CHAPTER 11 MORPHOLOGY OF THE PITUITARY IN HEALTH AND DISEASE
Principles and Practice of Endocrinology and Metabolism
CHAPTER 11 MORPHOLOGY OF THE PITUITARY IN HEALTH AND DISEASE
KAMAL THAPAR, KALMAN KOVACS, AND EVA HORVATH
The Normal Pituitary
The Abnormal Adenohypophysis
Inflammatory Disorders of the Pituitary
Adenohypophysial Cell Hyperplasia1
Classification of Pituitary Adenomas by Hormone Production
Malignant Pituitary Lesions
Pathology of the Neurohypophysis and Hypothalamus
Inappropriate Secretion of Vasopressin
Basophilic Cell Invasion
Interruption of the Hypophysial Stalk
In 1886, the French neurologist Pierre Marie proposed that the pituitary gland plays a fundamental role in the development of acromegaly. Since then, remarkable progress has been made in understanding hypophysial structure and function, the bio-chemistry of pituitary hormones, the regulation of pituitary hormone synthesis and release, and the morphologic and clinical manifestations of pituitary abnormalities. This chapter focuses on pituitary morphology in health and disease. Because the hypothalamus is closely related to the pituitary, diseases of the hypothalamus also are summarized.
THE NORMAL PITUITARY1,2
The pituitary gland is derived from two sources. The epithelial part, which includes the pars distalis, pars intermedia, and pars tuberalis, originates from an evagination of the stomodeal ectoderm called the Rathke pouch. The neural portion, which includes the pars infundibularis or infundibulum, the neural stalk, and the pars posterior or pars nervosa, arises from the floor of the diencephalon.
The Rathke pouch is detectable at approximately the third week of gestation as a small, thin-walled vesicle in the roof of the stomodeum, which is the primitive buccal cavity. After increasing in size, it adheres to the infundibulum. Its distal end becomes narrower and forms the craniopharyngeal canal, which subsequently is obliterated, although in some cases it may remain patent until the end of intrauterine life or even after birth. The anterior wall of its proximal portion, where cell replication is faster, gives rise to the pars distalis; the posterior wall develops to become the pars intermedia. The anterolateral part of the Rathke pouch grows upward on both sides, in front of the infundibulum, forming the pars tuberalis (Fig. 11-1).
FIGURE 11-1. Embryogenesis of pituitary gland. A, Early invagination of primitive stomodeum and infundibular process. B, Growth of mesoderm constricts Rathke pouch. C, Further development pinches off Rathke pouch from oral cavity. D, Rathke cleft components develop into the pars distalis, pars tuberalis, and possibly the pars intermedia. Infundibular process develops into infundibular stalk and pars nervosa. (From Tindall GT, Barrow DL. Disorders of the Pituitary. St Louis: Mosby, 1986:10, with permission.)
By the end of the third month of intrauterine life, the gross features of the pituitary gland are clearly recognizable. The infundibulum becomes elongated, and the pituitary is embedded deeper in the sella turcica. The neurohypophysis differentiates into the proximal median eminence and the distal posterior lobe, which are connected by the hypophysial stalk.
Pituitary hormones are synthesized early in embryonic life. In humans, growth hormone (GH) and adrenocorticotropic hormone (ACTH) can be demonstrated by immunocytology and radioimmunoassay at approximately the ninth week of gestation. These two hormones are soon followed by the appearance of the a and then the b subunits of glycoprotein hormones: thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Prolactin is the last adenohypophysial hormone to be produced; it can be detected at approximately the 20th week of intrauterine life. Vasopressin and oxytocin are found at ~10 weeks of gestation.
Histologic differentiation also takes place early. Acidophilic cells are noticeable at approximately the third month of gestation; basophilic cells appear a little later. In approximately the eighth week of embryonic life, a large connective tissue mass carrying blood vessels to the developing anterior lobe becomes visible. The neurosecretory material in the posterior lobe can be recognized at approximately the fifth month of gestation.
The pituitary lies in the sella turcica, or hypophysial fossa, at the base of the brain; it is surrounded by the sphenoid bone. The pituitary gland is an oval, bean-shaped, bilaterally symmetric organ measuring ~13 mm transversely, 9 mm anteroposteriorly, and 6 mm vertically.
The average weight of the pituitary is 0.6 g; it ranges from 0.4 g to 0.8 g in adults, and averages 0.1 g at birth. A reduction in weight is evident in old age, and an increase occurs during pregnancy and lactation. The pituitary gland weighs somewhat more in multiparous women than in nulliparous women or in men. The anterior lobe is larger than the posterior lobe, constituting ~80% of the organ. The cut surface of the adenohypophysis is brownish red and can be distinguished from the sharply demarcated grayish neurohypophysis.
The pituitary is covered by the dura, a dense layer of connective tissue that lines the sella. The sella diaphragm, the connective tissue dura covering the superior surface of the sella, has a small central opening that is penetrated by the hypophysial stalk. The diameter of the opening is ~5 mm.
Well protected in the bony sella, the pituitary is located in the vicinity of several structures. The lateral walls of the sella on both sides are close to the cavernous sinuses, the internal carotid arteries, and the oculomotor, trochlear, and abducent nerves. Below and in front of the sella lies the sphenoid sinus, which is separated from the sella by a thin layer of bone. Above the sellar diaphragm and in front of the hypophysial stalk is the optic chiasm. Above the roof of the sella is the median eminence, the hypothalamus, and the third ventricle of the brain.
Anatomically, the pituitary is divided into two different structures: the adenohypophysis, which consists of the pars distalis, the pars intermedia, and the pars tuberalis; and the neurohypophysis, which consists of the median eminence, the hypophysial stalk, and the pars posterior or pars nervosa. The pars distalis, the largest part of the adenohypophysis, is the main site of adenohypophysial hormone synthesis and discharge. In humans, the pars intermedia is rudimentary, and its functional significance is unknown. The pars tuberalis, the upward extension of the adenohypophysis, surrounds two sides of the hypophysial stalk and consists of adenohypophysial cells, primarily gonadotropes and thyrotropes. The pars nervosa, the downward extension of the brain, is connected to the hypothalamus by the hypophysial stalk (Fig. 11-2).
FIGURE 11-2. Sagittal diagram of the pituitary and its important anatomic features, including blood supply. (From Tindall GT, Barrow DL. Disorders of the Pituitary. St Louis: Mosby, 1986:11, with permission.)
Blood is supplied to the pituitary by the superior and inferior hypophysial arteries, which arise from the internal carotid arteries. The superior hypophysial arteries penetrate the infundibulum and terminate in the surrounding capillary network. The hypothalamic hormones are synthesized in different structural parts and are transported along the nerve fibers to the infundibulum, where they permeate through the capillary walls into the blood. The larger parallel veins deriving from these capillaries are the long portal vessels. They extend downward in the hypophysial stalk and terminate in adenohypophysial capillaries, which carry high concentrations of hypothalamic hormones. The short portal vessels, originating in the distal part of the hypophysial stalk and posterior lobe, also run to the adenohypophysis. Approximately 70% to 90% of the adenohypophysial blood supply is carried by long portal vessels and 10% to 30% is carried by short portal vessels. A descending branch of the superior hypophysial artery known as the loral artery provides some direct arterial blood supply to the anterior lobe without passing through the infundibulum. The capsular arteries, arising from the inferior hypophysial arteries, transport additional arterial blood to the pituitary capsule and a few rows of adenohypophysial cells under the capsule. The inferior hypophysial arteries carry blood to the neurohypophysis. Venous blood is transported from the pituitary by neighboring venous sinuses to the jugular veins. It appears that blood flow may be reversed, and some blood may flow from the adenohypophysis to the brain. The neurohypophysis has an important role in directing blood either to the adenohypophysis or to the hypothalamus. Electron microscopic studies show that the adenohypophysial capillaries are lined by fenestrated endothelium. A subendothelial space and a distinct basement membrane can be seen under the endothelial layer.
Despite its close proximity to the nervous system, the adenohypophysis has no direct nerve supply, except for a few sympathetic nerve fibers that penetrate the anterior lobe along the vessels. The nerve fibers may affect adenohypophysial blood flow but play no direct role in the regulation of adenohypophysial hormone secretion. The regulatory role of the hypothalamus is neurohumoral; it is manifested by stimulating and inhibiting hormones produced in the hypothalamus and transported by the portal vessels to the adenohypophysis.
The posterior lobe is richly innervated through the hypophysial stalk by the supraopticohypophysial and tuberohypophysial tracts. The former originates in the supraoptic and paraventricular nuclei, the two magnocellular nuclei of the anterior hypothalamus, and transports the neurosecretory material along the unmyelinated nerve fibers from the hypothalamus to the posterior lobe. The latter arises in the central and posterior hypothalamus.
Although cytologic details have been studied extensively, many questions remain unanswered. Immunocytologic and electron microscopic studies have helped investigators to define various cell types and to develop a functional cell classification that allows correlation of structural features with hormone production and endocrine activity.
The long-accepted notion that the adenohypophysis consists of three cell categories—acidophilic, basophilic, and chromophobic—no longer is tenable. However, because of its convenience and simplicity, and the weight of tradition, this concept continues to influence terminology, especially that related to pathology. An alternative functional nomenclature based on immunocytologic and ultrastructural findings has been developed and is gaining widespread acceptance. This nomenclature recognizes five different cell types that produce the six known adenohypophysial hormones. Of the five cell types, two—GH cells and prolactin cells—belong to the acidophilic series. The three other cell types belong to the basophilic series: corticotropes produce ACTH and other fractions of the pro-opiomelanocortin molecule, thyrotropes synthesize TSH, and gonadotropes make FSH and LH. Chromophobic cells are insufficiently granulated to be stained with acidic or basic dyes. Ultrastructurally, however, cells classed as chromophobes on the basis of light microscopic findings contain enough secretory granules and other characteristic fine structural features to be identified as distinct cell types.
The cellular composition of the human adenohypophysis probably results from competition among various inducers acting on pluripotential precursor cells. Although the cell population in the glandular acini is not homogeneous, a general pattern of distribution of various cell types usually can be discerned in the normal adenohypophysis. This pattern may be altered in various diseases, especially diseases of the target glands—the adrenal cortex, thyroid, and gonads.
Somatotropes. Growth hormone cells, or somatotropes, are stained by acid dyes. They usually are abundant, accounting for ~50% of the adenohypophysial cells, and are located mainly in the lateral wings. The association of gigantism and acromegaly with acidophilic tumors first suggested that GH is produced in acidophilic cells. On electron microscopic examination, GH cells are seen to contain well-developed rough-surfaced endoplasmic reticulum, prominent Golgi complexes, and numerous secretory granules measuring 300 to 600 nm. The relative numeric proportions, distribution, and morphologic features of GH cells are remarkably constant in the human adenohypophysis and are not noticeably affected by age, sex, or various diseases. Pituitaries of cretins may show a reduced number of GH cells, but this is not a common finding in adult primary hypothyroidism. Prepubertal GH deficiency is associated with dwarfism, but the number, size, and morphologic appearance of GH cells often are normal. This finding is consistent with the fact that growth hormone–releasing hormone (GHRH) administration increases blood GH levels in these dwarfs and accelerates growth. As might be expected, in the adenohypophyses of patients with tumors that produce GHRH, GH-cell hyperplasia, and, less frequently, adenoma formation may be evident.
Lactotropes. Prolactin cells, or lactotropes (or mammotropes), constitute ~15% to 20% of adenohypophysial cells. They are acidophilic or chromophobic and stain with erythrosin and carmoisin. However, these stains are not reliable and should be replaced by immunocytologic techniques, which demonstrate prolactin in the Golgi apparatus and secretory granules. Prolactin cells are randomly scattered throughout the adenohypophysis, showing a concentration at the posterolateral edges, close to the neural lobe. On electron microscopic examination, prolactin cells appear either densely granulated, containing large secretory granules measuring up to 700 nm, or sparsely granulated, possessing prominent rough-surfaced endoplasmic reticulum, conspicuous Golgi complexes, and sparse, spherical, oval, or irregular secretory granules measuring 150 to 300 nm. The densely granulated cells are thought to be resting cells; sparsely granulated cells are assumed to be engaged in hormone secretion. Granule extrusion, regarded as a morphologic sign of hormone secretion, occurs on the capillary side of prolactin cells. A characteristic ultrastructural feature of prolactin cells is misplaced exocytosis, or extrusion of secretory granules from the cell on the lateral cell surface distant from capillaries, and intracellular extensions of the basement membranes.
The number of prolactin cells varies considerably under certain conditions. Prolactin cells are the last to appear in the fetal pituitary. Because of the effect of maternal estrogen, they are numerous in the adenohypophyses of newborns. With the cessation of the estrogen effect, their numbers soon decrease and remain low during childhood. The number of prolactin cells increases spectacularly during pregnancy and lactation. This is a true hyperplasia and may explain the greater weight of the pituitary found in multiparous women. Nonetheless, there are no significant differences in the number of prolactin cells between men and nulliparous women, and no regression of prolactin cells is found in old age. Estrogen treatment and primary hypothyroidism of long duration may result in hyperplasia of prolactin cells.
Corticotropes. Corticotropes are ACTH-producing cells that make up ~15% to 20% of adenohypophysial cells. They stain positively with periodic acid–Schiff (PAS) stain and lead hematoxylin, stain with basic dyes, and are located mainly in the central mucoid wedge, where they are the predominant cell type. Corticotropes produce ACTH and other fragments of the pro-opiomelanocortin molecule, such as b-lipotropin (b-LPH) and endorphins. Positivity to PAS stain is explained by the carbohydrate moiety of the prohormone. Corticotropes are also seen lining the cystic cavities of the pars intermedia. Cells containing immunoreactive ACTH frequently spread into the posterior lobe. The endocrinologic significance of this change, called basophilic cell invasion, is unknown. On electron microscopic examination, corticotropes contain a widely dispersed, moderately developed, rough-surfaced endoplasmic reticulum, a prominent Golgi apparatus, a few bundles of microfilaments, and numerous spherical or irregular secretory granules that vary in electron density, often line up along the cell membrane, and measure 300 to 600 nm. In anencephaly, corticotropes fail to show a normal development and are nearly absent from the adenohypophysis. In long-standing hypocortisolism, corticotropes may increase in number and size and become vacuolated. In patients with tumors that produce corticotropin-releasing hormone (CRH), corticotropes may undergo hyperplasia, indicating that CRH induces their proliferation.
The best-known morphologic abnormality of corticotropes in postnatal life is Crooke hyaline change,1 the deposition of a homogeneous, glassy, PAS-negative material in the cytoplasm that contains no ACTH. It corresponds to an accumulation of microfilaments seen in electron microscopic studies (Fig. 11-3). Crooke hyalinization, which is caused by cortisol excess, occurs in patients with Cushing disease, glucocorticoid hormone– producing adrenal tumors, and paraneoplastic (“ectopic”) ACTH syndrome, and after protracted treatment with pharmacologic doses of cortisol or its derivatives. The changes are reversible: the hyaline material disappears with the removal of cortisol- or ACTH-producing tumors, or with the discontinuation of glucocorticoid therapy.
FIGURE 11-3. Crooke cells. Note accumulation of microfilaments (arrow) in the nontumorous portion of the adenohypophysis harboring an adrenocorticotropic hormone–secreting adenoma. ×7800
Thyrotropes. Thyrotropes are TSH-producing cells that constitute ~5% of adenohypophysial cells, making them the least numerous in this structure. They are basophilic, stain positively with PAS, aldehyde fuchsin, and aldehyde thionin, and are located mainly in the anteromedial portion of the pars distalis in the mucoid wedge. On electron microscopic examination, they usually have large cytoplasmic processes and contain short, rough-surfaced endoplasmic reticulum membranes, well-developed Golgi complexes, numerous microtubules, and spherical secretory granules that often line up along the cell membrane and measure 100 to 250 nm.
Thyrotropes often increase in number and size in patients with long-standing primary hypothyroidism and transform. into so-called thyroidectomy cells. These cells are large thyrotropes with a vacuolated cytoplasm, dilated endoplasmic reticulum cisternae, and large PAS-positive lysosomal globules. Diffuse or nodular thyrotrope hyperplasia may be marked in untreated long-standing primary hypothyroidism; adenomas composed of thyrotropes may be noted. In patients with hyperthyroidism, thyrotropes are sparse, small, and dense.
Gonadotropes. Gonadotropes are FSH/LH-producing cells that constitute about 10% of adenohypophysial cells. Many gonadotropes are found in the central mucoid wedge, but they are also randomly distributed in the lateral wings, often close to prolactin cells. Gonadotropes are basophilic, PAS-positive cells. Most produce both FSH and LH, which can be demonstrated immunocytologically in the cytoplasm. Some gonadotropes, however, contain only FSH or LH. On electron microscopic examination, gonadotropes are characterized by a spherical nucleus and an abundant cytoplasm with a well-developed rough-surfaced endoplasmic reticulum, a conspicuous Golgi complex, and two populations of secretory granules, one with a mean diameter of 250 nm and the other with a diameter of 400 nm or more. Other gonadotropes contain only secretory granules averaging 250 nm in diameter. There are several transitional forms, indicating that gonadotropes derive from the same precursor with the ability to produce both FSH and LH.
After removal of the gonads, castration cells (gonadectomy cells) are apparent in the pituitary. These cells are large gonadotropes with pale vacuolated cytoplasm and a peripherally located nucleus. In some castration cells, the entire cytoplasm appears to be transformed into one large vacuole, endowing the cell with a signet-ring appearance. On electron microscopic examination, the most prominent finding is marked dilation of the endoplasmic reticulum membrane network and a reduced number of secretory granules. The effect of gonadal steroids on the morphology of human gonadotropes has not been sufficiently documented.
POSTERIOR LOBE AND PITUITARY STALK
The posterior lobe, the downward extension of the central nervous system, is composed of nerve fibers, axon terminals, glial cells called pituicytes, and neurosecretory material stored in nerve endings in the form of granules that stain with Gomori chromalum-hematoxylin, aldehyde fuchsin, and aldehyde thionin. Immunocytologic techniques conclusively reveal the presence of vasopressin, oxytocin, and their carrier protein, neurophysin, in the neurosecretory material.
The pituitary stalk, which connects the hypothalamus and median eminence with the pituitary, contains unmyelinated nerve fibers that terminate in the posterior lobe and portal vessels, and transport releasing and inhibiting hormones to the anterior lobe.
THE ABNORMAL ADENOHYPOPHYSIS1a,2
Diseases of the adenohypophysis can be broadly divided into (a) developmental abnormalities; (b) vascular disorders; (c) inflammatory conditions; (d) miscellaneous alterations, including deposition of various substances; (e) hyperplasias; and (f) neoplasms.
Pituitary Aplasia. Pituitary aplasia, the congenital absence of the hypophysis, is a rare abnormality that is often accompanied by other malformations. The agenesis may involve the entire pituitary gland or the adenohypophysis and is caused by defective formation of the Rathke pouch. If the affected new-born survives, severe hypopituitarism develops. Pituitary hypoplasia is the milder form of the same defect.
