Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com)

Aggressive Pituitary Tumors Review Article [1] | September 01, 1998 By Lewis S. Blevins, Jr, MD [2], Denise K. Verity, MSN, RN, CS [3], and George Allen, MD [4] Although almost all pituitary tumors are benign adenomas, a surprisingly large number of these tumors invade tissues outside of the pituitary gland. Such invasion, by itself, is not diagnostic of pituitary carcinomas, which are

Introduction Autopsy studies have demonstrated clinically unsuspected adenomas in as many as 27% of pituitary glands examined.[1] Most of these adenomas are presumed to be insignificant because the mean annual incidence of clinically important pituitary tumors is only 8 per 100,000 adult women.[2] Pituitary adenomas do account for 10% of all intracranial neoplasms, however, and many tertiary-care centers evaluate and treat over 100 affected patients each year. Most pituitary adenomas are benign, slow-growing neoplasms that arise from the epithelial cells comprising the anterior pituitary gland. Some exhibit rather aggressive growth patterns, however, and may invade and destroy parasellar structures, recur and exhibit relentlessly progressive growth despite intensive antitumor therapy, and metastasize to intracranial and other distant sites. This review will focus on the biology, clinical presentations, and responses to treatment of the aggressive pituitary tumor subtypes.

Invasive Pituitary Adenomas One of the more important determinants of surgical success is whether the patient’s pituitary adenoma has escaped the confines of the sella turcica and invaded parasellar structures. Several studies have clearly illustrated that cure rates are lower and recurrence rates are higher in patients with invasive adenomas.[3-5] Accurate and reliable methods to identify patients with clinically significant invasion at the outset are needed. Radiologic and Intraoperative Biopsy Findings Magnetic resonance imaging (MRI) and computed tomography (CT) are widely employed in the evaluation of patients with pituitary adenomas. These imaging modalities provide excellent definition of intrasellar and parasellar tissue planes (MRI) and the bony limits of the sella (CT). Many expansive noninvasive adenomas remodel and erode the bony confines of the sella and simply compress parasellar structures. Thus, radiologic features, such as erosion of the sellar floor and lateral tumor growth "into" the cavernous sinuses, are not reliable indicators of invasion. Reliable radiologic signs of invasion include: (1) a tumor that completely encircles or extends beyond the lateral limit of the intracavernous carotid artery, (2) complete erosion of the clivus, and (3) the presence of tumor within the sphenoid sinuses (Figure 1). In many cases, intraoperative inspection of the sellar walls and parasellar tissues is necessary in order to determine whether invasion has occurred. Attempts to determine whether intraoperative biopsies of intrasellar and parasellar tissues may be worthwhile measures of invasion have revealed that, surprisingly, most adenomas are invasive.[6,7] Selman et al evaluated biopsies of the dura from 60 patients who underwent transsphenoidal surgery for pituitary adenomas.[6] They noted gross invasiveness in 40% of patients at the time of surgery but found dural microinvasion in 85% of patients. Microinvasion was seen with 69% of microadenomas and with 94% of macroadenomas that extended into the suprasellar region. Pituitary adenomas are often cured by surgery, and recurrences are much less common than would Page 1 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) be expected based on these rates of dural invasion. Most pituitary specialists, therefore, believe that radiologic and gross intraoperative findings of invasion correlate better with clinical outcomes. Scheithauer et al summarized their findings of gross invasion by 365 pituitary adenomas.[8] Invasion by macroadenomas was more common than invasion by microadenomas. The frequencies of invasion by some of the more aggressive pituitary adenoma subtypes are shown in Table 1. Signs and Symptoms Invasive adenomas infiltrate and often destroy parasellar tissues, including the dura, bone, cavernous venous sinuses, cranial nerves, paranasal sinuses, subarachnoid space, and leptomeninges. Symptoms and signs depend on the direction and extent of tumoral growth. Patients with indolent tumors may be entirely asymptomatic or have features attributable to anterior pituitary hormonal hypersecretion or pituitary hypofunction. Anterior-inferior growth into the sphenoid may be accompanied by sinus headaches, cerebrospinal fluid (CSF) rhinorrhea, and epistaxis. Rare patients present with a nasopharyngeal mass. Posterior-inferior growth into the bones comprising the base of the skull may cause headaches, marked bone destruction, and structural abnormalities. Lateral extension into the cavernous sinuses may be accompanied by headache and ophthalmoplegia or facial pain due to compression or, rarely, invasion of the cranial nerves traversing the cavernous sinuses. Suprasellar extension may be rather impressive and can result in headaches, visual compromise, hypothalamic dysfunction, and other problems related to compression of the brain. Immunohistochemical Studies Routine histologic and cytologic features have not been shown to reliably correlate with the biological behavior of pituitary tumors.[9] A number of immunohistochemical tools that are more sophisticated than routine immunohistochemical tests used to detect anterior pituitary hormones have been applied to the study of pituitary adenomas.[10-18] Determinations of the proliferation rates of pituitary adenomas by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), Ki-67, and MIB-1 have shown that invasive and recurrent adenomas have higher growth fractions than do noninvasive adenomas.[10-15] Thapar et al employed MIB-1 immunochemistry to study the proliferation rates in 70 patients with pituitary adenomas, 33 of whom had invasive tumors, and in 7 patients with pituitary carcinomas.[14] They found higher mean proliferative indices in invasive adenomas and carcinomas than in noninvasive adenomas and normal pituitary glands (Table 2). These findings indicate that the growth fraction of pituitary tumors may be a reliable predictor of tumor behavior.[14] Additional studies should be performed to determine whether the results of MIB-1 immunohistochemistry would be useful in designing a therapeutic plan for pituitary tumor patients. Preliminary studies have illustrated that decreased immunohistochemical staining of pituitary tumors for the purine-binding factor product of nm23, a metastasizing-suppressor gene, may be a sensitive marker of adenoma invasiveness.[16] Definitive p53 expression, overexpression of epidermal growth factor receptor, and increased protein kinase C activity in pituitary tumors have also been shown to correlate with aggressive behavior.[17-19]

