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Pituitary Adenoma
Classification and external resources
T1 Coronal MRI of a pituitary adenoma
ICD-10	H35.2
ICD-9	237.0
ICD-O:	M8272/0
MedlinePlus	000704
eMedicine	neuro/312
MeSH	D010911

Pituitary adenomas are a collection of tumors that arise from the pituitary gland. They are the most common cause of Optic chiasm compression.^[1][2] Ophthalmologic pathology typically involves Visual field defects, although less commonly patients may also have Ocular motility deficits and/or Diplopia, certain forms of Nystagmus, signs and symptoms of Increased intracranial pressure due to mass effect, Optic atrophy, or sequelae of Pituitary apoplexy.^[3][4][5]

Contents 1 Disease Entity 1.1 General 1.1.1 Epidemiology 1.1.2 Classification 1.1.2.1 Size 1.1.2.2 Hormonal Activity 1.1.2.3 Staining Pattern 1.2 Pathology 1.2.1 Pathogenesis 1.2.2 Morphology 1.2.3 Histopathology 1.2.4 Functional Tumors 1.2.4.1 Lactotroph Adenomas (Prolactinomas) 1.2.4.2 Somatotroph Adenomas (Growth Hormone Adenomas) 1.2.4.3 Corticotroph Adenomas 1.2.4.3.1 Cushing Disease 1.2.4.3.2 Cushing Syndrome 1.2.4.3.3 Nelson Syndrome 1.2.4.4 Gonadotroph Adenomas 1.2.4.5 Thyrotroph Adenomas 1.2.5 Nonfunctional tumors 1.2.6 Incidentalomas 1.3 Pathophysiology 2 Diagnosis 2.1 History 2.2 Physical examination 2.3 Signs 2.4 Symptoms 2.4.1 Headache 2.4.2 Decreased Vision 2.4.3 Diplopia 2.4.3.1 Extraocular Muscle Paresis 2.4.3.2 Hemifield Slide 2.5 Clinical diagnosis 2.6 Diagnostic procedures 2.6.1 Visual Field Testing 2.7 Laboratory test 2.8 Differential diagnosis 3 Management 3.1 General treatment 3.2 Medical therapy 3.3 Medical follow up 3.4 Surgery 3.5 Surgical follow up 3.6 Complications 3.7 Prognosis 4 Additional Resources 5 References

Disease Entity

General

Epidemiology

Pituitary adenomas are reported to account for 12-15% of symptomatic intracranial neoplasms.^[2] Overall, it is estimated that in upwards of 25% of the population have pituitary adenomas, most of which are incidentally found.^[3] One review found an average incidence of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies).^[6]
Pituitary adenomas usually occur in adults; they rarely occur in childhood.^[1][3] Various articles have reported both male and female predilections.^[6][7] While most pituitary adenomas occur in isolation, 3% of cases are associated with multiple endocrine neoplasia type 1.^[3][8]

Classification

Pituitary adenomas can be classified by different methods, including size, hormonal activity, and histologic staining pattern.

Size

Historically, pituitary adenomas have been described by their size. This is performed radiographically with CT or MRI. ^[6][3]

• Macroadenomas: ≥10 mm
• Microadenomas: <10 mm

Hormonal Activity

Adenomas can also be differentiated based on their hormonal activity in vivo as determined by immunohistochemistry and electron microscopy.

• Functional (secreting) tumors are associated with hormonal secretion. Because of the clinical effects of hormonal disturbances, these tumors are more likely to be detected while they are still small. They are divided according to the hormone(s) produced. Prolactinomas are the most common type of functional pituitary adenoma.
• Nonfunctional (nonsecreting) tumors do not produce excess hormones. They may cause hypopituitarism due to mass effect. Gonadotrophic adenomas are the most common type of nonfunctional pituitary adenoma.^[9]

Staining Pattern

Pituitary adenomas can also be divided by their staining pattern on histology.^[3] This classification is no longer clinically significant due to the more specific immunohistochemistry stains that can differentiate the hormones being secreted.^[5]

• Acidophils contain eosinophilic granules in their cytoplasm that stain brightly with acid fuschin.
• Basophils contain basophilic granules in their cytoplasm that stain brightly with aniline blue.
• Chromophobes contain agranular cytoplasm. This term is often associated with nonfunctioning adenomas, although some hormone-secreting adenomas may also have chromophobic features.

