Special Article

Protocol for the Examination of Specimens From Patients With Primary Pituitary Tumors Vania Nose´, MD, PhD; Shereen Ezzat, MD; Eva Horvath, PhD; Kalman Kovacs, MD, PhD; Edward R. Laws, MD; Ricardo Lloyd, MD, PhD; M. Beatriz S. Lopes, MD, PhD; Sylvia L. Asa, MD, PhD

an effort to improve the diagnosis of pituitary tumors, NweIn propose a synoptic approach to pituitary pathology reporting that will provide clear information to endocrinologists, neurosurgeons, neuropathologists, and surgical pathologists to advance the diagnosis and classification of pituitary adenomas. (Arch Pathol Lab Med. 2011;135:640–646) t is clear that thorough evaluation of histology and Ification immunohistochemistry provides the basis for a classiof pituitary tumors that correlates with clinical findings, imaging, surgical findings, and responses to therapies. Consensus has shown that comprehensive clinical and radiologic information is required for reporting, and pituitary reports should now include the morpho-functional diagnosis specifying World Health Organization (WHO) tumor type, which is determined by standard immunohistochemical as well as histopathologic findings. The importance of following the guidelines in this proposal must be emphasized to ensure the highest quality of patient care. SCOPE OF GUIDELINES The reporting of pituitary tumors is facilitated by the provision of a checklist illustrating the features required for comprehensive patient care. However, there are many cases in which the individual practicalities of applying such a checklist may not be straightforward. Common examples include the inability to perform the appropriate immunohistochemical stains to determine the cytogenesis of these lesions and situations in which the tissue received Accepted for publication January 12, 2011. From the Department of Pathology, University of Miami, Miami, Florida (Dr Nose´); the Departments of Medicine (Dr Ezzat) and Pathology (Dr Asa), University Health Network, Toronto, Ontario, Canada; the Department of Laboratory Medicine, St Michael’s Hospital, Toronto, Ontario, Canada (Drs Horvath and Kovacs); the Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts (Dr Laws); the Department of Pathology, University of Wisconsin, Madison (Dr Lloyd); and the Department of Pathology, University of Virginia, Charlottesville (Dr Lopes). The authors have no relevant financial interest in the products or companies described in this article. Presented at the International Pituitary Pathology Congress, Awaji Islands, Japan, October 2009. Reprints: Vania Nose´, MD, PhD, University of Miami, Miller School of Medicine, Clinical Research Building (R-5), 1120 NW 14 St, Suite 1411, Miami, FL 33136 (e-mail: [email protected]). 640

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in the surgical pathology laboratory is too small to allow complete evaluation. Checklists have evolved to include clinical, radiographic, morphologic, immunohistochemical, and molecular results in an effort to guide clinical management. This checklist tries to remain simple while still incorporating important pathologic features as proposed by the WHO classification of tumors of endocrine organs.1 This checklist is to be used as a guide and resource, an adjunct to diagnosing and managing tumors of the pituitary gland in a standardized manner. It does not review the histologic, immunohistochemical, and ultrastructural parameters that provide the information to reach the diagnosis; that is provided elsewhere.2 Elements listed are not meant to be arbitrary but are meant to provide uniformity of reporting across all the disciplines that use the information. It is a foundation of practical information that will help to meet the requirements of daily practice to benefit clinicians and patients alike. For editorial comment, see p 534. This protocol applies only to pituitary adenomas, hyperplasias, and carcinomas and to craniopharyngiomas. It does not apply to neuronal or astrocytic lesions found in this region that have protocols defined in other checklists nor does it apply to lymphomas, sarcomas, or metastatic tumors to the pituitary gland. PATHOLOGY CASE SUMMARY (CHECKLIST) Select a Single Response Unless Otherwise Indicated * Data elements with asterisks are not required. However, these elements may be important but are not yet validated or regularly used in patient management. Procedure (select all that apply) (note A) ___ Transsphenoidal resection ___ Transcranial resection ___ Other (specify): _______________________________ ___ Not specified Clinical Features (note B) ___ Functional Hormone excess (specify): ______________________ ___ Clinically nonfunctioning Tumor Size (from imaging) (note C) ___ Microadenoma (,1 cm) ___ Macroadenoma ($1 cm) Protocol for Primary Pituitary Tumors—Nose´ et al