Pituitary Carcinomas Pituitary carcinomas accounted for 0.13% of 2,342 pituitary tumors treated surgically at Marienkrankenhaus in Hamburg, Germany, between 1970 and 1994.[20] As of 1996, at least 67 cases had been described.[20] In most published series of pituitary carcinoma, men and women have been affected equally.[20-22] The majority of affected patients were middle-aged, but patients ranged in age from 7 to 75 years. In many cases, a diagnosis of carcinoma was not established until the postmortem demonstration of distant metastases in patients with preexisting tumors.[21] In other cases, signs and symptoms of metastatic disease prompted evaluations, which revealed that affected patients actually had Page 2 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) carcinomas. Known pituitary disease had been present for more than 10 years prior to a diagnosis of carcinoma in some patients.[20] Invasion by itself is not diagnostic of carcinoma. Accordingly, a diagnosis of pituitary carcinoma should not be made unless the following criteria are fulfilled:

The patient must have a documented history of a pituitary tumor;

A carcinomatous metastasis must be present;

The primary tumor and metastatic deposits must be histologically and immunohistochemically similar; and

Alternative primary and metastatic tumors must be excluded.[20]

Metastases to other intracranial sites, the leptomeninges, spinal cord, and cauda equina occur via subarachnoid spread of the primary tumor. Hematogenous metastases to viscera, including the liver, lungs, kidneys, and heart, as well as the lymph nodes and skeletal system, are common. About two-thirds of reported carcinomas have been hormone-producing tumors (Table 3).[20] The mean survival following the onset of signs and symptoms of pituitary disease is approximately 4 years.[21] Pituitary carcinomas have been shown to have higher proliferative indices and are more commonly p53-immunopositive than are invasive and noninvasive adenomas (Table 2 and Table 4).[14,17] An increasing load of genetic abnormalities and loss of heterozygosity at several loci known to harbor tumor-suppressor genes (11q13, 13q12-14, 10q26, 1p31-35) have been demonstrated in both invasive adenomas and carcinomas.[23,24] A long-term, prospective study is reportedly underway to determine whether loss of heterozygosity provides useful information for therapeutic decision-making.[24]

