Endometrial cancer pathophysiology: Difference between revisions

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__NOTOC__
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{{Infobox_Disease |
 
  Name          = Endometrial cancer |
  Image          = Endometrial adenocarcinoma (1).jpg|
  Caption        = A histologic view of an endometrial adenocarcinoma showing many abnormal nuclei|
}}
{{CMG}}{{AE}}{{MD}}
{{CMG}}{{AE}}{{MD}}
{{Endometrial cancer}}
{{Endometrial cancer}}
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==Pathogenesis==
==Pathogenesis==
* Endometrial cancer forms when there are errors in normal endometrial [[cell cycle|cell growth]].<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue=  | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918  }} </ref><ref>What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.</ref>
* Endometrial cancer forms when there are errors in normal endometrial [[cell cycle|cell growth]].<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue=  | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918  }} </ref><ref>What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.</ref>
* Development of an [[endometrial hyperplasia]] (overgrowth of endometrial cells) is a significant risk factor because [[hyperplasia]] can and often do develop into [[adenocarcinoma]], though cancer can develop without the presence of a hyperplasia. Within ten years, 8–30% of atypical endometrial hyperplasias develop into [[cancer]], whereas 1–3% of non-atypical hyperplasias do so.<ref name=Cochrane0613>{{cite journal|last1=Luo|first1=L|last2=Luo|first2=B|last3=Zheng|first3=Y|last4=Zhang|first4=H|last5=Li|first5=J|last6=Sidell|first6=N|title=Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia.|journal=The Cochrane database of systematic reviews|date=5 June 2013|volume=6|pages=CD009458|pmid=23737032|doi=10.1002/14651858.CD009458.pub2}}</ref>  
* Development of an [[endometrial hyperplasia]] (overgrowth of endometrial cells) is a significant risk factor because [[hyperplasia]] can and often do develop into [[adenocarcinoma]], though cancer can develop without the presence of a hyperplasia. Within ten years, 8–30% of atypical endometrial hyperplasias develop into [[cancer]], whereas 1–3% of non-atypical hyperplasias do so.<ref name="Cochrane0613">{{cite journal|last1=Luo|first1=L|last2=Luo|first2=B|last3=Zheng|first3=Y|last4=Zhang|first4=H|last5=Li|first5=J|last6=Sidell|first6=N|title=Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia.|journal=The Cochrane database of systematic reviews|date=5 June 2013|volume=6|pages=CD009458|pmid=23737032|doi=10.1002/14651858.CD009458.pub2}}</ref>  
* Mutations in the ''[[KRAS]]'' gene can cause endometrial hyperplasia and therefore type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of ''[[TP53]]'', and develops into a serous carcinoma (type II endometrial cancer).<ref name=bmj>{{cite journal |last1=Saso |first1=S |last2=Chatterjee |first2=J |last3=Georgiou |first3=E |last4=Ditri |first4=AM |last5=Smith |first5=JR |last6=Ghaem-Maghami |first6=S |year=2011 |title=Endometrial cancer |journal=BMJ |volume=343 |issue= |pages=d3954–d3954 |doi=10.1136/bmj.d3954 |pmid=21734165}}</ref>
* Mutations in the ''[[KRAS]]'' gene can cause endometrial hyperplasia and therefore type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of ''[[TP53]]'', and develops into a serous carcinoma (type II endometrial cancer).<ref name="bmj">{{cite journal |last1=Saso |first1=S |last2=Chatterjee |first2=J |last3=Georgiou |first3=E |last4=Ditri |first4=AM |last5=Smith |first5=JR |last6=Ghaem-Maghami |first6=S |year=2011 |title=Endometrial cancer |journal=BMJ |volume=343 |issue= |pages=d3954–d3954 |doi=10.1136/bmj.d3954 |pmid=21734165}}</ref>
* Endometrial cancer frequently metastasizes to the ovaries and fallopian tubes when the cancer is located in the upper part of the uterus and the cervix when the cancer is in the lower part of the uterus.  
* Endometrial cancer frequently metastasizes to the ovaries and fallopian tubes when the cancer is located in the upper part of the uterus and the cervix when the cancer is in the lower part of the uterus.  
* The cancer usually first spreads into the myometrium and the [[serosa]], then into other reproductive and pelvic structures. When the [[lymphatic system]] is involved, the pelvic lymph nodes and para-aortic lymph nodes are usually first to become involved, but in no specific pattern, unlike cervical cancer.
* The cancer usually first spreads into the myometrium and the [[serosa]], then into other reproductive and pelvic structures. When the [[lymphatic system]] is involved, the pelvic lymph nodes and para-aortic lymph nodes are usually first to become involved, but in no specific pattern, unlike cervical cancer.
* More distant metastases are spread by the blood and often occur in the lungs, as well as the liver, brain, and bone.<ref name="pmid23545091">{{cite journal| author=Kurra V, Krajewski KM, Jagannathan J, Giardino A, Berlin S, Ramaiya N| title=Typical and atypical metastatic sites of recurrent endometrial carcinoma. | journal=Cancer Imaging | year= 2013 | volume= 13 | issue=  | pages= 113-22 | pmid=23545091 | doi=10.1102/1470-7330.2013.0011 | pmc=PMC3613792 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23545091  }} </ref>
* More distant metastases are spread by the blood and often occur in the [[lungs]], as well as the [[liver]], brain, and bone.<ref name="pmid23545091">{{cite journal| author=Kurra V, Krajewski KM, Jagannathan J, Giardino A, Berlin S, Ramaiya N| title=Typical and atypical metastatic sites of recurrent endometrial carcinoma. | journal=Cancer Imaging | year= 2013 | volume= 13 | issue=  | pages= 113-22 | pmid=23545091 | doi=10.1102/1470-7330.2013.0011 | pmc=PMC3613792 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23545091  }} </ref>


