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NCI/PDQ^® Health professionals: Pituitary Tumors Treatment (PDQ®)

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National Cancer Institute
Last Modified: July 27, 2012

TABLE OF CONTENTS

• General Information About Pituitary Tumors
  • Clinical Presentation
    • Prolactin-producing pituitary tumors
    • Adrenocorticotrophic hormone-producing pituitary tumors
    • Growth hormone-producing pituitary tumors
    • Thyrotropin-producing pituitary tumors
    • Nonfunctioning adenomas

• Cellular Classification of Pituitary Tumors
  • Prolactin (PRL)-Producing Pituitary Tumors
  • Adrenocorticotrophic Hormone (ACTH)-Producing Pituitary Tumors
  • Growth Hormone (GH)-Producing Pituitary Tumors
  • Thyrotropin-Producing Pituitary Tumors
  • Gonadotroph (FSH-Producing and/or LH-Producing) Adenomas
  • Plurihormonal Adenomas
  • Nonfunctioning (Endocrine-Inactive) Adenomas
  • Oncocytic Tumors
  • Carcinomas
  • Metastatic Tumors
  • Other Tumors

• Stage Information for Pituitary Tumors

• Treatment Option Overview

• Prolactin-Producing Pituitary Tumors Treatment
  • Standard Treatment Options for Prolactin (PRL)-Producing Pituitary Tumors
  • Current Clinical Trials

• Adrenocorticotropic Hormone-Producing Pituitary Tumors Treatment
  • Standard Treatment Options for Adrenocorticotropic Hormone (ACTH)-Producing Pituitary Tumors
  • Treatment Options Under Clinical Evaluation for ACTH-Producing Pituitary Tumors
  • Current Clinical Trials

• Growth Hormone-Producing Pituitary Tumors Treatment
  • Standard Treatment Options for Growth Hormone (GH)-Producing Pituitary Tumors
  • Current Clinical Trials

• Thyrotropin-Producing Tumors Treatment
  • Standard Treatment Options for Thyrotropin-Producing Tumors
  • Current Clinical Trials

• Nonfunctioning Pituitary Tumors Treatment
  • Standard Treatment Options for Nonfunctioning Pituitary Tumors
  • Current Clinical Trials

• Pituitary Carcinomas Treatment
  • Standard Treatment Options for Pituitary Carcinomas
  • Current Clinical Trials

• Recurrent Pituitary Tumors Treatment
  • Standard Treatment Options for Recurrent Pituitary Tumors
  • Treatment Options Under Clinical Evaluation for Recurrent Pituitary Tumors
  • Current Clinical Trials

• Changes to This Summary (07/27/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
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General Information About Pituitary Tumors

Pituitary tumors represent from 10% to 25% of all intracranial neoplasms. Depending on the study cited, pituitary tumors can be classified into three groups according to their biological behavior: 1 2

• Benign adenoma.
• Invasive adenoma.
• Carcinoma.

Adenomas comprise the largest portion of pituitary neoplasms with an overall estimated prevalence of approximately 17%. Only a minority of adenomas are symptomatic. 3 In addition, pituitary adenomas may be distinguished anatomically as intrapituitary, intrasellar, diffuse, and invasive. 4 Invasive adenomas, which account for approximately 35% of all pituitary neoplasms, may invade the dura mater, cranial bone, or sphenoid sinus. 5 Carcinomas account for 0.1% to 0.2% of all pituitary tumors. 6 7

Clinical Presentation

The most characteristic-presenting features of pituitary adenomas include inappropriate pituitary hormone secretion and visual field deficits. 8

Rare signs and symptoms of pituitary disease include: 8

• Cranial nerve palsies.
• Temporal lobe epilepsy.
• Hydrocephalus.
• Cerebrospinal fluid rhinorrhea.

The signs and symptoms commonly associated with pituitary tumors derived from each specific cell type (i.e., prolactinomas, corticotroph adenomas, somatotroph adenomas, thyrotroph adenomas, and nonfunctioning adenomas) are as follows:

Prolactin-producing pituitary tumors

Signs and symptoms of prolactin (PRL)-producing pituitary tumors, also known as prolactinomas and lactotroph adenomas, may include: 8

• Headache. (Refer to the PDQ® summary on Pain for more information.)
• Visual field deficits.
• Oligomenorrhea or amenorrhea.
• Reduced fertility. (Refer to the Fertility Issues section in the PDQ® summary on Sexuality and Reproductive Issues for more information.)
• Loss of libido. (Refer to the Treatment-related Factors Secondary to Radiation section in the Factors Affecting Sexual Function in People With Cancer section and the Selective Serotonin Reuptake Inhibitors section in the Pharmacological Effects of Supportive Care Medications on Sexual Function section of the PDQ® summary on Sexuality and Reproductive Issues for more information.)
• Erectile dysfunction.
• Galactorrhea in the estrogen-primed female breast.

Adrenocorticotrophic hormone-producing pituitary tumors

Signs and symptoms of adrenocorticotrophic hormone (ACTH)-producing pituitary tumors, also known as corticotroph adenomas, may include: 8

• Headache. (Refer to the PDQ® summary on Pain for more information.)
• Visual field deficits.
• Proximal myopathy.
• Centripetal fat distribution.
• Neuropsychiatric symptoms. (Refer to the PDQ® summary on Adjustment to Cancer: Anxiety and Distress and the Symptoms and Risk Factors section in the Assessment and Diagnosis section of the PDQ® summary on Depression for more information.)
• Striae.
• Ability to easily bruise.
• Skin thinning.
• Hirsutism.
• Osteopenia.

