DIAGNOSTIC AND THERAPEUTIC APPROACH TO PITUITARY INCIDENTALOMAS. Anastasios N. Mavrakis, MD, 1 and Nicholas A. Tritos, MD, DSc, MMSc, FACE, FACP 2

Transcription

1 Review Article DIAGNOSTIC AND THERAPEUTIC APPROACH TO PITUITARY INCIDENTALOMAS Anastasios N. Mavrakis, MD, 1 and Nicholas A. Tritos, MD, DSc, MMSc, FACE, FACP 2 ABSTRACT Objective: To review data on epidemiology, differential diagnosis, clinical, laboratory, and imaging findings, natural history, and management of incidentally discovered pituitary lesions (pituitary incidentalomas). Methods: A nonsystematic review was conducted, including articles indexed in Index Medicus that contained reference to incidentally discovered pituitary masses (pituitary incidentalomas). Results: Both autopsy and sensitive neuroimaging studies (including magnetic resonance imaging) suggest that pituitary incidentalomas are common, affecting approximately 10% of the general population. Although typically small (less than 10 mm in greatest diameter) and clinically silent, some pituitary incidentalomas may be hormonally active or cause mass effects by compressing neighboring structures. In addition, a minority of these lesions may grow over time; hence, long-term follow-up is necessary. Therapeutic interventions, including dopamine agonist therapy (in the case of prolactin-secreting adenomas) or transsphenoidal resection, are indicated in the case of pituitary lesions that are hormonally active, cause mass effects, or increase in size. Conclusion: Pituitary incidentalomas are common and constitute a heterogeneous group with regard to pathologic features, clinical, laboratory, and imaging characteristics, natural history, and growth potential. Currently available evidence suggests that many hormonally nonfunctioning pituitary incidentalomas causing no mass effects can be safely managed by follow-up surveillance. Nonetheless, more data are needed for further elucidation of the natural history of these lesions and for improvement in accurate and noninvasive diagnosis and in prediction of Submitted for publication March 31, 2004 Accepted for publication July 1, 2004 From the 1 Brain Tumor Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, and 2 Department of Obstetrics and Gynecology, Dartmouth Medical School, Hanover, New Hampshire. Address correspondence and reprint requests to Dr. N. A. Tritos, 5 Coliseum Avenue, Suite 209, Nashua, NH AACE. growth potential of pituitary incidentalomas. Improved understanding of the pathogenesis of this heterogeneous group of lesions may also lead to the development of novel, noninvasive therapeutic agents, rationally designed to interact with well-characterized molecular targets. (Endocr Pract. 2004;10: ) Abbreviations: MRI = magnetic resonance imaging; TSH = thyroidstimulating hormone (thyrotropin) INTRODUCTION During the past several years, the widespread use of sensitive neuroimaging diagnostic techniques, including magnetic resonance imaging (MRI) of the brain, has frequently led to the detection of clinically unsuspected lesions (termed pituitary incidentalomas ) in the pituitary gland of patients with apparently unrelated presentations, such as trauma or sinusitis (1-6). The pathologic range of pituitary incidentalomas is diverse, including pituitary cysts, adenomas, and various other lesions. Some investigators have suggested that the term pituitary incidentaloma should be reserved for incidentally discovered sellar lesions smaller than 10 mm in maximal diameter (7). In the broadest (and more commonly accepted) definition, however, all incidentally discovered pituitary lesions are considered incidentalomas, regardless of size at the time of detection (3,8-10). Despite the apparent frequency of pituitary incidentalomas, the natural history and the prognostic factors predicting tumor growth have not been clearly elucidated. Therefore, it is not surprising that the incidental detection of pituitary lesions poses major diagnostic and therapeutic challenges in clinical practice. In the current review, data on the prevalence, pathologic features, and natural history of pituitary incidentalomas will be discussed, and controversies in the diagnostic and therapeutic approach to incidentally discovered pituitary lesions will be presented. Areas in need of further study will also be suggested. 438 ENDOCRINE PRACTICE Vol 10 No. 5 September/October 2004