Anencephaly. In anencephaly, the brain, including the hypothalamus, is missing; thus, no neurohumoral regulation is exerted on the pituitary. The posterior lobe is present in some cases and absent in others. The anterior lobe is reduced in size and contains decreased numbers of corticotropes. The other adenohypophysial cell types are well developed and show no major abnormalities.
Persistent Remnants of the Rathke Pouch. Remnants of the Rathke pouch persist in 20% to 50% of human pituitaries in the form of squamous cell nests. The nests vary in size and are located at the distal end of the stalk close to the anterior lobe.
Persistent Cleft of the Rathke Pouch. Persistence of the cleft of the Rathke pouch is a harmless congenital defect and a common autopsy finding. The cleft fails to close and a distended, colloid-filled space is seen between the anterior and posterior lobes. Although this cleft is generally microscopic in proportion, it rarely may accumulate sufficient colloidal material to become an expansile and clinically significant intrasellar and suprasellar mass. These are known as Rathke cleft cysts, as discussed later (see the section on neoplasms). Although these lesions are most certainly not neoplastic in nature, they are discussed under the heading of neoplasms both for convenience and because they frequently mimic clinically and radiologically true cystic neoplasms of the sellar region.
Pituitary Dystopia. Pituitary dystopia is a rare condition characterized by a failure of union of the neurohypophysis and adenohypophysis during early development. The pituitary stalk is foreshortened, resulting in an extrasellar location of the neural lobe and a failure of the latter to descend into the sella. Usually, there is no physical attachment between the neurohypophyses and the adenohypophyses, although, occasionally, the two may be tenuously attached by strands of tissue. The anomaly is generally inconsequential, most cases being incidental autopsy findings. Rarely, it may be accompanied by other abnormalities such as hypogonadism, growth retardation, or other congenital anomalies.
Septo-Optic Dysplasia. Septo-optic dysplasia is a complex developmental disorder characterized by variable and often partial expression of midline structural abnormalities of the brain, hypoplasia of the optic nerves, and hypothalamic dysfunction. The last may manifest as anterior and posterior pituitary failure on a hypothalamic basis. Additional features of hypothalamic dysfunction may also be present, including alterations of temperature regulation, hyperphagia, and precocious puberty. The full syndrome is expressed in only a few cases; most patients come to medical attention during early childhood with pituitary insufficiency and visual dysfunction. Septo-optic dysplasia is a medically treatable condition that is wholly compatible with life.
Anatomic Variations. Anatomic variations in the shape and position of the pituitary and its relationships to neighboring tissues are common. Although these differences have no major clinical significance, they may be important to radiologists and neurosurgeons.
Pharyngeal Pituitary. In virtually all persons, a small ectopic focus of anterior pituitary tissue persists throughout life, and can usually be identified as a minute, oval, midline nodule embedded within the sphenoid bone. Known as the pharyngeal pituitary, this remnant of the Rathke pouch is usually <5 mm in size and is most frequently located deep within the mucosa or periosteum, beneath or near the vomerosphenoidal articulation; less often, it may be found in the nasopharynx or even within the nasal cavity. It is surrounded by a thin connective tissue capsule and consists of small clusters of chromophobic cells mixed with a few acidophilic and basophilic cells. In contrast to the pars distalis, the pharyngeal pituitary is richly innervated but has no portal blood supply; thus, it receives no hypothalamic hormones directly that might otherwise affect its secretory activity. Although immunocytologic techniques have disclosed various adenohypophysial hormones in the pharyngeal pituitary, this structure has no major endocrinologic significance and shows no marked histologic changes in patients with endocrine disorders. It cannot take over the function of the adenohypophysis after hypophysectomy or destructive adenohypophysial disease. The only clinically relevant feature of the pharyngeal pituitary is that it rarely may be the site for pituitary adenoma development.1,2 and 3 Most such tumors have been situated within the sphenoid sinus, and both nonfunctioning and hormonally active tumors have been reported. With respect to the latter, GH-producing tumors have been reported most commonly, followed in frequency by prolactin-producing and ACTH-producing adenomas. In the true “ectopic” pituitary adenoma, the intrasellar pituitary should be normal, although rarely, simultaneous development of an intrasellar and noncontiguous ectopic pituitary tumor has been reported. Another rare site for ectopic pituitary adenomas is the suprasellar region. Such “ectopic” tumors presumably arise from adenohypophysial cells of the pars tuberalis situated on the supradiaphragmatic portion of the pituitary stalk.
Empty Sella Syndrome. The term empty sella refers to the anatomic state resulting from the intrasellar herniation of the subarachnoid space through a defective and enlarged diaphragmatic aperture. The result is compression and posterior displacement of the pituitary gland, enlargement of the sella, and a seemingly “empty” appearance of the sella on both gross and radiologic examination. It is of clinical and pathophysiologic importance to distinguish those cases of empty sella occurring without identifiable cause (i.e., primary empty sella) from those resulting from a loss of intrasellar volume, such as would occur after an infarction, surgery, or the radionecrosis of an intrasellar neoplasm (i.e., secondary empty sella).
PRIMARY EMPTY SELLA SYNDROME.4 Anatomic defects in the diaphragma sellae of 5 mm or more have been demonstrated in ~40% of consecutive autopsies, with >20% exhibiting intrasellar extension of the subarachnoid space5 and 5% showing a fully developed empty sella.6 Whether such abnormalities alone are the cause of primary empty sella syndrome, a predisposing factor to it, or simply the result of some other process remains uncertain. Because most of these features have been incidental autopsy findings in persons without neurologic or endocrine symptoms, it is likely that additional factors contribute to the clinical syndrome. Elevated intracranial pressure is a potentially important contributing factor because it has been documented in patients with primary empty sella syndrome. Ten percent of patients with benign intracranial hypertension have a coexisting empty sella. This latter relationship is especially intriguing because both conditions share overlapping clinical profiles.7
Most cases of primary empty sella are discovered incidentally in patients who do not have symptoms. In the few patients who do have symptoms, the clinical profile is characteristic. Eighty percent of cases occur in middle-aged women, many of whom are obese and hypertensive. Spontaneous cerebrospinal fluid rhinorrhea, usually through a markedly thinned and eroded sellar floor, may complicate the primary empty sella in up to 10% of cases involving symptoms. Clinically evident pituitary dysfunction is unusual. Subtle abnormalities of the GH axis, appreciable only on dynamic endocrine testing, have been reported, as have rare accounts of panhypopituitarism.8 A modest hyperprolactinemia on the basis of stalk distortion occurs in fewer than 10% of patients. (The occasional occurrence of a pituitary microadenoma, most often a prolactin-producing adenoma, in association with primary empty sellar syndrome is purely coincidental.) In the most exceptional instances, intrasellar prolapse of the optic chiasm may be a source of visual dysfunction. In most cases, objective ophthalmologic findings, although rarely present, are the result of coexisting benign intracranial hypertension and not of the empty sella per se.
The gross pathologic features of the condition include an enlarged and thin-walled, thinned-floor sella, the diaphragm of which consists of a narrow rim. A markedly flattened pituitary gland can be seen displaced against the posterior sellar wall. Despite marked distortion of the gland, its histologic appearance and immunochemical integrity remain largely intact.
SECONDARY EMPTY SELLA SYNDROME. A secondary empty sella most commonly occurs after surgical extirpation or radiotherapy of a pituitary adenoma. The diaphragm may be developmentally deficient, eroded by the primary tumor, or affected by its treatment, permitting the descent of both the chiasm and the chiasmatic cistern into the sella. Because the latter may become entrapped and kinked by arachnoid adhesions and scar tissue, visual dysfunction is a common mode of presentation in patients with secondary empty sella syndrome. Secondary empty sella syndrome also may occur in the setting of atrophy of a nontumorous pituitary or of pituitary adenomas that have previously undergone massive hemorrhage or infarction, as in Sheehan syndrome and pituitary apoplexy, respectively.
Pituitary Hemorrhage. Hemorrhages of the pituitary are rare. They may develop in patients with head trauma, various hematologic abnormalities, or increased intracranial tension. In rapidly growing pituitary adenomas, intrahypophysial pressure may increase, leading to compression of intrahypophysial or extrahypophysial portal vessels and the arrest of portal circulation. Vessels may undergo a subtle, hypoxic injury noticeable on electron microscopic examination. If the damage is severe, the vascular walls cannot withstand the elevations in blood pressure and they rupture, resulting in hemorrhage. Pituitary apoplexy is the extreme variant of this process (see later in this chapter).
Pituitary Infarction. Pituitary infarction is a noninflammatory, coagulative necrosis caused by ischemia secondary to interruption of the blood supply. Small adenohypophysial infarcts are common, being found in ~1% to 6% of autopsies of unselected adult subjects. The lesions remain unrecognized clinically and can be detected only by histologic examination. A loss of 75% of adenohypophysial tissue produces no clinical symptoms of hypopituitarism and no biochemical abnormalities.
Pituitary necrosis can be associated with several diseases. Postpartum pituitary necrosis (Sheehan syndrome) occurs in women who experienced severe blood loss and were in hypovolemic shock about the time of delivery. During shock, the. pituitary circulation may be interrupted and the anterior lobe undergoes ischemic infarction. Adenohypophysial necrosis also may occur in nonobstetric shock, but less frequently than in women with severe circulatory failure secondary to obstetric hemorrhage. This suggests that pregnancy predisposes women to pituitary necrosis, but neither the site of sensitization nor the mechanism leading to necrosis is known (see Chap. 17).
Necrotic foci of varying sizes can be found in the pituitaries of patients with diabetes mellitus, head trauma, cerebrovascular accidents, increased intracranial pressure, and epidemic hemorrhagic fever. Pituitary infarction develops after disruption of the pituitary stalk, which causes an arrest of the adenohypophysial circulation. Adenohypophysial infarcts often can be seen in patients who were maintained on mechanical respirators before they died. The lesions represent coagulative infarcts and often are accompanied by severe hypoxic lesions of the brain.
The pathogenesis of pituitary infarction is unclear, and the mechanism of arrest of the adenohypophysial circulation is not known. Proposed causes include embolism, thrombosis, disseminated intravascular coagulation, vascular compression, vasospasm, and primary capillary damage.
In postpartum pituitary necrosis, Sheehan postulated that severe spasm develops in those arterioles from which portal vessels arise.2 Vasospasm is followed by hypophysial ischemia and secondary thrombosis, resulting in coagulative infarcts that usually spare the posterior lobe and hypophysial stalk because these areas have a rich arterial blood supply.
In cases of postpartum pituitary necrosis, infarcted areas may be large, involving more than 90% of the anterior lobe. Adenohypophysial cells are not capable of sufficient regeneration. Thus, when there is extensive infarction, permanent hypopituitarism develops. Because modern obstetric care usually prevents blood loss and obstetric shock in pregnant women, Sheehan syndrome has become rarer.
Fibrous atrophy is the final phase of ischemic necrosis of the anterior lobe. The necrotic areas are replaced by fibrous tissue. The sequence of events is identical to that occurring in infarcts of other organs.
Necrotic foci may occur in the posterior lobe and hypophysial stalk in association with head injuries, increased intracranial pressure, and obstetric and nonobstetric shock. These patients may develop diabetes insipidus.
Pituitary Apoplexy. Classically defined, pituitary apoplexy9,10 refers to the abrupt and occasionally catastrophic occurrence of acute hemorrhagic infarction of a pituitary adenoma. The clinical syndrome is easily recognized, consisting of acute headache, meningismus, visual impairment, ophthalmoplegia, and alterations in consciousness. Without timely intervention, patients may die of subarachnoid hemorrhage or acute, life-threatening hypopituitarism. As defined herein, pituitary apoplexy is a complication in 1% to 2% of all pituitary adenomas. “Silent,” or subclinical, hemorrhage into a pituitary adenoma is considerably more common, as evidenced by the finding of hemorrhage, necrosis, or cystic change in up to 10% of all surgical specimens. There is little consensus as to which tumor types, if any, are most susceptible to apoplectic hemorrhage. Some have suggested that hormonally active tumors associated with acromegaly and Cushing disease are especially prone to apoplexy, whereas others have found large nonfunctioning tumors to bear the greatest risk. In the experience of the authors, large nonfunctioning pituitary tumors, particularly silent corticotrope adenomas, appear to have the highest inherent tendency to undergo apoplectic hemorrhage.
The pathophysiologic basis of pituitary apoplexy remains speculative. Ischemic necrosis of a rapidly growing tumor, intrinsic vascular abnormalities peculiar to pituitary tumors, and compression of the superior hypophysial artery against the sellar diaphragm have all been suggested as mechanisms contributing to apoplectic hemorrhage.11 Predisposing factors loosely associated with apoplexy include bromocriptine therapy, anticoagulation, diabetic ketoacidosis, head trauma, estrogen therapy, and pituitary irradiation. Most cases, however, occur in the absence of any known predisposing condition.
Chronologically, apoplexy begins with infarction of the tumor and the surrounding gland and is followed by hemorrhage and edema. This sudden increase in both pressure and volume within the tumor causes precipitous expansion of the tumor followed by mechanical compression of the optic apparatus and of structures within the cavernous sinus. The bulk of the hemorrhage is generally contained within a tense tumor “capsule,” although an extravasation of blood into the subarachnoid space frequently occurs. Obstructive hydrocephalus may further complicate apoplexy in large macroadenomas, particularly those having a significant suprasellar component. Glandular destruction of varying degree is a regular pathologic feature of apoplexy; this results in partial or total and transient or permanent hypopituitarism. Fortunately, the anterior pituitary has an astonishing reserve capacity; at least 75% to 90% of the gland must be destroyed before permanent endocrine deficits develop. The posterior pituitary, which has its own blood supply, generally escapes injury. Accordingly, diabetes insipidus only rarely is a complication of pituitary apoplexy (see Chap. 26).
Histologically, most pituitary apoplexy specimens have a fairly uniform appearance, consisting primarily of blood and necrotic tumor. Often, only “ghosts” of neoplastic cells remain. A typical adenoma pattern still may be demonstrated with reticulin stains, thus confirming the presence of an underlying adenoma.
Rare instances of pituitary apoplexy causing complete autoinfarction of a pituitary adenoma and resulting in spontaneous endocrinologic cure have been known to occur. In addition to the acute and subacute complications noted previously, a late manifestation of pituitary apoplexy is the secondary empty sella syndrome.
INFLAMMATORY DISORDERS OF THE PITUITARY
Inflammation. The pituitary gland rarely may be subject to a variety of inflammatory disorders, the pathogenesis of which ranges from acute suppuration to chronic granulomatous conditions to autoimmune processes. Despite the diversity of pathologic processes represented, their somewhat generic clinical presentation as nonfunctioning sellar masses frequently prompts a preoperative diagnosis of pituitary adenoma; their inflammatory nature is revealed only after pathologic examination of the surgical specimen.
Infectious Diseases of the Pituitary Gland.4,12 With the availability of effective antimicrobial therapy, acute bacterial infection of the pituitary gland has become an exceedingly rare event that periodically surfaces in the form of isolated case reports. In many cases, neither a cause nor a predisposing condition can be found. Those of known etiology, however, appear to arise in one of two clinical settings. The first, and perhaps most important, mechanism involves secondary extension from a preexisting, anatomically contiguous purulent focus. An acute sphenoid sinusitis is most often implicated; less commonly, osteomyelitis of the sphenoid bone, cavernous sinus thrombophlebitis, peritonsillar abscess, mastoiditis, purulent otitis media, or bacterial meningitis serves as the inciting focus. The second mechanism underlying purulent hypophysitis is septicemia, with pituitary infection being a complication of hematogenous dissemination from any of numerous distant septic foci (pneumonia, osteomyelitis, endocarditis, septic abortion, retroperitoneal abscess). Microabscesses, particularly of the posterior lobe, are occasional autopsy findings in patients succumbing to overwhelming sepsis. In this context, they likely represent a clinically insignificant preterminal complication. Of note, postoperative pituitary abscess complicating transsphenoidal surgery is exceedingly rare.
The symptoms of pituitary abscess often are indistinguishable from those of other sellar masses (headache, chiasmatic syndrome, hypopituitarism). When they are accompanied by symptoms of meningitis, however, the possibility of pituitary abscess should always be strongly considered.13 The bacteriology of pituitary abscess is diverse. When an organism can be isolated, Staphylococcus aureus, Diplococcus pneumoniae, group A Streptococcus, Klebsiella sp., and Citrobacter diversus have been reported most often.12 A surprising number of pituitary abscesses has developed in the setting of a preexisting sellar lesion, such as pituitary adenoma, craniopharyngioma, or Rathke cleft cyst.12,13 Why such lesions should be especially vulnerable to abscess formation remains speculative, but it may be related to poor circulation or areas of necrosis present in some such lesions. The histologic picture of pituitary abscess is remarkable for extensive tissue destruction, as evidenced by necrosis and a dense polymorphonuclear inflammatory infiltrate. The mortality associated with pituitary abscess is high, approaching 28% in the absence of meningitis, and 45% when associated with meningitis.13
Pituitary infections also may be caused by a variety of other agents. Tuberculosis, still endemic in certain areas, was historically an important cause of hypopituitarism.12 In most instances, parapituitary involvement has been secondary to dense, plaque-like basilar meningitis. Secondary arteritis, a frequent accompaniment, can result in infarction of the pituitary stalk. Intrasellar “tuberculomas” usually are associated with widespread destruction of the pituitary, frequently are calcified, and almost always are associated with active tuberculosis elsewhere. When it causes symptoms, tuberculous involvement of the pituitary or its stalk manifests as anterior pituitary failure or diabetes insipidus. Syphilis, now uncommon in its consummate forms, was historically an important cause of destructive granulomatous inflammation of the pituitary. Manifesting as a discrete gummatous lesion or as diffuse scarring, the eventual result of syphilitic infection is massive destruction of the gland and, in some cases, hypopituitarism.8
Mycotic infection, notably aspergillosis, also has been reported to involve the sellar, parasellar, and orbital regions, presenting as an inflammatory mass. Parasitic infiltration of the sellar and parapituitary regions by Cysticercus and Echinococcus organisms has been known to produce a mass in this region. Finally, in the context of the acquired immunodeficiency syndrome and other immunosuppressed states, an additional spectrum of pituitary infection has emerged, including agents such as Pneumocystis carinii, Toxoplasma gondii, and cytomegalovirus.14 The clinical significance of pituitary involvement by these agents is still poorly understood.
Lymphocytic Hypophysitis. Lymphocytic hypophysitis is a destructive, inflammatory disorder of the anterior pituitary; it is presumed to be autoimmune in nature.1,2,15,16 and 17 Occurring almost exclusively in women, the disease is often temporally related to pregnancy. Almost 70% of reported cases have occurred either during pregnancy or within the first postpartum year; only occasionally are women beyond reproductive age affected. Rarely, lymphocytic hypophysitis may occur in men.17 Aside from the fact that women are generally more prone to autoimmune conditions, no explanations exist for the strong female preponderance in lymphocytic hypophysitis. Frequently, concurrent or prior autoimmune disease of other endocrine glands (i.e., Hashimoto thyroiditis, adrenalitis) can be demonstrated, suggesting that lymphocytic hypophysitis is but one component of a generalized polyglandular autoimmune syndrome. That antipituitary antibodies, most often directed against the prolactin cell, have been detected in the serum of some affected patients strongly supports an autoimmune etiology. Whether the process is generated by humoral as well as cell-mediated mechanisms remains uncertain. The clinical presentation includes headache and visual defects caused by an expanding sellar mass, amenorrhea and galactorrhea as the result of moderate hyperprolactinemia, and varying degrees of hypopituitarism.