Growth hormone-producing pituitary tumors

Signs and symptoms of growth hormone (GH)-producing pituitary tumors, also known as somatotroph adenomas, may include: 8

• Headache. (Refer to the PDQ® summary on Pain for more information.)
• Visual field deficits.
• Growth of hands and feet.
• Coarsening of facial features.
• Carpal tunnel syndrome.
• Snoring and obstructive sleep apnea. (Refer to the Assessment section and the Special Considerations section in the PDQ® summary on Sleep Disorders for more information.)
• Jaw growth and prognathism.
• Osteoarthritis and arthralgia. (Refer to the PDQ® summary on Pain for more information.)
• Excessive sweating. (Refer to the PDQ® summary on Fever, Sweats, and Hot Flashes for more information.)
• Dysmorphophobia.

Thyrotropin-producing pituitary tumors

Signs and symptoms of thyrotropin (thyroid-stimulating hormone [TSH])-producing tumors, also known as thyrotroph adenomas, may include: 9

• Palpitations.
• Tremor.
• Weight loss. (Refer to the PDQ® summary on Nutrition in Cancer Care for more information.)
• Insomnia. (Refer to the PDQ® summary on Sleep Disorders for more information.)
• Hyperdefecation.
• Sweating. (Refer to the PDQ® summary on Fever, Sweats, and Hot Flashes for more information.)

Nonfunctioning adenomas

Signs and symptoms of nonfunctioning adenomas (most commonly gonadotroph adenomas) may include: 10

• Headache. (Refer to the PDQ® summary on Pain for more information.)
• Visual field deficits.
• Pituitary insufficiency, which is due to compression of the pituitary stalk or destruction of normal pituitary tissue by the tumor, and predominantly manifests as secondary hypogonadism.
• Rarely, ovarian overstimulation, testicular enlargement, or increased testosterone levels.

In addition to cell-type specific presentations, pituitary apoplexy (i.e., pituitary adenoma apoplexy) represents another important clinical presentation of pituitary adenomas. Pituitary apoplexy can result from an acute hemorrhagic or ischemic infarction of the pituitary in patients harboring often unrecognized secreting or nonfunctioning pituitary adenomas. In a series analyzing 40 cases of pituitary apoplexy, the presenting signs and symptoms included headache (63%), vomiting (50%), visual field defects (61%), ocular paresis (40%), mental deterioration (13%), hyponatremia (13%), and syncope (5%); in only four cases pituitary tumor was diagnosed prior to presentation. 11

The development of pituitary adenomas may also occur as a component of three familial cancer syndromes: 8

• Multiple endocrine neoplasia 1 (MEN 1).
• Carney complex (e.g., cardiac myxomas, spotty skin pigmentation, and tumors of the adrenal gland and anterior pituitary).
• Isolated familial acromegaly.

A number of other lesions should be considered in the differential diagnosis of sellar masses. Although rare, lymphocytic (i.e., autoimmune) hypophysitis should be considered in the differential diagnosis of any nonsecreting pituitary mass, especially when occurring during pregnancy or postpartum. 12 In addition, the clinician should consider craniopharyngioma and Rathke cleft cyst in the differential diagnosis of pituitary tumors. Sellar masses may also result from tumors that are metastatic to the pituitary. This typically occurs as a part of a generalized metastatic spread and is usually associated with five or more additional metastatic sites, especially osseous; breast and lung cancer are the most common primary neoplasms metastasizing to the pituitary. 13

References:

1. Asa SL, Ezzat S: The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19 (6): 798-827, 1998. [PUBMED Abstract]
2. Landman RE, Horwith M, Peterson RE, et al.: Long-term survival with ACTH-secreting carcinoma of the pituitary: a case report and review of the literature. J Clin Endocrinol Metab 87 (7): 3084-9, 2002. [PUBMED Abstract]
3. Ezzat S, Asa SL, Couldwell WT, et al.: The prevalence of pituitary adenomas: a systematic review. Cancer 101 (3): 613-9, 2004. [PUBMED Abstract]
4. Kovacs K, Horvath E, Vidal S: Classification of pituitary adenomas. J Neurooncol 54 (2): 121-7, 2001. [PUBMED Abstract]
5. Scheithauer BW, Kovacs KT, Laws ER Jr, et al.: Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg 65 (6): 733-44, 1986. [PUBMED Abstract]
6. Pernicone PJ, Scheithauer BW, Sebo TJ, et al.: Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79 (4): 804-12, 1997. [PUBMED Abstract]
7. Ragel BT, Couldwell WT: Pituitary carcinoma: a review of the literature. Neurosurg Focus 16 (4): E7, 2004. [PUBMED Abstract]
8. Levy A: Pituitary disease: presentation, diagnosis, and management. J Neurol Neurosurg Psychiatry 75 (Suppl 3): iii47-52, 2004. [PUBMED Abstract]
9. Vance ML: Treatment of patients with a pituitary adenoma: one clinician's experience. Neurosurg Focus 16 (4): E1, 2004. [PUBMED Abstract]
10. Losa M, Mortini P, Barzaghi R, et al.: Endocrine inactive and gonadotroph adenomas: diagnosis and management. J Neurooncol 54 (2): 167-77, 2001. [PUBMED Abstract]
11. Lubina A, Olchovsky D, Berezin M, et al.: Management of pituitary apoplexy: clinical experience with 40 patients. Acta Neurochir (Wien) 147 (2): 151-7; discussion 157, 2005. [PUBMED Abstract]
12. Caturegli P, Newschaffer C, Olivi A, et al.: Autoimmune hypophysitis. Endocr Rev 26 (5): 599-614, 2005. [PUBMED Abstract]
13. Komninos J, Vlassopoulou V, Protopapa D, et al.: Tumors metastatic to the pituitary gland: case report and literature review. J Clin Endocrinol Metab 89 (2): 574-80, 2004. [PUBMED Abstract]

