Prolactinoma pathophysiology: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Prolactinoma}} | {{Prolactinoma}} | ||
{{CMG}} {{AE}}{{Anmol}}, {{Faizan}} | {{CMG}};{{AE}} {{Anmol}}, {{Faizan}} | ||
==Overview== | ==Overview== | ||
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==Pathophysiology== | ==Pathophysiology== | ||
*[[Prolactinoma]] arises from [[lactotrophs]], which are secretory cells of [[anterior pituitary]] lobe and are normally involved in secretion of [[prolactin]] hormone. | |||
*The increase in amount of [[Lactotroph|lactotrophs]] produces excess amount of [[prolactin]] causing [[hyperprolactinemia]]. | |||
*[[Hyperprolactinemia]] causes symptoms such as [[Amenorrhea|amenorrhoea]]/[[Oligomenorrhea|oligomenorrhoea]] and [[galactorrhea]] in females and [[impotence]] in males. [[Hyperprolactinemia]] also causes [[infertility]], [[decreased libido]] and [[osteoporosis]] in both sexes. | |||
*As [[prolactinoma]] increase in size, it causes mass effect. The most common mass effect include [[headache]] and defect in [[peripheral vision]] ([[bitemporal hemianopsia]]). | |||
==Associated Diseases== | |||
[[Prolactinoma]] may be associated with:<ref name="pmid16411062">{{cite journal| author=Ciccarelli A, Daly AF, Beckers A| title=The epidemiology of prolactinomas. | journal=Pituitary | year= 2005 | volume= 8 | issue= 1 | pages= 3-6 | pmid=16411062 | doi=10.1007/s11102-005-5079-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16411062 }} </ref> | |||
* [[Multiple endocrine neoplasia type 1]] ([[Multiple endocrine neoplasia type 1|MEN 1]]) | |||
*[[Carney complex]] | |||
*[[McCune-Albright Syndrome]] | |||
==Genetics== | |||
*[[Prolactinoma]] are [[monoclonal]] in nature. This suggests that the [[somatic]] [[Cell (biology)|cell]] [[mutation]] responsible for the development of prolactionoma, occurs before clonal expansion of [[Lactotroph|lactotrophs]].<ref name="pmid1977759">{{cite journal| author=Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S| title=Clonal origin of pituitary adenomas. | journal=J Clin Endocrinol Metab | year= 1990 | volume= 71 | issue= 6 | pages= 1427-33 | pmid=1977759 | doi=10.1210/jcem-71-6-1427 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1977759 }} </ref> | *[[Prolactinoma]] are [[monoclonal]] in nature. This suggests that the [[somatic]] [[Cell (biology)|cell]] [[mutation]] responsible for the development of prolactionoma, occurs before clonal expansion of [[Lactotroph|lactotrophs]].<ref name="pmid1977759">{{cite journal| author=Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S| title=Clonal origin of pituitary adenomas. | journal=J Clin Endocrinol Metab | year= 1990 | volume= 71 | issue= 6 | pages= 1427-33 | pmid=1977759 | doi=10.1210/jcem-71-6-1427 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1977759 }} </ref> | ||
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**The consequence of this mode of [[tumor]] development is that if one [[allele]] for the [[gene]] is damaged, the second can still produce the correct form of normal [[protein]]. | **The consequence of this mode of [[tumor]] development is that if one [[allele]] for the [[gene]] is damaged, the second can still produce the correct form of normal [[protein]]. | ||
**Affected individuals carry one altered copy of the [[MEN1]] [[gene]] and the other copy is lost due to [[somatic]] [[mutation]]. | **Affected individuals carry one altered copy of the [[MEN1]] [[gene]] and the other copy is lost due to [[somatic]] [[mutation]]. | ||
====Familial pituitary adenomas==== | ====Familial pituitary adenomas==== | ||