Grossly, the inflammatory response underlying lymphocytic hypophysitis produces an enlarged, firm pituitary gland, which often extends into the suprasellar space and may be accompanied by enlargement of the sella. Microscopically, the process is restricted to the anterior pituitary, where normal glandular architecture is disrupted by an extensive infiltration of lymphocytes, plasma cells, eosinophils, and macrophages15 (Fig. 11-4). Both the structural and the immunohistochemical integrity of involved cells are lost. In especially extensive cases, loosely organized lymphoid follicles and germinal centers may be present. The chronicity of the process is evidenced by varying degrees of fibrotic change. At the microscopic level, tuberculosis, syphilis, sarcoidosis, giant-cell granuloma, and postpartum pituitary infarction all may be considered in the differential diagnosis. Because the posterior lobe escapes injury, diabetes insipidus is not a feature of this condition.
FIGURE 11-4. Lymphocytic hypophysitis. Note massive mononuclear cell infiltration and extensive destruction of adenohypophysial parenchyma. Hematoxylineosin stain; ×100.
The potentially lethal nature of lymphocytic hypophysitis is illustrated by the fact that many early descriptions of the condition stemmed from necropsy studies. Improved recognition of this condition coupled with hormone replacement therapy has rendered lymphocytic hypophysitis a curable disease.
Granulomas. In addition to tuberculosis and syphilis, which are the two principal granulomatous infections affecting the pituitary, two additional noninfectious granulomatous processes may present as pituitary granulomas: sarcoidosis and giant-cell granuloma.
SARCOIDOSIS. Considered one of the “great imitators,” sarcoidosis is known for its tendency to involve pituitary-hypothalamic structures.1,2,4,18,19 Therefore, it serves as a diagnosis of exclusion for masses and other destructive inflammatory processes occurring in this region. Sarcoidosis is a relatively common, multisystem inflammatory disorder of unknown origin. It most commonly affects the lungs, lymph nodes, skin, and eyes, but virtually no organ system is spared. Clinically apparent nervous system involvement occurs in ~5% of cases and may involve the cranial, spinal, or peripheral compartments.
Within the cranium, sarcoidosis has a predilection for the base of the brain, where it entraps cranial nerves and hypothalamic-pituitary structures in an adhesive and infiltrative arachnoiditis. Discrete parenchymal masses occur much less frequently. Involvement of the pituitary, infundibulum, and hypothalamic structures occurs in ~1% of patients with established systemic disease. Rarely, isolated involvement of these structures may be the initial or sole feature of sarcoidosis.
The clinical manifestations of sellar region sarcoidosis are variable and generally reflect hypothalamic or infundibular damage. Diabetes insipidus, somnolence, obesity, abnormal temperature regulation, hyperprolactinemia, and hypopituitarism have all been reported. With respect to the last of these, gonadotropic, thyrotropic, and adrenocorticotropic function is most commonly impaired. Although pathologic involvement of the adenohypophysis may be demonstrated, hypopituitarism in the setting of sarcoidosis is generally considered to be the result of injury to the hypophysiotropic areas of the hypothalamus or to the pituitary stalk. That many patients with diminished pituitary function retain responsiveness to exogenously administered hypothalamic releasing factors argues against excessive functional damage to hormone-producing cells of the anterior pituitary.
The histologic appearance of sarcoidosis in the pituitary-hypothalamic region is similar to that of sarcoidosis in other organs. Noncaseating granulomas, consisting of giant cells, lymphocytes, and macrophages, can be seen in the anterior and posterior pituitary, the infundibulum, and the hypothalamus. Blood vessels often are involved by the inflammatory process. Depending on the stage of the disease, scar formation of varying degrees may be evident. Although necrosis—the histologic hallmark of tuberculosis and other infectious processes—is absent in sarcoidosis, noncaseating granulomas may be a feature of numerous infectious processes. Thus, special stains and cultures for fungi and tubercle bacilli must be performed to exclude an infectious cause, particularly in the absence of known systemic sarcoidosis.
GIANT-CELL GRANULOMA. Giant-cell granuloma of the pituitary1,2,19 is a rare condition, the earliest description of which stemmed from autopsy studies. Although historically the disease was seldom diagnosed during life, increasing awareness of giant-cell granuloma as a distinct clinicopathologic entity has led to its periodic detection among surgical specimens from patients harboring mass lesions of the sella. Like that of sarcoidosis, the etiology of giant-cell granuloma remains obscure. Because some histopathologic features are common to both conditions, immunemediated mechanisms, perhaps similar to those postulated for sarcoidosis, have been invoked as underlying the development of giant-cell granuloma as well. In contrast to sarcoidosis, however, giant-cell granuloma is a disease virtually exclusive to the pituitary gland; exceptional accounts of histologically similar granulomas have been reported in the adrenals.
Topologically, the anterior lobe of the pituitary is hardest hit by giant-cell granuloma; neurohypophysial involvement occurs less frequently, and hypothalamic involvement is distinctly unusual. Histologically, the appearance is that of a noncaseating granulomatous inflammation, with giant cells bearing Schumann bodies, abundant histiocytes, and occasional lymphocytes. Extensive parenchymal destruction is the rule, eventually accompanied by fibrosis and scar formation. The clinical picture generally is dominated by hypopituitarism, which also may be accompanied by diabetes insipidus and moderate hyperprolactinemia, depending on the degree of damage to the pituitary stalk. The inflammatory process often is a source of considerable glandular enlargement, so much so that most surgically treated cases have masqueraded preoperatively as non-functioning pituitary macroadenomas.
Langerhans Cell Histiocytosis (Histiocytosis X). Classified under the rubric Langerhans cell histiocytosis1,2,4,19,20 are several related but poorly understood nonneoplastic processes that are unified pathologically by their content of highly characteristic histiocyte-like cells. The extent and nature of organ involvement as well as the clinical course in Langerhans cell histiocytosis is variable. Ranging from the fulminant, generalized, and frequently lethal Letterer-Siwe disease, to the multifocal eosinophilic granulomas of Hand-Schüller-Christian disease, to the relatively innocent solitary eosinophilic granuloma of bone, hypothalamic-pituitary involvement may be a feature of each.
Central nervous system involvement is a common feature of Langerhans cell histiocytosis, although only rarely do central nervous system lesions occur in the absence of disease elsewhere.20 There is an apparent predilection for involvement of the hypothalamus, infundibulum, and posterior pituitary.19,20 The anterior lobe is affected far less often. In most cases, involvement of these structures represents extension from an adjacent bony lesion, although occasionally, in the context of disseminated disease, parapituitary and meningeal involvement occurs in the absence of bony disease. Diabetes insipidus generally is the earliest and most prominent feature of pituitary involvement, reflecting posterior pituitary, infundibular, or hypothalamic infiltration. Perturbations of anterior pituitary function (typically GH deficiency) may occur; less often there may be a deficiency of other hormones. These are considered to be secondary to disease of the hypothalamus or pituitary stalk. Sometimes, damage to the stalk may be so extreme as to render the anterior lobe functionally, if not physically, disconnected from the hypothalamus. Moderate degrees of hyperprolactinemia also may be a feature of the condition, again reflecting hypothalamic or stalk injury.
The histologic picture of Langerhans cell histiocytosis is typical of disease elsewhere and is characterized by infiltrates of histiocytes (often foamy in appearance), eosinophils, and lymphocytes. The essential component of the infiltrate is the Langerhans cell, a large mononuclear cell resembling a histiocyte and expressing S-100 protein as well as HLA-DR and CD1 antigens. The ultrastructural presence of Birbeck granules, which are pentalaminar tubular structures found in the cytoplasm of the Langerhans cell, is pathognomonic. A definitive diagnosis of Langerhans cell histiocytosis rests on the characteristic cytologic features of the Langerhans cell and the accompanying infiltrate. The identification of Birbeck granules and the antigenic determinant CD1 is confirmatory.
Idiopathic Medical Conditions. Dysfunction of the hypothalamic-pituitary axis remains a poorly characterized component of many idiopathic medical conditions.1,2,9 These include the Laurence-Moon-Biedl syndrome, cerebral gigantism or Sotos syndrome, the Prader-Willi syndrome, and anorexia nervosa. Even at a purely clinical level, the endocrinologic aberrations accompanying these disorders are, at best, incompletely understood. Correspondingly, pathologic studies of hypothalamic and pituitary tissues in each of these conditions have been few and the findings inconsistent. In all cases, if pathologic correlates of hypothalamic-pituitary dysfunction can be identified, it is usually the hypothalamus that shows a more consistent pattern of pathologic change; primary pathologic features in the pituitary are inconspicuous or absent in these disorders.19
Deposits. Deposits of various substances may be accompanied by anterior hypopituitarism. Amyloid deposits in the pituitary occur outside the cell in the walls of blood vessels and the interstitium and are part of the amyloidosis of other organs, mainly the kidneys, liver, spleen, and intestines. Pituitary amyloid is regarded as immune amyloid and has the same staining characteristics and ultrastructural appearance as amyloid in other organs. In some pituitary adenomas, especially prolactin-producing adenomas, the adenoma cells may produce amyloid that is different ultra-structurally from immune amyloid. In cells with massive amyloid accumulation, the plasmalemma becomes disrupted, and amyloid can be identified in the extracellular space. In hemochromatosis and hemosiderosis, iron pigment may be deposited in the cytoplasm of adenohypophysial cells (see Chap. 131). Iron storage is uneven, it occurs most extensively in the cytoplasm of gonadotropes compared with other cell types. Preferential iron deposits in gonadotropes may explain the occurrence of hypogonadism with iron overload. Electron microscopic examination demonstrates hemosiderin and ferritin particles in the cytoplasm of the adenohypophysial cells; this is incorporated into lysosomal dense bodies. Prussian blue staining combined with an immunoperoxidase technique discloses iron and adenohypophysial hormones in the cytoplasm of the same cells, which is consistent with the assumption that iron uptake does not block hormone production. Iron accumulation may be accompanied by fibrosis, which accounts for the development of adenohypophysial insufficiency. In some pituitary tumors, transferrin has been shown to exhibit stimulatory growth factor-like properties.21
Calcium deposits can be demonstrated at the site of necrosis or in pituitary tumors, especially craniopharyngiomas and prolactin-producing adenomas. Calcification is not so marked as to cause hypopituitarism.
In Hurler syndrome, or gargoylism, mucopolysaccharides accumulate in the pituitary. The adenohypophysial cells, mainly acidophilic cells, exhibit marked cytoplasmic vacuolization. Electron microscopic studies show granular membranous bodies and prominent lipidladen lysosomes in some basophilic cells.
ADENOHYPOPHYSIAL CELL HYPERPLASIA1,2,10,22
By definition, hyperplasia refers to a nonneoplastic increase in cell number. Although it is generally accepted that physiologic hyper-plasia regularly affects the pituitary gland (e.g., prolactin cell hyperplasia of pregnancy), the occurrence of pathologic forms of pituitary cell hyperplasia has long been questioned. It is now certain that pathologic forms of hyperplasia, although rare, do occur, and occasionally can be the source of both pituitary enlargement and a hypersecretory state in the absence of pituitary adenoma formation.22 Although a small increase in prolactin, ACTH, and TSH adenomas or “tumorlets” occurs in the setting of protracted estrogen administration, Addison disease, and hypothyroidism, respectively, there is little evidence to suggest that pituitary cell hyperplasia is a common precursor of adenoma formation in humans.10,23 Moreover, pituitary adenomas are rarely surrounded by a zone of hyperplastic cells of similar type.
Beyond the conceptual uncertainties surrounding adenohypophysial cell hyperplasia are the real practical difficulties confounding its detection. Even when present, pituitary hyperplasia is difficult to diagnose, even by experienced pituitary pathologists. The small and frequently fragmented nature of surgical specimens coupled with the normal acinar, and sometimes nodular, histologic pattern of normal pituitary cells significantly complicates the identification of hyperplastic foci. Hyperplasia is best recognized on reticulin-stained specimens and by immunohis-tochemical techniques. The essential pathologic feature is expansion of acini with retention of the overall acinar morphology. Morphologically, pituitary cell hyperplasia can be focal, nodular, or diffuse, and generally involves cells of a single type; rarely, several cell types may be affected simultaneously.
Prolactin Cell Hyperplasia. The most common form of prolactin cell hyperplasia is physiologic and occurs during pregnancy and lactation. In this context, proliferation of prolactin cells results in a doubling of the size of the gland. Another common form of prolactin cell hyperplasia is that which occurs as the result of the stalk section effect (i.e., interruption of dopamine delivery to the anterior lobe caused by any of several sellar and suprasellar lesions). The presence of prolactin hyperplasia adjacent to some corticotrope adenomas remains unexplained. In cases of long-standing primary hypothyroidism, prolactin cell hyperplasia is an occasional accompaniment, one that presumably reflects the trophic effects of thyrotropin-releasing hormone (TRH) on pituitary lactotropes. Furthermore, stores of hypothalamic dopamine are known to be diminished in untreated hypothyroidism. Accordingly, loss of tonic dopaminergic inhibition provides an additional neuroendocrine mechanism for lactotrope hyperplasia in this circumstance. Isolated lactotrope hyperplasia as the primary cause of hyperprolactinemia is exquisitely rare, as is the coexistence of prolactin cell hyperplasia with a prolactinoma.
Growth Hormone Cell Hyperplasia. Growth hormone cell hyperplasia is a rare phenomenon. In virtually all instances, somatotrope hyperplasia occurs as the result of an extrapituitary GHRH-producing tumor (e.g., pancreatic islet cell tumor, pheochromocytoma, bronchial and intestinal carcinoids, small-cell carcinoma of the lung).24 In response to the stimulatory effect of GHRH, pituitary somatotropes enlarge, proliferate, and produce excess GH; acromegaly is the clinical result. Despite persistent stimulation by GHRH and the development of somatotrope hyperplasia, adenomatous transformation rarely occurs in this setting, even after protracted periods of stimulation. Although GHRH-producing tumors are rare causes of acromegaly, they should always be considered in the differential diagnosis. Idiopathic GH cell hyperplasia has yet to be conclusively demonstrated as a cause of acromegaly (see Chap. 219).
Corticotrope Cell Hyperplasia. Considerable debate surrounds the role of idiopathic corticotrope hyperplasia as a cause of Cushing disease. In the experience of the authors, corticotrope hyperplasia alone, or in combination with a corticotrope adenoma, is responsible for up to 10% of all cases of pituitary-dependent Cushing disease.22 Theoretically, such cases of Cushing disease should be more refractory to cure by all but total hypophysectomy because hyperplastic foci either remain or are newly induced from the ongoing hyperplastic stimulus. Less controversial, and generally acknowledged, is the occurrence of corticotrope hyperplasia in response to a variety of extrapituitary CRH-producing tumors (e.g., neuroendocrine neoplasms, hypothalamic or adenohypophysial gangliocytomas; see Chap. 75 and Chap. 219). In this setting, hyperplasia may result in considerable glandular enlargement, at times sufficient to mimic a pituitary adenoma. Not surprisingly, nodular hyperplasia of pituitary corticotropes is regularly seen in untreated Addison disease.25
Thyrotrope Hyperplasia. Hyperplasia of TSH-producing cells occurs exclusively in the context of long-standing primary hypothyroidism.26 Frequently, such hyperplasia can be so pronounced as to enlarge the pituitary and simulate an adenoma. Pituitary surgeons should be aware of this lesion because numerous cases of thyrotrope hyperplasia have inadvertently been treated with surgical resection without the benefit of medical therapy. Thyroid hormone replacement alone is curative in many cases. Given the trophic effect of TRH on lactotropes, prolactin cell hyperplasia may be found to coexist with thyrotrope hyperplasia.
Gonadotrope Hyperplasia. Hyperplasia of gonadotropes is a rare occurrence that often is difficult to recognize, even in pronounced cases. It has been found in the pituitaries of patients in whom primary hypogonadism commenced at a young age, although it is not encountered among autopsied pituitaries of postmenopausal women. Gonadotrope hyperplasia is not a cause of pituitary enlargement, nor is it an accompanying feature or a likely predecessor to gonadotrope adenoma formation.
Numerous tumor types occur in the sellar region; they can be epithelial or mesenchymal and benign or malignant4,10 (Table 11-1). Some tumors also occur elsewhere; their histologic appearance is the same in the pituitary as in other organs. Some small tumors cause no clinical or biochemical abnormalities, whereas others destroy large areas of the pituitary, resulting in anterior hypopituitarism, diabetes insipidus, and hyperprolactinemia. Other tumors cause syndromes of hormonal hyperfunction (see Chap. 12, Chap. 13, Chap. 14, Chap. 15 and Chap. 16).
TABLE 11-1. Tumors and Nontumorous Lesions of the Sellar Region
Pituitary adenomas are benign epithelial neoplasms derived from and composed of adenohypophysial cells. They account for ~10% to 15% of all intracranial neoplasms. Depending on the population surveyed, their reported annual incidence varies from 1.0 to 7.6 per 100,000 population.1,10 By this measure, pituitary tumors not only are the dominant form of neoplasia arising in the sellar region, but also are among the most frequent primary intracranial tumors encountered in clinical practice. These figures, derived primarily from neurosurgical series, may even underestimate the true incidence of pituitary adenomas, because their frequency in unselected autopsy cases approaches 25%.10 Thus, neoplastic transformation in the pituitary can be considered an exceedingly common event, albeit one that may not always manifest itself clinically.
Although no age group is exempt from the development of pituitary tumors, there is a clear tendency for these lesions to become more common with age, with the highest incidence occurring between the third and sixth decades of life. Only rarely are they diagnosed in prepubertal patients. Based on surgical series, a female preponderance appears to exist, with women of child-bearing age being at greatest risk for tumor development. The basis of this increased susceptibility in women is uncertain. It may be that the susceptibility is more apparent than real, because manifestations of pituitary dysfunction are generally more conspicuous in premenopausal women, prompting earlier diagnosis by both patients and physicians. Moreover, the incidence of pituitary adenomas in autopsy series is equally distributed between the sexes.10
PATHOGENESIS AND MOLECULAR BIOLOGY2,10,23
Accumulating evidence indicates the development of pituitary adenomas to be a multistep and multicausal process that, in its most abbreviated form, consists of an irreversible tumor initiation phase followed by a tumor promotion phase (Fig. 11-5). The events necessary to accomplish the process are only superficially understood. Nonetheless, it is known that hereditary predisposition, endocrine and hypothalamic factors, and specific genomic mutations all appear to have some pathophysiologic role in the initiation or progression of pituitary adenomas. Before considering the relative contribution of each of these to pituitary tumor development, it is important to acknowledge that tumor development in the pituitary is a monoclonal process. This observation is of considerable conceptual relevance and provides the background on which other pathophysiologic events must be integrated.
