Tumors of the pituitary gland and sellar region represent approximately 10-15% of all brain tumors,  of which the great majority in this region are pituitary adenomas. Pituitary adenomas predominantly affect females between the third and sixth decades of life; however, no age group is spared.  Pituitary adenomas are uncommon in the pediatric population, but most tumors of childhood are clinically functioning adenomas and are thought to be more aggressive. 
Rates for pituitary tumors in the United States are slightly higher among black persons (2.92 per 100,000 person-years) than among white persons (1.82 per 100,000 person-years).  Incidental adenomas can be found in nearly 10% of autopsied patients. [4, 5]
Comparatively, primary tumors of the neurohypophysis are rare, and in general, they are similar to primary tumors of the central nervous system (CNS). The neurohypophysis, however, is a common site for metastases. 
The following are histologic examples of the normal pituitary gland and a pituitary adenoma for comparison.
Numerous types of tumors may involve the pituitary gland and sellar region, reflecting the complex anatomy of this area. These may be classified as shown in Table 1, below).
Table 1. Tumors and Tumorlike Lesions of the Pituitary Gland and Sellar Region (Open Table in a new window)
|Tumors of anterior pituitary||
Spindle cell oncocytoma
|Tumors of posterior pituitary||
Granular cell tumor
|Tumors of nonpituitary origin||
Langerhans cell histiocytosis
Rathke’s cleft cyst
As noted earlier, the most common tumors, by far, are the pituitary adenomas. In addition to tumors, a variety of nonneoplastic lesions may affect the pituitary gland, bringing a number of processes into the differential diagnosis of the tumors involving this region.
The more common lesion types are defined as follows:
Pituitary adenomas are benign epithelial tumors derived from intrinsic cells of the adenohypophysis
Pituitary carcinomas are characterized by the presence of either craniospinal dissemination or systemic metastases 
Spindle cell oncocytoma is a rare primary tumor for which histogenesis is still not completely understood. Although initially believed to be derived from the follicle-stellate cells of the anterior pituitary gland,  new evidence has demonstrated that these tumors may also be derived from pituicytes, the intrinsic glia cells of the posterior pituitary. 
Granular cell tumors are glial tumors that arise either in the pituitary stalk or posterior pituitary—they are usually incidental tumors found in adults at autopsies and only rarely present as symptomatic masses (there are about 60 reported cases in the literature  ); granular cell tumors of the sella are also known as choristoma of the neurohypophysis, granular cell pituicytoma, granular cell myoblastoma, and granular cell tumorette
Craniopharyngiomas represent 1–2% of all intracranial neoplasms and about 10% of the tumors of the sellar region  ; they are histogenetically related to Rathke’s cleft and derive from the pituitary anlagen; although the majority of craniopharyngiomas differ markedly from Rathke’s cleft cysts, rare tumors demonstrating features of both have been described 
Inflammatory hypophysitis is a rare disorder of the pituitary gland characterized by focal or diffuse inflammatory infiltration and ultimate destruction of the gland.
Anterior Pituitary Gland Tumors – Pituitary Adenomas
In this section the general characteristics of pituitary adenomas are discussed, followed by separate sections on subtypes of pituitary adenomas, atypical adenomas, pituitary carcinomas, and spindle cell oncocytomas.
General characteristics of pituitary adenomas
Pituitary adenomas are classified clinically into 2 groups--clinically functioning adenomas and clinically nonfunctioning adenomas--according to whether an endocrine syndrome is present or absent. Most adenomas are functioning tumors; these include prolactin (PRL)–producing, growth hormone (GH)–producing, adrenocorticotropic hormone (ACTH)–producing, and thyroid-stimulating hormone (TSH)–producing adenomas (see Table 2, below). 
Table 2. Surgical Frequency of Pituitary Adenoma Types at University of Virginia, 1992-2006* (Open Table in a new window)
|Pituitary Adenoma Type||Frequency, %|
|Null cell adenomas||19|
|GH- and PRL-secreting adenomas||3|
* N = approximately 2600.
† Includes silent corticotroph adenomas.
ACTH = adrenocorticotropic hormone; GH = growth hormone; PRL = prolactin; TSH = thyroid-stimulating hormone.
About one third of all pituitary adenomas are unassociated with either clinical or biochemical evidence of hormone excess.  In this group are included adenomas that produce both follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the less differentiated null cell adenomas, and silent adenomas. These clinically nonfunctioning adenomas commonly present with signs and symptoms related to local mass effect, such as headaches, neurologic deficits of the cranial nerves (including visual field disturbances), and mild hyperprolactinemia due to pituitary stalk compression ("stalk effect").
Classifications based on size, anatomic features, histologic patterns, and hormone content
On the basis of size and anatomic features, adenomas are divided into microadenomas (tumors < 1 cm in diameter) and macroadenomas (tumors >1 cm in diameter). Giant adenomas (tumors > 4 cm) may occur but are rare. Macroadenomas show an increased tendency toward suprasellar extension, gross invasion, and recurrence (see the following image). A radiologic classification proposed by Hardy  is the one most often used in clinical practice.
Grossly, pituitary adenomas are soft lesions with a tan-brown discoloration. Morphologically, they may show a variety of histologic patterns, including diffuse, papillary, and trabecular arrangements similar to those of other neuroendocrine tumors. Cytologically, tumor cells may be acidophilic, basophilic, or chromophobic; however, these tinctorial characteristics do not identify specific adenoma types (see the images below).
Pituitary adenomas are also classified according to the hormone content of the tumor cells as determined by immunohistochemistry (IHC). This classification provides significant information for clinical practice.  In a few tumors, however, analysis of the adenoma's ultrastructural aspects is necessary.  In this article, we follow the guidelines and classification scheme for pituitary gland tumors that was released by the World Health Organization (WHO) in 2004 (see Table 3, below). 
