Pituitary adenomas aretumors that occur in thepituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% arecarcinomas.[1] Pituitary adenomas represent from 10% to 25% of all intracranialneoplasms, with an estimatedprevalence rate in the general population of approximately 17%.[1][2]
Non-invasive and non-secreting pituitary adenomas are considered to bebenign in the literal as well as the clinical sense, though a 2011meta-analysis of available research showed that research to either support or refute this assumption was scant and of questionable quality.[3]
Adenomas exceeding 10 mm (0.39 in) in size are defined asmacroadenomas, while those smaller than 10 mm (0.39 in) are referred to asmicroadenomas. Most pituitary adenomas are microadenomas and have an estimated prevalence of 16.7% (14.4% inautopsy studies and 22.5% inradiologic studies).[2][4] The majority of pituitary microadenomas remain undiagnosed, and those that are diagnosed are often found as anincidental finding and are referred to asincidentalomas.
While pituitary adenomas are common, affecting approximately 1 in 6 members of the general population, clinically active pituitary adenomas that require surgical treatment are more rare, affecting approximately 1 in 1,000.[7]
Compressive symptoms of pituitary adenomas (visual field deficits, decreased visual acuity, headaches) are more commonly seen with macroadenomas (which are greater than 10 mm in diameter) than with microadenomas (which are less than 10 mm in diameter).[15]
Non-secreting adenomas can go undetected for an extended time because no obvious abnormalities are seen; the gradual reduction in normal activities due to decreased production of hormones is rather less evident. For example, insufficientadrenocorticotropic hormone means that theadrenal glands will not produce sufficientcortisol, resulting in slow recovery from illness, inflammation, and chronic fatigue; insufficient growth hormone in children and adolescents leads to diminished stature but which can have many other explanations.[citation needed]
Various psychiatric manifestations have been associated with pituitary disorders including pituitary adenomas. Psychiatric symptoms such as depression, anxiety[16] apathy, emotional instability, easy irritability and hostility have been noted.[17]
Acromegaly is asyndrome that results when theanterior pituitary gland produces excessgrowth hormone (GH). Approximately 90–95% of acromegaly cases are caused by a pituitary adenoma and it most commonly affects middle aged adults,[18] Acromegly can result in severe disfigurement, serious complicating conditions, and premature death if unchecked. The disease which is often also associated withgigantism, is difficult to diagnose in the early stages and is frequently missed for many years, until changes in external features, especially of the face, become noticeable with the median time from the development of initial symptoms to diagnosis being twelve years.[19]
Cushing's syndrome is a hormonal disorder that causes hypercortisolism, which is elevated levels ofcortisol in the blood.Cushing's disease (CD) is the most frequent cause of Cushing's syndrome, responsible for approximately 70% of cases.[20] CD results when a pituitary adenoma causes excessive secretion ofadrenocorticotropic hormone (ACTH) that stimulates theadrenal glands to produce excessive amounts ofcortisol.[21]
Cushing's disease may cause fatigue, weight gain, fatty deposits around the abdomen and lower back (truncal obesity) and face ("moon face"), stretch marks (striae) on the skin of the abdomen, thighs, breasts, and arms,hypertension,glucose intolerance, and various infections. In women, it may cause excessive growth of facial hair (hirsutism) and in menerectile dysfunction. Psychiatric manifestations may include depression,anxiety, easy irritability, and emotional instability. It may also result in variouscognitive difficulties.[citation needed]
Hyperpituitarism is a disease of the anterior lobe of the pituitary gland which is usually caused by a functional pituitary adenoma and results in hypersecretion of adenohypophyseal hormones such as growth hormone; prolactin; thyrotropin; luteinizing hormone; follicle-stimulating hormone; and adrenocorticotropic hormone.[citation needed]