FIGURE 11-5. Molecular events that are considered important in the development and progression of pituitary adenomas. Conceptually, the events contributing to pituitary tumor development can be distinguished as tumor induction events (right panel) and tumor promotion events (left panel). Tumor induction events represent specific genomic mutations that may be early transforming events (gsp, multiple endocrine neoplasia type 1 [MEN1]). Tumor promotion events represent growth-promoting events, which include additional mutations (PKC-a, H-ras), stimulation by hypothalamic hormones, or modulation by the endocrine status of the patient (i.e., Nelson syndrome).
One of the most fundamental and historically contentious issues surrounding pituitary tumorigenesis relates to whether transformation in the pituitary is primarily the product of hypothalamic dysfunction or simply the result of an acquired transforming mutation intrinsic to an isolated adenohypophysial cell. The hypothalamic hypothesis suggests that pituitary adenomas arise as the eventual, downstream, and seemingly passive consequence of excessive trophic influences, emanating from a dysfunctional hypothalamus. Alternatively, the pituitary hypothesis suggests that pituitary adenomas arise as the direct result of an intrinsic pituitary defect, with neoplastic transformation occurring in relative autonomy of hypothalamic trophic influence. Whereas substantial evidence exists in support of both possibilities, the latter concept has been especially favored in view of the lack of peritumoral hyperplasia in association with pituitary adenomas and because many pituitary tumors can be definitively “cured” when completely removed. Neither of these would be expected were hypothalamic overstimulation the dominant tumorigenic mechanism.
Further strengthening the idea that pituitary adenomas result from somatic mutations that occur at the level of a single, susceptible, adenohypophysial cell have been reports concerning their clonal composition. Using the strategy of allelic X-chromosome inactivation analysis, which assesses restriction fragment length polymorphisms and differential methylation patterns in various X-linked genes, several independent laboratories have confirmed a monoclonal composition for virtually all pituitary adenomas.27,28 Validation of the monoclonal nature of pituitary adenomas has been an important conceptual advance because it has established pituitary adenomas as monoclonal expansions of a single, somatically mutated, and transformed adenohypophysial cell. Were hypothalamic overstimulation the dominant initiating event, then a population of anterior pituitary cells should simultaneously be affected and a polyclonal tumor would be the expected result; this has not been the case.
HYPOTHALAMIC FACTORS AND PITUITARY TUMORIGENESIS
Whereas the demonstration that pituitary adenomas are monoclonal derivatives of a single transformed adenohypophysial cell does conform well to existing paradigms of human tumorigenesis, it should not be interpreted as somehow exonerating hypothalamic influences of a role in pituitary tumor development. On the contrary, the culpability of hypothalamic hormones in pituitary tumorigenesis continues to gain strength, and there has been renewed interest in integrating a role for these hormones in the current multistep monoclonal model.29 The class of hypothalamic hormones at issue are the hypothalamic hypophysiotropic hormones, which primarily include GHRH, somatostatin (SRIF), CRH, TRH, gonadotropin-releasing hormone (GnRH), and dopamine. Produced in hypothalamic nuclei, descending via the portal circulation, and binding to specific membrane receptors on their respective adenohypophysial target cells, these hormones govern the secretory and proliferative activity of each of the principal pituitary cell types. In logical extension of their physiologic trophic activities has been the implication that aberrant activity of these regulatory hormones in the form of excess stimulation or deficient inhibition may contribute to the genesis and/or progression of pituitary adenomas. For example, in states of pathologic GHRH excess, as occurs with rare GHRH-producing tumors (pancreatic endocrine tumors, carcinoids, pheochromocytomas, and hypothalamic hamartomas/gangliocytomas), chronic GHRH stimulation leads to hyperplasia of pituitary somatotropes, GH hypersecretion, and clinical acromegaly. Depending on the duration of exposure to the excess GHRH, progression from somatotrope hyperplasia to adenomatous transformation has been documented in some, but not all instances.24 A parallel phenomenon has been demonstrated in transgenic mice bearing the human GHRH transgene. That these animals develop gigantism, elevated GH levels, somatotrope hyperplasia, and, eventually, GH-producing pituitary adenomas, provides compelling and conclusive evidence of the tumor-promoting properties of GHRH.30 To date, analogous data implicating other hypophysiotropic hormones have been comparatively few; however, the convincing precedence provided by these GHRH data lends, at the very least, some plausibility to the idea that other hypophysiotropic hormones may also share similar tumorigenic potential. Whereas a specific somatic mutation of an adenohypophysial cell is requisite to adenomatous transformation, hypophysiotropic hormones may modify the cell’s susceptibility for such a mutation to occur. Some hypophysiotropic hormones (GHRH, CRH, TRH) are known to induce early-response genes in their respective adenohypophysial target cells, mustering a potent, yet physiologic mitogenic response. Were it to occur, not only would the aberrant overactivity of these regulatory hormones be accompanied by increased proliferative activity of relevant adenohypophysial cells, but the possibility for a transforming mutation also would be correspondingly increased. The extent to which this actually does occur among pituitary adenomas is unknown, although abnormal hypothalamic and other neuroendocrine responses have been demonstrated in patients with pituitary adenomas, including those having undergone “successful” tumor removal.31
Tumor initiation aside, a more persuasive role for hypothalamic hormones can be envisaged during the tumor progression phase of pituitary tumorigenesis. Given that pituitary adenomas frequently express and retain responsiveness to hypothalamic hormones, the latter have been implicated in facilitating proliferation of the transformed clone. Of particular interest have been a number of reports wherein pituitary tumors themselves were shown to express at the protein and/or mRNA level various hypophysiotropic hormones together with their corresponding receptors. Somatotrope adenomas have been shown to express both GHRH-mRNA transcripts and protein,32,33 experimental corticotrope adenomas have been shown to express CRH-mRNA transcripts,34 thyrotrope adenomas have been shown to express TRH mRNA,35 and gonadotrope adenomas have been shown to express GnRH mRNA and protein.36 These data strongly suggest the possibility that pituitary adenomas may be subject to autocrine and/or paracrine regulation by endogenously produced hypophysiotropic hormones. In the case of GH-secreting pituitary adenomas, tumoral expression of GHRH mRNA was shown to be an adverse event—one associated with higher proliferative activity, invasiveness, increased secretory activity, and a reduced likelihood of postoperative remission.37
In view of the foregoing, it should be clear that despite the monoclonal constitution of pituitary adenomas, a potential role of hypothalamic hormones in their genesis and/or progression is not easily dismissed (see Fig. 11-5).
A recurring theme, one borne from both experimental study and clinical observation, relates to the possible predisposing, promoting, or perhaps even the inductive effect of certain altered endocrine states to the development of pituitary adenomas. Of particular relevance are those states of target-gland failure wherein the pituitary is no longer subject to negative feedback effects imposed by target-gland hormones. For example, within the pituitary glands of patients with Addison disease and primary hypothyroidism of long duration, the respective frequencies of corticotrope and thyrotrope “tumorlets” was higher than that observed in control individuals.25,26 Admittedly, only a loose correlation, but stronger still, and of greater clinical concern is the behavior of corticotrope adenomas and thyrotrope adenomas in the setting of bilateral adrenalectomy (Nelson syndrome) and prior thyroidectomy, respectively.38 That such tumors tend to be notoriously more aggressive than those having an intact pituitary-target gland axis emphasizes the potential importance of negative-feedback inhibition in modulating the behavior and progression of these neoplasms.
A final endocrine issue, one having been repeatedly implicated in pituitary adenoma development, particularly PRL-producing adenomas, concerns the role of estrogen as a contributor to transformation and/or neoplastic progression in the pituitary. The tumor-promoting properties of this sex steroid are mediated by specific estrogen receptors which, when ligand activated, dimerize and bind to specific DNA-addressing sites to induce transcription of various target genes governing cell proliferation. Whereas chronic estrogen administration routinely induces prolactinomas in rodents, evidence in favor of a similar relationship in humans has been less convincing. The increasing frequency with which prolactinomas were being diagnosed in the 1970s paralleled the use of oral contraceptives in women, a phenomenon that once invited speculation about a possible causal or predisposing effect of the latter in the development of the former. Several case-controlled studies, however, have failed to substantiate such a relationship.39 Still, estrogens are known to alter the morphology and secretory activity of human adenohypophysial cells, indicating that the anterior pituitary is an important target tissue for estrogen action.40 The observation that the hormonal milieu of pregnancy can, in some instances, stimulate prolactinoma growth indicates a potential responsiveness of these tumors to estrogenic stimulation. That human pituitary adenomas express estrogen receptors has been recognized for some time. In addition, estrogen receptor mRNA transcripts are present in all types of pituitary adenomas and in all cell types of the normal anterior pituitary gland.41 In at least a single but noteworthy instance, one involving a transsexual patient, high-dose estrogen therapy. correlated with the development of a human PRL-producing pituitary adenoma.42 Thus, the link between estrogens and human pituitary tumor formation remains somewhat circumstantial, but sufficiently so, that it cannot be entirely dismissed.
Genomic Alterations: Oncogene Activation. Accompanying the realization that the somatic mutation of an isolated adenohypophysial cell is an event requisite to pituitary tumorigenesis has been a vigorous attempt to identify and characterize the responsible mutation. Of the genomic and cellular alterations known to occur in pituitary adenomas, relatively few appear to involve activating mutations of known oncogenes. To date, activating mutations of only two oncogenes have been reported in pituitary adenomas: gsp and H-ras. Whereas the former is encountered with some regularity in somatotrope adenomas and periodically in other pituitary adenoma types, the latter has been identified in only isolated instances.
The only consistent evidence favoring oncogene activation as a transforming mechanism in the pituitary stems from the discovery and characterization of the gsp oncogene, an oncogene first identified in GH-producing pituitary adenomas.43,44 The signal transduction cascades governing the secretory and proliferative functions of pituitary somatotropes converge on the adenylate cyclase second messenger system. In the normal state, the hypothalamic hypophysiotropic hormone (GHRH) is the principal positive regulator of somatotrope function. After binding to its membrane receptor on the somatotrope cell surface, the GHRH-proliferative signal is coupled to a stimulatory, heterotrimeric G-protein, termed Gs, which binds GTP and activates adenylate cyclase. This results in elevations of cAMP levels that, through a series of poorly characterized downstream events, ultimately lead to GH secretion and somatotrope proliferation. Adenylate cyclase activation is normally a self-limiting, transient, and tightly regulated event. This is because one structural component of Gs, known as thea chain, maintains intrinsic GTPase activity that, after transducing the signal, hydrolyzes GTP and returns Gs to its inactive state, thus terminating the trophic signal. Activating mutations of gsp are the result of point mutations in the a chain gene of Gs. The mutant alpha chain has deficient GTPase activity and is therefore incapable of hydrolyzing GTP and “turning off” the proliferative signal. Therefore, such mutant forms of the a chain stabilize Gs in its active configuration, thus mimicking the trophic effects of persistent GHRH action. Bypassing the tight regulatory control normally provided by GHRH, somatotropes bearing the mutant a chain of Gs constitutively activate adenylate cyclase, providing an autonomous and unrestrained capacity for cell proliferation and GH secretion.
Whereas in North American and European studies, activating mutations of gsp have been reported in ~40% of somatotrope adenomas,44 in Japan, such mutations are rare events.45 In neither geographic setting, however, does their presence confer any significantly distinctive clinical, behavioral, biochemical, or radiologic characteristics to the tumor. In one report, tumors exhibiting gsp mutations occurred in older patients, were smaller, and had lower basal GH levels than wild-type tumors, although this has not been uniformly observed.31,44
Activating mutations of the Gs a chain have also been identified in 10% of clinically nonfunctioning pituitary adenomas and very recently, in 5% of corticotrope adenomas.46,47 and 48 That such mutations should occur in tumors not somatotropic in nature suggests that stimulatory G proteins may underlie intracellular signaling in other cell types as well. As in the case of somatotrope adenomas, nonfunctioning and corticotrope adenomas bearing mutations of gsp do not appear to differ clinically from those tumors lacking this mutation.
Aside from gsp mutations that have been identified with some regularity, the search for additional activating mutations involving other candidate oncogenes has not proved particularly informative. The only relevant finding concerns the very occasional demonstration of mutations involving the H-ras oncogene among isolated pituitary tumors. The first dedicated study of ras mutations in the pituitary involved the screening of 19 pituitary adenomas wherein an activating mutation of ras was identified in only a single instance.49 The noteworthy feature of this case, a prolactinoma, pertained to the unusual aggressiveness of the tumor; the tumor was remarkable for a rather early age of onset, multiple recurrences, very high prolactin levels, resistance to dopamine agonist therapy, and unrelenting invasiveness that ultimately proved fatal. In a subsequent genomic screening of 44 pituitary adenomas, none were found to have mutations of ras.50 In a third study, one focusing on pituitary carcinomas, mutations of H-ras were demonstrated in three of five distant metastases but in none of the primary pituitary lesions, nor in any invasive pituitary adenoma.51 Of these, two were corticotrope carcinomas and the third was a lactotrope carcinoma. Collectively, these data suggest that mutations of ras, while uncommon events in pituitary tumorigenesis, do appear to be associated with an unusually aggressive phenotype and are likely late events in pituitary tumor progression. Furthermore, the presence of H-ras mutations in secondary deposits but not in the primary lesion of pituitary carcinomas is especially intriguing for it suggests that this mutation may play a role in initiating and/or sustaining distant pituitary metastases (see Fig. 11-5).
GENOMIC ALTERATIONS: TUMOR-SUPPRESSOR GENE INACTIVATION
MEN1 Tumor-Suppressor Gene. Genetic predisposition to pituitary tumor development is restricted to a single and uncommon condition, the MEN1 syndrome. This autosomal-dominant condition is characterized by the simultaneous development of tumors involving the parathyroid glands, pancreatic islet cells, and the pituitary. A variably penetrant condition, only 25% of patients develop pituitary tumors, the majority of which are macroadenomas associated primarily with GH and/or PRL hypersecretion.1,10 Approximately 3% of all pituitary adenomas occur in the context of MEN1. The nature of the genetic defect in MEN1 has recently been identified and involves allelic loss of a putative tumor-suppressor gene at the 11q13 locus.52,53 In its recessive behavior, the MEN1 gene is typical of a tumor-suppressor gene, with susceptible individuals inheriting a germline mutation of one of the two 11q13 alleles. Subsequent spontaneous mutation, inactivation, or deletion of the remaining normal 11q13 locus in susceptible endocrine tissues ultimately leads to tumor formation in the involved tissue.
Once believed to be a genetic defect that accounted for pituitary adenomas occurring exclusively in the context of MEN1, several studies have also demonstrated loss of the 11q13 locus in seemingly sporadic pituitary adenomas. In the earliest of these, allelic deletions of 11q13 were found in two of three sporadic prolactinomas.52 Subsequently, 4 of 12 sporadic GH cell adenomas were found to have deletions involving the 11q13 locus.54 More recently, allelic deletions of chromosome 11 were found in 18% of pituitary adenomas of all major types.55 Collectively, these data suggest that the 11q13 locus is the site of an important tumor-suppressor gene, the inactivation of which may be of pathogenic relevance to the development of both sporadic and MEN1–related pituitary adenomas.
p53 Tumor-Suppressor Gene. Mutations of the p53 gene represent the single most common nonrandom genomic alteration encountered in human cancer.56 The contribution of p53 gene mutations to pituitary tumorigenesis remains unsettled. Much of the difficulty in implicating or excluding a role for p53 mutations in these tumors has centered on the apparent incongruity between data obtained by conventional genomic screening from that provided by p53 immunohistochemistry studies.57 On the one hand, in all of three studies wherein the p53 gene was screened at the usual mutational “hot spots,” not a single pituitary tumor was identified as having a p53 mutation.50,58 Alternatively, in several reports wherein pituitary. tumors were studied immunohistochemically, conclusive nuclear accumulation of p53 protein was demonstrated in some pituitary tumors.57,59 In one report, nuclear accumulation of p53 was selectively present in none, 15%, and 100% of noninvasive adenomas, invasive adenomas, and pituitary carcinomas, respectively. Moreover, the growth fractions of p53 immunopositive tumors were significantly higher than those immunonegative for p53.59 In reconciling the genomic screening and immunohis-tochemical data, it is important to acknowledge the different inferences permissible by each methodology. Whereas p53 immunohistochemistry analysis was once regarded as a surrogate means of detecting underlying gene mutations, the concordance between these two methods has not proved as strong as previously believed, and the former cannot be regarded as unequivocal proof of the latter. Therefore, the weight of existing evidence argues against p53 gene mutations as events that contribute to pituitary tumor development and/or their progression. Still, the inability to invoke an underlying gene mutation as the basis for the observed accumulation of p53 protein among aggressive pituitary tumors should not diminish the practical utility of this protein as an immunohistochemical marker of aggressive behavior in this tumor system. Moreover, alternative and equally relevant pathophysiologic mechanisms other than p53 gene mutations may account for p53 immuno-positivity. Precedence in support of this has been provided by other human tumors, such as sarcomas and cervical carcinomas, wherein immunohistochemically apparent p53 accumulation reflects complex formation, sequestration, and resultant inactivation of wild-type p53 by other proteins, producing a state functionally equivalent to that occurring with a gene mutation; similar mechanisms may be operative in pituitary tumors.56
13q14. The first of the tumor-suppressor genes to be identified, the retinoblastoma gene (Rb) remains the prototypical example of this class of genes. Beyond its role in the development of familial retinoblastoma and various other malignancies and its overall contribution to cell-cycle regulatory control, studies of the Rb gene added a new dimension to the very concept of human cancer, illuminating recessive aspects of the process and the oncogenic consequences that accompany loss of protective genomic elements. The implication that the Rb gene might be involved in pituitary tumorigenesis had a somewhat serendipitous beginning. Transgenic mice in which one of the two germline Rb alleles had been deactivated failed to develop retinoblastomas as anticipated; instead they developed large, high-grade, invasive pituitary tumors.60 On further analysis, these tumors were shown to have lost the remaining normal Rb allele, convincingly implicating a second Rb “hit” as the basis for pituitary tumor development in this model. All of these tumors were found to be corticotropic in nature, immunoreactive for ACTH, and of pars intermedia origin (unpublished observations).
