The pituitary gland is a common substrate for neoplastic transformation, giving rise to approximately 15 percent of all intracranial tumors. It is a composite neuroendocrine structure, consisting of two distinct lobes, each differing in embryonic origin, morphology, function, and pathologic processes.

In addition to tumors of the pituitary proper, neoplasms in the sellar region may derive from any of a variety of meningeal, neural, glial, vascular, osseous, and embryonal elements that converge on the region. Such tumors, though histologically distinct and biologically diverse, frequently masquerade as pituitary adenomas and a preoperative distinction may be difficult to make. Adding further to the differential diagnosis of a sellar mass are a variety of non-neoplastic "tumor-like" inflammatory and miscellaneous conditions, which occasionally cause pituitary enlargement radiographically and almost always cause diagnostic confusion clinically. The differential diagnosis of the many tumors and tumor­like conditions occurring in the sellar region are listed in Table-1.

Because of their numerical predominance and overall clinical significance, the tumors of the anterior pituitary are reviewed in detail. Primary tumors of the posterior pituitary are rarely of neurosurgical concern, and their pathology is only briefly discussed. Craniopharyngiomas represent the other dominant form of sellar region neoplasia, and, accordingly, their histopathology is reviewed. The remaining tumors and tumor-like conditions of the sella are mentioned only for completeness. as they either are exotic rarities or are covered elsewhere.

Nonfunctioning tumors are so designated because they produce neither clinical nor biochemical evidence of hormone excess. More than 20 percent of all pituitary adenomas seem to fall in this category, the predominant types being null cell adenomas, oncocytomas, gonadotrope adenomas, and silent corticotrope adenomas. These non functioning tumors invariably contain cytoplasmic secretory granules, suggesting that they do produce specific substances, be they unidentified hormones, biologically inactive precursors, or hormone fragments. Some of these hormonally silent tumors are revealed by immunohistochemistry to contain hormones, but they appear to be incapable of discharging these hormones in sufficient quantities to disturb endocrine equilibrium. Molecular techniques (in situ hybridization and Northern blot analysis) have confirmed that many nonfunctioning tumors, although incapable of producing measurable hormone elevations in the blood, do indeed transcribe the genes for anterior pituitary hormones, primarily for glycoprotein hormones and, less often, for other anterior pituitary hormones. The "nonfunctioning" status of these endocrine-inactive tumors has been further challenged by a variety of in vitro techniques. A number of tissue culture studies have confirmed that nonfunctioning tumors are not hormonally inert; indeed, they are capable of low-level hormone release, and many retain responsiveness to a variety of stimulatory and suppressive agents. Considering that nonfunctioning tumors represent at least one-fifth of all pituitary tumors, much remains to be learned about their cellular origins, functionality, and overall biology.

Classification of pituitary adenomas according to their morphologic features (Tables-4 and 5) has undergone a substantial change. On the basis of the staining properties of the cell cytoplasm, pituitary adenomas were previously defined as one of three morphologic entities: chromophobic, acidophilic, and basophilic adenomas. Chromophobic adenomas were assumed to be endocrinologically inactive tumors not capable of secreting hormones. Acidophilic adenomas were thought to secrete GH and to be associated with acromegaly or gigantism. Basophilic adenomas were regarded as ACTH-producing tumors accompanied by Cushing's disease. Since the tinctorial characteristics of adenoma cells cannot be correlated reliably with cell type, secretory activity, or cytogenesis, however, this basis for classification is no longer considered useful.

Progress in methodology, especially the introduction of immunocytology and electron microscopy, has resulted in a new and more meaningful morphologic classification, which separates pituitary adenomas into distinct entities on the basis of hormone content, cellular composition, fine structural features, and cytogenesis.

Immunocytologic procedures make it possible to specifically and reliably demonstrate the hormones present in the cell cytoplasm. The immunoperoxidase technique has proved to be especially valuable; this method can be used on formalin-fixed and paraffin­embedded material; even on pituitary glands harvested at autopsy and stored for several years. At the electron microscopic level, the immunoperoxidase technique can reveal the subcellular sites at which the various hormones are located. Electron microscopy has shed light on the ultrastructural features of the cell; the result has been the distinction of various cell types, the classification of adenomas, and a deeper insight into the details of the secretory process.

More recently, at a time when many thought that the yield from morphologic appraisal of pituitary tumors had peaked, the field of pituitary oncology was rejuvenated with the new and powerful applications of molecular science. The recent interface of molecular technology with conventional pathologic methods has provided novel in sights into some of the most fundamental questions concerning the biology, pathogenesis, and cytogenesis of pituitary tumors. In this regard, the methodologies of in situ hybridization and the polymerase chain reaction have been most informative. The former permits the visualization of mRNAs of interest directly within individual tumors cells, highlighting the differences in the processing, transcription, and expression of various genes that govern the secretory process among different pituitary tumor types. By facilitating the identification of specific genomic alterations within tumor tissue, the polymerase chain reaction has been instrumental in demonstrating certain mutations that may contribute to pituitary tumorigenesis. Although this technology is currently of research interest only. emerging molecular strategies such as these will in the foreseeable future. likely assume increasing importance in precisely classifying and predicting the prognosis of pituitary adenomas.