Aggressive Pituitary Tumor Subtypes Corticotroph Tumors Corticotroph tumors arise from the adrenocorticotropic hormone (ACTH)-producing cells of the anterior pituitary gland. A majority (80%) of patients with endogenous Cushing’s syndrome harbor ACTH-secreting pituitary tumors. Three-quarters of these patients have microadenomas, one-fifth harbor macroadenomas, and the rest have corticotroph hyperplasia.[3] Corticotroph Macroadenomas--Blevins et al found similar clinical and biochemical features in macroadenoma and microadenoma patients, but tumor-related mass effects were more common in patients with larger tumors.[3] About two-thirds of macroadenomas were invasive. Cavernous sinus invasion and a tumor size ≥ 2.0 cm predicted failure of initial transsphenoidal surgery. Only two-thirds of macroadenoma patients entered remission following initial surgery. Adjuvant surgical procedures proved useful in the management of tumor-related mass effects and hypercortisolism but not in producing remission. Recurrences plagued 36% of patients whose disease had remitted. Adjuvant conventional radiotherapy resulted in normalization of cortisol levels and clinical improvement in some patients, but eucortisolism was not sustained. Silent Corticotroph Adenomas--Patients harboring these neoplasms typically present with tumor-related mass effects due to macroadenomas and, by definition, exhibit no clinical and biochemical features of hypercortisolism.[25,26] Pituitary apoplexy occurs in nearly one-third of patients. These tumors are invasive, relentlessly progressive, and have a tendency to recur following Page 3 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) surgery. Silent corticotroph adenomas are usually first recognized at the time of an immunohistochemical examination of resected tumor tissue from patients presumed to have "nonfunctional" tumors. These ACTH-immunopositive tumors account for 2% to 6% of all resected nonfunctional pituitary adenomas and for 43% of all corticotroph adenomas.[25] Rarely, they secrete biologically inactive ACTH precursors and proopiomelanicortin (POMC) fragments that can be detected by specific immunoradiometric assays.[26,27] In some cases, these tumors acquired the ability to secrete biologically active ACTH, and the patients developed Cushing’s syndrome.[23] Nelson’s syndrome has been characterized by a constellation of features, including an expanding ACTH-secreting pituitary tumor, widespread hyperpigmentation, and markedly elevated ACTH levels in patients treated with bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome.[28] Nelson’s syndrome has been reported in as many as 50% of patients within 1.5 to 13 years following bilateral adrenalectomy.[28-30] Patients < 35 years old are at a greater risk for this disorder.[30] Prophylactic sellar irradiation has been reported to reduce the incidence of Nelson’s syndrome from 50% to 25%.[29] This disorder is not as common as it once was because of advances in microsurgical techniques; transsphenoidal surgical resection is now the preferred treatment for ACTH-secreting pituitary tumors. Large tumors are invasive in about two-thirds of patients.[8] Tumor progression can result in extensive destruction of parasellar tissues and complications, including CSF rhinorrhea and meningitis.[3] Death ensues because of uncontrolled tumor growth in some patients.[3] Surgical debulking and radiotherapy are the mainstays of therapy for these tumors. Corticotroph Carcinomas--Most corticotroph carcinomas present as invasive ACTH-secreting adenomas refractory to standard therapy.[20-23] Distant visceral, nodal, and skeletal metastases follow a protracted course of multiple recurrences and progression of residual tumors. A majority of patients succumb to complications related to either hypercortisolism or direct intracranial invasion of vital structures, including the hypothalamus and brainstem. Lactotroph Tumors Lactotroph tumors arise from the prolactin-producing cells of the anterior pituitary gland. These tumors account for 40% of all pituitary adenomas. Women typically have microadenomas and men usually have macroadenomas. The biological basis of this sexual dimorphism has not been fully established. Macroprolactinomas are invasive in more than one-half of patients.