Endometrial hyperplasia pathophysiology: Difference between revisions
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* Oncogene bcl-2 in complex hyperplasia<ref name="pmid1458483">{{cite journal |vauthors=McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML |title=Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer |journal=Cancer Res. |volume=52 |issue=24 |pages=6940–4 |date=December 1992 |pmid=1458483 |doi= |url=}}</ref><ref>{{cite journal|doi=10.1002/1097-0142(19950501)75:9<2209}}</ref> | * Oncogene bcl-2 in complex hyperplasia<ref name="pmid1458483">{{cite journal |vauthors=McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML |title=Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer |journal=Cancer Res. |volume=52 |issue=24 |pages=6940–4 |date=December 1992 |pmid=1458483 |doi= |url=}}</ref><ref>{{cite journal|doi=10.1002/1097-0142(19950501)75:9<2209}}</ref> | ||
* Mutations in PTEN and KRAS PTEN tumor suppressor gene mutations have also been found<ref name="pmid8617450">{{cite journal |vauthors=Lu QL, Abel P, Foster CS, Lalani EN |title=bcl-2: role in epithelial differentiation and oncogenesis |journal=Hum. Pathol. |volume=27 |issue=2 |pages=102–10 |date=February 1996 |pmid=8617450 |doi= |url=}}</ref> | * Mutations in [[PTEN]] and [[KRAS]] [[PTEN]] [[tumor suppressor gene]] [[mutations]] have also been found<ref name="pmid8617450">{{cite journal |vauthors=Lu QL, Abel P, Foster CS, Lalani EN |title=bcl-2: role in epithelial differentiation and oncogenesis |journal=Hum. Pathol. |volume=27 |issue=2 |pages=102–10 |date=February 1996 |pmid=8617450 |doi= |url=}}</ref> | ||
* Fas/FasL gene also has been investigated recently in the development of endometrial | * [[Fas/FasL]] [[gene]] also has been investigated recently in the development of endometrial hyperplasia | ||
===Mtor Signallin pathway=== | ===Mtor Signallin pathway=== | ||
* mTOR signaling is required for estrogen-mediated growth of [[endometrial cells]] | * [[mTOR]] signaling is required for [[estrogen]]-mediated growth of [[endometrial cells]] | ||
* Dysregulated [[mTOR]] signaling leads to female infertility due to defects in ovarian, oviductal, and endometrial functions .<ref name="pmid22128018">{{cite journal |vauthors=Tanaka Y, Park JH, Tanwar PS, Kaneko-Tarui T, Mittal S, Lee HJ, Teixeira JM |title=Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility |journal=Endocrinology |volume=153 |issue=1 |pages=404–16 |date=January 2012 |pmid=22128018 |pmc=3249683 |doi=10.1210/en.2011-1191 |url=}}</ref><ref name="pmid25733860">{{cite journal |vauthors=Wang Y, Zhu L, Kuokkanen S, Pollard JW |title=Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=112 |issue=11 |pages=E1382–91 |date=March 2015 |pmid=25733860 |pmc=4371960 |doi=10.1073/pnas.1418973112 |url=}}</ref><ref name="pmid20519781">{{cite journal |vauthors=Blagosklonny MV |title=Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives |journal=Aging (Albany NY) |volume=2 |issue=5 |pages=265–73 |date=May 2010 |pmid=20519781 |pmc=2898017 |doi=10.18632/aging.100149 |url=}}</ref> | * Dysregulated [[mTOR]] signaling leads to female [[infertility]] due to defects in [[ovarian]], oviductal, and [[endometrial]] functions .<ref name="pmid22128018">{{cite journal |vauthors=Tanaka Y, Park JH, Tanwar PS, Kaneko-Tarui T, Mittal S, Lee HJ, Teixeira JM |title=Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility |journal=Endocrinology |volume=153 |issue=1 |pages=404–16 |date=January 2012 |pmid=22128018 |pmc=3249683 |doi=10.1210/en.2011-1191 |url=}}</ref><ref name="pmid25733860">{{cite journal |vauthors=Wang Y, Zhu L, Kuokkanen S, Pollard JW |title=Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=112 |issue=11 |pages=E1382–91 |date=March 2015 |pmid=25733860 |pmc=4371960 |doi=10.1073/pnas.1418973112 |url=}}</ref><ref name="pmid20519781">{{cite journal |vauthors=Blagosklonny MV |title=Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives |journal=Aging (Albany NY) |volume=2 |issue=5 |pages=265–73 |date=May 2010 |pmid=20519781 |pmc=2898017 |doi=10.18632/aging.100149 |url=}}</ref> | ||