==Genetics==
==Genetics==
{| align=right<!--Placing these in a table with no border will keep them together/aligned in any browser-->
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|-
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{| class="wikitable sortable" align="right"
{| class="wikitable sortable"
|+Mutations found in Type I and Type II endometrial cancers<ref>International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.</ref>  
|+Mutations found in Type I and Type II endometrial cancers<ref>International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.</ref>  
|-
|-
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|17–41%
|17–41%
|-
|-
| ''CDH1 (gene)|CDH1''
| ''CDH1 (gene) |CDH1
|[[loss of heterozygosity]]
|[[loss of heterozygosity]]
|unknown
|unknown
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|-
|-
| ''PIK3CA'' ([[oncogene]])
| ''PIK3CA'' ([[oncogene]])
|point mutation or amplification (molecular biology)|amplification
| point mutation or amplification (molecular biology) |amplification
|24–39%
|24–39%
|20–30%
|20–30%
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Genes involved in pathogenesis of endometrial cancer involve:
Genes involved in pathogenesis of endometrial cancer involve:
* In 10–20% of endometrial cancers, mostly grade&nbsp;3 (the highest [[Grading (tumors)|histologic grade]]), [[mutation]]s are found in a [[tumor suppressor]] gene, commonly ''[[TP53]]'' or ''[[PTEN (gene)|PTEN]]''.  
* In 10–20% of endometrial cancers, mostly grade&nbsp;3 (the highest [[Grading (tumors)|histologic grade]]), [[mutation]]s are found in a [[tumor suppressor]] gene, commonly ''[[TP53]]'' or ''[[PTEN (gene)|PTEN]]''.  
* In 20% of [[endometrial hyperplasia]]s and 50% of endometrioid cancers, ''[[PTEN]]'' suffers a loss-of-function mutation or a null mutation, making it less effective or completely ineffective.<ref name=ComprehensiveGyn26/> Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }} </ref>  
* In 20% of [[endometrial hyperplasia]]s and 50% of endometrioid cancers, ''[[PTEN]]'' suffers a loss-of-function mutation or a null mutation, making it less effective or completely ineffective.<ref name="ComprehensiveGyn26" /> Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }} </ref>  
* The ''[[TP53]]'' pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of ''[[TP53]]'' is overexpressed, the cancer tends to be particularly aggressive. [[TP53]] mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }} </ref>
* The ''[[TP53]]'' pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of ''[[TP53]]'' is overexpressed, the cancer tends to be particularly aggressive. [[TP53]] mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }} </ref>
* ''[[PTEN]]'' and ''[[p27 (gene)|p27]]'' loss of function mutations are associated with a good prognosis, particularly in obese women. The ''Her2/neu'' [[oncogene]], which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. ''CTNNB1'' (beta-catenin; a [[transcription (genetics)|transcription]] gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with [[squamous cell]]s.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up}}. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }</ref>  
* ''[[PTEN]]'' and ''[[p27 (gene)|p27]]'' loss of function mutations are associated with a good prognosis, particularly in obese women. The ''Her2/neu'' [[oncogene]], which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. ''CTNNB1'' (beta-catenin; a [[transcription (genetics)|transcription]] gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with [[squamous cell]]s.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up}}. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }</ref>  