Pathology

Pathogenesis

Many animal studies have suggested one or more genetic factors that may contribute to the formation of pituitary adenomas. For example, the pituitary tumor-transforming gene (PTTG) has been shown to be overexpressed in hormone-secreting adenomas.^[10] There is evidence as well that adult pituitary stem cells may contribute to the development of pituitary adenomas.^[11] Various cell markers have also been implicated in the behaviors of various pituitary tumors, including type of hormone produced, recurrence, regression, and response to treatment.^[12][9][13]

Morphology

Most pituitary adenomas are soft, well-circumscribed lesions that are confined to the sella turcica. As these adenomas grow, they tend to extend superiorly and may eventually compress the optic chiasm and various cranial nerves. Expansion may lead to bony erosion of the anterior clinoid processes and sella turcica, as well as extending into the cavernous and sphenoid sinuses.^[3]

Histopathology

Pituitary adenomas have a monomorphic appearance and are arranged in sheets or cords. Adenoma cells stain on immunohistochemistry based on the type of hormone they typically secrete. The cytoplasm of these cells may be acidophilic, basophilic, or chromophobic, and is generally uniform in its appearance. These tumors also have a poor reticulin network, which distinguishes the tumor from non-neoplastic tissue, which tends to have a heterogenous appearance with an extensive reticulin network.^[3]

Table 1. Types of Pituitary Adenomas and Their Reported Incidence^[14]

Type of adenoma	Secreting Hormone	Staining	Reported Incidence[15]
Lactotrophic (Prolactinoma)	Prolactin	Acidophilic or chromophobic	29%
Somatotrophic	Growth hormone (GH)	Acidophilic	14%
Corticotrophic	Adrenocorticotropic hormone (ACTH)	Basophilic	13%
Gonadotrophic	Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) and their subunits	Basophilic	13%
Thyrotrophic	Thyroid-stimulating hormone (TSH)	Basophilic to chromophobic	Less than 1%
Other pituitary adenomas	Some multiple hormones, others are nonsecreting		30%

Functional Tumors

Lactotroph Adenomas (Prolactinomas)

See also Prolactinoma

Table 2. Serum Prolactin Levels^[5]

Condition	Prolactin Level (ng/mL)
Normal Male	< 20
Normal Female	< 25
Pregnancy	~200
Prolactinomas	> 200 (can exceed 10,000)

Prolactinomas are the most common type of hypersecreting pituitary adenoma. The size of these lesions varies, with women often reported to have smaller tumors than men. High prolactin levels cause amenorrhea, galactorrhea, and infertility in women, and hypogonadism and impotence in men. Galactorrhea with amenorrhea in the setting of a prolactinoma is also called Forbes-Albright syndrome. Gynecomastia can be seen in both men and women. In adolescents, elevated prolactin levels can delay puberty. Because the symptoms in males are more subtle, pituitary adenomas tend to be detected later in males than in females.^[16]

Prolactinomas tend to undergo dystrophic calcification, which can appear microscopically as psammoma bodies or encompass the entire mass ("pituitary stone").^[3] Most prolactinomas are sparsely granulated; on histology these tumor cells are weakly acidophilic or chromophobic. Rarely these cells will be strongly acidophilic and are classified as densely granulated prolactinomas.^[3]

Other conditions can cause elevated prolactin levels, including pregnancy, medications that affect dopamine metabolism (e.g., phenothiazines, metochlorpramide, risperidone, verapamil), renal failure, and primary hypothyroidism. Other pituitary tumors can also cause elevated prolactin levels by the decrease in dopaminergic inhibition as these tumors enlarge and compress the pituitary stalk. These other conditions typically do not cause serum prolactin levels as high as those seen in prolactinomas.^[5]

Somatotroph Adenomas (Growth Hormone Adenomas)

Growth hormone (GH)-secreting adenomas are the second most common type of hypersecreting pituitary adenomas. They tend to be large at time of clinical diagnosis due to the subtle manifestations of excess growth hormone.

GH-secreting adenomas can be either densely-granulated or sparsely granulated and share features similar to prolactinomas on hematoxylin-eosin staining. The densely-granulated adenomas are acidophilic, whereas the sparsely granulated adenomas are weakly acidophilic or chromophobic.

Many of the features of GH-secreting adenomas are related to the stimulation of insulin-like growth factor I (IGF-I or somatomedin C) by the liver in response to excess growth hormone. In children who have epiphyses that have not yet closed, the GH and IGF-I cause gigantism. If the epiphyses have closed, the result is acromegaly. There are also associations with gonadal dysfunction, diabetes mellitus, generalized muscle weakness, hypertension, arthritis, congestive heart failure, and an increased risk of gastrointestinal cancers.