Table 3. Morphofunctional Classification of Pituitary Adenomas (Open Table in a new window)
|Clinical Presentation||Pituitary Adenoma Type|
|ACTH-secreting adenomas||Corticotroph adenoma|
Sparsely granulated lactotroph adenoma
Densely granulated lactotroph adenoma
Densely granulated somatotroph adenoma
Sparsely granulated somatotroph adenoma
|GH- and PRL-secreting adenomas||
Mixed GH- and PRL-cell adenoma
Acidophilic stem-cell adenoma 3
|TSH-secreting adenomas||Thyrotroph adenoma|
|Gonadotropin-secreting adenomas||Gonadotroph adenoma|
Silent corticotroph adenoma (subtypes I and II)
Silent adenoma subtype III
|ACTH = adrenocorticotropic hormone; GH = growth hormone; PRL = prolactin; TSH = thyroid-stimulating hormone.|
The mechanisms involved in human pituitary tumorigenesis and tumor progression are still not well understood. Pituitary adenomas appear to develop through a multistep and multicausal process to which endocrine factors, hereditary genetic disposition, and specific somatic mutations may all contribute. An extended review of the mechanisms of pituitary tumorigenesis is beyond the scope of this article.
Pituitary adenomas arise mostly in a sporadic manner, and only a minority occur as part of hereditary or familial syndromes.  The large majority of adenomas are monoclonal expansions, as demonstrated by X-chromosomal inactivation analysis.  Hereditary conditions associated with development of pituitary adenomas include the following:
Multiple endocrine neoplasia type 1 (MEN-1), linked to somatic mutations of the MEN-1 gene
Carney complex, linked to mutations of the tumor suppressor gene PRKAR1A
McCune-Albright syndrome, linked to activating mutation of the gsp oncogene (discussed below)
A few other rare familial syndromes are also associated with pituitary adenomas:
Pituitary adenoma predisposition (PAP), associated with a germline mutation of the AIP (aryl hydrocarbon receptor-interacting protein) gene
Isolated familial somatotrophinoma (IFS), associated with a loss of heterozygosity at the 11q13 locus but not with the MEN-1 gene
Familial isolated pituitary adenoma (FIPA), for which a single genetic alteration has not been characterized, although mutations of the AIP gene have been reported to occur in about 15% of families 
In the majority of sporadic adenomas, however, the primary genetic defect remains unknown. A number of oncogenes and tumor suppressor genes have been recognized as potential participants in the tumorigenesis of pituitary adenomas.
The most commonly found genetic alteration in sporadic tumors is an activating mutation of the gsp gene, an oncogene mostly identified in GH-cell adenomas. [23, 24, 25] The gsp mutation has been identified in about 40% of GH-secreting adenomas, [24, 25, 26] but it is rare in other pituitary tumor subtypes, occurring in only 10% of clinically nonfunctioning pituitary adenomas and 5% of corticotroph adenomas. 
Other oncogenes and tumor suppressor genes that have been shown to be linked to pituitary tumorigenesis include the oncogene PTTG (pituitary tumor-transforming gene), the proto-oncogene H-ras, and the tumor suppressor genes RB and TP53. However, it seems that these genes are not directly associated with pituitary adenoma tumorigenesis but may play a role during the progression and malignant transformation of these tumors.  For details, readers may consult any of several outstanding reviews on the subject.
A study by de Laat et al reported that systematic presymptomatic screening for pituitary adenomas in patients with multiple endocrine neoplasia type 1 (MEN1) predominantly results in detection of nonfunctioning microadenomas. 
Pituitary Adenoma Subtypes
This section will discuss subtypes of pituitary adenomas—such as prolactin (PRL)–secreting, growth hormone (GH)–secreting, mixed GH- and PRL-secreting, adrenocorticotropic hormone (ACTH)–secreting, thyroid-stimulating hormone (TSH)–secreting, gonadotropin-secreting adenomas, and null cell adenomas and oncocytomas, silent adenomas, and plurihormonal adenomas.
PRL-secreting adenomas, or prolactinomas, account for nearly 80% of functioning adenomas and about 40–50% of all pituitary adenomas. [28, 29] However, most patients with prolactinomas are treated clinically with dopamine agonists. Therefore, the frequency of prolactinomas in surgical series tends to be smaller.
In women, the majority of prolactinomas are microadenomas and occur during the reproductive age period, presenting with oligomenorrhea or amenorrhea, galactorrhea, and infertility. [28, 29] In contrast, in men and elderly women, prolactinomas are usually macroadenomas and are most commonly associated with symptoms of tumoral mass, including headaches, neurologic defects, and visual loss.  Impotence and decreased libido are also common symptoms of hyperprolactinemia in males. The diagnosis of a prolactinoma is confirmed by sustained hyperprolactinemia and neuroradiologic evidence of a pituitary tumor. [2, 28]
Histologically, prolactinomas are composed of medium-sized cells with chromophobic or slightly acidophilic cytoplasm and a central, oval nucleus (see the image below); small nucleoli can be present. Approximately 10-20% of cases show microcalcifications. Calcifications and amyloid bodies, although frequently seen in prolactinomas, are not pathognomonic of this type of adenoma. 
Immunohistochemistry (IHC) shows reactivity for PRL in a very characteristic pattern of staining, with localization near the nucleus in a dotlike pattern, also known as a Golgi pattern.  On ultrastructural analysis, prolactinomas may be divided into densely and sparsely granulated variants, although the clinical significance of this distinction is questionable. [14, 30]
Sparsely granulated PRL cell adenomas are the most common tumors, and their cells resemble actively secreting lactotrophs of the normal pituitary gland. The adenoma cells are characterized by a prominent rough endoplasmic reticulum (RER) network, conspicuous Golgi complexes, and a sparse number of small (150-300 nm) secretory granules. Misplaced exocytosis (ie, granule extrusions on the lateral cell surfaces) is typical of these tumors.
