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'''Endometrial carcinoma''' is a common gynecologic malingnancy<ref name=pmid19072487>{{cite journal |author=Fowler W, Mutch D |title=Management of endometrial cancer |journal=Womens Health (Lond Engl) |volume=4 |issue=5 |pages=479–89 |year=2008 |month=September |pmid=19072487 |doi=10.2217/17455057.4.5.479 |url=}}</ref> that often arises from [[endometrial hyperplasia]].  The incidence of endometrial carcinoma is increasing, as the proportion of obese individuals is increasing.
[[Image:Endometrial_adenocarcinoma_gross.jpg|thumb|300px|right|Gross image of endometrial adenocarcinoma.]]
'''Endometrial carcinoma''', also '''endometrial adenocarcinoma''', is a common gynecologic malingnancy<ref name=pmid19072487>{{cite journal |author=Fowler W, Mutch D |title=Management of endometrial cancer |journal=Womens Health (Lond Engl) |volume=4 |issue=5 |pages=479–89 |year=2008 |month=September |pmid=19072487 |doi=10.2217/17455057.4.5.479 |url=}}</ref> that often arises from [[endometrial hyperplasia]].  The incidence of endometrial carcinoma is increasing, as the proportion of [[obese]] individuals is increasing.


==Clinical==
An introduction to the endometrium is in the article ''[[endometrium]]''.
 
=Clinical=
===Risk factors===
===Risk factors===
Risk factors for endometrial carcinoma - mnemonic ''COLD NUT'':<ref>TN07 GY40</ref>
Risk factors for endometrial carcinoma - mnemonic ''COLD NUT'':<ref name=Ref_TN2007_GY40>{{Ref TN2007|GY40}}</ref>
*Cancer Hx (ovarian, breast, colon).
*Cancer Hx (ovarian, breast, colon).
*Obesity.
*[[Obesity]].
*Late menopause.
*Late menopause.
*Diabetes.
*Diabetes.
*Nulliparity.
*Nulliparity.
*Unopposed estrogen (polycystic ovarian syndrome (PCOS), anovulation, hormone replacement therapy (HRT)).
*Unopposed estrogen ([[polycystic ovarian syndrome]] (PCOS), anovulation, hormone replacement therapy (HRT)).
*Tamoxifen use.
*[[Tamoxifen]] use.
**Used for breast cancer; the risk is quite small<ref name=pmid19505894>{{Cite journal  | last1 = Brown | first1 = K. | title = Is tamoxifen a genotoxic carcinogen in women? | journal = Mutagenesis | volume = 24 | issue = 5 | pages = 391-404 | month = Sep | year = 2009 | doi = 10.1093/mutage/gep022 | PMID = 19505894 }}</ref> or possibly negligent.<ref name=pmid19827879>{{Cite journal  | last1 = Ashraf | first1 = M. | last2 = Biswas | first2 = J. | last3 = Majumdar | first3 = S. | last4 = Nayak | first4 = S. | last5 = Alam | first5 = N. | last6 = Mukherjee | first6 = KK. | last7 = Gupta | first7 = S. | title = Tamoxifen use in Indian women--adverse effects revisited. | journal = Asian Pac J Cancer Prev | volume = 10 | issue = 4 | pages = 609-12 | month =  | year =  | doi =  | PMID = 19827879 }}</ref>   
**Used for breast cancer; the risk is quite small<ref name=pmid19505894>{{Cite journal  | last1 = Brown | first1 = K. | title = Is tamoxifen a genotoxic carcinogen in women? | journal = Mutagenesis | volume = 24 | issue = 5 | pages = 391-404 | month = Sep | year = 2009 | doi = 10.1093/mutage/gep022 | PMID = 19505894 }}</ref> or possibly negligent.<ref name=pmid19827879>{{Cite journal  | last1 = Ashraf | first1 = M. | last2 = Biswas | first2 = J. | last3 = Majumdar | first3 = S. | last4 = Nayak | first4 = S. | last5 = Alam | first5 = N. | last6 = Mukherjee | first6 = KK. | last7 = Gupta | first7 = S. | title = Tamoxifen use in Indian women--adverse effects revisited. | journal = Asian Pac J Cancer Prev | volume = 10 | issue = 4 | pages = 609-12 | month =  | year =  | doi =  | PMID = 19827879 }}</ref>   