==Gross pathology== | ==Gross pathology== | ||
Endometrial hyperplasia typically represents as: <ref name="LaceyIoffe2007">{{cite journal|last1=Lacey|first1=J V|last2=Ioffe|first2=O B|last3=Ronnett|first3=B M|last4=Rush|first4=B B|last5=Richesson|first5=D A|last6=Chatterjee|first6=N|last7=Langholz|first7=B|last8=Glass|first8=A G|last9=Sherman|first9=M E|title=Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan|journal=British Journal of Cancer|volume=98|issue=1|year=2007|pages=45–53|issn=0007-0920|doi=10.1038/sj.bjc.6604102}}</ref> | [[Endometrial]] [[hyperplasia]] typically represents as: <ref name="LaceyIoffe2007">{{cite journal|last1=Lacey|first1=J V|last2=Ioffe|first2=O B|last3=Ronnett|first3=B M|last4=Rush|first4=B B|last5=Richesson|first5=D A|last6=Chatterjee|first6=N|last7=Langholz|first7=B|last8=Glass|first8=A G|last9=Sherman|first9=M E|title=Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan|journal=British Journal of Cancer|volume=98|issue=1|year=2007|pages=45–53|issn=0007-0920|doi=10.1038/sj.bjc.6604102}}</ref> | ||
* A thickened endometrial stripe on transvaginal ultrasound | * A thickened [[endometrial]] stripe on [[transvaginal ultrasound]] | ||
* Increased volume of endometrial tissue on hysteroscopy or curettage | * Increased volume of [[endometrial]] tissue on [[hysteroscopy]] or curettage | ||
* Hyperplasia may be associated with abundant endometrial tissue | * [[Hyperplasia]] may be associated with abundant [[endometrial]] tissue | ||
* In some | * In some cases, localized [[hyperplasia]] may mimic a [[polyp]], arise in a background of a [[polyp]], or involve [[adenomyosis]], including deep [[foci]] | ||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
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** Irregular nuclear borders | ** Irregular nuclear borders | ||
** Vesicular chromatin | ** Vesicular chromatin | ||
** Clumped chromatin | ** Clumped chromatin | ||
** Atypical cells may show tufting and focal stratification | ** Atypical cells may show tufting and focal stratification | ||
=== World Health Organization classification of endometrial hyperplasia=== | === World Health Organization classification of endometrial hyperplasia=== | ||
Revision as of 18:06, 21 February 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Soujanya Thummathati, MBBS [3]
Overview
Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio. The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.
Pathophysiology
Pathogenesis
- Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio.
- The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.[1]
- Normal endometrial changes during menstrual cycle:[2]
- The proliferative phase is the second phase in normal mentrual cycle when estrogen causes the lining of the uterus to proliferate. As the ovarian follicles mature, they begin to secrete increasing amounts of estradiol and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium.
- After ovulation, the remains of the dominant follicle in the ovary become a corpus luteum which produces large amounts of progesterone.
- Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium.
- Unopposed estrogen stimulation may be either from an endogenous or exogenous source.[3][1]
- Excessive endogenous estrogen in pre or perimenopausal women may result from chronic anovulation caused by obesity, polycystic ovary disease, and estrogen producing tumors (e.g. granulosa cell tumor).
- Excessive exogenous estrogen may result from hormone replacement therapy or non-prescription herbal medications.