Cellular Classification of Pituitary Tumors

Pituitary adenomas can be classified according to staining affinities of the cell cytoplasm, size, endocrine activity, histologic characteristics, hormone production and contents, ultrastructural features, granularity of the cell cytoplasm, cellular composition, cytogenesis, and growth pattern. 1 Recent classifications, however, omit criteria based on tinctorial stains (i.e., acidophilic, basophilic, and chromophobic) because of the poor correlation between staining affinities of the cell cytoplasm and other pathological features of pituitary tumors, such as the type of hormone produced and cellular derivation. 1 2

A unifying pituitary adenoma classification incorporates the histological, immunocytochemical, and electron microscopic studies of the tumor cells, and stresses the importance of hormone production, cellular composition, and cytogenesis. This classification emphasizes the structure-function relationship and attempts to correlate morphologic features with secretory activity. 1

Pituitary adenomas may be classified based on: 2

1. An anatomical approach, which classifies pituitary tumors by size based on radiological findings. Tumors are divided into microadenomas (i.e., the greatest diameter is <10 mm) and macroadenomas (i.e., the greatest diameter is I0 mm). 3 Most pituitary adenomas are microadenomas. Historically, the most widely used radioanatomical classification was based primarily on a neuroradiological examination including skull x-rays, pneumoencephalography, polytomography, and carotid angiography 4 and subsequently validated by the application of more accurate computed tomography (CT) and magnetic resonance imaging (MRI).

   An MRI scan is now considered the imaging modality of choice for the diagnosis of pituitary disorders because of its multiplanar capability and good soft tissue contrast enhancement. 3 Sagittal T1-weighted images, clearly displaying the anterior and posterior lobes and the stalk on the same plane, and coronal images, displaying the relation between the pituitary and cavernous sinuses, are optimal for identifying a pituitary adenoma. A 3-mm thin slice typically is used to obtain optimal resolution. Sagittal T1-weighted images, clearly displaying the anterior and posterior lobes and the stalk on the same plane, and coronal images, displaying the relation between the pituitary and cavernous sinuses, are optimal for identifying a pituitary adenoma. A 3-mm thin slice typically is used to obtain optimal resolution. 5 A computed tomography (CT) scan may also be a useful diagnostic tool with coronal scans providing the optimal view; A computed tomography (CT) scan may also be a useful diagnostic tool with coronal scans providing the optimal view; 6 however, CT scans appear to be less sensitive than MRI scans in this application. however, CT scans appear to be less sensitive than MRI scans in this application. 7 For each imaging technique, a focal hypointensity within the pituitary gland is considered abnormal and suggestive of an adenoma. An MRI scan is also the best diagnostic imaging choice for pituitary carcinomas; metastases may be found in the cerebral lobes, cerebellum, spinal cord, leptomeninges, and subarachnoid space. For each imaging technique, a focal hypointensity within the pituitary gland is considered abnormal and suggestive of an adenoma. An MRI scan is also the best diagnostic imaging choice for pituitary carcinomas; metastases may be found in the cerebral lobes, cerebellum, spinal cord, leptomeninges, and subarachnoid space. 8

   This radioanatomical classification places adenomas into 1 of 4 grades (IIV). 9 (Refer to the (Refer to the Stage Information For Pituitary Tumors section of this summary for more information.) The grades are as follows: section of this summary for more information.) The grades are as follows:

   • Stage I are microadenomas (<1 cm) without sella expansion.
   • Stage II are macroadenomas (1 cm) and may extend above the sella.
   • Stage III are macroadenomas with enlargement and invasion of the floor or suprasellar extension.
   • Stage IV is destruction of the sella.

2. Histological criteria, which use:
   • Immunohistological characterization of the tumors in terms of hormone production. Immunocytochemical staining for pituitary hormones generally correlates with hormone serum levels. Twenty percent of pituitary adenomas have no readily identifiable hormone production.
   • Ultrastructural criteria, which can confirm that nonfunctional lesions are of pituitary origin and characterize the cytological differentiation of tumor cells in terms of anterior pituitary cell types.

