Endometrial cancer pathophysiology: Difference between revisions
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{{Endometrial cancer}} | {{Endometrial cancer}} | ||
==Overview== | ==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. | 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== | ==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 | * 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 | * 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 | * 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== | ||
{| | {|<!--Placing these in a table with no border will keep them together/aligned in any browser--> | ||
|- | |- | ||
| | | | ||
{| class="wikitable sortable | {| 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 | ||
| Line 97: | Line 93: | ||
|- | |- | ||
| ''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% | ||
| Line 128: | Line 124: | ||
|} | |} | ||
* In 10–20% of endometrial cancers, mostly | Genes involved in pathogenesis of endometrial cancer involve: | ||
* 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 10–20% of endometrial cancers, mostly grade 3 (the highest [[Grading (tumors)|histologic grade]]), [[mutation]]s are found in a [[tumor suppressor]] gene, commonly ''[[TP53]]'' or ''[[PTEN (gene)|PTEN]]''. | ||
* 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 | * 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> | ||
* ''[[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. | * 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> | ||
* ''[[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> | * ''[[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> | |||
* ''[[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 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 | * 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 | * 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== | ||
: 1. Endometrioid (75%–80% | 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 (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 | |||
{| class="wikitable" | {| class="wikitable" | ||
| Line 188: | Line 193: | ||
| Good | | Good | ||
| Poor | | Poor | ||
|} | |} | ||
= | {| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center" | ||
| valign="top" | | |||
|+ | |||
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Types of endometrial cancer}} | |||
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Histopathological features}} | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" | | |||
Endometrioid adenocarcinoma | |||
| style="padding: 5px 5px; background: #F5F5F5;" | | |||
: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 [[stroma (animal tissue)|stromal]] tissue that separates them. | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" | | |||
Serous carcinoma | |||
| style="padding: 5px 5px; background: #F5F5F5;" | | |||
: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. | |||
|- | |||
| 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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Endometrial cancer Microchapters |
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Diagnosis |
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Treatment |
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Endometrial cancer pathophysiology On the Web |
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American Roentgen Ray Society Images of Endometrial cancer pathophysiology |
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Risk calculators and risk factors for Endometrial cancer pathophysiology |
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
|
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 |
|
|
Serous carcinoma |
|
|
Clear cell carcinoma |
|
|
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
- ↑ 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.
- ↑ What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
- ↑ 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.
- ↑ 8.0 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.
- ↑ 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
- ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Hoffman, Barbara (2012). Williams gynecology. New York: McGraw-Hill Medical. ISBN 9780071716727.