====Family history====
====Family history====
Several syndromes are seen in association with endometrial cancer:<ref>{{cite journal |author=Okuda T, Sekizawa A, Purwosunu Y, ''et al.'' |title=Genetics of endometrial cancers |journal=Obstet Gynecol Int |volume=2010 |issue= |pages=984013 |year=2010 |pmid=20396392 |pmc=2852605 |doi=10.1155/2010/984013 |url=}}</ref>
Several syndromes are seen in association with endometrial cancer:<ref name=pmid20396392>{{cite journal |author=Okuda T, Sekizawa A, Purwosunu Y, ''et al.'' |title=Genetics of endometrial cancers |journal=Obstet Gynecol Int |volume=2010 |issue= |pages=984013 |year=2010 |pmid=20396392 |pmc=2852605 |doi=10.1155/2010/984013 |url=}}</ref>
*[[Cowden syndrome]] (PTEN mutation) - most common.
*[[Cowden syndrome]] (PTEN mutation) - most common.
**Associated with ''endometrioid endometrial carcinoma''.
**Associated with ''endometrioid endometrial carcinoma''.
*[[Lynch syndrome]] (MSH2/MSH6 protein complex - mutations).
*[[Lynch syndrome]] (mutation of a mismatch repair gene - there are several<ref>{{OMIM|120435}}</ref>).
**Associated with ''non-endometrioid endometrial carcinoma''.
**Associated with ''non-endometrioid endometrial carcinoma''.<ref name=pmid20396392>{{cite journal |author=Okuda T, Sekizawa A, Purwosunu Y, ''et al.'' |title=Genetics of endometrial cancers |journal=Obstet Gynecol Int |volume=2010 |issue= |pages=984013 |year=2010 |pmid=20396392 |pmc=2852605 |doi=10.1155/2010/984013 |url=}}</ref>
**Autosomal dominant.
**Autosomal dominant.


===Management===
===Management===
"Hysterectomy" is the standard treatment for endometrial carcinoma.
*Hysterectomy is the standard treatment for endometrial carcinoma.
**In low-grade carcinomas (i.e. low grade endometrioid type), if the woman isn't done with their childbearing, the treatment may be hormones and surveillance biopsies.<ref name=pmid19758691>{{cite journal |author=Zivanovic O, Carter J, Kauff ND, Barakat RR |title=A review of the challenges faced in the conservative treatment of young women with endometrial carcinoma and risk of ovarian cancer |journal=Gynecol. Oncol. |volume=115 |issue=3 |pages=504–9 |year=2009 |month=December |pmid=19758691 |doi=10.1016/j.ygyno.2009.08.011 |url=}}</ref>
**In low-grade carcinomas (i.e. low grade endometrioid type), if the woman isn't done with their childbearing, the treatment may be hormones and surveillance biopsies.<ref name=pmid19758691>{{cite journal |author=Zivanovic O, Carter J, Kauff ND, Barakat RR |title=A review of the challenges faced in the conservative treatment of young women with endometrial carcinoma and risk of ovarian cancer |journal=Gynecol. Oncol. |volume=115 |issue=3 |pages=504–9 |year=2009 |month=December |pmid=19758691 |doi=10.1016/j.ygyno.2009.08.011 |url=}}</ref>
**Endometrial carcinomas with involvement of the endocervical canal are treated with a ''radical hysterectomy''.<ref name=pmid20871657>{{Cite journal  | last1 = Ware | first1 = RA. | last2 = van Nagell | first2 = JR. | title = Radical hysterectomy with pelvic lymphadenectomy: indications, technique, and complications. | journal = Obstet Gynecol Int | volume = 2010 | issue =  | pages =  | month =  | year = 2010 | doi = 10.1155/2010/587610 | PMID = 20871657 }}</ref>


Details:  
Details:  
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*Non-endometrioid ''or'' high stage endometrioid ''or'' high-grade endometrioid: ''radical hysterectomy'' (includes cervix, vaginal cuff, parametrial tissue).
*Non-endometrioid ''or'' high stage endometrioid ''or'' high-grade endometrioid: ''radical hysterectomy'' (includes cervix, vaginal cuff, parametrial tissue).