2 Pituitary Incidentalomas, Endocr Pract. 2004;10(No. 5) 439 PREVALENCE In one study, examination of the brain by MRI in 100 normal healthy volunteers identified the presence of previously unsuspected pituitary adenomas in 10% of women and 10% of men studied (Table 1) (11). Virtually all these lesions were microadenomas, ranging from 3 to 6 mm in greatest diameter (11). A recent search of the Mayo Clinic database, however, suggested that the prevalence of pituitary incidentalomas among 4,692 MRI studies performed during the period 1995 through 1999 was 0.62% (12). The reasons for the lower prevalence of pituitary incidentalomas in the latter study are not clear. In addition, the findings in a review of 13 autopsy studies, including almost 10,000 pituitaries, suggested that clinically unsuspected pituitary adenomas are present in more than 10% of the pituitaries examined, including more than 1,000 pituitary microadenomas (~10%) and 3 pituitary macroadenomas (~0.03%) (Table 1) (1,13-26). Individual autopsy studies, however, have provided varied estimates of the prevalence of clinically unsuspected pituitary adenomas, ranging from 1.5 to 26.7%, likely because of methodologic differences (1,13-26). PATHOLOGY AND DIFFERENTIAL DIAGNOSIS In an autopsy study of 1,000 unselected pituitaries, 61 pituitary incidentalomas, which were more than 2 mm in maximal diameter, were identified (27). These lesions consisted of 37 Rathke s cleft cysts, 18 pituitary adenomas, 2 hyperplastic pituitary glands, 2 pituitary infarctions, and 2 hemorrhagic pituitaries. In this study, 70% of the lesions that were located laterally were adenomas, whereas 87% of the medially located lesions were Rathke s cleft cysts. Of clinically unsuspected pituitary adenomas detected at autopsy, 41 to 50% show no immunoreactivity against any of the pituitary hormones, whereas 42 to 55% of these lesions demonstrate positive prolactin immunoreactivity, and 8% have positive immunoreactivity to another pituitary hormone (growth hormone, corticotropin, thyrotropin [thyroid-stimulating hormone or TSH], or gonadotropins) (1,21,28). In contrast to the high prevalence of cysts among incidentally discovered pituitary lesions, data from surgical case series suggest that pituitary adenomas account for more than 90% of symptomatic sellar masses removed through the transsphenoidal route (29). In addition to pituitary adenomas, several diagnoses should be considered in symptomatic patients presenting with a sellar mass (Table 2) (1,29). The exact frequency of these conditions among pituitary incidentalomas has not been established. Nevertheless, the same list of differential diagnoses pertaining to a symptomatic patient with a sellar mass should also be considered in the case of a pituitary incidentaloma (Table 2). Physiologic pituitary hypertrophy should also be considered in the relevant clinical context (in healthy adolescents or young women, pregnant women, or patients with primary hypothyroidism or hypogonadism) and distinguished from an incidentally detected, pathologic pituitary lesion (Table 2) (30). CLINICAL FEATURES Pituitary incidentalomas are, by definition, lesions detected during the course of evaluation of apparently unrelated symptoms. Most likely, however, several of the involved patients have had subtle symptoms attributable to pituitary pathologic conditions, which were not brought to medical attention. The detection of a sellar macroincidentaloma (measuring at least 10 mm in greatest diameter) should prompt the clinician to elicit the presence of symptoms attributable to local pressure (mass) effects, including headache, visual field deficits, and cranial nerve palsies (III, IV, V, and VI), as well as clinical evidence of hypopituitarism. In addition to clinical evaluation, visual field testing by perimetry should be performed in patients found to have sellar masses impinging on the optic chiasm on MRI examination. The presence of a sellar mass should also alert the physician to seek clinical evidence of pituitary hormone excess syndromes, including hyperprolactinemia, acromegaly, Cushing s syndrome, or thyrotropin-mediated hyperthyroidism, even though most incidentally detected pituitary adenomas are likely to be clinically silent (1,3,4). Table 1 Reported Prevalence of Pituitary Incidentalomas Reference Study type Prevalence Hall et al (11), 1994 Magnetic resonance imaging 10 of 100 subjects (10%, all microincidentalomas) Baker et al (12), 2003 Magnetic resonance imaging 29 of 4,692 patients (0.62%) Molitch & Russell (1), 1990 Review of 13 autopsy studies 1,065 microadenomas (~10.9%) and 3 macroadenomas (~0.03%) of 9,737 pituitaries

