Pituitary Tumors Pathology

Pituitary tumorigenesis is driven by germline and somatic mutations as well as genetic and epigenetic mechanisms, interacting in complex ways still not entirely understood and influencing tumor formation, growth, and invasion. ^[1] ​

Tumors of the pituitary gland and sellar region represent approximately 10-15% of all brain tumors, ^[2] 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. ^[3] Pituitary adenomas are uncommon in the pediatric population, but most tumors of childhood are clinically functioning adenomas and are thought to be more aggressive. ^[4]

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). ^[2] Incidental adenomas can be found in nearly 10% of autopsied patients. ^{[5, 6]}

Comparatively, primary tumors of the neurohypophysis are rare. The neurohypophysis, however, is a common site for metastases. ^[7]

See the images below.

Classification

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)

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 neuroendocrine tumors derived from intrinsic cells of the adenohypophysis.

• Pituitary carcinomas are characterized by the presence of either craniospinal dissemination or systemic metastases ^[8]

• Pituicytoma, granular cell tumor of the neurohypophysis, and spindle cell oncocytoma are nonneuroendocrine tumors arising in the posterior pituitary and occur much less frequently than pituitary adenomas. ^{[9, 10, 11]} Although these three tumor have specific histologic features, they shared a common nuclear expression of the thyroid transcription factor-1 (TTF-1) similar to that seen in pituicytes, the specialized glia of the neurohypophysis and pituitary stalk. ^[12]

• Craniopharyngiomas represent 1-2% of all intracranial neoplasms and about 10% of the tumors of the sellar region. ^[13] Two variants of craniopharyngiomas are described with specific histopathologic and molecular genetic characteristics: the adamantinomatous craniopharyngioma and the papillary craniopharyngioma.

• Inflammatory hypophysitis is a rare disorder of the pituitary gland characterized by focal or diffuse inflammatory infiltration and, ultimately, destruction of the gland.

See also Pituitary Tumors, Pituitary Macroadenomas, Pituitary Microadenomas, Pituitary Apoplexy, and Pituitary Disease and Pregnancy.

In this section the general characteristics of pituitary adenomas are discussed, followed by separate sections on subtypes of pituitary adenomas, pituitary neuroendocrine tumors grading, and pituitary carcinomas.

General characteristics of pituitary adenomas

Pituitary adenomas are classified clinically into two 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). ^{[14, 15]}

Table 2. Surgical Frequency of Pituitary Adenoma Types* at University of Virginia, 1992-2008 (Open Table in a new window)

About one third of all pituitary adenomas are unassociated with either clinical or biochemical evidence of hormone excess. ^{[14, 15, 16]} This group includes adenomas that produce the gonadotropin hormones [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)], the less differentiated null cell adenomas, and the 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, and histopathologic features and patterns

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 ^[17] 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 histopathologically classified by the World Health Organization (WHO) classification according to the hormone content of the tumor cells as assessed by immunohistochemical stains (Table 3, below). ^{[18, 19]} This immunohistochemical classification provides significant information for clinical practice. The fourth edition of the WHO classification of pituitary neuroendocrine tumors recognizes the role of transcription factors associated with the cellular differentiation of pituitary tumors in the classification of pituitary adenomas. ^{[18, 19]} Recognizing these new data, the current WHO classification has adopted the pituitary-cell lineage for designation of the adenomas. In this article, we will follow the WHO guidelines and classification scheme for pituitary gland tumors (see Table 3, below).

Table 3. Pathological Classification of Pituitary Adenomas According the 2017 WHO Classification (Open Table in a new window)

Tumorigenesis

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. ^{[20, 21]} 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 ^{[21, 22, 23]} :

• 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. ^{[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. ^[26]

Mutations in the USP8 (encoding ubiquitin-specific protease 8) gene, leading to an upregulated EGFR pathway, have been identified in about 36-62% of sporadic corticotroph adenomas. ^[27]

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. ^[28] For details, readers may consult any of several outstanding reviews on the subject.