Pituitary apoplexy is a condition that occurs when pituitary adenomas suddenly hemorrhage internally, causing a rapid increase in size or when the tumor outgrows its blood supply which causestissue necrosis and subsequent swelling of the dead tissue. Pituitary apoplexy often presents with visual loss and sudden onset headache and requires timely treatment often withcorticosteroids and if necessary surgical intervention.[22]
Adenomas of the anterior pituitary gland are a major clinical feature ofmultiple endocrine neoplasia type 1 (MEN1), a rare inherited endocrine syndrome that affects 1 person in every 30,000. MEN causes various combinations of benign or malignant tumors in various glands in the endocrine system or may cause the glands to becomeenlarged without forming tumors. It often affects theparathyroid glands, pancreatic islet cells, and anterior lobe of the pituitary gland. MEN1 may also cause non-endocrine tumors such as facialangiofibromas,collagenomas,lipomas,meningiomas,ependymomas, andleiomyomas. Approximately 25 percent of patients with MEN1 develop pituitary adenomas.[25][26]
Carney complex (CNC), also known asLAMB syndrome[27] andNAME syndrome[27] is anautosomal dominant condition comprisingmyxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), andendocrine overactivity and is distinct fromCarney's triad.[28][29] Approximately 7% of all cardiac myxomas are associated with Carney complex.[30] Patients with CNC developgrowth hormone (GH)-producing pituitary tumors and in some instances these same tumors also secreteprolactin. There are however no isolated prolactinomas or any other type of pituitary tumor. In some patients with CNC, the pituitary gland is characterized byhyperplastic areas with the hyperplasia most likely preceding the formation of GH-producing adenomas.[31]
Familial isolated pituitary adenoma (FIPA) is a term that is used to identify a condition that displays anautosomal dominant inheritance and is characterised by the presence of two or more related patients affected by adenomas of the pituitary gland only, with no other associated symptoms that occur inmultiple endocrine neoplasia type 1 (MEN-1),Carney complex and with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene.[32][33][34] FIPA was first described in a limited cohort of families byAlbert Beckers group in Liège, Belgium;[35] later FIPA was fully characterized in a multicenter international study of 64 families.[33] FIPA families are divided into those that are homogenous and have the same type of pituitary adenoma in all the affected family members (e.g. onlyacromegaly, onlyprolactinoma, etc.), while heterogeneous FIPA families can have different pituitary adenomas in affected family members.[36]
FIPA has two known genetic causes,mutations in the AH receptor-interacting protein (AIP) gene[37] and duplications in chromosome Xq26.3 that include theGPR101 gene that also causes X-linked acrogigantism (X-LAG) syndrome.[38] About 15–20% of FIPA families carry a germlineAIP gene mutation or deletion, and the disease occurs as autosomal dominant with incomplete penetrance, meaning that about 20% of AIP mutation carriers will develop a pituitary adenoma.[36]AIP mutation associated pituitary adenomas (either presenting as FIPA or as individual, non familial cases) are usually growth hormone-secreting (acromegaly) or prolactin-secreting (prolactinoma) adenomas that are large (macroadenomas) and often occur in children, adolescents and young adults. Daly and colleagues showed that acromegaly cases withAIP mutations occurred about 20 years before acromegaly cases withoutAIP mutations and these tumors are large and relatively treatment-resistant.[39] Due to their young age at onset,AIP mutations are the most frequent genetic cause ofpituitary gigantism (29% of cases).[40]