Greatest dimension: ___ cm *Additional dimensions: ___ 3 ___ cm ___ Cannot be determined *Received *___ Fresh *___ In formalin *___ Other *Specimen Integrity *___ Intact *___ Fragmented Specimen Size ___3 ____3 ____cm *Specimen Weight *___ grams Histologic Features (note D) Reticulin ___ Intact ___ Expanded ___ Disrupted Periodic acid–Schiff stain ___ Positive ___ Negative Infiltrating tumor (note E) ___ Positive (specify tissue): _______________________________ ___ Negative ___ Cannot be determined Immunohistochemistry (select all positive) (note F) ___ Pit-1 ___ Estrogen receptor ___ Tpit ___ SF1 ___ Adrenocorticotropin ___ Growth hormone (GH) ___ Prolactin ___ b-Thyrotropin ___ b–Follicle-stimulating hormone ___ b–Luteinizing hormone ___ a-Subunit ___ Keratin (CAM 5.2) Diffuse: ______________________________________ Fibrous bodies ________________________________ Perinuclear ___________________________________ Membranous _________________________________ ___% MIB-1/Ki-67 proliferative index ___ p53 ___ Synaptophysin ___ Chromogranin ___ Others (specify):_______________________________ Additional Ancillary Studies (note G) ____ Specify: _____________________________________ Tumor Type (note H) Pituitary adenoma Subtype ___ Densely granulated corticotroph adenoma ___ Sparsely granulated corticotroph adenoma ___ Crooke cell adenoma ___ Densely granulated somatotroph adenoma ___ Sparsely granulated somatotroph adenoma Arch Pathol Lab Med—Vol 135, May 2011

___ Mammosomatotroph adenoma ___ Mixed somatotroph-lactotroph adenoma ___ Sparsely granulated lactotroph adenoma ___ Densely granulated lactotroph adenoma ___ Acidophil stem cell adenoma ___ Thyrotroph adenoma ___ Gonadotroph adenoma ___ Unusual plurihormonal adenoma ___ Null cell adenoma ___ Oncocytoma ___ Other (specify): ___________________________ *___ Typical *___ Atypical Hyperplasia ___ Cell type (specify): ____________________________ Pituitary carcinoma ___ Cell type (specify): ____________________________ ___ Location of metastases _________________________ Craniopharyngioma ___ Papillary ___ Adamantinomatous Other ___ Gangliocytoma ___ Paraganglioma ___ Spindle cell oncocytoma ___ Pituicytoma ___ Granular cell tumor ___ Other (specify): _______________________________ Additional Pathologic Findings (note I) Nontumorous adenohypophysis ___ Present *___ Crooke hyaline change ___ Not identified Neurohypophysis ___ Present ___ Not identified *Comment(s): _____________________________________ EXPLANATORY NOTES A: Anatomical Sites of the Pituitary Gland.—The pituitary lies in the sella turcica, a concave structure in the superior sphenoid bone at the base of the brain (Figure 1). Lateral to the sella, the cavernous sinuses contain the internal carotid arteries and the oculomotor, trochlear, abducens, and first division of the trigeminal nerves. Inferior and anterior is the sphenoid sinus. Superior to the gland is the hypothalamus and superoanteriorly is the optic chiasm. The bilaterally symmetrical gland has 2 distinct parts, the adenohypophysis and the neurohypophysis. As their names suggest, these 2 parts are structurally and functionally different. The adenohypophysis is a redbrown epithelial gland; the neurohypophysis is a firm grey neural structure that is composed of axons of hypothalamic neurons and their supporting stroma. The hypophysis is enveloped by dura that lines the sella turcica. The diaphragma sellae, a reflection of the dura that constitutes the roof of the sella turcica, has a small central opening for the hypophysial stalk, the connection to the hypothalamus. The sellar diaphragm protects the pituitary from the pressure of cerebrospinal fluid. Protocol for Primary Pituitary Tumors—Nose´ et al