More recently, there has been focus placed on pioneer transcription factor Pax7, which specifies intermediate lobe melanotrope fate during pituitary development. ^[29] Its function and properties are under investigation in pituitary development and tumorigenesis.

Grading of neuroendocrine tumors of the pituitary gland

A notable change in the 2017 WHO classification of pituitary neuroendocrine tumors is related to histologic grading of these tumors. ^{[18, 19]} The 2004 WHO classification ^[30] recommended grading of pituitary neuroendocrine tumors in three categories—adenoma, atypical adenoma, and carcinoma—according to a certain number of histologic features. However, this grading system did not provide an efficient assessment for tumor behavior. Most significantly, the guidelines for the diagnosis of the so-called "atypical adenomas" were vague and unreliable when comparing;amongst different laboratories. ^{[31, 32, 33]} The new WHO classification has therefore abandoned the diagnosis “atypical adenoma.” ^[18]

No changes have been made for establishing the diagnosis of pituitary carcinomas, and the process is based on the presence of cerebrospinal fluid and/or systemic metastasis. Pituitary carcinomas are extremely rare, constituting less than 0.5% of all pituitary masses. ^[34] Most commonly, these tumors evolve from invasive, aggressive adenomas that recur over several years rather than presenting as a de novo neoplasm. ^{[35, 36]}

In any pituitary adenoma, emphasis is placed on the evaluation of tumor proliferation by mitotic count and/or Ki-67 index; however, no specific Ki-67 cutoff value is recommended. A second feature to be aware of in these tumors is the presence of tumor invasion. Both features, tumor proliferative potential and tumor invasiveness, have been demonstrated to correlate with a more aggressive clinical behavior of tumors. ^{[31, 32, 33, 37]} Adenomas with rapid growth, radiologic invasion, and a high Ki-67 proliferation index are considere high-risk adenomas for recurrence; they are referred as clinically aggressive adenomas. ^[19]

This section will discuss subtypes of pituitary adenomas—including lactotroph adenomas (prolactin [PRL]–secreting), somatotroph adenomas (growth hormone [GH]-secreting), corticotroph adenomas (adrenocorticotropic hormone [ACTH]–secreting), thyrotroph adenomas (thyroid-stimulating hormone [TSH]–secreting, gonadotroph adenomas (follicle-stimulating hormone [FSH] and/or luteinizing hormone [LH]-secreting), null cell adenomas, and plurihormonal adenomas.

Lactotroph adenomas

PRL-secreting adenomas, or prolactinomas, account for nearly 80% of functioning adenomas and about 40-50% of all pituitary adenomas. ^{[38, 39]} 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. ^{[38, 39]} 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. ^[39] 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. ^{[3, 38]}

Histologically, PRL-secreting adenomas are classified in three variants, the common sparsely granulated lactotroph adenomas, the less common densely granulated lactotroph adenomas, and the acidophilic stem cell adenomas. ^[40]

Sparsely granulated lactotroph adenomas 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 lactotroph adenomas, are not pathognomonic of this type of adenoma. ^[40]

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. ^[40] Unlike sparsely granulated lactotroph adenomas, densely granulated tumors are characterized by diffuse IHC for PRL. Both variants also express the acidophilic-lineage transcription factor PIT-1 (pituitary-specific POU-class homeodomain transcription factor 1), and estrogen receptor α (ER-α). ^{[40, 41, 42, 43]}

As noted above, most patients with lactotroph adenomas are treated to some degree with dopamine agonists. These drugs act directly on the tumor cells, inducing atrophy of lactotrophs and resulting in tumor shrinkage. ^{[38, 39]} 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. ^{[44, 45]}

Acidophilic stem cell adenomas

Acidophilic stem cell adenoma is a very rare variant of PRL-secreting adenoma. ^[40] The majority of the tumors are rapidly growing macroadenomas with invasive features. Because most affected 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. The adenomas also express PIT-1 and ER-α. ^[40]

Electron microscopy may be necessary for precise identification of these adenomas. ^[46] They are composed of a single population of immature cells exhibiting features reminiscent of both sparsely granulated somatotroph cells and lactotroph cells. Oncocytic change, with the presence of giant mitochondria, is characteristic of these adenomas.