[8] Some of these tumors remain within the sella, while others extend beyond its confines and extensively invade the bones comprising the base of the skull (Figure 1). Fortunately, most macroprolactinomas are sensitive to the inhibitory effects of dopamine and dopamine agonists (eg, bromocriptine [Parlodel], cabergoline [Dostinex], and pergolide [Permax]).[31,32] In a multicenter study conducted by Molitch et al, prolactin levels normalized in 12 of 16 women and 6 of 11 men with macroprolactinomas during treatment with bromocriptine.[31] Prolactin levels decreased to < 11% of baseline in all but one patient. Tumor size decreased by 50% or more in 64% of patients. Nearly one-fifth of prolactinomas have been resistant to treatment with dopamine agonists,[33,34] and, in some cases, paradoxical rapid growth has occurred in response to such treatment. Only about one-third of macroprolactinoma patients have achieved remission following surgery.[32] Recurrences have occurred in 20% to 40% of patients.[32] Normalization of prolactin levels following adjuvant radiotherapy has been unusual. Giant Prolactinomas--These rather large (> 4 cm) tumors are five times more common in men than in women.[35-37] Giant prolactinomas are aggressive and have a propensity to invade destructively the cavernous sinuses, sphenoid bone, orbit, nasopharynx, and auditory canal. These Page 4 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) tumors often extend suprasellarly, invade the subarachnoid space, and displace brain tissue as they grow. Marked hyperprolactinemia is the rule. In a review of 12 patients, Loh et al reported prolactin levels ranging from 1,173 to 29,180 ng/mL (mean, 6,937 ng/mL).[35] Treatment with dopamine agonists reduces prolactin concentrations by ≥ 90% in most patients, but levels rarely normalize.[35-37] Marked reductions in tumor size have been observed. Reported complications of dopamine agonist treatment in these patients include CSF rhinorrhea, meningitis, and pneumocephalus.[38] Lactotroph carcinomas most often spread to other intracranial sites; however, distant metastases are also common. Resistance to treatment with dopamine agonists has been described in one affected patient.[39] Somatotroph Tumors Somatotroph tumors stem from the growth hormone (GH)-producing cells of the anterior pituitary gland. Acromegaly is the constellation of clinical features that occur as a result of GH and resultant insulin-like growth factor-1 (IGF-1) hypersecretion.[40] More than 95% of cases of acromegaly are due to a GH-secreting pituitary adenoma. Nabarro described a series of 256 patients with acromegaly[41]; 18% of these patients had microadenomas, 47% had intrasellar macroadenomas, and 35% had invasive macroadenomas. Invasive and Giant Somatotroph Adenomas--Between one-third and one-half of acromegalic patients have invasive macroadenomas, one-fifth have suprasellar extension, and one-tenth have giant adenomas that extend far beyond the confines of the sella.[4,40] Morbidity and mortality in these patients are more often due to complications of persistently elevated GH levels (eg, diabetes mellitus, hypertension, heart disease, and neoplasia) than to local tumor progression. Fahlbusch et al reported their results using surgery to treat 53 acromegalic patients with invasive adenomas.[4] Only 25% to 40% of patients with invasive tumors and 17% of patients with giant adenomas entered remission following surgery. In a review of the literature on the treatment of acromegaly with dopamine agonists, Jaffe and Barkan found that bromocriptine normalized IGF-1 levels in 10% of patients.[42] In one double-blind, randomized trial, octreotide (Sandostatin) decreased GH and IGF-1 levels in nearly two-thirds of patients and resulted in some degree of tumor shrinkage in 50% of patients.[43] Clinical indicators of disease activity improved significantly in most patients. Conventional radiotherapy is used widely in the management of patients with residual and recurrent disease. Levels of GH and IGF-1 decrease significantly in patients treated with radiotherapy, but normalization of the dynamics of GH secretion and cure, according to strict definitions, are uncommon.[44] Radiotherapy has been shown to prevent further tumor growth in patients with residual disease.[44] Sparsely and Densely Granulated Somatotroph Adenomas--Growth hormone-secreting pituitary adenomas constitute a heterogeneous group of tumors. Each tumor type has well-defined histologic and electron microscopic characteristics.