3 440 Pituitary Incidentalomas, Endocr Pract. 2004;10(No. 5) Table 2 Differential Diagnosis of Sellar Masses* Pituitary adenomas Either nonsecreting or hormone-secreting (prolactin, gonadotropins, GH, ACTH, TSH) Cell rest tumors Craniopharyngiomas, Rathke s cleft cysts, epidermoid cysts, lipomas Benign primary brain tumors Meningiomas, enchondromas, hamartomas, gangliocytomas, some gliomas Malignant primary brain tumors Germ cell tumors, some gliomas, sarcomas, chordomas, lymphomas, pituitary carcinomas Metastatic tumors Breast, prostate, lung, renal cell carcinomas Infectious, inflammatory, or granulomatous lesions Sarcoidosis, histiocytosis X, hypophysitis, tuberculosis, abscess, mucocele Vascular lesions Carotid aneurysms Miscellaneous lesions Colloid cysts, arachnoid cysts Physiologic pituitary hypertrophy In healthy adolescents, young women, pregnant women, patients with primary hypothyroidism or hypogonadism *ACTH = adrenocorticotropic hormone; GH = growth hormone; TSH = thyroid-stimulating hormone (thyrotropin). NATURAL HISTORY The natural history of pituitary incidentalomas has not been fully elucidated. Other than their size at initial manifestation, the risk factors predictive of the growth potential of incidentally discovered pituitary masses have not been well characterized. Data from prospective studies support the association between tumor size at initial assessment and increased growth potential during follow-up (Table 3). In a prospective study by Reincke et al (31), 14 patients with incidental pituitary masses, including 7 patients with macro-- incidentalomas and 7 with microincidentalomas (less than 10 mm in greatest diameter), underwent follow-up for a mean of 22 months (range, 11 to 96). Of the 7 patients with a macroincidentaloma, 2 (29%) experienced an increase in tumor size, with gradual development of central hypogonadism in 1 of them. None of these patients underwent surgical treatment. Among the 7 patients with microincidentalomas, an increase in tumor size was noted in only 1 (14%), and a spontaneous decrease in tumor size was noted in another (14%) (31). These changes were not considered clinically significant. In another prospective study, by Donovan and Corenblum (32), 31 patients with incidentally detected pituitary masses, including 16 patients with macroincidentalomas and 15 with microincidentalomas, were under surveillance for 6.1 ± 2.2 years (mean ± SD) and 6.7 ± 1.1 years, respectively. Four of the 16 patients with macroincidentalomas (25%) had an increase in tumor size during follow-up, with development of visual field deficits in 1 of them. This patient underwent transsphenoidal tumor resection and was found to have a craniopharyngioma. In 1 additional patient with a macroincidentaloma (6%), pituitary apoplexy developed after heparinization for coronary angiography. In contrast, none of the 15 patients with microincidentalomas had tumor growth (32). In a prospective study by Feldkamp et al (33), 50 patients with incidentally detected pituitary masses, including 19 patients with macroincidentalomas and 31 with microincidentalomas, had a mean follow-up period of 2.7 years (including a minimal period of 2 years). Five of the 19 patients with macroincidentalomas (26%) experienced an increase in tumor size, and in 1 additional patient from this group (5%), a decrease in tumor size was noted. In contrast, only 1 of the 31 patients with microincidentalomas (3%) demonstrated evidence of tumor growth, and in 1 additional patient from this group (3%), a decrease in tumor size was noted. In this study, none of the 6 patients with tumor growth had visual field deficits during followup (33). In contrast, a retrospective survey of 239 patients with pituitary incidentalomas and a mean duration of follow-up of 26.9 months (range, 6 to 173) did not reveal an associ-