==Subtypes==
==Subtypes - overview==
#Endometrioid - '''most common''', patient typically is 55-65 years old and obese.
They are commonly grouped based on clinicopathologic features:<ref name=pmid21309259>{{Cite journal  | last1 = Lim | first1 = D. | last2 = Oliva | first2 = E. | title = Nonendometrioid endometrial carcinomas. | journal = Semin Diagn Pathol | volume = 27 | issue = 4 | pages = 241-60 | month = Nov | year = 2010 | doi =  | PMID = 21309259 }}</ref><ref name=Ref_GP241>{{Ref GP|241}}</ref>
#Serous - patients classically older than endometrioid subtype, arise in atrophic endometrium.
{| class="wikitable sortable"
#Clear cell.
!Feature
!Type I
!Type II
|-
|Histologic types
|[[endometrioid endometrial carcinoma]], [[mucinous endometrial carcinoma]]
|[[serous carcinoma of the endometrium]], [[clear cell carcinoma of the endometrium]], undifferentiated carcinoma
|-
|Clinical <br>characteristics
| premenopausal, estrogen excess, obesity
| postmenopausal, no estrogen excess, atrophic endometrium
|-
|Prognosis
| good
| poor
|-
|Genetic <br>abnormalities
| microsatellite instability, PTEN & [[KRAS mutation]]s
| p53 mutations
|-
|Precursor lesion(s)
| [[endometrial hyperplasia]]
| possibly ''endometrial intraepithelial carcinoma''<ref name=pmid22249577>{{Cite journal  | last1 = Roelofsen | first1 = T. | last2 = van Kempen | first2 = LC. | last3 = van der Laak | first3 = JA. | last4 = van Ham | first4 = MA. | last5 = Bulten | first5 = J. | last6 = Massuger | first6 = LF. | title = Concurrent endometrial intraepithelial carcinoma (EIC) and serous ovarian cancer: can EIC be seen as the precursor lesion? | journal = Int J Gynecol Cancer | volume = 22 | issue = 3 | pages = 457-64 | month = Mar | year = 2012 | doi = 10.1097/IGC.0b013e3182434a81 | PMID = 22249577 }}</ref> †
|}


===Microscopic (summary)===
Notes:
Features in most common subtypes (in short):
* † ''Endometrial intraepithelial carcinoma'' should '''not''' be confused with ''[[endometrial intraepithelial neoplasia]]'' (EIN).
*Serous:
**Columnar cells.
**Cilia.
**Psammoma bodies.
**Papillae.
*Endometrioid:
**Tubular glands.
**Squamous metaplasia.
***Look for ''squamous morules'':
****Ball of cells with intensely eosinophilic cytoplasm, dyskeratotic cell(s) - ([http://www.diagnosticpathology.org/content/2/1/40/figure/F1?highres=y image of squamous morule with dyskeratotic cell (diagnosticpathology.org)]).
*Clear cell.
**Classically clear cells... but not always.
**Hobnailing (apical cytoplasm > cytoplasm on basement membrane).


