Endometrial intraepithelial neoplasia: Difference between revisions

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{{SK}} Atypical endometrial hyperplasia;  Minimal uterine serous cancer (MUSC); Serous endometrial intraepithelial carcinoma (EIC); MUSC; Minimal uterine serous cancer
{{SK}} Atypical endometrial hyperplasia;  Minimal uterine serous cancer (MUSC); Serous endometrial intraepithelial carcinoma (EIC); MUSC; Minimal uterine serous cancer
==Overview==
==Overview==
Endometrial intraepithelial neoplasia [[Lesion|lesions]] have been discovered beginning in the 1990s which provide a multifaceted characterization of this [[disease]]. The endometrial intraepithelial neoplasia diagnostic [[Schema (psychology)|schema]] is intended to replace the previous "[[endometrial hyperplasia]]" classification as defined by the [[World Health Organization]] in 1994, which have been separated into [[benign]] ([[benign]] [[endometrial]] [[hyperplasia]]) and [[premalignant]] (EIN) classes in accordance with their behavior and [[clinical]] management.Endometrial intraepithelial neoplasia may be classified according to [[WHO]]94 schema classifies [[histology]] based on [[glandular]] complexity and [[nuclear]] [[atypia]] into 4 groups: simple [[hyperplasia]], complex [[hyperplasia]], simple [[hyperplasia]] with [[atypia]], and complex [[hyperplasia]] with [[atypia]]. On microscopic [[histopathological]] [[analysis]], indiidual [[Gland|glands]] lined by an [[Pseudostratified epithelium|pseudostratified]] [[epithelium]] one cell layer thick is a characteristic finding of endometrial intraepithelial neoplasia. [[Hysterectomy]] is recommended following the [[diagnosis|diagn]]<nowiki/>v[[diagnosis|osis]] of endometrial intraepithelial neoplasia to prevent [[Endometrial Carcinoma|endometrial carcinoma]].
 
Endometrial intraepithelial neoplasia [[Lesion|lesions]] was first described in the 1990s. Endometrial [[hyperplasia]] may be classified according to new [[World Health Organization]] ([[WHO]]2014) into two groups; [[hyperplasia]] without [[atypia]] (non-neoplastic) and atypical [[hyperplasia]] (endometrial intraepithelial neoplasm). Endometrial intraepithelial neoplasia arises from [[premalignant]] [[endometrial]] [[Gland|glands]] , which are risk of transmutatain to [[Endometrium|endometrial]] [[Endometrioid tumor|edometrioid]] [[carcinoma]]. Inactivation ([[mutation]] or [[Deletion (genetics)|deletion]]) of the ''[[PTEN (gene)|PTEN]]'' [[tumor]] [[Suppressor mutation|suppressor]] [[gene]], inactivation of [[PAX2]] [[gene]], [[KRAS]] [[Mutation|mutations]], [[Microsatellite]] [[instability]], [[Mutation]] in [[TP53 (gene)|p53 gene]] are involved in the [[pathogenesis]] of endometrial intraepithelial neoplasia (EIN). Endometrial intraepithelial neoplasia may be caused by [[estrogenic]] stimulation of the [[endometrium]] that is unopposed by [[Progestin|progestin]]. On [[microscopic]] [[Histopathology|histopathological]] [[analysis]], individual [[Gland|glands]] are lined by a single layer of [[pseudostratified epithelium]] which is a characteristic finding of endometrial intraepithelial neoplasia. In 2002, the incidence of endometrial intraepithelial neoplasia (EIN) was estimated to be 144 cases per 100,000 individuals worldwide. The [[hallmark]] symptom of endometrial intraepithelial neoplasia is [[postmenopausal]] [[abnormal]] [[Uterus|uterine]] [[bleeding]]. There are no specific [[Medical laboratory|laboratory]] findings associated with endometrial intraepithelial neoplasia. [[Gynecologic ultrasonography|Transvaginal ultrasonography]] is the [[imaging]] modality of choice for endometrial intraepithelial neoplasia. [[Progestin]] [[therapy]] is recommended among [[Patient|patients]] with endometrial intraepithelial neoplasia. [[Hysterectomy]] is the mainstay of [[Treatment Planning|treatment]] for endometrial intraepithelial neoplasia to [[Prevention|prevent]] [[endometrial]] [[carcinoma]].
==Historaical Perspective==
==Historaical Perspective==
*Endometrial intraepithelial neoplasia  was first discovered by a combination of [[molecular]], [[histologic]], and [[clinical]] outcome studies beginning in the 1990s which provide a multifaceted characterization of this [[disease]].
*Endometrial intraepithelial neoplasia  was first discovered through a combination of [[molecular]], [[histologic]], and [[clinical]] outcome studies beginning in the 1990s which provided a multifaceted characterization of this [[disease]].
*They are a subset of a larger mixed group of lesions previously called "[[endometrial]] [[hyperplasia]]" The Endometrial intraepithelial neoplasia [[Diagnosis|diagnostic]] [[schema]] is intended to replace the previous "[[endometrial hyperplasia]]" classification as defined by the [[World Health Organization]] in 1994, which have been separated into [[benign]] ([[benign]] [[endometrial]] [[hyperplasia]]) and [[premalignant]] (EIN) classes in accordance with their behavior and [[clinical]] management.<ref name="A">{{cite book |author=Mutter GL, Duska L, Crum CP |chapter=Endometrial Intraepithelial Neoplasia |editor=Crum CP, Lee K |title=Diagnostic Gynecologic and Obstetric Pathology |publisher=Saunders |location=Philadelphia PA |year=2005 |pages=493–518 }}</ref><ref name="B">{{cite book |author=Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales F, Tavassoli FA |chapter=Tumors of the uterine corpus: epithelial tumors and related lesions |editor=Tavassoli FA, Stratton MR |title=WHO Classification of Tumors: Pathology and Genetics of Tumors of the Breast and Female Genital Organs |publisher=IARC Press |location=Lyon, France |year=2003 |pages=221–232 }}</ref><br>
*EIN is a subset of a larger mixed group of lesions previously called "[[endometrial]] [[hyperplasia]]" The Endometrial intraepithelial neoplasia [[Diagnosis|diagnostic]] [[schema|scheme]] was intended to replace the previous "[[endometrial hyperplasia]]" classification as defined by the [[World Health Organization]] in 1994, which has been divided into [[benign]] ([[benign]] [[endometrial]] [[hyperplasia]]) and [[premalignant]] (EIN) classes in accordance to their behavior and [[clinical]] management.<ref name="A">{{cite book |author=Mutter GL, Duska L, Crum CP |chapter=Endometrial Intraepithelial Neoplasia |editor=Crum CP, Lee K |title=Diagnostic Gynecologic and Obstetric Pathology |publisher=Saunders |location=Philadelphia PA |year=2005 |pages=493–518 }}</ref><ref name="B">{{cite book |author=Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales F, Tavassoli FA |chapter=Tumors of the uterine corpus: epithelial tumors and related lesions |editor=Tavassoli FA, Stratton MR |title=WHO Classification of Tumors: Pathology and Genetics of Tumors of the Breast and Female Genital Organs |publisher=IARC Press |location=Lyon, France |year=2003 |pages=221–232 }}</ref><br>