As noted above, most patients with prolactinomas are treated to some degree with dopamine agonists. These drugs act directly on the tumor cells, inducing atrophy of lactotrophs and resultant tumor shrinkage. [28, 29] Histologically, tumors from patients previously treated with such drugs are composed of smaller tumor cells, with shrinkage of the cytoplasm and hyperchromasia of the nuclei, in addition to various degrees of perivascular and interstitial tumoral fibrosis. [31, 32]
Growth hormone–secreting adenomas
GH-secreting adenomas account for about 20% of pituitary adenomas. Patients present with signs and symptoms of acromegaly, gigantism, or both, as well as high serum GH and insulinlike growth factor I (IGF-I) levels.  Acromegaly affects both sexes with similar incidence, and the mean age at diagnosis is 40–45 years. 
Symptoms of acromegaly are usually slowly progressive, with an average delay of approximately 10 years before diagnosis.  Less commonly, adenomas arise in children and adolescents before the epiphyseal closure of the long bones, resulting in gigantism. Most acromegalic patients have macroadenomas when first diagnosed; many of these lesions show suprasellar expansion and parasellar invasion.  Consequently, symptoms secondary to an expanding tumor mass, including headaches and visual field defects, may also be present.
Densely vs sparsely granulated GH cell adenomas
Histologically, GH-secreting adenomas are either eosinophilic or chromophobic on hematoxylin and eosin (H&E) staining. These histologic attributes reflect the amount of secretory granules present in the cell cytoplasm and characterize the 2 types of GH cell adenomas--namely, densely granulated and sparsely granulated.
Densely granulated adenomas are characterized by eosinophilic tumor cells, with the cytoplasm showing considerable granularity and reflecting great numbers of secretory granules seen at the ultrastructural level. The nucleus tends to be central and oval, with prominent nucleoli (see the image below).
Sparsely granulated GH cell adenomas are composed of smaller tumor cells, with chromophobic cytoplasm and an eccentric nucleus. In the cytoplasm, paranuclear eosinophilic structures (fibrous bodies) are seen.  These structures represent accumulations of intermediate filaments and tubular formations at the ultrastructural level and are strongly immunoreactive for cytokeratin (see the following image).
IHC staining shows a variable degree of GH immunoreactivity (see the image above). In densely granulated adenomas, GH immunostain diffusely occupies the entire cytoplasm of the tumor cells and tends to be dispersed diffusely within the entire tumor. By contrast, in sparsely granulated adenomas, GH immunostain is focal within the tumor and tends to be localized in a paranuclear distribution, similar to the Golgi pattern seen in prolactinomas. 
A number of GH-secreting adenomas show secondary reactivity for other pituitary hormones. [34, 36] Immunopositivity for PRL can be seen focally, even in patients without clinical or biochemical evidence of hyperprolactinemia. Similarly, the presence of immunoreactivity for the glycoprotein hormones β–follicle-stimulating hormone (FSH), β–luteinizing hormone (LH), and β-TSH can be demonstrated in a number of GH-secreting adenomas. 
Apart from the well-characterized mixed GH-/PRL-secreting adenomas (see below), plurihormonal differentiation is not clinically symptomatic in the majority of cases. 
The 2 subtypes of GH cell adenomas--densely and sparsely granulated--are well characterized by ultrastructural analysis.  Densely granulated adenomas are composed of adenomatous cells that resemble the normal somatotrophs of the pituitary gland and are characterized by a well-developed rough endoplasmic reticulum (RER) network, prominent Golgi complexes, and numerous large (300-600 nm) secretory granules.
Sparsely granulated adenomas have fewer and smaller (100-250 nm) secretory granules. The most characteristic feature of these adenomas is the presence of fibrous bodies, which consist of an accumulation of intermediate filaments and tubular smooth-surfaced endoplasmic reticulum (see the previous image).
The distinction between the 2 subtypes of GH cell adenomas is important in that the subtypes tumors appear to have different clinical behavior. Sparsely granulated GH adenomas exhibit more aggressive biologic behavior than densely granulated tumors do. [34, 38, 39] In addition, the response of tumors to adjuvant medical treatment also differs according to the subtype of GH cell adenoma. 
As with prolactinomas, medical therapy for acromegaly with somatostatin receptor ligands, mainly octreotide, is common practice in endocrinology. [2, 41] However, in treated GH cell adenomas, significant reduction of tumor cell size is not commonly seen; the most common changes are varying degrees of perivascular and interstitial fibrosis. [42, 43]
Mixed GH- and PRL-secreting adenomas
As noted in the discussion of GH-secreting adenomas above), a large percentage of these adenomas also secrete PRL. These tumors overall constitute about 8% of pituitary adenomas.  Patients with such mixed tumors present signs and symptoms of both acromegaly and hyperprolactinemia.  In this group of adenomas, 3 morphologic tumor types can be identified: (1) mixed GH cell/PRL cell adenoma, (2) mammosomatotroph cell adenoma, and (3) acidophilic stem cell adenoma. [34, 45]
Diagnosis of these adenomas requires a more complex IHC and ultrastructural analysis of the tissues. Moreover, their distinction is of fundamental importance in that it has clinical and prognostic implications. Both mixed GH cell/PRL cell adenomas and mammosomatotroph adenomas tend to grow more slowly than acidophilic stem cell adenomas do. [44, 46] In the authors' experience, these mixed tumors behave more aggressively than any pure GH-secreting adenomas, and the surgical cure rate is lower. 
