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Table-1 Classification of pituitary tumors and tumor-like conditions

Tumors derived from adenohypophyseal cells
   Adenoma
   Carcinoma
Other primary tumors of the sella turcica
   Angioma and angiosarcoma
   Chordoma
   Choristoma
   Craniopharyngioma
   Fibroma and fibrosarcoma
   Glioma (optic nerve, infundibulum. posterior lobe. hypothalamus)
   Granular cell tumor (posterior lobe, pituitary stalk)
    Ganglioglioma
   Ganglioneuroma
   Germinoma (ectopic pinealoma)
   Hamartoma (hypothalamus)
   Melanoma
   Meningioma
   Paraganglioma
   Sarcoma
   Teratoma
Metastatic tumors
Carcinoma
Sarcoma, leukaemia, lymphoma. histiocytosis-X
Tumor-like conditions
Inflammatory

Infectious

Lymphocytic hypophysitis
Sarcoidosis, giant cell granuloma
Pseudotumor
Mucocele
Infiltrative
Amyloidosis
Hemochromatosis
Mucopolysaccharidosis

TABLE-2 Classification of Pituitary Adenomas According to Radiographic Appearance

Grade 0 Intrapituitary adenoma: diameter < I cm, normal sella
Grade 1

Intrapituitary adenoma: diameter < I cm, focal bulging or other minor changes in sellar appearance

Grade 2 Intrasellar adenoma: diameter> 1 cm. enlarged sella. no erosion
Grade 3  Diffuse adenoma: diameter> 1 cm. enlarged sella, localized erosion/destruction
Grade 4 Invasive adenoma: diameter> 1 cm, extensive destruction of bony structures, "ghost" sella

Tumors can be further subclassified by the degree of suprasellar extension:

A:

Extension to suprasellar cistern only

B: Extension to recesses of the third ventricle
C: Extension to involve the whole anterior third ventricle

Table-3 Classification of Pituitary Adenomas According to Endocrine Function

Adenomas with growth hormone excess
Adenomas with prolactin excess
Adenomas with ACTH excess
Adenomas with TSH excess
Adenomas with FSH/LH excess
Plurihormonal adenomas
Adenomas with no apparent hormonal function

TABLE-4 Classification of Pituitary Adenomas According to Staining Properties: Correlation with Cytogenesis

Chromophobic adenomas
Sparsely granulated GH-cell adenoma
Sparsely granulated PRL-cell adenoma
Mixed GH/PRL-cell adenoma
Acidophil stem cell adenoma
Corticotropic cell adenoma. functioning
Corticotropic cell adenoma. silent
TSH-cell adenoma
FSH/LH-cell adenoma
Null cell adenoma
Oncocytoma
Plurihormonal adenoma
Acidophilic adenomas
Densely granulated GH-cell adenoma
Densely granulated PRL-cell adenoma
Mixed GH/PRL-cell adenoma
Acidophil stem cell adenoma
Mammosomatotropic cell adenoma
Oncocytoma
Plurihormonal adenoma
Basophilic adenomas
Corticotropic cell adenoma
Functioning

Silent

TABLE-5 Classification of Pituitary Adenomas According to Cytogenesis Type of Adenoma

Prevalence, %

Growth hormone cell adenoma
Densely granulated 7.0
Sparsely granulated 9.0
Prolactin cell adenoma
Densely granulated 0.3
Sparsely granulated 28.6
Corticotropic cell adenoma
With ACTH excess 8.4
With no ACTH excess 6.0
Thyrotropic cell adenoma 0.5
Gonadotropic cell adenoma 3.3
Plurihormonal adenoma
Mixed growth hormone cell-prolactin cell adenoma 4.6
Acidophil stem cell adenoma 3.1
Mammosomatotropic cell adenoma 1.3
Unclassified 2.8
Null cell adenoma 18.2
Oncocytoma 6.7


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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.

Pituitary Adenomas

General Features and Classification

Pituitary adenomas are common epithelial neoplasms that are composed of and derive from adenohypophyseal cells. They represent between 10 and 15 percent of all intracranial tumors. Histologic studies of pituitary glands obtained from unselected routine adult autopsies show the presence of incidental adenomas in 8 to 23 percent, suggesting that transformation in adenohypophyseal cells is a relatively common event, albeit one that is not always apparent clinically.