==Classification==
==Classification==
*Endometrial [[hyperplasia]] may be classified according to new [[World Health Organization]] ([[WHO]]2014) into two groups:<ref name="pmid25797956">{{cite journal |vauthors=Emons G, Beckmann MW, Schmidt D, Mallmann P |title=New WHO Classification of Endometrial Hyperplasias |journal=Geburtshilfe Frauenheilkd |volume=75 |issue=2 |pages=135–136 |date=February 2015 |pmid=25797956 |pmc=4361167 |doi=10.1055/s-0034-1396256 |url=}}</ref>
*Endometrial [[hyperplasia]] may be classified according to the new [[World Health Organization]] ([[WHO]] 2014) classification into two groups:<ref name="pmid25797956">{{cite journal |vauthors=Emons G, Beckmann MW, Schmidt D, Mallmann P |title=New WHO Classification of Endometrial Hyperplasias |journal=Geburtshilfe Frauenheilkd |volume=75 |issue=2 |pages=135–136 |date=February 2015 |pmid=25797956 |pmc=4361167 |doi=10.1055/s-0034-1396256 |url=}}</ref>
:*Hyperplasia without atypia (non-neoplastic)
:*[[Hyperplasia]] without [[atypia]] (non-neoplastic)
:*Atypical hyperplasia (endometrial intraepithelial neoplasm)
:*Atypical [[hyperplasia]] (endometrial intraepithelial neoplasm)
*Endometrial [[hyperplasia]] may be classified according to new [[World Health Organization]] ([[WHO]]1994) into 4 groups:<ref name="WangWang2015">{{cite journal|last1=Wang|first1=Steven|last2=Wang|first2=Zhenglong|last3=Mittal|first3=Khushbakhat|title=Concurrent endometrial intraepithelial carcinoma (EIC) and endometrial hyperplasia|journal=Human Pathology: Case Reports|volume=2|issue=1|year=2015|pages=1–4|issn=22143300|doi=10.1016/j.ehpc.2014.07.003}}</ref>
*Endometrial [[hyperplasia]] may be classified according to new [[World Health Organization]] ([[WHO]]1994) into 4 groups:<ref name="WangWang2015">{{cite journal|last1=Wang|first1=Steven|last2=Wang|first2=Zhenglong|last3=Mittal|first3=Khushbakhat|title=Concurrent endometrial intraepithelial carcinoma (EIC) and endometrial hyperplasia|journal=Human Pathology: Case Reports|volume=2|issue=1|year=2015|pages=1–4|issn=22143300|doi=10.1016/j.ehpc.2014.07.003}}</ref>
:*Simple hyperplasia without atypia
:*Simple [[hyperplasia]] without [[atypia]]
:*Complex hyperplasia without atypia
:*Complex [[hyperplasia]] without [[atypia]]
:*Simple atypical hyperplasia
:*Simple atypical [[hyperplasia]]
:*Complex atypical hyperplasia
:*Complex atypical [[hyperplasia]]
 
==Pathophysiology==
==Pathophysiology==
* Endometrial intraepithelial neoplasia, (EIN) is a premalignant [[lesion]] of the [[Uterus|uterine]] lining that predisposes to [[endometrial cancer|endometrioid endometrial adenocarcinoma]].  It is composed of a collection of abnormal [[endometrial]] cells, arising from the glands that line the [[uterus]], which have a tendency over time to progress to the most common form of uterine [[cancer]] —  endometrial [[adenocarcinoma]], endometrioid type.
* Endometrial intraepithelial neoplasia arises from [[premalignant]] [[Gland|glands]] , which risk of transmutatain to [[Endometrium|endometrial]] [[Endometrioid tumor|endometrioid]] [[carcinoma]].<ref name="pmid21309257">{{cite journal |vauthors=Jarboe EA, Mutter GL |title=Endometrial intraepithelial neoplasia |journal=Semin Diagn Pathol |volume=27 |issue=4 |pages=215–25 |date=November 2010 |pmid=21309257 |doi= |url=}}</ref>
* Endometrial intraepithelial neoplasia lesions demonstrate all of the behaviors and characteristics of a premalignant, or precancerous, lesion.
*[[Gene|Genes]] involved in the [[pathogenesis]] of endometrial intraepithelial neoplasia (EIN) includ:<ref name="pmid11389050">{{cite journal |vauthors=Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C |title=Molecular identification of latent precancers in histologically normal endometrium |journal=Cancer Res. |volume=61 |issue=11 |pages=4311–4 |date=June 2001 |pmid=11389050 |doi= |url=}}</ref><ref name="pmid10787358">{{cite journal |vauthors=Faquin WC, Fitzgerald JT, Lin MC, Boynton KA, Muto MG, Mutter GL |title=Sporadic microsatellite instability is specific to neoplastic and preneoplastic endometrial tissues |journal=Am. J. Clin. Pathol. |volume=113 |issue=4 |pages=576–82 |date=April 2000 |pmid=10787358 |doi=10.1309/F4TU-6AFE-R7NU-39Y3 |url=}}</ref><ref name="pmid20631067">{{cite journal |vauthors=Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL |title=Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer |journal=Cancer Res. |volume=70 |issue=15 |pages=6225–32 |date=August 2010 |pmid=20631067 |pmc=2912978 |doi=10.1158/0008-5472.CAN-10-0149 |url=}}</ref><ref name="pmid113890502">{{cite journal |vauthors=Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C |title=Molecular identification of latent precancers in histologically normal endometrium |journal=Cancer Res. |volume=61 |issue=11 |pages=4311–4 |date=June 2001 |pmid=11389050 |doi= |url=}}</ref><ref name="pmid22888282">{{cite journal |vauthors=O'Hara AJ, Bell DW |title=The genomics and genetics of endometrial cancer |journal=Adv Genomics Genet |volume=2012 |issue=2 |pages=33–47 |date=March 2012 |pmid=22888282 |pmc=3415201 |doi=10.2147/AGG.S28953 |url=}}</ref>
* Precancer Features of EIN (Table I). The cells of an EIN lesion are genetically different than normal and malignant tissues, and have a distinctive appearance under the light microscope.  EIN cells are already [[neoplasm|neoplastic]], demonstrating a [[monoclonal growth pattern]] and clonally distributed mutations.  Progression of EIN to carcinoma, effectively a conversion from a benign neoplasm to a malignant neoplasm, is accomplished through acquisition of additional mutations and accompanied by a change in behavior characterized by the ability to invade local tissues and metastasize to regional and distant sites.
**Inactivation ([[mutation]] or [[Deletion (genetics)|deletion]]) of the ''[[PTEN (gene)|PTEN]]'' [[tumor]] [[Suppressor mutation|suppressor]] [[gene]]
<br>
**Inactivation of [[PAX2]] [[gene]]
* Endometrial intraepithelial carcinoma (EIC) to be the precursor of serous adenocarcinoma.
**[[KRAS]] [[Mutation|mutations]]
*The mutation in ''p53 gene'' has been associated with the development of endometrial intraepithelial neoplasia.
**[[Microsatellite]] [[instability]]
*On microscopic histopathological analysis, individual glands lined by an pseudostratified epithelium one cell layer thick are characteristic finding of endometrial intraepithelial neoplasia.
**[[Mutation]] in ''[[TP53 (gene)|p53 gene]]''
 