Prompted by the provocative nature of these findings, a number of recent studies have sought to determine the relevance of Rb mutations in human pituitary tumors. In the first report, none of 18 informative pituitary tumors exhibited allelic Rb loss.61 This was further confirmed in a study of 30 informative pituitary adenomas wherein none was found to exhibit loss of heterozygosity (LOH) at the Rb gene locus.62 In another study, however, LOH was found at the Rb locus in all of seven pituitary carcinomas, including their metastatic deposits, and in all of six highly invasive pituitary adenomas.63 The significance of these latter observations vis-à-vis Rb gene mutations, however, was undermined by the finding of Rb protein in tumors exhibiting LOH at the Rb locus. In reconciling the apparent discordance between Rb gene and protein status, together with the two previous studies that excluded Rb mutations within pituitary tumors, the conclusion was made that another putative tumor-suppressor gene, one present on 13q14 but distinct from Rb, must be involved in pituitary tumor progression (see Fig. 11-5).63
OTHER GENOMIC ALTERATIONS
Protein Kinase C Gene. Another genomic alteration identified in pituitary adenomas, specifically invasive ones, relates to the protein kinase C (PKC) family of second messengers. PKC family members are ubiquitous, membrane-bound, intra-cellular kinases whose function is to phosphorylate serine or threonine residues on important substrate proteins. Such kinase activity is thought to govern several important cellular processes, including the transmembrane signaling underlying cell proliferation and differentiation. Altered or aberrant PKC activity has been demonstrated in several human tumors, including pituitary adenomas. In comparison with normal pituitary tissue, increased PKC protein expression was identified in pituitary adenomas. More recently, it has been demonstrated that the specific PKC isoform that is overexpressed in pituitary tumors is PKC-a. Interestingly, this particular PKC isoform has been favored as the isoform that mediates the mitogenic functions of PKC. Not only was PKC-a found to be overexpressed in pituitary adenomas, but invasive adenomas also exhibited a conserved point mutation of the PKC-a gene.64
Cytogenetic Changes. Perhaps the most graphic evidence in support of the concept that neoplasia represents the successive accumulation of genetic alterations is derived from cytogenetic studies of tumor cells. In the case of pituitary adenomas, given their low intrinsic mitotic activity and overall benign constitution, metaphase preparations are not easily procured, and few direct cytogenetic analyses have been successfully performed. Of those that have, cytogenetic aberrations appeared more commonly among functioning pituitary adenomas than in endocrine-inactive ones.65,66 Overall, rearrangements involving chromosomes 17 and 19 were most commonly observed; trisomy of chromosome 7 as well as structural abnormalities of chromosomes 18p, 1, and 4 were observed less often. Given the limited number of cytogenetic analyses performed on pituitary adenomas to date, it is impossible to determine the pathophysiologic significance of the chromosomal aberrations so far cataloged. Whether such alterations are nonrandom events that contribute to tumor initiation and/or progression remains uncertain. Alternatively, such alterations may simply represent genetic instability inherent to neoplastic cells, being neither important nor informative to the evolution or progression of pituitary adenomas.
GENERAL FEATURES OF PITUITARY ADENOMAS1,10
From clinical, pathologic, and biologic standpoints, tumors of the pituitary gland are a heterogeneous group. Underlying much of this heterogeneity is the fact that the normal adenohy-pophysis is composed of five principal cell types, each of which is susceptible to neoplastic transformation. The resulting adenoma tends to maintain the secretory activity nomenclature and some of the morphologic features of the cell of origin. Up to 70% of pituitary adenomas are hormonally active lesions that produce distinctive alterations in the endocrine equilibrium. The remainder are incapable of secreting a biologically active hormonal product and are referred to as nonfunctional. Further contributing to their overall heterogeneity are their variable and often unpredictable growth characteristics. Whereas some tumors exist largely as microadenomas, maintain a well-defined margin, and show little appreciable growth over time, others exhibit rapid proliferation rates and are markedly invasive or compressive of adjacent bony, neural, or vascular structures. This tremendous variation in biologic behavior cannot be predicted on morphologic grounds alone. Even the exceptional pituitary carcinoma, so defined on the basis of its metastatic capability, may appear entirely benign histologically.
The clinical presentation of pituitary adenomas also is variable, although three principal patterns are recognized. The first involves pituitary hyperfunction, in the form of several characteristic hypersecretory states. Hypersecretion of prolactin, GH, ACTH, and, rarely, TSH, produces their corresponding clinical phenotypes: amenorrhea-galactorrhea syndrome, acromegaly or gigantism, Cushing disease, and secondary hyperthyroidism, respectively.1,4,67 By contrast, some pituitary adenomas produce symptoms of anterior pituitary deficiency, resulting from compression of the nontumorous pituitary or damage to the pituitary stalk or hypophysiotropic areas of the hypothalamus. This usually occurs insidiously in the context of large, nonfunctioning pituitary adenomas, but occasionally it may occur acutely in the setting of pituitary apoplexy. In the face of chronic compression, the various secretory cells of the pituitary differ in their functional reserve. Because gonadotropes are the most vulnerable, they usually are affected first, followed sequentially by thyrotropes and somatotropes. Corticotropes demonstrate the greatest functional resilience and generally are the last to be affected. Finally, the clinical presentation of a pituitary adenoma may be a neurologic one, with or without coexisting endocrinopathy. Given its strategic location at the skull base, a growing adenoma produces a predictable array of neurologic signs and symptoms. Suprasellar extension with compression of the optic chiasm results in a characteristic bitemporal hemianopic pattern of vision loss (see Chap. 20). Encroachment on the hypothalamus causes alterations of sleep alertness and behavior (see Chap. 9). Transgression of the lamina terminalis can bring these tumors into the region of the third ventricle, where obstruction to the flow of cerebrospinal fluid results in obstructive hydrocephalus. Lateral penetration of the tumor into the cavernous sinus occurs commonly, occasionally ensheathing the cavernous segment of the carotid artery and functionally compromising cranial nerves transiting the sinus. Some tumors extend in other directions and, if sufficiently large, can involve the anterior, middle, and, occasionally, posterior cranial fossae to produce a full spectrum of neurologic deficits.
A final endocrinologic feature of pituitary adenomas, one that is common to many neoplastic, compressive, or infiltrative lesions affecting the sellar region, is moderate hyperprolactinemia. The blood prolactin levels are not extremely high, usually below 200 ng/mL. In addition, TRH stimulation, although not reliable as a test, may further increase the blood prolactin levels, whereas patients with prolactin-producing pituitary adenomas may exhibit no response or a blunted response to TRH. In patients with non–prolactin-producing tumors, the mechanism of hyperprolactinemia is explained by the so-called “stalk section effect.” Because prolactin secretion is suppressed by hypothalamic dopamine, interference with the synthesis, discharge, or adenohypophysial transport of dopamine may relieve pituitary prolactin cells from dopaminergic inhibition, resulting in increased prolactin release and hyperprolactinemia (see Chap. 13).
As a rule, prolactin elevations in excess of 200 ng/mL are virtually always indicative of autonomous prolactin secretion from a neoplasm, either a prolactinoma or a plurihormonal pituitary tumor with a lactotropic component.
MEANS OF CLASSIFICATION
Since pituitary adenomas were first recognized, substantial effort has been devoted to classifying them into distinct groups. Endocrinologic classifications emphasize clinical manifestations of the disease or the dominant endocrine abnormality as assessed biochemically, most often with radioimmunoassay of blood hormone levels. Pathologic classifications hinge on structural features of adenoma cells and emphasize morphologic tumor markers. Modern pathologic classifications are based on sophisticated morphologic methods, such as immunocy-tochemistry analysis, ultrastructural analysis, immunoelectron microscopy, and morphometry. The conventional pathologic methods have been integrated with the powerful applications of molecular science. Methodologies such as in situ hybridization and Northern blot analysis permit the classification of pituitary adenomas on the basis of specific gene expression patterns (Fig. 11-6). Although these methods as well as those that catalog pituitary adenomas on the basis of specific genomic alterations are currently of research interest only, they will assume increasing importance in both the classification of pituitary adenomas and the prediction of their biologic behavior.
FIGURE 11-6. Cellular distribution of pro-opiomelanocortin (POMC) mRNA in a corticotrope adenoma from a patient with Nelson syndrome as demonstrated by the method of in situ hybridization. The distribution of the black silver grains corresponds to the distribution of POMC mRNA. Original magnification ×400.
Useful classifications are those that permit conclusions based on biologic behavior, prognosis, and response to various treatment modalities. Thus, pituitary adenomas are classified according to the staining affinities of the cell cytoplasm, size, growth pattern, endocrine activity, histologic features, hormone synthesis and content, granularity of cell cytoplasm, cellular composition and cytogenesis, or electron microscopic characteristics.
On the basis of tinctorial features of the cell cytoplasm, acidophilic, basophilic, and chromophobic adenomas can be distinguished. Acidophilic adenomas were assumed to cause GH overproduction and, consequently, gigantism and acromegaly. Basophilic adenomas were thought to secrete ACTH and were linked to Cushing disease. Chromophobic adenomas were considered endocrinologically inactive tumors not associated with hormone excess. However, it has been clearly shown that acido-philic adenomas can synthesize hormones other than GH, such as prolactin, or can be endocrinologically inactive. Some basophilic adenomas represent silent corticotrope cell adenomas unaccompanied by ACTH excess or they produce hormones other than ACTH. Chromophobic adenomas may not be associated with hormone overproduction; however, this is not a general rule because more than half of all chromophobic adenomas are endocrinologically active tumors, secreting GH, prolactin, ACTH, TSH, FSH, LH, or the a subunit. The classification of pituitary adenomas on the grounds of the staining affinities of the cell cytoplasm has limited value because it does not consider hormone production, cellular composition, or cytogenesis, and because it fails to correlate structural features with secretory activity.
Based on size, pituitary adenomas can be divided into microadenomas and macroadenomas. Microadenomas measure <10 mm in greatest diameter and macroadenomas measure >10 mm. This classification is useful because a prognosis can be based on tumor size. Large tumors usually are difficult to remove completely, and recurrences are more frequent than with small, well-demarcated tumors confined to the sella. There are no light or electron microscopic differences between microadenomas and macroadenomas.
Pituitary tumors grow either by expansion or by invasion and can be divided on the basis of growth patterns as follows:
Grade 0: Intrapituitary microadenoma; normal sellar appearance.
Grade 1: Intrapituitary microadenoma; focal bulging of sellar wall.
Grade 2: Intrasellar macroadenoma; diffusely enlarged sella; no invasion.
Grade 3: Macroadenoma; localized sellar invasion and/or destruction.
Grade 4: Macroadenoma; extensive sellar invasion and/or destruction.
Tumors are further subclassified on the basis of their extrasellar extensions, whether suprasellar or parasellar. Pituitary carcinomas (i.e., pituitary tumors with demonstrated metastatic spread) are sometimes designated as Grade 5.
Intrapituitary and Intrasellar Adenomas. Intrapituitary adenomas are confined to the substance of the pituitary; intrasellar adenomas are located in the sella. These adenomas neither erode the sella nor invade parasellar tissue. They grow slowly, are well circumscribed, and are surrounded by a pseudocapsule consisting of condensed reticulin fibers and compressed rows of adenohypophysial cells; they have no fibrous capsule such as benign tumors may have elsewhere.
Diffuse Adenomas. Diffuse adenomas are large and expansive; they may fill the entire sella and cause focal erosion of the sellar wall.
Invasive Adenomas. Invasive adenomas grow more rapidly than do expansive adenomas. They have no sharp borders, they erode the sella and spread into neighboring tissue, they may infiltrate the sphenoid bone and invade the posterior lobe and cavernous sinus, and they may compress the optic nerve and other cranial nerves in the vicinity. Invasive adenomas may spread into the brain, penetrate into the third ventricle, and compress or destroy the hypothalamus and pituitary stalk. The aggressive behavior of invasive adenomas, although frequently translated into diminished surgical cure rates, is generally not reflected in their histologic features. Invasive adenomas exhibiting extreme local aggressiveness frequently maintain a deceptively innocent histologic appearance. In general, the usual morphologic markers of tumor aggressiveness (i.e., pleomorphism, nuclear atypia, increased cellularity, mitotic activity) correlate poorly with the invasive tendency, proliferative capacity, potential for recurrence, or overall biologic behavior of an adenoma.
The incidence of local invasion depends not only on the different pituitary tumor types, but also on how the phenomenon is defined. Depending on the criteria used, invasion can be demonstrated radiologically, intraoperatively, and microscopically in 10%, 35%, and 90% of all pituitary adenomas, respectively.68 Not surprisingly, microscopic evidence of dural invasion increases with tumor size, being evident in 66% of microadenomas, 87% of macroadenomas, and 94% of macroadenomas with suprasellar extension. Because microscopic evidence of dural invasion is so ubiquitous a finding, it is a poor index of tumor aggressiveness. Therefore, it has become common practice to designate adenomas as “invasive” on the basis of radiologic or intraoperative evidence of gross invasion. The frequency of invasion among the various tumor types is presented in Table 11-2.
TABLE 11-2. Size and Frequency of Gross Local Invasion among the Major Pituitary Tumor Types
Because the histopathologic features of pituitary adenomas correlate poorly with their clinical aggressiveness, the development of a reliable and informative strategy to predict their biologic behavior has remained one of the most inscrutable aspects of pituitary tumor biology. During the past decade, numerous strategies have been applied to the problem of predicting the proliferative potential of pituitary adenomas.10 Previously considered to be of research interest only, some of these methods are beginning to reach levels of clinical applicability.
In attempting to distinguish mitotically active pituitary adenomas, which are prone to recurrence, from the more indolent ones, which are amenable to surgical cure, the presence of several cell-cycle–specific proliferation markers has been studied in pituitary adenomas. Two of these, Ki67 and proliferating cell nuclear antigen (PCNA), have been particularly informative from a clinical standpoint. The former is a cell-cycle–specific, nuclear-associated antigen of uncertain function whose expression is restricted to proliferating cells in the G1-to-M phase of the cell cycle. Thus, its immunochemical presence and relative abundance in tumor tissue provides some measure of the proliferative activity of a tumor. In one study, invasive adenomas expressed twice the amount of Ki67 protein as did noninvasive adenomas.69 Subsequent studies of Ki67 expression using MIB-1, an antibody that recognizes the Ki67 on better preserved and formalin-fixed preparations, have expanded our understanding of the cell kinetics of pituitary tumors.70 Specifically, (a) the growth fractions of pituitary tumors are low, most indices being <5%; (b) mean growth fractions are significantly higher among invasive adenomas and highest among pituitary carcinomas when compared with noninvasive adenomas (4.7%, 11.9%, and 1.4%, respectively); (c) virtually all noninvasive adenomas had growth fractions <3%, whereas those of most invasive adenomas and pituitary carcinomas were higher; and (d) the growth fraction of hormonally active pituitary tumors was significantly higher than that of endocrinologically inactive pituitary adenomas. Although these data suggest that a significant correlation does exist between Ki67 expression and pituitary tumor behavior, all reports to date have been retrospective in nature. Accordingly, prospective studies will be required to determine the long-term prognostic significance of this marker.
PCNA is a critical accessory protein of the enzyme DNA polymerase-d. The former is an essential component of the replicon, the multimeric complex that polymerizes DNA nucleotides during leading-strand DNA replication just before cell division. Therefore, the nuclear expression of PCNA is a requirement for all replicating cells. PCNA expression has been studied in a large group of pituitary adenomas of all sizes and various immunotypes, including nonrecurrent and recurrent tumors.71 The expression of PCNA was significantly higher among recurrent pituitary adenomas than among nonrecurrent ones. Furthermore, the PCNA index was higher in larger tumors, particularly those exhibiting extrasellar extension. Among recurrent tumors, a higher PCNA index tended to be accompanied by a shorter disease-free interval.
Flow cytometric analysis, although prognostically informative for many human epithelial malignancies, has been less than enlightening when applied to pituitary adenomas.23 Although ploidy analyses have shown many pituitary adenomas to have either diploid or aneuploid complements, neither have been reliably correlated with the invasiveness or potential for recurrence of an adenoma. Similarly, S-phase fractions of pituitary adenomas, as determined by flow cytometry, do not appear to be prognostically informative. The S-phase fraction of cycling cells also has been determined in situ after the in vivo administration of bromodeoxyuridine (BrDU), a thymidine analog. The incorporated BrDU in cycling cells is revealed by immunohistochemistry analysis using an anti-BrDU antibody. Because pituitary adenomas have relatively low proliferation rates overall, the S-phase fractions usually are small, generally <0.5%. The consistent finding that tumors associated with Nelson syndrome have the highest S-phase fractions validates the aggressiveness observed clinically in this group of tumors. The narrow range of observed S-phase fractions in pituitary adenomas overall, however, limits the sensitivity of this technique in distinguishing subtle differences in S-phase fractions between aggressive and nonaggressive pituitary adenoma variants.
Carcinoma of the Pituitary Gland. Despite their epithelial nature and the regularity with which many pituitary adenomas exhibit aggressive local behavior, it remains a mystery why so few are capable of metastatic dissemination. Metastasizing pituitary tumors of adenohypophysial origin (i.e., pituitary carcinomas) are rare. A recent review identified 52 cases of pituitary carcinoma to which 12 new cases were added.72 Pituitary carcinoma is a precisely defined entity that includes only those tumors of adenohypophysial type with demonstrated craniospinal or systemic metastases.1,10 In contrast to most human carcinomas, the usual histologic markers of malignancy (nuclear atypia and pleomorphism, mitotic activity, necrosis, hemorrhage, invasiveness) are insufficient to permit an unqualified diagnosis of pituitary carcinoma; these features are commonly seen in ordinary pituitary adenomas. Instead, the diagnosis is predicated on tumor behavior, being relatively independent of histologic features. Among reported cases of pituitary carcinoma, metastatic dissemination most often involved the cerebrospinal fluid axis. Numerous extraneural metastatic sites have also been reported, including bone, liver, lymph nodes, lung, kidney, and heart.
Pituitary carcinomas primarily affect adults, although their clinical presentation is variable. In some patients, the initial course is indistinguishable from that of a benign pituitary adenoma. Local invasion is variably present, and the histologic characteristics of the tumor may be entirely benign. A protracted course, often punctuated by multiple local recurrences, is then followed by metastatic dissemination. In many such cases, a clear escalation in histologic abnormalities is observed when primary tumors are compared with metastatic deposits. In this setting, the process appears to be one of malignant transformation in a preexisting benign adenoma. Alternatively, the behavior of other pituitary carcinomas is indicative of de novo malignancy. Such tumors are biologically malignant from the onset, beginning as rapidly growing, relentlessly invasive, cytologically atypical tumors that promptly give way to metastatic dissemination.
Although both hormonally active and nonfunctioning pituitary carcinomas have been described, the former appear to pre-dominate. Pituitary carcinomas composed of ACTH cells (particularly in the context of Nelson syndrome), prolactin cells, and GH cells are most frequently represented. As a rule, metastatic deposits should retain the immunotype of the primary tumor. Because the pituitary is often the recipient of metastatic carcinomas originating systemically, the far more common occurrence of metastatic deposits to the pituitary must be excluded by careful clinical and pathologic examination before arriving at a diagnosis of primary pituitary carcinoma.
The factors that underlie the capacity for metastatic dissemination in pituitary carcinomas remain obscure. Their mode of spread, however, is more fully understood. Craniospinal involvement appears to begin with invasion of the subarachnoid space and eventual dissemination by cerebrospinal fluid flow. Intracranial deposits involving brain parenchyma likely develop as the result of tumor permeation into perivascular (Virchow-Robin) spaces or by venous sinus invasion. Extracranial spread of pituitary carcinomas involves both hematogenous and lymphatic routes. Invasion of the cavernous sinus provides the necessary venous access for transport of tumor cells to the internal jugular vein through the petrosal system. Whereas the pituitary lacks lymphatic drainage, invasion of the tumor into the skull base provides access to the rich lymphatic network, permitting systemic dissemination. Death from pituitary carcinoma usually is the consequence of extensive intracranial disease and not the result of extraneural deposits per se. Because neither the presence nor the treatment of systemic metastases appears to alter the prognosis of pituitary carcinomas, the frequency of metastases, particularly nonfunctioning ones, is likely underreported.