Notes:
*Dyskeratosis = abnormal keratinization;<ref>[http://dictionary.reference.com/browse/dyskeratosis http://dictionary.reference.com/browse/dyskeratosis]</ref> classically have intensely eosinophilic cytoplasm +/- nuclear fragmentation ([http://dictionary.reference.com/browse/karyolysis?db=medical&q=karyolysis karyorrhexis]) - see: [http://www.drmihm.com/pictures/Figure%203.jpg several dyskeratotic cells].
==Grading (FIGO)==
==Grading (FIGO)==
*Based on gland formation & adjusted by nuclear pleomorphism:<ref>{{Ref PBoD|1087-8}}</ref><ref>URL: [http://www.pathologyoutlines.com/uterus.html#endometrialcarc http://www.pathologyoutlines.com/uterus.html#endometrialcarc].</ref><ref>URL: [http://www.emedicine.com/med/topic2832.htm http://www.emedicine.com/med/topic2832.htm].</ref><ref name=pmid12496701>{{cite journal |author=Ayhan A, Taskiran C, Yuce K, Kucukali T |title=The prognostic value of nuclear grading and the revised FIGO grading of endometrial adenocarcinoma |journal=Int. J. Gynecol. Pathol. |volume=22 |issue=1 |pages=71–4 |year=2003 |month=January |pmid=12496701 |doi= |url=}}</ref>
Based on gland formation & adjusted by nuclear pleomorphism:<ref>{{Ref PBoD|1087-8}}</ref><ref>URL: [http://www.pathologyoutlines.com/uterus.html#endometrialcarc http://www.pathologyoutlines.com/uterus.html#endometrialcarc].</ref><ref>URL: [http://www.emedicine.com/med/topic2832.htm http://www.emedicine.com/med/topic2832.htm].</ref><ref name=pmid12496701>{{cite journal |author=Ayhan A, Taskiran C, Yuce K, Kucukali T |title=The prognostic value of nuclear grading and the revised FIGO grading of endometrial adenocarcinoma |journal=Int. J. Gynecol. Pathol. |volume=22 |issue=1 |pages=71–4 |year=2003 |month=January |pmid=12496701 |doi= |url=}}</ref>
**Grade 1: <5% solid component.  
*Grade 1: <5% solid component.  
**Grade 2: 5-50% solid component.  
*Grade 2: 5-50% solid component.  
**Grade 3: >50% solid component.  
*Grade 3: >50% solid component.  


Modifiers/adjustment:
Modifiers/adjustment:
*High grade nuclei upgrades cancer by one; high grade nuclei = increased size, irregular large nucleoli, irregular chromatin pattern (clumped, coarse).<ref>{{Ref DCHH|240}}</ref>
*High grade nuclei upgrades cancer by one; high grade nuclei = increased size, irregular large nucleoli, irregular chromatin pattern (clumped, coarse).<ref>{{Ref DCHH|240}}</ref>
*Grading for endometrioid subtype ONLY --papillary serous carcinoma and clear cell carcinomas are grade 3 by definition.
 
Notes:
*Officially only sanctioned for ''[[endometrioid endometrial carcinoma]]''.
**May be used for [[mucinous endometrial carcinoma]].
**Papillary serous carcinoma and clear cell carcinomas are ''not'' assigned a grade; however, can be thought of as grade 3 by definition.


==Staging==
==Staging==
*Stage I: confined to uterine body.
*Stage I: confined to uterine body.
**Ia = endometrium only.
**Ia = less than half of myometrium.
**Ib = less than half of myometrium.
**Ib = greater than half of myometrium.
**Ic = greater than half of myometrium.
*Stage II: uterus + cervix.
*Stage II: uterus + cervix.
**IIa = endocervical glands only.
**II = cervical stroma involved.
**IIb = cervix stroma.
***Cervical epithelium involvement does not change stage.
*Stage III: outside uterus - but inside pelvis.
*Stage III: outside uterus - but inside pelvis.
**IIIa = serosal or adnexal involvement or peritoneal cytology positive.
**IIIa - involves serosa and/or adnexa (direct extension or metastasis)
**IIIb = vaginal metstases.
**IIIb - vaginal involvement (direct extension or metastasis) or parametrial involvement
**IIIc = pelvic or paraaortic nodes.
*Stage IV: outside true pelvis or in mucosa of bladder or GI tract.
*Stage IV: outside true pelvis or in mucosa of bladder or GI tract.
**IVa = bladder or bowel mucosa.
References: <ref>{{Ref PBoD|1088}}</ref><ref>[http://www.emedicine.com/med/topic2832.htm http://www.emedicine.com/med/topic2832.htm]</ref><ref>[http://www.cancerfacts.com/GeneralContent/Uterine/Gen_Diagnosis.asp?CB=11 Staging with groovy graphics (cancerfacts.com)]</ref><ref>URL: [http://en.wikibooks.org/wiki/Radiation_Oncology/Endometrium/Staging http://en.wikibooks.org/wiki/Radiation_Oncology/Endometrium/Staging]. Accessed on: 2 May 2012.</ref>.
**IVb = distant mets (intraabdominal, inguinal nodes).
 