Like tumors of other endocrine glands, pituitary adenomas vary considerably in size, growth rate, radiologic appearance, clinical presentation, endocrine function, cellular composition, and morphology. In most cases they are histologically benign, slow-growing, small neoplasms confined to the sella turcica. Some, however. grow faster, invade surrounding tissues, and cause local symptoms such as visual disturbances, headache. and compression of the non­tumorous pituitary, resulting in varying degrees of hypopituitarism.

Pituitary adenomas are usually well demarcated and are separated from the adjacent compressed nontumorous adenohypophysis by a pseudocapsule that consists of condensed reticulin fibers. Unlike many benign tumors of other locations, these lesions have no fibrous capsule. Some histologically benign tumors have an indistinct border, and clusters of adenoma cells may be found to spread deeply into the adjacent nontumorous adenohypophysis.

Within the anterior pituitary, the various hormone-producing cells are distributed in a fairly definite arrangement. Accordingly, different pituitary tumor types have different preferential sites of origin. An awareness of the general topologic organization of the pituitary is important for the surgeon who is dissecting through the gland in search of a presumed microadenoma. which may or may not be evident radiologically . When the pituitary is viewed In horizontal cross section, it is seen to be composed of two lateral "wings" and a trapezoidal "central wedge." The cells that produce growth hormone (GH) populate the lateral wings, being especially abundant near the anterior face. GH-producing microadenomas generally arise at this site. Cells that produce prolactin (PRL) can be found throughout the gland but are most abundant in the posterior part of the lateral wings, adjacent to the posterior lobe. This is the favoured site of PRL-producing microadenomas. Cells that produce adrenocorticotropic hormone (ACTH) are located in the central wedge, just anterior to the posterior lobe. Accordingly, corticotrope microadenomas are predictably located in this region. Thyrotropes, the cells that produce thyroid-stimulating hormone (TSH), occupy a small area in the anterior portion of the central wedge. The rare TSH-producing adenomas originate at this site. Gonadotropes are the cells that produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH). They are widely distributed throughout the anterior lobe, and, correspondingly, their tumors have no set site of origin.

Pituitary adenomas can be classified according to their size, radiographic appearance, endocrine function, morphology, and cytogenesis. Neurosurgeons frequently classify pituitary adenomas on the basis of size and invasiveness, as determined by imaging studies (magnetic resonance imaging, computed tomography, and x-ray films of the skull). With respect to size, microadenomas are smaller than 1 cm in greatest diameter, and macro adenomas are larger than this. Invasiveness is evaluated from the radiographic appearance of the sella. Microadenomas are designated as grade 0 or grade 1 tumors, depending on whether the sellar appearance is normal, or whether minor, focal sellar changes are present, respectively. Macroadenomas that cause diffuse sellar enlargement, focal destruction, and extensive sellar destruction and erosion are classified as grade 2, grade 3, and grade 4, respectively. Macroadenomas are further subclassified by the degree of suprasellar extension. (Table-2).

The classification of pituitary adenomas on the basis of their endocrine activity (Table-3) has considerable practical appeal for both the clinical endocrinologist and the neurosurgeon. Based on physical examination and measurements of blood hormone levels in basal and provoked states, pituitary tumors can be broadly distinguished as being either functioning or non functioning. The former category comprises the pituitary tumors that produce GH, PRL, ACTH, and TSH, which generate the clinical phenotypes, respectively, of acromegaly, of the amenorrhea-galactorrhea syndrome in women and decreased libido and impotence in men, of Cushing's disease, and of hyperthyroidism. Tumors that hypersecrete the gonadotropic hormones (LH/FSH) and the glycoprotein hormonal alpha subunit also occur, but they do not generate a clinically recognizable endocrine syndrome and are therefore generally classified as nonfunctioning. Some pituitary adenomas cosecrete more than one hormonal product, and these are designated plurihormonal pituitary adenomas.

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.

Plurihormonal tumors are either monomorphous or plurimorphous. Monomorphous adenomas are composed of one cell type containing two or more hormones in the same cell; electron microscopy reveals only one cell type. Plurimorphous adenomas consist of more than one cell type; immunocytologic techniques demonstrate different hormones in different cell populations, which can also be distinguished ultrastructurally. In some cases, the cells are well differentiated and resemble their non tumorous counterparts; in other cases the cellular derivation of the tumor cannot be established. It is difficult to understand the formation of a cell type that produces several distinct hormones, different in chemical composition, immunoreactivity, and biological action. These unusual plurihormonal pituitary adenomas have been insufficiently explored, and more cases must be investigated to elucidate their cytogenesis.