* ''[[FGFR2]]'' mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.<ref name=ComprehensiveGyn26>{{cite book |last1=Thaker |first1=PH |last2=Sood |first2=AK |chapter=Molecular Oncology in Gynecologic Cancer |editor-last1=Lentz |editor-first1=GM |editor-last2=Lobo |editor-first2=RA |editor-last3=Gershenson |editor-first3=DM |editor-last4=Katz |editor-first4=VL|displayeditors=4 |title=Comprehensive Gynecology |edition=6th |isbn=978-0-323-06986-1 |publisher=[[Mosby (publisher)|Mosby]]}}</ref>  
* ''[[FGFR2]]'' mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.<ref name="ComprehensiveGyn26">{{cite book |last1=Thaker |first1=PH |last2=Sood |first2=AK |chapter=Molecular Oncology in Gynecologic Cancer |editor-last1=Lentz |editor-first1=GM |editor-last2=Lobo |editor-first2=RA |editor-last3=Gershenson |editor-first3=DM |editor-last4=Katz |editor-first4=VL|displayeditors=4 |title=Comprehensive Gynecology |edition=6th |isbn=978-0-323-06986-1 |publisher=[[Mosby (publisher)|Mosby]]}}</ref>  
* ''[[SPOP]]'' is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.<ref>{{cite journal|last1=Mani|first1=RS|title=The emerging role of speckle-type POZ protein (SPOP) in cancer development.|journal=Drug Discovery Today|date=September  2014|volume=19|issue=9|pages=1498–1502|doi=10.1016/j.drudis.2014.07.009|pmid=25058385|quote="A recent exome-sequencing study revealed that 8% of serious endometrial cancers and 9% of clear cell endometrial cancers have SPOP mutations"}}</ref>
* ''[[SPOP]]'' is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.<ref>{{cite journal|last1=Mani|first1=RS|title=The emerging role of speckle-type POZ protein (SPOP) in cancer development.|journal=Drug Discovery Today|date=September  2014|volume=19|issue=9|pages=1498–1502|doi=10.1016/j.drudis.2014.07.009|pmid=25058385|quote="A recent exome-sequencing study revealed that 8% of serious endometrial cancers and 9% of clear cell endometrial cancers have SPOP mutations"}}</ref>
* Type I and type II cancers (explained below) tend to have different mutations involved. ''ARID1A'', which often carries a [[point mutation]] in type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium, and 18% of serous carcinomas. [[Gene silencing|Epigenetic silencing]] and [[point mutations]] of several genes are commonly found in type I endometrial cancer.<ref>International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.</ref>  
* Type I and type II cancers (explained below) tend to have different mutations involved. ''ARID1A'', which often carries a [[point mutation]] in type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium, and 18% of serous carcinomas. [[Gene silencing|Epigenetic silencing]] and [[point mutations]] of several genes are commonly found in type I endometrial cancer.<ref>International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.</ref>  
* Mutations in tumor suppressor genes are common in type II endometrial cancer. ''PIK3CA'' is commonly mutated in both type I and type II cancers. In women with Lynch syndrome-associated endometrial cancer, [[microsatellite instability]] is common.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }} </ref>