CLASSIFICATION OF PITUITARY ADENOMAS BY HORMONE PRODUCTION1,2,10
Pituitary adenomas can be classified according to hormone production, on the basis of clinical presentation and blood hormone levels as assessed by radioimmunoassay. Thus, functioning adenomas, which produce GH, prolactin, ACTH, TSH, FSH, LH, or the a subunit, can be distinguished clinically from non-functioning adenomas, which are not associated with hormone excess. It is evident that all known adenohypophysial hormones can be secreted by pituitary adenoma cells.
A unifying pituitary adenoma classification encompasses histologic, immunocytochemical, and ultrastructural features of tumor cells and emphasizes the importance of hormone production, cellular composition, and cytogenesis. Such a classification stresses structure–function relationships and correlates the morphologic appearance of adenoma cells with their secretory activity.
All known adenohypophysial cell types can give rise to adenoma. The prevalence of each type is as follows: prolactin cell adenoma, 26%; null cell adenoma, 17%; GH cell adenoma, 14%; corticotrope cell adenoma, 15%; plurihormonal adenoma, 13%; oncocytoma, 6%; gonadotrope cell adenoma, 8%; and thyrotrope cell adenoma, 1%. The morphologic features of pituitary adenomas can reveal their cellular composition, hormone production, and, in some cases, cytogenesis.
Growth Hormone Cell Adenomas. Growth hormone cell adenomas are associated with elevated blood GH concentrations and acromegaly or gigantism (see Chap. 12). On light. microscopic examination they appear either acidophilic or chromophobic. On electron microscopic examination, acidophilic adenomas are densely granulated, and chromophobic adenomas are sparsely granulated. Separating these two subtypes has practical importance. Densely granulated tumors have a better prognosis; they have a slower growth rate, tend to be easier to remove surgically, and recur less frequently after surgery. The densely granulated adenoma cells resemble GH cells seen in the nontumorous pituitary and are characterized by well-developed, rough-surfaced endoplasmic reticulum, a conspicuous Golgi apparatus, and numerous spherical, evenly electron-dense secretory granules measuring 250 to 650 nm (Fig. 11-7). The cells constituting sparsely granulated adenomas differ from GH cells of the nontumorous adenohypophysis. They possess irregular indented nuclei, rough-surfaced and smooth-surfaced endoplasmic reticulum, a conspicuous Golgi apparatus, several centrioles and cilia, fibrous bodies composed of microfilaments and smooth-walled tubules, and a few spherical, evenly electron-dense secretory granules measuring 100 to 300 nm (Fig. 11-8). No correlation has been noted between serum GH levels and granularity of the cell cytoplasm; both densely and sparsely granulated GH cell adenomas can be associated with markedly or slightly elevated GH levels as well as with severe and rapidly progressing or mild and slowly advancing acromegaly.
FIGURE 11-7. Ultrastructural features of densely granulated growth hormone cell adenoma. Note well-developed, rough-surfaced endoplasmic reticulum (arrows) and numerous large secretory granules. ×5600
FIGURE 11-8. Sparsely granulated growth hormone–producing adenoma with fibrous bodies (arrows). The secretory granules are sparse and small. ×5600
Prolactin Cell Adenomas. Prolactin cell adenomas are associated with hyperprolactinemia, amenorrhea, galactorrhea, and infertility (see Chap. 13). In men, symptoms include decreased libido and impotence. In some cases, endocrine manifestations are subtle or absent, and only local symptoms call attention to a pituitary tumor. Markedly elevated serum prolactin levels (i.e., >150–200 ng/mL) confirm the clinical diagnosis of a prolactin-producing pituitary adenoma.
Prolactin-producing adenomas can occur at any age but most often are diagnosed in young women. Based on surgical material, women are more frequently affected than men, but in unselected adult autopsies, no sex difference can be demonstrated. Since the introduction of bromocriptine therapy, the number of prolactin-producing tumors treated surgically has declined.
Patients with prolactin cell adenomas can be effectively treated with various dopaminergic agonists. Depending on the sex of the patient, the treatment abolishes the amenorrhea, stops the galactorrhea, increases the libido, and cures the infertility (see Chap. 13); serum prolactin levels show a marked decline. The tumor regresses, as assessed by various imaging techniques. Local symptoms, such as visual disturbances, often disappear. The effects of treatment are reversible; if drug administration is discontinued, the tumor regrows, serum prolactin levels rise, and clinical symptoms reappear. As a result of bromocriptine medication, the tumor cells themselves decrease in size, indicating that tumor regression is mainly a result of a reduction in cell volume. In addition to an overall reduction in cytoplasmic volume, there also is a significant reduction in the volume density of the hormone’s synthetic and secretory apparatus (rough endoplasmic reticulum and Golgi complex). Overall, this gives a hypercellular appearance to the tumor. The tumoristatic effects of bromocriptine are especially well visualized by electron microscopic examination, in which cells become irregularly shaped, contain heterochromatic nuclei, and maintain a scant cytoplasm with markedly involuted Golgi complexes. The size and volume density of secretory granules remain unaffected. All these ultrastructural changes are fully reversible on discontinuation of the drug. Prolonged exposure to bromocriptine also may result in fibrotic change within the tumor, an alteration that may adversely complicate surgical extirpation. The presence of cell necrosis after bromocriptine administration also has been reported. Whether bromocriptine is cytotoxic is difficult to assess because foci of necrosis, hemorrhage, and fibrosis may occur in prolactin-producing adenomas without dopaminergic agonist treatment.
HISTOPATHOLOGY. Histologically, prolactin cell adenomas most often are chromophobic or slightly acidophilic, exhibiting distinct prolactin immunostaining in the Golgi complex and secretory granules. On electron microscopic examination, prolactin cell adenomas can be separated into densely granulated and sparsely granulated variants. Densely granulated prolactin cell adenomas are rare. The adenoma cells resemble nontumorous resting prolactin cells and are characterized by prominent rough-surfaced endoplasmic reticulum, conspicuous Golgi complexes, and numerous spherical, oval, or irregularly shaped secretory granules measuring up to 700 nm. Sparsely granulated prolactin cell adenomas are the most frequent tumor type in the human pituitary. The adenoma cells possess a prominent rough-surfaced endoplasmic reticulum, a conspicuous Golgi apparatus, and sparse, spherical, and oval, or irregularly shaped, evenly electron-dense secretory granules measuring 150 to 300 nm (Fig. 11-9). The rough-surfaced endoplasmic reticulum membranes form concentric cytoplasmic whorls, called nebenkerns. Another characteristic ultrastructural feature of prolactin cell adenomas is the presence of misplaced exocytosis—extrusion of secretory granules on the lateral side of the cell, distant from capillaries and intercellular extensions of the basement membrane. Granule extrusion also occurs on the capillary side of prolactin cells.
FIGURE 11-9. Sparsely granulated prolactin cell adenoma with prominent rough-surfaced endoplasmic reticulum membranes (arrows) and misplaced exocytosis (extrusion of secretory granules into the extracellular space, distant from the basement membrane; arrowheads). ×7800
Prolactin cell adenomas may produce an amyloid-like substance and exhibit various degrees of calcification, sometimes so extensive as to be visible with imaging techniques. Amyloid deposition and calcification are characteristic but not pathognomonic; they most frequently occur in prolactin cell adenomas but occasionally may be present in other adenoma types.
Corticotrope Adenomas. Corticotrope adenomas produce ACTH and other peptides of the pro-opiomelanocortin molecule, such as b-LPH and endorphins. They may secrete hormones excessively and may be associated with Cushing disease or Nelson syndrome (see Chap. 75). In Cushing disease, the excess ACTH stimulates the adrenal cortex and causes various degrees of hypercortisolism. Historically, bilateral adrenalectomy was undertaken because the ACTH-producing pituitary adenoma either was unrecognized or was unsuccessfully treated. With the development of increasingly precise imaging technology and superior microsurgical techniques, bilateral adrenalectomy is now a procedure of last resort that is rarely required in the management of Cushing disease. Accordingly, new cases of Nelson syndrome are becoming increasingly uncommon. When bilateral adrenalectomy is necessary to control refractory Cushing disease, the clinical picture is characteristic. As hypercortisolism regresses, the tumor frequently behaves in a “disinhibited” fashion, tending to grow more rapidly and to produce large amounts of ACTH and other pro-opiomelanocortin–derived peptides. Patients become hyperpigmented, and the tumor tends to be far more aggressive and invasive than are those corticotropic adenomas that have an intact pituitary-adrenal axis. Furthermore, only a few patients with Nelson syndrome are cured by surgery and radiotherapy; up to 20% of these patients succumb to uncontrolled local tumor growth. Such aggressive behavior has been ascribed to the loss of negative glucocorticoid feedback resulting from the adrenalectomy; this suggests that corticotrope adenomas, as a whole, are not entirely autonomous, but are subject to feedback and modulation of their secretory activity and growth rate by glucocorticoid hormones.
Importantly, more than 80% of the adenomas responsible for Cushing disease are microadenomas. Because many are only a few millimeters in diameter, they frequently evade detection, even with the most sophisticated imaging techniques. Given their small size, these tumors present technical difficulties, both to surgeons and to pathologists. From a surgical standpoint, corticotrope microadenomas rarely are situated on the surface of the gland and are exposed only after a thorough dissection of a seemingly normal gland. Most arise in the midline of the pituitary, within the so-called mucoid wedge, an area in which corticotropes are most numerous. The surgical specimen provided to the pathologist frequently is small and fragmented; as a result, considerable patience and skill are required to differentiate adenomatous elements from the normal glandular tissue. Whereas 10% to 15% of microadenomas demonstrate local invasion, fully 60% of macroadenomas are grossly invasive.
HISTOPATHOLOGY. Histologically, corticotrope adenomas usually are basophilic and exhibit various degrees of PAS and lead-hematoxylin positivity. Immunoperoxidase staining reveals ACTH and other fragments of the pro-opiomelanocortin molecule in the cytoplasm of adenoma cells. On electron microscopic examination, adenomatous corticotropes often resemble nonad-enomatous corticotropes; they possess well-developed, rough-surfaced endoplasmic reticulum, prominent Golgi apparatuses, and numerous spherical secretory granules that vary in electron density, often line up along the cell membrane, and measure 250 to 700 nm (Fig. 11-10). In corticotrope adenomas removed from patients with Cushing disease, bundles of microfilaments usually are present, whereas in adenomas removed from patients with Nelson syndrome, microfilaments are inconspicuous or absent. Otherwise, no ultrastructural differences exist between the corticotrope adenomas of patients with Cushing disease and Nelson syndrome.
FIGURE 11-10. Electron microscopic appearance of densely granulated corticotrope cell adenoma. Note the irregular or dented shape of secretory granules and bundles of type I filaments (arrows). ×9800.
A few actively secreting corticotrope adenomas are chromophobic and possess only sparse, fine, PAS-positive cytoplasmic granules. These tumors immunostain for ACTH and related peptides, indicating that they arise in and consist of corticotropes. On electron microscopic examination, chromophobic corticotrope adenoma cells are sparsely granulated and appear less differentiated than their basophilic, densely granulated counterparts. Chromophobic tumors usually are larger, grow faster, tend to be invasive, and recur more frequently than basophilic adenomas, which generally are small, measuring only a few millimeters in diameter.
Silent Corticotrope Adenomas.1,2,10,22 Silent corticotrope adenomas immunostain for ACTH and related peptides but are not associated with clinical or biochemical evidence of ACTH excess. On light microscopic examination, these tumors are basophilic or chromophobic, show various degrees of PAS positivity, and immunostain for ACTH, b-LPH, and endorphins. On electron microscopic examination, silent corticotrope cell adenomas are a heterogeneous group. In some cases, the ultrastructural features of tumor cells are indistinguishable from those of actively secreting tumors, such as are associated with Cushing disease or Nelson syndrome. In other cases, an increase in the size and number of lysosomes, crinophagy (uptake of secretory granules by lysosomes), and marked underdevelopment or involution of the Golgi apparatus suggest a defect in various steps involving hormone synthesis, packaging, or discharge. Two distinct silent corticotrope adenomas, designated silent corticotrope adenomas subtypes I and II, have been identified as specific clinicopathologic entities. A third, no longer considered corticotropic in nature, is designated silent subtype III. For the most part, silent subtypes I through III present clinically as large and invasive nonfunctioning sellar masses.1,17 In some instances, hyperprolactinemia is present, sometimes at a level higher than that attributable to the stalk section effect. Accordingly, it has been suggested that some silent subtypes may facilitate prolactin release from nontumorous lactotropes or are themselves capable of prolactin secretion. These findings are particularly applicable to silent subtype III, a tumor frequently seen in women, and therefore often is diagnosed before operation as a prolactinoma. The reason that some silent subtype III tumors have been responsible for acromegaly remains a total mystery. A peculiarity of silent subtype tumors relates to their propensity to undergo apoplectic hemorrhage. In the experience of the authors, more than 40% of silent subtype adenomas presented in this fashion.22 In all, the silent subtype tumors are enigmatic entities, whose cytogenesis and overall biology warrants further study.
Thyrotrope Adenomas. With fewer than 100 cases reported, TSH-secreting adenomas are the least common pituitary tumor phenotype, accounting for only 1% of all pituitary adenomas. Of reported cases, most thyrotrope adenomas have been large, aggressive macroadenomas, both compressive and invasive of surrounding structures.73 Usually, the accompanying clinical history is remarkable for some form of thyroid dysfunction. It once was believed that most arose in the context of long-standing primary hypothyroidism, presumably by way of feedback inhibitory loss, induction of thyrotrope hyperplasia, and, later, adenoma formation. Although such a perspective was compatible with earlier experimental studies in which thyroidectomy induced pituitary thyrotrope adenomas in rodents, careful clinicopathologic correlations of human thyrotrope adenomas indicate an alternate sequence of likely events.10,23 In many patients, the initial manifestations appear to be those of hyperthyroidism and goiter, events wholly compatible with TSH hypersecretion by the tumor. Because secondary (i.e., pituitary-dependent) hyperthyroidism previously was not a well-recognized condition, many such patients were incorrectly thought to have primary hyperthyroidism and were subjected to some form of thyroid ablation. This served to ameliorate symptoms, but sometimes was followed later by accelerated tumor growth, optic nerve compression, or recurrence of the hyperthyroid state. Only then was the pituitary correctly identified as the site of pathologic involvement. The invasive nature of these tumors appears to be related to two factors, the first of which is the typical diagnostic delay. A more cogent factor, however, is the loss of feedback inhibition. In the same way that endorgan ablation contributes to tumor aggressiveness in the context of Nelson syndrome, similar disinhibiting influences may be operative in the progression of TSH adenomas in the setting of prior thyroidectomy. The routine availability of sensitive TSH assays coupled with general awareness of the thyrotrope adenoma as a potential, though rare, cause of hyperthyroidism should permit more expeditious diagnosis of this tumor type, perhaps while it is still in the microadenoma stage.67 Furthermore, thyrotrope adenomas commonly cosecrete in excess a free a subunit that, if present, may be a helpful diagnostic clue suggesting a pituitary source over a primary thyroid cause of hyperthyroidism (see Chap. 15 and Chap. 42).
HISTOPATHOLOGY. On light microscopic examination, thyrotrope adenomas are chromophobic, containing a few small cytoplasmic granules mainly at the cell periphery that stain for PAS, aldehyde fuchsin, and aldehyde thionin. TSH can be demonstrated immunocytologically in the cytoplasm of the adenoma cells. Occasionally, immunostaining shows only slight or no TSH immunopositivity, suggesting that little hormone is stored in the cytoplasm or that abnormal TSH is produced that is not immunoreactive but may have bioactivity. On electron microscopic examination, thyrotrope adenomas consist of elongated, angular, or irregular cells with long cytoplasmic processes, scanty rough-surfaced endoplasmic reticulum, an inconspicuous Golgi apparatus, and numerous microtubules. Secretory granules are sparse and spherical, vary slightly in electron density, line up along the cell membrane, and measure 50 to 200 nm. Thyrotrope adenomas often differ in their ultra-structural appearance from nontumorous thyrotropes. In some cases, they consist of highly differentiated thyrotropes with an abundant, slightly dilated, rough-surfaced endoplasmic reticulum, a conspicuous Golgi apparatus, and varying numbers of secretory granules in the range of 50 to 250 nm.
Gonadotrope Adenomas. Gonadotrope adenomas produce FSH, FSH and LH, or, rarely, LH alone. They are identified more frequently in older patients. The clinical manifestations of gonadotrope cell adenomas are not clearly defined; patients may show varying degrees of hypogonadism, decreased libido, impotence, and elevated serum FSH/LH concentrations.
HISTOPATHOLOGY. On light microscopic examination, gonadotrope adenomas appear chromophobic and may contain sparse PAS-positive cytoplasmic granules. Immunostaining reveals FSH, LH, or both in the cytoplasm of adenoma cells. On electron microscopic examination, sexual dichotomy is evident. In men, adenomatous gonadotropes usually are less differentiated and have a few rough-surfaced endoplasmic reticulum membranes, a moderately developed Golgi apparatus, several microtubules, and sparse, spherical secretory granules that vary slightly in electron density, line up along the cell membrane, and measure 100 to 300 nm. In women, adenomatous gonadotropes are more differentiated and resemble their non-tumorous counterparts. The prominent honeycomb-like Golgi complex consists of several dilated sacculi and vesicles containing a few immature secretory granules. Secretory granules are sparse and randomly distributed, vary slightly in electron density, and measure 50 to 150 nm.
Null Cell Adenomas. Null cell adenomas have no histologic, immunocytologic, or electron microscopic markers and are not associated clinically and biochemically with any known hormone excess. Although these tumors are endocrinologically inactive and contain no known hormones, they possess the organelles necessary for hormone secretion and have secretory granules.1 It may be that these tumors produce biologically inactive hormone fragments, precursor molecules, or hormones unidentified at present.
Together, null cell adenomas and their oncocytic variants (discussed later) account for almost one-fourth of all pituitary adenomas. Both are nonfunctioning sellar masses and are typically seen during middle or old age. They tend to be slow-growing lesions, with some likely growing for years subclinically before manifesting themselves clinically. Despite the regularity with which these tumors are encountered in clinical practice, and the fact that their existence has been known for almost two decades, fundamental questions concerning their causation, cytogenesis, and biology remain unanswered.2,10,74 That these tumors frequently share morphologic similarities with undifferentiated gonadotrope adenomas has fueled speculation that null cell adenomas may be neoplastic offshoots of gonadotropic lineage. Compelling support for such a notion was provided by the finding that 80% of null cell adenomas and oncocytomas express glycoprotein hormone genes.10 Furthermore, both gonadotropin release and gonadotropin-releasing hormone responsiveness have been demonstrated in null cell adenomas maintained in tissue culture. Alternatively, there is preliminary evidence favoring the existence of nonneoplastic null cells scattered throughout the normal pituitary.75 It is speculated that such “normal” null cells may be transitional, undifferentiated, or precursor cells that are capable of shifting from hormonally inactive to hormonally active states. Should null cells be validated as cellular constituents of the normal pituitary, null cell adenomas could be envisioned as their neoplastic derivatives.