Beyond the academic considerations, the issue of plurihormonality has practical importance because there is a suspicion that plurihormonal tumors may be more biologically aggressive than their monohormonal counterparts. This phenomenon has been observed in tumors of other endocrine organs (pancreatic tumors, medullary carcinoma of the thyroid), where the plurihormonal versions are thought to take a more malignant clinical course. There is increasing evidence for a similar phenomenon in pituitary tumors, but the data are inconclusive. It is known, however, that the over­whelming majority of plurihormonal tumors are macroadenomas at presentation, and more than 50 percent of these are locally invasive.

Corticotrope adenomas, like nontumorous corticotropic cells, secrete not only ACTH but also the related peptides β-LPH and endorphins, which are part of the pro-opiomelanocortin molecule, the prohormone of ACTH. Gonadotrope adenomas often secrete FSH and LH simultaneously. This, however, is not surprising, since non tumorous gonadotropic cells are capable of synthesizing and discharging FSH and LH as well. Hence corticotrope adenomas and gonadotrope adenomas, although they secrete more than one hormone, are not regarded as plurihormonal tumors and are not classified as such.

Null Cell Adenomas and Oncocytomas. These adenomas lack immunocytochemical or fine structural markers, and their cellular origin cannot be established. They are diagnosed in older patients; usually patients over 40 years of age. They are clinically unassociated with hormone excess, although in some cases mild hyperprolactinemia may be present. This prolactinemia is due to a stalk sectioning effect-that is, the excessive PRL is secreted by non tumorous prolactin cells and not by the tumor. Null cell adenomas, when operated on, are usually found to be large tumors showing suprasellar extension and invasion of neighbouring tissues. Various degrees of hypopituitarism may be caused by a reduction in the number of hormone-producing nontumorous adenohypophyseal cells owing to compression by the tumor or to suppression of blood flow to the nonadenomatous anterior lobe. Morphologically, null cell adenomas are chromophobic and exhibit negative staining for all adenohypophyseal hormones by immunocytologic techniques. In some tumors, however, a few cells may contain different adenohypophyseal hormones, suggesting that, during neoplastic transformation or subsequent cellular proliferation, adenohypophyseal cells dedifferentiate and lose their ability to synthesize hormone or, alternatively, that null cells tend to differentiate into a specific hormone-producing cell line. By electron microscopy, null cell adenomas are seen to be composed of polyhedral cells with poorly developed cytoplasm, inconspicuous rough endoplasmic reticulum and Golgi apparatus, numerous microtubules, and sparse, small secretory granules measuring 100 to 250 nm. Although secretory granules frequently line up along the cell membranes, no exocytoses are seen.

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.

The incidence of invasion in pituitary adenomas depends not only on the type of tumor involved but also on how invasion is defined. Radiologic, intraoperative, and microscopic criteria find invasion respectively in 10 percent, 35 percent, and 90 percent of all pituitary adenomas. Not surprisingly, microscopic evidence of dural invasion increases with tumor size, being present in 66 percent of microadenomas, 87 percent of macroadenomas, and 94 percent of macroadenomas with suprasellar extension. Given that microscopic dural invasion is so regular an accompaniment of pituitary adenomas, including the most indolent of microadenomas, it is of little diagnostic use either as an index of biological aggressiveness or as a criterion for designating an adenoma as invasive. It has become practice, therefore, to designate an adenoma as "invasive" on the basis of radiologic or intraoperative evidence of gross invasion. The incidence of gross invasion among the various pituitary tumors types is summarized in Table-6.

Although aggressive behaviour of invasive adenomas lowers the rate of surgical cures, it is generally not reflected in the histologic appearance of the tumors. Even the most locally aggressive adenomas may have an entirely innocent histology. Cellular pleomorphism, nuclear atypia, increased cellularity, focal necrosis, and mitotic figures are sometimes but not always present. Furthermore, as any of these features may be seen in non invasive adenomas, they are without practical, prognostic, or biological significance.

Given the unreliability of conventional histologic markers of tumor aggressiveness in predicting the biological behaviour of pituitary adenomas, a number of strategies have recently emerged to assess the proliferative potential of pituitary adenomas. Ki-67 is a cell-cycle-specific nuclear-associated antigen of uncertain function that is expressed only in the G 1 to M phase of proliferating cells. Its immunohistochemical abundance in tumor tissue provides some measure of a tumor's proliferative capacity. In one study, invasive adenomas expressed twice the amount of Ki-67 protein as noninvasive adenomas. Other cell cycle proliferation markers such as PCNA (proliferating cell nuclear antigen) and MIB-1 have captured  attention, and their utility in predicting the proliferative potential in pituitary adenomas is currently under evaluation.

