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: benign, invasive adenoma, and carcinoma.[1,2] Adenomas comprise the largest portion of pituitary neoplasms with an overall estimated prevalence of approximately 17%. Only a minority of adenomas are symptomatic.[3] Invasive adenomas, which account for approximately 35% of all pituitary neoplasms, may invade the dura mater, cranial bone, or sphenoid sinus.[4] Carcinomas account for 0.1% to 0.2% of all pituitary tumors.[5,6]

Pituitary adenomas may be classified based on:[7]

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 [8] 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.[9] A CT scan may also be a useful diagnostic tool with coronal scans providing the optimal view;[10] however, CT scans appear to be less sensitive than MRI scans in this application.[11] 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.[6]

   This radioanatomical classification places adenomas into 1 of 4 grades (I–IV).[1] (See Stage Information 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.[3,12] 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.[13]

   Using functional criteria, pituitary adenomas can be characterized as:[1]

   • 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.[6] 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.[4,14,15] 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.[16] 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.[6] 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%.[5,16-19] 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.[5]

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:

1. Signs and symptoms of prolactinomas may include:[20]
   • Headache.
   • Visual field deficits.
   • Oligomenorrhea or amenorrhea.
   • Reduced fertility.
   • Loss of libido.
   • Erectile dysfunction.
   • Galactorrhea in the estrogen-primed female breast.



2. Signs and symptoms of corticotroph adenomas may include:[20]
   • Headache.
   • Visual field deficits.
   • Proximal myopathy.
   • Centripetal fat distribution.
   • Neuropsychiatric symptoms.
   • Striae.
   • Ability to easily bruise.
   • Skin thinning.
   • Hirsutism.
   • Osteopenia.



3. Signs and symptoms of somatotroph adenomas may include:[20]
   • Headache.
   • Visual field deficits.
   • Growth of hands and feet.
   • Coarsening of facial features.
   • Carpal tunnel syndrome.
   • Snoring and obstructive sleep apnea.
   • Jaw growth and prognathism.
   • Osteoarthritis and arthralgia.
   • Excessive sweating.
   • Dysmorphophobia.



4. Signs and symptoms of thyrotroph adenomas may include:[21]
   • Palpitations.
   • Tremor.
   • Weight loss.
   • Insomnia.
   • Hyperdefecation.
   • Sweating.



5. Signs and symptoms of nonfunctioning adenomas (most commonly gonadotroph adenomas) may include:[22]
   • Headache.
   • 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), which can result from an acute hemorrhagic or ischemic infarction of the pituitary in patients harboring often unrecognized secreting or nonfunctioning pituitary adenomas, represents another important clinical presentation of 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.[23] The development of pituitary adenomas may also occur as a component of three familial cancer syndromes: multiple endocrine neoplasia 1 (MEN 1), Carney complex (e.g., cardiac myxomas, spotty skin pigmentation, and tumors of the adrenal gland and anterior pituitary), and isolated familial acromegaly.[20]

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.[24] 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.[25]

References

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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. 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]
   
   
5. Pernicone PJ, Scheithauer BW, Sebo TJ, et al.: Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79 (4): 804-12, 1997.  [PUBMED Abstract]
   
   
6. Ragel BT, Couldwell WT: Pituitary carcinoma: a review of the literature. Neurosurg Focus 16 (4): E7, 2004.  [PUBMED Abstract]
   
   
7. Ironside JW: Best Practice No 172: pituitary gland pathology. J Clin Pathol 56 (8): 561-8, 2003.  [PUBMED Abstract]
   
   
8. 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. 
   
   
9. Elster AD: Modern imaging of the pituitary. Radiology 187 (1): 1-14, 1993.  [PUBMED Abstract]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. Yeh PJ, Chen JW: Pituitary tumors: surgical and medical management. Surg Oncol 6 (2): 67-92, 1997.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. 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]
    
    
16. Kaltsas GA, Grossman AB: Malignant pituitary tumours. Pituitary 1 (1): 69-81, 1998.  [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. Garrão 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. Levy A: Pituitary disease: presentation, diagnosis, and management. J Neurol Neurosurg Psychiatry 75 (Suppl 3): iii47-52, 2004.  [PUBMED Abstract]
    
    
21. Vance ML: Treatment of patients with a pituitary adenoma: one clinician's experience. Neurosurg Focus 16 (4): E1, 2004.  [PUBMED Abstract]
    
    
22. 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]
    
    
23. 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]
    
    
24. Caturegli P, Newschaffer C, Olivi A, et al.: Autoimmune hypophysitis. Endocr Rev 26 (5): 599-614, 2005.  [PUBMED Abstract]
    
    
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