- Tamoxifen therapy in breast cancer patients results in an endometrial lesion within 6-36 months of therapy.[4]
- Tamoxifen is a non-steroidal anti-estrogen that binds to the estrogen receptor and is used primarily for adjuvant therapy in breast cancer
- Tamoxifen may also act as an estrogen agonist in a low estradiol environment
- Any patient who develops bleeding while on tamoxifen needs evaluation
- Endometrial hyperplasia may rarely result from the peripheral conversion of androgens to estrogens in androgen-secreting tumors of the adrenal cortex.[5][6]
Genetics
It is assumed that there is association between endometrial hyperplasia and DNA repair gene (XPD, XRCC4, and XRCC1) polymorphisms. After experiments, it became evident the DNA repair gene XPD and XRCC4 polymorphisms had a role in the pathophysiology of endometrial hyperplasia.[7]
Other Genes involved
Mtor Signallin pathway
- mTOR signaling is required for estrogen-mediated growth of endometrial cells
- Dysregulated mTOR signaling leads to female infertility due to defects in ovarian, oviductal, and endometrial functions .[11][12][13]
Gross pathology
Endometrial hyperplasia typically represents as: [14]
- A thickened endometrial stripe on transvaginal ultrasound
- Increased volume of endometrial tissue on hysteroscopy or curettage
- Hyperplasia may be associated with abundant endometrial tissue
- In some cases, localized hyperplasia may mimic a polyp, arise in a background of a polyp, or involve adenomyosis, including deep foci
Microscopic Pathology
- Prolonged estrogenic stimulation results in larger, more complex, and proliferating endometrial glands.[3]
- On microscopic histopathological analysis, the proliferating endometrium is characterized by the following:[15]
| Character | Simple hyperplasia | Complex hyperplasia |
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Gland to stroma ratio |
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Endometrium |
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Mitoses |
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Location |
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Nuclear atypia |
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- Endometrial hyperplasia is morphologically defined as proliferating endometrium with architectural abnormalities.
- These architectural changes range as :
- Cystic dilatation
- Budding and branching
- Papillary infoldings
- Villous and villoglandular growths
- Cribriform structures.
- In addition to abnormal architecture, a diagnosis of hyperplasia usually requires increased glandular density with a gland-to-stroma ratio of ∼3:1.
- Luminal spaces and villoglandular structures are also included in the glandular component for this calculation.
- If the gland-to-stroma ratio fails to meet the required cut-off, a lesion is probably best classified as disordered proliferative endometrium rather than hyperplasia.
- Although hyperplastic endometrium might have cytologic atypia, this criterion is neither required nor sufficient for this diagnosis.
- The assessment of cytologic atypia is poorly understood, but the various criteria include:
- Nuclear rounding and enlargement
- Nuclear pleomorphism
- Loss of polarity
- Increased nuclear-to-cytoplasm ratio
- Prominent nucleoli
- Irregular nuclear borders
- Vesicular chromatin
- Clumped chromatin
- Atypical cells may show tufting and focal stratification
World Health Organization classification of endometrial hyperplasia
- Simple hyperplasia without atypia
- Simple hyperplasia is characterized by:
- Densely packed, cystically dilated, variable sized glands separated by normal intervening stroma ( Figure 10 ). Although
- 3:1 gland-to-stroma ratio.
- Ciliated cells
- squamous morular metaplasia
- Complex hyperplasia without atypia
- Complex hyperplasia without atypia is defined as:
- Glands with abnormal, irregular architecture set in a background of scant intervening stroma
- Some stroma must be present,
- Basement membrane lining individual glands and a rim of intervening endometrial-type stroma between them. In addition to back-to-back and cribriform-like arrangements, other glandular architectural abnormalities warranting designation of complex hyperplasia include
- Outpouchings,
- Infoldings, and budding
- Squamous or morular metaplasia
- Eosinophilic and ciliated cell changes
- Simple hyperplasia with atypia
- Complex hyperplasia with atypia
- Increased gland-to-stroma ratio (≥3:1)
- Gland complexity—caused by:
- Branching
- Outward budding
- Internal papillary infoldings
- Internal bridge
Gallery
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![Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle[16]](/images/9/9f/Lining_of_Uterine_Wall.jpg)
Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle[16]
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![Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands[17]](/images/3/3d/Simple_endometrial_hyperplasia_-_low_mag_%281%29.jpg)
Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands[17]
![Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle[16]](/index.php/File:Lining_of_Uterine_Wall.jpg)
![Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands[17]](/index.php/File:Simple_endometrial_hyperplasia_-_low_mag_(1).jpg)
References
- ↑ 1.0 1.1 Endometrial hyperplasia. Wikipedia. https://en.wikipedia.org/wiki/Endometrial_hyperplasia Accessed on March 7, 2016.