4 Pituitary Incidentalomas, Endocr Pract. 2004;10(No. 5) 441 Table 3 Reported Natural History of Pituitary Incidentalomas* Reference No. of patients Mean follow-up (yr) Lesion growth Reincke et al (31), (7 macro, 7 micro) macro (29%) 1 micro (14%) Donovan & Corenblum (32), (16 macro, 15 micro) 6.1 (macro) 4 macro (25%) 6.7 (micro) 0 micro (0%) Feldkamp et al (33), (19 macro, 31 micro) macro (26%) 1 micro (3%) Sanno et al (34), (165 macro, 74 micro) macro (12%) 10 micro (14%) *Macro = macroincidentalomas; micro = microincidentalomas. ation between tumor size at presentation of the patients and growth potential (Table 3) (34). In this study, 20 of 165 patients with macroincidentalomas (12%) and 10 of 74 patients with microincidentalomas (14%) demonstrated tumor growth during follow-up. Six of the 20 patients with macroincidentalomas whose tumors enlarged during follow-up underwent transsphenoidal surgical resection of the tumor, including 1 in whom visual field deficits had developed (as a consequence of pituitary apoplexy) (34). The apparent discrepancy between these findings and the results of the 3 aforementioned prospective studies that suggested an increased likelihood of tumor growth among patients with macroincidentalomas may reflect differences in study design (retrospective versus prospective data collection and analysis) or study population characteristics. In addition, in the same retrospective survey (34), 23 of 115 patients with tumors thought to represent nonfunctioning pituitary adenomas (20%) demonstrated tumor growth, whereas only 5 of 94 patients with Rathke s cleft cysts (5%) demonstrated growth of that lesion during follow-up. The retrospective nature of this study may limit the general applicability of these findings, which should be verified in a prospective investigation. LABORATORY DIAGNOSTIC EVALUATION Hypopituitarism is not uncommon in patients with macroincidentalomas (35). In one study, laboratory findings suggestive of at least one pituitary hormone deficiency were found in 6 of 10 patients with a pituitary macroincidentaloma (35). Therefore, such patients should undergo appropriate screening tests of pituitary function, including serum levels of cortisol (early morning), free thyroxine, follicle-stimulating hormone, luteinizing hormone, and total testosterone (early morning) in male patients. In contrast, hypopituitarism is unlikely in patients with microincidentalomas. In our experience with these patients, extensive evaluation of pituitary reserve is usually not necessary. The most cost-effective approach to the laboratory investigation of hormone hypersecretion in the presence of a pituitary incidentaloma, however, has not been clearly established. Some investigators have suggested that measurement of serum prolactin is the only cost-effective test routinely indicated in patients with pituitary incidentalomas who lack clinical evidence of pituitary hormone hypersecretion (36). In the absence of extensive data on the natural history of pituitary incidentalomas, it seems reasonable to measure serum insulin-like growth factor I as a screening test for acromegaly, with the rationale that early detection and treatment will likely minimize the morbidity and mortality associated with this condition (37-40). In addition, screening these patients for thyrotropinmediated hyperthyroidism may be appropriate because this condition has been reported in 2 patients with a pituitary incidentaloma (41,42). High serum levels of free thyroid hormones in the setting of normal or high serum TSH, however, may occur in patients with thyrotropin-mediated hyperthyroidism as well as in patients with resistance to thyroid hormone. Further testing (including thyrotropinreleasing hormone stimulation and triiodothyronine suppression testing, measurement of the alpha subunit- to- TSH molar ratio, and thyroid receptor sequence analysis) is needed to distinguish between these two conditions, which also applies in the case of a pituitary incidentaloma (43). Among patients with pituitary incidentalomas and clinical suspicion of Cushing s syndrome, appropriate screening tests should be performed, including 24-hour urine free cortisol, 11 PM salivary cortisol, or measurement of early morning serum cortisol after administration of 1 mg of dexamethasone the night before (11 PM) (44). In contrast, the routine performance of pituitary imaging as a screening test for Cushing s syndrome should be discouraged, in order to avoid diagnostic confusion between an incidental pituitary mass and a pituitary adenoma leading to hypersecretion of corticotropin.