*On [[microscopic]] [[Histopathology|histopathological]] [[analysis]], individual [[Gland|glands]] are lined by a single layer of [[pseudostratified epithelium]] which is a characteristic finding of endometrial intraepithelial neoplasia.<ref name="pmid16873562">{{cite journal |vauthors=McCluggage WG |title=My approach to the interpretation of endometrial biopsies and curettings |journal=J. Clin. Pathol. |volume=59 |issue=8 |pages=801–12 |date=August 2006 |pmid=16873562 |pmc=1860448 |doi=10.1136/jcp.2005.029702 |url=}}</ref><ref name="pmid23090535">{{cite journal |vauthors=Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL |title=Management of endometrial precancers |journal=Obstet Gynecol |volume=120 |issue=5 |pages=1160–75 |date=November 2012 |pmid=23090535 |pmc=3800154 |doi=http://10.1097/AOG.0b013e31826bb121 |url=}}</ref>
==Causes==
==Causes==
* Endometrial intraepithelial neoplasia may be caused by either estrogenic stimulation of the endometrium, unopposed by progestins.<ref name="OwingsQuick2014">{{cite journal|last1=Owings|first1=Richard A.|last2=Quick|first2=Charles M.|title=Endometrial Intraepithelial Neoplasia|journal=Archives of Pathology & Laboratory Medicine|volume=138|issue=4|year=2014|pages=484–491|issn=0003-9985|doi=10.5858/arpa.2012-0709-RA}}</ref>
* Endometrial intraepithelial neoplasia may be caused by [[estrogenic]] stimulation of the [[endometrium]] unopposed by [[Progestin|progestins]].<ref name="OwingsQuick2014">{{cite journal|last1=Owings|first1=Richard A.|last2=Quick|first2=Charles M.|title=Endometrial Intraepithelial Neoplasia|journal=Archives of Pathology & Laboratory Medicine|volume=138|issue=4|year=2014|pages=484–491|issn=0003-9985|doi=10.5858/arpa.2012-0709-RA}}</ref>
==Differentiating Endometrial intraepithelial neoplasia from other Diseases==
==Differentiating Endometrial intraepithelial neoplasia from other Diseases==
*Endometrial intraepithelial neoplasia must be differentiated from other diseases that cause endometrial disorders such as:
*Endometrial intraepithelial neoplasia must be differentiated from other causes of [[postmenopausal]] differentiated from:<ref name="pmid16873562" /><ref name="McCluggage2011">{{cite journal|last1=McCluggage|first1=W. Glenn|title=Benign Diseases of the Endometrium|year=2011|pages=305–358|doi=10.1007/978-1-4419-0489-8_7}}</ref>
:* Endometrial glandular dysplasia
:* [[Benign]] (non atypical [[hyperplasia]])
:* Endometrial intraepithelial neoplasia
:* [[Benign]] [[Endometrium|endometrial]] [[metaplasia]] ([[Tubal branch of uterine artery|tubal]], secretory, [[mucinous]])
:* Hyperplastic polyp
:* [[Endometrial]] [[glandular]] [[dysplasia]]
:* Metastatic carcinoma
:* [[Hyperplasia|Hyperplastic]] [[polyp|polyps]]
* The spectrum of disease which must be distinguished from endometrial intraepithelial neoplasia includes benign endometrial hyperplasia and carcinoma:
:* [[Metastatic]] [[carcinoma]]
:* [[Serous]]  [[clear cell]] [[carcinoma]]
==Epidemiology and Demographics==
==Epidemiology and Demographics==
===Prevalence and Incidence===
*In 2002, the incidence of endometrial intraepithelial neoplasia (EIN) was estimated to be 144 cases per 100,000 individuals worldwide.<ref name="pmid22290745">{{cite journal |vauthors=Lacey JV, Chia VM, Rush BB, Carreon DJ, Richesson DA, Ioffe OB, Ronnett BM, Chatterjee N, Langholz B, Sherman ME, Glass AG |title=Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan |journal=Int. J. Cancer |volume=131 |issue=8 |pages=1921–9 |date=October 2012 |pmid=22290745 |doi=10.1002/ijc.27457 |url=}}</ref>
===Age===
===Age===
*The average age at time of endometrial intraepithelial neoplasia diagnosis is approximately 52 years, compared to approximately 61 years for carcinoma.
*The incidence of endometrial intraepithelial neoplasia (EIN) increases with age; the median age at [[diagnosis]] is 52 years.<ref name="pmid18637968">{{cite journal |vauthors=Carlson JW, Mutter GL |title=Endometrial intraepithelial neoplasia is associated with polyps and frequently has metaplastic change |journal=Histopathology |volume=53 |issue=3 |pages=325–32 |date=September 2008 |pmid=18637968 |pmc=2574678 |doi=10.1111/j.1365-2559.2008.03104.x |url=}}</ref>
===Gender===
===Race===
*Females are affected with endometrial intraepithelial neoplasia.
*Endometrial intraepithelial neoplasia (EIN) usually affects individuals of the African American [[race]]. Asian individuals are less likely to develop endometrial intraepithelial neoplasia.<ref name="HouMcAndrew2013">{{cite journal|last1=Hou|first1=June Y.|last2=McAndrew|first2=Thomas C.|last3=Goldberg|first3=Gary L.|last4=Whitney|first4=Kathleen|last5=Shahabi|first5=Shohreh|title=A Clinical and Pathologic Comparison Between Stage-Matched Endometrial Intraepithelial Carcinoma and Uterine Serous Carcinoma|journal=Reproductive Sciences|volume=21|issue=4|year=2013|pages=532–537|issn=1933-7191|doi=10.1177/1933719113503414}}</ref>
 