Pathogenesis and Molecular Biology

Despite decades of thoughtful experimental morphologic and epidemiologic study, the etiologic basis of pituitary tumorigenesis remains uncertain. A genetic predisposition for pituitary tumor development is known only in one uncommon condition. the multiple endocrine neoplasia type- 1 (MEN-1) syndrome. This autosomal dominant disorder is characterized by parathyroid hyperplasia and adenomas and by tumors of the endocrine pancreas and anterior pituitary. The condition has variable penetrance. and only 25 percent of MEN- 1 patients develop pituitary tumors. most of which are macroadenomas associated with GH and/or PRL hypersecretion. The genetic defect in MEN- 1 has been localized to a putative tumor suppressor gene on chromosome 11 (11q 13 ). Susceptible individuals exhibit a hereditary (germ-line) mutation of one of the two 11 q 13 alleles. Subsequent inactivation of the remaining allele in endocrine tissues is thought to initiate tumor formation. Tumor suppressor gene loss at 11q13 seems to be a tumorigenic mechanism primarily applicable to the pituitary adenomas that occur in the context of MEN-1: sporadic pituitary adenomas do not appear to exhibit similar genomic alterations at this locus.

Because only 3 percent of all pituitary adenomas occur in the context of MEN-1, the overwhelming majority of pituitary adenomas can be considered to have a somatic basis. No environmental, pharmacologic, or hormonal agent has been definitely identified as causing the development of pituitary adenomas. Although chronic estrogen administration has been shown to regularly induce PRL­producing adenomas in rats, only once has the inductive effect of estrogens been causally implicated in the genesis of a morphologically proven human prolactinoma.

A fundamental question regarding the pathogenesis of pituitary adenomas is whether transformation in the pituitary is the result of an inductive effect of aberrant hypothalamic trophic influences or simply an acquired intrinsic abnormality of an isolated adenohypophyseal cell. Although hypothalamic dysfunction was historically considered an important initiator or mediator of the tumorigenic process, and this idea continues to have some conceptual and experimental support, compelling evidence of a clinical, pathologic, and molecular nature has provided increasing support for the idea that tumorigenic mechanisms occur at the level of a single, susceptible adenohypophyseal cell, and in relative autonomy from hypothalamic influences. The facts that many pituitary adenomas can be cured by surgical removal and that pituitary adenomas are rarely accompanied by a zone of peritumoral hyperplasia together suggest that these tumors arise as the result of an intrinsic pituitary cell defect, not as the result of aberrant hypothalamic overstimulation. Further support of a de novo adenohypophyseal origin for pituitary adenomas was provided by a number of recent molecular studies concerning their clonality. Using the technique of allelic X-chromosomal inactivation analysis, which assesses restriction length polymorphisms and differential methylation patterns in X-linked genes, several groups have confirmed that both functioning and nonfunctioning pituitary adenomas are monoclonal. This finding is conceptually important, because it indicates that these tumors are the monoclonal expansions of a single, somatically mutated adenohypophyseal cell. If aberrant hypothalamic stimulation were the dominant underlying mechanism of pituitary tumorigenesis, a population of anterior pituitary cells would simultaneously be affected, and a polyclonal tumor would be the expected result.

Compatible with contemporary paradigms of human carcinogenesis, the emerging consensus regarding pituitary tumorigenesis emphasizes a multi step process occurring in a single adenohypophyseal cell, beginning with a somatic mutation(s) and followed by transformation and eventual monoclonal proliferation. Although the nature of the genomic alterations necessary to accomplish the process are still obscure, oncogene activation seems to be one mechanism in a minority of pituitary tumors. Amplification of V-fos and point mutations of H-ras oncogenes have been identified in isolated cases of PRL-producing adenomas. Mutations of the gsp oncogene have been identified in up to 40 percent of cases of GH-producing adenomas. These mutations encode a mutant stimulatory G protein that constitutively activates GTP, resulting in persistently elevated adenylate cyclase activity. Because the latter is the second messenger mediating somatotrope proliferation (and GH secretion), accumulation of adenylate cyclase results in a persistent, dysregulated signal for cell proliferation. and, ostensibly, tumor formation. In one study, acromegalic patients whose pituitary tumors exhibited gsp mutations tended to be older and had smaller tumors, lower basal GH levels, and retained GH suppressibility. Mutations of the p53 gene, although present in some experimental rodent pituitary tumors, do not seem to be a common contributor to human pituitary tumorigenesis.