TABLE-6 Frequency of Gross Local Invasion among the Major Pituitary Tumor Types According to Tumor Size

 

Microadenomas

Macroadenomas

Overall Incidence of

 Pituitary Tumor Type

%

% Invasive

%

% Invasive

Invasion (%)

 GH-cell adenoma

14

0

86

50

50

 PRL-cell adenoma

33

 

67

 

52

 Mixed GH/PRL-cell adenoma

26

0

74

31

31

 ACTH-cell adenoma (Cushing's disease)

87

8

13

62

IS

 ACTH-cell adenoma (Nelson's syndrome)

30

17

70

64

50

 Silent ACTH adenoma

0

0

100

82

82

 Gonadotrope adenoma

0

0

100

21

21

 Thyrotrope adenoma

0

0

l00

75

75

 Null cell adenoma

2

 

98

 

42

 Plurihormonal adenoma

25

31

75

59

52

Earlier strategies for evaluating tumor growth fractions, such as standard flow cytometry, ploidy analysis, quantification of the nuclear antigen p105, BUdR (Bromodeoxyuridine) immunolabeling, and AgNOR (argyrophilic nucleolar organizer regions) quantification, although variably informative as proliferation indices in other forms of human neoplasia, have shown limited practical usefulness in predicting the biological behaviour of pituitary adenomas.

Ectopic Pituitary Adenomas. Deposited along the route of the anterior pituitary's embryologic development are small ectopic foci of adenohypophyseal tissue. They assume the form of tiny midline nodules, usually embedded in the sphenoid bone. Known as the "pharyngeal pituitary" and present in virtually all individuals, these cell nests on rare occasion give rise to pituitary adenomas. Most of these ectopic adenomas occur extracranially, usually in the sphenoid sinus and less often in the nasal cavity or elsewhere along the anterior or middle cranial fossa. Rare intracranial ectopic pituitary adenomas have also been reported. Most of these are located in the supra- or parasellar regions, presumably arising from anterior pituitary cells attached to the supradiaphragmatic portion of the pituitary stalk. Rare and unexplained are ectopic adenomas found deeply embedded in the brain substance. Ectopic adenomas may produce GH, PRL, or ACTH, each resulting in the corresponding clinical phenotype. Hormonally inactive ectopic adenomas have also been reported.

Pituitary Carcinomas

Primary pituitary carcinoma is a rare entity, operationally defined as any tumor of adenohypophyseal origin with demonstrated craniospinal and/or extracranial metastatic dissemination. Using this definition, Mountcastle and colleagues found fewer than 40 cases of pituitary carcinoma in the world literature. Unlike other forms of human cancer, the generic morphologic features of malignancy, such as cellular and nuclear pleomorphism, increased mitotic activity, necrosis, hemorrhage, and invasiveness, are not sufficient to constitute a diagnosis of pituitary carcinoma, for all of these may be present in benign pituitary adenomas. The diagnosis is based on the biological behaviour of the tumor rather than on its histologic characteristics. In this regard, metastatic dissemination seems to occur most often within the CSF axis (spinal cord, posterior fossa), although a variety of extraneural metastatic sites have also been reported (liver, lungs, lymph nodes, heart, bones, and kidneys). The mode of extracranial dissemination is presumed to be both hematogenous and lymphatic. The former is a venous phenomenon, presumably beginning with tumor penetration into the cavernous sinus, with subsequent transport to the internal jugular vein via the petrosal sinuses. Although the pituitary lacks lymphatic drainage, the tumor can reach lymphatics by penetrating into the skull base, the latter having a rich lymphatic network.

Both hormonally active (ACTH-, GH-, and PRL-producing) and hormonally inactive forms of pituitary carcinoma have been reported. In most cases, the metastatic deposits retain the immunotype of the primary tumor. Given the regularity with which pituitary adenomas invade adjacent structures, including the cavernous sinus, it is unclear why metastatic dissemination is so exceedingly rare. Equally variable are the clinical profiles of patients with pituitary carcinoma. In some, the initial clinical course is indistinguishable from that of a typical pituitary adenoma, except that it is followed by protracted recurrences and eventual dissemination. In others, however, the malignant biology of the tumor is evident from the onset, beginning with unrelenting local aggression and progressing promptly to metastatic dissemination. It is of interest that virtually all patients reported to date have died of complications of their intracranial disease, and not directly as the result of the systemic dissemination.