5 442 Pituitary Incidentalomas, Endocr Pract. 2004;10(No. 5) It should also be noted that administration of thyrotropin-releasing hormone may provoke an increase in secretion of beta gonadotropin subunit in 73% of patients with microincidentalomas, as has been previously demonstrated in many patients with gonadotroph pituitary adenomas (45). The diagnostic accuracy of this test among patients with pituitary incidentalomas, however, has not been established. THERAPY AND FOLLOW-UP Therapeutic recommendations for patients with pituitary incidentalomas have been based on clinical experience and reported data from available studies on the natural history of incidentally discovered sellar masses (1,3,4,8-10,46). An issue that should be taken into consideration when the diagnosis of a pituitary incidentaloma is made known to patients is that considerable anxiety may be provoked, which, on the basis of our experience, has the potential to diminish their quality of life. Therefore, substantial time should be spent thoroughly counseling patients on the relevant diagnostic and therapeutic issues. Patients with hormone excess syndromes should receive appropriate medical and surgical therapy (for example, dopamine agonist therapy for patients with prolactinomas or a transsphenoidal surgical procedure for patients with acromegaly, Cushing s disease, or thyrotropin-mediated hyperthyroidism). Among patients with macroincidentalomas, the presence of chiasmal distortion or visual field deficits is a clear indication for therapy. If prolactinoma is the most likely diagnosis, then a trial of dopamine agonist therapy is warranted (47). In all other cases, surgical removal of the tumor, preferably by the transsphenoidal route, is indicated in order to improve vision. Even in the absence of chiasmal compression, appreciable suprasellar extension of the tumor may be an additional indication for surgical treatment in women who are interested in pregnancy. A study from Japan (48) suggested that patients with suprasellar extension of pituitary incidentalomas (grade A and even grade B in the Hardy classification) in the absence of chiasmal compression can be safely managed by follow-up surveillance. Nevertheless, the unusually high incidence of pituitary apoplexy (in 2 of 28 patients) during follow-up in that study suggests that more data are needed. Some investigators have suggested that hypopituitarism may be an appropriate indication for surgical decompression (4). Many endocrinologists and neurosurgeons (as well as the current authors), however, do not recommend surgical treatment on this basis because tumor resection may fail to restore pituitary function or, even worse, may lead to the development of additional pituitary hormone deficiencies postoperatively. Patients with nonfunctioning macroincidentalomas that are not causing mass effects, as well as patients with nonfunctioning microincidentalomas, may be conservatively managed by surveillance, as long as tumor growth is not detected on follow-up MRI examinations. Currently, however, data on the most cost-effective approach regarding the frequency of follow-up examinations are not available. It appears prudent to recommend an MRI examination at 6 months and annually thereafter for 2 years for patients with macroincidentalomas and an MRI examination annually for 2 years for patients with microincidentalomas, as well as at 4 years for all patients. Clearly, all patients require continued long-term follow-up beyond this period because they remain at risk for tumor growth or complications, including pituitary apoplexy (48). The optimal frequency of follow-up examinations and duration of observation, however, have not been established. A proposed algorithm for the management of patients with pituitary incidentalomas is shown in Figure 1. FUTURE DIRECTIONS Advances in neuroimaging have increasingly led to the early detection of generally small pituitary lesions (pituitary incidentalomas). Clearly, these lesions constitute a very heterogeneous group with regard to their pathologic features, natural history, growth potential, and response to therapy. Available data suggest that many pituitary incidentalomas that are not hormonally active and are not causing mass effects can be safely managed by observation and follow-up. Despite the abundance of information on pituitary incidentalomas provided by recent studies, however, several questions remain unanswered. The pathogenesis and natural history of pituitary incidentalomas have not been completely understood. Moreover, the factors associated with increased risk of tumor growth have not been fully elucidated, and the optimal type, frequency, and duration of follow-up of incidentally discovered pituitary lesions have not been thoroughly investigated. In addition to providing these data, future studies may help establish biomarkers (including laboratory tests or lesion characteristics on novel imaging studies, such as radiolabeled ligand scintigraphy or positron emission tomography) that will improve our diagnostic accuracy and ability to predict tumor growth potential reliably. It is also expected that a better understanding of the molecular pathogenesis and pathophysiology of these lesions may ultimately lead to the development of novel drug therapies for pituitary incidentalomas, rationally designed to interact with well-characterized molecular targets. REFERENCES 1. Molitch ME, Russell EJ. The pituitary incidentaloma. Ann Intern Med. 1990;112: Howlett TA, Como J, Aron DC. Management of pituitary incidentalomas: a survey of British and American endocrinologists. Endocrinol Metab Clin North Am. 2000;29: , xi.