Another genomic alteration common to pituitary adenomas is aneuploidy, which is a feature in up to 40 percent of pituitary adenomas. Such aberrations are considered to represent genetic instability in an established adenoma, and seem to have neither etiologic nor prognostic significance.

A variety of growth factors, cytokines, and novel peptides are present in varying abundance in the normal pituitary. Through mechanisms of aberrant autocrine and paracrine stimulatory activity, some of these growth factors may be implicated in the genesis or progression of pituitary adenomas. The potential roles of growth factors in the development of pituitary adenomas is addressed elsewhere.

Morphologic Features

Histopathology of Pituitary Adenomas

Although electron microscopy remains the "gold standard" for the diagnosis and classification of pituitary adenomas, the mere presence of a pituitary adenoma in a surgical specimen can virtually always be determined with a few routine histologic stains. The most important histologic stain for the diagnosis of pituitary adenomas is the hematoxylin-eosin preparation. The periodic acid Schiff (PAS) stain is also used routinely because it is frequently positive in corticotrope and some glycoprotein-hormone­producing adenomas. When evaluating a surgical specimen suspected of being a pituitary adenoma, the principal entities that must be distinguished are normal pituitary, pituitary adenoma, and pituitary hyperplasia. Other primary and secondary tumors and tumor-like conditions occurring in the sella figure occasionally in the differential diagnosis, but they can usually be distinguished from primary pituitary pathology on the basis of their clinical history and pathologic features. As the neurosurgeon's primary concern is whether or not the surgical specimen contains an adenoma, the morphologic features distinguishing normal from neoplastic pituitary are reviewed here. Hyperplasia is reviewed later.

Distinctions between normal pituitary gland and pituitary adenoma may be obvious grossly, as the firmness of the former contrasts well with the soft, semisolid consistency of the latter. Microscopically, several essential features distinguish normal from neoplastic pituitary. The normal pituitary contains a variety of different cell types, which exhibit various sizes, shapes, and cytoplas­mic staining affinities and are arranged in a fairly regimented acinar pattern. In sharp contrast, pituitary adenomas are generally monomorphous proliferations, consisting of a single, relatively uniform, homogeneously staining cell population with no acinar arrangement. The lack of an acinar pattern is one of the most essential diagnostic features of pituitary adenomas, and it may be highlighted with the application of a silver stain for reticulin fibers. Eye-catching, and at the same time diagnostic, is the interface between adenoma and nontumorous pituitary. When such borders are present in the surgical specimen, distinctions in cellularity and acinar structure between normal and neoplastic pituitary are especially obvious, as is the compressed rim of nontumorous pituitary and its condensed reticulin fiber network, which collectively constitute the adenoma's "pseudocapsule". Multinucleated cells, nuclear pleomorphism, increased cellularity, focal necrosis, and mitotic figures are variably present; although they favour a diagnosis of adenoma, none is a reliable index of biological aggressiveness or potential for tumor recurrence.

Of practical concern is the rapid intraoperative confirmation of an adenoma in the surgical specimen. In most cases, simple cytological touch preparations will reliably reveal the cellular monotony, increased cellularity, and nuclear atypia consistent with a diagnosis of adenoma. Although frequently requested, an intraoperative assessment of turn or-free resection margins is difficult to make with certainty. In our experience, the fragmented nature of the surgical specimen and lack of well-defined cleavage planes, further complicated by the loss of architectural detail inherent to frozen and smear preparations, renders any assessment of tumor margins difficult at best. Nevertheless, some centers rely heavily on frozen section appraisal of sequentially obtained biopsies from the tumor margin to ensure complete tumor removal.

Once the basic histologic diagnosis of a pituitary adenoma is established, immunohistochemistry is essential for its proper classification. The standard immunohistochemical battery necessary to functionally classify pituitary adenomas includes antibodies to GH, PRL, ACTH, TSH, FSH/LH, and the glycoprotein hormone alpha subunit. Further subclassification requires electron microscopy.

GH-Producing Adenomas. These tumors consist of growth hormone cells and are accompanied by acromegaly or gigantism. They can be divided into densely and sparsely granulated growth hormone cell adenomas. Densely granulated growth hormone cell adenomas are slow-growing, well-differentiated tumors that can be removed with a high surgical cure rate. Sparsely granulated growth hormone cell adenomas are more aggressive and are composed of more poorly differentiated cells. They grow faster, may invade neighbouring tissues, are more prevalent in women, and have a less favourable surgical cure rate. There is no correlation between the granularity, blood GH levels, and clinical phenotype of GH­producing tumors.