Gigantism: Generalized increase in body size with disproportionately long arms and legs Acromegaly: Accentuated growth in skin and soft tissues, bones, and viscera

One of the most sensitive tests for acromegaly is the failure to suppress GH production in a response to an oral load of glucose.^[3]

Corticotroph Adenomas

Corticotroph adenomas secrete adrenocorticotropic hormone (ACTH), which triggers the adrenal glands to secrete cortisol. The densely granulated variant is more common and is usually basophilic, and the sparsely granulated variant is chromophobic. These tumors stain positively with periodic acid-Schiff (PAS) because of the carbohydrates present in pre-opiomelanocorticotropin (POMC), the precursor molecule to ACTH.

Cushing Disease

Cushing disease is hypercortisolism that is caused by excess production of ACTH from a corticotroph adenoma.

Cushing Syndrome

Cushing syndrome is the term used for the many other causes of elevated serum cortisol levels due to elevated ACTH.

Nelson Syndrome

Nelson syndrome is a phenomenon described by the enlargement of an ACTH-secreting pituitary adenoma following surgical removal of the adrenal glands for treating Cushing syndrome. The adenoma grows precipitously because of the removal of the feedback inhibition of adrenal corticosteroids on the pituitary tissue. Hypercortisolism is not present because of the absence of the adrenal glands. Patients will complain of symptoms consistent with the mass effects of a pituitary tumor. They may also develop hyperpigmentation, which occurs due to the stimulation of melanocytes by POMC.

Gonadotroph Adenomas

Gonadotrophic adenomas secrete lutenizing hormone (LH) and follicle-stimulating hormone (FSH). They are variable in their secretion, and often do not cause clinical symptoms related to their hormone products. As such, they tend to become symptomatic when they grow large enough to cause the associated neurological symptoms of pituitary tumors. These tumors can also have decreased pituitary hormones, most commonly related to decreased LH. LH deficiency is manifested by decreased energy and libido in men due to decreased testosterone levels, and amenorrhea in premenopausal women. Most gonadotrophic adenomas contain chromophobic cells that react to common gonadotropin &alpha-subunit and &beta-FSH and &beta-LH subunits, with FSH being the predominantly secreted hormone.

Thyrotroph Adenomas

Thyrotrophic adenomas are one of the rarest types of secreting pituitary adenomas. Thyrotropin, or thyroid-stimulating hormone (TSH) is secreted by the pituitary gland and induces the thyroid gland to produce thyroid hormone (thyroxine). Thyrotrophic adenomas will usually induce a hyperthyroid state due to the high levels of TSH. These tumors tend to be large and invade adjoining structures, which can cause visual field defects. Because this is not an autoimmune process, the hyperthyroid state induced by these adenomas is not associated with thyroid eye disease.

Nonfunctional tumors

Incidentalomas

Pathophysiology

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Diagnosis

History

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Physical examination

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Signs

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Symptoms

Patients with secretory tumors may have systemic complaints that are associated with their corresponding hormonal imbalance. Most ophthalmologic complaints are secondary to mass effects caused by macroadenomas.

Headache

Decreased Vision

Diplopia

Extraocular Muscle Paresis

Hemifield Slide

Diplopia may occur as the result of a loss in the physiologic linkage between the two functioning hemifields, termed "hemifield slide phenomenon" by Kirkham in 1972.^[17] This binocular diplopia occurs in the presence of intact ocular motility. While the exact pathophysiology is not completely understood, it is hypothesized that when the degree of overlap between one eye's temporal visual field and the contralateral eye's nasal visual field decreases to a certain point, the brain is unable to maintain fusion.^[5] This can occur with vertical hemifield defects such as those seen in pituitary adenomas, as well as altitudinal hemifield defects from optic nerve disease.^[18] Patients may experience overlapping images or divergent images corresponding to esodeviation, exodeviation, or hyperdeviation.^[17]

Clinical diagnosis

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Diagnostic procedures

Visual Field Testing

Automated static perimetry or kinetic perimetry are used to formally assess visual fields. In an undiagnosed patient with a history suspicious for pituitary disease, this often confirms the presence of a compressive chiasmal lesion. Visual fields are also commonly documented prior and following neurosurgical intervention.