3. Functional criteria, which are used to define tumors in terms of their endocrine activity. Clinical endocrinologists often use the functional classification of pituitary adenomas and define these tumors based on their hormonal activity in vivo. A retrospective review of the pituitary adenoma literature indicates that prolactinomas are by far the most common form of pituitary adenoma as determined by immunohistochemical criteria; tumors secreting adrenocorticotropic hormone (ACTH), growth hormone (GH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) follow in decreasing frequency. 3 10 Functionally inactive pituitary adenomas, however, comprise approximately 30% to 35% of the pituitary tumors in most series and are the most common type of macroadenoma. 11

   Using functional criteria, pituitary adenomas can be characterized as: 9

   • Prolactin (PRL)-producing, also known as lactotroph, adenomas causing hyperprolactinemia and its clinical sequelae.
   • ACTH-producing, also known as corticotroph, adenomas associated with Cushing or Nelson syndromes.
   • GH-producing, also known as somatotroph, adenomas associated with acromegaly and/or gigantism.
   • Rare thyrotropin TSH-producing, also known as thyrotroph, tumors.
   • The large group of clinically nonfunctioning (i.e., the endocrine-inactive) adenomas. This group is comprised predominantly of gonadotroph adenomas. Gonadotroph adenomas synthesize follicle-stimulating hormone-(FSH) and/or LH, or the alpha or beta subunits of these heterodimers. They are usually detected incidentally or because of the presence of neurologic symptoms. Gonadotroph adenomas are inefficient secretors of the hormones they produce, so they rarely result in a clinically recognizable hormonal hypersecretion syndrome.
   • Because of the relative abundance of adenomas that secrete both GH and PRL, the category of mixed adenomas has also become a designation.

   Hormone-secreting pituitary carcinomas may elicit similar signs and symptoms according to the particular hormone that is secreted; they may also produce signs and symptoms related to malignant spread. 8 Because no unequivocal histopathologic features of carcinoma exist, the diagnosis of malignancy is reserved for pituitary neoplasms that have metastasized to remote areas of the central nervous system (CNS) or outside of the CNS. 12 13 14 In a review of 95 cases of pituitary carcinoma, 68% of the cases were found to be hormone-producing and PRL (26%) and ACTH (25%) were the most common hormonal subtypes. 15 Pituitary carcinomas producing GH were the second most common of the hormonal subtypes, and FSH/LH-producing and TSH-producing carcinomas were even more rarely reported. Other reports indicate that as many as 88% of pituitary carcinomas are endocrinologically active, and ACTH-secreting tumors are the most common. 8 Although only 2% to 10% of pituitary adenomas are ACTH-secreting, the percentage of pituitary carcinomas that secrete ACTH is estimated to be much higher at 25% to 34%. 15 16 17 18 19 In a series of 15 cases, carcinomas showed a greater tendency toward systemic metastasis than craniospinal metastasis; the rate of systemic metastasis was 71% for PRL-producing cell tumors and 57% for ACTH-producing tumors. 16

Prolactin (PRL)-Producing Pituitary Tumors

PRL-producing pituitary tumors, also known as prolactinomas and lactotroph adenomas, secrete PRL and are typically an intrasellar tumor. In women, these adenomas are often small (<10 mm). In either sex, however, they can become large enough to enlarge the sella turcica. These adenomas represent the most common hormone-producing pituitary tumors and account for 25% to 41% of tumor specimens. 3

Adrenocorticotrophic Hormone (ACTH)-Producing Pituitary Tumors

The major manifestation of ACTH-producing pituitary tumors, also know as corticotroph adenomas, is secretion of adrenocorticotropic hormone (ACTH), which results in Cushing syndrome. These tumors are initially confined to the sella turcica, but they may enlarge and become invasive after bilateral adrenalectomy (i.e., Nelson syndrome). These adenomas represent the second or third most common hormone-producing pituitary tumors, depending on the series; in one series, these tumors accounted for 10% of all tumor specimens. 1 3

Growth Hormone (GH)-Producing Pituitary Tumors

GH-producing pituitary tumors, also known as somatotroph adenomas, produce GH, resulting in gigantism in younger patients and acromegaly in others. Suprasellar extension is not uncommon. These adenomas represent the second or third most common hormone-producing pituitary tumors, depending on the series; in one series these adenomas accounted for 13% of tumor specimens. 1 3

Thyrotropin-Producing Pituitary Tumors

Thyrotroph-producing pituitary tumors, also known as thyrotroph adenomas, secrete thyroid-stimulating hormone (TSH), also known as thyrotropin, which results in hyperthyroidism without TSH suppression. Many are large and invasive, may be plurihormonal, and secrete both GH and/or PRL. 20 These tumors are rare and account for no more than 2% of tumor specimens. 1 3 20

Gonadotroph (FSH-Producing and/or LH-Producing) Adenomas

Gonadotroph adenomas may secrete FSH and/or LH, or the alpha or beta subunits that comprise these heterodimers, which, depending on gender, may result in ovarian overstimulation, increased testosterone levels, testicular enlargement, and pituitary insufficiency caused by compression of the pituitary stalk or destruction of normal pituitary tissue by tumor. Many gonadotroph tumors, however, are unassociated with clinical or biochemical evidence of hormone excess and may be considered to be nonfunctioning or endocrine-inactive tumors. 21 Functional, clinically detectable gonadotroph adenomas are rare. 9

Plurihormonal Adenomas

Plurihormonal tumors produce more than one hormone. Morphologically, they can be either monomorphous or plurimorphous. Monomorphous plurihormonal adenomas consist of one cell population that produces two or more hormones. The adenoma cells often differ from nontumorous adenohypophysial cells, and their cellular derivation may remain obscure despite extensive morphological studies. Plurimorphous plurihormonal adenomas consist of two or more distinct cell types, and each produces one hormone. 1 Thyrotroph adenomas are often plurihormonal. 20