==Risk Factors==
==Risk Factors==
*The most potent [[risk factor]] in the development of endometrial intraepithelial neoplasia (EIN) is [[Exposure (photography)|exposure]] to [[endogenous]] ([[exogenous]] [[estrogen]] without opposing by a [[progestin]]).<ref name="pmid26463434">{{cite journal |vauthors=Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R |title=Therapeutic options for management of endometrial hyperplasia |journal=J Gynecol Oncol |volume=27 |issue=1 |pages=e8 |date=January 2016 |pmid=26463434 |pmc=4695458 |doi=10.3802/jgo.2016.27.e8 |url=}}</ref>
*The most potent [[risk factor]] in the development of endometrial intraepithelial neoplasia (EIN) is [[Exposure (photography)|exposure]] to [[endogenous]] ([[exogenous]] [[estrogen]] without opposing by a [[progestin]]).<ref name="pmid26463434">{{cite journal |vauthors=Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R |title=Therapeutic options for management of endometrial hyperplasia |journal=J Gynecol Oncol |volume=27 |issue=1 |pages=e8 |date=January 2016 |pmid=26463434 |pmc=4695458 |doi=10.3802/jgo.2016.27.e8 |url=}}</ref>
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             Epidemiology of Endometrial Cancer
             Epidemiology of Endometrial Cancer
             2
             2
           |journal=JNCI: Journal of the National Cancer Institute|volume=59|issue=4|year=1977|pages=1055–1060|issn=1460-2105|doi=10.1093/jnci/59.4.1055}}</ref><ref name="pmid6590913">{{cite journal |vauthors=La Vecchia C, Franceschi S, Decarli A, Gallus G, Tognoni G |title=Risk factors for endometrial cancer at different ages |journal=J. Natl. Cancer Inst. |volume=73 |issue=3 |pages=667–71 |date=September 1984 |pmid=6590913 |doi= |url=}}</ref><ref name="pmid23344409">{{cite journal |vauthors=Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P |title=Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer |journal=Obstet Gynecol |volume=121 |issue=2 Pt 2 Suppl 1 |pages=461–4 |date=February 2013 |pmid=23344409 |pmc=3799979 |doi=http://10 1097/AOG.0b013e318270444f |url=}}</ref>
           |journal=JNCI: Journal of the National Cancer Institute|volume=59|issue=4|year=1977|pages=1055–1060|issn=1460-2105|doi=10.1093/jnci/59.4.1055}}</ref><ref name="pmid6590913">{{cite journal |vauthors=La Vecchia C, Franceschi S, Decarli A, Gallus G, Tognoni G |title=Risk factors for endometrial cancer at different ages |journal=J. Natl. Cancer Inst. |volume=73 |issue=3 |pages=667–71 |date=September 1984 |pmid=6590913 |doi= |url=}}</ref><ref name="pmid23344409">{{cite journal |vauthors=Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P |title=Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer |journal=Obstet Gynecol |volume=121 |issue=2 Pt 2 Suppl 1 |pages=461–4 |date=February 2013 |pmid=23344409 |pmc=3799979 |doi=http://10 1097/AOG.0b013e318270444f |url=}}</ref><ref name="pmid264634342">{{cite journal |vauthors=Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R |title=Therapeutic options for management of endometrial hyperplasia |journal=J Gynecol Oncol |volume=27 |issue=1 |pages=e8 |date=January 2016 |pmid=26463434 |pmc=4695458 |doi=10.3802/jgo.2016.27.e8 |url=}}</ref>
:*[[Ageing|Aging]]  
:*[[Ageing|Aging]]  
:*Early [[menarche]]  
:*Early [[menarche]]  
Line 57: Line 61:
:*[[Polycystic ovary syndrome (patient information)|Polycystic ovary syndrome]] ([[Chronic (medical)|chronic]] [[anovulation]])
:*[[Polycystic ovary syndrome (patient information)|Polycystic ovary syndrome]] ([[Chronic (medical)|chronic]] [[anovulation]])
:*Nulliparity
:*Nulliparity
:*[[Infertility|Infertile]] women
:*[[Hypertension]]
:*[[Cowden syndrome]]
:*[[Cowden syndrome]]
:*[[Hereditary nonpolyposis colorectal cancer|Lynch syndrome]] ([[hereditary nonpolyposis colorectal cancer|hereditary conditions such as hereditary nonpolyposis colorectal cancer]])
:*[[Hereditary nonpolyposis colorectal cancer|Lynch syndrome]] ([[hereditary nonpolyposis colorectal cancer|hereditary conditions such as hereditary nonpolyposis colorectal cancer]])
:*Family history ([[Endometrium|endometrial]], [[Ovary|ovarian]], [[breast]], [[Colon (anatomy)|colon]] [[cancer]])
:*Family history ([[Endometrium|endometrial]], [[Ovary|ovarian]], [[breast]], [[Colon (anatomy)|colon]] [[cancer]])
:*White [[race]]
:*[[Smoking|Cigarette smoking]]
== Natural History, Complications and Prognosis==
*If left untreated, 38% of the [[Patient|patients]] with endometrial intraepithelial neoplasia may progress to develop [[endometrial]] [[cancer]].<ref name="pmid233444092">{{cite journal |vauthors=Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P |title=Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer |journal=Obstet Gynecol |volume=121 |issue=2 Pt 2 Suppl 1 |pages=461–4 |date=February 2013 |pmid=23344409 |pmc=3799979 |doi=http://10 1097/AOG.0b013e318270444f |url=}}</ref>
*Common [[Complication (medicine)|complications]] of endometrial intraepithelial neoplasia include:<ref name="pmid26715174">{{cite journal |vauthors=Soslow RA |title=Practical issues related to uterine pathology: staging, frozen section, artifacts, and Lynch syndrome |journal=Mod. Pathol. |volume=29 Suppl 1 |issue= |pages=S59–77 |date=January 2016 |pmid=26715174 |pmc=4821462 |doi=10.1038/modpathol.2015.127 |url=}}</ref>
**[[Carcinoma]]
**[[Metastasis|Metastases]]
**Death
*The [[Prognosis]] of endometrial intraepithelial neoplasia is generally good with treatment.


