idiopathic granulomatous hypophysis is the other major pattern of primary autoimmune pituitary disease, although it is controversial as to whether it is immunologically similar to lymphocytic hypophysitis (12).
Granulomatous inflammation in the pituitary can also be secondary to a number of other processes, including tuberculosis, sarcoidosis, syphilis, or Rathke cyst rupture, so the idiopathic form is fundamentally a diagnosis of exclusion (13). Women are more affected than men. The patients tend to present with headache and visual disturbance and are treated with either partial excision to relieve mass effect, or excision plus corticosteroid replacement. Histologically, the process is characterized by lymphocytic inflammation with granulomas and usually giant cells. Necrosis, fibrosis, plasma cells and macrophages may also be seen in some cases.

Xanthomatous Hypophysitis

This form of hypophysitis is probably the least common and shares with lymphocytic and granulomatous hypophysitis similar age and sex distributions. At least one reported case evolved from lymphocytic hypophysitis (14). The salient histologic finding in this process is that of lipid-laden macrophages, typically in a milieu of chronic lymphoplasmacytic inflammation. As with granulomatous hypophysitis, there may be an association, possibly even in a majority of cases, with rupture of a Rathke cleft cyst and potential evolution to xanthogranuloma (15).

IgG4-Related Plasma Cell Hypophysitis

Sclerosis associated with IgG4 plasmacytosis, in addition to retroperitoneal fibrosis, autoimmune pancreatitis, and sclerosing sialadenitis, may involve the pituitary gland, where it tends to cause panhypopituitarism and/or central diabetes insipidus (16). Some cases of lymphocytic hypophysitis also have large complements of IgG4-expressing plasma cells, with or without sclerosis, so the boundary between those entities is somewhat amorphous and open to subjective judgment diagnostically. The relevance of the distinction may be insignificant clinically because both are treated with glucocorticoids.

Secondary Hypophysitis

The pituitary can suffer damage from systemic diseases such as sarcoidosis, granulomatosis with polyangiitis, syphilis, Langerhans cell histiocytosis, and tuberculosis. There is an iatrogenic secondary hypophysitis that is associated with administration of immunomodulatory therapy, typically as chemotherapy for malignancy. The strongest association is with the drug ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte–associated protein 4 (CTLA4), resulting in upregulation of immune response. It is thought the hypophysitis is related to expression of CTLA4 on the adenohypophyseal epithelial cells (17).

Hypothalamic Hamartoma

Clinical Context

The clinical and radiologic presentations of this lesion are so distinct that biopsy is frequently foregone due to the risk of damaging adjacent structures. There are two classic presenting syndromes associated
with hypothalamic hamartomas: central precocious puberty and gelastic seizures, sometimes occurring in combination. Gelastic seizures, which are uncontrollable fits of “pressured” laughter, probably originate from activity of the neurons within the lesion (18). Surgical ablation or disconnection of the hamartoma from surrounding tissue can cure or greatly reduce seizure activity. Other successful treatment approaches include stereotactic radiosurgery, radiofrequency ablation, and thermal coagulation.

Hypothalamic hamartoma is a defining feature, along with cutaneous syndactyly of Pallister–Hall syndrome, which occurs in the setting of germline GLI3 gene mutations (19). Sporadic hypothalamic hamartomas, which constitute the majority, have been shown to have somatic GLI3 mutations (20) or other defects in the sonic hedgehog pathway (21).

Histopathology

Small mature granule-type neurons are clustered in a background of granular, gray-matter type neuropil with individual neurons and astroglia at the periphery. The overall visual impression is that of gray matter but without organization or orientation of its elements like what is seen in cortex. Just as with normal gray matter, hypothalamic hamartomas show NeuN and synaptophysin staining in neurons and GFAP in scattered glial cells. Beyond recognizing the atypical appearance of the hamartomatous gray matter, one could potentially assess for sonic hedgehog pathway defects if necessary.