*A [[pituitary adenoma]] may be part of a familial syndrome:<ref name="pmid17613551">{{cite journal| author=Karhu A, Aaltonen LA| title=Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B and AIP mutations: an update. | journal=Hum Mol Genet | year= 2007 | volume= 16 Spec No 1 | issue= | pages= R73-9 | pmid=17613551 | doi=10.1093/hmg/ddm036 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17613551 }} </ref> | *A [[pituitary adenoma]] may be part of a familial syndrome:<ref name="pmid17613551">{{cite journal| author=Karhu A, Aaltonen LA| title=Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B and AIP mutations: an update. | journal=Hum Mol Genet | year= 2007 | volume= 16 Spec No 1 | issue= | pages= R73-9 | pmid=17613551 | doi=10.1093/hmg/ddm036 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17613551 }} </ref> | ||
{| | {| | ||
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Syndrome}} | |||
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Gene}} | |||
! Gene locus | ! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Gene locus}} | ||
! | ! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Features}} | ||
|- | |- | ||
| [[Multiple endocrine neoplasia type 1|Multiple endocrine neoplasia I]] | | style="background: #DCDCDC; text-align: center;" | [[Multiple endocrine neoplasia type 1|Multiple endocrine neoplasia I]] | ||
| [[MEN1]] | | style="background: #F5F5F5; text-align: center;" | [[MEN1]] | ||
| 11q13 | | style="background: #F5F5F5; text-align: center;" | 11q13 | ||
| Characterized by the 3 Ps: [[Pituitary adenoma|'''p'''ituitary adenoma]], [[parathyroid adenoma|'''p'''arathyroid adenoma]], [[Pancreatic neuroendocrine tumor|'''p'''ancreatic neuroendocrine tumor]] | | style="background: #F5F5F5;" | | ||
*Characterized by the 3 Ps: [[Pituitary adenoma|'''p'''ituitary adenoma]], [[parathyroid adenoma|'''p'''arathyroid adenoma]], [[Pancreatic neuroendocrine tumor|'''p'''ancreatic neuroendocrine tumor]] | |||
|- | |- | ||
| MEN1-like syndrome | | style="background: #DCDCDC; text-align: center;" | MEN1-like syndrome | ||
| CDKN1B | | style="background: #F5F5F5; text-align: center;" | CDKN1B | ||
| 12q13 | | style="background: #F5F5F5; text-align: center;" | 12q13 | ||
| Associated with [[pituitary adenoma]], [[parathyroid adenoma]], [[neuroendocrine tumor]] | | style="background: #F5F5F5;" | | ||
*Associated with [[pituitary adenoma]], [[parathyroid adenoma]], [[neuroendocrine tumor]] | |||
|- | |- | ||
| [[Carney complex]] | | style="background: #DCDCDC; text-align: center;" | [[Carney complex]] | ||
| [[PRKAR1A]] | | style="background: #F5F5F5; text-align: center;" | [[PRKAR1A]] | ||
| 17q24 | | style="background: #F5F5F5; text-align: center;" | 17q24 | ||
| Other findings (mnemonic ''NAME''): [[Nevus|nevi]], [[atrial myxoma]], myxoid [[neurofibroma]], ephelides ([[freckles]]) | | style="background: #F5F5F5;" | | ||
*Other findings (mnemonic ''NAME''): [[Nevus|nevi]], [[atrial myxoma]], myxoid [[neurofibroma]], ephelides ([[freckles]]) | |||
|- | |- | ||
| Familial isolated [[pituitary adenoma]] | | style="background: #DCDCDC; text-align: center;" | Familial isolated [[pituitary adenoma]] | ||
| AIP | | style="background: #F5F5F5; text-align: center;" | AIP | ||
| 11q13 | | style="background: #F5F5F5; text-align: center;" | 11q13 | ||
| | | style="background: #F5F5F5;" | | ||
*Classically [[growth hormone]]-producing [[adenoma]], leads to [[acromegaly]] | *Classically [[growth hormone]]-producing [[adenoma]], leads to [[acromegaly]] | ||
*May also be associated with prolactinomas<ref name="pmid22612670">{{cite journal| author=Korbonits M, Storr H, Kumar AV| title=Familial pituitary adenomas - who should be tested for AIP mutations? | journal=Clin Endocrinol (Oxf) | year= 2012 | volume= 77 | issue= 3 | pages= 351-6 | pmid=22612670 | doi=10.1111/j.1365-2265.2012.04445.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22612670 }} </ref> | *May also be associated with prolactinomas<ref name="pmid22612670">{{cite journal| author=Korbonits M, Storr H, Kumar AV| title=Familial pituitary adenomas - who should be tested for AIP mutations? | journal=Clin Endocrinol (Oxf) | year= 2012 | volume= 77 | issue= 3 | pages= 351-6 | pmid=22612670 | doi=10.1111/j.1365-2265.2012.04445.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22612670 }} </ref> | ||