Nonfunctioning (Endocrine-Inactive) Adenomas

These tumors arise from the adenohypophysis and cause symptoms when they extend beyond the sella, which results in pressure on the surrounding structures rather than secretion of a hormonally active substance. Endocrine-inactive adenomas show positive immunostaining for one or more pituitary hormones; 1 however, they are not associated with clinical and biochemical evidence of hormone excess. Gonadotrophic hormones, as detected by antisera to beta-FSH and beta-LH, are present in many clinically nonfunctioning adenomas. Some of these adenomas are recognized by electron microscopy to have gonadotrophic differentiation, but some have characteristics of less well-differentiated cells and resemble the null cells that were initially thought to be undifferentiated precursors of adenohypophysial cells. 9 Endocrine-inactive pituitary adenomas comprise approximately 30% to 35% of the pituitary tumors in most series and are the most common type of macroadenoma. 11

Oncocytic Tumors

Oncocytic tumors of the pituitary, also known as pituitary oncocytomas, are characterized by an abundance of mitochondria, which may fill up to 50% of the cytoplasmic area, which is normally around 8%, and obscure other organelles. These tumors are usually unassociated with clinical and biochemical evidence of hormone excess; in some cases, they may be accompanied by various degrees of hypopituitarism and/or mild hyperprolactinemia. Oncocytic change may occur in several other pituitary tumor types. 1

Carcinomas

Pituitary carcinomas are usually endocrinologically functional, and ACTH-producing and PRL-producing tumors are the most frequent. 2 8 The histological and cytological characteristics of pituitary carcinomas vary from bland and monotonous to frankly malignant. 22 Carcinomas show a variable degree of nuclear atypia and cellular pleomorphism, but they also show significantly higher mitotic rates and cell proliferation indices than adenomas. 2 Carcinomas account for 0.1% to 0.2% of all pituitary tumors. 8 16

Metastatic Tumors

Breast and lung cancer are the most common primary neoplasms metastasizing to the pituitary. Although tumors that are metastatic to the pituitary have been reported to be as high as 28% in autopsy series, the majority of metastatic tumors are clinically silent. 23

Other Tumors

Other tumors that arise in the pituitary include craniopharyngiomas, meningiomas, and germ cell tumors; the rare granular cell tumors, pituicytomas, and gangliogliomas; and the even rarer gangliocytomas, lymphomas, astrocytomas, and ependymomas. 2

References:

1. Kovacs K, Horvath E, Vidal S: Classification of pituitary adenomas. J Neurooncol 54 (2): 121-7, 2001. [PUBMED Abstract]
2. Ironside JW: Best Practice No 172: pituitary gland pathology. J Clin Pathol 56 (8): 561-8, 2003. [PUBMED Abstract]
3. Ezzat S, Asa SL, Couldwell WT, et al.: The prevalence of pituitary adenomas: a systematic review. Cancer 101 (3): 613-9, 2004. [PUBMED Abstract]
4. Hardy J: Transsphenoidal surgery of hypersecreting pituitary tumors. In: Kohler PO, Ross GT, eds.: Diagnosis and treatment of pituitary tumors: proceedings of a conference sponsored jointly by the National Institute of Child Health and Human Development and the National Cancer Institute, January 15-17, 1973, Bethesda, Md. Amsterdam, The Netherlands: Excerpta medica, 1973, pp 179-98. [PUBMED Abstract]
5. Elster AD: Modern imaging of the pituitary. Radiology 187 (1): 1-14, 1993. [PUBMED Abstract]
6. Chambers EF, Turski PA, LaMasters D, et al.: Regions of low density in the contrast-enhanced pituitary gland: normal and pathologic processes. Radiology 144 (1): 109-13, 1982. [PUBMED Abstract]
7. Hall WA, Luciano MG, Doppman JL, et al.: Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 120 (10): 817-20, 1994. [PUBMED Abstract]
8. Ragel BT, Couldwell WT: Pituitary carcinoma: a review of the literature. Neurosurg Focus 16 (4): E7, 2004. [PUBMED Abstract]
9. Asa SL, Ezzat S: The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19 (6): 798-827, 1998. [PUBMED Abstract]
10. McComb DJ, Ryan N, Horvath E, et al.: Subclinical adenomas of the human pituitary. New light on old problems. Arch Pathol Lab Med 107 (9): 488-91, 1983. [PUBMED Abstract]
11. Yeh PJ, Chen JW: Pituitary tumors: surgical and medical management. Surg Oncol 6 (2): 67-92, 1997. [PUBMED Abstract]
12. Scheithauer BW, Kovacs KT, Laws ER Jr, et al.: Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg 65 (6): 733-44, 1986. [PUBMED Abstract]
13. Della Casa S, Corsello SM, Satta MA, et al.: Intracranial and spinal dissemination of an ACTH secreting pituitary neoplasia. Case report and review of the literature. Ann Endocrinol (Paris) 58 (6): 503-9, 1997. [PUBMED Abstract]
14. Kemink SA, Wesseling P, Pieters GF, et al.: Progression of a Nelson's adenoma to pituitary carcinoma; a case report and review of the literature. J Endocrinol Invest 22 (1): 70-5, 1999. [PUBMED Abstract]
15. Kaltsas GA, Grossman AB: Malignant pituitary tumours. Pituitary 1 (1): 69-81, 1998. [PUBMED Abstract]
16. Pernicone PJ, Scheithauer BW, Sebo TJ, et al.: Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79 (4): 804-12, 1997. [PUBMED Abstract]
17. Kovacs K, Horvath E: Pathology of pituitary tumors. Endocrinol Metab Clin North Am 16 (3): 529-51, 1987. [PUBMED Abstract]
18. Thapar K, Scheithauer BW, Kovacs K, et al.: p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 38 (4): 765-70; discussion 770-1, 1996. [PUBMED Abstract]
19. Garrío AF, Sobrinho LG, Pedro-Oliveira, et al.: ACTH-producing carcinoma of the pituitary with haematogenic metastases. Eur J Endocrinol 137 (2): 176-80, 1997. [PUBMED Abstract]
20. Teramoto A, Sanno N, Tahara S, et al.: Pathological study of thyrotropin-secreting pituitary adenoma: plurihormonality and medical treatment. Acta Neuropathol (Berl) 108 (2): 147-53, 2004. [PUBMED Abstract]
21. Snyder PJ: Extensive personal experience: gonadotroph adenomas. J Clin Endocrinol Metab 80 (4): 1059-61, 1995. [PUBMED Abstract]
22. Pernicone PJ, Scheithauer BW: Invasive pituitary adenoma and pituitary carcinoma. In: Thapar K, Kovacs K, Scheithauer BW, et al., eds.: Diagnosis and Management of Pituitary Tumors. Totowa, NJ: Humana Press, 2001, pp 369-86. [PUBMED Abstract]
23. Komninos J, Vlassopoulou V, Protopapa D, et al.: Tumors metastatic to the pituitary gland: case report and literature review. J Clin Endocrinol Metab 89 (2): 574-80, 2004. [PUBMED Abstract]