Somatotroph 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. ^[3] Acromegaly affects both sexes with similar incidence, and the mean age at diagnosis is 40-45 years. ^[47]

Symptoms of acromegaly are usually slowly progressive, with an average delay of approximately 10 years before diagnosis. ^[47] 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. ^[48] Consequently, symptoms secondary to an expanding tumor mass, including headaches and visual field defects, may also be present.

In about 30-50% of patients, co-secretion of PRL with GH by the tumor results in signs and symptoms of hyperprolactinemia. ^{[47, 48]} Mixed GH- and PRL-secreting tumors are discussed below.

Densely and sparsely granulated somatotroph adenomas

Histologically, somatotroph 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 two types of somatotroph adenomas—namely, densely granulated and sparsely granulated adenomas. ^[49]

Densely granulated somatotroph 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). 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.

Sparsely granulated somatotroph adenomas are composed of smaller tumor cells, with chromophobic cytoplasm and an eccentric nucleus. In the cytoplasm, paranuclear eosinophilic structures (fibrous bodies) are seen. ^{[49, 50]} These structures represent accumulations of intermediate filaments and tubular formations at the ultrastructural level, and are easily highlight by strong cytokeratin immunoreactivity (see the following image). In contrast to densely granulated adenomas, in sparsely granulated adenomas the GH immunostain is focal within the tumor and tends to be localized in a paranuclear distribution, similar to the Golgi pattern seen in prolactinomas. ^{[49, 50]}

A number of somatotroph adenomas show secondary immunoreactivity for other pituitary hormones. ^{[48, 49, 51]} 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–FSH, β–LH, and β-TSH can be demonstrated in a number of somatotroph adenomas. ^[48]

Apart from the well-characterized mixed GH-/PRL-secreting adenomas (see below), plurihormonal differentiation is not clinically symptomatic in the majority of cases. ^[52]

The distinction between the two subtypes of somatotroph adenomas is important in that the subtype tumors appear to have different clinical behavior. Sparsely granulated somatotroph adenomas exhibit more aggressive biologic behavior than densely granulated tumors do. ^{[48, 50, 53]} In addition, the response of tumors to adjuvant medical treatment also differs according to the subtype of GH cell adenoma. ^[54]

As with prolactinomas, medical therapy for acromegaly with somatostatin receptor ligands, mainly octreotide, is common practice in endocrinology. ^{[3, 55]} However, in treated somatotroph adenomas, significant reduction of tumor cell size is not commonly seen; the most common changes are varying degrees of perivascular and interstitial fibrosis. ^{[56, 57]}

Mixed GH- and PRL-secreting adenomas

As noted in the discussion above, a large percentage of somatotroph adenomas may also secrete PRL. These adenomas overall constitute about 8% of pituitary adenomas. ^[34] Patients with such mixed tumors present signs and symptoms of both acromegaly and hyperprolactinemia. ^{[48, 49]} In this group of adenomas, two morphologic tumor types can be identified: mixed somatotroph / lacotroph adenoma and mammosomatotroph adenoma. ^[49]

Diagnosis of the mixed adenomas requires a more complex IHC study and, in some instances, ultrastructural analysis of the tissues. The distinction in these adenomas is significant because it has clinical and prognostic implications. Both mixed somatotroph / lacotroph adenomas and mammosomatotroph adenomas tend to behave more aggressively than any pure somatotroph adenomas, and the surgical cure rate is lower. ^[48]

Mixed somatotroph / lactotroh adenomas

The predominant clinical feature of these mixed adenomas is acromegaly. Signs and symptoms of hyperprolactinemia may not always be apparent.

