Prolactinoma pathophysiology: Difference between revisions

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{{Prolactinoma}}
{{Prolactinoma}}
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{{CMG}};{{AE}} {{Anmol}}, {{Faizan}}
 
==Overview==
==Overview==
[[Prolactinoma]] may occur as part of a hereditary disorder called multiple endocrine neoplasia type 1 (MEN 1). A minority of prolactinomas are associated with Carney complex, McCune-Albright Syndrome, MEN like syndrome ( CKDN1B loss of function).<ref>http://radiopaedia.org/articles/pituitary-adenoma</ref>
[[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 [[Multiple endocrine neoplasia type 1|MEN1 syndrome]]. There have been [[familial]] cases of [[prolactinoma]] unrelated to [[Multiple endocrine neoplasia type 1|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==
==Pathophysiology==
[[Prolactinoma]] may occur as part of a hereditary disorder called multiple endocrine neoplasia type 1 (MEN 1). A minority of prolactinomas are associated with:
*[[Prolactinoma]] arises from [[lactotrophs]], which are secretory cells of [[anterior pituitary]] lobe and are normally involved in secretion of [[prolactin]] hormone.
*Multiple endocrine neoplasia type I (MEN I)
*The increase in amount of [[Lactotroph|lactotrophs]]  produces excess amount of [[prolactin]] causing [[hyperprolactinemia]].
*Carney complex
*[[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.
*McCune-Albright Syndrome
*As [[prolactinoma]] increase in size, it causes mass effect. The most common mass effect include [[headache]] and defect in [[peripheral vision]] ([[bitemporal hemianopsia]]).
*MEN like syndrome ( CKDN1B loss of function)<ref>http://radiopaedia.org/articles/pituitary-adenoma</ref>
 
==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>
 
=== '''PTTG-1 gene''' ===
*One [[gene]] involved in the pathogenesis of [[prolactinoma]] is the [[PTTG1|pituitary tumor transforming gene-1]] ([[PTTG1|PTTG-1]]).<ref name="pmid17325339">{{cite journal| author=Vlotides G, Eigler T, Melmed S| title=Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. | journal=Endocr Rev | year= 2007 | volume= 28 | issue= 2 | pages= 165-86 | pmid=17325339 | doi=10.1210/er.2006-0042 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17325339  }} </ref><ref name="pmid10022450">{{cite journal| author=Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD et al.| title=Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. | journal=J Clin Endocrinol Metab | year= 1999 | volume= 84 | issue= 2 | pages= 761-7 | pmid=10022450 | doi=10.1210/jcem.84.2.5432 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10022450  }} </ref>
**The [[PTTG1|PTTG-1 gene]] is related to various [[endocrine]] and non-endocrine [[tumors]] such as:
***'''[[Endocrine]] related [[tumors]]''': [[pituitary]], [[thyroid]], [[breast]], [[ovarian]], and [[uterine]] [[tumors]].
***'''Non-endocrine related [[tumors]]''': [[central nervous system]], [[pulmonary]], and [[gastrointestinal]] tumors.
**[[Prolactinomas]] with a higher expression of the [[PTTG1|PTTG-1 gene]] tend to be more [[invasive]].
 