* Mutations in tumor suppressor genes are common in type II endometrial cancer. ''PIK3CA'' is commonly mutated in both type I and type II cancers. In women with Lynch syndrome-associated endometrial cancer, [[microsatellite instability]] is common.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue=  | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661  }} </ref>
* The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes ''[[PTEN]]'', a tumor suppressor; ''PIK3CA'', a [[kinase]]; ''[[KRAS]]'', a [[GTPase]] that functions in [[signal transduction]]; and ''CTNNB1'', involved in adhesion and cell signaling. The ''CTNNB1'' (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.<ref name=annonc>{{cite journal |last1=Colombo |first1=N |last2=Preti |first2=E |last3=Landoni |first3=F |last4=Carinelli |first4=S |last5=Colombo |first5=A |last6=Marini |first6=C |last7=Sessa |first7=C |year=2011 |title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Annals of Oncology |volume=22 |issue=Supplement 6 |pages=vi35–vi39 |doi=10.1093/annonc/mdr374 |pmid=21908501}}</ref>
* The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes ''[[PTEN]]'', a tumor suppressor gene, ''PIK3CA'' (expresses a [[kinase]]), ''[[KRAS]]'' (expresses [[GTPase]] that functions in [[signal transduction]]), and ''CTNNB1'' that expresses a protein involved in adhesion and cell signaling. The ''CTNNB1'' (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.<ref name="annonc">{{cite journal |last1=Colombo |first1=N |last2=Preti |first2=E |last3=Landoni |first3=F |last4=Carinelli |first4=S |last5=Colombo |first5=A |last6=Marini |first6=C |last7=Sessa |first7=C |year=2011 |title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Annals of Oncology |volume=22 |issue=Supplement 6 |pages=vi35–vi39 |doi=10.1093/annonc/mdr374 |pmid=21908501}}</ref>
* The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in ''[[TP53]]'', an important tumor suppressor gene.<ref name="pmid21975736">{{cite journal| author=Johnson N, Bryant A, Miles T, Hogberg T, Cornes P| title=Adjuvant chemotherapy for endometrial cancer after hysterectomy. | journal=Cochrane Database Syst Rev | year= 2011 | volume=  | issue= 10 | pages= CD003175 | pmid=21975736 | doi=10.1002/14651858.CD003175.pub2 | pmc=PMC4164379 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21975736  }} </ref>
* The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in ''[[TP53]]'', an important tumor suppressor gene.<ref name="pmid21975736">{{cite journal| author=Johnson N, Bryant A, Miles T, Hogberg T, Cornes P| title=Adjuvant chemotherapy for endometrial cancer after hysterectomy. | journal=Cochrane Database Syst Rev | year= 2011 | volume=  | issue= 10 | pages= CD003175 | pmid=21975736 | doi=10.1002/14651858.CD003175.pub2 | pmc=PMC4164379 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21975736  }} </ref>
* The p53 cell signaling system is not active in endometrial clear cell carcinoma.<ref name="pmid21734165">{{cite journal| author=Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-Maghami S| title=Endometrial cancer. | journal=BMJ | year= 2011 | volume= 343 | issue=  | pages= d3954 | pmid=21734165 | doi=10.1136/bmj.d3954 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21734165  }} </ref>
* The p53 cell signaling system is not active in endometrial clear cell carcinoma.<ref name="pmid21734165">{{cite journal| author=Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-Maghami S| title=Endometrial cancer. | journal=BMJ | year= 2011 | volume= 343 | issue=  | pages= d3954 | pmid=21734165 | doi=10.1136/bmj.d3954 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21734165  }} </ref>