Morphologically, the tumors are similar to somatotroph 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). Both cell types may form small groups, or they may be scattered. The adenomas show focal ER-α immunoreactivity labeling the lactotroph cell component of these adenomas. In addition, the adenomas show diffuse immunoreactivity for the transcription factor PIT-1. ^[49] At the ultrastructural level, these adenomas are bimorphous tumors, consisting of two separate cell populations: densely or sparsely granulated somatotroph cells, and lactotroph cells (see the second image below). ^[58]

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. ^{[34, 59]} Like mixed somatotroph / lactotroph adenomas, these tumors are associated with elevated circulating GH levels and acromegaly; hyperprolactinemia is less common. ^[49]

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. ^[59] The tumor cells are focally immunoreactive for ER-α, and diffusely immunoreactive for the transcription factor PIT-1. ^[49]

Ultrastructural analysis demonstrates a monomorphous cell population that contains features of GH and PRL cells. ^[59] 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).

Corticotroph adenomas

ACTH-secreting adenomas associated with Cushing disease represent approximately 5-10% of all adenomas. ^{[14, 60]} 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). ^[61] In children, Cushing disease is rare and tends to have a more aggressive clinical course and lower cure rate. ^{[62, 63]} Cushing disease arising in prepubertal children is more common in males than females—the opposite of the adult preponderance. ^[64] (See also Cushing Syndrome.) The great majority of ACTH-secreting adenomas are microadenomas, and approximately 15% are invasive at the time of surgery. ^[65]

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. ^[60]

Histologically, ACTH-secreting adenomas are divided into densely granulated corticotroph and sparsely granulated corticotroph adenomas. ^[60] Densely granulated adenomas is the most common variant. They are usually composed of basophilic cells on H&E staining and often strongly positive with periodic acid-Schiff (PAS) staining. 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 tile-like arrangement. Papillary formations are very common.

IHC demonstrates diffuse and strong immunoreactivity of ACTH in the densely granulated adenomas. whereas various degrees of immunoreactivity are seen in the less common sparsely granulated adenomas. 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. ^[66] 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 changes. Corticotroph adenomas also express the transcription factor T-PIT. ^[60]

In some corticotroph adenomas, hyaline bundles that encircle the cytoplasm, yielding a "target cell" appearance, are observed. These represent Crooke cells (or Crooke hyaline cells), which correspond to the accumulation of cytokeratin intermediate filaments. Adenomas with significant numbers of Crooke cells (more than 60% by some authors) are called Crooke cell adenomas. ^{[60, 67]}

Crooke cells may also be found in the normal pituitary gland of patients with Cushing disease (see the image below) and in patients with other pathologic or iatrogenic hypercortisolemic states. These changes appear to be a direct effect of high serum levels of cortisol on pituitary cells. ^[68]

Silent corticotroph adenomas are characterized by immunoreactivity for ACTH presenting in patients that lack both clinical signs of Cushing disease and serum levels reflecting excess ACTH secretion. Most of these tumors are macroadenomas, and patients present with signs and symptoms of a mass lesion. ^{[69, 70, 71]} Characteristically, silent corticotroph adenomas show a high tendency for hemorrhage and apoplexy (see the image in the "Silent adenomas" section below), which may be the presenting symptoms in about one third of the patients. ^{[69, 70]} These tumors tend to arise in patients older than those with Cushing disease. ^[70]

Thyrotroph adenomas

Thyrotroph adenomas are the least frequent pituitary adenomas. ^[72] Clinically, patients 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. ^[73] Most thyrotroph adenoma are invasive macroadenomas. ^[73]

Histologically, thyrotroph 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. ^[72] Immunostains usually reveal variable β-TSH positivity. The adenomas are also commonly positive for the alpha subunit (α-SU) of the glycoproteins.The acidophilic-lineage transcription factor PIT-1 is expressed in these adenomas. ^[72]