Figure 1. Humphrey visual field 24-2 showing a bitemporal hemianopsia.
Figure 2. Goldmann visual field showing a bitemporal hemianopsia.^[19]

Laboratory test

An endocrine workup is important for determining the functional status of a pituitary adenoma. This is often performed with the guidance of an endocrinologist.

Differential diagnosis

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Management

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General treatment

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Medical therapy

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Medical follow up

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Surgery

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Surgical follow up

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Complications

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Prognosis

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Additional Resources

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References

1. ↑ ^{1.0 1.1} Neuro-Ophthalmology. Basic and Clinical Science Course, Section 5. American Academy of Ophthalmology; 2010:159-165.
2. ↑ ^{2.0 2.1} Yanoff M, Duker JS. Ophthalmology, 3rd Ed. Elsevier; 2009:986-994.
3. ↑ ^{3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10} Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease, 7th Ed. Elsevier; 2005:1156-1164.
4. ↑ Kanski JJ, Bowling B. Clinical Ophthalmology: A Systematic Approach, 7th Ed. Elsevier; 2011:816-827.
5. ↑ ^{5.0 5.1 5.2 5.3 5.4} Gittinger JW. "Tumors of the Pituitary Gland." In: Miller NR, Newman NJ, eds. Walsh and Hoyt's Clinical Neuro-Ophthalmology, 6th Ed. Volume Two. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1531-1546.
6. ↑ ^{6.0 6.1 6.2} Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE. The Prevalence of Pituitary Adenomas: A Systematic Review. Cancer. 2004;101(3):613-9. doi:10.1002/cncr.20412. PMID 15274075.
7. ↑ Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A. High Prevalence of Pituitary Adenomas: A Cross-Sectional Study in the Province of Liege, Belgium. J Clin Endocrinol Metab. 2006 Dec;91(12):4769-75. Epub 2006 Sep 12. PMID 16968795.
8. ↑ Marini F, Falchetti A, Luzi E, Tonelli F, Luisa BM. Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. NCBI Bookshelf. 9 Aug 2008.PMID 21249756.
9. ↑ ^{9.0 9.1} Asa SL. Practical Pituitary Pathology: what does the pathologist need to know? Arch. Pathol. Lab. Med. 2008 Aug;132(8):1231–40. PMID 18684022.
10. ↑ Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, Melmed S. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab. 1999 Feb;84(2):761–767. doi:10.1210/jc.84.2.761. PMID 10022450.
11. ↑ Florio T. Adult Pituitary Stem Cells: From Pituitary Plasticity to Adenoma Development. Neuroendocrinology 2011;94:265–277. doi:10.1159/000330857. PMID 22116388.
12. ↑ Fideleff HL, Boquete HR, Suárez MG, Azaretzky M. Prolactinoma in children and adolescents. Horm Res. 2009;72(4):197-205. Epub 2009 Sep 29. doi:10.1159/000236081. Available online. PMID 19786791.
13. ↑ Righi A, Agati P, Sisto A, Frank G, Faustini-Fustini M, Agati R, Mazzatenta D, Farnedi A, Menetti F, Marucci G, Foschini MP. A classification tree approach for pituitary adenomas. Hum Pathol. 2012 Mar 23. [Epub ahead of print]. doi:10.1016/j.humpath.2011.12.003. PMID 22446019.
14. ↑ Adapted from Pituitary Adenoma. Wikipedia. Accessed 04-28-2012.
15. ↑ Ironside JW. Best Practice No 172: Pituitary Gland Pathology. J Clin Pathol. 2003 Aug;56(8):561-8. PMID 12890801
16. ↑ Spark RF, Wills CA, O'Reilly G, Ransil BJ, Bergland R. Hyperprolactinaemia in males with and without pituitary macroadenomas. Lancet. 1982 Jul 17;2(8290):129-32. PMID 6123841.
17. ↑ ^{17.0 17.1} Kirkham TH. The ocular symptomatology of pituitary tumours. Proc R Soc Med. 1972 Jun;65(6):517-8. PMID 5035898.
18. ↑ Borchert MS, Lessell S, Hoyt WF. Hemifield slide diplopia from altitudinal visual field defects. J Neuroophthalmol. 1996 Jun;16(2):107-9. PMID 8797166.
19. ↑ Moura FC, Gonçalves AC, Monteiro ML. Seesaw nystagmus caused by giant pituitary adenoma: case report. Arq Neuropsiquiatr. 2006 Mar;64(1):139-41. Epub 2006 Apr 5. doi:10.1590/S0004-282X2006000100030. PMID 16622572.