==Microscopic Pathology==  
==Microscopic Pathology==  
On microscopic histopathological analysis, endometrial cancer is characterized by:
On microscopic histopathological analysis, endometrial cancer is characterized by:<ref>{{cite book | last = Hoffman | first = Barbara | title = Williams gynecology | publisher = McGraw-Hill Medical | location = New York | year = 2012 | isbn = 9780071716727 }}
</ref>


1. Endometrioid (75%–80%), (The most common endometrial cancer cell type is endometrioid adenocarcinoma, which is composed of malignant [[glandular]] epithelial elements)
1. Endometrioid (most common; 75%–80%)
:* Ciliated adenocarcinoma
:* Ciliated adenocarcinoma
:* Secretory adenocarcinoma
:* Secretory adenocarcinoma
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| Good
| Good
| Poor  
| Poor  
|}<ref>{{cite book | last = Hoffman | first = Barbara | title = Williams gynecology | publisher = McGraw-Hill Medical | location = New York | year = 2012 | isbn = 9780071716727 }}
|}
</ref>


===Endometrioid adenocarcinoma===
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center"
* In endometrioid adenocarcinoma, the cancer cells grow in patterns reminiscent of normal endometrium, with many new glands formed from [[columnar epithelium]] with some nuclear atypia|abnormal nuclei.  
| valign="top" |
* Low-grade endometrioid adenocarcinomas have well differentiated cells, have not invaded the myometrium, and are seen alongside endometrial hyperplasia. The tumor's glands form very close together, without the [[stroma (animal tissue)|stromal]] tissue that normally separates them.  
|+
* Higher-grade endometrioid adenocarcinomas have less well-differentiated cells, have more solid sheets of tumor cells no longer organized into glands, and are associated with an [[atrophy|atrophied]] endometrium. There are several subtypes of endometrioid adenocarcinoma with similar prognoses, including villoglandular, secretory, and ciliated cell variants. There is also a subtype characterized by [[squamous]] differentiation. Some endometrioid adenocarcinomas have foci of mucinous carcinoma.
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Types of endometrial cancer}}
 
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Histopathological features}}
===Serous carcinoma===
|-
* Serous endometrial carcinoma is aggressive and often invades the myometrium and metastasizes within the peritoneum seen as omental cake or the lymphatic system.  
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
* Histologically, it appears with many atypical nuclei, [[papilloma|papillary structures]], and, in contrast to endometrioid adenocarcinomas, rounded cells instead of columnar cells. Roughly 30% of endometrial serous carcinomas also have psammoma bodies.  
Endometrioid adenocarcinoma
* Serous carcinomas spread differently than most other endometrial cancers; they can spread outside the uterus without invading the myometrium.
| style="padding: 5px 5px; background: #F5F5F5;" |
 
:1. Cancer cells grow in patterns reminiscent of normal endometrium
===Clear cell carcinoma===
:2. Glands formed from [[columnar epithelium]] with abnormal nuclei
* Clear cell carcinoma, histologically, it is characterized by the features common to all [[clear cell]]s: the eponymous clear cytoplasm when [[H&E stain]]ed and visible, distinct cell membranes.
:3. Low-grade endometrioid adenocarcinomas
 
:*Well differentiated cells
===Mucinous carcinoma===
:*No invasion to the myometrium
* Mucinous endometrial carcinomas, typically have well-differentiated columnar cells organized into glands with the characteristic [[mucin]] in the cytoplasm.
:*Observed alongside endometrial hyperplasia
* Mucinous carcinomas must be differentiated from cervical adenocarcinoma.
:*Glands without the [[stroma (animal tissue)|stromal]] tissue that separates them.  
 