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Tumors that are predominantly or exclusively suprasellar require a transcranial approach. Some large tumors are resected using a combined approach with both a transsphenoidal approach from below and a transcranial resection from above. Pituitary Adenomas B: Clinical Features.—A functional classification of pituitary adenomas characterizes pituitary adenomas based on their hormonal activity in vivo. Growth hormone–producing adenomas are associated with acromegaly and/or gigantism, prolactin-producing adenomas cause hyperprolactinemia and its clinical sequela, adrenocorticotropin-producing adenomas are associated with Cushing or Nelson syndromes, thyrotropin-producing tumors are associated with disturbances of thyroid function, and rare clinically detectable gonadotroph adenomas usually result in hypogonadism. Clinically nonfunctioning adenomas present with headaches, visual field loss, and various degrees of hypopituitarism due to tissue destruction. Diabetes insipidus is exceptionally uncommon and usually signifies a nonadenomatous lesion. C: Tumor Size.—Pituitary adenomas usually grow by expansion locally within the sella and upward toward the optic chiasm. Lateral invasion into the cavernous sinus is not unusual in large tumors that can infiltrate around the carotid artery, rendering the lesion surgically unresectable. Rarely, they grow downward to erode the bone of the sellar floor, into the sphenoid sinus, and even into the nasal cavity9 or may invade posteriorly to involve or destroy the clivus.10 Tumor size has a significant impact on prognosis. Microadenomas are usually amenable to surgical resection. Larger tumors may be resectable, but lesions that extend into the cavernous sinuses laterally or very high into the brain superiorly cannot be completely resected by surgery and the patients may require postoperative medical therapy to control hormone hypersecretion and/or radiotherapy to control tumor growth. Neuroradiologic examination classifies pituitary adenomas based on tumor size and degree of local invasion. These data are of critical importance to the surgeon when planning an operative approach for tumor resection. The most widely used classification, proposed by Hardy11 in the 1970s, remains valid with the use of computed tomography scanning and magnetic resonance imaging (Figure 2). This classification places adenomas into 1 of 4 grades: Figure 1. Sella turcica and the surrounding structures. Figure 2. Imaging of a large pituitary adenoma involving extrasellar structures.

Ectopic pituitary tumors can arise along the path of embryonic development of the pituitary gland, usually in the sphenoid sinus.3–8 The surgical resection of tumors in this region usually involves a transsphenoidal approach with or without endoscopic assistance. Larger tumors may be resectable by this approach, but lesions that extend into the cavernous sinuses laterally or very high into the brain superiorly cannot be completely resected by surgery. 642

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Grade I adenomas, or microadenomas, are intrapituitary lesions that measure less than 1 cm in diameter Grade II adenomas are larger than 1 cm in diameter (macroadenomas) but still remain intrasellar or exhibit suprasellar expansion without invasion Grade III adenomas are small or large locally invasive tumors that cause bony erosion of the sella turcica Grade IV adenomas are large invasive tumors that involve extrasellar structures including bone, hypothalamus, and the cavernous sinus A subclassification of grade I, II, and III tumors identifies the degree of suprasellar invasion as small (A), moderate (B), or large (C). Protocol for Primary Pituitary Tumors—Nose´ et al

