CHAPTER 134 Pituitary Tumors
Functioning and Nonfunctioning
Pituitary Surgery: Historical Considerations
Most accounts of the history of pituitary surgery begin with an operation performed more than a century ago (1892) when Paul,1 a British surgeon, undertook the surgical management of an acromegalic patient. The patient, a 34-year-old woman, suffered from headache, facial pain, and vision loss. At the suggestion of Horsely, Paul performed a subtemporal decompression, but the tumor proved inaccessible. The patient’s symptoms, presumably caused by elevated intracranial pressure, were alleviated. The patient died about 3 months later, and the autopsy revealed a tangerine-sized pituitary tumor. The histologic diagnosis was “round cell sarcoma,” the prevailing nosology for pituitary adenomas at the time. Horsely2 subsequently used temporal and subfrontal approaches to treat 10 patients with pituitary tumors and reported this series in 1906.
The next major technical and conceptual advance came from Vienna, where a number of surgeons devised and successfully applied extracranial approaches to the sella. Schloffer3 was the first in 1907, employing an extensive lateral rhinotomy type of incision, with resection of the septum and turbinates en route to the sella. A variation of this approach was advocated by von Eisenberg4 and subsequently modified by Hochenegg,5 who accessed the sella through the frontal sinus.5 In 1909 Cushing6 used a variation of Schloffer’s method in an acromegalic patient, subsequently refining the technique and adopting the sublabial incision that was later described by Halstead7,8 and Kanavel.9 Contemporaneously, major contributions to the evolution of the transsphenoidal approach were provided by Hirsch,10 who described the endonasal approach in 1910 and later described the submucosal transseptal transsphenoidal approach.
As cranial neurosurgery continued to evolve, so did transcranial approaches to pituitary tumors. The second decade of the 20th century brought an escalating enthusiasm for transcranial approaches, and transsphenoidal approaches were all but abandoned, particularly in North America. Owing to technical contributions by Heuer, Frazier, Krause, Elsberg, Cushing, and others, transcranial approaches to the pituitary became routine. Fortunately, transsphenoidal methods were sustained by a few. Most notable among these was Dott of Edinburgh. A former pupil of Cushing, Dott continued to practice, refine, and teach transsphenoidal techniques. One of his students, Guiot,11 popularized the procedure in France and became one of its major advocates. Guiot passed on transsphenoidal methods to Hardy12 of Montreal, who reintroduced this approach to the neurosurgical mainstream in North America. In doing so, Hardy merged the procedure with the operating microscope, illuminating the microsurgical aspects of the technique, promulgating the concept of microadenoma, and showing the feasibility of selective tumor removal while preserving normal pituitary tissue and function. Together, Guiot and Hardy popularized their work in the 1960s and established the technical and conceptual elements of the procedure that form the basis of transsphenoidal microsurgery as it is practiced today.
The procedure has continued to evolve.13,14 Technical adjuncts include the application of transsphenoidal endoscopy, frameless stereotaxy for transsphenoidal surgery, and intrasellar ultrasonography.15–18 Transsphenoidal microsurgery is the preferred approach for more than 95% of pituitary tumors and for a large proportion of other sellar abnormalities. Further evolution of the transsphenoidal approach occurred with the introduction of the endoscope. Although used intermittently as an adjunct to microscopic transsphenoidal surgery,19,20 the concept of a pure endoscopic transsphenoidal technique (without the use of the operating microscope) was introduced in the 1990s and has recently become popular.21–30 The multidisciplinary neurosurgical and otolaryngologic team at the University of Pittsburgh Medical Center has broadened the scope of pathology that can be approached endonasally, including complex skull base pathology extending from the crista galli to the upper cervical spine.28,31 Whether performed microscopically or endoscopically, the transsphenoidal approach is preferred for more than 95% of pituitary tumors and for an expanding proportion of parasellar pathologies as well.