Rathke Cleft Cyst

General

The Rathke cleft is the plane of fusion between the adenohypophysis and the neurohypophysis created from the migration of the Rathke pouch from the palate and, in humans, contains the vestigial remnants of the intermediate lobe of the pituitary seen in lower animals. Small cystic spaces containing mucoid secretions normally inhabit the cleft, and the cuboidal to columnar cells do not have ciliated epithelium. Because they are lined with respiratory-type epithelium, Rathke cleft cysts fall within the rubric of benign endodermal cysts, along with colloid and “enterogenous” cysts (see Chapter 1).

Clinical Context

Most Rathke cleft cysts are asymptomatic and found incidentally on imaging or at autopsy. Women are overrepresented in reported cases, but the overall numbers are too small to draw firm conclusions. Symptomatic cases present with signs and symptoms similar to other sellar lesions, with headaches, visual deficits, and hypopituitarism, mostly in adults and occasionally in children (22,23). Most Rathke cleft cysts arise from the Rathke cleft, yet can be found along the infundibulum and be completely suprasellar (24). Magnetic resonance imaging (MRI) shows them to be T2/FLAIR hypointense relative to brain and of variable intensity on T1-weighted images with a characteristic indentation posteriorly in sagittal images (“ledge sign”) (25). The cysts are noncontrast enhancing. Rathke cleft cysts are occasionally seen in collision with other lesions, mostly pituitary adenoma (26,27,28). A handful of reports have shown
granulomatous hypophysitis after rupture of a Rathke cleft cyst (29,30,31). Hemorrhage into a Rathke cleft cyst can create “machinery oil” contents similar to that seen in adamantinomatous craniopharyngiomas (ACPs), giving the surgeon a strong suspicion for craniopharyngioma.

Histopathology

A thin layer of epithelial cells surrounds the contents of a Rathke cleft cyst, ranging from one to several layers of columnar or cuboidal cells, often ciliated and showing interspersed goblet cells (Figure 8-7). The epithelium rests on a thin outer wall of paucicellular collagen and can become stretched to a single thin layer by the pressure of cyst contents. A potentially misleading finding is squamous metaplasia, which develops as a layer underneath the original epithelium and eventually can form dry, flaky keratin. The contents are inspissated mucous secretions that range from eosinophilic to amphophilic and are PAS positive with a gross appearance similar to thyroid cyst contents. Some Rathke cleft cysts show xanthogranulomatous degeneration that ranges from aggregates of macrophages to inflamed debris with cholesterol clefts, hemosiderin, and giant cells, similar to that seen in ACPs.

Differential Diagnosis

Cases with ciliated columnar cells require little consideration, but squamous metaplasia can cause a degree of overlap with epidermoid cysts. Epidermoid cysts, however, have a granular layer within the epithelium, but metaplastic cysts do not. In order to diagnose squamous metaplasia in a Rathke cleft cyst, one must observe dry keratin. Thin papillary craniopharyngiomas (PCPs), which do not produce any keratin, may develop inside of, or collide with, Rathke cleft cysts and have a higher potential for recurrence.

FIGURE 8-7 Rathke cleft cyst lining with ciliated columnar epithelium punctuated by mucin-bearing goblet cells.

Xanthogranuloma of the Sella

General

Xanthogranuloma, or cholesterol granuloma, of the sella remains a cryptic diagnosis. It is most often used to describe degenerating cellular debris found in and around the sella and occasionally elsewhere. The debris has no identifiable epithelium, yet many believe the findings are secondary to degeneration of other well-established epithelial lesions. Both ACPs and Rathke cleft cysts can develop similar xanthogranulomatous material, as can old hemorrhage or any other collection of degenerating cells. The term xanthogranuloma of the sella is essentially a stopgap used when a biopsy fails to yield a more specific diagnostic entity and indicates a short list of possible causes that should be considered. Whether sellar xanthogranulomas represent a common underlying process, or are a common endpoint for several processes, remains to be demonstrated.