D: Histologic Features.—The histologic diagnosis of pituitary adenomas classifies tumors as acidophilic, basophilic, and chromophobic using conventional stains; acidophilic adenomas were said to be associated with acromegaly or gigantism, basophilic adenomas were thought to be the cause of Cushing disease, and chromophobic tumors were considered to be nonfunctioning from the endocrine perspective. However, the value of such classification was questioned when it became obvious that some chromophobic adenomas were associated with florid clinical symptomatology of hormone excess, and some acidophilic or basophilic adenomas were clinically hormonally inactive. A number of histochemical stains have been applied to the analysis of pituitary tissues, including various trichrome stains, aldehyde fuchsin and aldehyde thionin techniques, orange G, Herlant erythrosin, or Brookes carmoisine. In the era of immunohistochemistry, these relatively nonspecific stains are not recommended.2 The major exception to this rule is the reticulin stain, which is essential to distinguish normal adenohypophysial architecture, hyperplasia, and adenoma.12,13 The periodic acid–Schiff stain is very helpful to identify corticotrophs and is valuable to identify hyperplastic thyrotrophs that exhibit cytoplasmic periodic acid-Schiff–positive droplets. In rare instances, pituitary adenomas may contain amyloid material that stains with Congo red and has apple-green birefringence with polarized light.14–18 E: Invasiveness.—Invasive adenomas are a subject of controversy. Although it has been suggested that significant local invasion is indicative of malignancy, the WHO has restricted the use of the diagnosis of pituitary carcinoma to lesions that metastasize. Infiltration of dura, bone, nasal sinuses, and the cavernous sinus are relatively common19–21 in benign but aggressive adenomas. The incidence of invasion varies depending on whether the lesion is examined grossly or microscopically. Invasive lesions are less frequently identified by imaging techniques or by the surgeon than by the pathologist examining dural biopsies by microscopy.20 Documentation of infiltration of dura, bone, nasal sinuses, and the cavernous sinus should be included in the protocol when known. Invasiveness appears to correlate to some extent with tumor type and size. Invasion is characteristic of thyrotroph adenomas, silent corticotroph adenomas, and the unusual plurihormonal silent subtype 3 adenomas.22 Macroadenomas are more often invasive than are microadenomas. Grossly invasive adenomas are recognized by the surgeon and are usually not amenable to complete resection; however, there are no well-accepted markers to predict invasive behavior or to predict recurrence for smaller lesions. Cytologic features are not valid because they do not differ in recurrent and nonrecurrent tumors. Ploidy analyses have not found aneuploidy to correlate with hormone profile or recurrence.23,24 Some authors have suggested that the proliferation markers Ki-67, PCNA or p105,24–29 the purine-binding factor nm23,30 or topoisomerase II alpha31 may be useful in this regard. F: Immunohistochemical Profile.—The classification of pituitary adenomas relies on the application of immunohistochemical characteristics of tumor cells.2 There is still controversy concerning the most important reactivities of Arch Pathol Lab Med—Vol 135, May 2011

adenomas. From the clinical perspective, hormonal activity is the basis for diagnosis and therapy. Biologically, however, it remains to be established whether other characteristics, such as proliferation markers, growth factor and receptor expression, or oncogene product expression, will prove to be predictors of tumor behavior, such as invasive growth, recurrence, or metastasis. Pituitary adenomas are classified mainly by hormone content. This functional approach correlates with the clinical presentation of the patients. Other markers of cell differentiation, such as the transcription factors that regulate hormone expression and keratins that have different patterns of reactivities in different tumor subtypes, can also be used to classify and subclassify these tumors.1,2 Other predictive indicators, such as proliferation markers, can be incorporated into this type of classification; however, the best predictive markers remain those that subclassify adenomas accurately based on hormone content and cell structure.32 G: Electron Microscopy.—Electron microscopy was critical in the initial classification of pituitary adenomas.33 However, with current knowledge of structure-function correlations, the major tumor types can be distinguished on the basis of immunohistochemistry. Even variants derived from a single cell type can be distinguished; for example, the subtypes of somatotroph adenomas are conveniently recognized with the application of keratin stains because sparsely granulated somatotroph adenomas are characterized by scant GH immunoreactivity and conspicuous fibrous bodies that are stained by the CAM 5.2 antibody, whereas their densely granulated counterparts have intense GH reactivity and a delicate perinuclear keratin pattern of staining. Subclassification of GHand prolactin-producing adenomas as densely granulated somatotroph adenomas with prolactin content, mammosomatotroph adenomas, or mixed somatotroph-lactotroph adenomas can be difficult without ultrastructural analysis, but the significance of these subtleties for clinical management remains unclear. In the family of glycoprotein-producing adenomas, there has been some controversy concerning the diagnosis of gonadotroph adenomas without ultrastructural confirmation of cytodifferentiation. The development of sensitive and specific antisera and improvements in tissue fixation allow better antigen recognition and gonadotropic hormones are detected by antisera to b–follicle-stimulating hormone and b–luteinizing hormone in many clinically nonfunctioning adenomas. The application of immunohistochemistry for transcription factors allows identification of cell lineage even in the absence of hormone immunoreactivity. Some clinically silent tumors are recognized by electron microscopy as having gonadotropic differentiation, but some have characteristics of less well differentiated cells, resembling the ‘‘null’’ cells that were initially thought to be undifferentiated precursors of adenohypophysial cells.34 The role of electron microscopy in the classification of these tumors remains a subject of controversy, but because there is little clinical impact, the need for this expensive and time-consuming exercise remains academic. Electron microscopy may still be helpful for the diagnoses of some pituitary tumors including the rare acidophil stem cell adenomas or the unusual lesion known Protocol for Primary Pituitary Tumors—Nose´ et al

