Neuro-Endocrine/Endocrine System: Pituitary adenomas

Identity

ICD-Topo	C751 PITUITARY GLAND
ICD-Morpho	8140/0 Adenoma, NOS
Atlas_Id	5051
Phylum	Neuro-Endocrine/Endocrine system: Pituitary gland::Adenoma
Note	Pituitary adenomas are common benign monoclonal neoplasms accounting for approximately 15% of intracranial tumors, while occult adenomas are discovered in as many as 25% of unselected autopsies. Pituitary tumors are usually benign, but cause significant morbidity due to their critical location, expanding size, and/or inappropriate pituitary hormone expression. True malignant behaviour with metastatic spread is very rare.

Classification

Note	The relative incidence of the different pituitary adenomas subtypes is diagrammed in Fig.1
	Various subtypes have been recognized on the basis of clinical presentation, as well as immunocytological and ultrastructural characteristics. About one-third of pituitary adenomas are not associated with clinical hypersecretory syndromes, but with symptoms of an intracranial mass such as headaches, hypopituitarism, or visual field disturbances, and are classified as nonfunctioning pituitary adenomas (NFPAs). Clinically non-functioning adenomas (NFPA) are actually a diverse group of tumors that include LH-, FSH- secreting adenomas, null cell adenoma and oncocytoma. The clinical features of all other pituitary adenomas are linked to the hypersecreted hormone(s) which mark the specific cell origin, allowing the tumors to be classified as: Prolactinomas or PRL-secreting PA, the most common of all functional pituitary adenomas. The patients usually present with amenorrhea, infertility, and galactorrhea (females), impotence or infertility (males). Tumors expressing both PRL and GH are thought to originate from a common mammosomatotroph precursor cell. Somatotropinomas or GH-secreting PA, which cause acromegaly in adults, with bony acral changes in soft tissues and bone, and increased risk of hypertension, cardiac disease, and diabetes. Corticotropinomas or ACTH-secreting PA, leading to Cushing disease and adrenal steroid overstimulation. Features of hypercortisolism include truncal obesity, striae, muscle wasting, hirsutism, cardiovascular complications, osteoporosis, and psychiatric disturbances. Pure gonadotropinomas secreting intact FSH or LH are rarely encountered and may cause sexual dysfunction and hypogonadism. Thyrotropinomas cause a mild increase in thyroxine levels with inappropriate TSH levels.

Clinics and Pathology

Treatment	PRL: medical therapy to reduce prolactin secretion and tumor size by using dopamine agonists such as bromocriptine, cabergoline and quinagolide. Trans-sphenoidal surgery may be required for drug resistant tumours or drug-intolerant individuals. NFPA: in the presence of clinical signs,the primary treatment is trans-sphenoidal surgery. Medical and radiation therapy are considered following incomplete tumor resection. Patients without clinical signs are followed-up by MRI scans and visual field checks GH: treatment depends on the adenoma size/activity and patient's age. Trans-sphenoidal surgery is the treatment of choice in most cases and can be dramatically effective, especially for microadenomas. Following surgery some patients may need radiotherapy and medical treatment with bromocriptine or somatostatin analogues to reduce prolactin secretion or inhibiting GH release from the pituitary. ACTH: the usual treatment is trans-sphenoidal surgery which leads to rapid disappearance of cortisol from the blood. When surgery is unsuccessful, radiotherapy is administered. Drugs such as metyrapone, ketoconazole and o,p'DDD are used to control cortisol levels, particularly before surgery.
Evolution	is dependent on adenoma subtype. A significantly higher frequency of multiple allelic deletions were found in invasive tumors compared to non-invasive tumors.
Prognosis	Usually favourable. Truly malignant metastatic behaviour is extremely rare. The unresponsiveness to pharmacological treatment is associated with more aggressive behaviour.

Genetics

Note

Little is known about the genetic defects leading to pituitary tumor formation, which likely involves multiple initiating and promoting factors. With the exception of activating mutations of GNAS1 which have been associated with 40% of somatotrophic adenomas and 10% of NFPAs, none of the candidate cell cycle, receptor, second messenger or related genes examined thus far appears to be responsible individually for more than a few percent of sporadic pituitary adenomas. Inactivation of p27kip1 and RB1 has been associated with the development of pituitary adenomas in mice, but no similar evidence has been achieved in human. MEN1A mutations, commonly found in patients affected by the MEN-1 syndrome, are rarely found in sporadic pituitary adenomas, despite a menin variably diminished expression has been demonstrated. Increased expression of pituitary tumor transforming gene (PTTG) has been found in sporadic pituitary adenomas, and a role for this gene in pituitary cell proliferation is supported by development of multifocal plurihormonal focal pituitary adenomas in transgenic male mice overexpressing PTTG. A role for HMGA2 gene in pituitary oncogenesis has been pointed out by development of PRL adenomas in HMGA2 transgenic mice and the finding of HMGA2 expression, which is switched off in the adult pituitary gland, in human prolactinomas. Amplification and/or rearrangement of the HMGA2 gene, mapping to 12q14, was observed in most of the PRLs analyzed. Increased dosage of chromosome 12 appears to be a condition predisposing to selective overrepresentation of the 12q14 region and/or rearrangement of the HMGA2 gene. Expression of HMGA2 has been recorded also in human NFPA, which rarely harbor trisomy 12, suggesting a mechanism of activation different from that mainly operating in PRLs (Figure 2). It remains to be determined which of the many oncogenes/growth factors and oncosuppressors reported overexpressed or underexpressed contribute to pituitary oncogenesis to identify the pathogenetic pathways which are altered in pituitary adenomas.