Clinical Context

The defining series examining this lesion suggests that it is a unique and separate process from ACP, although some clinical features overlap. In that series, the peak age of incidence was in the second and third decades, coincident with the first peak of ACP occurrence. However, there was no second peak corresponding to that of ACP occurrence in middle age. Xanthogranulomas occurred around the sella but were more likely than ACP to have an intrasellar component. The most important differences between xanthogranuloma and ACP were that the former had a higher rate of gross total resection and better overall outcome, although the xanthogranuloma patients suffer higher rates of marked endocrine deficits (32). Additional investigation has strengthened the association between sellar xanthogranulomas and Rathke cleft cysts (15,33).

Histopathology

By definition, all xanthogranulomas show cholesterol clefts with associated histiocytic inflammatory infiltrates (Figure 8-8). They also commonly show lymphoplasmacytic infiltrates, hemosiderin deposition, and granular necrotic debris (32). Minute fragments of squamous or cuboidal epithelium may be present but in such small quantities as to prohibit further classification. Scrupulous examination of deeper levels is warranted to search for potentially diagnostic epithelium.

Tumors of the Sellar Region

Pituitary Adenoma (Pituitary Neuroendocrine Tumor)

Classification

If one were to fill two pails, one with pituitary “adenomas” and the other with pituitary “carcinomas,” and then pour them into one pile on the floor, there would be no way, using any histopathologic, immunohistochemical, ultrastructural, or even genetic means, that one could confidently sort them back into their respective pails, the difference being a purely ex post facto designation based on demonstration of metastasis. Because pathologic examination cannot predict clinical behavior, and neuroendocrine tumors of other organs have undergone
similar renaming, the term pituitary neuroendocrine tumor (PitNET) has been proposed to represent all tumors arising from the anterior pituitary epithelium. This terminology is not a part of the 2017 WHO endocrine tumor update, but is preferred by the International Pituitary Pathology Club (34). Nevertheless, because the new PitNET terminology is not yet in wide use, the adenoma–carcinoma nomenclature is retained here for the sake of consistency.

FIGURE 8-8 Xanthogranuloma of the sellar region usually results from degeneration and/or hemorrhage into a Rathke cleft cyst, yet can also result from several other precursor lesions.

Several tools are used to subdivide pituitary adenomas into meaningful groups: imaging, histology, immunohistochemistry, and electron microscopy. Grouping the adenomas by pure H&E morphology into acidophils, basophils, and chromophobes was common practice at one time but is unreliable and obsolete. The most common pathologic classification is based on hormones expressed immunohistochemically, described below. A further refinement is to immunostain for cell lineage groupings. Electron microscopy helps to further split adenoma types but is not practical for most community (and many academic) pathology practices and may be entirely supplanted by immunostaining for arguably its most important role, detecting the more aggressive “silent subtype III” (now plurihormonal Pit-1 lineage) adenomas.

Demographics

Pituitary adenomas account for greater than 10% of all primary intracranial neoplasms in adults, putting them third in overall prevalence after meningeal and diffuse glial tumors. The incidence of adenomas in children is low, but increases with age, with those from 15 to 19 years constituting the majority (35). No clear sex predilection is evident for pituitary adenomas overall. Some variability in population characteristics
is observed among the specific subtypes of pituitary adenoma, discussed later. Individuals with type I multiple endocrine neoplasia (MEN1) syndrome develop pituitary adenomas because of their disease, but syndromic tumor characteristics do not seem to substantially differ from those that are sporadic.