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as the silent subtype 3 adenoma. For some plurihormonal adenomas, electron microscopy continues to play an important role in determining cytodifferentiation and structure-function correlations. H: Classification.—The ideal classification of any group of tumors is one that maximizes the ability to reflect clinical and morphologic features.2 The endocrine manifestations and aggressivity of pituitary adenomas are usually correlated with specific morphologic phenotypes.32 Generally, aggressive behavior is a phenomenon of clinically silent hormone-containing adenomas and unusual plurihormonal adenomas as well as the rare lactotroph adenoma with GH immunoreactivity, known as the ‘‘acidophil stem cell adenoma.’’ Additional information, such as tumor size, radiologic, gross, or microscopic evidence of invasion, and the proliferative activity level of a tumor as identified by immunohistochemical proliferation markers, can be incorporated in a multidisciplinary fashion to determine the optimal therapeutic approach to management of the individual patient. The recent WHO classification of these tumors separates them into typical and atypical adenoma.1 However, the distinction is not entirely clear.32 Atypical morphologic features include invasive growth, high mitotic index, a MIB-1 labeling index greater than 3%, and extensive nuclear reactivity for p53. These features are not characteristic of pituitary adenomas, as they are usually devoid of mitoses, have MIB-1 labeling indices of 3% or less, and rarely show more than focal p53 immunopositivity. The definition of invasive growth is usually based on magnetic resonance imaging rather than morphology, but invasion of bone or dura can be documented histologically. Despite this classification into typical and atypical adenomas, the bulk of the WHO classification reflects the classification of adenomas by structure and function. International Classification of Disease codes are not provided for these distinct and clinically relevant lesions; instead they are only provided for typical pituitary adenoma (8272/0), atypical pituitary adenoma (8272/1), and pituitary carcinoma (8272/3). The most important clinical and prognostic features of pituitary adenomas remain the hormonal profile and subtype classification.32 Some hormone-containing tumors may be clinically silent. These clinically silent tumors should be classified according to the immunohistochemical profile and hormone production. The clinical symptoms should be documented in the appropriate field of the report when known, and the combined information identifying the lesion as a silent variant of that tumor type should be incorporated in the final diagnosis whenever possible. The following recommended histologic classification is modified from the WHO published recommendations.1 WHO Classification of Pituitary Adenomas Typical or Atypical Adenomas ___ Densely granulated corticotroph adenoma ___ Sparsely granulated corticotroph adenoma ___ Crooke cell adenoma ___ Densely granulated somatotroph adenoma ___ Sparsely granulated somatotroph adenoma ___ Mammosomatotroph adenoma ___ Mixed somatotroph-lactotroph adenoma ___ Sparsely granulated lactotroph adenoma ___ Densely granulated lactotroph adenoma 644

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___ ___ ___ ___ ___ ___ ___

Acidophil stem cell adenoma Thyrotroph adenoma Gonadotroph adenoma Unusual plurihormonal adenoma Null cell adenoma Oncocytoma Other (specify): _____________________________