Densely granulated growth hormone cell adenomas are identified as acidophilic adenomas by light microscopy. The cytoplasm of these adenoma cells stains positively with various acid dyes and is a diffusely positive for GH by the immunoperoxidase technique. Seen by electron microscopy, densely granulated adenomatous growth hormone cells closely resemble nontumorous growth hormone cells; they contain well-developed rough endoplasmic reticulum (RER) membranes, Golgi complexes, and numerous spherical, evenly electron-dense secretory granules measuring 300 to 600 nm.

Sparsely granulated growth hormone cell adenomas are diagnosed as chromophobic adenomas by light microscopy. The cytoplasm of these cells stains positively for GH by the immunoperoxidase technique. The characteristic fine structural features include irregular nuclei, dispersed rough endoplasmic reticulum profiles, aggregates of smooth-surfaced endoplasmic reticulum membranes, conspicuous Golgi complexes, and fibrous bodies composed of type 2 microfilaments and smooth-walled tubules, as well as sev­eral centrioles and cilia. The secretory granules are sparse, spherical, and evenly electron-dense, and measure 100 to 500 nm

Although their effectiveness and precise therapeutic indications are the subject of ongoing study. somatostatin analogues have shown some promise as an adjunctive medical therapy for GH­secreting pituitary adenomas. Acromegalic patients so treated often show dramatic improvement in clinical symptoms. Although tumor shrinkage occurs in approximately half of cases. it is frequently minimal. The morphologic changes induced by such therapy have had only preliminary study on a limited number of cases. Gross alterations in tumor consistency have been noted in treated tumors: they appeared to assume a softer texture. which. according to some, facilitated their surgical extirpation. Microscopically and ultrastructurally no consistent morphologic changes have been noted. In some cases. there appears to be a slight to moderate reduction in cell volume. an increase in the number of lysosomes, and an increase in the size and density of GH secretory granules. None of these changes are a constant feature of treated tumors, however, even in patients who showed a clinical response to the drug.

Although more than 99 percent of all cases of acromegaly are caused by a GH-secreting pituitary tumor, on rare occasions the condition results from an extrapituitary tumor that secretes growth­hormone releasing hormone (GHRH). Because such ectopic etiologies of acromegaly mediate their effects via GH cell hyperplasia, they are considered below (see Adenohypophyseal Cell Hyperplasia). A single case of acromegaly arising from a GH-producing tumor of pancreatic islets cells has been reported.

PRL-Cell Adenomas. PRL-producing adenomas consist of prolactin cells and are sometimes associated with amenorrhea, galactorrhea, infertility, loss of libido, and impotence. In other cases, mainly in men and postmenopausal women, the endocrine symptoms are inconspicuous or absent, and only an elevation of blood PRL level may indicate PRL production by the tumor. It must be emphasized. however, that hyperprolactinemia itself provides no direct evidence that PRL is synthesized by the adenoma cells; compression or damage of certain hypothalamic structures and the pituitary stalk may interfere with the production or release of hypothalamic PRL-inhibiting factors (dopamine being the most important) or their transport to the anterior lobe. thus causing hyperprolactinemia. Morphologic investigation can determine whether PRL is produced by the adenoma, emphasizing the significance of morphologic studies in the diagnosis of pituitary adenomas. Blood PRL levels over 200 ng/ml are almost always due to PRL-secreting adenomas. Moderately high blood PRL levels (under 200 ng/ml), however, can be secondary to many other conditions. such as corticotropic cell adenoma, null cell adenoma, oncocytoma, TSH cell hyperplasia, lymphocytic hypophysitis, metastatic carcinoma, craniopharyngioma. or any mass. infiltrative or inflammatory lesion affecting the sella. There is a correlation between tumor size and the degree of hyperprolactinemia. Larger and more invasive tumors are accompanied by higher blood PRL levels.

Two types of PRL-cell adenomas-densely and sparsely granulated-can be distinguished. Densely granulated prolactin cell adenomas are rare. By light microscopy, they are acidophilic and indistinguishable from densely granulated GH-cell adenomas. The immunoperoxidase technique reveals the presence of PRL in the cytoplasm of the adenoma cells. By electron microscopy, densely granulated adenomatous prolactin cells resemble their resting nontumorous counterparts and are characterized by the presence of numerous spherical. oval, or irregular, evenly electron-dense secretory granules, that measure 300 to 700 nm. The rough endoplasmic reticulum and the Golgi complexes are well developed.

Sparsely granulated prolactin cell adenomas are identified as chromophobic adenomas by light microscopy. The immunoperoxidase technique is of fundamental importance in the diagnosis of this tumor type, since it clearly demonstrates the presence of PRL in the cell cytoplasm. The fine structural features of sparsely granulated prolactin cell adenomas are similar to those of stimulated nontumorous prolactin cells and include prominent rough endoplasmic reticulum membranes often forming whorls, conspicuous Golgi complexes, and misplaced exocytosis, i.e., extrusion of secretory granules on the lateral cell surfaces, distant from capillaries and intercellular extensions of basement membrane. The secretory granules are sparse, spherical, oval, or irregular, and evenly electron-dense and measure 150 to 300 nm.