Adenohypophyseal Cell Hyperplasia

Adenohypophyseal cell hyperplasia refers to a non-neoplastic increase in the number of pituitary parenchymal cells. It has long been known that this phenomenon can be a normal occurrence (e.g., PRL cell hyperplasia of pregnancy), however, its role as a primary pathologic phenomenon responsible for a hypersecretory endocrine state remains a topic of controversy. Its incidence, its relative contribution to hypersecretory pituitary states, and its very existence have all been questioned. Nevertheless, there is no doubt that primary pituitary hyperplasia does exist and that it is a rare cause of clinically and biochemically manifest hypersecretory states. It is conceptually important to emphasize, however, that little evidence supports the notion that pituitary hyperplasia is a frequent predecessor to frank adenoma formation.

Beyond the conceptual controversies surrounding pituitary hyperplasia are the practical problems concerning its recognition. Hyperplasia can appear histologically as either a diffuse or nodular process; the former type is difficult to distinguish from normal pituitary; and the latter type is difficult to differentiate from adenoma. The frequently fragmented nature of the surgical specimen further complicates the matter. In both forms of hyperplasia, the most essential pathologic feature is the expansion of acini with the retention of overall acinar morphology. Silver stains for reticulin and immunohistochemical stains are crucial to the diagnosis. In most cases, the hyperplastic process is limited to a single cell type; however, simultaneous involvement of multiple cell types is rarely encountered.

ACTH-Cell Hyperplasia

Of the various adenohypophyseal cells, the corticotrope appear most susceptible to pathologic hyperplastic change. In our experience, primary corticotrope hyperplasia is the pathologic lesion in up to 10 percent of Cushing's disease cases. Theoretically, a case of Cushing's disease with this etiology should be more refractory to surgical cure; the implication being that although the hyperplastic focus is removed by surgery, the hyperplastic stimulus remains, and ACTH excess should persist. Corticotrope hyperplasia can also be induced by a variety of rare tumors that elaborate cortico­tropin releasing hormone (CRH), and may be of a sufficient degree to cause pituitary enlargement. These rare CRH-producing tumors include bronchial and intestinal carcinoids, pheochromocytomas, and intrasellar neuronal choristomas. Understandably, nodular corticotrope hyperplasia is a frequent feature in untreated Addison's disease

PRL-Cell Hyperplasia

The most common form of PRL-cell hyperplasia is a normal phenomenon and occurs during pregnancy and lactation. The enlargement of the pituitary gland is often considerable, and on occasion may mimic an adenoma. The other common form of PRL cell hyperplasia is that which occurs in association with any of a variety of sellar and suprasellar lesions. In this context, compression of the hypothalamus or pituitary stalk impedes adenohypophyseal transfer of prolactin inhibiting factor (dopamine), resulting in PRL hyperplasia. Isolated PRL-cell hyperplasia as a primary cause of hyperprolactinemia is exquisitely rare, although it occasionally coexists with a PRL-cell adenoma.

GH-Cell Hyperplasia

In virtually all cases, GH-cell hyperplasia occurs as a result of an extrapituitary GHRH-producing tumor (a pancreatic tumor, pheochromocytoma, bronchial or intestinal carcinoid, or small cell car­cinoma of the lung). The stimulatory effect of GHRH induces somatotrope hyperplasia, pituitary enlargement, and clinical acromegaly; a situation indistinguishable from a GH-producing pituitary adenoma. A similar phenomenon occurs with GHRH-producing hypothalamic hamartomas and adenohypophyseal neuronal choristomas, although, in the latter, a GH adenoma frequently co­exists. Although these GHRH-producing tumors are a rare cause of acromegaly, they must always be considered in the differential diagnosis. Because they are often difficult to distinguish from GH­producing pituitary adenomas, some physicians have advocated the routine measurement of GHRH in all acromegalic patients. Idiopathic GH-cell hyperplasia is a rare condition. It has been the cause of several cases of childhood gigantism.

TSH-Cell Hyperplasia

Thyrotrope hyperplasia occurs almost exclusively in the setting of long-standing primary hypothyroidism. Although this entity should never be of neurosurgical concern, the hyperplasia is sometimes so massive that the pituitary gland becomes grossly enlarged and mimics an adenoma. The pituitary surgeon should be aware of this condition, insofar as recognition of the hypothyroid state and thyroid hormone replacement alone will ameliorate the pituitary mass. Nevertheless, a number of cases of thyrotrope hyperplasia have inadvertently, indeed unsuccessfully, been treated by surgical resection.