Ref: <ref>{{Ref PBoD|1088}}</ref>, <ref>[http://www.emedicine.com/med/topic2832.htm http://www.emedicine.com/med/topic2832.htm]</ref>, <ref>[http://www.cancerfacts.com/GeneralContent/Uterine/Gen_Diagnosis.asp?CB=11 Staging with groovy graphics (cancerfacts.com)]</ref>
=Specific types=
==Endometrioid endometrial carcinoma==
*[[AKA]] ''endometrioid endometrial adenocarcinoma''.
{{Main|Endometrioid endometrial carcinoma}}
 
==Mucinous carcinoma of the endometrium==
*[[AKA]] ''endometrial mucinous carcinoma''.
===General===
*Type I endometrial carcinoma.{{fact}}
*Good prognosis.
 
===Microscopic===
Features:<ref name=Ref_GP241>{{Ref GP|241}}</ref>
*Cells with intracytoplasmic mucin (>50% of tumour).
*Usu. mild-to-moderate nuclear atypia.
 
DDx:
*[[Endometrioid endometrial carcinoma]].
*Metastatic [[mucinous carcinoma]].
 
===IHC===
Features:<ref name=pmid17649817>{{Cite journal  | last1 = Shabani | first1 = N. | last2 = Mylonas | first2 = I. | last3 = Jeschke | first3 = U. | last4 = Thaqi | first4 = A. | last5 = Kuhn | first5 = C. | last6 = Puchner | first6 = T. | last7 = Friese | first7 = K. | title = Expression of estrogen receptors alpha and beta, and progesterone receptors A and B in human mucinous carcinoma of the endometrium. | journal = Anticancer Res | volume = 27 | issue = 4A | pages = 2027-33 | month =  | year =  | doi =  | PMID = 17649817 }}</ref>
*ER-alpha +ve.
*PR-alpha +ve.
*PR-beta +ve.
 
==Serous carcinoma of the endometrium==
*[[AKA]] ''serous endometrial carcinoma''.
*AKA ''serous carcinoma of the uterus''.
*AKA ''uterine serous carcinoma''.
*AKA ''uterine papillary serous carcinoma''.
{{Main|Serous carcinoma of the endometrium}}
 
==Clear cell carcinoma of the endometrium==
*[[AKA]] ''clear cell endometrial carcinoma''.
*[[AKA]] ''endometrial clear cell carcinoma''.
 
===General===
*Ten-year survival ~ 40%.<ref name=pmid8859187>{{Cite journal  | last1 = Abeler | first1 = VM. | last2 = Vergote | first2 = IB. | last3 = Kjørstad | first3 = KE. | last4 = Tropé | first4 = CG. | title = Clear cell carcinoma of the endometrium. Prognosis and metastatic pattern. | journal = Cancer | volume = 78 | issue = 8 | pages = 1740-7 | month = Oct | year = 1996 | doi =  | PMID = 8859187 }}</ref>
*Uncommon <=5 % of endometrial carcinomas.<ref name=pmid22885379>{{Cite journal  | last1 = Offman | first1 = SL. | last2 = Longacre | first2 = TA. | title = Clear cell carcinoma of the female genital tract (not everything is as clear as it seems). | journal = Adv Anat Pathol | volume = 19 | issue = 5 | pages = 296-312 | month = Sep | year = 2012 | doi = 10.1097/PAP.0b013e31826663b1 | PMID = 22885379 }}</ref>
*Type II endometrial cancer - estrogen-independent, usually post-menopausal women.
 
===Microscopic===
Features:<ref name=pmid22885379/>
*Clear cells - with moderate nuclear pleomorphism - '''key feature'''.
**Classically clear cells... but not always.
*[[Hobnail pattern]] -- apical cytoplasm > cytoplasm on basement membrane.
*Usually tubular/cystic, may be solid or papillary.
**Papillae may be pseudopapillae -- with edema instead of vessels.
 
Notes:
*May have [[psammoma bodies]] - esp. in papillary area; may lead to confusion with serous carcinoma.
 
DDx:
*[[Serous endometrial carcinoma]] - usually has more nuclear pleomorphism, esp. cell size variation.
*High grade [[endometrioid endometrial carcinoma]] - have non-clear areas.<ref name=pmid22885379/>
*[[Arias-Stella reaction]] - esp. in the context of [[pregnancy]].
*Papillary cystadenoma - benign; bland nuclei.<ref name=pmid22885379/>
 
DDx weird stuff:<ref name=pmid22885379/>
*[[PEComa]].
*Epithelioid [[uterine leiomyosarcoma|leiomyosarcoma]].
 