6 Pituitary Incidentalomas, Endocr Pract. 2004;10(No. 5) 443 Pituitary incidentaloma Hormonally inactive Hormonally active Macroincidentalomas Microincidentalomas Prolactinomas Non - prolactinomas Not causing mass effects Causing mass effects Dopamine agonist therapy Transsphenoidal surgery Follow-up at 6 months, 1, 2 and 4 yr Transsphenoidal surgery Follow-up at 1, 2 and 4 yr Increase in size? Yes No Transsphenoidal surgery Continued observation Fig. 1. Suggested approach to management of incidentally discovered pituitary lesions (pituitary incidentalomas). 3. Aron DC, Howlett TA. Pituitary incidentalomas. Endocrinol Metab Clin North Am. 2000;29: Soule SG, Jacobs HS. The evaluation and management of subclinical pituitary disease. Postgrad Med J. 1996;72: Chacko AG, Chandy MJ. Incidental pituitary macroadenomas. Br J Neurosurg. 1992;6: Westbrook JI, Braithwaite J, McIntosh JH. The outcomes for patients with incidental lesions: serendipitous or iatrogenic? AJR Am J Roentgenol. 1998;171: Turner HE, Moore NR, Byrne JV, Wass JA. Pituitary, adrenal and thyroid incidentalomas. Endocr Relat Cancer. 1998;5: Molitch ME. Incidental pituitary adenomas. Am J Med Sci. 1993;306: Molitch ME. Pituitary incidentalomas. Endocrinol Metab Clin North Am. 1997;26: Molitch ME. Clinical review 65: evaluation and treatment of the patient with a pituitary incidentaloma. J Clin Endocrinol Metab. 1995;80: Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH. Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med. 1994;120: Baker CH, Erickson BJ, Young WF, Vella A. The Mayo Clinic experience with pituitary incidentaloma. In: Program and abstracts of the 85th Annual Meeting of the Endocrine Society, 2003, San Francisco, California. Abstract P Coulon G, Fellmann D, Arbez-Gindre F, Pageaut G. Latent pituitary adenomas: autopsy study [article in French]. Arch Anat Cytol Pathol. 1984;32: Coulon G, Fellmann D, Arbez-Gindre F, Pageaut G. Latent pituitary adenoma: autopsy study [article in French]. Sem Hop. 1983;59: Susman W. Pituitary adenoma. Br Med J. 1933;2: Costello RT. Subclinical adenoma of the pituitary gland. Am J Pathol. 1936;12: Parent AD, Bebin J, Smith RR. Incidental pituitary adenomas. J Neurosurg. 1981;54: Parent AD, Brown B, Smith EE. Incidental pituitary adenomas: a retrospective study. Surgery. 1982;92: McCormick WF, Halmi NS. Absence of chromophobe adenomas from a large series of pituitary tumors. Arch Pathol. 1971;92: Sommers SC. Pituitary cell relations to body states. Lab Invest. 1959;8: Kovacs K, Ryan N, Horvath E, Singer W, Ezrin C. Pituitary adenomas in old age. J Gerontol. 1980;35: Burrow GN, Wortzman G, Rewcastle NB, Holgate RC, Kovacs K. Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N Engl J Med. 1981;304: Muhr C, Bergstrom K, Grimelius L, Larsson SG. A parallel study of the roentgen anatomy of the sella turcica and the histopathology of the pituitary gland in 205 autopsy specimens. Neuroradiology. 1981;21: Schwesinger G, Warzok R. Hyperplasias and adenomas of the pituitary gland in an unselected autopsy material [article in German]. Zentralbl Allg Pathol. 1982;126: Mosca L, Solcia E, Capella C, Buffa R. Pituitary adenomas: surgical versus postmortem findings today. In: Faglia G, Giovanelli MA, MacLeod RM, eds. Pituitary Microadenomas. New York, NY: Academic Press, 1980: Landolt AM. Biology of pituitary microadenomas. In: Faglia G, Giovanelli MA, MacLeod RM, eds. Pituitary Microadenomas. New York, NY: Academic Press, 1980: Teramoto A, Hirakawa K, Sanno N, Osamura Y. Incidental pituitary lesions in 1,000 unselected autopsy specimens. Radiology. 1994;193: McComb DJ, Ryan N, Horvath E, Kovacs K. Subclinical adenomas of the human pituitary: new light on old problems. Arch Pathol Lab Med. 1983;107: Freda PU, Post KD. Differential diagnosis of sellar masses. Endocrinol Metab Clin North Am. 1999;28:81-117, vi.