HISTOPATHOLOGIC CHARACTERISTICS. On light microscopic examination, null cell adenomas are chromophobic; immunocytologically, they contain no adenohypophysial hormones. In many tumors, however, small groups of adenoma cells or randomly scattered individual cells immunostain for one or more pituitary hormones, most frequently FSH or the a subunit, less frequently TSH, LH, and prolactin, and occasionally GH or ACTH. Consistent with these findings, in vitro studies reveal that most null cell adenomas produce FSH, TSH, LH, or the a subunit; these hormones can be demonstrated by radioimmunoassay in tumor culture. It is not clear whether this means multidirectional differentiation from an uncommitted precursor, tumor cell heterogeneity, or gradual dedifferentiation. On electron microscopic examination, null cell adenomas are characterized by closely apposed, polyhedral or irregularly shaped cells with pleomorphic or indented nuclei and poorly developed cytoplasm possessing a few rough endoplasmic reticulum profiles, a moderately developed Golgi apparatus, and microtubules, which may be abundant in some cells. The secretory granules are sparse and spherical, vary slightly in electron density, line up along the cell membrane, and measure 100 to 200 nm (Fig. 11-11). Oncocytic transformation (i.e., the increase of cytoplasmic volume occupied by mitochondria) is common in null cell adenomas.
FIGURE 11-11. Null cell adenoma. The small adenoma cells contain poorly developed cytoplasmic organelles and sparse, small secretory granules. ×9800
Because of the lack of endocrine symptoms, some null cell adenomas are recognized only when they enlarge and spread outside the sella, causing local symptoms such as visual disturbances, headache, or injury of cranial nerves.
Oncocytomas. Oncocytomas represent the oncocytic variant of null cell adenomas. The term oncocytosis is used to describe tumor cells that exhibit intracellular mitochondrial accumulation. Thus, oncocytomas differ from null cell adenomas only insofar as the cells of the former contain massive numbers of large mitochondria. Both tumors share a similar clinical profile that is dominated by the neurologic and endocrinologic sequelae of an expansile, nonfunctioning sellar mass. Like null cell adenomas, oncocytomas are unaccompanied by clinical or biochemical evidence of oversecretion of adenohypophysial hormones, have no morphologic markers that would reveal their cytogenesis, occur most frequently in older men and women, and are rarely diagnosed in patients younger than 40 years.
HISTOPATHOLOGY. On light microscopic examination, oncocytomas are chromophobic or acidophilic. The acidophilia is not the result of staining of secretory granules but of the uptake of acid dyes by accumulating mitochondria. Immunostaining of oncocytoma cells fails to demonstrate pituitary hormones. In many cases, however, small groups of adenoma cells or randomly scattered individual cells immunostain for FSH, the alpha subunit, LH, or TSH, indicating that oncocytoma cells do not lose their potential to produce hormones or that they can differentiate to a hormone-producing cell line. Electron microscopic examination reveals abundant cytoplasmic mitochondria (Fig. 11-12), which may be extensive, filling as much as 50% of the cytoplasm (compared with ~8% normally). In some tumors, a transition can be seen between null cell adenoma and oncocytoma. The authors use the term oncocytoma only when abundant mitochondria are evident in practically every adenoma cell.
FIGURE 11-12. Pituitary oncocytoma showing abundance of mitochondria. ×7000
Plurihormonal Adenomas. Plurihormonal adenomas produce more than one hormone and can be divided into monomorphous and plurimorphous types. Monomorphous plurihormonal adenomas consist of one morphologically distinct cell type that produces two or more hormones; the cell may differ morphologically from known adenohypophysial cells. Plurimorphous plurihormonal adenomas are composed of two or more morphologically distinct cell types, each producing different hormones; they are similar in ultrastructural appearance to their nontumorous counterparts. Immunocytologic techniques are required to establish the diagnosis. Electron microscopic examination may fail to reveal the cellular origin of the adenoma because ultrastructural features may not be distinct or the tumor may consist of cells not recognized in nontumorous adenohypophyses.
In the experience of the authors, 12% of surgically removed pituitary adenomas are plurihormonal. The most frequent hormonal combination produced is GH and prolactin. Three morphologically distinct adenoma types produce GH and prolactin simultaneously: acidophil stem cell adenoma, mammosomatotrope adenoma, and mixed GH cell–prolactin adenoma.
ACIDOPHIL STEM CELL ADENOMAS. Acidophil stem cell adenomas grow rapidly, often spreading into neighboring tissues. They are associated with various degrees of hyperprolactinemia. In some patients, clinical features of acromegaly may be apparent despite normal serum GH levels. Acidophil stem cell adenomas are monomorphous, bihormonal tumors that consist of one cell type, which is assumed to represent the common progenitor of GH cells and prolactin cells. Immunocytologic techniques demonstrate both prolactin and GH in the cytoplasm of the same adenoma cells. Immunostaining for GH often is weak or absent. On electron microscopic examination, acidophil stem cell adenomas are composed of closely apposed elongated cells with irregular nuclei and well-developed cytoplasm containing dispersed, short profiles of rough-surfaced endoplasmic reticulum, an inconspicuous Golgi apparatus, fibrous bodies containing microfilaments and smooth-walled tubules, multiple centrioles and cilia, and sparse, irregular secretory granules measuring 100 to 300 nm. Some exocytosis may be evident. Oncocytic change and mitochondrial gigantism occur in most tumors. The correlation between tumor size and blood prolactin concentrations, which is apparent in patients with sparsely granulated prolactin cell adenomas, is often absent in patients with acidophil stem cell adenomas; relatively large tumors may be accompanied by only slight or moderate hyperprolactinemia.
MAMMOSOMATOTROPE CELL ADENOMAS. Mammosomatotrope cell adenomas are slowly growing tumors accompanied by elevated serum GH concentrations, acromegaly, and, in some cases, mild hyperprolactinemia. These monomorphous, bihormonal tumors consist of acidophilic cells. Immunocytologic methods demonstrate GH and prolactin in the cytoplasm of the same adenoma cells. On electron microscopic examination, the adenoma cells appear to be well differentiated and resemble densely granulated GH cells. The secretory granules are often irregular; they may be evenly electron dense or have a mottled appearance, and they measure 200 to 2000 nm. Exocytosis and large extracellular deposits of secretory material are characteristic features.
MIXED GROWTH HORMONE CELL–PROLACTIN CELL ADENOMAS. Mixed GH cell–prolactin cell adenomas are associated with elevated serum GH levels, acromegaly, hyperprolactinemia, and, occasionally, galactorrhea, amenorrhea, decreased libido, and impotence. These bimorphous, bihormonal tumors are composed of two morphologically distinct cell types: densely or sparsely granulated GH cells and prolactin cells. The two cell types form small groups; in several areas, individual cells are interspersed. Immunostaining demonstrates GH and prolactin in the two different cell populations. Electron microscopic examination shows two morphologically distinct cell types. Every combination may occur; most frequently, densely granulated GH cells and sparsely granulated prolactin cells are identified.
UNUSUAL PLURIHORMONAL ADENOMAS. Occasional, unusual plurihormonal pituitary adenomas produce bizarre combinations of two or more hormones, such as GH and TSH; prolactin and TSH; GH, prolactin, and TSH; and, less frequently, GH, prolactin, and ACTH, or GH, prolactin, FSH/LH, and the a subunit. Such tumors may be monomorphous or plurimorphous. The cell type or types constituting the tumors often cannot be identified, even with detailed electron microscopic investigation. In a few cases, however, two or more ultrastructurally distinct cell types resembling their nontumorous counterparts can be recognized. The hormone content and ultrastructural features of adenomas cannot always be correlated.
On light microscopic examination, the unusual plurihormonal adenomas consist of chromophobic, acidophilic, or basophilic cells, or a mixture of cells that stain differently with different histologic techniques. Clinically and biochemically, the secretion of several hormones may be apparent; acromegaly may be accompanied by hyperthyroidism, hypercorticism, or hyperprolactinemia. Some components may be silent. Immunostaining demonstrates hormones in the cell cytoplasm, but hormone production is not always reflected in hypersecretory symptoms clinically, or in increased serum hormone levels.
Plurihormonal adenomas, which are difficult to classify, clearly show that the one cell–one hormone theory, which has dominated pituitary cytophysiology and cytopathology for many years, is oversimplified and requires revision.
Beyond the conceptual importance underlying the phenomenon of plurihormonality is a potentially important clinical issue. Although unproven, there is some suggestion that some plurihormonal tumors behave more aggressively than do their monohormonal counterparts.10,75,76 In the case of other endocrine tumors (e.g., pancreatic tumors, medullary carcinoma of the thyroid), plurihormonal tumors are thought to portend a more malignant course than that of monohormonal tumors. Evidence in support of a similar occurrence in the pituitary remains inconclusive. It is known, however, that most plurihormonal pituitary adenomas are macroadenomas at presentation, even in the presence of a hypersecretory syndrome. Further-more, ~50% of all plurihormonal pituitary adenomas are grossly invasive at the time of diagnosis.76
MALIGNANT PITUITARY LESIONS
PRIMARY MALIGNANT NEOPLASMS
Primary malignant neoplasms of the hypophysis include carcinomas and sarcomas; they are extremely rare.
Primary Adenohypophysial Carcinomas. Primary adenohypophysial carcinomas, which are derived from anterior pituitary cells, may secrete GH, prolactin, or ACTH or may not be associated with hormone production. They are rare and were discussed earlier. Electron microscopic and immunocytologic studies fail to distinguish between benign and malignant tumors.
Sarcomas. Sarcomas of the adenohypophysis include fibrosarcoma, osteosarcoma, and undifferentiated sarcoma. With few exceptions, virtually all have occurred after radiotherapy for either pituitary adenoma, craniopharyngioma, or retinoblastoma. Fibrosarcomas, in particular, are most commonly the consequence of radiotherapy to a pituitary adenoma. Histologically, these tumors exhibit marked cellular and nuclear pleomorphism, replete with mitotic figures, areas of necrosis, and hemorrhage. In many instances, the sarcomatous component can be seen to be intimately admixed within the substance of a persistent pituitary adenoma. Thus, it has been suggested that radiotherapy induces fibrosarcoma formation by transforming fibroblastic elements within the original adenoma. The latency period for sarcomatous transformation is variable; an average period of 11 years has been reported.10,19 Postirradiation sarcomas are virtually always high-grade malignancies typified by rapid growth, relentless local invasion, and a survival period rarely exceeding a few months.
Secondary neoplasms of the pituitary most often are found incidentally at autopsy and are not associated with clinical symptoms or biochemical abnormalities. They occur in 1% to 5% of patients with cancer. The most commonly observed endocrine abnormality is diabetes insipidus (see Chap. 26), which occurs in patients with metastatic carcinoma of the posterior lobe, hypophysial stalk, or hypothalamus. Compression or destruction of the production site of hypothalamic releasing and suppressing hormones or interference with adenohypophysial blood flow (either by blocking transport of hypothalamic hormones to the adenohypophysis or by inducing ischemia) also may account for the development of endocrine symptoms. Local symptoms may be apparent; however, anterior hypopituitarism is rare because a substantial part of the adenohypophysis must be destroyed before a decrease in adenohypophysial hormone secretion becomes manifest clinically and biochemically. Hypophysial metastases usually occur at an advanced stage of neoplastic disease, when the malignant process involves several organs. Affected patients rarely live long enough to develop anterior hypopituitarism. Only rarely are symptoms of pituitary metastases the first manifestation of a systemic malignancy.77
Hypophysial metastases may come from different primary sources, such as carcinomas of the bronchus, colon, prostate, larynx, or kidney; malignant melanoma; sarcomas; and hematologic malignancies. In the last of these categories, plasmacytoma is notorious for its periodic presentation in the sellar region. Many plasmacytomas of the sellar region have occurred in the absence of known systemic disease, presenting as seemingly ordinary pituitary adenomas. Regardless of therapy, most eventually evolve into full-blown multiple myeloma. For women, carcinoma of the breast is the most common primary lesion that metastasizes to the pituitary. In men, carcinoma of the lung is the most culpable primary tumor.
Metastases to the posterior lobe are more frequent than to the anterior lobe, presumably because the posterior lobe has a rich direct arterial blood supply. Metastatic tumor deposits usually occur first in the pituitary stalk or posterior lobe and permeate the anterior lobe, either by direct extension from the hypophysial stalk or posterior lobe, or through the portal circulation, by long or short portal vessels. However, isolated metastases may occur in the anterior lobe, indicating that the secondary tumor in the adenohypophysis is not invariably the result of prior involvement of the posterior lobe and hypophysial stalk; in the genesis of adenohypophysial metastases, routes other than the portal circulation must be considered. Tumor cells may also spread from perihypophysial tissues to the pituitary.
In patients with disseminated carcinomatosis, infiltration of long portal vessels by carcinoma cells leads to vascular occlusion and subsequent ischemia, causing adenohypophysial infarcts. The necrotic foci are not large enough to cause hypopituitarism.
Craniopharyngiomas are histologically benign tumors that are thought to arise from remnants of the Rathke pouch. Such embryonic squamous cell “nests” extend from the tuber cinereum to the pituitary gland, presumably along the track of an incompletely involuted hypophysial-pharyngeal duct. By virtue of their location, craniopharyngiomas simultaneously compromise the function of several intracranial structures and produce numerous clinical effects, including vision loss, anterior and posterior pituitary dysfunction, and increased intracranial pressure. Despite their “benign” nature, craniopharyngiomas can offer considerable resistance to successful treatment.
Craniopharyngiomas account for ~3% of intracranial tumors. They primarily affect children, for whom they represent the most common nonglial brain tumor and 10% of all intracranial neoplasms. The age-related incidence of craniopharyngiomas is bimodal, with a major, early peak between 5 and 10 years of age, and a second, smaller peak between 50 and 60 years of age. A slight male preponderance has generally been noted.
Topologically, most craniopharyngiomas are suprasellar in location. Those so situated can compress the optic apparatus, cause hydrocephalus by indenting the third ventricle, encroach on hypothalamic structures, distort the infundibulum and pituitary, and penetrate cerebrospinal fluid spaces to gain access to the middle and posterior cranial fossae. Twenty percent of craniopharyngiomas originate within the sella, producing sellar enlargement in a fashion similar to that produced by pituitary adenomas. Almost half of all craniopharyngiomas are cystic, 15% are solid, and the remainder are made up of both solid and cystic elements. Although generally well circumscribed, craniopharyngiomas are not encapsulated lesions and therefore are often tenaciously adherent to basal neural and vascular structures. It is this feature of craniopharyngiomas that frequently undermines successful attempts at a safe and curative resection.
There has been an increasing tendency to view craniopharyngiomas as being either classically adamantinomatous or papillary in nature, which is a distinction that some believe to be of clinical, pathologic, and prognostic significance.78,79
Adamantinomatous Craniopharyngioma. Adamantinomatous craniopharyngioma represents the classic cystic craniopharyngioma of childhood. It frequently is a bulky, partially calcified tumor that tenaciously insinuates itself around basal brain structures. On gross sectioning, it oozes a viscid admixture of shimmering cholesterol crystals and calcific desquamated debris that, in appearance and consistency, often is described as “machinery oil.” On light microscopic examination, this variant exhibits an intricate pattern of epithelial growth, including intermixed islands of solid and cystic epithelium within a matrix of variably cellular connective tissue. Nests or cords of columnar and squamous epithelial cells can be demonstrated. Lymphocytes, macrophages, clusters of foamy cells, cholesterol crystals, keratin deposits, necrotic debris, and polymorphonuclear leukocytes often are present. Calcification, ranging from areas visible only with a microscope to palpable concretions, is common. Rarely, frank bone formation may be present. Cyst formation is presumably the result of degeneration of squamous cells, accumulation of keratinous debris, and perivascular stromal degeneration. The results of immunohistochemical studies are conclusively negative for adenohypophysial hormones, indicating that craniopharyngiomas do not originate in adenohypophysial cells and are not capable of hormone production. The results of immunostaining for keratin are positive. Electron microscopic examination shows bundles of tonofilaments, prominent desmosomal attachments, and an absence of secretory granules (Fig. 11-13).
FIGURE 11-13. Epithelial component of craniopharyngioma showing tonofilaments (arrows) and absence of secretory granules. ×8000
Papillary Craniopharyngioma. The clinical, radiologic, and pathologic profile of papillary craniopharyngioma deviates considerably from that of the conventional adamantinomatous variant.78,79 Accounting for ~10% of all craniopharyngiomas, the papillary variant occurs almost exclusively in adults. It usually is suprasellar in location and frequently involves, or arises within, the third ventricle. Most papillary variants are solid or have only a relatively minor cystic component. Papillary craniopharyngiomas are more discretely circumscribed than classic craniopharyngiomas and lack the calcification and “machinery oil” content so typical of adamantinomatous tumors. Liquid contents, although rarely present, generally are clear. Lacking tenacious adhesions to basal brain structures, the papillary craniopharyngioma is reputed to be more readily separable from surrounding structures. Histologically, it consists of a well-differentiated, albeit less complex, epithelial pattern than that of the adamantinomatous variant. Prominent, stratified, squamous-lined papillae, devoid of columnar palisading, microcystic degeneration, calcification, keratinous nodules, and cholesterol clefts, are characteristic. Whereas the papillary variant is regarded by some as being more amenable to complete and curative resection, not all are in agreement with this view.78,79,80 and 81
Both forms of craniopharyngioma are histologically benign. Mitotic figures and other features of histologic aggressiveness generally are not seen. Despite their histologic benignity, craniopharyngiomas, particularly the adamantinomatous type, are notorious for their high rate of postoperative recurrence. Even among tumors resected radically, a procedure sometimes accompanied by considerable functional deficit, recurrence rates as high as 25% have been reported. For lesser degrees of resection, recurrence of symptoms is virtually guaranteed, often within 3 years of surgery. Radiotherapy for incompletely excised lesions has proved effective in forestalling recurrence (see Chap. 22). Malignant transformation is exquisitely rare; only a single case of malignant craniopharyngioma has been described.
Craniopharyngiomas, both adamantinomatous and papillary, have been shown to express estrogen receptor mRNA and protein. The significance of this finding remains to be determined.82
Rathke Cleft Cysts. Rathke cleft cysts are epithelial cysts apparently derived from remnants of the Rathke pouch. At autopsy, roughly one-fifth of pituitaries contain macroscopic remnants of the Rathke pouch in the form of discontinuous cystic remnants or microscopic clefts at the interface of the anterior and posterior lobes. Occasionally, these Rathke cleft remnants, as the result of progressive accumulation of colloidal secretions, become sufficiently large and compress surrounding structures. Most cases involving symptoms present as expansile intrasellar masses, occasionally having a suprasellar component. Only exceptionally are they entirely suprasellar in location. Local compressive effects are the basis for presentation in most cases involving symptoms, with headache, hypopituitarism, hyperprolactinemia, visual disturbance, and, rarely, diabetes insipidus being the principal clinical features.83
Rathke cleft cysts are thin-walled, uniloculate, and filled with fluid, the composition of which ranges from watery to mucinous. The cyst wall frequently is composed of a single layer of cuboidal or columnar, ciliated, or mucin-producing epithelium. Small numbers of adenohypophysial cells also may be evident. Calcification is rare, as is amyloid deposition. Although the epithelial pattern is considerably less complex than that of craniopharyngioma, the distinction between these two entities occasionally can be troublesome, emphasizing the importance of generous tissue sampling. Rarely, pituitary adenomas can be found to be admixed with elements of a Rathke cleft cyst. Such biopsy results usually represent the simultaneous sampling of two distinct lesions. Even rarer are more complex lesions, in which Rathke cyst components are intimately associated with adenoma and even squamous metaplasia; such lesions have been termed transitional cell tumors of the pituitary. Whether these are distinct clinicopathologic entities or simply the collision of two distinct lesions remains to be determined.