Stage Information for Pituitary Tumors

As with other tumors of the central nervous system (CNS), no tumor, nodes, metastases-based American Joint Committee on Cancer classification and staging system for pituitary tumors exists. 1 Pituitary tumors are classified according to size and divided into microadenomas (i.e., the greatest diameter is <10 mm) and macroadenomas (i.e., the greatest diameter is I0 mm). 2 Most pituitary adenomas are microadenomas.

The most widely used radioanatomical classification was based primarily on a neuroradiological examination including skull x-rays, pneumoencephalography, polytomography, and carotid angiography. 3 Subsequently validated by the application of more accurate magnetic resonance imaging (MRI) and computed tomography, this radioanatomical classification places adenomas into 1 of 4 grades (IIV) and has been augmented by additional studies including immunohistochemistry and electron microscopy. 4

Currently, MRI is considered the imaging modality of choice for the diagnosis of pituitary disorders because of its multiplanar capability and good soft tissue contrast enhancement. 2 Because no unequivocal histopathologic features of pituitary carcinoma exist, the diagnosis of malignancy is reserved for pituitary neoplasms that have metastasized to remote areas of the CNS or to outside of the CNS. 5 6 7

The radiographical classification for pituitary adenomas is as follows: 3 8

• 0: Normal pituitary appearance.
• I: Enclosed within the sella turcica, microadenoma, smaller than 10 mm.
• II: Enclosed within the sella turcica, macroadenoma, 10 mm or larger.
• III: Invasive, locally, into the sella.
• IV: Invasive, diffusely, into the sella.

The grading schema for suprasellar extensions is as follows: 3 8

• A: 0 to 10 mm suprasellar extension occupying the suprasellar cistern.
• B: 10 mm to 20 mm extension and elevation of the third ventricle.
• C: 20 mm to 30 mm extension occupying the anterior of the third ventricle.
• D: A larger than 30 mm extension, beyond the foramen of Monro, or Grade C with lateral extensions.

References:

1. Brain and spinal cord. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 593-7. [PUBMED Abstract]
2. Ezzat S, Asa SL, Couldwell WT, et al.: The prevalence of pituitary adenomas: a systematic review. Cancer 101 (3): 613-9, 2004. [PUBMED Abstract]
3. Hardy J: Transsphenoidal surgery of hypersecreting pituitary tumors. In: Kohler PO, Ross GT, eds.: Diagnosis and treatment of pituitary tumors: proceedings of a conference sponsored jointly by the National Institute of Child Health and Human Development and the National Cancer Institute, January 15-17, 1973, Bethesda, Md. Amsterdam, The Netherlands: Excerpta medica, 1973, pp 179-98. [PUBMED Abstract]
4. Asa SL, Ezzat S: The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19 (6): 798-827, 1998. [PUBMED Abstract]
5. Scheithauer BW, Kovacs KT, Laws ER Jr, et al.: Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg 65 (6): 733-44, 1986. [PUBMED Abstract]
6. Della Casa S, Corsello SM, Satta MA, et al.: Intracranial and spinal dissemination of an ACTH secreting pituitary neoplasia. Case report and review of the literature. Ann Endocrinol (Paris) 58 (6): 503-9, 1997. [PUBMED Abstract]
7. Kemink SA, Wesseling P, Pieters GF, et al.: Progression of a Nelson's adenoma to pituitary carcinoma; a case report and review of the literature. J Endocrinol Invest 22 (1): 70-5, 1999. [PUBMED Abstract]
8. Yeh PJ, Chen JW: Pituitary tumors: surgical and medical management. Surg Oncol 6 (2): 67-92, 1997. [PUBMED Abstract]

Treatment Option Overview

The goals of treatment of pituitary adenomas include normalization of hormonal secretion (i.e., normalization of hypersecretion and improvement in hypofunction) and resolution or cessation of the progression of neurological defects.