|-
===Mixed or undifferentiated carcinoma===
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
* Histologically, these tumors show sheets of identical epithelial cells with no identifiable pattern.
Serous carcinoma
 
| style="padding: 5px 5px; background: #F5F5F5;" |
===Other carcinomas===
:1. Cancer cells appears with many atypical nuclei, papillary structures, rounded cells
* Non-metastatic [[squamous cell carcinoma]] and [[transitional cell carcinoma]] are very rare in the endometrium.
:2. Aggressive and often invades the myometrium and metastasizes within the peritoneum seen as omental cake or the lymphatic system.
* For primary squamous cell carcinoma of the endometrium (PSCCE) to be diagnosed, there must be no other primary cancer in the endometrium or cervix and it must not be connected to the cervical epithelium. The common genetic causes remain uncharacterized.<ref name=Goodrich>{{cite journal |last1=Goodrich |first1 = S |last2 = Kebria-Moslemi |first2 = M |last3 = Broshears |first3 = J |last4 = Sutton |first4 = GP |last5 = Rose |first5 = P |title=Primary squamous cell carcinoma of the endometrium: two cases and a review of the literature |journal=Diagnostic Cytopathology |volume=41 |issue=9 |pages=817–20 |date=September 2013  |pmid=22241749 |doi=10.1002/dc.22814 |url=}}</ref><ref name=Marino>{{cite journal |last1 =Mariño-Enríquez |first1 = A |last2 = González-Rocha |first2 = T |last3 = Burgos |first3 = E |others = et al. |title=Transitional cell carcinoma of the endometrium and endometrial carcinoma with transitional cell differentiation: a clinicopathologic study of 5 cases and review of the literature |journal=Human Pathology |volume=39 |issue=11 |pages=1606–13 |date=November 2008  |pmid=18620731 |doi=10.1016/j.humpath.2008.03.005 |url=}}</ref>
:3. They can spread outside the uterus without invading the myometrium.
*Histologically, TCCE resembles endometrioid carcinoma and is distinct from other transitional cell carcinomas.<ref>{{cite journal |last1 = Ahluwalia |first1 = M |last2 = Light |first2 = AM |last3 = Surampudi |first3 = K |last4 = Finn |first4 = CB |title=Transitional cell carcinoma of the endometrium: a case report and review of the literature |journal= International Journal of Gynecological Pathology |volume=25 |issue=4 |pages=378–82 |date=October 2006  |pmid=16990716 |doi=10.1097/01.pgp.0000215296.53361.4b |url=}}</ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Clear cell carcinoma
| style="padding: 5px 5px; background: #F5F5F5;" |
:1. Common to all clear cells visible
:2. Distinct cell membranes
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Mucinous carcinoma
| style="padding: 5px 5px; background: #F5F5F5;" |
Well-differentiated columnar cells organized into glands with the characteristic mucin in the cytoplasm.
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Mixed or undifferentiated carcinoma
| style="padding: 5px 5px; background: #F5F5F5;" |
Sheets of identical epithelial cells with no identifiable pattern
|}


==References==
==References==
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[[Category:Gynecology]]
[[Category:Gynecology]]
[[Category:Disease]]
[[Category:Disease]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Gynecology]]
[[Category:Surgery]]

Latest revision as of 23:01, 23 May 2019


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Monalisa Dmello, M.B,B.S., M.D. [2]

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Overview

Development of endometrial cancer is the result of multiple genetic mutations. Genes involved in the pathogenesis of endometrial cancer include TP53, KRAS, and PTEN. The pathophysiology of endometrial cancer depends on the histological subtype.

Pathogenesis

  • Endometrial cancer forms when there are errors in normal endometrial cell growth.[1][2]
  • Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasia can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.[3]
  • Mutations in the KRAS gene can cause endometrial hyperplasia and therefore type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of TP53, and develops into a serous carcinoma (type II endometrial cancer).[4]
  • Endometrial cancer frequently metastasizes to the ovaries and fallopian tubes when the cancer is located in the upper part of the uterus and the cervix when the cancer is in the lower part of the uterus.
  • The cancer usually first spreads into the myometrium and the serosa, then into other reproductive and pelvic structures. When the lymphatic system is involved, the pelvic lymph nodes and para-aortic lymph nodes are usually first to become involved, but in no specific pattern, unlike cervical cancer.
  • More distant metastases are spread by the blood and often occur in the lungs, as well as the liver, brain, and bone.[5]