7 444 Pituitary Incidentalomas, Endocr Pract. 2004;10(No. 5) 30. Chanson P, Daujat F, Young J, et al. Normal pituitary hypertrophy as a frequent cause of pituitary incidentaloma: a follow-up study. J Clin Endocrinol Metab. 2001;86: Reincke M, Allolio B, Saeger W, Menzel J, Winkelmann W. The incidentaloma of the pituitary gland: is neurosurgery required? JAMA. 1990;263: Donovan LE, Corenblum B. The natural history of the pituitary incidentaloma. Arch Intern Med. 1995;155: Feldkamp J, Santen R, Harms E, Aulich A, Modder U, Scherbaum WA. Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas results of a prospective study. Clin Endocrinol (Oxf). 1999;51: Sanno N, Oyama K, Tahara S, Teramoto A, Kato Y. A survey of pituitary incidentaloma in Japan. Eur J Endocrinol. 2003;149: Nammour GM, Ybarra J, Naheedy MH, Romeo JH, Aron DC. Incidental pituitary macroadenoma: a population-based study. Am J Med Sci. 1997;314: King JT Jr, Justice AC, Aron DC. Management of incidental pituitary microadenomas: a cost-effectiveness analysis. J Clin Endocrinol Metab. 1997;82: Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab. 2000;85: Melmed S, Jackson I, Kleinberg D, Klibanski A. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab. 1998;83: Melmed S, Vance ML, Barkan AL, et al. Current status and future opportunities for controlling acromegaly. Pituitary. 2002;5: Swearingen B, Barker FG II, Katznelson L, et al. Longterm mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. 1998; 83: Yamakita N, Ikeda T, Murai T, Komaki T, Hirata T, Miura K. Thyrotropin-producing pituitary adenoma discovered as a pituitary incidentaloma. Intern Med. 1995; 34: Akiyoshi F, Okamura K, Fujikawa M, et al. Difficulty in differentiating thyrotropin secreting pituitary microadenoma from pituitary-selective thyroid hormone resistance accompanied by pituitary incidentaloma. Thyroid. 1996;6: Safer JD, Colan SD, Fraser LM, Wondisford FE. A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma. Thyroid. 2001;11: Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88: Greenman Y, Trostanetsky Y, Somjen D, Tordjman K, Kohen F, Stern N. Effect of TRH on beta-gonadotropin subunits in patients with pituitary microincidentalomas. Eur J Endocrinol. 1999;141: Molitch ME. Approach to the incidentally discovered pituitary mass. Cancer Treat Res. 1997;89: Schlechte JA. Clinical practice: prolactinoma. N Engl J Med. 2003;349: Nishizawa S, Ohta S, Yokoyama T, Uemura K. Therapeutic strategy for incidentally found pituitary tumors ( pituitary incidentalomas ) [with discussion]. Neurosurgery. 1998;43: