Difference between revisions of "Pituitary gland"

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Divisions:<ref>[http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo.html]</ref>
Divisions:<ref>[http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo.html]</ref>
*Anterior pituitary ([[AKA]] adenohypophysis).
*Anterior pituitary ([[AKA]] adenohypophysis, pars distalis).
*Posterior pituitary (AKA neurohypophysis, neural pituitary).
*Posterior pituitary (AKA neurohypophysis, neural pituitary, pars nervosa).


==Function==
=Function=
Anterior part:<ref name=rcn_com>[http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pituitary.html http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pituitary.html]</ref>
===Anterior===  
Hormones:<ref name=rcn_com>[http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pituitary.html http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pituitary.html]</ref>
*Growth hormone (GH).
*Growth hormone (GH).
*Luteinizing hormone (LH)
*Luteinizing hormone (LH)
Line 16: Line 17:
Mnemonic: "Go Look For The Adenoma Please" = GH, LH, FSH, TSH, ACTH, PRL.
Mnemonic: "Go Look For The Adenoma Please" = GH, LH, FSH, TSH, ACTH, PRL.


Posterior part:<ref name=rcn_com/>
===Intermedia===
* Originates from the posterior wall of the Rathke’s pouch.
* Hormones: MSH, ACTH precursor.
* Contains colloid cysts.
 
===Posterior===
Hormones:<ref name=rcn_com/>
*Oxytocin.
*Oxytocin.
*Antidiuretic hormone (ADH).
*Antidiuretic hormone (ADH).


==Anatomy and histology==
=Anatomy and histology=
===Anatomy===
Basic anatomy (simplified):<ref name=bowen>URL: [http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo_pit.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo_pit.html]. Accessed on: 31 October 2010.</ref>
Basic anatomy (simplified):<ref name=bowen>URL: [http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo_pit.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo_pit.html]. Accessed on: 31 October 2010.</ref>
*Anterior:
*Anterior:
Line 32: Line 40:
*Posterior - diencephalon (ventral aspect).
*Posterior - diencephalon (ventral aspect).


Image:
Images:
*[http://www.ouhsc.edu/histology/Glass%20slides/38_01.jpg Pituitary gland (ouhsc.edu)].
*[http://www.ouhsc.edu/histology/Glass%20slides/38_01.jpg Pituitary gland (ouhsc.edu)].
*[http://www.lab.anhb.uwa.edu.au/mb140/corepages/endocrines/Images/HypDevAni.gif Development of the pituitary - animation (anhb.uwa.edu)].


==Histology==
===Histology===
===Anterior===
====Anterior====
*Acidophils (40% of cells) = red or orange.
*Acidophils (40% of cells) = red or orange.
**GH, PRL.
**GH, PRL.
*Basophils (10% of cells) = basophilic (light blue).
*Basophils (10% of cells) = basophilic (light blue).
**TSH, LH, FSH.
**TSH, LH, FSH, ACTH.
*Chromophobes (50% of cells) = amphophilic (purplish/grey).
*Chromophobes (50% of cells) = amphophilic (purplish/grey).


Notes:
Notes:
*The cellular product (i.e. hormone produced) is not strictly correlated with the cell type.<ref name=Ref_PSNP26>{{Ref PSNP|26}}</ref>
*The cellular product (i.e. hormone produced) is not strictly correlated with the cell type.<ref name=Ref_PSNP26>{{Ref PSNP|26}}</ref>
*The cells can be typed using [[IHC]]; somatotrophs (GH), lactotrophs (PRL), corticotrophs (ACTH), thyrotrophs (TSH), gonadotrophs (FSH, LH).<ref>{{Ref PBoD8|1098-9}}</ref>


===Posterior===
====Posterior====
Features:<ref name=Ref_PSNP26>{{Ref PSNP|26}}</ref>
Features:<ref name=Ref_PSNP26>{{Ref PSNP|26}}</ref>
*Herring bodies - '''key feature'''.
*Herring bodies - '''key feature'''.
Line 52: Line 62:
*Less cellular.
*Less cellular.
**Usually more cellular in perivascular location.
**Usually more cellular in perivascular location.
Image: [http://www.ouhsc.edu/histology/Glass%20slides/38_09.jpg Herring bodies (ouhsc.edu)].
<gallery>
File:Pituitary gland histology 2014.jpg | Pituitary gland, low magnification (WC/Athikhun.suw)
</gallery>
=DDx for sella turcica lesions=
*[[Pituitary adenoma|PitNET]].
*[[Rathke cleft cyst]].
*[[Craniopharyngioma]].
*[[Germ cell tumour]].
*[[Meningioma]].
=Pituitary necrosis=
*Rare.
===Causes of pituitary necrosis===
*Sheehan syndrome - secondary to blood loss in childbirth.<ref>URL: [http://www.mayoclinic.com/health/sheehans-syndrome/DS00889 http://www.mayoclinic.com/health/sheehans-syndrome/DS00889]. Accessed on: 16 November 2010.</ref>
*[[Syphilis]] (fetal-maternal transmission).<ref>URL: [http://pediatrics.aappublications.org/cgi/content/full/104/1/e4 http://pediatrics.aappublications.org/cgi/content/full/104/1/e4]. Accessed on: 16 November 2010.</ref>
*Mollaret's meningitis - very rare.<ref name=pmid18715308>{{cite journal |author=Dancer CM, Woods ML, Henderson RD, Robertson T, Mungomery M, Allworth A |title=Mollaret's meningitis and pituitary failure associated with a Rathke's cleft cyst |journal=Intern Med J |volume=38 |issue=7 |pages=609–11 |year=2008 |month=July |pmid=18715308 |doi=10.1111/j.1445-5994.2008.01709.x |url=}}</ref> (???)
*Spontaneous necrosis of pituitary tumours - case reports.<ref>{{cite journal |author=Sachdev Y, Evered DC, Hall R |title=Spontaneous pituitary necrosis |journal=Br Med J |volume=1 |issue=6015 |pages=942 |year=1976 |month=April |pmid=1268492 |pmc=1639254 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1639254/pdf/brmedj00512-0028a.pdf}}</ref>
Images:
*[http://path.upmc.edu/cases/case288.html Pituitary necrosis - several images (upmc.edu)].
=Specific entities=
==Pituitary neuroendocrine tumor (PitNET)==
Old terminology '''Pituitary adenoma''' is depreceated.
The WHO 2022 Classification of tumours of endocrine organs recoginizes following tumours:<ref>{{cite journal |vauthors=Asa SL, Mete O, Perry A, Osamura RY |title=Overview of the 2022 WHO Classification of Pituitary Tumors |journal=Endocr Pathol |volume=33 |issue=1 |pages=6–26 |date=March 2022 |pmid=35291028 |doi=10.1007/s12022-022-09703-7 |url=}}</ref>


Image: [http://www.ouhsc.edu/histology/Glass%20slides/38_09.jpg Herring bodies (ouhsc.edu)].


==DDx for stellar lesions==
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
*Pituitary adenoma.
! PitNET lineage
*Rathke cleft cyst.
! PitNET type
*Craniopharyngioma.
! subtypes
*Germ cell tumour.
! Hormone IHC
*Meningioma.
! Transcription factor IHC
|-
| PIT1
| Somatotroph tumor
| Densely and sparsely granulated tumor
| GH, a-subunit+/-, CK+
| PIT1
|-
| PIT1
| Lactotroph tumor
| Densely and sparsely granulated tumor
| PRL, CK-ve or weak
| PIT1, [[Estrogen receptor|ER]]
|-
| PIT1
| Mammosomatotroph tumor
|
| GH, PRL (usu. less), CK perinuclear +ve
| PIT1, [[Estrogen receptor|ER]]
|-
| PIT1
| Thyrotroph tumor
|
| TSH, CK-ve or weak
| PIT1, GATA3
|-
| PIT1
| Mature plurihormonal PIT1 lineage tumor
|
| GH, PRL, TSH, a-subunit +/-ve, CK perinuclear
| PIT1, [[Estrogen receptor|ER]], GATA3
|-
| PIT1
| Immature PIT1 lineage tumor
|
| Only focal GH, PRL, TSH, a-subunit +/-ve, CK variable
| PIT1, [[Estrogen receptor|ER]] +/-ve, GATA3 +/-ve
|-
| PIT1
| Acidophilic stem cell tumor
|
| PRL, GH (focal/variable), CK fibrous bodies
| PIT1, [[Estrogen receptor|ER]]
|-
| PIT1
| Mixed somatotroph and lactotroph tumor
|
| PRL, GH (in separate cells)
| PIT1, [[Estrogen receptor|ER]] (only in lactotroph component) 
|-
| TPIT
| Corticotroph tumor
| Densely and sparsely granulated tumors, Crooke cell adenoma
| ACTH,CK+ve
| TPIT
|-
| SF1
| Gonadotroph tumor
|
| FSH, LH, a-Subunit or none
| SF1, ER, GATA3, CK+/-ve
|-
| None
| Plurihormonal tumor
|
| All combinations possible
| All combinations possible, CK+/-ve
|-
| None
| Null cell adenoma
|
| None (adenohypophyseal?)
| None
|}
 
Other tumours may be classified as plurhormonal or double adenomas or as adenomas with unusual IHC combination.
 
===General===
*Clinical:<ref>{{Ref PBoD8|1100}}</ref>
**Classically: visual field defects (bitemporal hemianopsia).
**Others (increased intracranial pressure): headache, nausea, vomiting.
**Tumor of adults.
 
Morphologic Classification:
#Microtumor <= 1 cm.
#Macrotumor 1-4 cm.
#Giant tumor > 4cm.
 
May be classified by what they secrete.
#Functional (endocrine hyperfunction).
#*Acromegaly/giantism.
#*Hyperprolactinemia.
#*Cushing disease.
#*Hyperthyroidism.
#*Significant elevation of FSH/LH.
#Clinically nonfunctioning.
 
Notes:
''Cushing disease'' is due to pituitary gland hypersecretion of ACTH (due to a pituitary adenoma ''or'' CRH hypersecretion from the hypothalamus).<ref name=Ref_PBoD8_1148>{{Ref PBoD8|1148}}</ref>  [[Cushing syndrome]] is hypercortisolism ''not'' due to pituitary gland pathology.
 
Imaging:
*Sellar enlargement.
*Bone erosion, invasive growth esp. cavernous sinus (35-45%).
*Inhomogenous signal in T1w MRI.
 
====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>
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
! Syndrome
! Gene
! Notes
|-
| [[Multiple endocrine neoplasia]] I
| MEN1
| characterized by the 3 Ps: '''p'''ituitary adenoma, [[parathyroid adenoma|'''p'''arathyroid adenoma]], [[pancreatic neuroendocrine tumour|'''p'''ancreatic neuroendocrine tumour]]
|-
| MEN-1-like syndrome
| CDKN1B<ref name=omim600778>{{OMIM|600778}}</ref>
| also known as ''Multiple endocrine neoplasia IV'' <ref name=omim600778>{{OMIM|600778}}</ref>
|-
| [[Carney syndrome]]
| PRKAR1A
| other findings (mnemonic ''NAME''): 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>
| AIP
| classically GH-producing adenoma - leads to acromegaly
|}


==Pituitary adenoma==
===Microscopic===
Features:<ref name=Ref_PSNP36>{{Ref PSNP|36}}</ref>
Features:<ref name=Ref_PSNP36>{{Ref PSNP|36}}</ref>
*Loss of fibrous stroma.
*Loss of fibrous stroma.
**The cells of a normal (anterior) pituitary are nested.
*Basophilic cells (corticotrophs).
*Eosinophilic cells(somatotrophs).
*Extensive fibrosis often seen in TSH-producing tumors.
Notes:
*Smears very well.<ref>MUN. 24 November 2010.</ref>
====Images====
<gallery>
Image:Nonfunctioning_pituitary_adenoma_%281%29.jpg | Pituitary adenoma - non-functioning. (WC/KGH)
File:HE fibrosis pituitary adenoma.jpg | Extensive interstitial and perivascular fibrosis in a pituitary adenoma (WC/jensflorian)
File:PRL HE histology.jpg | Pituitary adenoma - PRL producing, HE. Note the basophilic appearance of the cells (WC/jensflorian)
File:PRL adenoma treatment HE.jpg | Pituitary adenoma - PRL producing, HE. Extensive regressive changes after after dopamine agonist treatment (WC/jensflorian)
File:PRL IHC pituitary adenoma.jpg | Pituitary adenoma - PRL producing, Prolactin IHC (WC/jensflorian)
File:Densely granulated HGH producing adenoma.jpg | Pituitary adenoma - HGH producing, HE. The cells have a slightly eosinophilic appearance (WC/jensflorian)
File:Sparsely granulated HGH adenoma.jpg | Sparsely granulated adenoma - HGH producing. Note the numerous fibrous bodies in HE stain (WC/jensflorian)
File:HGH adenoma CK8.jpg | Sparsely granulated adenoma - HGH producing. CK8 IHC highlighting fibrous bodies (WC/jensflorian)
File:TSHoma HE.jpg | Pituitary adenoma - TSH producing. HE stain showing pleomorphism (WC/jensflorian)
File:TSHoma IHC-TSH.jpg |  Pituitary adenoma - TSH producing. TSH IHC can be heterogeneous (WC/jensflorian)
Image:Pituitary_adenoma_%281%29_GH_production.jpg | Pituitary adenoma - GH producing. (WC/KGH)
File:HE-GHoma.jpg | Pituitary adenoma , HE. This gonadotropin producing adenoma has a papillary architecture (WC/jensflorian)
File:FSH-GHoma.jpg | Pituitary adenoma, IHC for FSH (WC/jensflorian)
File:LH-GHoma.jpg | Pituitary adenoma, IHC for LH (WC/jensflorian)
File:ACTHoma-PAS-O-G.jpg | Pituitary adenoma , ACTH producing. PAS-O-G stain showing basophilic adenoma cells (WC/jensflorian)
File:ACTHoma-IHC.jpg | Pituitary adenoma , ACTH producing. Strong ACTH IHC in this basophilic adenoma (WC/jensflorian)
File:Pituitary_adenoma-nonfunctioning.jpg |Pituitary adenoma with vascular pseudorosettes, nonfunctioning (WC/jensflorian)
Crooke_HE_40x.jpg | Crooke cell adenoma, HE (WC/Marvin101)
File:Crooke Cytokeratins.jpg | Crooke cell adenoma, panCK (WC/Marvin101)
HE_fibrosis_pituitary_adenoma.jpg | Fibrosis in pituitary adenoma.
</gallery>
===Stains===
*Reticulin - loss of reticulin between tumour cells.
===IHC===
*LH.
*FSH.
*TSH - [[Hyperthyroidism]]
*GH - [[Acromegaly]].
*Prolactin -Galactorrhea, Amenorrhea, Gynecomastia. Golgi staining pattern in sparsely granulated cases.
*ACTH - [[Cushing syndrome]].
*PIT-1: stains somatotrophs, lactotrophs and thyrothrops.
*TPIT: stains corticotrophs.
*SF1: stains gonadotrophs.
*Chromogranin A +ve
*Synaptophysin strongly +ve (except lactotrophs)
*CAM5.2: fibrous bodies in sparsely granulated somatotroph adenoma, Ring-like staining in Crooke cell adenoma.
*MIB-1: Usu less than 3%.
Note:
Null-cell adenoma must be hormone immunonegative and negative for transcription factors.
===Variants===
*Corticotroph adenomas exhibiting Crooke's hyaline change: agressive course.<ref>{{Cite journal  | last1 = George | first1 = DH. | last2 = Scheithauer | first2 = BW. | last3 = Kovacs | first3 = K. | last4 = Horvath | first4 = E. | last5 = Young | first5 = WF. | last6 = Lloyd | first6 = RV. | last7 = Meyer | first7 = FB. | title = Crooke's cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma. | journal = Am J Surg Pathol | volume = 27 | issue = 10 | pages = 1330-6 | month = Oct | year = 2003 | doi =  | PMID = 14508394 }}</ref>
*Acidophilic stem cell adenomas: large, locally invasive adenoma with low GH activity. <ref>{{Cite journal  | last1 = Horvath | first1 = E. | last2 = Kovacs | first2 = K. | last3 = Singer | first3 = W. | last4 = Smyth | first4 = HS. | last5 = Killinger | first5 = DW. | last6 = Erzin | first6 = C. | last7 = Weiss | first7 = MH. | title = Acidophil stem cell adenoma of the human pituitary: clinicopathologic analysis of 15 cases. | journal = Cancer | volume = 47 | issue = 4 | pages = 761-71 | month = Feb | year = 1981 | doi =  | PMID = 6261917 }}</ref>
*Sparsely granulated somatotroph adenomas are more invasive than other variants and respond less to medical treatment. <ref>{{Cite journal  | last1 = Kato | first1 = M. | last2 = Inoshita | first2 = N. | last3 = Sugiyama | first3 = T. | last4 = Tani | first4 = Y. | last5 = Shichiri | first5 = M. | last6 = Sano | first6 = T. | last7 = Yamada | first7 = S. | last8 = Hirata | first8 = Y. | title = Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas. | journal = Endocr J | volume = 59 | issue = 3 | pages = 221-8 | month =  | year = 2012 | doi =  | PMID = 22200580 }}</ref>
* Lactotroph adenomas in men may show aggressive clinical behavior. <ref>{{Cite journal  | last1 = Delgrange | first1 = E. | last2 = Vasiljevic | first2 = A. | last3 = Wierinckx | first3 = A. | last4 = François | first4 = P. | last5 = Jouanneau | first5 = E. | last6 = Raverot | first6 = G. | last7 = Trouillas | first7 = J. | title = Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth. | journal = Eur J Endocrinol | volume = 172 | issue = 6 | pages = 791-801 | month = Jun | year = 2015 | doi = 10.1530/EJE-14-0990 | PMID = 25792376 }}</ref>
*Immature PIT-1 lineage tumors may show aggresive growth. <ref> {{Cite journal  | last1 = Mete | first1 = O. | last2 = Gomez-Hernandez | first2 = K. | last3 = Kucharczyk | first3 = W. | last4 = Ridout | first4 = R. | last5 = Zadeh | first5 = G. | last6 = Gentili | first6 = F. | last7 = Ezzat | first7 = S. | last8 = Asa | first8 = SL. | title = Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas. | journal = Mod Pathol | volume = 29 | issue = 2 | pages = 131-42 | month = Feb | year = 2016 | doi = 10.1038/modpathol.2015.151 | PMID = 26743473 }}</ref>
===Molecular===
*GNAS mutations frequently in densely granulated somatotroph tumors.
==Pituitary blastoma==
* New entity introduced in 2017<ref>{{Cite journal  | last1 = Lopes | first1 = MBS. | title = The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. | journal = Acta Neuropathol | volume = 134 | issue = 4 | pages = 521-535 | month = Oct | year = 2017 | doi = 10.1007/s00401-017-1769-8 | PMID = 28821944 }}</ref>
* Epithelial glands with rosette-like formations resembling immature Rathke epithelium.
* Synaptophysin +ve, usu. ACTH+ve
* DICER1 mutations<ref>{{Cite journal  | last1 = de Kock | first1 = L. | last2 = Sabbaghian | first2 = N. | last3 = Plourde | first3 = F. | last4 = Srivastava | first4 = A. | last5 = Weber | first5 = E. | last6 = Bouron-Dal Soglio | first6 = D. | last7 = Hamel | first7 = N. | last8 = Choi | first8 = JH. | last9 = Park | first9 = SH. | title = Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations. | journal = Acta Neuropathol | volume = 128 | issue = 1 | pages = 111-22 | month = Jul | year = 2014 | doi = 10.1007/s00401-014-1285-z | PMID = 24839956 }}</ref>
==Pituitary carcinoma==
* Depreceated in the WHO2022 classification.
* It is acknowledged that PitNETs can be invasive or spread to other sites.


==Rathke cleft cyst==
==Rathke cleft cyst==
:See ''[[Head and neck pathology]]''.
===General===
*Arises from ''intermediate lobe''.
*Benign counterpart of [[craniopharyngioma]].
*Arises from intermediate lobe of pituitary gland (''pars intermedia of pituitary gland'').
 
Radiology:
*Typically no calcifications.<ref name=emed_rcc>URL: [http://emedicine.medscape.com/article/343629-overview http://emedicine.medscape.com/article/343629-overview]. Accessed on: 14 November 2010.</ref>
 
Radiologic DDx:<ref name=emed_rcc>URL: [http://emedicine.medscape.com/article/343629-overview http://emedicine.medscape.com/article/343629-overview]. Accessed on: 14 November 2010.</ref>
*Arachnoid cyst.
*[[Craniopharyngioma]].
*[[Cysticercosis]].
*[[Pituitary adenoma]].
*Epidermoid of brain.
 
===Microscopic===
Features:
*Lined by a layer of cuboidal ''or'' columnar epithelial with cilia.
*+/-Goblet cells.<ref>URL: [http://www.endotext.org/neuroendo/neuroendo3/neuroendo3.html http://www.endotext.org/neuroendo/neuroendo3/neuroendo3.html]. Accessed on: 27 May 2010.</ref>
*+/-Squamous metaplasia ~ may be several layers thick.
**May be confused with ''[[papillary craniopharyngioma]]''.<ref name=Ref_PSNP408>{{Ref PSNP|408}}</ref>
*Cholesterol clefts may be seen in association with rupture.<ref>URL: [http://path.upmc.edu/cases/case177/dx.html http://path.upmc.edu/cases/case177/dx.html]. Accessed on: 8 January 2012.</ref>
 
DDx:
*[[Papillary craniopharyngioma]].
 
Images:
*[http://www.endotext.org/neuroendo/neuroendo3/figures/figure11.jpg Rathke cleft cyst (endotext.org)].
*[http://path.upmc.edu/cases/case177/micro.html Rathke cleft cyst (upmc.edu)].


==Craniopharyngioma==
==Craniopharyngioma==
:See ''[[Head and neck pathology]]''.
{{Main|Craniopharyngioma}}
 
==Gangliocytoma==
* Neuronal cells in abundant neuropil.
* S-100, Synaptophysin +ve.
* Isolated sellar cases are very rare.
 
Image: [[https://twitter.com/sty_md/status/664676241111252992]]
 
==Mixed Gangliocytoma-adenoma==
AKA: ganglioneuroma, pituitary adenoma with neuronal choristoma (PANCH)
*Neuronal cells mixed with pituitary adenoma cells.
* Approx. 0.25% of all pituitary adenomas.
* Association with somatotroph adenomas (acromegaly).
 
==Pituicytoma==
{{Main|Pituicytoma}}
 
==Spindle cell oncocytoma==
*Origin: Neurohypophysis or infundibulum.
*Benign clinical course - WHO grade I.
*Elongated bipolar, spindle cells.
*Fascicular or storiform growth patterns.
*EMA: patchy, S-100+/-ve, GFAP+/-ve, TTF1+ve.
 
*It is thought that Spindle cell oncocytomas and Granular cell tumors of the neurohypophysis are variants of Pituicyoma.<ref>{{Cite journal  | last1 = Mete | first1 = O. | last2 = Lopes | first2 = MB. | last3 = Asa | first3 = SL. | title = Spindle cell oncocytomas and granular cell tumors of the pituitary are variants of pituicytoma. | journal = Am J Surg Pathol | volume = 37 | issue = 11 | pages = 1694-9 | month = Nov | year = 2013 | doi = 10.1097/PAS.0b013e31829723e7 | PMID = 23887161 }}</ref>
 
==Granular cell tumor of the sellar region==
{{Main|Granular_cell_tumour}}
 
*Origin: Neurohypophysis or infundibulum.
*Benign clinical course - WHO grade I.
*Well circumscribed.
*Polygonal cells with abundant granular cytoplasm.
*CD68+ve, S-100+/-ve, GFAP+/-ve, TTF1+ve.
 
<gallery>
File:Granular_cell_tumor_pituitary.jpg | Granular cell tumor of the sellar region (HE).
</gallery>
 
==Autoimmune hypophysitis==
===General===
Features:<ref name=pmid18388197/>
*Rare.
*Autoantigens are unknown.
*May occur in pregnancy.
*May be misdiagnosed as a nonsecreting adenoma.
 
===Microscopic===
Features:<ref name=pmid18388197>{{cite journal |author=Tzou SC, Lupi I, Landek M, ''et al.'' |title=Autoimmune hypophysitis of SJL mice: clinical insights from a new animal model |journal=Endocrinology |volume=149 |issue=7 |pages=3461–9 |year=2008 |month=July |pmid=18388197 |pmc=2453094 |doi=10.1210/en.2007-1692 |url=}}</ref>
*Lymphocytic infiltration.


==Necrosis==
<gallery>
*Sheehan syndrome - blood loss in childbirth.<ref>URL: [http://www.mayoclinic.com/health/sheehans-syndrome/DS00889 http://www.mayoclinic.com/health/sheehans-syndrome/DS00889]. Accessed on: 16 November 2010.</ref>
File:Lymphocytic_hypophysitis_CD3.jpg | Lymphocytic hypophysitis, CD3 IHC. (WC/jensflorian)
*Syphilis (paediatric).<ref>URL: [http://pediatrics.aappublications.org/cgi/content/full/104/1/e4 http://pediatrics.aappublications.org/cgi/content/full/104/1/e4]. Accessed on: 16 November 2010.</ref>
</gallery>
*Mollaret's meningitis.<ref name=pmid18715308>{{cite journal |author=Dancer CM, Woods ML, Henderson RD, Robertson T, Mungomery M, Allworth A |title=Mollaret's meningitis and pituitary failure associated with a Rathke's cleft cyst |journal=Intern Med J |volume=38 |issue=7 |pages=609–11 |year=2008 |month=July |pmid=18715308 |doi=10.1111/j.1445-5994.2008.01709.x |url=}}</ref> (???)
*Spontaneous necrosis of pituitary tumours - rare.<ref>{{cite journal |author=Sachdev Y, Evered DC, Hall R |title=Spontaneous pituitary necrosis |journal=Br Med J |volume=1 |issue=6015 |pages=942 |year=1976 |month=April |pmid=1268492 |pmc=1639254 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1639254/pdf/brmedj00512-0028a.pdf}}</ref>


==See also==
=See also=
*[[CNS cytopathology]].
*[[Neuropathology]].
*[[Neuropathology]].
*[[Brain tumours]].
*[[Brain tumours]].


==References==
=References=
{{reflist|2}}
{{reflist|2}}


==External links==
=External links=
*[http://www.neuropathologyweb.org/ Neuropathology] - neuropathologyweb.org.
*[http://www.neuropathologyweb.org/ Neuropathology] - neuropathologyweb.org.
*[http://www.lab.anhb.uwa.edu.au/mb140/corepages/endocrines/endocrin.htm Endocrine histology (anhb.uwa.edu.au)].


[[Category:Neuropathology]]
[[Category:Neuropathology]]

Latest revision as of 11:30, 30 September 2022

The pituitary gland is known as the master gland.

Divisions:[1]

  • Anterior pituitary (AKA adenohypophysis, pars distalis).
  • Posterior pituitary (AKA neurohypophysis, neural pituitary, pars nervosa).

Function

Anterior

Hormones:[2]

  • Growth hormone (GH).
  • Luteinizing hormone (LH)
  • Follicle-stimulating hormone (FSH)
  • Thyroid stimulating hormone (TSH)
  • Adrenocorticotropic hormone (ACTH)
  • Prolactin (PRL)

Mnemonic: "Go Look For The Adenoma Please" = GH, LH, FSH, TSH, ACTH, PRL.

Intermedia

  • Originates from the posterior wall of the Rathke’s pouch.
  • Hormones: MSH, ACTH precursor.
  • Contains colloid cysts.

Posterior

Hormones:[2]

  • Oxytocin.
  • Antidiuretic hormone (ADH).

Anatomy and histology

Anatomy

Basic anatomy (simplified):[3]

  • Anterior:
    • Pars distalis.
    • Pars intermedia.
  • Posterior:
    • Pars nervosa.

Embryological origin:[3]

  • Anterior - Rathke's pouch (roof of mouth).
  • Posterior - diencephalon (ventral aspect).

Images:

Histology

Anterior

  • Acidophils (40% of cells) = red or orange.
    • GH, PRL.
  • Basophils (10% of cells) = basophilic (light blue).
    • TSH, LH, FSH, ACTH.
  • Chromophobes (50% of cells) = amphophilic (purplish/grey).

Notes:

  • The cellular product (i.e. hormone produced) is not strictly correlated with the cell type.[4]
  • The cells can be typed using IHC; somatotrophs (GH), lactotrophs (PRL), corticotrophs (ACTH), thyrotrophs (TSH), gonadotrophs (FSH, LH).[5]

Posterior

Features:[4]

  • Herring bodies - key feature.
    • Eosinophilic axonal dilations filled with lysosomes and neurosecretory granules.
  • Less cellular.
    • Usually more cellular in perivascular location.

Image: Herring bodies (ouhsc.edu).

  • Pituitary gland, low magnification (WC/Athikhun.suw)

DDx for sella turcica lesions

Pituitary necrosis

  • Rare.

Causes of pituitary necrosis

  • Sheehan syndrome - secondary to blood loss in childbirth.[6]
  • Syphilis (fetal-maternal transmission).[7]
  • Mollaret's meningitis - very rare.[8] (???)
  • Spontaneous necrosis of pituitary tumours - case reports.[9]

Images:

Specific entities

Pituitary neuroendocrine tumor (PitNET)

Old terminology Pituitary adenoma is depreceated. The WHO 2022 Classification of tumours of endocrine organs recoginizes following tumours:[10]


PitNET lineage PitNET type subtypes Hormone IHC Transcription factor IHC
PIT1 Somatotroph tumor Densely and sparsely granulated tumor GH, a-subunit+/-, CK+ PIT1
PIT1 Lactotroph tumor Densely and sparsely granulated tumor PRL, CK-ve or weak PIT1, ER
PIT1 Mammosomatotroph tumor GH, PRL (usu. less), CK perinuclear +ve PIT1, ER
PIT1 Thyrotroph tumor TSH, CK-ve or weak PIT1, GATA3
PIT1 Mature plurihormonal PIT1 lineage tumor GH, PRL, TSH, a-subunit +/-ve, CK perinuclear PIT1, ER, GATA3
PIT1 Immature PIT1 lineage tumor Only focal GH, PRL, TSH, a-subunit +/-ve, CK variable PIT1, ER +/-ve, GATA3 +/-ve
PIT1 Acidophilic stem cell tumor PRL, GH (focal/variable), CK fibrous bodies PIT1, ER
PIT1 Mixed somatotroph and lactotroph tumor PRL, GH (in separate cells) PIT1, ER (only in lactotroph component)
TPIT Corticotroph tumor Densely and sparsely granulated tumors, Crooke cell adenoma ACTH,CK+ve TPIT
SF1 Gonadotroph tumor FSH, LH, a-Subunit or none SF1, ER, GATA3, CK+/-ve
None Plurihormonal tumor All combinations possible All combinations possible, CK+/-ve
None Null cell adenoma None (adenohypophyseal?) None

Other tumours may be classified as plurhormonal or double adenomas or as adenomas with unusual IHC combination.

General

  • Clinical:[11]
    • Classically: visual field defects (bitemporal hemianopsia).
    • Others (increased intracranial pressure): headache, nausea, vomiting.
    • Tumor of adults.

Morphologic Classification:

  1. Microtumor <= 1 cm.
  2. Macrotumor 1-4 cm.
  3. Giant tumor > 4cm.

May be classified by what they secrete.

  1. Functional (endocrine hyperfunction).
    • Acromegaly/giantism.
    • Hyperprolactinemia.
    • Cushing disease.
    • Hyperthyroidism.
    • Significant elevation of FSH/LH.
  2. Clinically nonfunctioning.

Notes: 

Cushing disease is due to pituitary gland hypersecretion of ACTH (due to a pituitary adenoma or CRH hypersecretion from the hypothalamus).[12]  Cushing syndrome is hypercortisolism not due to pituitary gland pathology.

Imaging:

  • Sellar enlargement.
  • Bone erosion, invasive growth esp. cavernous sinus (35-45%).
  • Inhomogenous signal in T1w MRI.

Familial pituitary adenomas

A pituitary adenoma may be part of a familial syndrome:[13][14]

Syndrome Gene Notes
Multiple endocrine neoplasia I MEN1 characterized by the 3 Ps: pituitary adenoma, parathyroid adenoma, pancreatic neuroendocrine tumour
MEN-1-like syndrome CDKN1B[15] also known as Multiple endocrine neoplasia IV [15]
Carney syndrome PRKAR1A other findings (mnemonic NAME): nevi, atrial myxoma, myxoid neurofibroma, ephelides (freckles)
Isolated pituitary adenoma[16] AIP classically GH-producing adenoma - leads to acromegaly

Microscopic

Features:[17]

  • Loss of fibrous stroma.
    • The cells of a normal (anterior) pituitary are nested.
  • Basophilic cells (corticotrophs).
  • Eosinophilic cells(somatotrophs).
  • Extensive fibrosis often seen in TSH-producing tumors.

Notes:

  • Smears very well.[18]

Images

  • Pituitary adenoma - non-functioning. (WC/KGH)

  • Extensive interstitial and perivascular fibrosis in a pituitary adenoma (WC/jensflorian)

  • Pituitary adenoma - PRL producing, HE. Note the basophilic appearance of the cells (WC/jensflorian)

  • Pituitary adenoma - PRL producing, HE. Extensive regressive changes after after dopamine agonist treatment (WC/jensflorian)

  • Pituitary adenoma - PRL producing, Prolactin IHC (WC/jensflorian)

  • Pituitary adenoma - HGH producing, HE. The cells have a slightly eosinophilic appearance (WC/jensflorian)

  • Sparsely granulated adenoma - HGH producing. Note the numerous fibrous bodies in HE stain (WC/jensflorian)

  • Sparsely granulated adenoma - HGH producing. CK8 IHC highlighting fibrous bodies (WC/jensflorian)

  • Pituitary adenoma - TSH producing. HE stain showing pleomorphism (WC/jensflorian)

  • Pituitary adenoma - TSH producing. TSH IHC can be heterogeneous (WC/jensflorian)

  • Pituitary adenoma - GH producing. (WC/KGH)

  • Pituitary adenoma , HE. This gonadotropin producing adenoma has a papillary architecture (WC/jensflorian)

  • Pituitary adenoma, IHC for FSH (WC/jensflorian)

  • Pituitary adenoma, IHC for LH (WC/jensflorian)

  • Pituitary adenoma , ACTH producing. PAS-O-G stain showing basophilic adenoma cells (WC/jensflorian)

  • Pituitary adenoma , ACTH producing. Strong ACTH IHC in this basophilic adenoma (WC/jensflorian)

  • Pituitary adenoma with vascular pseudorosettes, nonfunctioning (WC/jensflorian)

  • Crooke cell adenoma, HE (WC/Marvin101)

  • Crooke cell adenoma, panCK (WC/Marvin101)

  • Fibrosis in pituitary adenoma.

Stains

  • Reticulin - loss of reticulin between tumour cells.

IHC

  • LH.
  • FSH.
  • TSH - Hyperthyroidism
  • GH - Acromegaly.
  • Prolactin -Galactorrhea, Amenorrhea, Gynecomastia. Golgi staining pattern in sparsely granulated cases.
  • ACTH - Cushing syndrome.
  • PIT-1: stains somatotrophs, lactotrophs and thyrothrops.
  • TPIT: stains corticotrophs.
  • SF1: stains gonadotrophs.
  • Chromogranin A +ve
  • Synaptophysin strongly +ve (except lactotrophs)
  • CAM5.2: fibrous bodies in sparsely granulated somatotroph adenoma, Ring-like staining in Crooke cell adenoma.
  • MIB-1: Usu less than 3%.

Note: Null-cell adenoma must be hormone immunonegative and negative for transcription factors.

Variants

  • Corticotroph adenomas exhibiting Crooke's hyaline change: agressive course.[19]
  • Acidophilic stem cell adenomas: large, locally invasive adenoma with low GH activity. [20]
  • Sparsely granulated somatotroph adenomas are more invasive than other variants and respond less to medical treatment. [21]
  • Lactotroph adenomas in men may show aggressive clinical behavior. [22]
  • Immature PIT-1 lineage tumors may show aggresive growth. [23]

Molecular

  • GNAS mutations frequently in densely granulated somatotroph tumors.

Pituitary blastoma

  • New entity introduced in 2017[24]
  • Epithelial glands with rosette-like formations resembling immature Rathke epithelium.
  • Synaptophysin +ve, usu. ACTH+ve
  • DICER1 mutations[25]

Pituitary carcinoma

  • Depreceated in the WHO2022 classification.
  • It is acknowledged that PitNETs can be invasive or spread to other sites.

Rathke cleft cyst

General

  • Benign counterpart of craniopharyngioma.
  • Arises from intermediate lobe of pituitary gland (pars intermedia of pituitary gland).

Radiology:

  • Typically no calcifications.[26]

Radiologic DDx:[26]

Microscopic

Features:

  • Lined by a layer of cuboidal or columnar epithelial with cilia.
  • +/-Goblet cells.[27]
  • +/-Squamous metaplasia ~ may be several layers thick.
  • Cholesterol clefts may be seen in association with rupture.[29]

DDx:

Images:

Craniopharyngioma

Main article: Craniopharyngioma

Gangliocytoma

  • Neuronal cells in abundant neuropil.
  • S-100, Synaptophysin +ve.
  • Isolated sellar cases are very rare.

Image: [[1]]

Mixed Gangliocytoma-adenoma

AKA: ganglioneuroma, pituitary adenoma with neuronal choristoma (PANCH)

  • Neuronal cells mixed with pituitary adenoma cells.
  • Approx. 0.25% of all pituitary adenomas.
  • Association with somatotroph adenomas (acromegaly).

Pituicytoma

Main article: Pituicytoma

Spindle cell oncocytoma

  • Origin: Neurohypophysis or infundibulum.
  • Benign clinical course - WHO grade I.
  • Elongated bipolar, spindle cells.
  • Fascicular or storiform growth patterns.
  • EMA: patchy, S-100+/-ve, GFAP+/-ve, TTF1+ve.
  • It is thought that Spindle cell oncocytomas and Granular cell tumors of the neurohypophysis are variants of Pituicyoma.[30]

Granular cell tumor of the sellar region

Main article: Granular_cell_tumour
  • Origin: Neurohypophysis or infundibulum.
  • Benign clinical course - WHO grade I.
  • Well circumscribed.
  • Polygonal cells with abundant granular cytoplasm.
  • CD68+ve, S-100+/-ve, GFAP+/-ve, TTF1+ve.

  • Granular cell tumor of the sellar region (HE).

Autoimmune hypophysitis

General

Features:[31]

  • Rare.
  • Autoantigens are unknown.
  • May occur in pregnancy.
  • May be misdiagnosed as a nonsecreting adenoma.

Microscopic

Features:[31]

  • Lymphocytic infiltration.

  • Lymphocytic hypophysitis, CD3 IHC. (WC/jensflorian)

See also

References

  1. ↑ http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo.html
  2. ↑ 2.0 2.1 http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pituitary.html
  3. ↑ 3.0 3.1 URL: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo_pit.html. Accessed on: 31 October 2010.
  4. ↑ 4.0 4.1 Perry, Arie; Brat, Daniel J. (2010). Practical Surgical Neuropathology: A Diagnostic Approach: A Volume in the Pattern Recognition series (1st ed.). Churchill Livingstone. pp. 26. ISBN 978-0443069826.
  5. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1098-9. ISBN 978-1416031215.
  6. ↑ URL: http://www.mayoclinic.com/health/sheehans-syndrome/DS00889. Accessed on: 16 November 2010.
  7. ↑ URL: http://pediatrics.aappublications.org/cgi/content/full/104/1/e4. Accessed on: 16 November 2010.
  8. ↑ Dancer CM, Woods ML, Henderson RD, Robertson T, Mungomery M, Allworth A (July 2008). "Mollaret's meningitis and pituitary failure associated with a Rathke's cleft cyst". Intern Med J 38 (7): 609–11. doi:10.1111/j.1445-5994.2008.01709.x. PMID 18715308.
  9. ↑ Sachdev Y, Evered DC, Hall R (April 1976). "Spontaneous pituitary necrosis". Br Med J 1 (6015): 942. PMC 1639254. PMID 1268492. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1639254/pdf/brmedj00512-0028a.pdf.
  10. ↑ "Overview of the 2022 WHO Classification of Pituitary Tumors". Endocr Pathol 33 (1): 6–26. March 2022. doi:10.1007/s12022-022-09703-7. PMID 35291028.
  11. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1100. ISBN 978-1416031215.
  12. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1148. ISBN 978-1416031215.
  13. ↑ Elston, MS.; McDonald, KL.; Clifton-Bligh, RJ.; Robinson, BG. (Aug 2009). "Familial pituitary tumor syndromes.". Nat Rev Endocrinol 5 (8): 453-61. doi:10.1038/nrendo.2009.126. PMID 19564887.
  14. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 554. ISBN 978-1416054542.
  15. ↑ 15.0 15.1 Online 'Mendelian Inheritance in Man' (OMIM) 600778
  16. ↑ Korbonits, M.; Storr, H.; Kumar, AV. (May 2012). "Familial pituitary adenomas - Who should be tested for AIP mutations?". Clin Endocrinol (Oxf). doi:10.1111/j.1365-2265.2012.04445.x. PMID 22612670.
  17. ↑ Perry, Arie; Brat, Daniel J. (2010). Practical Surgical Neuropathology: A Diagnostic Approach: A Volume in the Pattern Recognition series (1st ed.). Churchill Livingstone. pp. 36. ISBN 978-0443069826.
  18. ↑ MUN. 24 November 2010.
  19. ↑ George, DH.; Scheithauer, BW.; Kovacs, K.; Horvath, E.; Young, WF.; Lloyd, RV.; Meyer, FB. (Oct 2003). "Crooke's cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma.". Am J Surg Pathol 27 (10): 1330-6. PMID 14508394.
  20. ↑ Horvath, E.; Kovacs, K.; Singer, W.; Smyth, HS.; Killinger, DW.; Erzin, C.; Weiss, MH. (Feb 1981). "Acidophil stem cell adenoma of the human pituitary: clinicopathologic analysis of 15 cases.". Cancer 47 (4): 761-71. PMID 6261917.
  21. ↑ Kato, M.; Inoshita, N.; Sugiyama, T.; Tani, Y.; Shichiri, M.; Sano, T.; Yamada, S.; Hirata, Y. (2012). "Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas.". Endocr J 59 (3): 221-8. PMID 22200580.
  22. ↑ Delgrange, E.; Vasiljevic, A.; Wierinckx, A.; François, P.; Jouanneau, E.; Raverot, G.; Trouillas, J. (Jun 2015). "Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth.". Eur J Endocrinol 172 (6): 791-801. doi:10.1530/EJE-14-0990. PMID 25792376.
  23. ↑ Mete, O.; Gomez-Hernandez, K.; Kucharczyk, W.; Ridout, R.; Zadeh, G.; Gentili, F.; Ezzat, S.; Asa, SL. (Feb 2016). "Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas.". Mod Pathol 29 (2): 131-42. doi:10.1038/modpathol.2015.151. PMID 26743473.
  24. ↑ Lopes, MBS. (Oct 2017). "The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.". Acta Neuropathol 134 (4): 521-535. doi:10.1007/s00401-017-1769-8. PMID 28821944.
  25. ↑ de Kock, L.; Sabbaghian, N.; Plourde, F.; Srivastava, A.; Weber, E.; Bouron-Dal Soglio, D.; Hamel, N.; Choi, JH. et al. (Jul 2014). "Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.". Acta Neuropathol 128 (1): 111-22. doi:10.1007/s00401-014-1285-z. PMID 24839956.
  26. ↑ 26.0 26.1 URL: http://emedicine.medscape.com/article/343629-overview. Accessed on: 14 November 2010.
  27. ↑ URL: http://www.endotext.org/neuroendo/neuroendo3/neuroendo3.html. Accessed on: 27 May 2010.
  28. ↑ Perry, Arie; Brat, Daniel J. (2010). Practical Surgical Neuropathology: A Diagnostic Approach: A Volume in the Pattern Recognition series (1st ed.). Churchill Livingstone. pp. 408. ISBN 978-0443069826.
  29. ↑ URL: http://path.upmc.edu/cases/case177/dx.html. Accessed on: 8 January 2012.
  30. ↑ Mete, O.; Lopes, MB.; Asa, SL. (Nov 2013). "Spindle cell oncocytomas and granular cell tumors of the pituitary are variants of pituicytoma.". Am J Surg Pathol 37 (11): 1694-9. doi:10.1097/PAS.0b013e31829723e7. PMID 23887161.
  31. ↑ 31.0 31.1 Tzou SC, Lupi I, Landek M, et al. (July 2008). "Autoimmune hypophysitis of SJL mice: clinical insights from a new animal model". Endocrinology 149 (7): 3461–9. doi:10.1210/en.2007-1692. PMC 2453094. PMID 18388197. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453094/.

External links

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