Gonadotrope Hyperplasia

Hyperplasia of gonadotrope is extremely rare, and even when mas­sive may be difficult to recognize. Although it has been reported in the pituitaries of patients in whom primary hypogonadism commenced at a young age, it is rarely a feature of surgical pathology. It is not known to be a cause of pituitary enlargement; neither is it an accompanying feature nor a predecessor of gonadotrope adenomas.

Tumors of the Neurohypophysis

The posterior pituitary is of diencephalic origin and can be consid­ered an extension of the central nervous system. Together with the infundibulum, which is a funnel-shaped extension of the tuber cinereum, and the pituitary stalk, the collective functional unit is known as the neurohypophysis. Clinically significant primary tumors of the neurohypophysis are rare, including the granular cell tumor and various gliomas of the neurohypophyseal region.

Granular Cell Tumors

Granular cell tumors are the most common tumors of the posterior lobe, and although their histogenesis has long been debated, the emerging hypothesis suggests that they derive from supporting glial elements of the infundibulum and posterior lobe (pituicytes). As incidental autopsy findings, granular cell tumors are seen with some regularity, being present in up to 17 percent of random post­mortem specimens. That they are rarely seen in autopsies of persons less than 20 years old suggests that they are acquired lesions. They usually assume the form of barely visible cryptic aggregates or "tumorettes," which are often multiple and are distributed equally between the posterior lobe and the infundibulum. Occasionally, granular cell tumors become large and symptomatic, causing diabetes insipidus, visual disturbance, and other symptoms of an expansile intra- and suprasellar mass. In these rare instances, surgical intervention may be necessary. Their histologic appearance is characteristic, consisting of large, polygonal cells that are loosely disposed in sheets or ill-defined nodules. Most conspicuous are the abundant cytoplasmic granules, which are strongly positive by the PAS method and are diastase resistant, and which electron microscopy shows to be lysosomes. These tumors are immunonegative for all anterior pituitary hormones, variably positive for S-100 protein, and generally negative for glial fibrillary acidic protein (GFAP).

Neurohypophyseal Gliomas

Gliomas arising in the neurohypophysis are rare. Most of the few reported cases have been low-grade pilocytic astrocytomas. Although various names have been applied to these tumors, including "infundibulomas" and "pituicytomas," they are simply astrocytomas and are indistinguishable from astrocytomas arising elsewhere in the neuraxis. Parasellar gliomas arising from the optic nerve or chiasm, the hypothalamus, or the third ventricle may also secondarily infiltrate the neurohypophysis, such that the precise origin of the tumor may not be readily discerned.

Hamartomas, Choristomas, and Gangliocytomas of the Sellar Region

An occasional type of sellar region mass, sometimes found in association with acromegaly or Cushing's disease, is the group of histologically similar but topologically distinct lesions of neuronal origin. Although these lesions are all conceptually and morphologically similar, they have acquired a confusing terminology, in which the names hamartoma, gangliocytoma, and choristoma have been inconsistently, interchangeably, and sometimes inappropriately used. In all cases, the basic lesion is the same, consisting of mature neurons of varying size, clustered among axons and astroglial elements. In some cases, these neurons produce hypothalamic peptides, raising the possibility that they may induce hyperplastic or neoplastic changes in adenohypophyseal cells and a corresponding, clinically evident hypersecretory state. Although some investigators consider these lesions to be true neoplasms, justifying the term gangliocytoma, others believe them to be hamartomatous growths. The experience has impression with the mature and non-neoplastic morphology of the neuronal cells and suggests a non-neoplastic designation. Therefore, when such lesions arise in the hypothalamus, they should be called hypothalamic hamartomas. Those arising in the sella and without physical attachment to hypothalamic structures should be called choristomas. Implicit in the latter term is their heterotopic and non-neoplastic nature.

Hypothalamic Hamartomas (Gangliocytomas)

Nodular, hamartomatous foci of hypothalamic tissue are not unusual autopsy findings. Most are small and insignificant, and they usually occur as discrete lesions in the region of the ventral hypothalamus. Rarely these nodules may become several centimeters in size, extend into the third ventricle, descend into the sella or hang in the interpeduncular cistern, producing a variety of compressive and endocrinologic effects. Most of these lesions retain some anatomic continuity with the hypothalamus, tuber cinereum, or mamillary bodies. Because of their location, a variety of autonomic disturbances may occur, including hyperphagia and somnolence. Their best-known manifestation, however, is precocious puberty, which results from either simple hypothalamic compression or from the liberation of gonadotrophin-releasing hormone (GnRH). Other tumors elaborate GHRH, which may induce both GH-cell hyperplasia and GH-producing adenomas in the pituitary, which acromegaly being the clinical result. Their histologic picture is characteristic, consisting of mature neurons of varying size clustered on a background of axons and astroglial elements. Immunopositivity for hypothalamic hormones may be demonstrated in the neurons of these lesions