[45] The most common tumor subtypes are the sparsely and densely granulated variants, which can be distinguished by electron microscopy and, to some extent, by routine histology. The distinction is important clinically because sparsely granulated tumors have a worse overall prognosis, than the densely granulated variants.[45] On routine hematoxylin and eosin (H&E) stains, the sparsely granulated tumors are chromophobic, whereas the densely granulated tumors are eosinophilic. Sparsely granulated tumors are usually histologically diffuse, rather than trabecular or sinusoidal like their densely granulated counterparts. Nuclear and cellular pleomorphism is not uncommon in the sparsely granulated tumors. Silent Somatotroph Adenomas--Patients harboring these tumors usually present with signs and symptoms due to tumoral mass effects and, by definition, have no clinical features of Page 5 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) acromegaly.[46-48] Most patients are young women who also have mild to moderate hyperprolactinemia, galactorrhea, and menstrual disturbances. Some patients have elevated GH levels and oral glucose suppression tests characteristic of pathologic GH secretion, but clinical stigmata of acromegaly are usually not present.[47] These rather large, often invasive, and rapidly growing tumors are GH-immunopositive. Somatotroph carcinomas are uncommon among pituitary carcinomas. Treatment with bromocriptine decreased GH levels by 46% and improved symptoms related to metastases in one patient.[21] Resection of isolated distant metastases resulted in clinical and biochemical remission of acromegaly in two patients.[49,50] Acidophil Stem-Cell Tumors These undifferentiated tumors arise from the candidate progenitor of the GH-prolactin cell lines.[51-53] They are usually large, aggressive tumors that extensively erode parasellar bony structures. One-half of affected patients harbor tumors that invade the sphenoid sinus and/or extend into the nasopharynx.[51,53] The duration of clinical symptoms is usually rather short, suggesting that these tumors progress very rapidly. Varying degrees of hyperprolactinemia are present, and one-fifth of patients have acromegaly.[51] Thyrotroph Tumors Thyroid-stimulating hormone (TSH)-producing cells of the anterior pituitary give rise to thyrotroph tumors. A majority of these are aggressive, rather large macroadenomas.[5,54-58] Three-quarters of patients have invasive tumors. A greater number of patients with microadenomas are being diagnosed in recent years because treating physicians increasingly recognize the clinical importance of inappropriate TSH secretion in patients who are hyperthyroid. Most affected patients present with goiter, thyrotoxicosis, and tumoral mass effects.[54,55] Many have been treated with thyroid ablation for presumed Grave’s disease or toxic multinodular goiter. In these patients, a decline in thyroid hormone levels and lack of tumor response to thyroid hormone may explain the aggressive behavior of the tumors. Surgery results in cure in only one-third of patients. A combination of radiotherapy and surgery probably results in a higher cure rate than does surgery alone (42% vs 31%).[55,59] Normalization of TSH and T4 levels does not always imply that antitumor therapy has eradicated the tumor.[58] Treatment with octreotide normalizes T4 and T3 levels in nearly three-quarters of patients and results in partial tumor shrinkage in about 40%.[59] Thyrotroph Carcinoma--Only one thyrotroph carcinoma has been described thus far.[60] The patient underwent transsphenoidal and transcranial surgery, as well as radiotherapy for a TSH-secreting macroadenoma. Her residual tumor was stable for 4 years and then rapidly increased in size. Additional radiotherapy and treatment with octreotide resulted in tumor shrinkage. Eight months later, she presented with a sacral mass and was subsequently diagnosed with widespread metastases to lung, liver, and bone. Gonadotroph Tumors About one-fifth of "nonfunctional" tumors are invasive.[8] Nearly one-half of null cell adenomas are invasive.[8] About two-fifths of patients have either residual or recurrent tumor after initial surgery.[61] One gonadotroph cell carcinoma has been described in the literature.[62]