Standard treatments for patients with pituitary tumors include:

• Surgery.
• Radiation therapy.
• Medical therapy.
• A combination of surgery, radiation therapy, and medical therapy.

The treatment of choice must be individualized and is dictated by the type of tumor, the nature of the excessive hormonal expression, and whether or not the tumor extends into the brain around the pituitary. 1 2

The transsphenoidal microsurgical approach to a pituitary lesion is the most widely employed surgical approach to pituitary lesions and represents a major development in the safe surgical treatment of both hormonally active and nonfunctioning tumors. 3 4 5 This approach is often successful in debulking tumors, even those that have a significant suprasellar extension.

A contraindication to this approach includes tumors with a significant suprasellar extension with an hourglass-shaped narrowing between the intrasellar and suprasellar component because blind attempts to reach the suprasellar tumor may lead to cerebral damage. In addition, an infection in the sphenoid sinus is potentially a contraindication to the transsphenoidal approach. In such cases, craniotomies via a pterional or subfrontal approach may be performed. Rapid deterioration of vision is an immediate indication for surgery to relieve pressure produced by an expanding tumor mass, except in the case of macroprolactinomas (where intensive observation with a patient on dopaminergic agonists may be an acceptable alternative). Progressive deterioration of visual fields is often the primary neurological criterion on which surgical management decisions are based. 6

Conventional radiation therapy is an effective adjunct to the treatment of pituitary tumors. 3 The advantages of radiation therapy are that it is noninvasive and suitable for surgically high-risk patients. The clinical and biochemical response, however, is slow and may require from 2 years to 10 years for complete and sustained remission. In addition, radiation therapy carries a substantial risk of hypopituitarism (i.e., approximately 30% at 10 years).

Hormone-secreting tumors may be treated with surgery or radiation therapy. Surgical therapy is the treatment of choice for growth hormone-(GH) producing, adrenocorticotropic hormone-(ACTH) producing, and endocrine-inactive adenomas. GH-secreting tumors can be treated with somatostatin analogues, dopamine analogues, and the newer GH-receptor antagonists, such as pegvisomant. 6 Ketoconazole, an inhibitor of steroidogenesis, is considered the first drug of choice as adjunctive medical therapy for ACTH-producing tumors. 3 Somatostatin analogues are the drugs of choice for treatment of thyroid-stimulating, hormone-producing adenomas; however, the efficacy of treatment may wane with time. 6

The natural history of growth hormone-secreting and ACTH-secreting pituitary tumors is usually one of slowly progressive enlargement. 3 Microprolactinomas, however, often remain unchanged, or decrease in size over time, and have been observed to undergo complete, spontaneous resolution on occasion. 6

Treatments under clinical evaluation for patients with pituitary tumors include:

• Stereotactic radiation surgery. 7

References:

1. Asa SL, Ezzat S: The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19 (6): 798-827, 1998. [PUBMED Abstract]
2. Landman RE, Horwith M, Peterson RE, et al.: Long-term survival with ACTH-secreting carcinoma of the pituitary: a case report and review of the literature. J Clin Endocrinol Metab 87 (7): 3084-9, 2002. [PUBMED Abstract]
3. Yeh PJ, Chen JW: Pituitary tumors: surgical and medical management. Surg Oncol 6 (2): 67-92, 1997. [PUBMED Abstract]
4. Hardy J: Transsphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg 16: 185-217, 1969. [PUBMED Abstract]
5. Hardy J: Transsphenoidal hypophysectomy. J Neurosurg 34 (4): 582-94, 1971. [PUBMED Abstract]
6. Levy A: Pituitary disease: presentation, diagnosis, and management. J Neurol Neurosurg Psychiatry 75 (Suppl 3): iii47-52, 2004. [PUBMED Abstract]
7. Laws ER, Sheehan JP, Sheehan JM, et al.: Stereotactic radiosurgery for pituitary adenomas: a review of the literature. J Neurooncol 69 (1-3): 257-72, 2004 Aug-Sep. [PUBMED Abstract]

Prolactin-Producing Pituitary Tumors Treatment

Standard Treatment Options for Prolactin (PRL)-Producing Pituitary Tumors

Standard treatment options for PRL-producing pituitary tumors include the following:

1. Dopamine agonists, such as cabergoline and bromocriptine. 1 2 3 4 5
2. Surgery (second-line). 1 2
3. Radiation therapy (occasionally). 1 2

When the pituitary tumor secretes PRL, treatment will depend on tumor size and the symptoms that result from excessive hormone production. Patients with PRL-secreting tumors are treated with surgery and radiation therapy. 1