X-LAG is a rare syndrome of very early childhood onset pituitary tumors/hyperplasia that leads to growth hormone excess and severe overgrowth and pituitary gigantism.[38][41] Three FIPA families with X-LAG have been reported to date all of which had transmission of a chromosome Xq26.3 duplication from affected mother to affected son.[41][38] The disease characteristics of very young onsetpituitary gigantism leads to severe overgrowth if not treated adequately; many of the tallest humans in history (e.g.Robert Pershing Wadlow;Sandy Allen,André Rousimoff (Andre the Giant),Zeng Jinlian) had a similar clinical history to patients with X-LAG syndrome.[42] The tallest historical individual with a known genetic cause wasJulius Koch (Geant Constantin) who was found to have X-LAG on genetic study of his skeleton.[43] X-LAG has 100% penetrance so far (all affected with the Xq26.3 duplication have the disease and it affects predominantly females.[38] Isolated non familial cases of X-LAG can either have a constitutional duplication of a chromosome Xq26.3 includingGPR101, ormosaicism for the duplication (present in a minority of cells) in the case of isolated male patients.[44] X-LAG causes about 10% of cases ofpituitary gigantism.[40]
The pituitary gland is divided into two lobes, the anterior lobe (which accounts for two thirds of the volume of the gland), and the posterior lobe (one third of the volume) separated by thepars intermedia.[8]
Theposterior lobe (the neural lobe or neurohypophysis) of the pituitary gland is not, despite its name, a truegland. The posterior lobe containsaxons ofneurons that extend from thehypothalamus to which it is connected via the pituitary stalk. The hormonesvasopressin andoxytocin, produced by the neurons of thesupraoptic andparaventricular nuclei of the hypothalamus, are stored in the posterior lobe and released from axon endings (dendrites) within the lobe.[46]
Diagnosis of pituitary adenoma can be made, or at least suspected, by a constellation of related symptoms presented above.[9]
The differential diagnosis includes pituitary tuberculoma, especially in developing countries and in immumocompromised patients.[48] The diagnosis is confirmed by testing hormone levels, and by radiographic imaging of the pituitary (for example, byCT scan orMRI).[citation needed]
Pituitary adenomas are classified as endocrine tumors and also as brain tumors, though some patient groups prefer not to refer to them as brain tumors.[49][50][51][52] Pituitary adenomas are classified based uponanatomical,histological and functional criteria.[53]
Anatomically pituitary tumors are classified by their size based on radiological findings; either microadenomas (less than <10 mm) or macroadenomas (equal or greater than ≥10 mm).
Classification based on radioanatomical findings places adenomas into 1 of 4 grades (I–IV):[54]
Stage I: microadenomas (<1 cm) without sella expansion.
Stage II: macroadenomas (≥1 cm) and may extend above the sella.
Stage III: macroadenomas with enlargement and invasion of the floor or suprasellar extension.
Stage IV: destruction of the sella.
Histological classification utilizes an immunohistological characterization of the tumors in terms of their hormone production.[53] Historically they were classed as eitherbasophilic,acidophilic, orchromophobic on the basis of whether or not they took up thetinctorial stainshematoxylin andeosin. This classification has fallen into disuse, in favor of a classification based on what type ofhormone is secreted by the tumor. Approximately 20–25% of adenomas do not secrete any readily identifiable active hormones ('non-functioning tumors') yet they are still sometimes referred to as 'chromophobic'.[citation needed]
Functional classification is based upon the tumors endocrine activity as determined byserum hormone levels and pituitary tissue cellular hormone secretion detected viaimmunohistochemical staining.[55] The "Percentage of hormone production cases" values are the fractions of adenomas producing each related hormone of each tumor type as compared to all cases of pituitary tumors, and does not directly correlate to the percentages of each tumor type because of lower or greater incidence of absence of secretion of the expected hormone. Thus, non secretive adenomas may be eithernull cell adenomas or a more specific adenoma that, however, remains non-secretive.[citation needed]
Any type of pituitary adenocarcinoma listed in the table below may cause compressive symptoms due to local expansion in addition to the systemic effects of secreted hormones listed in the pathology column.[citation needed]