Gonadotroph adenomas

Gonadotropin-secreting adenomas are adenomas that secrete the gonadotropins FSH and/or 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. ^[74]

Gonadotroph adenomas are most frequent in the sixth decade of age and older, and they have a slight male predominance. ^[16] Typically, they present as clinically nonfunctioning tumors with symptoms related to local mass effects, including visual deficits, hypopituitarism, headaches, and cranial nerve palsies. ^{[74, 75, 76]}

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. ^[74] 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 units are recommended for IHC characterization of gonadotroph adenomas, because these lesions may demonstrate varying degrees of reactivity for one 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. ^[74] In addition, gonadotroph adenomas are immunoreactive for the transcription factor steroidogenic factor (SF-1). ^{[77, 78]}

Null cell adenomas

Approximately 20% of adenomas show neither clinical nor IHC evidence of hormone production. ^{[16, 79]} By the new definition of the fourth edition of the WHO classification, null cell adenomas are adenomas that do not demonstrate immunoreactivity for both pituitary hormones and pituitary cellular lineage transcription factors (PIT-1, T-PIT and SF-1). ^[79]

The clinical presentation of null cell adenoma resembles that of gonadotroph adenoma; patients present with signs and symptoms of a mass lesion. ^{[16, 79]} 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 the designation of oncocytoma (oncocytic variant of null cell adenoma) may be applied to these adenomas. ^[79]

As discussed above, null cell adenomas lack immunoreactivity for any pituitary hormone (so-called immunonegative adenomas) and transcription factors. ^{[78, 79]}

Silent adenomas

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 the most significant clinical implications are the silent corticotroph adenomas, as described earlier. ^{[69, 70, 71]}

Plurihormonal adenomas

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. ^[52] 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. This category of adenomas includes the newly described PIT-1 positive plurihormonal adenoma (previously called "silent subtype 3 adenoma"), clinically functioning adenomas such as GH/PRL/TSH-producing adenomas with acromegaly and thyroid dysfunction, and adenomas with unusual combinations of hormones shown by immunostaining that cannot be explained by cytodifferentiation. ^{[80, 81]} All these adenomas are extremely rare, in particular those with unusual combinations of different cellular lineages such as GH/ACTH-producing adenomas. ^[81]

PIT-1 positive plurihormonal adenomas

The PIT-1 positive plurihormonal adenoma, previously named "silent subtype 3 adenoma," is a rare adenoma classically characterized by a monomorphous population of poorly-differentiated cells displaying distinctive nuclear inclusions called nuclear spheridea. ^[82] Although the majority of the tumors present as clinically silent tumors, some patients harboring these adenomas may present with low hyperprolactinemia and/or signs of acromegaly. ^{[83, 84]}

Histologically, the adenomas are composed of a monomorphous population of poorly-differentiated cells displaying various levels of immunoreactivity for GH, PRL, β-TSH, and α-subunit. Significantly, these tumors are PIT-1 immunoreactive and likely belong to the acidophilic lineage of adenomas. ^[84] The diagnosis of these adenomas is important because of their intrinsic aggressive behavior and high degree of invasiveness, low rates of disease-free survival, and high propensity for recurrence. ^{[82, 83, 84]}

Pituitary carcinomas are very rare, accounting for fewer than 1% of all pituitary neoplasms. ^{[8, 35]} The majority are endocrinologically functioning tumors; prolactin (PRL)–secreting tumors are the most common, followed by adrenocorticotropic hormone (ACTH)–secreting tumors. ^[8] Nonfunctioning tumors, including silent corticotroph, gonadotroph, and even rare null cell carcinoma, account for about 15-20% of the cases. ^{[8, 35]}

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. ^[35]

The diagnosis of pituitary carcinoma depends on the demonstration of metastatic spread. ^[8] There are no morphologic criteria to distinguish ordinary 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 they 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. ^[8] A few examples of silent corticotroph carcinomas have also been described. Pituitary carcinomas are only rarely immunoreactive for GH, gonadotropins (ie, luteinizing hormone [LH] or follicle-stimulating hormone [FSH]), or thyroid-stimulating hormone (TSH).