====Images====
www:
*[http://www.webpathology.com/image.asp?n=29&Case=569 Clear cell carcinoma of the endometrium - classical - high mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?case=569&n=27 Clear cell carcinoma of the endometrium - high mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=28&Case=569 Clear cell carcinoma of the endometrium - low mag. (webpathology.com)].
 
===Stains===
*[[PAS-D stain]] +ve ~ glycogen.<ref name=pmid22885379/>
 
===IHC===
Features:<ref name=Ref_GP250>{{Ref GP|250}}</ref>
*p53 -ve usu. - unlike [[uterine serous carcinoma]].
*ER -ve.
*PR -ve.
 
Others:<ref name=pmid22885379/>
*CAM5.2 +ve.
*CK34betaE12 +ve.
*WT1 -ve.<ref name=pmid15084838>{{Cite journal  | last1 = Acs | first1 = G. | last2 = Pasha | first2 = T. | last3 = Zhang | first3 = PJ. | title = WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium. | journal = Int J Gynecol Pathol | volume = 23 | issue = 2 | pages = 110-8 | month = Apr | year = 2004 | doi =  | PMID = 15084838 }}</ref>
**Often +ve/-ve in serous carcinoma of the endometrium.
*CK7 +ve.<ref name=pmid11444201>{{Cite journal  | last1 = Vang | first1 = R. | last2 = Whitaker | first2 = BP. | last3 = Farhood | first3 = AI. | last4 = Silva | first4 = EG. | last5 = Ro | first5 = JY. | last6 = Deavers | first6 = MT. | title = Immunohistochemical analysis of clear cell carcinoma of the gynecologic tract. | journal = Int J Gynecol Pathol | volume = 20 | issue = 3 | pages = 252-9 | month = Jul | year = 2001 | doi =  | PMID = 11444201 }}</ref>
*CK20 -ve.<ref name=pmid11444201/>
*Vimentin +ve.<ref name=pmid11444201/>
*Napsin A +ve.<ref name=pmid25971546>{{Cite journal  | last1 = Iwamoto | first1 = M. | last2 = Nakatani | first2 = Y. | last3 = Fugo | first3 = K. | last4 = Kishimoto | first4 = T. | last5 = Kiyokawa | first5 = T. | title = Napsin A is frequently expressed in clear cell carcinoma of the ovary and endometrium. | journal = Hum Pathol | volume = 46 | issue = 7 | pages = 957-62 | month = Jul | year = 2015 | doi = 10.1016/j.humpath.2015.03.008 | PMID = 25971546 }}</ref>
 
Note:
*HNF1beta - not useful<ref name=pmid22495362>{{Cite journal  | last1 = Fadare | first1 = O. | last2 = Liang | first2 = SX. | title = Diagnostic Utility of Hepatocyte Nuclear Factor 1-Beta Immunoreactivity in Endometrial Carcinomas: Lack of Specificity For Endometrial Clear Cell Carcinoma. | journal = Appl Immunohistochem Mol Morphol | volume =  | issue =  | pages =  | month = Apr | year = 2012 | doi = 10.1097/PAI.0b013e31824973d1 | PMID = 22495362 }}</ref> - unlike for [[ovarian clear cell carcinoma]].


==See also==
=See also=
*[[Endometrium]].
*[[Endometrium]].
*[[Uterine tumours]] - other uterine tumours, e.g. carcinosarcoma, endometrial stromal sarcoma.
*[[Uterine tumours]] - other uterine tumours, e.g. carcinosarcoma, endometrial stromal sarcoma.
*[[Uterine cervix]].
*[[Gynecologic pathology]] - overview.
*[[Gynecologic pathology]] - overview.


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


==External links==
=External links=
*[http://www.diagnosticpathology.org/content/2/1/40/figure/F1?highres=y Image of squamous morule with dyskeratotic cell (diagnosticpathology.org)].
*[http://www.cancer.org/cancer/endometrialcancer/detailedguide/endometrial-uterine-cancer-staging Endometrial cancer staging (cancer.org)].


[[Category:Gynecologic pathology]]
[[Category:Gynecologic pathology]]
Michael
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