Intrasellar Neuronal Choristomas (Gangliocytomas)

This lesion is histologically similar to the hypothalamic variant but has a primary intrasellar origin, lacks anatomic continuity with the hypothalamus, and is almost invariably associated with a hypersecretory pituitary adenoma. It has been speculated that choristomas release hypothalamic hormones by way of a paracrine mechanism, which could induce adenomatous transformation of adjacent adenohypophyseal cells. Among the cases reported to date, GHRH is the most common product, resulting in a GH-producing pituitary adenoma and clinical acromegaly. CRH-producing choristomas have also been reported, with a concurrent corticotrope adenoma or corticotrope hyperplasia, and Cushing's disease clinically. The typical histologic picture consists of mature neurons and accompanying neuropil interspersed in the substance of a pituitary adenoma. With immunohistochemistry, hypothalamic hormones (GHRH, CRH, GnRH) may be demonstrated in the neurons of the choristoma, and, correspondingly, GH, ACTH, and FSH/LH, may be demonstrated in the pituitary adenoma.

Craniopharyngiomas

Craniopharyngiomas are epithelial neoplasms that occur exclusively in the region of the sella turcica and are thought to derive from squamous cell nests of the pars tuberalis. They produce no hormones, account for approximately 3 percent of intracranial neoplasms, and are most common in childhood and adolescence. Craniopharyngiomas may be intrasellar or suprasellar and may cause various degrees of hypopituitarism by compression of the adenohypophysis, pituitary stalk, or hypothalamus. They are almost always benign; however, surgical extirpation is difficult, and postoperative recurrence is common.

The histologic appearance of craniopharyngiomas is distinctive, with cords of squamous and columnar epithelium, keratin pearls, and cystic areas filled with necrotic debris. Calcification is common, and bone formation may occur. Special stains and electron microscopy are usually not required to confirm the diagnosis. Immunohistochemistry reveals keratin in epithelial cells and is negative for adenohypophyseal hormones. Electron microscopy shows that the epithelial cells have prominent bundles of tonofibrils, with desmosomes but no secretory granules.

Other Primary Tumors of the Sellar Region

Although pituitary adenomas and craniopharyngiomas are the main neoplasms occurring in the sellar region, a variety of other primary tumors periodically involve parasellar structures. The relatively generic symptom complex of sellar region masses (visual dysfunction, low-grade hyperprolactinemia, and various degrees of hypopituitarism) coupled with the similar radiologic profiles of different tumor types, frequently makes it impossible to distinguish preoperatively between these various tumors and nonfunctioning pituitary adenomas.

Approximately 10 to 20 percent of intracranial meningiomas involve parasellar structures. Most of these assume a suprasellar location, taking dural origin from the tuberculum sellae, planum sphenoidale, diaphragma sellae, olfactory groove, medial sphenoid wing, or optic nerve sheath. Pure intrasellar meningiomas are rare. Chordomas arising from the upper clivus and dorsum sellae (basisphenoidal chordomas) occasionally involve the sella. Exceptional cases of pure intracellar chordomas have also been reported. Germ cell tumors, particularly suprasellar germinomas, are an important diagnostic consideration in suprasellar masses, especially in children. Tumors of disordered embryogenesis, such as epidermoid tumors and, less frequently, dermoid tumors, occasionally involve the parasellar region, often with intrasellar extension. Pure intrasellar versions of these tumors have also been known to occur, but are exceptional. Although rarities, intrasellar schwannomas, paragangliomas, glomangiomas, cavernous hemangiomas, hemangioblastomas, and primary melanomas of the pituitary have all been reported.

Occasional rapidly growing, pleomorphic sarcomas have been reported following irradiation for pituitary adenomas, suggesting a possible inductive effect of such exposure.

Metastatic Tumors

Metastatic carcinoma involves the pituitary in patients with advanced, widely disseminated malignant disease. Autopsy series have documented adenohypophyseal metastases in 1 to 5 percent of cancer patients. In many cases, pituitary involvement is subclinical, with patients succumbing to their systemic disease before the pituitary deposit becomes manifest. However, as an increasing number of cancer patients are surviving long enough to incur the eventual complications of widespread tumor dissemination, clinically significant pituitary deposits are increasingly recognized.