Calcification is not uncommon in PRL-producing adenomas. Amorphous calcium apatite deposits and psammoma bodies are readily noticed under the light microscope. If extensive, calcification is often accompanied by fibrosis. In some cases the tumor is transformed into a calcified fibrous mass; these lesions are called pituitary stones. Marked calcification can also be demonstrated by various x-ray techniques. Calcification as well as amyloid deposition, although characteristic features of PRL-producing adenomas, may be found in other adenoma types; the reason for the more common occurrence of these changes in prolactin-producing adenomas are not known.

Some PRL-producing microadenomas have a very slow growth rate and never turn into macroadenomas. Indeed, the cumulative results of a number of natural history studies have confirmed that less than 7 percent of PRL-secreting microadenomas progress to become macroadenomas. Other PRL-producing adenomas grow relentlessly, often eroding the sella and invading neighboring tissues. Because many PRL-secreting microadenomas never require surgery, it is impossible to estimate the relative incidence of micro- and macroadenomas from surgical series. Among surgically treated cases, 50 percent of all prolactinomas will exhibit gross local invasion. Differences in biological behaviour are not reflected in the morphologic features, which show little variation from case to case. Thus, the search continues for morphologic changes that will predict the pace of growth of PRL-cell adenomas.

Dopaminergic agonists have assumed an important primary role in the management of PRL-producing pituitary adenomas. It is well established that bromocriptine will suppress PRL levels in 80 to 90 percent of patients and effect tumor shrinkage in approximately 77 percent of patients. The morphologic changes of such therapy on PRL-producing tumors have been well established and parallel the observed clinical effects. As determined by morphometry, there is a significant decrease in cell volume, with both a reduction in the overall cytoplasmic volume and a decreases in the volume density of the secretory apparatus (rough endoplasmic reticulum and Golgi membranes). These pharmacologic effects are especially obvious with electron microscopy, which reveals markedly irregular, heterochromatic nuclei, a diminished cytoplasm with scanty rough endoplasmic reticulum, and profoundly involuted Golgi complexes. There is no appreciable change in the size and density of secretory granules. Termination of therapy is followed by a prompt reversal to the original PRL-adenoma morphology. Protracted exposure to bromocriptine results in a number of regressive changes, including marked calcification, deposition of endocrine amyloid, and perivascular and interstitial fibrosis. The latter, if extensive, may complicate surgical extirpation of the tumor.

ACTH-Producing Adenomas. ACTH-secreting tumors are composed of corticotropic cells. They produce ACTH, ßlipotropin (β-LPH), and endorphins and are associated with Cushing's disease or Nelson's syndrome. By light microscopy, most corticotropic cell adenomas are basophilic adenomas and contain secretory granules that stain positively with the PAS method. A few corticotropic cell adenomas are chromophobic and have little or no PAS positivity. The presence of ACTH can be demonstrated in the cytoplasm of adenoma cells by the immunoperoxidase technique. Positive immunostaining is also noted for β-LPH and endorphins. By electron microscopy, adenomatous corticotropic cells resemble those found in the nontumorous pituitary, having well­developed rough endoplasmic reticulum membranes and conspicuous Golgi complexes. The secretory granules are spherical or slightly irregular, vary in electron density, often line up along the cell membranes, and measure 250 to 450 nm. In corticotropic cell adenomas associated with Cushing's disease, bundles of type 1 microfilaments are frequently observed in the cytoplasm, principally adjacent to the nucleus. They are identical to Crooke's hyaline material noted in nontumorous corticotropic cells in patients treated with pharmacologic doses of cortisol or its derivatives, and in cases of the ectopic ACTH syndrome. Type 1 microfilaments are inconspicuous or absent in corticotropic cell adenomas of patients with Nelson's syndrome-that is, in those who have undergone bilateral adrenalectomy for pre-existing hypercorticism.

More than 80 percent of corticotrope adenomas responsible for Cushing's disease are microadenomas. and approximately 10 percent of these are locally invasive. Of the remaining macroadenomas, gross local invasion is evident in more than 60 percent. By contrast, corticotrope adenomas in patients with Nelson's syndrome are usually larger and faster growing, and aggressively invade adjacent structures. Overall, 70 percent of Nelson's syndrome tumors are macroadenomas, and 65 percent of these are invasive.

It is important to recognize that pituitary adenomas (i.e., Cushing's disease) are responsible for only 70 to 80 percent of all cases of the Cushing syndrome. The other causes of endogenous hypercortisolemia, which must be distinguished from Cushing's disease, include ectopic sources of ACTH production (small cell carcinoma of the lung, carcinoid tumors, pheochromocytoma, ovarian tumors), rare ectopic sources of corticotropin releasing hormone (pheochromocytomas and carcinoid tumors), and tumors of the adrenal medulla that autonomously secrete cortisol.