Hyperplasia Hyperplasia of adenohypophysial cells can give rise to clinical syndromes and even radiologic features that are indistinguishable from pituitary adenomas. The use of gadolinium enhancement provides a helpful tool because adenomas are delineated from the enhancing rim of normal adenohypophysis, whereas hyperplasias are uniform. The gland expands upward as it enlarges, resulting in ballooning of the diaphragma sellae; in some patients, suprasellar extension is found.13,35–37 Adenohypophysial hyperplasia can be distinguished from adenoma histologically with a reticulin stain.38,39 The normal adenohypophysis is composed of acini with a well-developed reticulin fiber network; hyperplasia results in expanded acini that preserve their reticulin, whereas adenomas exhibit total breakdown of the reticulin pattern.2 In hyperplasia, other nontumorous cell types are recognized by their profile of hormone content on immunohistochemistry. Electron microscopy is not useful to distinguish hyperplasia from neoplasia.40,41 Pituitary Carcinoma The diagnosis of primary pituitary carcinoma requires the identification of cerebrospinal and/or systemic metastasis.1 The criterion of invasive growth, although relatively common in pituitary tumors,19–21 is not generally accepted as indicative of malignancy because invasive adenomas do not have the potential to metastasize. Markers that have been suggested to be helpful in predicting malignancy include a higher microvascular density,42 high Ki-67 labeling index with the MIB-1 antibody,27 high p53 labeling,43 loss of p27 immunoreactivity,44,45 and increased topisomerase-2a.31 Overexpression of HER2/neu has been reported in some pituitary carcinomas.46 Despite these reported differences in number of positive cells or staining intensity of the various markers, none is able to accurately discriminate between pituitary adenoma and carcinoma, and the diagnosis is only confirmed when the tumor is identified in metastatic foci. Craniopharyngioma Craniopharyngiomas usually present with effects of a sellar mass.47,48 Approximately 75% of patients have headache and visual disturbances.48 Less frequently, there are mental changes, nausea, vomiting, somnolence, or pituitary hormone deficiency. Diabetes insipidus is present in approximately 25% of patients. Severe cases with extensive invasion can exhibit the full-blown hypothalamic syndrome with morbid obesity, temperature and sleep disorders, panhypopituitarism, and seizures. Most tumors are suprasellar49; only 15% have an intrasellar component. Calcification is often identified. Craniopharyngiomas are usually cystic or partially cystic and solid; rarely, they have no cystic component. They usually contain a thick oil-like fluid, which is described as Protocol for Primary Pituitary Tumors—Nose´ et al