Genetics

Mutations found in Type I and Type II endometrial cancers[6]
Gene mutated Mutation type Type I prevalence Type II prevalence
ARID1A point mutation 40% unknown
CTNNB1 point mutation 14–44% unknown
FGFR2 point mutation 16% unknown
KRAS point mutation 10–20% unknown
PIK3R1 point mutation 43% unknown
TP53 point mutation 10–20% 90%
PTEN point mutation 37–61% unknown
MLH1 epigenetic silencing 30% unknown
RASSF1A epigenetic silencing 48% unknown
SPRY2 epigenetic silencing 20% unknown
PPP2R1A point mutation unknown 17–41%
CDH1 loss of heterozygosity unknown 80–90%
CDKN2A loss of heterozygosity and/or
epigenetic silencing 		20% 40%
PIK3CA (oncogene) amplification 24–39% 20–30%
PIK3R1 (oncogene) point mutation unknown 12%
STK15 (oncogene) amplification unknown 60%
CCNE1 (oncogene) amplification unknown 55%
ERBB2 (oncogene) amplification unknown 30%
CCND1 (oncogene) amplification unknown 26%

Genes involved in pathogenesis of endometrial cancer involve:

  • In 10–20% of endometrial cancers, mostly grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly TP53 or PTEN.
  • In 20% of endometrial hyperplasias and 50% of endometrioid cancers, PTEN suffers a loss-of-function mutation or a null mutation, making it less effective or completely ineffective.[7] Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.[8]
  • The TP53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of TP53 is overexpressed, the cancer tends to be particularly aggressive. TP53 mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.[8]
  • PTEN and p27 loss of function mutations are associated with a good prognosis, particularly in obese women. The Her2/neu oncogene, which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. CTNNB1 (beta-catenin; a transcription gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with squamous cells.[8]
  • FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.[7]
  • SPOP is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.[9]
  • Type I and type II cancers (explained below) tend to have different mutations involved. ARID1A, which often carries a point mutation in type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium, and 18% of serous carcinomas. Epigenetic silencing and point mutations of several genes are commonly found in type I endometrial cancer.[10]
  • Mutations in tumor suppressor genes are common in type II endometrial cancer. PIK3CA is commonly mutated in both type I and type II cancers. In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.[8]
  • The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes PTEN, a tumor suppressor gene, PIK3CA (expresses a kinase), KRAS (expresses GTPase that functions in signal transduction), and CTNNB1 that expresses a protein involved in adhesion and cell signaling. The CTNNB1 (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.[11]
  • The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in TP53, an important tumor suppressor gene.[12]
  • The p53 cell signaling system is not active in endometrial clear cell carcinoma.[13]

Microscopic Pathology

On microscopic histopathological analysis, endometrial cancer is characterized by:[14]

1. Endometrioid (most common; 75%–80%)

  • Ciliated adenocarcinoma
  • Secretory adenocarcinoma
  • Papillary or villoglandular
  • Adenocarcinoma with squamous differentiation
  • Adenoacanthoma
  • Adenosquamous (Adenosquamous tumors contain malignant elements of both glandular and squamous epithelium)

2. Uterine papillary serous (<10%)

3. Mucinous (1%)

4. Clear cell (4%)

5. Squamous cell (<1%)

6. Mixed (10%)

7. Undifferentiated

Characteristic/Parameter Type I endometrial cancers Type II endometrial cancers
Time of onset Occur most commonly before and around the time of menopause Occur in older, post-menopausal
Race White Black
Grade of tumor Low-grade High-grade
Invasive Minimally invasive into the underlying uterine wall myometrium Deep invasion into the underlying myometrium
Estrogen Dependent Independent
Type Endometrioid Uterine papillary serous carcinoma, clear cell carcinoma
Prognosis. Good Poor
Types of endometrial cancer Histopathological features

Endometrioid adenocarcinoma

1. Cancer cells grow in patterns reminiscent of normal endometrium
2. Glands formed from columnar epithelium with abnormal nuclei
3. Low-grade endometrioid adenocarcinomas
  • Well differentiated cells
  • No invasion to the myometrium
  • Observed alongside endometrial hyperplasia
  • Glands without the stromal tissue that separates them.

