Prolactinoma pathophysiology: Difference between revisions

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Latest revision as of 23:50, 29 July 2020

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]

Multiple endocrine neoplasia type 1 (MEN 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:
  - 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 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	Characterized by the 3 Ps: pituitary adenoma, parathyroid adenoma, pancreatic neuroendocrine tumor
MEN1-like syndrome	CDKN1B	12q13	Associated with pituitary adenoma, parathyroid adenoma, neuroendocrine tumor
Carney complex	PRKAR1A	17q24	Other findings (mnemonic NAME): nevi, atrial myxoma, myxoid neurofibroma, ephelides (freckles)
Familial isolated pituitary adenoma	AIP	11q13	Classically growth hormone-producing adenoma, leads to acromegaly May also be associated with prolactinomas^[7]

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.

Template:WikiDoc Sources

[pmid16411062-1] 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.

[pmid1977759-2] 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.

[pmid17325339-3] 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.

[pmid10022450-4] 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.

[pmid15153434-5] 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.

[pmid17613551-6] 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.

[pmid22612670-7] 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.

[Russell-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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@@ Line 1: / Line 1: @@
 __NOTOC__
 {{Prolactinoma}}
-{{CMG}} {{AE}}{{Faizan}}
+{{CMG}};{{AE}} {{Anmol}}, {{Faizan}}
 ==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 name="Radiopedia">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==
+*[[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 occur as part of a hereditary disorder called [[multiple endocrine neoplasia type 1]] (MEN 1). A minority of prolactinomas are associated with:<ref name="Radiopedia">http://radiopaedia.org/articles/pituitary-adenoma</ref>
+[[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 I]] ([[Multiple endocrine neoplasia type 1|MEN I]])
+* [[Multiple endocrine neoplasia type 1]] ([[Multiple endocrine neoplasia type 1|MEN 1]])
 *[[Carney complex]]
 *[[McCune-Albright Syndrome]]
-*MEN like syndrome (''CKDN1B'' loss of function)
+==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====
-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>
+*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 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]]
-| characterized by the 3 Ps: '''p'''ituitary adenoma, [[parathyroid adenoma|'''p'''arathyroid adenoma]], '''p'''ancreatic neuroendocrine tumor
+| 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 growth hormone-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 Pathology===
-Features of prolactinoma include:
+==Gross Pathology==
-*Loss of [[fibrous]] stroma
+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>
-*Normal (anterior) [[pituitary]] cells are nested
+*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]].
-Notes:
+*Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause [[Sella turcica|sellar]] expansion while others invade the base of the  [[skull]].
-*Smears very well
+*About 50% of all [[prolactinoma]] grossly invade surrounding structures.
-===Stains===
-*[[Reticulin]] - loss of reticulin between tumor cells
+==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 ==
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