‘‘black sludge.’’ Cholesterol crystals and calcification may be seen. Rarely, these tumors may contain bone and/or teeth. Microscopically, 2 subtypes of craniopharyngioma are recognized50; however, there is extensive overlap. The adamantinomatous type resembles the dental ameloblastic organ and is similar to that seen in adamantinoma; it more frequently exhibits calcification, foreign body reaction with inflammation, and giant cells around cholesterol clefts. The papillary variant is less common, is rare in children, and is said to have a better prognosis. I: Nontumorous Pituitary.—The identification of nontumorous pituitary in surgical specimens is important to document. Normal adenohypophysis provides an internal control for immunostaining of hormones and is usually present as trapped elements within adenomas that grow by infiltration of surrounding parenchyma. A rim of nontumorous tissue is found around the edges of small adenomas if they are carefully resected. The identification of neurohypophysis should also be documented. Evaluation of nontumorous adenohypophysis is particularly important in patients with Cushing disease. Exposure to glucocorticoid excess causes corticotrophs to undergo the morphologic alteration known as Crooke hyaline change,51 accumulation of glassy, homogeneous, pale acidophilic keratin filaments in the cytoplasm,52,53 that is identified using CAM 5.2 or equivalent antibodies and with antibodies to cytokeratin 20.54 In patients with very small adenomas that may not be documented at surgery, the distinction of pseudo-Cushing syndrome is a difficult clinical dilemma.55 If these patients come to surgery, usually no pituitary adenoma is identified, or there may be an incidental lesion that is not a corticotroph adenoma. In this situation, the nontumorous corticotrophs do not exhibit Crooke hyaline change; this is an important negative finding that should be reported and becomes the subject for clinicopathologic correlation. In contrast, the documentation of Crooke hyaline change confirms the diagnosis of pathologic glucocorticoid excess that may have been cured by the surgery even if no adenoma is identified by the pathologist. References 1. DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours; vol 8. 2. Asa SL. Tumors of the Pituitary Gland. Washington, DC: Armed Forces Institute of Pathology; 1998. Rosai J, ed. Atlas of Tumor Pathology; 3rd series, fascicle 22. 3. Coire CI, Horvath E, Kovacs K, Smyth HS, Ezzat S. Cushing’s syndrome from an ectopic pituitary adenoma with peliosis: a histological, immunohistochemical and ultrastructural study and review of the literature. Endocr Pathol. 1997;8(1): 65–74. 4. Kikuchi K, Kowada M, Sasaki J, Sageshima M. Large pituitary adenoma of the sphenoid sinus and the nasopharynx: report of a case with ultrastructural evaluations. Surg Neurol. 1994;42(4):330–334. 5. Slonim SM, Haykal HA, Cushing GW, Freidberg SR, Lee AK. MRI appearances of an ectopic pituitary adenoma: case report and review of the literature. Neuroradiology. 1993;35(7):546–548. 6. Lloyd RV, Chandler WF, Kovacs K, Ryan N. Ectopic pituitary adenomas with normal anterior pituitary glands. Am J Surg Pathol. 1986;10(8):546–552. 7. Lewin R, Ruffolo E, Saraceno C. Craniopharyngioma arising in the pharyngeal hypophysis. Southern Med J. 1984;77(12):519–523. 8. Koral K, Weprin B, Rollins NK. Sphenoid sinus craniopharyngioma simulating mucocele. Acta Radiol. 2006;47(5):494–496. 9. van der Mey AG, van Seters AP, van Krieken JH, Vielvoye J, Van Dulken H, Hulshof JH. Large pituitary adenomas with extension into the nasopharynx: report of three cases with a review of the literature. Ann Otol Rhinol Laryngol. 1989; 98(8, pt 1):618–624. 10. Wong K, Raisanen J, Taylor SL, McDermott MW, Wilson CB, Gutin PH. Pituitary adenoma as an unsuspected clival tumor. Am J Surg Pathol. 1995;19(8): 900–903.