Serous carcinoma

1. Cancer cells appears with many atypical nuclei, papillary structures, rounded cells
2. Aggressive and often invades the myometrium and metastasizes within the peritoneum seen as omental cake or the lymphatic system.
3. They can spread outside the uterus without invading the myometrium.

Clear cell carcinoma

1. Common to all clear cells visible
2. Distinct cell membranes

Mucinous carcinoma

Well-differentiated columnar cells organized into glands with the characteristic mucin in the cytoplasm.

Mixed or undifferentiated carcinoma

Sheets of identical epithelial cells with no identifiable pattern

References

  1. ↑ Kong A, Johnson N, Kitchener HC, Lawrie TA (2012). "Adjuvant radiotherapy for stage I endometrial cancer". Cochrane Database Syst Rev. 4: CD003916. doi:10.1002/14651858.CD003916.pub4. PMC 4164955. PMID 22513918.
  2. ↑ What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.
  3. ↑ Luo, L; Luo, B; Zheng, Y; Zhang, H; Li, J; Sidell, N (5 June 2013). "Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia". The Cochrane database of systematic reviews. 6: CD009458. doi:10.1002/14651858.CD009458.pub2. PMID 23737032.
  4. ↑ Saso, S; Chatterjee, J; Georgiou, E; Ditri, AM; Smith, JR; Ghaem-Maghami, S (2011). "Endometrial cancer". BMJ. 343: d3954–d3954. doi:10.1136/bmj.d3954. PMID 21734165.
  5. ↑ Kurra V, Krajewski KM, Jagannathan J, Giardino A, Berlin S, Ramaiya N (2013). "Typical and atypical metastatic sites of recurrent endometrial carcinoma". Cancer Imaging. 13: 113–22. doi:10.1102/1470-7330.2013.0011. PMC 3613792. PMID 23545091.
  6. ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
  7. ↑ 7.0 7.1 Thaker, PH; Sood, AK. "Molecular Oncology in Gynecologic Cancer". In Lentz, GM; Lobo, RA; Gershenson, DM; Katz, VL. Comprehensive Gynecology (6th ed.). Mosby. ISBN 978-0-323-06986-1.
  8. ↑ 8.0 8.1 8.2 8.3 Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C; et al. (2013). "Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Ann Oncol. 24 Suppl 6: vi33–8. doi:10.1093/annonc/mdt353. PMID 24078661.
  9. ↑ Mani, RS (September 2014). "The emerging role of speckle-type POZ protein (SPOP) in cancer development". Drug Discovery Today. 19 (9): 1498–1502. doi:10.1016/j.drudis.2014.07.009. PMID 25058385. A recent exome-sequencing study revealed that 8% of serious endometrial cancers and 9% of clear cell endometrial cancers have SPOP mutations
  10. ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
  11. ↑ Colombo, N; Preti, E; Landoni, F; Carinelli, S; Colombo, A; Marini, C; Sessa, C (2011). "Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology. 22 (Supplement 6): vi35–vi39. doi:10.1093/annonc/mdr374. PMID 21908501.
  12. ↑ Johnson N, Bryant A, Miles T, Hogberg T, Cornes P (2011). "Adjuvant chemotherapy for endometrial cancer after hysterectomy". Cochrane Database Syst Rev (10): CD003175. doi:10.1002/14651858.CD003175.pub2. PMC 4164379. PMID 21975736.
  13. ↑ Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-Maghami S (2011). "Endometrial cancer". BMJ. 343: d3954. doi:10.1136/bmj.d3954. PMID 21734165.
  14. ↑ Hoffman, Barbara (2012). Williams gynecology. New York: McGraw-Hill Medical. ISBN 9780071716727.


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