=== MEN1 syndrome ===
*Many [[prolactinomas]] are related to [[multiple endocrine neoplasia type 1]].<ref name="pmid15153434">{{cite journal| author=Agarwal SK, Lee Burns A, Sukhodolets KE, Kennedy PA, Obungu VH, Hickman AB et al.| title=Molecular pathology of the MEN1 gene. | journal=Ann N Y Acad Sci | year= 2004 | volume= 1014 | issue=  | pages= 189-98 | pmid=15153434 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15153434  }} </ref>
** The [[MEN1]] [[gene]] is located on 11q13.
** The [[MEN1]] [[gene]] is a [[tumor suppressor gene]] that follows the concept of '[[Tumor suppressor gene|two-hit hypothesis]],' which implies that both [[Allele|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====
====Familial pituitary adenomas====
A pituitary adenoma may be part of a familial syndrome:<ref name=pmid19564887>{{Cite journal | last1 = Elston | first1 = MS. | last2 = McDonald | first2 = KL. | last3 = Clifton-Bligh | first3 = RJ. | last4 = Robinson | first4 = BG. | title = Familial pituitary tumor syndromes. | journal = Nat Rev Endocrinol | volume = 5 | issue = 8 | pages = 453-61 | month = Aug | year = 2009 | doi = 10.1038/nrendo.2009.126 | PMID = 19564887 }}</ref><ref name=Ref_PCPBoD8|554>{{Ref PCPBoD8|554}}</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>
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
{|
! Syndrome
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Syndrome}}
! Gene
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Gene}}
! Notes
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Gene locus}}
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Features}}
|-
|-
| [[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]]
| characterized by the 3 Ps: '''p'''ituitary adenoma, [[parathyroid adenoma|'''p'''arathyroid adenoma]], [[pancreatic neuroendocrine tumour|'''p'''ancreatic neuroendocrine tumour]]
| style="background: #F5F5F5; text-align: center;" | 11q13
| 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]]
|-
|-
| MEN-1-like syndrome
| style="background: #DCDCDC; text-align: center;" | MEN1-like syndrome
| CDKN1B<ref name=omim600778>{{OMIM|600778}}</ref>
| style="background: #F5F5F5; text-align: center;" | CDKN1B
| also known as ''Multiple endocrine neoplasia IV'' <ref name=omim600778>{{OMIM|600778}}</ref>
| style="background: #F5F5F5; text-align: center;" | 12q13
| style="background: #F5F5F5;" |
*Associated with [[pituitary adenoma]], [[parathyroid adenoma]], [[neuroendocrine tumor]]
|-
|-
| [[Carney syndrome]]
| style="background: #DCDCDC; text-align: center;" | [[Carney complex]]
| PRKAR1A
| style="background: #F5F5F5; text-align: center;" | [[PRKAR1A]]
| other findings (mnemonic ''NAME''): nevi, [[atrial myxoma]], myxoid neurofibroma, ephelides (freckles)
| style="background: #F5F5F5; text-align: center;" | 17q24
| style="background: #F5F5F5;" |
*Other findings (mnemonic ''NAME''): [[Nevus|nevi]], [[atrial myxoma]], myxoid [[neurofibroma]], ephelides ([[freckles]])
|-
|-
| Isolated pituitary adenoma<ref name=pmid22612670>{{Cite journal | last1 = Korbonits | first1 = M. | last2 = Storr | first2 = H. | last3 = Kumar | first3 = AV. | title = Familial pituitary adenomas - Who should be tested for AIP mutations? | journal = Clin Endocrinol (Oxf) | volume = | issue = | pages = | month = May | year = 2012 | doi = 10.1111/j.1365-2265.2012.04445.x | PMID = 22612670 }}</ref>
| style="background: #DCDCDC; text-align: center;" | Familial isolated [[pituitary adenoma]]
| AIP
| style="background: #F5F5F5; text-align: center;" | AIP
| classically GH-producing adenoma - leads to acromegaly
| style="background: #F5F5F5; text-align: center;" | 11q13
| style="background: #F5F5F5;" |
*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>
|}
|}
===Microscopic===
Features:<ref name=Ref_PSNP36>{{Ref PSNP|36}}</ref>
*Loss of fibrous stroma.
**The cells of a normal (anterior) pituitary are nested.
Notes:
*Smears very well.<ref>MUN. 24 November 2010.</ref>
[[File:PRL adenoma treatment HE.jpg|PRL adenoma treatment HE]]


===Stains===
==Gross Pathology==
*Reticulin - loss of reticulin between tumour cells.
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]].
*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.
 
==Microscopic Pathology==
*[[Prolactinoma]] are divded into two types based on [[microscopy]]:<ref name="Russell" />
* Sparsely granulated variant
**This is common type of variant.
**This contains [[chromophobic]] [[Cells (biology)|cells]].
* Densely granulated variant
**This is a rare varaint.
**This contains [[acidophilic]] [[Cells (biology)|cells]].
:'''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

Associated Diseases

Prolactinoma may be associated with:[1]

Genetics

PTTG-1 gene

MEN1 syndrome

Familial pituitary adenomas

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

Note: There is no clinical, biological and prognostic difference between the two variants.

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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. 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.

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