Cytogenetics

Note	Cytogenetic analysis failed for some time to identify recurrent chromosomal anomalies which might correlate with a clinical adenoma subtype or with a defined tumor stage. Technical difficulties related to the size of the samples available after surgery and the low proliferative rate of pituitary cells account for the limited cytogenetic findings. Despite these constraints a small fraction of pituitary adenomas showed an abnormal karyotype characterized by hyperdiploid or near triploid modal chromosome numbers and rare random structural abnormalities. Microsatellite and interphase FISH studies indicated that trisomy of chromosome 12 is pathogenetically important, and represents the most frequent cytogenetic alteration in human PRL. Chromosomes 5, 8 and X were also found to be preferentially overrepresented (Figure 3). Combined gains of the above chromosomes appear a non random pattern in pituitary adenoma. Comparative genomic hybridization (CGH) studies confirmed the cytogenetic and FISH evidence, but did not provide significant clues to specific subchromosomal regions.
	Figure 2. Interphase and metaphase FISH of HMGA2 dosage in human pituitary adenomas. Dual-color FISH of 669g18 +698i6 BACs(targeting the entire HMGA2 genomic region, red) and pBR12 (alphoid-specific probe of chromosome 12,D12Z3locus, green) showing: (a) disomy of both regions in a NFPA tumor expressing HMGA2 and (b) increased number of signals given by HMGA2-specific BACs as compared to that given by the alphoid probe on a NFPA expressing HMGA2. Note one HMGA2 signal on a marker chromosome (arrowed). Figure 3. Interphase dual-color FISH of probes pBR12 (D12Z3 locus, green fluorescence) and pDMX1 (DXZ1 locus, red) showing trisomic and disomic dosage of chromosomes 12 and X respectively, in a PRL pituitary adenoma.

Bibliography

Early multipotential pituitary focal hyperplasia in the alpha-subunit of glycoprotein hormone-driven pituitary tumor-transforming gene transgenic mice.

Abbud RA, Takumi I, Barker EM, Ren SG, Chen DY, Wawrowsky K, Melmed S

Molecular endocrinology (Baltimore, Md.). 2005 ; 19 (5) : 1383-1391.

PMID 15677710

The cytogenesis and pathogenesis of pituitary adenomas.

Asa SL, Ezzat S

Endocrine reviews. 1998 ; 19 (6) : 798-827.

PMID 9861546

Cytogenetic study of pituitary adenomas.

Bettio D, Rizzi N, Giardino D, Persani L, Pecori-Giraldi F, Losa M, Larizza L

Cancer genetics and cytogenetics. 1997 ; 98 (2) : 131-136.

PMID 9332478

Non-random trisomies of chromosomes 5, 8 and 12 in the prolactinoma sub-type of pituitary adenomas: conventional cytogenetics and interphase FISH study.

Finelli P, Giardino D, Rizzi N, Buiatiotis S, Virduci T, Franzin A, Losa M, Larizza L

International journal of cancer. Journal international du cancer. 2000 ; 86 (3) : 344-350.

PMID 10760821

The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas.

Finelli P, Pierantoni GM, Giardino D, Losa M, Rodeschini O, Fedele M, Valtorta E, Mortini P, Croce CM, Larizza L, Fusco A

Cancer research. 2002 ; 62 (8) : 2398-2405.

PMID 11956103

Simple numerical chromosome aberrations characterize pituitary adenomas.

Larsen JB, Schr&oring;der HD, S&oring;rensen AG, Bjerre P, Heim S

Cancer genetics and cytogenetics. 1999 ; 114 (2) : 144-149.

PMID 10549272

Pituitary disease: presentation, diagnosis, and management.

Levy A

Journal of neurology, neurosurgery, and psychiatry. 2004 ; 75 Suppl 3 : iii47-iii52.

PMID 15316045

Molecular defects in the pathogenesis of pituitary tumours.

Levy A, Lightman S

Frontiers in neuroendocrinology. 2003 ; 24 (2) : 94-127.

PMID 12763000

The epidemiology of endocrine tumours.

Monson JP

Endocrine-related cancer. 2000 ; 7 (1) : 29-36.

PMID 10808194

Incidence, Pathology, and Recurrence of Pituitary Adenomas: Study of 647 Unselected Surgical Cases.

Terada T, Kovacs K, Stefaneanu L, Horvath E

Endocrine pathology. 1995 ; 6 (4) : 301-310.

PMID 12114812

Chromosomal aberrations in sporadic pituitary tumors.

Trautmann K, Thakker RV, Ellison DW, Ibrahim A, Lees PD, Harding B, Fischer C, Popp S, Bartram CR, Jauch A

International journal of cancer. Journal international du cancer. 2001 ; 91 (6) : 809-814.

PMID 11275984

Citation

This paper should be referenced as such :

Finelli, P ; Larizza, L

Endocrine/neuroendocrine glands: Pituitary adenomas

Atlas Genet Cytogenet Oncol Haematol. 2005;9(4):338-340.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/PituitAdenomID5051.html

Other genes implicated (Data extracted from papers in the Atlas) [ 13 ]

Genes	AIP	CALR	CTSL	DDR1	MEN1	MIR107	NKX2-1	NR3C1	POU1F1	POU4F1
	RAC2	RAC3	SH3GL2

External links

arrayMap	Topo ( C75) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Other database	Pituitary Cancer Overview - Disease Synopsis [canSAR]
Disease database	Neuro-Endocrine/Endocrine System: Pituitary adenomas

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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