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The gross pathology of [[prolactinoma]] is as follows:<ref name="Russell">{{cite book | last = Bigner | first = D. D. | title = Russell and Rubinstein's pathology of tumors of the nervous system | publisher = Hodder Arnold Distributed in the United States of America by Oxford University Press | location = London New York, NY | year = 2006 | isbn = 978-0340810071 }}</ref> | The gross pathology of [[prolactinoma]] is as follows:<ref name="Russell">{{cite book | last = Bigner | first = D. D. | title = Russell and Rubinstein's pathology of tumors of the nervous system | publisher = Hodder Arnold Distributed in the United States of America by Oxford University Press | location = London New York, NY | year = 2006 | isbn = 978-0340810071 }}</ref> | ||
*Microprolactinomas (<10mm size) are usually found in the [[lateral]] wing of the [[pituitary gland]]. They are most often surrounded by well defined pseudocapsules composed of [[reticulin]]. | *Microprolactinomas (<10mm size) are usually found in the [[lateral]] wing of the [[pituitary gland]]. They are most often surrounded by well defined pseudocapsules composed of [[reticulin]]. | ||
*Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause [[Sella turcica|sellar]] expansion while others invade the [[skull]] | *Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause [[Sella turcica|sellar]] expansion while others invade the base of the [[skull]]. | ||
*About 50% of all [[prolactinoma]] grossly invade surrounding structures. | *About 50% of all [[prolactinoma]] grossly invade surrounding structures. | ||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
*[[Prolactinoma]] are divded into two types based on microscopy:<ref name="Russell" | *[[Prolactinoma]] are divded into two types based on [[microscopy]]:<ref name="Russell" /> | ||
* Sparsely granulated variant | * Sparsely granulated variant | ||
**This is common type of variant. | **This is common type of variant. | ||
**This contains chromophobic cells. | **This contains [[chromophobic]] [[Cells (biology)|cells]]. | ||
* Densely granulated variant | * Densely granulated variant | ||
**This is a rare varaint. | **This is a rare varaint. | ||
**This contains acidophilic cells. | **This contains [[acidophilic]] [[Cells (biology)|cells]]. | ||
:'''Note:''' There is no clinical, biological and prognostic difference between the | :'''Note:''' There is no clinical, biological and [[Prognosis|prognostic]] difference between the two variants. | ||
== References == | == References == | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]
Overview
Prolactinoma is the most common type of pituitary adenoma. Prolactinoma may occur in approximately 30% of multiple endocrine neoplasia type 1 patients. It may also occur with Carney complex or McCune-Albright syndrome. Prolactinoma is also associated with various familial syndromes for example MEN1 syndrome. There have been familial cases of prolactinoma unrelated to MEN 1 syndrome as well. On gross pathology, prolactinoma is divided on the basis of size into microprolactinoma and macroprolactinoma. On histological analysis, prolactinoma may be divided into sparsely granulated and densely granulated.
Pathophysiology
- Prolactinoma arises from lactotrophs, which are secretory cells of anterior pituitary lobe and are normally involved in secretion of prolactin hormone.
- The increase in amount of lactotrophs produces excess amount of prolactin causing hyperprolactinemia.
- Hyperprolactinemia causes symptoms such as amenorrhoea/oligomenorrhoea and galactorrhea in females and impotence in males. Hyperprolactinemia also causes infertility, decreased libido and osteoporosis in both sexes.
- As prolactinoma increase in size, it causes mass effect. The most common mass effect include headache and defect in peripheral vision (bitemporal hemianopsia).