Most microprolactinomas and macroprolactinomas respond well to medical therapy with ergot-derived dopamine agonists, including bromocriptine and cabergoline. 2 For many patients, cabergoline has a more satisfactory side effect profile than bromocriptine. Cabergoline therapy may be successful in treating patients whose prolactinomas are resistant to bromocriptine or who cannot tolerate bromocriptine, and this treatment has a success rate of more than 90% in patients with newly diagnosed prolactinomas. 3 4 5 In a prospective study, cabergoline was safely withdrawn in patients with normalized prolactin levels and no evidence of tumor, which may effect a cure rate of approximately 70%. 6 On the basis of its safety record in pregnancy, however, bromocriptine is the treatment of choice when restoration of fertility is the patient's goal. 7

Microprolactinomas change little in size with treatment, but macroprolactinomas can be expected to shrink, sometimes quite dramatically. Microprolactinomas may decrease in size over time and have been observed to undergo complete, spontaneous resolution on occasion. 8 Surgery is typically reserved for those patients who cannot tolerate dopamine agonists, who suffer pituitary apoplexy during treatment, or whose macroprolactinomas are not responsive to medical therapy. 2 Occasionally, these tumors may ultimately require radiation therapy. 9

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with pituitary tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Yeh PJ, Chen JW: Pituitary tumors: surgical and medical management. Surg Oncol 6 (2): 67-92, 1997. [PUBMED Abstract]
2. Levy A: Pituitary disease: presentation, diagnosis, and management. J Neurol Neurosurg Psychiatry 75 (Suppl 3): iii47-52, 2004. [PUBMED Abstract]
3. Colao A, Di Sarno A, Landi ML, et al.: Macroprolactinoma shrinkage during cabergoline treatment is greater in naive patients than in patients pretreated with other dopamine agonists: a prospective study in 110 patients. J Clin Endocrinol Metab 85 (6): 2247-52, 2000. [PUBMED Abstract]
4. Cannaví S, Curtí L, Squadrito S, et al.: Cabergoline: a first-choice treatment in patients with previously untreated prolactin-secreting pituitary adenoma. J Endocrinol Invest 22 (5): 354-9, 1999. [PUBMED Abstract]
5. Colao A, Di Sarno A, Landi ML, et al.: Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab 82 (11): 3574-9, 1997. [PUBMED Abstract]
6. Colao A, Di Sarno A, Cappabianca P, et al.: Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med 349 (21): 2023-33, 2003. [PUBMED Abstract]
7. Schlechte JA: Clinical practice. Prolactinoma. N Engl J Med 349 (21): 2035-41, 2003. [PUBMED Abstract]
8. Ezzat S, Asa SL, Couldwell WT, et al.: The prevalence of pituitary adenomas: a systematic review. Cancer 101 (3): 613-9, 2004. [PUBMED Abstract]
9. Nomikos P, Buchfelder M, Fahlbusch R: Current management of prolactinomas. J Neurooncol 54 (2): 139-50, 2001. [PUBMED Abstract]

Adrenocorticotropic Hormone-Producing Pituitary Tumors Treatment

Standard Treatment Options for Adrenocorticotropic Hormone (ACTH)-Producing Pituitary Tumors

Standard treatment options for ACTH-producing pituitary tumors include the following:

1. Surgery (usually a transsphenoidal approach). 1 2 3
2. Surgery plus radiation therapy. 1 2 4
3. Radiation therapy. 1 2 4
4. Steroidogenesis inhibitors, including mitotane, metyrapone, ketoconazole, and aminoglutethimide. 1 2 5

For patients with corticotroph adenomas, transsphenoidal microsurgery is the treatment of choice. 1 2 Remission rates reported in most series are approximately 70% to 90%. 1 In a series of 216 patients, who were operated on using a transsphenoidal approach, 75% experienced long-term remission, 21% experienced persistence of Cushing disease, and 9% had recurrence after the initial correction of the hypercortisolism. 3 The average time interval for reoperation was 3.8 years. Seventy-nine percent of the tumors were microadenomas, and 18% were macroadenomas; 86% of the cases with microadenoma had long-term remission, whereas, only 46% of those with macroadenoma had remission. In cases in which hypercortisolemia persists, early repeat exploration and/or radiation therapy or laparoscopic bilateral adrenalectomy may be required. 2

Radiation therapy has been used in patients who are deemed to be poor surgical candidates and has also been used as adjunctive therapy in patients with residual or recurrent active tumor. 1 4

Drug therapy is considered to be an adjunct to transsphenoidal microsurgery in cases in which there is a residual tumor and in cases in which one is awaiting the effects of the radiation therapy. 1 Steroidogenesis inhibitors, including mitotane, metyrapone, ketoconazole, and aminoglutethimide are used. Ketoconazole is the best tolerated of these agents and is effective as monotherapy in about 70% of patients. 5

If untreated, patients frequently succumb to cardiovascular disease or infection.

Treatment Options Under Clinical Evaluation for ACTH-Producing Pituitary Tumors

Treatment options under clinical evaluation for ACTH-producing pituitary tumors include the following:

• Stereotactic radiation surgery. 4 6 7

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with pituitary tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Yeh PJ, Chen JW: Pituitary tumors: surgical and medical management. Surg Oncol 6 (2): 67-92, 1997. [PUBMED Abstract]
2. Levy A: Pituitary disease: presentation, diagnosis, and management. J Neurol Neurosurg Psychiatry 75 (Suppl 3): iii47-52, 2004. [PUBMED Abstract]
3. Mampalam TJ, Tyrrell JB, Wilson CB: Transsphenoidal microsurgery for