Some corticotropic cell adenomas ("silent" corticotroph adenomas) are not associated with clinical and biochemical evidence of ACTH excess. These tumors show positive immunostaining for ACTH, but biologically active ACTH is not released into the circulation in amounts sufficient to cause endocrine abnormalities. The reasons for the lack of ACTH hypersecretion are not understood. In a few cases, crinophagy-that is, the uptake of secretory granules-by accumulated lysosomes is seen by electron microscopy, suggesting an intracellular degradation of the hormone. Underdevelopment of the Golgi complex may also be a conspicuous finding, indicating a defect in hormone synthesis. It may well be that in silent corticotropic cell adenomas an abnormal hormone is produced that has ACTH immunoreactivity but no biological activity.

Two silent versions of corticotrope adenoma have been recognized, and although both have similar morphologic features, their clinical profiles differ. The first is known as silent corticotrope adenoma subtype 1. Although morphologically indistinguishable from the classic basophilic adenomas responsible for Cushing's disease, silent sub type 1 adenomas are virtually all large macroadenomas at presentation, often with a high degree of local invasiveness. An unexplained peculiarity of this tumor type is its propensity for spontaneous hemorrhage and infarction. In a report, more than 40 percent of all subtype 1 tumors were heralded by an apoplectic presentation.

Silent corticotrope adenoma subtype 2 is similar morphologically to subtype 1, being distinguished only by subtle but definite differences in ultrastructure. These tumors occur predominantly in men, where they present as large, invasive sellar masses, often with some degree of hyperprolactinemia. In some cases, the PRL elevation may exceed the threshold attributable to the "stalk sectioning effect" alone, suggesting some additional induction of adjacent nontumorous lactotrophs. Accordingly, most of these patients have clinical evidence of hyperprolactinemia, and the tumors are often diagnosed preoperatively as prolactinomas.

A third type of silent adenoma has been identified.  Known as silent subtype 3, this adenoma was originally thought to be of corticotrope derivation; however, its morphologic features and clinical profile are so peculiar that its cellular origins have since been questioned, On preliminary staining, this tumor may appear chromophobic or acidophilic. Its immunohistochemical profile is also inconsistent, with some tumors showing diffuse immunopositivity for all known anterior pituitary hormones and others being entirely immunonegative. The ultrastructural features are reminiscent of well-differentiated glycoprotein-hormone­producing cells. Even less intuitive is the clinical presentation of these tumors. Although they occur with equal frequency in both sexes, they present during middle age in men and during the mid­twenties in women. In women, the presentation often mimics a PRL-producing adenoma, and PRL levels higher than expected from simple stalk compression routinely occur. Thus, the amenorrhea-galactorrhea syndrome is usually a conspicuous presenting feature in women. Treatment with bromocriptine causes prolactin levels to normalize, but the tumor often continues to grow. In men, these tumors are virtually all macroadenomas at presentation, and many are locally invasive. Accordingly, symptoms referable to a mass effect usually dominate; however, bizarre and unexplained acromegalic presentations have also been reported, presumably reflecting plurimorphous differentiation of the tumor.

TSH-Producing Adenomas. TSH-secreting adenomas are rare lesions, accounting for less than 1 percent of all pituitary adenomas, That fewer than 100 cases have so far been reported emphasizes the relatively limited clinical and pathological experience with this entity.

At the time of diagnosis, most TSH-producing adenomas are large, invasive macroadenomas that have transgressed the sellar confines and invaded adjacent parasellar structures. The clinical history in most patients is remarkable for some form of thyroid dysfunction, typically hyperthyroidism; less often these tumors occur in the context of long-standing hypothyroidism or even in euthyroid states, Of the reported cases, the most typical scenario begins with a hyperthyroid presentation, often with goitre, both of which are attributable to excess TSH production by the tumor. Historically, the hyperthyroid state was erroneously attributed to a primary thyroid condition such as Graves' disease, presumably because of a lack of general awareness of this entity. These patients have usually been treated with some form of thyroid ablation, which temporarily ameliorates the symptoms, only to be followed later by accelerated tumor growth and either recurrence of a hyperthyroid state or compressive symptoms of an expansile sellar mass. It is at this point that a pituitary adenoma is recognized as the source of the thyroid dysfunction. The invasive nature of these tumors seems to be related to two factors. The first is the typical delay in arriving at a definitive diagnosis. The second, which may be more important, relates to loss of feedback inhibition; just as target gland ablation confers well-known aggressive properties to ACTH adenomas in Nelson's syndrome, similar disinhibiting influences seem to operate in TSH adenomas that manifest or progress after thyroid ablation. Fortunately, the routine availability of TSH assays, which in this condition will demonstrate nonsuppressible TSH elevation, coupled with a general awareness of TSH adenomas as a potential cause of hyperthyroidism, should permit a more expeditious diagnosis of these tumors.