Pituitary Tumors: General Considerations
Epidemiology
Pituitary tumors are common lesions believed to account for 10% to 15% of all primary brain tumors.32 More precise estimates on their incidence and prevalence vary to some degree, depending on the means of survey, the population studied, and the period of the study. Data from academic medical centers suggest that pituitary tumors represent as many as 20% of surgically resected primary brain tumors.33 Epidemiologic estimates indicate an annual incidence of 8.2 to 14.7 cases per 100,000 people.34 A recent Belgian study reported a prevalence of 94 cases per 100,000.35 By these measures, pituitary tumors are the third most common primary intracranial tumor, preceded in frequency only by gliomas and meningiomas. These data underestimate the true frequency of pituitary tumors, however. Unselected autopsy studies have repeatedly shown that 20% to 25% of the general population harbor small pituitary microadenomas. These lesions are clinically silent; occur in patients without apparent endocrine symptoms; have the morphology of null cell, gonadotroph, or lactotroph adenomas; and are identified only after careful microscopic postmortem examination of a serially sectioned pituitary gland.32,36 The high subclinical prevalence of these so-called incidentalomas has also been validated with magnetic resonance imaging (MRI). When carefully sought, subtle signal changes in the pituitary gland indicative of a clinically occult microadenoma can be identified in 10% or more of routine MRI scans.37–39 It therefore follows that neoplastic transformation is a frequent occurrence in the pituitary, although it reaches clinical attention and requires intervention in relatively few cases.
Although pituitary adenomas occur in all age groups, the highest incidence is between the third and sixth decades of life. As a general rule, functioning pituitary tumors tend to be more common among younger adults, whereas nonfunctioning adenomas become more prominent with increasing age.40–42 Pituitary adenomas are uncommon in the pediatric population, representing only 2% of all primary pediatric brain tumors.43 The relative rarity of these lesions in the pediatric population is also reflected in several large institutional series of pituitary adenomas. At the Centre Foch, the Mayo Clinic, and the University of San Francisco, the respective proportions of pediatric pituitary tumors were 2.1% (66 of 3200 patients), 2.03% (36 of 1776), and 5.34% (119 of 2330).41,44,45 In most surgical series, pituitary tumors are distinctly more common among women, particularly premenopausal women. The basis of the higher prevalence in women is unclear, especially because incidental pituitary tumors are equally distributed between the sexes in autopsy series.36 One plausible explanation is that the clinical manifestations of pituitary adenomas, most notably menstrual dysfunction, are more conspicuous in women and are more readily diagnosed in premenopausal women than in men. The fact that Cushing’s disease is much more prevalent in women than men may contribute to this phenomenon.
Genetic predisposition to pituitary tumors is restricted to a single uncommon condition: multiple endocrine neoplasia type 1 (MEN-1) syndrome. Only 3% of all pituitary tumors occur in the context of this disorder. An autosomal dominant condition, MEN-1 syndrome is characterized by tumors of the parathyroid glands, pancreatic islet cells, and pituitary. Because the condition is variably penetrant, only 25% of affected patients develop pituitary adenomas, and most of these are macroadenomas associated with excess levels of growth hormone (GH) or prolactin (PRL), or both.46,47
Pathology
Because pituitary adenoma is clinically and numerically the most significant neoplastic process affecting the pituitary gland, only this lesion is discussed in this chapter. However, a diverse collection of other abnormalities can occur in the sellar region. Often masquerading as nonfunctioning pituitary adenomas, these lesions include a wide variety of neoplasms, developmental lesions, cysts, inflammatory processes, and aneurysms (Table 134-1).
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Tumors of Adenohypophysial Origin Tumors of Neurohypophysial Origin Rare Tumors of Nonpituitary Origin |
Normal Adenohypophysial Morphology
Collectively, the adenohypophysis includes the pars distalis (anterior lobe), pars intermedia (intermediate lobe), and pars tuberalis (funnel-shaped upward extension of anterior lobe cells on the anterior face of the pituitary stalk). It is the site of meticulously regulated hormone synthesis and release. Representing approximately 80% of the entire pituitary, the adenohypophysis is the primary intrasellar site for most pathologic processes, including neoplastic disease. The anterior lobe is composed of five principal secretory cell types, each functionally and ultrastructurally distinct, and each distributed in a fairly consistent topologic arrangement within the gland. These five cell types are somatotrophs, lactotrophs, corticotrophs, thyrotrophs, and gonadotrophs, and they are distinguished functionally by their secretion of GH, PRL, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), respectively. In a remarkably integrated fashion, the secretory and proliferative capabilities of these cells are governed by a precise and continuously regulated balance between stimulatory and suppressive hypothalamic influences and the negative feedback effects imposed by target organ hormones.48,49 Although susceptibilities vary, any of these cell types may be subject to neoplastic transformation. The resulting adenoma generally retains the secretory capabilities, some of the morphologic characteristics, and the nomenclature of the cell of origin.48,49