Null cell adenomas by definition do not secrete hormones, but they commonly cause compressive effects on thepituitary stalk (stalk effect). This leads to decreased levels ofdopamine from the hypothalamus reaching the anterior pituitary gland. Dopamine exerts an inhibitory effect on prolactin secretion. With the absence of this inhibitory effect, prolactin levels increase and are often increased in null cell adenomas. This leads to symptoms of hypogonadism.[15]
A silent gonadotroph pituitary adenoma which is, in this case, eosinophilic (contrary to normal, basophilic, gonadotroph cells)
True null cell adenomas are typically composed of uniform, mildly atypical cells with chromophobic cytoplasm. This case has papillary architecture similar to gonadotroph adenomas.[59]
Pituitary incidentalomas are pituitary tumors that are characterized as anincidental finding. They are often discovered bycomputed tomography (CT) ormagnetic resonance imaging (MRI), performed in the evaluation of unrelated medical conditions such as suspectedhead trauma, incancer staging or in the evaluation ofnonspecific symptoms such asdizziness andheadache. It is not uncommon for them to be discovered atautopsy. In ameta-analysis, adenomas were found in an average of 16.7% in postmortem studies, with most being microadenomas (<10mm); macrodenomas accounted for only 0.16% to 0.2% of the decedents.[2] While non-secreting, noninvasive pituitary microadenomas are generally considered to be literally as well asclinically benign, a 2011meta-analysis of available research showed there were, to that time, scant studies of low quality to support this assertion.[3]
The Clinical Practice Guidelines, as published in April 2011 inThe Journal of Clinical Endocrinology and Metabolism by theEndocrine Society (a professional, international medical organization), recommend that all patients with pituitary incidentalomas undergo a completemedical history andphysical examination, laboratory evaluations to screen for hormone hypersecretion and forhypopituitarism. If the lesion is in close proximity to theoptic nerves oroptic chiasm, avisual field examination should be performed. For those with incidentalomas which do not require surgical removal, follow up clinical assessments and neuroimaging should be performed as well follow-up visual field examinations for incidentalomas that abut or compress the optic nerve and chiasm and follow-up endocrine testing for macroincidentalomas.[60]
Carcinomas thatmetastasize into the pituitary gland are uncommon and typically seen in the elderly,[63][64] withlung andbreast cancers being the most prevalent,[65] In breast cancer patients, metastases to the pituitary gland occur in approximately 6–8% of cases.[66]
Symptomatic pituitary metastases account for only 7% of reported cases. In those who are symptomaticdiabetes insipidus often occurs, with rates approximately 29–71%. Other commonly reported symptoms include anterior pituitary dysfunction, visual field defects, headache/pain, andophthalmoplegia.[67]
Treatment options depend on the type of tumor and on its size:
Prolactinomas (microadenomas and macroadenomas) are most often treated withcabergoline orbromocriptine (bothdopamine agonists) as the first line of treatment.[68] Medical treatment usually effectively decreases tumor size as well as alleviates symptoms.[68] Pituitary adenomas are also followed by serial imaging (usuallyMRI) to detect any increase in size or mass effect on nearby structures. If medical therapy fails, the second option is usuallytransphenoidal pituitary surgery.[68] A third line therapy isradiation therapy, proton therapy to shrink the tumor.[68]
Thyrotropinomas are treated with transsphenoidal pituitary surgery as the first line treatment option.[68] Medical therapy is a second line treatment, and thyrotropinomas respond to treatment with somatostatin receptor ligands such asoctreotide orlanreotide.[68] In people with thyrotropinomas, treatment with somatostatin receptor ligands normalized thyroid hormone levels in 80-90% of people, and 42% of people had a decreased tumor size.[68]