Both clinical and autopsy studies have shown that TSH adenomas may also arise in the context of long-standing hypothyroidism. This association is consistent with the view that deficiency of thyroid hormones causes stimulation of thyrotropes, leading to thyrotrope hyperplasia and eventual adenoma formation.

By light microscopy, thyrotrope adenomas are chromophobic tumors that display few, small, PAS-positive cytoplasmic granules. Immunopositivity for TSH and the alpha subunit should be evident. Scattered immunopositivity for GH may be seen; when the tumor is strongly GH-positive, the patients may also have clinical evidence of acromegaly. By electron microscopy, thyrotrope adenomas exhibit varying degrees of differentiation. In most cases, the tumor is well differentiated, consisting of angular cells with a well­developed secretory apparatus and a sparsely granulated cytoplasm. Secretory granules are small (100 to 250 nm) and are frequently seen to line up along the cell membrane. The overall ultrastructure resembles that of the non tumorous thyrotrope. Less differentiated forms also occur. These tumors are composed of small elongated cells with long cytoplasmic processes and an abundance of microtubules. Some of the less differentiated tumors may also resemble null cell adenomas. Neither the ultrastructure nor the immunohistochemical profile correlates with the thyroid state of the patient.

FSH- and/or LH-Secreting Adenomas. Gonadotrope adenomas were the last of the major pituitary tumor types to be characterized, and their morphologic features and clinicopathologic correlates studied systematically. It was once thought that these tumors arose from the inductive effect of primary gonadal failure; however, it is now generally accepted that most of them occur spontaneously. Gonadotrope adenomas are generally tumors of middle age, and they have been variably reported to represent between 3 and I5 percent of all pituitary adenomas. The usual clinical presentation is one of a "nonfunctioning" expansile sellar mass, often accompanied by hypopituitarism and visual disturbance. Although they do not generate any characteristic hypersecretory syndrome, many gonadotrope adenomas do actively secrete gonadotropic hormones; FSH and the alpha subunit are most commonly elevated, with LH elevations occurring much less frequently. In men, such measurable hormone elevations provide biochemical evidence of a gonadotrope adenoma, facilitating their recognition. The same is not true in middle-age women, for the postmenopausal state is normally accompanied by high gonadotropin levels, and the contribution of an actively secreting gonadotrope adenoma may be impossible to discern. Such differences in biochemical recognition may account for the predominance of males in most clinical series of gonadotrope adenomas.

Gonadotropic cell adenomas appear chromophobic by light microscopy. A few PAS-positive granules can usually be noted in the cytoplasm of some of the adenoma cells, and immunohistochemistry may reveal positivity for FSH and/or LH and the α subunit. Immunocytologic techniques are valuable in the diagnosis, since in some cases the adenoma cells are so immature that their derivation cannot be established even by detailed ultrastructural studies.

The most impressive ultrastructural feature of gonadotrope adenomas is their well-defined sexual dimorphism: the tumors are sharply different in men and in women. Gonadotrope adenomas in men tend to show varying degrees of differentiation, and the cells often differ considerably from the gonadotropic cells of the nontumorous adenohypophysis. They are characterized by a few rough endoplasmic reticulum cisternae, a prominent Golgi apparatus, and numerous microtubules. The secretory granules are spherical and evenly electron-dense, are often lined up along the cell membranes, and measure 50 to I50 nm. In contrast to this relatively bland ultrastructure, the tumors in women tend to be better differentiated. Their cytoplasmic hallmark is the Golgi apparatus, which is architecturally unique to this tumor type. It consists of an even, vesicular dilation of Golgi saccules that resembles the trabecular pattern of a honeycomb.

Despite their frequently large size at presentation, gonadotrope adenomas have a relatively indolent biology. They tend to be compressive in nature, having the lowest rate of invasiveness (20 percent) of any macroadenoma. Accordingly, most can be removed successfully, and recurrence rates are generally low.

Plurihormonal Adenomas Plurihormonal adenomas produce two or more separate adenohypophyseal hormones. Endocrinologically, the most common combination is growth hormone and prolactin. These two hormones can be secreted simultaneously by three pituitary tumor types: mixed growth hormone cell­prolactin cell adenomas, acidophil stem cell adenomas, and mammosomatotropic cell adenomas.

Mixed growth hormone cell-prolactin cell adenomas consist of two distinct cell types: growth hormone cells that produce GH and prolactin cells which produce PRL. The adenoma cells may be densely or sparsely granulated; every combination may occur. The patients have acromegaly or gigantism, with elevated blood GH concentrations and hyperprolactinemia. In some cases blood PRL levels are within the normal range, indicating that the PRL being synthesized is not being discharged into the circulation. Most mixed GH-PRL cell adenomas are macroadenomas (75 percent). Gross local invasion is identified intraoperatively in approximately 30 percent of cases.