- ↑ Menstrual cycle. Wikipedia. https://en.wikipedia.org/wiki/Menstrual_cycle Accessed on March 7, 2016
- ↑ 3.0 3.1 Owings RA, Quick CM (2014). "Endometrial intraepithelial neoplasia". Arch Pathol Lab Med. 138 (4): 484–91. doi:10.5858/arpa.2012-0709-RA. PMID 24678678.
- ↑ Tamoxifen associated endometrial changes. Radiopedia. http://radiopaedia.org/articles/tamoxifen-associated-endometrial-changes Accessed on March 10, 2016
- ↑ Endometrial hyperplasia. Wiley Online Library.http://onlinelibrary.wiley.com/doi/10.1576/toag.10.4.211.27436/full Accessed on March 7, 2016
- ↑ Wang S, Pudney J, Song J, Mor G, Schwartz PE, Zheng W (February 2003). "Mechanisms involved in the evolution of progestin resistance in human endometrial hyperplasia--precursor of endometrial cancer". Gynecol. Oncol. 88 (2): 108–17. PMID 12586588.
- ↑ Öztürk E, Pehlivan S, Balat O, Ugur MG, Ozcan HC, Erkılıç S (October 2018). "DNA Repair Gene (XPD, XRCC4, and XRCC1) Polymorphisms in Patients with Endometrial Hyperplasia: A Pilot Study". Med Sci Monit Basic Res. 24: 146–150. doi:10.12659/MSMBR.911041. PMID 30275440.
- ↑ McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML (December 1992). "Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer". Cancer Res. 52 (24): 6940–4. PMID 1458483.
- ↑ . doi:10.1002/1097-0142(19950501)75:9<2209. Missing or empty
|title=(help) - ↑ Lu QL, Abel P, Foster CS, Lalani EN (February 1996). "bcl-2: role in epithelial differentiation and oncogenesis". Hum. Pathol. 27 (2): 102–10. PMID 8617450.
- ↑ Tanaka Y, Park JH, Tanwar PS, Kaneko-Tarui T, Mittal S, Lee HJ, Teixeira JM (January 2012). "Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility". Endocrinology. 153 (1): 404–16. doi:10.1210/en.2011-1191. PMC 3249683. PMID 22128018.
- ↑ Wang Y, Zhu L, Kuokkanen S, Pollard JW (March 2015). "Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway". Proc. Natl. Acad. Sci. U.S.A. 112 (11): E1382–91. doi:10.1073/pnas.1418973112. PMC 4371960. PMID 25733860.
- ↑ Blagosklonny MV (May 2010). "Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives". Aging (Albany NY). 2 (5): 265–73. doi:10.18632/aging.100149. PMC 2898017. PMID 20519781.
- ↑ Lacey, J V; Ioffe, O B; Ronnett, B M; Rush, B B; Richesson, D A; Chatterjee, N; Langholz, B; Glass, A G; Sherman, M E (2007). "Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan". British Journal of Cancer. 98 (1): 45–53. doi:10.1038/sj.bjc.6604102. ISSN 0007-0920.
- ↑ McCluggage WG (2006). "My approach to the interpretation of endometrial biopsies and curettings". J Clin Pathol. 59 (8): 801–12. doi:10.1136/jcp.2005.029702. PMC 1860448. PMID 16873562.
- ↑ Menstrual cycle. Wikipedia. https://en.wikipedia.org/wiki/Menstrual_cycle Accessed on March 7, 2016
- ↑ Endometrial hyperplasia. Wikipedia. https://en.wikipedia.org/wiki/Endometrial_hyperplasia#/media/File:Simple_endometrial_hyperplasia_-_low_mag.jpg Accessed on March 7, 2016