Rathke cleft cysts are definitively treated by drainage and marsupialization of the cyst wall, a procedure that usually results in cure. Recurrences are unusual.
PATHOLOGY OF THE NEUROHYPOPHYSIS AND HYPOTHALAMUS2,4,10,19
Clinically significant diseases of the posterior lobe are rare. Endocrinologically, they can be divided into conditions associated with increased or decreased vasopressin secretion. Several abnormalities are unaccompanied by endocrine alterations.
INAPPROPRIATE SECRETION OF VASOPRESSIN
Inappropriate secretion of vasopressin, or the Schwartz-Bartter syndrome, is the result of vasopressin hypersecretion, either from the posterior pituitary or from extrahypophysial neoplasms (see Chap. 27 and Chap. 219). Renal sodium loss and hyponatremia are characteristic features. Several diseases, including meningitis, myxedema, and cerebral lesions, may be associated with increased vasopressin discharge. Paraneoplastic (“ectopic”) vasopressin secretion may occur in various neoplasms, but is seen mainly in carcinoma of the bronchus. Vasopressin can be extracted from the extrapituitary tumors of patients with vasopressin excess, providing evidence for paraneoplastic (“ectopic”) production of the hormone.
Diabetes insipidus is characterized clinically by polyuria and polydipsia (see Chap. 26). In most cases it is caused by vasopressin deficiency resulting from the destruction of supraoptic and paraventricular nuclei, which is where vasopressin is synthesized, or by organic damage to the hypophysial stalk or posterior lobe, which is the site of vasopressin discharge. Morphologically, various lesions can be seen in the hypothalamus, especially in the nucleus supraopticus or along the supraopticohypophysial tract. Selective destruction of the posterior lobe results in only moderate and temporary polyuria and polydipsia. Causes include lesions resulting from head trauma, transection of the hypophysial stalk, meningoencephalitis, sarcoidosis, granulomas, Langerhans histiocytosis, primary tumors, metastatic carcinomas, lymphomas, and leukemias. Of note, pituitary adenomas, including large and invasive ones, are virtually never accompanied by diabetes insipidus as an initial feature of the tumor. The preoperative presence of diabetes insipidus in association with a sellar region mass argues strongly against a diagnosis of pituitary adenoma, however suggestive the imaging studies may be. In idiopathic diabetes insipidus, no destructive lesions can be recognized grossly in the hypothalamus, hypophysial stalk, or posterior pituitary. Histologically, nerve cells of the supraoptic and paraventricular nuclei may show a marked reduction in number and size and loss of stainable neurosecretory material. Immunostaining demonstrates an absence of vasopressin in the hypothalamus, hypophysial stalk, and posterior lobe.
The renal form of diabetes insipidus (nephrogenic diabetes insipidus) is caused by endorgan failure. Renal tubular cells fail to respond to the antidiuretic effect of vasopressin, resulting in polyuria and polydipsia. No lesions are evident in the hypothalamus, hypophysial stalk, or posterior lobe. Vasopressin synthesis and release are not impaired.
BASOPHILIC CELL INVASION
Basophilic cell invasion of the pituitary is a frequent autopsy finding in older men. It causes no clinical symptoms and cannot be detected by gross examination of the pituitary. Histologically, single or small groups of basophilic cells are seen to creep into the posterior lobe. In some cases, large groups of basophilic cells deeply invade the posterior lobe. The cytoplasm of basophilic cells is PAS-positive and contains ACTH and other fragments of the pro-opiomelanocortin molecule, indicating that these cells are related to corticotropes. However, they differ from the corticotropes located in the anterior lobe: they are smaller and denser, and, except for occasional cases, do not show Crooke hyalinization as a result of cortisol excess. Baso-philic cell invasion is not apparent before puberty and cannot be correlated with any clinical endocrine abnormality. From a practical standpoint, the phenomenon of basophil invasion is important only insofar as its presence in a surgical specimen should not be mistaken for a corticotrope adenoma invading the neural lobe of the gland.
Squamous cell nests, which are glandular structures resembling salivary glands, and focal mononuclear cell infiltration are common incidental findings at autopsy in the posterior lobe and distal end of the hypophysial stalk. Hemorrhages, necroses, and granulomas were reviewed in the discussion on diseases of the anterior lobe.
INTERRUPTION OF THE HYPOPHYSIAL STALK
Interruption of the hypophysial stalk causes distinct changes along the entire supraopticohypophysial tract. Surgical transection or disruption of the hypophysial stalk secondary to head trauma or organic diseases leads to atrophy of the supraoptic and, to a lesser extent, the paraventricular nuclei, as well as the posterior lobe. Various diseases, such as infections, granulomas, sarcoidosis, and neoplasms, can destroy the supraoptic and paraventricular nuclei and disrupt the hypophysial stalk, thereby impairing the innervation of the posterior lobe. Because the normal functional activity of the posterior lobe depends on the integrity of its nerve supply, diabetes insipidus develops in the absence of innervation. Morphologically, the posterior lobe undergoes marked involution; loss of stainable neurosecretory material and hormone content can be demonstrated. On radio-immunoassay, vasopressin concentrations become undetectable; histologically, neurohypophysial tissue is replaced by a fibrous scar. Atrophy of the posterior lobe is noticeable in some cases of anterior hypopituitarism. In postpartum hypopituitarism, atrophy of the supraoptic and paraventricular nuclei and of the hypophysial stalk and posterior lobe may occur.
Neoplasms in the posterior lobe, hypophysial stalk, and hypothalamus are uncommon. Secondary carcinomas were discussed earlier in relation to the anterior lobe.
GRANULAR CELL TUMORS
Granular cell tumors (choristomas, or tumorlets) are the most common primary tumors in the posterior lobe and distal part of the hypophysial stalk. They are found in 1% to 8% of unselected adult autopsies, mainly in the elderly. Usually small (1–2 mm or less), they can be detected histologically. Granular cell tumors are slow-growing, histologically benign, sharply demarcated but unencapsulated nodules that usually are not associated with clinical symptoms or biochemical abnormalities and are recognized incidentally at autopsy. Rare granular cell tumors grow rapidly and become large, causing headaches, vision disturbances, diabetes insipidus, and anterior hypopituitarism.10 Because of increased intracranial pressure or cranial nerve compression, surgical removal of the tumor may be necessary.
Histologically, granular cell tumors consist of loosely apposed, large, spherical, oval, or polygonal cells with eccentric nuclei and abundant, coarsely granular cytoplasm. Numerous large granules that stain strongly with PAS, luxol fast blue, and alcian blue almost fill the entire cytoplasm. On electron microscopic examination, the granules correspond to large, membrane-bound, unevenly electron-dense lysosomes. Immunostains reveal an absence of adenohypophysial or neurohypophysial hormones, but may show S-100 protein in the cytoplasm. Granular cell tumors appear to originate in pituicytes, the special glial cells of the posterior lobe.
Other neoplasms are rare in the posterior lobe. Gliomas may originate in pituicytes of the posterior lobe; their histologic features are identical to those of glial tumors deriving from the central nervous system. Most gliomas involving the posterior lobe originate in the hypothalamus or median eminence and spread downward to the posterior lobe. Diabetes insipidus may develop as a result of massive destruction of the hypothalamus, the hypophysial stalk, or the posterior lobe.
Most gliomas that involve the hypothalamus, stalk, and posterior lobe are low-grade astrocytomas of pilocytic type. Malignant gliomas arising in these structures are extremely rare, most being a long-term complication of radiotherapy for a sellar region tumor. Postirradiation gliomas occurring in the region generally have been either anaplastic astrocytomas or glioblastomas. The mean latency period is ~10 years.19 They invariably are aggressive lesions, with most patients dying within months of the diagnosis.
GANGLIOCYTOMAS (HAMARTOMAS) OF THE SELLAR REGION
Lesions composed of neurons can occasionally form symptomatic masses in the sellar region. In fact, constituting this group are a collection of entities, ranging from simple hypothalamic hamartomatous growths on the one hand, to intriguing intra-sellar neoplasms composed of both neuronal and adenohypophysial elements. As a group, however, they remain unified by their content of fully differentiated ganglion cells that appear mature and are accompanied by neuropil.
The nomenclature surrounding these lesions has been as diverse as it has been confusing, wherein designations such as ganglioneuroma, neuronal hamartoma, gangliocytoma, choristoma, gangliocytoma-pituitary adenoma, pituitary adenoma–adenohypophysial choristoma, and a medley of neologisms of one form or another have been inconsistently, interchangeably, and, at times, arbitrarily applied. Understandably, some of this variation in terminology reflects differing views on the presumed histiogenetic origins of these lesions, an issue that currently is far from settled. It is important to recognize that two topologically distinct variants exist: one arising in the hypothalamus and the second within the sella. Of the former entities that arise in or remain physically attached to the hypothalamus, the term hypothalamic neuronal hamartoma is applied. Of the intrasellar variants, the majority of which are intimately admixed within the substance of a pituitary adenoma, the terms pituitary adenoma-adenohypophysial neuronal choristoma (PANCH)84 or mixed pituitary adenoma-gangliocytoma are applied.85 Both hypothalamic and intrasellar variants are discussed separately.
Hypothalamic Neuronal Hamartoma. Not uncommonly, a well-defined mass composed of mature central ganglionic tissue projecting in the leptomeninges from the base of the brain will be encountered. In fact, when carefully sought, minute, macroscopic and nodular foci of ectopic hypothalamic tissue may be found incidentally in ~20% of random autopsies. This is usually attached to the ventral hypothalamus, the adjacent pia, or on the surface of the proximal posterior cerebral arteries. Although such hamartomatous nodules are clinically insignificant, rarely they may grow to several centimeters in size and compress surrounding structures. Some retain a thick pedicular attachment to the hypothalamus, tuber cinereum, or mammillary bodies, whereas others form a sessile solitary mass.
Most symptomatic examples occur in young males, in whom precocious puberty is the best known manifestation. In some instances, GnRH can be detected immunohistochemically within the neurons of such hamartomas, providing a neuroen-docrinologic basis for accelerated sexual maturation. This is not, however, a universal nor a necessary finding. Precocious puberty in immunonegative cases is presumably the result of hypothalamic compression. Rarely, hypothalamic neuronal hamartomas may produce GHRH and clinical acromegaly on a hypothalamic basis, a condition dubbed hypothalamic acromegaly. In such cases, the pituitary may show either hyperplasia or adenomas of GH-producing cells. In addition to other features of hypothalamic dysfunction (somnolence, hyperphagia, autonomic disturbances, and diabetes insipidus), these tumors are associated with a peculiar form of epilepsy, one characterized by laughing (gelastic seizures).
Grossly, the mass in most symptomatic examples will be only 1 to 2 cm in size and often lies behind the pituitary stalk. It is pale, of firm consistency, and has homogeneous cut surfaces. Microscopically, the composition of the tissue resembles that of cerebral gray matter, both qualitatively and quantitatively. The neurons can vary in size, shape, and number, and both unipolar and multipolar forms are represented. Overall, these elements fully resemble mature hypothalamic neurons, although they are often disposed in clusters. Both myelinated and unmyelinated fibers course among them, forming compact bundles in some areas. Axonal processes may also appear to form ill-defined tracts, particularly among examples having pedicular attachment to the hypothalamus. In all examples, the neuronal elements are supported by a normal complement of glial cells of different kinds, although a variable amount of fibrillary gliosis may be found.
Immunohistochemical stains reveal a variety of hypothalamic-releasing peptides that normally reside within the cytoplasm of hypothalamic neurons: immunopositivity for GnRH, somatostatin, GHRH, and CRH may be detectable. In most cases, the immunohistochemical presence of these factors is regarded as a physiologic finding, and should not necessarily imply that these lesions are engaged in pathologic hormone hypersecretion. However, in the appropriate clinical context, such as with precocious puberty or the rare instance of acromegaly, the trophic effects of these hormones and their pathologic contribution to the endocrinopathy cannot be dismissed.
If they are symptomatic and surgically accessible, therapy for hypothalamic neuronal hamartomas is directed primarily at relief of the mass effect. When technically feasible, surgical resection has been successful not only in ameliorating mass effects, but also in regressing secondary sexual characteristics in those experiencing precocious puberty and in improving seizure control. For lesions less amenable to total resection by virtue of their deep intrahypothalamic location or other factors limiting surgical accessibility, partial resection may also be of some symptomatic benefit; residual hamartomatous tissue should grow slowly, if at all.
Hypothalamic Hamartoblastoma. A special variant of hypothalamic hamartoma is the hypothalamic hamartoblastoma, which occurs in infants and neonates and is associated with other multiple congenital abnormalities. The most frequent of the co-existing anomalies have included pituitary agenesis; dwarfism; dysmorphic facies; short, broad, or absent olfactory bulbs; hypoplastic thyroid and adrenals; cryptorchidism; various renal and cardiac malformations; anorectal atresia; syndactyly; and short metacarpals. This lethal syndrome is sometimes referred to as the Pallister-Hall syndrome. The hamartomatous lesion in this condition differs in several subtle respects from the more common hypothalamic hamartoma described earlier. As might be expected from the young age of affected patients, the lesion tends to be more cellular and less differentiated than the typical hypothalamic hamartoma found in older patients, hence the designation hamartoblastoma. A process morphologically intermediate between neoplasm and malformation, the hamartoblastoma is composed of ill-defined clusters of uniform, primitive-appearing, immature neurons unassociated with atypia or mitoses; neuronal differentiation appears incomplete.
Intrasellar Adenohypophysial Neuronal Choristoma. The intriguing neoplasm of the sellar region known as an intrasellar adenohypophysial neuronal choristoma, which, for lack of better designations, has previously been known under the terms intrasellar adenohypophysial neuronal choristoma or the intrasellar gangliocytoma. It is a composite neoplasm composed of adenohypophysial cells and ganglion-like cells to which the appellation pituitary adenoma-neuronal choristoma (PANCH) has been applied in an attempt to highlight the duality of its composition.84 In a comprehensive review reiterating the composite neuronal and adenohypophysial nature of this neoplasm, the authors indicated a preference for the appellation “mixed adenoma-gangliocytoma.”85
This lesion, although sharing some histologic similarities with the hypothalamic hamartoma, differs in several topologic and biologic respects. First and foremost, adenohypophysial neuronal choristomas are intrasellar lesions that have no physical attachment to the hypothalamus. Second, they are generally associated with—or more precisely—are intimately admixed with an endocrinologically functioning pituitary adenoma. Accordingly, they are virtually always symptomatic lesions of which the presence is heralded by a hypersecretory state. Finally, the neuronal component of this lesion, like the adenohy-pophysial component, are both genuinely neoplastic in nature.
The basic lesion consists of islands of ganglion-like cells and accompanying neuropil interspersed within the substance of a pituitary adenoma (Fig. 11-14). The ratio of adenohypophysial cells to neuronal elements can vary considerably, but as a rule, both will be strongly represented. The adenohypophysial cells in virtually all instances are chromophobic and sparsely granulated in nature. They may be disposed in nests, sheets, or otherwise scattered among the neuronal elements. With respect to the latter, the ganglion-like cells are of varying size and number, contain an abundant cytoplasm, complete with peripheral Nissl substance and neuronal processes containing Herring bodies. The ganglion cells fully resemble normal hypothalamic neurons.
FIGURE 11-14. Adenohypophysial neuronal choristoma. The specimen is from a patient with acromegaly and a large intrasellar and suprasellar mass that was presumed to be an ordinary growth hormone–secreting adenoma. After transsphenoidal resection, the surgical specimen revealed an adenohypophysial neuronal choristoma intermixed within the substance of a growth hormone–secreting pituitary adenoma. Adenoma cells (arrowhead) intermixed with fully differentiated neurons (arrow) are evident in the specimen. These neurons were shown to contain growth hormone–releasing hormone. Original magnification ×400
Of reported cases, most have occurred in the setting of acromegaly, wherein patients have had the clinical, radiologic, and endocrinologic features of a typical GH-producing pituitary adenoma. On examination of the surgical specimen, a somatotrope adenoma is encountered, invariably of the sparsely granulated type, in which are interspersed varying numbers of neuronal elements, the morphology of which resembles well-differentiated ganglionic cells. Some of these ganglion cells have been found to be immunoreactive for GHRH, whereas others are immunoreactive for somatostatin. Less frequently, the lesion occurs in the setting of Cushing disease, wherein the adenoma is of the corticotropic type accompanied by ganglion cells immunoreactive for CRH. Only rarely is the adenohypophysial tumor a prolactinoma or a clinically nonfunctioning-pituitary adenoma.
Previously, hypotheses concerning the origin of these lesions centered on the seemingly displaced hypothalamic neurons in the pituitary fossa that, as a result of their secretion of trophic factors, might have a paracrine inductive effect on adjacent adenohypophysial cells, stimulating their growth and eventual neoplastic transformation. According to this view, pituitary adenoma formation is regarded as a secondary, downstream event. Subsequently, however, an alternative hypothesis has been proposed that features adenohypophysial cells as the instigators of the process, rather than seemingly passive targets of paracrine effect.84 Supported by compelling morphologic evidence, this hypothesis suggests that pituitary adenoma formation is the primary event, and the ganglionic component of the lesion arises as the consequence of neuronal metaplasia of neoplastic adenohypophysial cells. When subjected to careful ultrastructural study, morphologic changes that are indicative of a metaplastic process beginning in adenohypophysial cells that gradually gives way to cells having intermediate and, eventually, fully neuronal features can be seen. Whereas metaplastic change is a well-known phenomenon in both normal and neoplastic adenohypophysial cells, as it is in other neuroendocrine neoplasms, actual induction of such metaplastic change has yet to be demonstrated experimentally. A third hypothesis is that both adenohypophysial and neuronal components of this tumor arise from a common, but as yet hypothetical, progenitor cell sequestrated in the sella as an embryonal tissue nest.
Because this entity is relatively new, with only small numbers of cases having been collected, and virtually no long-term follow-up data available, it is unclear whether the behavior of these mixed lesions differs significantly from that of the corresponding pituitary adenoma.
The isolated intrasellar gangliocytoma is a lesion unassociated with a pituitary adenoma and anatomically distinct from the hypothalamus.85 Although an adenoma was not found in any of seven cases, three examples were associated either with Cushing disease or with acromegaly, a situation not readily explained by a purely gangliocytic tumor. The authors have not encountered such a pure gangliocytic lesion in the sella, particularly in the setting of a hypersecretory state—when an accompanying pituitary adenoma or hyperplasia has always been present.
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