Acidophil stem cell adenomas consist of immature cells which are assumed to represent the common committed precursor of growth hormone cells and prolactin cells. They are rapidly growing tumors, frequently spreading outside the sella turcica and infiltrating neighbouring tissue such as the sphenoid bone, the optic nerve, and even the brain. As seen by light microscopy, they are chromophobic adenomas and consist of one cell type, which contains both GH and PRL as shown by the immunoperoxidase technique. The characteristic fine structural features of the adenoma cells are immature cytoplasm, poorly developed rough endoplasmic reticulum, giant mitochondria with alterations in their internal compartment and oncocytic changes, sparse secretory granules measuring 150 to 300 nm, fibrous bodies, and misplaced exocytosis. Clinically, the most important finding is hyperprolactinemia and its sequelae. Blood PRL levels, however, even with very large tumors, may be only moderately elevated. The patients may show acromegalic features, but blood GH levels are usually within the normal range.

Mammosomatotropic cell adenomas are thought to be the mature counterpart of acidophil stem cell adenomas. Clinically the patients have acromegaly or gigantism. Blood PRL levels are either moderately elevated or within the normal range. These slow­growing, benign tumors consist of one cell type, the mammosomatotropic cell, which contains both GH and PRL as seen by the immunoperoxidase technique. Ultrastructurally, the tumor cells are characterized by densely granulated cytoplasm, spherical or oval secretory granules measuring 300 to 2000 nm, exocytosis, and large extracellular deposits of secretory material.

In addition to the three well-defined bihormonal entities just described, another more diverse spectrum of plurihormonal entities has been encountered. Given that there are six main secretory products that can be expressed by pituitary tumors (GH, PRL, ACTH, TSH, LH, and FSH), the potential combinations of different hormones both in number and in kind are theoretically numerous. In practice, however, there seems to be some predictability to the general pattern of hormone expression among these plurihormonal entities, although unusual combinations may also occur. First, plurihormonal tumors occur most often in the context of acromegaly. Such tumors commonly coexpress GH and TSH, or GH, PRL, and TSH. The other common class of plurihormonal tumors includes those composed of cells resembling glycoprotein­hormone-producing cells, which express any combination of LH/ FSH, TSH, GH, and occasionally PRL. Less intuitive combinations, such as PRL and alpha subunit, or GH, PRL, and ACTH, also occur, but much less often. Although in some cases the immunohistochemical profile of the tumor mirrors the hormone elevations measured in the patient, often it does not. It is of interest that plurihormonal tumors appear with unexpected regularity in paediatric patients and in pituitary tumors associated with the MEN-1 syndrome.

Pituitary oncocytomas occur mainly in older men and women and clinically are unassociated with hormone excess. Biologically identical to null cell adenomas, these tumors are slow-growing, benign, chromophobic or acidophilic, and characterized by an abundance of mitochondria; they are similar to oncocytomas of other organs, such as Hϋrthle cell tumors of the thyroid, oxyphil cell adenomas of the parathyroid, and oncocytic tumors of the salivary glands and kidneys. The accumulation of mitochondria may be so great as to almost completely fill the cytoplasm. Oncocytomas usually do not contain immunoreactive adenohypophyseal hormones and can be diagnosed easily by electron microscopy. Null cell adenomas and oncocytomas are locally invasive in approximately 40 percent of cases.

Invasive Pituitary Adenomas. Although the expansile effects of a growing pituitary adenoma are generally mediated by simple compression, a substantial proportion of pituitary adenomas are also frankly invasive of surrounding structures. Depending on their direction of growth, invasive adenomas may transgress any or all of the adjacent meningeal, osseous, neural, or vascular boundaries. Lateral extension and permeation into the cavernous sinus is probably the most common pattern of gross local invasiveness. Only when cavernous sinus invasion is extreme do the carotid artery and cranial nerves located in it become ensheathed by tumor. Bony invasion is a regular feature of invasive adenomas and may range from localized infiltration of the sellar floor to extensive destruction of the skull base. Pituitary adenomas routinely extend into the suprasellar region, and, in addition to compressing the chiasm, may so deeply indent the third ventricle that they appear to lie inside it. Visual disturbance, obstructive hydrocephalus, and hypothalamic dysfunction are typical sequelae to such superior extensions. Finally, invasive adenomas may further extend into the anterior, middle, and posterior cranial fossae, where they will generate a full spectrum of neurologic symptoms and signs. Although the two are not always easily distinguished, "extension" implies tumor growth in a particular direction, whereas "invasion" suggests destructive infiltration. In most instances, invasive adenomas exhibit both features. As a rule, pituitary adenomas tend to displace rather than invade brain substance.