== Natural History, Complications and Prognosis==
*If left untreated, according to a study,  38% of patients with endometrial intraepithelial neoplasia may progress to develop  endometrial cancer.<ref name="pmid233444092">{{cite journal |vauthors=Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P |title=Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer |journal=Obstet Gynecol |volume=121 |issue=2 Pt 2 Suppl 1 |pages=461–4 |date=February 2013 |pmid=23344409 |pmc=3799979 |doi=http://10 1097/AOG.0b013e318270444f |url=}}</ref>
*Common complications of endometrial intraepithelial neoplasia include endometrial carcinoma, metastases and death.
*Prognosis is generally good with treatment.
== Diagnosis ==
== Diagnosis ==
===Diagnostic Criteria===
===Diagnostic Criteria===
*The diagnosis of endometrial intraepithelial neoplasia is made when the following diagnostic criteria are met:
*The [[diagnosis]] [[histologic]] criteria of endometrial intraepithelial neoplasia are:<ref name="OwingsQuick20142">{{cite journal|last1=Owings|first1=Richard A.|last2=Quick|first2=Charles M.|title=Endometrial Intraepithelial Neoplasia|journal=Archives of Pathology & Laboratory Medicine|volume=138|issue=4|year=2014|pages=484–491|issn=0003-9985|doi=10.5858/arpa.2012-0709-RA}}</ref>
:*Area of glands greater than stroma (volume percentage stroma less than 55%)
:*Area of glands is larger than [[stroma]] area
:*Cytology differs between architecturally crowded focus and background
:*[[Cytology]] differs between architecturally crowded focus and background
:*Maximum linear dimension exceeds 1 mm
:*size ≥ 1mm
:*Benign conditions with overlapping criteria (ie, basalis, secretory, polyps, repair)
:*Forbiddance of [[Endometrial cancer|adenocarcinoma]]
:*Carcinoma if maze-like glands, solid areas, or appreciable cribriforming
:*Forbiddance of [[mimics]]
{| border="1"  
=== Symptoms ===
|-
*The [[hallmark]] symptom of endometrial intraepithelial neoplasia is [[postmenopausal]] [[abnormal]] [[Uterus|uterine]] [[bleeding]]; [[Spot|spotting]] or [[staining]].<ref name="pmid17413975">{{cite journal |vauthors=Mutter GL, Zaino RJ, Baak JP, Bentley RC, Robboy SJ |title=Benign endometrial hyperplasia sequence and endometrial intraepithelial neoplasia |journal=Int. J. Gynecol. Pathol. |volume=26 |issue=2 |pages=103–14 |date=April 2007 |pmid=17413975 |doi=10.1097/PGP.0b013e31802e4696 |url=}}</ref><ref name="pmid16055605">{{cite journal |vauthors= |title=ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer |journal=Obstet Gynecol |volume=106 |issue=2 |pages=413–25 |date=August 2005 |pmid=16055605 |doi= |url=}}</ref>
!
*Premonpausal women with endometrial intraepithelial neoplasia may have a positive [[History and Physical examination|history]] of [[abnormal]] [[uterine]] [[bleeding]]:<ref name="pmid26528056">{{cite journal |vauthors=Nicula R, Costin N |title=Management of endometrial modifications in perimenopausal women |journal=Clujul Med |volume=88 |issue=2 |pages=101–10 |date=2015 |pmid=26528056 |pmc=4576794 |doi=10.15386/cjmed-421 |url=}}</ref><ref name="MarnachLaughlin-Tommaso2019">{{cite journal|last1=Marnach|first1=Mary L.|last2=Laughlin-Tommaso|first2=Shannon K.|title=Evaluation and Management of Abnormal Uterine Bleeding|journal=Mayo Clinic Proceedings|volume=94|issue=2|year=2019|pages=326–335|issn=00256196|doi=10.1016/j.mayocp.2018.12.012}}</ref>
! EIN Criterion
:*[[Bleeding|Intermenstrual beeding]]
!Comments
:*Frequent [[bleeding]] (episodes of [[bleeding]] that are less than 21 days long)
|-
:*Heavy [[bleeding]] ([[volume]] e more than 80 ml)
|1 || Architecture || Gland area exceeds that of stroma, usually in a localized region.
:*[[Prothrombin time|Prolonged]] [[bleeding]]  (more than 7 days)
|-
:*[[Prothrombin time|Prolonged]] [[amenorrhea]] (more than 6 months)
|2 || Cytological<br> Alterations || Cytology differs between architecturally crowded focus and background.
:*[[Chronic (medical)|Chronic]] [[anovulation]]
|-
|3 || Size greater than 1mm || Maximum linear dimension should exceed 1mm. Smaller lesions have unknown natural history.
|-
|4 || Exclude mimics || Basalis, normal secretory, polyps, repair, lower uterine segment, cystic atrophy, tangential sections, menstrual collapse, disruption artifact, etc.
|-
|5 || Exclude Cancer || Carcinoma should be diagnosed if: glands are mazelike and rambling, there are solid areas of epithelial growth, or there are significant bridges or cribriform areas.
|}


=== Symptoms ===
*The hallmark of endometrial intraepithelial neoplasia is postmenopausal bleeding.
:* Postmenopausal bleeding
=== Physical Examination ===
=== Physical Examination ===
*Physical examination may be remarkable for:
*[[Vaginal|Rectovaginal]] [[Physical examination|examination]] may be reveal:<ref name="pmid26713674">{{cite journal |vauthors=López F, Rodrigo JP, Silver CE, Haigentz M, Bishop JA, Strojan P, Hartl DM, Bradley PJ, Mendenhall WM, Suárez C, Takes RP, Hamoir M, Robbins KT, Shaha AR, Werner JA, Rinaldo A, Ferlito A |title=Cervical lymph node metastases from remote primary tumor sites |journal=Head Neck |volume=38 Suppl 1 |issue= |pages=E2374–85 |date=April 2016 |pmid=26713674 |doi=10.1002/hed.24344 |url=}}</ref>
:* Palpable pelvic masses
**[[Palpation|Palpable]] [[Pelvis|pelvic]] [[Mass|masses]]
**[[Supraclavicular]] nodes (in cases of advanced [[disease]])
 