Somatotrophic adenomas are primarily treated with transsphenoidal pituitary surgery, especially if symptoms of acromegaly are present.[68] A second line treatment strategy (which can be used if there is a persistent or recurrent mass or symptoms after surgery) utilizes medical therapy, includingoctreotide orlanreotide, which are long-actingsomatostatin analogs. These somatostatin receptor analogs inhibit secretion of growth hormone.[68] They were found to be about 50–55% effective in reducing tumor mass and reducing growth hormone and insulin like growth factor 1 (IGF-1) levels in studies.[15] The growth hormone receptor antagonistpegvisomant is also used in the treatment of somatotrophic adenomas. Pegvisomant blocks the action of growth hormone. It can either be used as monotherapy or combined with a somatostatin analog.[69]
Corticotropinomas are primarily treated with transsphenoidal pituitary surgery, especially if signs and symptoms ofCushing syndrome are present.[68] Medication therapy is second line, and includes steroidogenesis inhibitors (ketoconazole,metyrapone,osilodrostat,etomidate ormitotane) which decrease production of cortisol, pituitary blockers such as somatostatin receptor ligandpasireotide or the dopamine agonistcabergoline, or the glucocorticoid receptor antagonistmifepristone.[68] These medications can be combined for a synergistic effect. Medication therapy is often used in conjunction with radiation therapy for corticotropinomas.[68]
Surgery is a common treatment for pituitary tumors. The normal approach istrans-sphenoidal adenectomy, which usually can remove the tumor without affecting the brain or optic nerves.[70]
Radiation is also used to treat pituitary adenomas. Examples include external beam or proton beam radiation therapy or stereotactic radiosurgery. External radiation of pituitary adenomas can arrest tumor growth for several years but pituitary failure develops within 10 years in most patients necessitating lifelong hormone replacement.[15] Radiation therapy for pituitary adenomas is associated with a four-fold increase in mortality due to cerebrovascular disease.[15] Lifelong monitoring of pituitary hormones is recommended after radiation therapy ashypopituitarism developed in 17% of those undergoing radiation therapy.[68]
^Asa SL (August 2008). "Practical pituitary pathology: what does the pathologist need to know?".Archives of Pathology & Laboratory Medicine.132 (8):1231–1240.doi:10.5858/2008-132-1231-PPPWDT.PMID18684022.
^Hyperthyroidism unmasked several years after the medical and radiosurgical treatment of an invasive macroprolactinoma inducing hypopituitarism: a case report. L Foppiani, A Ruelle, P Cavazzani, P del Monte – Cases Journal, 2009
^abSerri O, Somma M, Rasio E, Brazeau P (January 1989). "Growth hormone-releasing factor increases serum prolactin concentrations in normal subjects and in patients with pituitary adenomas".Clinical Endocrinology.30 (1):65–75.doi:10.1111/j.1365-2265.1989.tb03728.x.PMID2505955.S2CID27780583.
^Weitzner MA, Kanfer S, Booth-Jones M (2005). "Apathy and pituitary disease: it has nothing to do with depression".The Journal of Neuropsychiatry and Clinical Neurosciences.17 (2):159–166.doi:10.1176/appi.neuropsych.17.2.159.PMID15939968.
^Cushing's SyndromeArchived 2011-04-10 at theWayback Machine at The National Endocrine and Metabolic Diseases Information Service. July 2008. In turn citing:Nieman LK, Ilias I (December 2005). "Evaluation and treatment of Cushing's syndrome".The American Journal of Medicine.118 (12):1340–1346.doi:10.1016/j.amjmed.2005.01.059.PMID16378774.
^Daly AF, Vanbellinghen JF, Beckers A (November 2007). "Characteristics of familial isolated pituitary adenomas".Expert Review of Endocrinology & Metabolism.2 (6):725–733.doi:10.1586/17446651.2.6.725.PMID30290472.S2CID52924983.
^Chanson P, Weintraub BD, Harris AG (August 1993). "Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas. A follow-up of 52 patients".Annals of Internal Medicine.119 (3):236–240.doi:10.7326/0003-4819-119-3-199308010-00010.PMID8323093.S2CID27660512.
^Bret P, Jouvet A, Madarassy G, Guyotat J, Trouillas J (May 2001). "Visceral cancer metastasis to pituitary adenoma: report of two cases".Surgical Neurology.55 (5):284–290.doi:10.1016/S0090-3019(01)00447-5.PMID11516470.
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![True null cell adenomas are typically composed of uniform, mildly atypical cells with chromophobic cytoplasm. This case has papillary architecture similar to gonadotroph adenomas.[59]](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aHistopathology_of_a_true_null_cell_adenoma.jpg)