Clinical Presentation

The clinical presentations of adenomas can be divided into two groups: endocrinologically apparent and anatomically apparent. Hormone-producing tumors typically present with syndromes attributable to excess of the secreted hormone: Cushing disease from ACTH, gigantism or acromegaly from GH, galactorrhea from prolactin (in women of reproductive age), and, rarely, hyperthyroidism from TSH. Adenomas that secrete FSH and LH, and prolactinomas in men and postmenopausal women, do not present with a specific hormonal syndrome, similar to nonsecreting tumors. Without a hormonal syndrome to herald their presence, these clinically silent tumors attain larger sizes and present with effects from anatomic disruption of neighboring structures. In this setting, headache, hypopituitarism, and loss of vision are the most common presentations.

Neuroimaging

MRI provides accurate preoperative diagnosis in most cases of pituitary adenoma. The main neuroimaging classification system assesses the extent to which the tumor expands and escapes the sella to invade adjacent structures, separating cases into invasive and noninvasive in five grades (36). A commonly used aspect of this system is that it categorizes by tumor size, those less than 1 cm being microadenomas and those greater being macroadenomas. “Giant” adenomas exceed 5 cm (37). With high-resolution techniques, microadenomas as small as 2 to 3 mm can be identified. On T1-weighted sequences, adenomas are slightly hypointense to adenohypophysis and do not enhance after-routine contrast administration. If T1-weighted images are taken quickly after contrast, adenomas can show early enhancement that is simultaneous with that of the posterior lobe (38). A small amount of delayed enhancement can also be seen (39).

Invasive Adenomas

Unlike adenomas occurring in other epithelial organs, pituitary adenomas have a tendency to invade adjacent tissue, specifically dura and bone. Most cases of macroadenoma show at least modest dural invasion if the dura is biopsied and inspected microscopically, with the presence of invasion increasing with tumor size and extension from the sella (40). The significance of this invasion is surprisingly little, with no evidence that it affects recurrence rates in one large series, although it may marginally increase mortality at 6 years (41). Invasion is also not correlated with the cytologic appearance of pituitary adenomas.

Extrasellar Adenomas

Ectopic adenomas can occur anywhere from the third ventricle (42) to the nasopharynx (43) but very rarely appear farther abroad. They most likely arise from cellular rests stranded while migrating with Rathke pouch during development. Being immediately
subjacent to the floor of the sella, the sphenoid sinus is the most common ectopic site for pituitary adenomas.

Pituitary Apoplexy

The term apoplexy (Greek: apo—away/from; plexia—to strike) originally referred to any precipitous, stroke-like onset of symptoms. In the context of the pituitary, the term is often used to refer to the lesion itself. Pituitary apoplexy is the sudden infarction and/or hemorrhage of a sellar tumor, usually a nonfunctioning pituitary adenoma, heralded by a syndrome of rapid-onset headache, vision problems, and hypopituitarism. Loss of consciousness, coma, and sudden death occur in a minority of cases (44). Emergent neurosurgery to preserve vision is necessary in cases where the lesion compresses the optic chiasm. Rarely, spontaneous infarction of an adenoma causes the lesion to vanish along with its symptoms (45). Incidental focal hemorrhage or necrosis within an adenoma is not unusual and, in the absence of the clinical syndrome, does not constitute apoplexy.

FIGURE 8-9 The typical sheetlike growth pattern of pituitary adenomas separates them from normal adenohypophysis.

Histopathology

The two core features that distinguish adenomas from normal pituitary tissue are loss of regular acinar architecture and cellular homogeneity. Most adenomas grow in a uniform sheetlike pattern punctuated by scattered blood vessels (Figure 8-9). Other patterns, including trabecular (Figure 8-10), papillary (Figure 8-11), oncocytic (not shown), fibrotic (Figure 8-12), nested (Figure 8-13), ribboned (Figure 8-14), and spindle cell/fascicular (Figure 8-15), are less common and have no practical significance other than to recognize that they are within the spectrum of morphologic appearance for pituitary adenomas. Papillary and trabecular patterns are associated with gonadotropin expression. The component epithelial cells vary
from elongate to polygonal and may be organized along blood vessels or haphazard.