Ki-67 labeling indices are quite variable and show considerable overlap with common pituitary adenomas ^[85] ; 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). ^[8]

Pituicytomas, granular cell tumors of the neurohypophysis, and spindle cell oncocytomas are reviewed in this section.

Posterior pituitary gland tumors are nonneuroendocrine tumors that most likely derived from the pituicyte, the specialized glial cell of the neurohypophysis and the pituitary stalk. ^[86] These tumors are much more rare than pituitary adenomas. As previously described, the NK2 homeobox 1 factor or thyroid transcription factor 1 (TTF-1) serve as an immunomarker for the diagnosis of these tumors with strong nuclear immunoreactivity in pituicytomas, granular cell tumors of the neurohypophysis, and spindle cell oncocytomas. ^{[12, 87]}

Pituicytomas

Pituicytomas (previously designated as posterior pituitary astrocytomas or infundibulomas) are rare tumors. ^{[11, 88]} The majority of pituicytomas have occurred in those in the fifth or sixth decade of life, with a slight male predominance. ^[11] 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. ^[89]

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 may resemble pilocytic astrocytomas (see the following image). Unlike pilocytic astrocytomas, however, pituicytomas lack a biphasic pattern and the characteristic Rosenthal fibers and eosinophilic granular bodies. Mitotic activity is mostly absent, and the Ki-67 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. ^{[11, 88]} Focal immunoreactivity for epithelial membrane antigen (EMA) has been reported in some cases. ^{[11, 88]} Tumor cells are immunoreactive for TTF–1. ^{[11, 87]}

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. ^[11]

Granular cell tumor of the neurohypophysis

Granular cell tumors of the neurohypophysis are glial tumors that arise either in the pituitary stalk or in the posterior pituitary. ^[9] They are usually incidental tumors that are found in adults at autopsies; only rarely do they present as symptomatic masses. These tumors of the sella used to be referred in the past as "choristoma of the neurohypophysis," "granular cell pituicytoma," "granular cell myoblastoma," or "granular cell tumorette."

Symptoms of granular cell tumors of the neurohypophysis are related to tumor size and mass effect, including visual deficits and hypopituitarism. ^[9] Rare cases presenting with diabetes insipidus and intraventricular hemorrhage have also been reported. ^{[9, 90, 91]} The tumors are generally slow-growing, benign neoplasms; there have been only a few cases of granular cell tumors with more aggressive clinical behavior. ^{[9, 91]}

Grossly, granular cell tumors are nearly indistinguishable from pituitary adenomas. However, they tend to be firmer and to have a darker tan discoloration. ^[9] 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, and represent abundant lysosomes at ultrastructure. Mitotic activity is minimal, and necrosis is only rarely seen. ^[9]

Tumors show variable immunoreactivity for GFAP and S100. ^[9] The tumors also express the macrophage/lysosome marker CD68. Similar to pituicytoma and spindle cell oncocytoma, granular cell tumors are strongly immunoreactive to TTF-1. ^{[12, 87]}

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. ^[10] Most tumors arise in adults. ^{[10, 92, 93]} 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. ^[92]

On light microscopy, SCOs are characterized by a spindled and oncocytic cellular appearance due to the extensive accumulation of mitochondria seeing at ultrastructure. ^[93] 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 only rarely GFAP. ^{[10, 92, 93]} Similar to the tumors previously discussed, TTF–1 expression in SCOs is well documented. ^{[12, 87]}

Aside from the tumors discussed in the previous sections, craniopharyngiomas and other tumors also comprise lesions in the pituitary and sella region.

Craniopharyngiomas

Craniopharyngiomas represent 1-2% of all intracranial neoplasms and about 10% of the tumors of the sellar region. ^[13] The majority are suprasellar, although some may have an intrasellar component and some arise entirely beneath the sellar diaphragm. ^[13] Large tumors may show growth in the parasellar region and into brain. ^{[94, 95]}

Most craniopharyngiomas arise in childhood and adolescence (5-15 years), but a second minor incidence peak is observed in adults (45-60 years). ^[13] In children, craniopharyngiomas most commonly present with endocrinologic abnormalities, such as growth retardation and diabetes insipidus. ^[94] In adults, symptoms of compressive effects, including visual defects and hypopituitarism, may be present. ^[95] 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. ^[13] Calcification on computed tomography (CT) scans is commonly seen with the adamantinomatous variant. ^[94]

Adamantinomatous and papillary variants

Histologically, craniopharyngiomas demonstrate a complex and characteristic pattern of epithelial growth. The 2007 World Health Organization (WHO) classification identifies two variants: adamantinomatous and papillary. ^[13]

Adamantinomatous craniopharyngioma is characterized by stratified epithelium with a palisading arrangement of the basal cells, keratin formation, and microcystic changes (see the image below). Papillary craniopharyngioma 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.

In addition to different histopathologic features, the two variants of craniopharyngiomas have unique molecular profiling. ^{[13, 96, 97, 98]} Activating mutations of the CTNNB1 gene, that encodes β-catenin, are present in the great majority of adamantinomatous craniopharyngiomas, ^{[13, 97, 98]} resulting in aberrant nuclear accumulation of β-catenin protein in the tumor cells. ^[98] However, mutations of BRAF (BRAF V600E) are the main oncogenic alteration in papillary craniopharyngiomas. ^{[13, 96]}

Craniopharyngiomas are histologically classified as grade I tumors according to WHO criteria ^[13] ; however, significant morbidity and recurrence as high as 20% are seen, particularly in cases with subtotal surgical resection. ^[94]

Miscellaneous lesions and tumors

A variety of other tumors may involve the pituitary and sellar region. ^[99] These include tumors originating from the dura and coverings of the sella (meningioma, hemangiopericytoma); the bony structures (chordoma, chondroma, chondrosarcoma); and 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 appears to be higher. ^[100] 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. ^[100]

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 Bellastella et al. ^[101]

Inflammatory hypophysitis has been classified into three categories on the basis of the clinicopathologic presentation: lymphocytic hypophysitis, granulomatous hypophysitis, and xanthomatous hypophysitis. ^{[101, 102, 103]} Of these, the most common is lymphocytic hypophysitis. Lymphocytic hypophysitis and granulomatous hypophysitis are discussed below.

Lymphocytic hypophysitis

Lymphocytic hypophysitis is a rare entity that most commonly affects women in late pregnancy or in the immediate postpartum period ^[101] ; this condition is very rare in males. ^{[102, 103, 104]} Lymphocytic hypophysitis is believed to have an autoimmune basis; antibodies directed against pituitary cells have been demonstrated. ^[101] In addition, the association of other endocrine or immune diseases has been reported in about 20% of patients. ^[101]

Patients may have symptoms of an expanding pituitary mass and/or evidence of partial hypopituitarism or panhypopituitarism. ^{[101, 102, 103, 104]} 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. ^[101] In this instance, the term "infundibuloneurohypophysitis" is appropriate.

Granulomatous hypophysitis

Unlike lymphocytic hypophysitis, granulomatous hypophysitis has no relation to pregnancy and has no sex predilection, ^{[104, 105]} but it most commonly involves middle-aged or elderly women. Most patients present with signs and symptoms of hypopituitarism. ^[105] Neuroradiologic studies show enlargement of the pituitary gland in the great majority of cases, with frequent evidence of suprasellar extension. ^[101]

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.