=== Laboratory Findings ===
=== Laboratory Findings ===
*There are no specific laboratory findings associated with endometrial intraepithelial neoplasia.
*There are no specific [[Medical laboratory|laboratory]] findings associated with endometrial intraepithelial neoplasia.
===Imaging Findings===
===Imaging Findings===
*Transvaginal ultrasonography is indicated for postmenopausal patient who has bleeding to detect malignancy.
*[[Gynecologic ultrasonography|Transvaginal ultrasonography]] is the [[imaging]] modality of choice for endometrial intraepithelial neoplasia.<ref name="pmid23833528">{{cite journal |vauthors=Kotdawala P, Kotdawala S, Nagar N |title=Evaluation of endometrium in peri-menopausal abnormal uterine bleeding |journal=J Midlife Health |volume=4 |issue=1 |pages=16–21 |date=January 2013 |pmid=23833528 |pmc=3702059 |doi=10.4103/0976-7800.109628 |url=}}</ref>
*If transvaginal ultrasonography demonstrate an endometrial thickness greater than 4 mm or an inability to adequately visualize endometrial thickness should warrant further evaluation using sonohysterography, office hysteroscopy, or endometrial biopsy.
*On [[transvaginal ultrasonography]], endometrial intraepithelial neoplasia is characterized by [[Endometrium|endometrial]] thickness > 4 mm.
**[[Biopsy]] should be performed for [[Patient|patients]] who have:
***[[Endometrium|Endometrial]] thickness > 4 mm
***[[Bleeding]] (even if the [[Endometrium|endometrial]] thickness is less than 4 mm)
 
=== Other Diagnostic Studies ===
=== Other Diagnostic Studies ===
*Endometrial intraepithelial neoplasia is mainly diagnosed using endometrial suction curette and hematoxylin and eosin staining.
*Endometrial intraepithelial neoplasia is mainly [[diagnose]]<nowiki/>d using [[endometrial]] [[suction]] [[curette]], [[hematoxylin]] and [[eosin]] [[staining]] and [[hysteroscopy]].<ref name="pmid24289604">{{cite journal |vauthors=Li XC, Song WJ |title=Endometrial Intraepithelial Neoplasia (EIN) in endometrial biopsy specimens categorized by the 1994 World Health Organization classification for endometrial hyperplasia |journal=Asian Pac. J. Cancer Prev. |volume=14 |issue=10 |pages=5935–9 |date=2013 |pmid=24289604 |doi= |url=}}</ref>
== Treatment ==
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
*The mainstay of medical therapy for endometrial intraepithelial neoplasia is progestin therapy.
*[[Progestin]] [[therapy]] is recommended for [[Patient|patients]] with endometrial intraepithelial neoplasia.
*[[patient]] should be followed up by [[biopsy]] every 6 months until obtaining 3 consecutive negative [[Biopsy|biopsies]] .<ref name="pmid230905353">{{cite journal |vauthors=Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL |title=Management of endometrial precancers |journal=Obstet Gynecol |volume=120 |issue=5 |pages=1160–75 |date=November 2012 |pmid=23090535 |pmc=3800154 |doi=http://10.1097/AOG.0b013e31826bb121 |url=}}</ref><ref name="OwingsQuick20143">{{cite journal|last1=Owings|first1=Richard A.|last2=Quick|first2=Charles M.|title=Endometrial Intraepithelial Neoplasia|journal=Archives of Pathology & Laboratory Medicine|volume=138|issue=4|year=2014|pages=484–491|issn=0003-9985|doi=10.5858/arpa.2012-0709-RA}}</ref>
=== Surgery ===
=== Surgery ===
*Hysterectomy is recommended following the diagnosis of endometrial intraepithelial neoplasia to prevent endometrial carcinoma.
*[[Hysterectomy]] is the mainstay of [[Treatment Planning|treatment]] for endometrial intraepithelial neoplasia to [[Prevention|prevent]] [[endometrial]] [[carcinoma]].<ref name="pmid23090535">{{cite journal |vauthors=Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL |title=Management of endometrial precancers |journal=Obstet Gynecol |volume=120 |issue=5 |pages=1160–75 |date=November 2012 |pmid=23090535 |pmc=3800154 |doi=http://10.1097/AOG.0b013e31826bb121 |url=}}</ref>
 
=== Prevention ===
=== Prevention ===
*Hysterectomy is recommended following the diagnosis of endometrial intraepithelial neoplasia to prevent endometrial carcinoma.
*Effective measures for the primary [[Prevention (medical)|prevention]] of endometrial intraepithelial neoplasia include:<ref name="pmid230905354">{{cite journal |vauthors=Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL |title=Management of endometrial precancers |journal=Obstet Gynecol |volume=120 |issue=5 |pages=1160–75 |date=November 2012 |pmid=23090535 |pmc=3800154 |doi=http://10.1097/AOG.0b013e31826bb121 |url=}}</ref>
**Combination of [[estrogen]] and [[progestin]] for [[hormone]] [[therapy]]
**[[Physical exercise]]
**Keep [[Health|healthy]] [[weight]] ( [[Body mass index|BMI]]: 18.5 - 24.9)
*Effective measures for the secondary [[Prevention (medical)|prevention]] of endometrial intraepithelial neoplasia include [[hysterectomy]] to prevent [[Endometrium|endometrial]] [[carcinoma]].<ref name="pmid230905352">{{cite journal |vauthors=Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL |title=Management of endometrial precancers |journal=Obstet Gynecol |volume=120 |issue=5 |pages=1160–75 |date=November 2012 |pmid=23090535 |pmc=3800154 |doi=http://10.1097/AOG.0b013e31826bb121 |url=}}</ref>
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Oncology]]
[[Category:Oncology]]
[[Category:Up-To-Date]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Medicine]]
[[Category:Gynecology]]
[[Category:Gynecology]]
[[Category:Surgery]]
[[Category:Surgery]]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

Synonyms and keywords: Atypical endometrial hyperplasia; Minimal uterine serous cancer (MUSC); Serous endometrial intraepithelial carcinoma (EIC); MUSC; Minimal uterine serous cancer

Overview

Endometrial intraepithelial neoplasia lesions was first described in the 1990s. Endometrial hyperplasia may be classified according to new World Health Organization (WHO2014) into two groups; hyperplasia without atypia (non-neoplastic) and atypical hyperplasia (endometrial intraepithelial neoplasm). Endometrial intraepithelial neoplasia arises from premalignant endometrial glands , which are risk of transmutatain to endometrial edometrioid carcinoma. Inactivation (mutation or deletion) of the PTEN tumor suppressor gene, inactivation of PAX2 gene, KRAS mutations, Microsatellite instability, Mutation in p53 gene are involved in the pathogenesis of endometrial intraepithelial neoplasia (EIN). Endometrial intraepithelial neoplasia may be caused by estrogenic stimulation of the endometrium that is unopposed by progestin. On microscopic histopathological analysis, individual glands are lined by a single layer of pseudostratified epithelium which is a characteristic finding of endometrial intraepithelial neoplasia. In 2002, the incidence of endometrial intraepithelial neoplasia (EIN) was estimated to be 144 cases per 100,000 individuals worldwide. The hallmark symptom of endometrial intraepithelial neoplasia is postmenopausal abnormal uterine bleeding. There are no specific laboratory findings associated with endometrial intraepithelial neoplasia. Transvaginal ultrasonography is the imaging modality of choice for endometrial intraepithelial neoplasia. Progestin therapy is recommended among patients with endometrial intraepithelial neoplasia. Hysterectomy is the mainstay of treatment for endometrial intraepithelial neoplasia to prevent endometrial carcinoma.

Historaical Perspective

Classification

Pathophysiology

Causes

Differentiating Endometrial intraepithelial neoplasia from other Diseases

  • Endometrial intraepithelial neoplasia must be differentiated from other causes of postmenopausal differentiated from:[11][14]

Epidemiology and Demographics

Prevalence and Incidence

  • In 2002, the incidence of endometrial intraepithelial neoplasia (EIN) was estimated to be 144 cases per 100,000 individuals worldwide.[15]

Age

  • The incidence of endometrial intraepithelial neoplasia (EIN) increases with age; the median age at diagnosis is 52 years.[16]

Race

  • Endometrial intraepithelial neoplasia (EIN) usually affects individuals of the African American race. Asian individuals are less likely to develop endometrial intraepithelial neoplasia.[17]

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

  • Area of glands is larger than stroma area
  • Cytology differs between architecturally crowded focus and background
  • size ≥ 1mm
  • Forbiddance of adenocarcinoma
  • Forbiddance of mimics

Symptoms

Physical Examination

Laboratory Findings

  • There are no specific laboratory findings associated with endometrial intraepithelial neoplasia.

Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Prevention

References

  1. ↑ Mutter GL, Duska L, Crum CP (2005). "Endometrial Intraepithelial Neoplasia". In Crum CP, Lee K. Diagnostic Gynecologic and Obstetric Pathology. Philadelphia PA: Saunders. pp. 493–518.
  2. ↑ Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales F, Tavassoli FA (2003). "Tumors of the uterine corpus: epithelial tumors and related lesions". In Tavassoli FA, Stratton MR. WHO Classification of Tumors: Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, France: IARC Press. pp. 221–232.
  3. ↑ Emons G, Beckmann MW, Schmidt D, Mallmann P (February 2015). "New WHO Classification of Endometrial Hyperplasias". Geburtshilfe Frauenheilkd. 75 (2): 135–136. doi:10.1055/s-0034-1396256. PMC 4361167. PMID 25797956.
  4. ↑ Wang, Steven; Wang, Zhenglong; Mittal, Khushbakhat (2015). "Concurrent endometrial intraepithelial carcinoma (EIC) and endometrial hyperplasia". Human Pathology: Case Reports. 2 (1): 1–4. doi:10.1016/j.ehpc.2014.07.003. ISSN 2214-3300.
  5. ↑ Jarboe EA, Mutter GL (November 2010). "Endometrial intraepithelial neoplasia". Semin Diagn Pathol. 27 (4): 215–25. PMID 21309257.
  6. ↑ Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C (June 2001). "Molecular identification of latent precancers in histologically normal endometrium". Cancer Res. 61 (11): 4311–4. PMID 11389050.
  7. ↑ Faquin WC, Fitzgerald JT, Lin MC, Boynton KA, Muto MG, Mutter GL (April 2000). "Sporadic microsatellite instability is specific to neoplastic and preneoplastic endometrial tissues". Am. J. Clin. Pathol. 113 (4): 576–82. doi:10.1309/F4TU-6AFE-R7NU-39Y3. PMID 10787358.
  8. ↑ Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL (August 2010). "Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer". Cancer Res. 70 (15): 6225–32. doi:10.1158/0008-5472.CAN-10-0149. PMC 2912978. PMID 20631067.
  9. ↑ Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C (June 2001). "Molecular identification of latent precancers in histologically normal endometrium". Cancer Res. 61 (11): 4311–4. PMID 11389050.
  10. ↑ O'Hara AJ, Bell DW (March 2012). "The genomics and genetics of endometrial cancer". Adv Genomics Genet. 2012 (2): 33–47. doi:10.2147/AGG.S28953. PMC 3415201. PMID 22888282.
  11. ↑ 11.0 11.1 McCluggage WG (August 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.
  12. ↑ 12.0 12.1 Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check |doi= value (help). PMC 3800154. PMID 23090535.
  13. ↑ Owings, Richard A.; Quick, Charles M. (2014). "Endometrial Intraepithelial Neoplasia". Archives of Pathology & Laboratory Medicine. 138 (4): 484–491. doi:10.5858/arpa.2012-0709-RA. ISSN 0003-9985.
  14. ↑ McCluggage, W. Glenn (2011). "Benign Diseases of the Endometrium": 305–358. doi:10.1007/978-1-4419-0489-8_7.
  15. ↑ Lacey JV, Chia VM, Rush BB, Carreon DJ, Richesson DA, Ioffe OB, Ronnett BM, Chatterjee N, Langholz B, Sherman ME, Glass AG (October 2012). "Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan". Int. J. Cancer. 131 (8): 1921–9. doi:10.1002/ijc.27457. PMID 22290745.
  16. ↑ Carlson JW, Mutter GL (September 2008). "Endometrial intraepithelial neoplasia is associated with polyps and frequently has metaplastic change". Histopathology. 53 (3): 325–32. doi:10.1111/j.1365-2559.2008.03104.x. PMC 2574678. PMID 18637968.
  17. ↑ Hou, June Y.; McAndrew, Thomas C.; Goldberg, Gary L.; Whitney, Kathleen; Shahabi, Shohreh (2013). "A Clinical and Pathologic Comparison Between Stage-Matched Endometrial Intraepithelial Carcinoma and Uterine Serous Carcinoma". Reproductive Sciences. 21 (4): 532–537. doi:10.1177/1933719113503414. ISSN 1933-7191.
  18. ↑ Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R (January 2016). "Therapeutic options for management of endometrial hyperplasia". J Gynecol Oncol. 27 (1): e8. doi:10.3802/jgo.2016.27.e8. PMC 4695458. PMID 26463434.
  19. ↑ Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, Wolk A, Wentzensen N, Weiss NS, Webb PM, van den Brandt PA, van de Vijver K, Thompson PJ, Strom BL, Spurdle AB, Soslow RA, Shu XO, Schairer C, Sacerdote C, Rohan TE, Robien K, Risch HA, Ricceri F, Rebbeck TR, Rastogi R, Prescott J, Polidoro S, Park Y, Olson SH, Moysich KB, Miller AB, McCullough ML, Matsuno RK, Magliocco AM, Lurie G, Lu L, Lissowska J, Liang X, Lacey JV, Kolonel LN, Henderson BE, Hankinson SE, Håkansson N, Goodman MT, Gaudet MM, Garcia-Closas M, Friedenreich CM, Freudenheim JL, Doherty J, De Vivo I, Courneya KS, Cook LS, Chen C, Cerhan JR, Cai H, Brinton LA, Bernstein L, Anderson KE, Anton-Culver H, Schouten LJ, Horn-Ross PL (July 2013). "Type I and II endometrial cancers: have they different risk factors?". J. Clin. Oncol. 31 (20): 2607–18. doi:10.1200/JCO.2012.48.2596. PMC 3699726. PMID 23733771.
  20. ↑ Smith RA, von Eschenbach AC, Wender R, Levin B, Byers T, Rothenberger D, Brooks D, Creasman W, Cohen C, Runowicz C, Saslow D, Cokkinides V, Eyre H (2001). "American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001--testing for early lung cancer detection". CA Cancer J Clin. 51 (1): 38–75, quiz 77–80. PMID 11577479.
  21. ↑ Elwood, J. Mark; Cole, Philip; Rothman, Kenneth J.; Kaplan, Samuel D. (1977). "Epidemiology of Endometrial Cancer 2". JNCI: Journal of the National Cancer Institute. 59 (4): 1055–1060. doi:10.1093/jnci/59.4.1055. ISSN 1460-2105. line feed character in |title= at position 35 (help)
  22. ↑ La Vecchia C, Franceschi S, Decarli A, Gallus G, Tognoni G (September 1984). "Risk factors for endometrial cancer at different ages". J. Natl. Cancer Inst. 73 (3): 667–71. PMID 6590913.
  23. ↑ Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P (February 2013). "Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer". Obstet Gynecol. 121 (2 Pt 2 Suppl 1): 461–4. doi:http://10 1097/AOG.0b013e318270444f Check |doi= value (help). PMC 3799979. PMID 23344409.
  24. ↑ Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R (January 2016). "Therapeutic options for management of endometrial hyperplasia". J Gynecol Oncol. 27 (1): e8. doi:10.3802/jgo.2016.27.e8. PMC 4695458. PMID 26463434.
  25. ↑ Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P (February 2013). "Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer". Obstet Gynecol. 121 (2 Pt 2 Suppl 1): 461–4. doi:http://10 1097/AOG.0b013e318270444f Check |doi= value (help). PMC 3799979. PMID 23344409.
  26. ↑ Soslow RA (January 2016). "Practical issues related to uterine pathology: staging, frozen section, artifacts, and Lynch syndrome". Mod. Pathol. 29 Suppl 1: S59–77. doi:10.1038/modpathol.2015.127. PMC 4821462. PMID 26715174.
  27. ↑ Owings, Richard A.; Quick, Charles M. (2014). "Endometrial Intraepithelial Neoplasia". Archives of Pathology & Laboratory Medicine. 138 (4): 484–491. doi:10.5858/arpa.2012-0709-RA. ISSN 0003-9985.
  28. ↑ Mutter GL, Zaino RJ, Baak JP, Bentley RC, Robboy SJ (April 2007). "Benign endometrial hyperplasia sequence and endometrial intraepithelial neoplasia". Int. J. Gynecol. Pathol. 26 (2): 103–14. doi:10.1097/PGP.0b013e31802e4696. PMID 17413975.
  29. ↑ "ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer". Obstet Gynecol. 106 (2): 413–25. August 2005. PMID 16055605.
  30. ↑ Nicula R, Costin N (2015). "Management of endometrial modifications in perimenopausal women". Clujul Med. 88 (2): 101–10. doi:10.15386/cjmed-421. PMC 4576794. PMID 26528056.
  31. ↑ Marnach, Mary L.; Laughlin-Tommaso, Shannon K. (2019). "Evaluation and Management of Abnormal Uterine Bleeding". Mayo Clinic Proceedings. 94 (2): 326–335. doi:10.1016/j.mayocp.2018.12.012. ISSN 0025-6196.
  32. ↑ López F, Rodrigo JP, Silver CE, Haigentz M, Bishop JA, Strojan P, Hartl DM, Bradley PJ, Mendenhall WM, Suárez C, Takes RP, Hamoir M, Robbins KT, Shaha AR, Werner JA, Rinaldo A, Ferlito A (April 2016). "Cervical lymph node metastases from remote primary tumor sites". Head Neck. 38 Suppl 1: E2374–85. doi:10.1002/hed.24344. PMID 26713674.
  33. ↑ Kotdawala P, Kotdawala S, Nagar N (January 2013). "Evaluation of endometrium in peri-menopausal abnormal uterine bleeding". J Midlife Health. 4 (1): 16–21. doi:10.4103/0976-7800.109628. PMC 3702059. PMID 23833528.
  34. ↑ Li XC, Song WJ (2013). "Endometrial Intraepithelial Neoplasia (EIN) in endometrial biopsy specimens categorized by the 1994 World Health Organization classification for endometrial hyperplasia". Asian Pac. J. Cancer Prev. 14 (10): 5935–9. PMID 24289604.
  35. ↑ Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check |doi= value (help). PMC 3800154. PMID 23090535.
  36. ↑ Owings, Richard A.; Quick, Charles M. (2014). "Endometrial Intraepithelial Neoplasia". Archives of Pathology & Laboratory Medicine. 138 (4): 484–491. doi:10.5858/arpa.2012-0709-RA. ISSN 0003-9985.
  37. ↑ Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check |doi= value (help). PMC 3800154. PMID 23090535.
  38. ↑ Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check |doi= value (help). PMC 3800154. PMID 23090535.
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