Associated Diseases
Prolactinoma may be associated with:[1]
Genetics
- Prolactinoma are monoclonal in nature. This suggests that the somatic cell mutation responsible for the development of prolactionoma, occurs before clonal expansion of lactotrophs.[2]
PTTG-1 gene
- One gene involved in the pathogenesis of prolactinoma is the pituitary tumor transforming gene-1 (PTTG-1).[3][4]
- The PTTG-1 gene is related to various endocrine and non-endocrine tumors such as:
- Prolactinomas with a higher expression of the PTTG-1 gene tend to be more invasive.
MEN1 syndrome
- Many prolactinomas are related to multiple endocrine neoplasia type 1.[5]
- The MEN1 gene is located on 11q13.
- The MEN1 gene is a tumor suppressor gene that follows the concept of 'two-hit hypothesis,' which implies that both alleles that code for a particular gene must be affected before an effect manifests.
- The consequence of this mode of tumor development is that if one allele for the gene is damaged, the second can still produce the correct form of normal protein.
- Affected individuals carry one altered copy of the MEN1 gene and the other copy is lost due to somatic mutation.
Familial pituitary adenomas
- A pituitary adenoma may be part of a familial syndrome:[6]
| Syndrome | Gene | Gene locus | Features |
|---|---|---|---|
| Multiple endocrine neoplasia I | MEN1 | 11q13 |
|
| MEN1-like syndrome | CDKN1B | 12q13 |
|
| Carney complex | PRKAR1A | 17q24 |
|
| Familial isolated pituitary adenoma | AIP | 11q13 |
|
Gross Pathology
The gross pathology of prolactinoma is as follows:[8]
- Microprolactinomas (<10mm size) are usually found in the lateral wing of the pituitary gland. They are most often surrounded by well defined pseudocapsules composed of reticulin.
- Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause sellar expansion while others invade the base of the skull.
- About 50% of all prolactinoma grossly invade surrounding structures.
Microscopic Pathology
- Prolactinoma are divded into two types based on microscopy:[8]
- Sparsely granulated variant
- This is common type of variant.
- This contains chromophobic cells.
- Densely granulated variant
- This is a rare varaint.
- This contains acidophilic cells.
- Note: There is no clinical, biological and prognostic difference between the two variants.
References
- ↑ Ciccarelli A, Daly AF, Beckers A (2005). "The epidemiology of prolactinomas". Pituitary. 8 (1): 3–6. doi:10.1007/s11102-005-5079-0. PMID 16411062.
- ↑ Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S (1990). "Clonal origin of pituitary adenomas". J Clin Endocrinol Metab. 71 (6): 1427–33. doi:10.1210/jcem-71-6-1427. PMID 1977759.
- ↑ Vlotides G, Eigler T, Melmed S (2007). "Pituitary tumor-transforming gene: physiology and implications for tumorigenesis". Endocr Rev. 28 (2): 165–86. doi:10.1210/er.2006-0042. PMID 17325339.
- ↑ Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD; et al. (1999). "Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas". J Clin Endocrinol Metab. 84 (2): 761–7. doi:10.1210/jcem.84.2.5432. PMID 10022450.
- ↑ Agarwal SK, Lee Burns A, Sukhodolets KE, Kennedy PA, Obungu VH, Hickman AB; et al. (2004). "Molecular pathology of the MEN1 gene". Ann N Y Acad Sci. 1014: 189–98. PMID 15153434.
- ↑ Karhu A, Aaltonen LA (2007). "Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B and AIP mutations: an update". Hum Mol Genet. 16 Spec No 1: R73–9. doi:10.1093/hmg/ddm036. PMID 17613551.
- ↑ Korbonits M, Storr H, Kumar AV (2012). "Familial pituitary adenomas - who should be tested for AIP mutations?". Clin Endocrinol (Oxf). 77 (3): 351–6. doi:10.1111/j.1365-2265.2012.04445.x. PMID 22612670.
- ↑ 8.0 8.1 Bigner, D. D. (2006). Russell and Rubinstein's pathology of tumors of the nervous system. London New York, NY: Hodder Arnold Distributed in the United States of America by Oxford University Press. ISBN 978-0340810071.