Microscopically, the anterior pituitary exhibits a delicate acinar architecture, and each acinus is composed of an admixture of various secretory cell types. Regionally within the gland, a definite and consistent topologic arrangement exists, in which different cell types are distributed at preferential intraglandular locations.32 Given these regional differences in the density of various adenohypophysial cells, different pituitary adenoma types vary correspondingly in their preferential site of intraglandular origin. An awareness of this topologic organization is important to neurosurgeons, who must occasionally dissect through a seemingly normal pituitary gland in search of a microadenoma. When visualized in horizontal cross section, the anterior lobe is composed of two lateral wings and a trapezoidal, central mucoid wedge. GH-producing cells populate the lateral wings and are especially abundant along its anterior face. Somatotroph adenomas usually arise at this site. PRL-producing cells can be found anywhere within the anterior lobe, although the densest accumulation occurs along the posterior aspect of the lateral wings, just anterior to the neural lobe. Most lactotroph adenomas also originate here. Corticotrophs, representing 10% to 15% of all adenohypophysial cells, usually reside within the central wedge, just anterior to the posterior lobe. This is a common but not invariable site for corticotroph adenomas. Thyrotrophs, accounting for less than 5% of all adenohypophysial cells, occupy a small zone in the anteromedial aspect of the central wedge. Although thyrotroph adenomas are seldom discovered while still microadenomas, most can be presumed to have originated at this site. Gonadotrophs are widely distributed throughout the pars distalis and have no favored site of accumulation. Gonadotroph adenomas do not have a stereotypical site of origin. They may be related to pituitary stem cells, “null cells,” and folliculostellate cells.
Histopathology of Pituitary Adenomas
Grossly, pituitary tumors are yellow-gray to purple; they often have a soft, fluid to creamy texture, in contrast to the firmness of the normal gland. The histologic growth pattern of pituitary adenomas varies, ranging from diffuse to sinusoidal to papillary. Beyond their descriptive merit, such designations are without prognostic significance. The most important histologic characteristics of pituitary adenomas are cellular monomorphism and a lack of acinar organization. In contrast, the normal pituitary exhibits an intimate admixture of different cell types arranged in a well-organized acinar pattern. Disruption of this acinar structure in adenomas is particularly well seen with silver stains for reticulin fibers. When studied in this manner, the presence of the interface between adenoma and nontumorous pituitary gland can be especially eye-catching, because the compressed rim of the latter forms a pseudocapsule around the former. This pseudocapsule of compressed normal gland, although thin, is often robust and in many cases fully contains the tumor.50
For the basic diagnosis of pituitary adenoma, light microscopy and hormone immunohistochemistry generally suffice. More precise classification requires ultrastructural examination. The ultrastructural profile of any given tumor provides information concerning tumor cytogenesis, degree of differentiation, and cellular constitution.32 The principal ultrastructural features used to distinguish and classify adenomas include cell size and shape, nuclear morphology, and the distribution and morphology of secretory granules, rough endoplasmic reticulum, Golgi apparatus, and microfilament accumulation. Morphologic details of this ultrastructural classification are presented elsewhere51; pertinent clinicopathologic aspects are discussed in the following sections.
Classification of Pituitary Adenomas
Pathologic Classification
Immunohistochemistry and electron microscopy represent the “gold standard” methods of classifying pituitary adenomas. Delineating tumors on the basis of hormonal content, ultrastructural morphology, and cellular derivation, these methods have led to a new classification of pituitary adenomas that reliably correlates structure with function and cytogenesis with biology.32 As outlined in Table 134-2, this classification recognizes 14 principal pituitary adenoma subtypes, each having its own immunohistochemical and ultrastructural profile. Adenomas are stratified first on the basis of cellular origin and hormonal content and secondarily on the basis of ultrastructure.32,51–54 Subtypes that appear to have a higher recurrence rate include sparsely granulated GH adenomas, mammosomatotroph adenomas, acidophil stem-cell adenomas, and silent adenomas (especially silent ACTH adenomas and silent subtype 3 tumors).32,53,54