Conclusions Aggressive pituitary tumors are relatively common. They are more difficult to ameliorate and tend to recur following initially successful surgery. Patients with pituitary tumors should be suspected of having aggressive neoplasms until proven otherwise. After primary therapy, they should be followed closely for the remainder of their lives to permit treatment of recurrent disease and comorbidities as Page 6 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) early as possible.

References: 1. Burrow GN, Wortzman G, Rewcastle NB, et al: Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N Engl J Med 304:156-158, 1981. 2. Annegers JF, Coulam CB, Abboud CF, et al: Pituitary adenoma in Olmstead County, Minnesota, 1935-1977: A report of an increasing incidence of diagnosis in women of childbearing age. Mayo Clin Proc 53:641-643, 1978. 3. Blevins LS, Christy JH, Khajavi M, et al: Outcomes of therapy for Cushing’s disease due to adrenocorticotropin-secreting pituitary macroadenomas. J Clin Endocrinol Metab 83:63-67, 1998. 4. Fahlbusch R, Honneger J, Buchfelder M: Surgical management of acromegaly. Endocrinol Metab Clin North Am 21:669-692, 1992. 5. Mindermann T, Wilson CB: Thyrotropin-producing pituitary adenomas. J Neurosurg 79:521-527, 1993. 6. Selman WR, Laws ER, Scheithauer BW, et al: The occurrence of dural invasion pituitary adenomas. J Neurosurg 64:402-407, 1986. 7. Sautner D, Saeger W: Invasiveness of pituitary adenomas. Pathol Res Pract 187:632-636, 1991. 8. Scheithauer BW, Kovacs KT, Laws ER, et al: Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg 65:733-744, 1986. 9. Pegolo G, Buckwalter JG, Weiss MH, et al: Pituitary adenomas: Correlation of the cytologic appearance with biologic behavior. Acta Cytol 39:887-892, 1995. 10. Landolt AM, Shibata T, Kleihues P: Growth rate of human pituitary adenomas. J Neurosurg 67:803-806, 1987. 11. Shivuya M, Saito F, Miwa T, et al: Histochemical study of pituitary adenomas with Ki-67 and anti-DNA polymerase a monoclonal antibodies, bromodeoxyuridine labeling, and nucleolar organizer region counts. Acta Neuropathol 84:178-183, 1992. 12. Hsu DW, Hakim F, Biller BMK, et al: Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence. J Neurosurg 78:753-761, 1993. 13. Gandour-Edwards R, Kapadia SB,Janecka IP, et al: Biologic markers of invasive pituitary adenomas involving the sphenoid sinus. Mod Pathol 8:160-164, 1995. 14. 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 38:99-107, 1996. 15. Knosp E, Kitz K, Pereczky A: Proliferation activity in pituitary adenomas: Measurement by monoclonal antibody Ki-67. Neurosurgery 25:927-930, 1989. 16. Takino H, Herman V, Weiss M, et al: Purine-binding factor (nm23) gene expression in pituitary tumors: Marker of adenoma invasiveness. J Clin Endocrinol Metab 80:1733-1738, 1995. 17. Thapar K, Scheithauer BW, Kovacs K, et al: p53 Expression in pituitary adenomas and carcinomas: Correlation with invasiveness and tumor growth fractions. Neurosurgery 38:765-771, 1996. 