Mixed GH cell/PRL cell adenomas
The predominant clinical feature of mixed GH cell/PRL cell adenomas is acromegaly. Signs and symptoms of hyperprolactinemia are not always apparent.
Morphologically, the tumors are similar to GH-secreting adenomas, with an eosinophilic or chromophobic appearance. Immunostains are demonstrated for both GH and PRL, with varying degrees of staining and distribution (see the first image below). The 2 cell types may form small groups, or they may be scattered. At the ultrastructural level, these adenomas are bimorphous tumors, consisting of 2 separate cell populations: (1) densely or sparsely granulated GH cells and (2) PRL cells (see the second image below). 
Mammosomatotroph cell adenomas
Mammosomatotroph cell adenoma is rare, accounting for fewer than 2% of all pituitary adenomas and about 8% of tumors associated with acromegaly. [44, 48, 49] Like mixed GH cell/PRL cell adenomas, these tumors are associated with elevated circulating GH levels and acromegaly; hyperprolactinemia is less common.
Histologically, these adenomas are acidophilic on H&E staining, and IHC demonstrates the presence of GH and PRL in the cytoplasm of the same tumor cell. These findings have been confirmed by double-labeling studies, as well as by immunoelectron microscopy. 
Ultrastructural analysis demonstrates a well-differentiated adenoma composed of a monomorphous cell population that contains features of GH and PRL cells.  The tumor cells are mostly similar to densely granulated GH cells, but with irregular secretory granules of variable sizes (200–2000 nm) and containing granule extrusions and extracellular deposits of secretory material, a feature consistent with PRL cell differentiation (see the image below).
Acidophilic stem cell adenomas
Acidophilic stem cell adenoma is very rare, representing only a small minority of GH-/PRL-producing tumors. [34, 44] Unlike patients with the other 2 subtypes, most patients with this tumor present with symptoms of hyperprolactinemia  ; acromegaly is uncommon, and GH levels are often normal.
The majority of the tumors are rapidly growing macroadenomas with invasive features. Because most of the patients have clinical features of hyperprolactinemia, the diagnosis is of clinical importance in that these tumors may be mistaken for the more benign prolactinomas.
By light microscopy, acidophilic stem cell adenomas are chromophobic, with focal oncocytic changes of the cytoplasm. Immunoreactivity for PRL and, to a lesser extent, GH is present in the cytoplasm of the same tumor cells.
Electron microscopy is necessary for precise identification of these adenomas. [14, 46] They are composed of a single population of immature cells exhibiting features reminiscent of both sparsely granulated GH cells and PRL cells. Oncocytic change, with the presence of giant mitochondria, is characteristic of these adenomas.
Adrenocorticotropic hormone–secreting adenomas
ACTH-secreting adenomas associated with Cushing disease represent approximately 10-15% of all adenomas.  Cushing disease has a peak incidence between the ages of 30 and 40 years and tends to be more frequent in females (3.5:1 female-to-male ratio).  In children, Cushing disease is rare and tends to have a more aggressive clinical course and lower cure rate. [52, 53] Cushing disease arising in prepubertal children is more common in males than females—the opposite of the adult preponderance.  (See also Cushing Syndrome.) The great majority of ACTH-secreting adenomas are microadenomas, and approximately 15% are invasive at the time of surgery. 
On rare occasions, corticotroph cell hyperplasia may be the source of Cushing disease. However, there is considerable controversy, from both clinical and pathologic viewpoints, regarding this event. 
Histologically, ACTH-secreting adenomas are usually basophilic on H&E staining and are often strongly positive with periodic acid-Schiff (PAS) staining (see the following image). The cytoplasm is very granular, and the nucleus is large, with coarse chromatin and a prominent nucleolus. Some degree of nuclear pleomorphism can be present. The cells have very distinct cytoplasmic borders and tend to touch each other in a tilelike arrangement. Papillary formations are very common.
Occasionally, hyaline bundles that encircle the cytoplasm, yielding a "target cell" appearance, are observed. These represent Crooke’s hyaline changes, which correspond to the accumulation of cytokeratin intermediate filaments and appear to be a direct effect of high serum levels of cortisol on pituitary cells.  Crooke’s changes are also present in the normal pituitary gland of Cushing disease patients (see the image below) and in patients with other pathologic or iatrogenic hypercortisolemic states.
IHC demonstrates the presence of ACTH with various degrees of immunoreactivity. In addition, other peptides related to the proopiomelanocortin (POMC) precursor molecule, including β-lipotropin, β-endorphin, and α-melanocyte-stimulating hormone, are also expressed by tumor cells.  In practice, demonstration of these related peptides is less relevant than demonstration of ACTH. Immunostaining for cytokeratin shows accumulation in the cytoplasm, either diffuse or forming Crooke’s changes (see the image above).
Ultrastructurally, ACTH-secreting adenomas are characterized by well-differentiated cells that resemble normal corticotrophs.  The cells contain well-developed organelles, including RER, smooth endoplasmic reticulum (SER), conspicuous Golgi complexes, and numerous large (250–500 nm) secretory granules. The secretory granules are often of different shapes (eg, spherical or heart-shaped) and vary in electron density. Bundles of intermediate filaments lying adjacent to the nucleus or forming large circles (Crooke’s changes) are easily identified.
Ultrastructural analysis of clinically functioning ACTH-cell adenomas is not obligatory; histologic and immunohistochemical studies are sufficient to provide an accurate diagnosis.
Thyroid-stimulating hormone–secreting adenomas
TSH-secreting, or thyrotroph cell, adenomas are the least frequent pituitary adenomas.  Clinically, they may present with inappropriately elevated TSH levels and hyperthyroidism, but these tumors may also arise in the setting of hypothyroidism or in clinically euthyroid patients.  Most TSH-secreting adenoma are invasive macroadenomas. 
Histologically, thyrotroph cell adenomas are frequently chromophobic by light microscopy and are composed of elongated, angular, or irregular cells. Some degree of desmoplasia is commonly seen within the tumors, which causes a slight firm consistency. 
Immunostains usually reveal variable β-TSH positivity. IHC is also commonly positive for the alpha subunit (α-SU) of the glycoproteins.
At the ultrastructural level, the cells are moderately differentiated, with scant RER network and Golgi complexes.  Secretory granules are small (100–200 nm), spherical, and evenly electron dense, and they are typically lined up along the cytoplasmic membrane.
The diagnosis of TSH-secreting adenoma can be problematic if the clinical presentation and TSH immunoreactivity are not convincing. In this situation, electron microscopy is mandatory for appropriate diagnosis.
Gonadotropin-secreting adenomas, or gonadotroph adenomas, are adenomas that secrete the gonadotropins FSH and LH. Unlike other secreting adenomas, gonadotroph adenomas do not usually cause a clinical syndrome related to hormone overproduction. The hormonal production from these tumors is inefficient, and the detection of excess hormone levels is challenging. Gonadotroph adenomas account for a large proportion of clinically nonfunctioning adenomas and about 20% of all adenomas. 
Gonadotroph adenomas are most frequent in the sixth decade of age and older and have a slight male predominance.  Typically, they present as clinically nonfunctioning tumors with symptoms related to local mass effects, including visual deficits, hypopituitarism, headaches, and cranial nerve palsies. [61, 62]
Histologically, most gonadotroph adenomas are composed of chromophobic cells with nuclei displaying a fine chromatin pattern. The tumor cells may be arranged in a diffuse pattern, but distinct papillary arrangements are commonly seen.  The papillary structures are characterized by elongated cytoplasmic processes around blood vessels, occurring in a pattern resembling perivascular pseudorosette formation.
Monoclonal antibodies to specific β-FSH, β-LH, and α-SU are recommended for IHC characterization of gonadotroph adenomas, because these lesions may demonstrate varying degrees of reactivity for 1 or more of the gonadotropin subunits. Immunoreactive cells may be scattered throughout the adenoma but are often clustered. Immunoreactivity for β-FSH tends to be more frequent, with a stronger and broadly distributed pattern than immunoreactivity for the other glycoproteins. 
Ultrastructurally, gonadotroph adenomas are characterized by elongated, polar cells containing scant numbers of small (50–200 nm) secretory granules. The secretory granules are distributed unevenly within the cytoplasm or, more commonly, along the cytoplasmic membrane. A sex-linked dichotomy between gonadotroph adenomas of male and female patients has been described. [14, 63] In women, most of the adenomas display a typical vacuolar transformation of the Golgi complex, giving the Golgi apparatus a honeycomb appearance.
Characterization of gonadotroph adenomas by ultrastructural means is of scientific interest but does not alter clinical patient management. The correlation between β-FSH and β-LH immunoreactivity, degree of ultrastructural differentiation, and clinical symptoms is relatively poor in patients with gonadotroph adenomas. At present, most patients are treated as having a clinically nonfunctioning adenoma, and the therapeutic goals are restoration of visual deficits, preservation of pituitary function, and prevention of recurrence. 
Null cell adenomas and oncocytomas
Approximately 20% of adenomas show neither clinical nor IHC evidence of hormone production. [15, 64] The term "null cell adenoma" is given to these tumors, based largely on the absence of ultrastructural features providing specific differentiation.
The clinical presentation of null cell adenoma resembles that of gonadotroph adenoma; patients present with signs and symptoms of a mass lesion. [15, 64] Null cell adenomas most commonly arise in postmenopausal females and elderly males, with the great majority macroadenomas at presentation.
Histologically, null cell adenomas are chromophobic on light microscopy, and the tumor cells may be arranged in several neuroendocrine patterns, including trabecular, papillary, and diffuse. Oncocytic change can be seen in a number of cases, and consequently, the designation of oncocytoma (oncocytic variant of null cell adenoma) may be applied to these adenomas. 
Null cell adenomas may lack immunoreactivity for any pituitary hormone (so-called immunonegative adenomas), or they may demonstrate focal and weak immunoreactivity for β-FSH, β-LH and α-SU (see the image below).  The presence of glycoprotein hormone immunoreactivity in null cell adenomas is corroborated by the occasional expression of glycoprotein hormone genes and the secretion of small quantities of these hormones in culture. 
On ultrastructural analysis, null cell adenomas demonstrate poorly developed organelles with only sparse small secretory granules, as depicted in the above image.  Large numbers of mitochondria are seen in the tumors, and oncocytic degeneration is visible. [14, 64]
The cytogenesis of null cell adenomas is still unknown. A considerable overlap exists between null cell adenomas and gonadotroph adenomas, as is indicated by the finding that some of these adenomas show focal immunoreactivity for glycoprotein hormones.
Many authors have suggested that these 2 tumor types are derived from a single progenitor cell that has the capacity to differentiate along a spectrum ranging from the more differentiated gonadotroph cell to a variety of less differentiated cells. In fact, most null cell adenomas express steroidogenic factor–1 (SF-1), a transcription factor whose pituitary expression is specific to the gonadotroph lineage.  However, from the viewpoint of patient management, differentiation between these 2 adenomas has little significant clinical value. 
A certain percentage of clinically nonfunctioning adenomas are tumors that, despite the patient’s lack of clinical syndrome or signs of hormone hypersecretion, have a pattern of IHC staining and an ultrastructural appearance that are consistent with a secreting adenoma. Although both silent somatotroph and silent lactotroph adenomas have been described, the adenomas with most significant clinical implications are the silent corticotroph adenomas.
Silent corticotroph adenomas are characterized by immunoreactivity for ACTH in the absence of either clinical signs of Cushing disease or serum levels reflecting excess ACTH secretion. Most are macroadenomas, and patients present with signs and symptoms of a mass lesion. [66, 67] Characteristically, silent corticotroph adenomas show a high tendency for hemorrhage and apoplexy (see the image below), which may be the presenting symptoms in about one third of the patients. [66, 67] These tumors tend to arise in patients older than those with Cushing disease. 
Silent corticotroph adenoma subtypes I and II
Two types of silent corticotroph adenoma have been distinguished on the basis of the tumor's ultrastructural appearance.  Silent corticotroph adenoma subtype I is morphologically indistinguishable from a functioning corticotroph adenoma associated with Cushing disease. [14, 68] Silent corticotroph adenoma subtype II is histologically amphophilic and resembles a nonfunctioning null cell adenoma. The ultrastructure bears less resemblance to a typical corticotroph cell adenoma or silent corticotroph subtype I adenoma. However, the morphology of the secretory granules has corticotroph characteristics.  The tumor cells normally do not contain cytokeratin filaments.
Silent subtype III adenomas
Silent subtype III adenoma is a rare plurihormonal tumor that has a typical ultrastructural appearance characterized by intranuclear inclusions known as spheridia.  Therefore, electron microscopy is required for confirmation of the diagnosis. Like other plurihormonal adenomas, these adenomas may exhibit immunoreactivity for pituitary hormones but are clinically nonfunctioning.  Silent subtype III adenomas tend to be invasive and generally have a higher rate of recurrence.
Plurihormonal adenomas are rare adenomas that have unusual immunoreactivity for multiple pituitary hormones that are not related through the normal cytogenesis and development of the anterior pituitary.  Because of their rarity, these tumors do not have a well-characterized clinical presentation. However, most of the cases reported in the literature exhibit symptoms of mass effect resulting from the large size of the adenomas at the time of diagnosis.
Plurihormonal adenomas do not have specific histopathologic features. On IHC, various combinations of hormones has been described, including FSH with GH as well as PRL with TSH.  However, such combinations do not include either (1) GH with PRL and TSH or (2) FSH with LH, because these 2 combinations are commonly seen in GH-secreting and gonadotroph adenomas, respectively (see the sections above).  Rarely, plurihormonal adenomas show immunoreactivity for ACTH.
In 2004, the World Health Organization (WHO) introduced the designation of atypical adenoma for tumors that show histologic features suggestive of aggressive clinical behavior.  These adenomas are characterized by an elevated mitotic index, a Ki67 labeling index greater than 3%, and overexpression of the p53 protein on immunohistochemistry (IHC) staining (see the image below).  Close follow-up of patients with atypical adenomas is highly recommended. 
The proliferative marker Ki67 (MIB-1) has been applied as an adjuvant tool for distinguishing aggressive pituitary adenomas from the most common benign tumors.  The majority of tumors show a low growth fraction, with most labeling indices being less than 3%. Clinically functioning adenomas have a significantly higher growth fraction than nonfunctioning adenomas.  The mean growth fractions are significantly higher in invasive adenomas and pituitary carcinomas than in noninvasive adenomas. [69, 70]
Although Ki67 labeling is one of the components employed in the identification of atypical adenomas, a significant correlation between proliferative index and tumor recurrence has not yet been demonstrated. 
Pituitary carcinomas are very rare, accounting for fewer than 1% of all pituitary neoplasms. [7, 71, 72] The majority are endocrinologically functioning tumors; prolactin (PRL)-secreting tumors are the most common, followed by adrenocorticotropic hormone (ACTH)–secreting tumors.  Nonfunctioning tumors, including silent corticotroph, gonadotroph, and even rare null cell carcinoma, account for about 15–20% of the cases. [71, 72]
The clinical course of pituitary carcinoma is quite variable. In most cases, the initial course is indistinguishable from that of a benign pituitary adenoma. An extended clinical course, often exhibiting multiple local recurrences, is then followed by metastatic dissemination. Only rarely do patients present with metastases concurrent with the initial sellar tumor (suggestive of a de novo malignancy). According to the literature, most patients survive for shorter than 1 year, and only 20% survive for longer than 8 years. 
At present, the diagnosis of pituitary carcinoma depends on the demonstration of metastatic spread. There are no morphologic criteria to distinguish locally aggressive, or even markedly atypical, adenomas from carcinomas when the tumor is confined to the sella. Standard morphologic features associated with malignancy (eg, hypercellularity, nuclear and cellular pleomorphism, increased mitotic activity, necrosis, and dural/osseous invasion) are commonly present but are not necessarily diagnostic of carcinoma.
Like pituitary adenomas, pituitary carcinomas are immunopositive for neuroendocrine markers, including synaptophysin and chromogranin A. As noted above, the majority of carcinomas are immunoreactive for PRL or ACTH. A few examples of silent corticotroph carcinomas have also been described. Pituitary carcinomas are only rarely immunoreactive for growth hormone (GH), gonadotropins (ie, luteinizing hormone [LH] or follicle-stimulating hormone [FSH]), or thyroid-stimulating hormone (TSH).
Ki67 labeling indices are quite variable and show considerable overlap with common pituitary adenomas; however, they are often higher in metastatic deposits. Additionally, unlike pituitary adenomas, pituitary carcinomas appear to show overexpression of the p53 protein on immunohistochemistry (IHC). 
Spindle Cell Oncocytomas
The clinical and neuroimaging features of spindle cell oncocytoma (SCO) are nonspecific, and the diagnosis is largely based on the pathologic characteristics of the tumor. Clinically, SCOs are indistinguishable from nonfunctioning adenomas, and patients may present with signs and symptoms of hypopituitarism and visual disturbances.  Most tumors arise in adults.  The majority of the cases reported in the literature have a benign clinical course; however, a few cases with incomplete surgical resection and a more aggressive clinical course have been described. 
On light microscopy, SCOs are characterized by a spindled and oncocytic cellular appearance. Unlike pituitary adenomas, SCOs lack immunoreactivity for neuroendocrine markers (eg, chromogranin and synaptophysin) and pituitary hormones. Tumor cells are immunoreactive for epithelial membrane antigen (EMA), vimentin, S100, and galectin-3; they do not express glial fibrillary acidic protein (GFAP). [8, 73, 74]
The relatively recent observation of thyroid transcription factor (TTF)–1 expression in normal pituicytes and tumors of the pituitary region, including pituicytomas, granular cell tumors of the neurohypophysis, and SCOs, raises the possibility that these tumors may represent different variants arising from a common pathogenetic origin. [9, 75]
The presence of abundant accumulation of mitochondria on ultrastructural analysis is a key element for the diagnosis of SCO (as the name of the tumor suggests). 
Posterior Pituitary Gland Tumors
Pituicytomas and granular cell tumors are reviewed in this section.
Pituicytomas (previously designated as posterior pituitary astrocytomas or infundibulomas) are rare tumors; the most comprehensive review of these tumors reported only 9 cases.  The majority of pituicytomas occurred in the fifth or sixth decade of life, with a slight male predominance. 
Most pituicytomas present with clinical signs and symptoms reflecting a mass effect on the adjacent structures of the sella, including visual impairment and signs of hypopituitarism. Rarely, patients present with signs and symptoms of diabetes insipidus.
Neuroimaging findings are not specific but usually reveal a well-circumscribed, solid intrasellar mass, most of the time with suprasellar extension. The tumors generally present low signal intensity on T1-weighted images (T1WIs), low to intermediate intensity on T2-weighted images (T2WIs), and fairly homogeneous enhancement on postcontrast T1WIs. 
Grossly, pituicytomas are soft, tan lesions that are indistinguishable from pituitary adenomas. Morphologically, the tumors are composed of elongated piloid cells arranged in fascicles in a pattern that resembles pilocytic astrocytoma (see the following image). Unlike pilocytic astrocytomas, however, most pituicytomas lack a biphasic pattern and the characteristic Rosenthal fibers and eosinophilic granular bodies. Mitotic activity is mostly absent, and the Ki67 labeling index is generally low.
On immunohistochemistry (IHC), pituicytomas do not show any immunoreactivity for neuroendocrine markers (including chromogranin) or pituitary hormones. The tumor cells are typically immunoreactive for vimentin and S100 protein.
Although most pituicytomas express glial fibrillary acidic protein (GFAP), the stain can be variable and even absent. [73, 74, 9] Focal immunoreactivity for epithelial membrane antigen (EMA) has been reported in some cases. [10, 76] Tumor cells are also immunoreactive for bcl-2 and thyroid transcription factor (TTF)–1. [78, 79]
It has been suggested that pituicytomas arise from pituicytes, modified glial cells of the neurohypophysis that are believed to regulate neurohypophysial hormone secretion. [10, 76, 77] An alternative hypothesis is that these tumors originated from the folliculostellate cells; this hypothesis is based on ultrastructural similarities between these cells and pituicytomas. 
Ultrastructural analysis reveals spindle cells with abundant intermediate filaments. The cells lack neurosecretory granules. There is no pericellular deposition of basal laminalike materials, and only scattered intercellular junctions are noted.
Because pituicytomas are so rare, their precise clinical behavior has not been well characterized. In most of the reported cases, they appear to behave as low-grade tumors, with some tendency for recurrence after subtotal excision. 
Granular cell tumors
Granular cell tumors are glial tumors that arise either in the pituitary stalk or in the posterior pituitary. They are usually incidental tumors that are found in adults at autopsies; only rarely do they present as symptomatic masses. There are about 60 reported cases of granular cell tumors in the literature.  These tumors of the sella are also referred to as choristoma of the neurohypophysis, granular cell pituicytoma, granular cell myoblastoma, or granular cell tumorette.
Symptoms of granular cell tumors are related to tumor size and mass effect, including visual deficits and hypopituitarism.  Rare cases presenting with diabetes insipidus and intraventricular hemorrhage have also been reported. [80, 81] Granular cell tumors are generally slow-growing, benign neoplasms; there have been only a few cases of granular cell tumors with more aggressive clinical behavior. [11, 81, 82]
Grossly, granular cell tumors are nearly indistinguishable from pituitary adenomas. However, they tend to be firmer and to have a darker tan discoloration.  Morphologically, granular cell tumors are composed of large polygonal cells with abundant granular cytoplasm, a round nucleus with delicate chromatin, and uniform nucleoli. The granular cytoplasm is strongly diastase-resistant and positive for period acid-Schiff (PAS) staining. Mitotic activity is minimal, and necrosis is only rarely seen. 
Although granular cell tumors of the neurohypophysis are believed to originate from pituicytes, the modified glia of the posterior pituitary and pituitary stalk,  GFAP immunoreactivity is quite variable. Unlike granular cell tumors arising in the peripheral nervous system (PNS), only a minority of sellar tumors are positive for S100.  The majority of the tumors are immunoreactive for neuron-specific enolase (NSE) and the macrophage/lysosome marker CD68. Similar to pituicytoma and spindle cell oncocytoma, granular cell tumors are strongly immunoreactive to TTF-1. 
The granular aspect of the cytoplasm is a result of the abundant membrane-bound inclusions in the lysosomal population seen at electron microscopy. Neurosecretory granules are absent.