The morphologic appraisal of pituitary adenomas has its limitations. Whether considered from the standpoints of routine histology, hormonal immunophenotype, or ultrastructural morphology, none of these techniques permits reliable inferences about tumor behavior or prognosis.51 Accordingly, pituitary adenomas are not amenable to any form of histopathologic grading, such as that available for astrocytic tumors, that could reliably distinguish aggressive variants from indolent ones. The usual morphologic markers of tumor aggressiveness—pleomorphism, nuclear atypia, increased cellularity, and mitotic activity—correlate poorly with an adenoma’s invasive tendency, proliferative capacity, potential for recurrence, and overall biologic behavior. In general, mitotic figures and other morphologic markers of aggressive behavior are neither sufficiently common among invasive tumors nor sufficiently rare among noninvasive tumors to be of routine prognostic use.55 Nevertheless, pituitary adenomas are graded as “typical adenomas,” “atypical adenomas,” and “pituitary carcinomas.”53 Atypical adenomas are characterized by atypical morphology, an elevated mitotic index, a Ki-67 (MIB-1) labeling index greater than 3%, and extensive p53 nuclear staining. Pituitary carcinoma is characterized by the presence of noncontiguous metastatic spread of an adenoma.53,54
Imaging Classification
From a surgical standpoint, pituitary tumors can be classified on the basis of their size and growth characteristics, as determined by imaging studies. The simplest system, based purely on size, classifies tumors as microadenomas (<1 cm in diameter) or macroadenomas (>1 cm in diameter). This system fails to account for the tremendous variability in the size and growth characteristics of macroadenomas. The most enduring classification is that devised by Hardy12,56 and modified by Wilson.57 This five-tiered radiologic classification first differentiates tumors as microadenomas or macroadenomas. Microadenomas are designated grade 0 or grade I tumors, depending on whether the sellar appearance is normal or minor sellar changes are present, respectively. Macroadenomas causing diffuse enlargement, focal destruction, and extensive destruction of the sella are referred to as grade II, grade III, and grade IV tumors, respectively. In this system, macroadenomas are also staged according to the degree and direction of extrasellar extension—extending to the suprasellar cistern only (stage A), to third ventricle floor (stage B), or into the third ventricle (stage C). Tumors that have extensive lateral intradural or extradural extension are referred to as stage D and stage E, respectively.
With the advent of high-quality MRI, Knosp and colleagues58 proposed a grading system that predicts cavernous sinus invasion based on the position of the tumor in relation to tangents drawn through the supra- and intracavernous carotid arteries in the coronal view. Tumors that encase the carotid artery are universally found to invade the cavernous sinus at surgery. Tumors that do not pass beyond a tangent along the medial border of the supra- and intracavernous sinus do not invade the cavernous sinus. However, no other radiographic findings can definitively predict cavernous sinus invasion or the lack thereof.59
World Health Organization Classification
A variety of approaches can be used to classify pituitary tumors, ranging from simple to sophisticated, with each having its own merits and limitations. The management of pituitary tumors is a multidisciplinary endeavor, and nosologic preferences vary among specialties; the pathologist may favor a morphologic classification, the endocrinologist may favor one based on endocrine activity, and the neurosurgeon may favor one based on tumor size and invasiveness. In a bid to create a comprehensive classification scheme universally acceptable to clinicians, pathologists, and surgeons alike, a seven-tiered classification of adenohypophysial tumors has been proposed by the World Health Organization.53 In this scheme, seven descriptive levels are applied to each adenoma:
Clinical Manifestation of Pituitary Tumors
The clinical manifestation of pituitary adenomas usually centers on one or more of three clinical scenarios.49,60,61 The first involves pituitary hyperfunction in the form of several characteristic hypersecretory states. Hypersecretion of PRL, GH, ACTH, and TSH (rarely) produces corresponding clinical syndromes: amenorrhea-galactorrhea syndrome, acromegaly or gigantism, Cushing’s disease, and secondary hyperthyroidism. Because as many as 70% of pituitary adenomas are endocrinologically active, the presence of a hypersecretory endocrine state is the most common mode of presentation.
The second type of manifestation involves pituitary insufficiency and is typically associated with larger tumors that compress the nontumorous pituitary gland or its stalk or, in the case of giant pituitary adenomas, compress hypophysiotropic areas of the hypothalamus. In general, the pituitary gland displays remarkable functional resilience to even chronic compression and distortion. Eventually, however, anterior pituitary failure supervenes. Each pituitary endocrine axis appears to have a different tolerance of chronic compression. Gonadotrophs are most vulnerable and are affected first. Thereafter, thyrotroph, somatotroph, and eventually corticotroph functions are sequentially compromised.49 Curiously, regardless of how large the tumor is or how extreme the glandular or stalk compression is, posterior pituitary failure (i.e., diabetes insipidus) is rarely a presenting feature of pituitary adenomas; its preoperative presence virtually excludes a diagnosis of pituitary adenoma. Hypopituitarism that accompanies pituitary adenomas is usually a chronic process, but in the setting of pituitary apoplexy, it can be an acute, unexpected, and immediately life-threatening event.