Uncommonly, a pituitary metastasis may occur in the absence of a known primary, providing the first indication of neoplastic disease. Because the posterior pituitary has a direct arterial blood supply, in contradistinction to the portal circulation of the anterior lobe, more than 70 percent of pituitary metastases involve the posterior lobe. Accordingly, diabetes insipidus is a common presenting feature. Headache and visual symptoms may also occur; however, hypopituitarism is infrequently an accompanying feature. The rarity of the latter reflects the tremendous functional reserve of the anterior pituitary, more than 90 percent of which must be destroyed before signs of hypopituitarism emerge. Contiguous bony involvement of the sella may also be seen.

The most common secondary tumor found in the pituitary is from breast carcinoma. Metastases may also originate from bronchogenic, colonic, and prostatic carcinomas.

Lymphomas, leukemias, and various sarcomas may be found in the pituitary, mainly in the posterior lobe. In cases of widespread tissue destruction, diabetes insipidus may develop.

Tumor-Like Conditions

Massive destruction and enlargement of the pituitary may occur with various non-neoplastic conditions, as listed in Table-1. When such processes converge on the sella, their ability to mimic pituitary adenomas is often striking, particularly when their compressive effects result in visual loss, hypopituitarism, and low-grade hyperprolactinemia; the latter being a consequence of hypothalamic or stalk injury. As individual entities, most of these tumor-like conditions are rare; however, as a group, they are common enough to merit some consideration in the differential diagnosis of a nonfunctioning sellar mass. The preoperative onset of diabetes insipidus is often a helpful clue; it sometimes occurs with these tumor-like conditions but is rarely, if ever, a presenting feature of pituitary adenomas.

A substantial proportion of these tumor-like conditions are of an inflammatory nature, including acute infections, chronic granulomatous conditions or infections, and autoimmune processes. A variety of infectious processes can afflict the pituitary and sella, ranging from acute suppuration (pyogenic bacteria), to chronic granulomatous infection (syphilis, tuberculosis), to parasitic infiltration (cysticercosis, echinococcosis). In patients with the acquired immunodeficiency syndrome and other immunocompromised states, an additional spectrum of pituitary infection has emerged, including agents such as Pneumocystis carinii, Toxoplasma gondii. and cytomegalovirus. Pituitary abscesses are discussed elsewhere.

Of the noninfective granulomatous inflammations affecting the pituitary, sarcoidosis is probably the most common. Neurosarcoidosis, known for its predilection for the basilar brain structures, frequently involves the hypothalamus and, less often, the infundibulum and pituitary. Giant cell granuloma of the pituitary is a rare, idiopathic inflammatory affliction known for its destructive effects on the anterior lobe. The inflammatory mass often extends into the suprasellar region, generating symptoms of a mass effect in addition to anterior pituitary failure. Another rare granulomatous condition of the sella region is pseudotumor, which, as with its occurrence elsewhere, is a diagnosis of exclusion.

Langerhans' cell histiocytosis (histiocytosis X) involves the nervous system in approximately one quarter of all cases, typically in the form of multifocal bony lesions. Hypothalamic, infundibular, posterior pituitary, and, less commonly, anterior pituitary involvement may occur following secondary extension from an adjacent bony lesion. Isolated pituitary involvement has also been reported.

Lymphocytic hypophysitis is a destructive, inflammatory disorder of the anterior pituitary, presumed to be of autoimmune origin. Occurring most frequently in women, and often associated with pregnancy, the condition is characterized pathologically by a destructive infiltrate of lymphocytes, plasma cells, eosinophils, and macrophages restricted to the anterior lobe.

The remaining tumor-like conditions affecting the sellar and suprasellar regions are discrete structural masses, and include Rathke's cleft cysts, suprasellar and (rarely) intrasellar arachnoid cysts, intrasellar mucoceles extending from the sphenoid or ethmoid sinuses, and cerebral aneurysms. The last most commonly arise from the cavernous portion of the internal carotid artery, but they can also arise from the supraclinoid carotid artery and the anterior communicating artery complex. In addition to aneurysms that mimick pituitary adenomas, an association between pituitary adenomas and cerebral aneurysms has been noted. In one series, the incidence of cerebral aneurysms coexisting with pituitary adenomas was 7.4 percent. GH-producing tumors, in particular, have been associated with incidental aneurysms at a frequency beyond what would be expected by chance alone.

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