Other Tumors of the Pituitary Region
Aside from the tumors discussed in the previous sections, craniopharyngiomas and other tumors also comprise lesions in the pituitary and sella region.
Craniopharyngiomas represent 1–2% of all intracranial neoplasms and about 10% of the tumors of the sellar region.  The majority are suprasellar, although some may have an intrasellar component and some arise entirely beneath the sellar diaphragm.  Large tumors may show growth in the parasellar region and into brain. [83, 84]
Craniopharyngiomas are histogenetically related to Rathke’s cleft and derive from the pituitary anlagen. Although the majority of craniopharyngiomas differ markedly from Rathke’s cleft cysts, rare tumors demonstrating features of both have been described. 
Most craniopharyngiomas arise in childhood and adolescence (5-15 y), but a second minor incidence peak is observed in adults (45-60 y).  In children, craniopharyngiomas most commonly present with endocrinologic abnormalities, such as growth retardation and diabetes insipidus.  In adults, symptoms of compressive effects, including visual defects and hypopituitarism, may be present.  In addition, mild hyperprolactinemia, due to stalk compression, may be present.
On neuroimaging, craniopharyngiomas are typically calcified, solid or cystic (or mixed solid-cystic) lesions that have a complex lobular appearance. The adamantinomatous variant (discussed below) is more likely to have a mixed solid-cystic appearance than is the papillary variant, which tends to be a solid tumor.  Calcification on computed tomography (CT) scans is commonly seen with the adamantinomatous variant. 
Adamantinomatous and papillary variants
Histologically, craniopharyngiomas demonstrate a complex and characteristic pattern of epithelial growth. The 2007 World Health Organization (WHO) classification identifies 2 variants: adamantinomatous and papillary.  Most commonly, the tumors contain both histologic patterns, in varying proportions.
The adamantinomatous pattern is characterized by stratified epithelium with a palisading arrangement of the basal cells, keratin formation, and microcystic changes (see the image below). The papillary pattern is characterized by simple stratified squamous epithelium resting on a connective tissue stroma, usually forming pseudopapillary structures. Both variants may infiltrate the adjacent brain parenchyma through fingerlike extensions and may trigger a dense gliotic reaction of the brain.
Craniopharyngiomas are histologically classified as grade I tumors according to WHO criteria; however, significant morbidity and recurrence rates as high as 20% are seen, particularly in cases with subtotal surgical resection. 
Miscellaneous lesions and tumors
A variety of other tumors may involve the pituitary and sellar region. These include tumors originating from: (1) the dura and coverings of the sella (meningioma, hemangiopericytoma), (2) the bony structures (chordoma, chondroma, chondrosarcoma), and (3) the bone marrow (plasmacytoma, Langerhans cell histiocytosis).
Metastases to the pituitary gland may account for 1% of surgical specimens, but the incidence of metastases found in the pituitary at autopsy seems to be higher.  The posterior pituitary is more commonly involved than the anterior gland. Breast and lung carcinomas are the most frequent primary sites.
Most metastases to the pituitary are clinically silent; however, they may occasionally present with signs and symptoms of diabetes insipidus attributable to the involvement of the posterior pituitary or the pituitary stalk and visual deficits. 
Inflammatory Lesions of the Pituitary Gland
Primary inflammatory diseases of the pituitary gland are uncommon and may mimic sellar masses. Autoimmune lymphocytic hypophysitis is the most clinically relevant of these disorders. Rarely, the pituitary gland can also be involved secondarily by systemic inflammatory and infectious processes. A comprehensive review of the clinical, radiologic, and pathologic spectrum of inflammatory diseases of the pituitary gland is provided by Carpinteri et al. 
Inflammatory hypophysitis has been classified into 3 categories on the basis of the clinicopathologic presentation: (1) lymphocytic hypophysitis, (2) granulomatous hypophysitis, and (3) xanthomatous hypophysitis. [87, 88] Of these, the most common is lymphocytic hypophysitis.
Lymphocytic hypophysitis is a rare entity that most commonly affects women in late pregnancy or in the immediate postpartum period  ; this condition is very rare in males. [87, 88, 89] Lymphocytic hypophysitis is believed to have an autoimmune basis; antibodies directed against pituitary cells have been demonstrated.  In addition, the association of other endocrine or immune diseases has been reported in about 20% of patients. 
Patients may have symptoms of an expanding pituitary mass and/or evidence of partial hypopituitarism or panhypopituitarism. [86, 87, 88, 89] Serum prolactin (PRL) levels may be mildly elevated as a result of stalk compression. Diabetes insipidus has also been described in some patients, indicating that the inflammatory process may involve the posterior pituitary gland and pituitary stalk.  In this instance, the term infundibuloneurohypophysitis is appropriate.
Unlike lymphocytic hypophysitis, granulomatous hypophysitis has no relation to pregnancy and has no sex predilection, [89, 90] but it most commonly involves middle-aged or elderly women. Most patients present with signs and symptoms of hypopituitarism. 
Neuroradiologic studies show enlargement of the pituitary gland in the great majority of cases, with frequent evidence of suprasellar extension. 
On gross examination, the surgical specimen is typically yellow and firm, unlike soft adenomas. Histologically, lymphocytic hypophysitis is characterized by infiltration of the anterior pituitary gland by lymphocytes and plasma cells (see the image below). Germinal centers are occasionally present. Later stages of the disease are characterized by atrophy of the gland parenchyma, a variable degree of fibrosis, and residual lymphocytic aggregates.
Granulomatous hypophysitis is characterized by well-formed noncaseating granulomas associated with variable lymphocytic infiltrates. A certain degree of parenchymal fibrosis may also be present. Other granulomatous diseases (eg, sarcoidosis and Langerhans cell histiocytosis) and infectious processes (eg, tuberculosis) must be excluded before the final diagnosis.