18. LeRiche VK, Asa SL, Ezzat S: Epidermal growth factor and its receptor (EGF-R) in human pituitary Page 7 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) adenomas: EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 81:656-662, 1996. 19. Alvaro V, Touraine P, Vozari RR, et al: Protein kinase C activity and expression in normal and adenomatous human pituitaries. Int J Cancer 50:724-730, 1992. 20. Saeger W, Lübke D: Pituitary carcinomas. Endocrinol Pathol 7:21-35, 1996. 21. Mountcastle RB, Roof BS, Mayfield RK, et al: Case report: Pituitary adenocarcinoma in an acromegalic patient: Response to bromocriptine in pituitary testing: A review of the literature on 36 cases of pituitary carcinoma. Am J Med Sci 298:109-118, 1989. 22. Pernicone PJ, Scheithauer BW, Sebo TJ, et al: Pituitary carcinoma: A clinical pathologic study of 15 cases. Cancer 79:804-812, 1997. 23. Bates AS, Buckley N, Boggild MD, et al: Clinical and genetic changes in a case of a Cushing’s carcinoma. Clin Endocrinol 42:663-670, 1995. 24. Bates AS, Farrell WE, Bicknell EJ, et al: Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab 82:818-824, 1997. 25. Horvath V, Kovacs K, Killinger DW, et al: Silent corticotrophic adenomas of the human pituitary gland. Am J Pathol 98:617-638, 1980. 26. Braithwaite SS, Clasen RA, D’Angelo CM: Silent corticotroph adenoma: Case report and literature review. Endocrinol Pract 3:297-301, 1997. 27. Raffin-Sanson M-L, Massias J-F, Dumont C, et al: High plasma proopiomelanocortin in aggressive adrenocorticotropin-secreting tumors. J Clin Endocrinol Metab 81:4272-4277, 1996. 28. Grua JR, Nelson DH: ACTH-producing pituitary tumors. Endocrinol Metab Clin North Am 20:319-362, 1991. 29. Jenkins PJ, Trainer PJ, Plowman PN, et al: The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab 79:165-171, 1994. 30. Kemink L, Pieters G, Hermus A, et al: Patient’s age is a simple predictive factor for the development of Nelson’s syndrome after total adrenalectomy for Cushing’s disease. J Clin Endocrinol Metab 79:887-889, 1994. 31. Molitch ME, Elton RL, Blackwell RE, et al: Bromocriptine as primary therapy for prolactin-secreting macroadenomas: Results of a prospective multicenter study. J Clin Endocrinol Metab 60:698-705, 1985. 32. Molitch ME, Thorner MO, Wilson C: Management of prolactinomas. J Clin Endocrinol Metab 82:996-1000, 1997. 33. Pellegrini I, Rasolonjanahary R, Gunz G, et al: Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 69:500-509, 1989. 34. Kovacs K, Stefaneanu L, Horvath E, et al: Prolactin-producing pituitary tumor: Resistance to dopamine agonist therapy. J Neurosurg 82:886-890, 1995. 35. Loh K-C, Shlossberg AH, Rittmaster RS, et al: Giant prolactinomas: A retrospective review. The Endocrinologist 6:257-263, 1996. 36. Davis JRE, Sheppard MC, Heath DA: Giant invasive prolactinoma: A case report and review of nine further cases. QJM 74:227-238, 1990. Page 8 of 10

Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com)

37. Murphy FY, Vesely DL, Jordan RM, et al: Giant invasive prolactinomas. Am J Med 83:995-1002, 1987. 38. Siegel RD, Lee SL: Pneumocephalus and cerebrospinal fluid rhinorrhea after bromocriptine therapy of an invasive prolactinoma: A case report and review of the literature. The Endocrinologist 6:148-152, 1996. 39. Cohen DL, Diengdoh JV, Thomas GT, et al: An intracranial metastasis from a PRL-secreting pituitary tumor. Clin Endocrinol 18:259-264, 1983. 40. Moltich ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am 21:597-614, 1992. 41. Nabarro JDN: Acromegaly. Clin Endocrinol 26:481-512, 1987. 42. Jaffe CA, Barkan AL: Treatment of acromegaly with dopamine agonists. Endocrinol Metab Clin North Am 21:713-735, 1992. 43. Ezzat S, Snyder PJ, Young WF, et al: Octreotide treatment of acromegaly. Ann Intern Med 117:711-718, 1992. 44. Eastman RC, Gordon P, Glatstein E, et al: Radiation therapy of acromegaly. Endocrinol Metab Clin North Am 21:693-712, 1992. 45. Kovacs K: Pathology of growth hormone excess. Pathol Res Pract 183:565-568, 1988. 46. Tourniaire J, Trouillas J, Chalendar D, et al: Somatotrophic adenoma manifested by galactorrhea without acromegaly. J Clin Endocrinol Metab 61:451-453, 1985. 47. Klibanski A, Xervas NT, Kovacs K, et al: Clinically silent hypersecretion of growth hormone in patients with pituitary tumors. J Neurosurg 66:806-811, 1987. 48. Kovacs K, Lloyd R, Horvath E, et al: Silent somatotroph adenomas of the human pituitary. Am J Pathol 134:345-353, 1989. 49. Greenman Y, Woolf P, Coniglio J, et al: Remission of acromegaly caused by pituitary carcinoma after sugical excision of growth hormone-secreting metastasis detected by 111-indium pentereotide scan. J Clin Endocrinol Metab 81:1628-1633, 1996. 50. Dayan C, Guilding T, Hearing S, et al: Biochemical cure of recurrent acromegaly by resection of cervical spinal canal metastasis. Clin Endocrinol 44:597-602, 1996. 51. Horvath E, Kovacs K, Sionger W, et al: Acidophil stem cell adenoma of the human pituitary: Clinicopathologic analysis of 15 cases. Cancer 47:761-771, 1981. 52. Page MD, Bridges LR, Barth JH, et al: Development of acromegaly during treatment of hyperprolactinemia with bromocriptine: An unusual acidophil stem cell adenoma. J Clin Endocrinol Metab 81:4484-4487, 1996. 53. Horvath E, Kovacs K, Singer W, et al: Acidophil stem cell adenoma of the human pituitary. Arch Pathol Lab Med 101:594-599, 1977. 54. Smallridge RC, Smith CE: Hyperthyroidism due to thyrotropin-secreting pituitary tumors. Arch Intern Med 143:503-507, 1983. 55. Gesundheit N, Petrick PA, Nissim M, et al: Thyrotropin-secreting pituitary adenomas: Clinical and biochemical heterogeneity. Ann Intern Med 111:827-835, 1989.

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Aggressive Pituitary Tumors Published on Physicians Practice (http://www.physicianspractice.com) 56. Beckers A, Abs R, Mahler C, et al: Thyrotropin-secreting pituitary adenomas: A report of seven cases. J Clin Endocrinol Metab 72:477-483, 1991. 57. Wynne AG, Ghaerib H, Scheithauer BW, et al: Hyperthyroidism due to inappropriate secretion of thyrotropin in ten patients. Am J Med 92:15-24, 1992. 58. Losa M, Giovanelli M, Persani L, et al: Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 81:3084-3090, 1996. 59. Chanson P, Weintraub BD, Harris AG: Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas. Ann Intern Med 119:236-240, 1993. 60. Mixson AJ, Friedman TC, Katz DA, et al: Thyrotropin-secreting pituitary carcinoma. J Clin Endocrinol Metab 76:529-533, 1993. 61. Young WF, Scheithauer BW, Kovacs KT, et al: Gonadotroph adenoma of the pituitary gland: A clinicopathologic analysis of 100 cases. Mayo Clin Proc 71:649-656, 1996. 62. Deauchesne P, Trouillas J, Varral F, et al: Gonadotropic pituitary carcinoma: Case report. Neurosurgery 37:810-815, 1995.

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