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11. Hardy J. Transsphenoidal surgery of hypersecreting pituitary tumors. In: Kohler PO, Ross GT, eds. Diagnosis and Treatment of Pituitary Tumors. Amsterdam, The Netherlands: Exerpta Medica; 1973:179–198. International Congress Series; No 303. 12. Stefaneanu L, Kovacs K. Light microscopic special stains and immunohistochemistry in the diagnosis of pituitary adenomas. In: Lloyd RV, ed. Surgical Pathology of the Pituitary Gland. Philadelphia, PA: WB Saunders Company; 1993:34–51. 13. Thorner MO, Perryman RL, Cronin MJ, et al. Somatotroph hyperplasia: successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor. J Clin Invest. 1982;70(5):965–977. 14. Bilbao JM, Horvath E, Hudson AR, Kovacs K. Pituitary adenoma producing amyloid-like substance. Arch Pathol Lab Med. 1975;99(8):411–415. 15. Landolt AM, Kleihues P, Heitz PhU. Amyloid deposits in pituitary adenomas: differentiation of two types. Arch Pathol Lab Med. 1987;111(5): 453–458. 16. Bilbao JM, Kovacs K, Horvath E, Higgins HP, Horsey WJ. Pituitary melanocorticotrophinoma with amyloid deposition. J Can Sci Neurol. 1975;2(3): 199–202. 17. Mori H, Mori S, Saitoh Y, Moriwaki K, Iida S, Matsumoto K. Growth hormone-producing pituitary adenoma with crystal-like amyloid immunohistochemically positive for growth hormone. Cancer. 1985;55(1):96–102. 18. Voigt C, Saeger W, Gerigk Ch, Lu¨decke DK. Amyloid in pituitary adenomas. Pathol Res Pract. 1988;183(5):555–557. 19. Scheithauer BW, Kovacs KT, Laws ER Jr, Randall RV. Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg. 1986;65(6):733–744. 20. Selman WR, Laws ER Jr, Scheithauer BW, Carpenter SM. The occurrence of dural invasion in pituitary adenomas. J Neurosurg. 1986;64(3):402–407. 21. Sautner D, Saeger W. Invasiveness of pituitary adenomas. Pathol Res Pract. 1991;187(5):632–636. 22. Horvath E, Kovacs K, Smyth HS, et al. A novel type of pituitary adenoma: morphological feature and clinical correlations. J Clin Endocrinol Metab. 1988; 66(6):1111–1118. 23. Anniko M, Tribukait B, Wersa¨ll J. DNA ploidy and cell phase in human pituitary tumors. Cancer. 1984;53(8):1708–1713. 24. Fitzgibbons PL, Appley AJ, Turner RR, et al. Flow cytometric analysis of pituitary tumors: correlation of nuclear antigen p105 and DNA content with clinical behavior. Cancer. 1988;62(8):1556–1560. 25. Landolt AM, Shibata T, Kleihues P. Growth rate of human pituitary adenomas. J Neurosurg. 1987;67(6):803–806. 26. Knosp E, Kitz K, Perneczky A. Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery. 1989;25(6):927– 930. 27. Thapar K, Kovacs K, Scheithauer BW, et al. Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery. 1996;38(1):99–107. 28. Hsu DW, Hakim F, Biller BMK, et al. Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence. J Neurosurg. 1993;78(5):753–761. 29. Gandour-Edwards R, Kapadia SB, Janecka IP, Martinez AJ, Barnes L. Biologic markers of invasive pituitary adenomas involving the sphenoid sinus. Mod Pathol. 1995;8(2):160–164. 30. Takino H, Herman V, Weiss M, Melmed S. Purine-binding factor (nm23) gene expression in pituitary tumors: marker of adenoma invasiveness. J Clin Endocrinol Metab. 1995;80(5):1733–1738. 31. Vidal S, Kovacs K, Horvath E, et al. Topoisomerase IIalpha expression in pituitary adenomas and carcinomas: relationship to tumor behavior. Mod Pathol. 2002;15(11):1205–1212. 32. Al Shraim M, Asa SL. The 2004 World Health Organization classification of pituitary tumors: what is new? Acta Neuropathol. 2006;111(1):1–7. 33. Kovacs K, Horvath E. Tumors of the Pituitary Gland. Washington, DC: Armed Forces Institute of Pathology; 1986. Atlas of Tumor Pathology; 2nd series, fascicle 21. 34. Kovacs K, Horvath E, Ryan N, Ezrin C. Null cell adenoma of the human pituitary. Virchows Arch [Pathol Anat]. 1980;387(2):165–174. 35. Barkan AL, Shenker Y, Grekin RJ, Vale WW, Lloyd RV, Beals TF. Acromegaly due to ectopic growth hormone (GH)-releasing hormone (GHRH) production: dynamic studies of GH and ectopic GHRH secretion. J Clin Endocrinol Metab. 1986;63(5):1057–1064. 36. Khalil A, Kovacs K, Sima AAF, Burrow GN, Horvath E. Pituitary thyrotroph hyperplasia mimicking prolactin-secreting adenoma. J Endocrinol Invest. 1984; 7(4):399–404. 37. Chan AW, MacFarlane IA, Foy PM, Miles JB. Pituitary enlargement and hyperprolactinaemia due to primary hypothyroidism: errors and delays in diagnosis. Br J Neurosurg. 1990;4(2):107–112. 38. Saeger W, Lu¨decke DK. Pituitary hyperplasia: definition, light and electron microscopical structures and significance in surgical specimens. Virchows Arch [A]. 1983;399(3):277–287. 39. Thorner MO, Frohman LA, Leong DA, et al. Extrahypothalamic growth hormone-releasing factor (GRF) secretion is a rare cause of acromegaly: plasma GRF levels in 177 acromegalic patients. J Clin Endocrinol Metab. 1984;59(5): 846–849.

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