Difference between revisions of "Endometrial cancer"

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}}
 
}}
 
==Presentations==
 
==Presentations==
 +
 
*[[Hysterectomy]]
 
*[[Hysterectomy]]
 
*[[Endometrial curettage]]
 
*[[Endometrial curettage]]
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[[File:Gross pathology of endometrial adenocarcinoma.jpg|thumb|240px|Gross pathology of extensive endometrial adenocarcinoma (endometrioid type).]]
 
[[File:Gross pathology of endometrial adenocarcinoma.jpg|thumb|240px|Gross pathology of extensive endometrial adenocarcinoma (endometrioid type).]]
 
A '''[[Hysterectomy|regular hysterectomy grossing]]''' is performed, but with the following sampling and additions:<ref>{{cite web|url=https://voices.uchicago.edu/grosspathology/gyne/uterus-endometrial-cancer/|title=Gross Pathology Manual - Uterus, Endometrial Cancer|website=The University of Chicago Department of Pathology|author=Nicole Cipriani|date=2020-06-22}}</ref>
 
A '''[[Hysterectomy|regular hysterectomy grossing]]''' is performed, but with the following sampling and additions:<ref>{{cite web|url=https://voices.uchicago.edu/grosspathology/gyne/uterus-endometrial-cancer/|title=Gross Pathology Manual - Uterus, Endometrial Cancer|website=The University of Chicago Department of Pathology|author=Nicole Cipriani|date=2020-06-22}}</ref>
 +
 
*2 longitudinal sections through '''ecto/endocervix''' (1 anterior and 1 posterior).
 
*2 longitudinal sections through '''ecto/endocervix''' (1 anterior and 1 posterior).
 
*2 longitudinal sections through '''upper endocervix/lower uterine segment''' (1 anterior and 1 posterior), contiguous with sections taken from cervix.
 
*2 longitudinal sections through '''upper endocervix/lower uterine segment''' (1 anterior and 1 posterior), contiguous with sections taken from cervix.
 
*'''Tumor''':  
 
*'''Tumor''':  
:*Measure greatest dimension of tumor.
+
 
::*If tumor is less than 3 cm, submit entirely.
+
:*Measure '''greatest dimension''' of tumor.
::*If tumor > 3 cm, submit 1 per cm.
+
::*If tumor is '''smaller''' than 3 cm, submit entirely.
:*Measure tumor '''thickness''' (cavity to border of invasion) and entire thickness of the wall (cavity to serosa), at the location of greatest percentage of tumor relative to wall thickness.
+
::*If tumor is '''larger''' than 3 cm, submit 1 per cm.
:*Include 2 full-thickness sections (1 anterior and 1 posterior), including location with greatest percentage. It may need multiply contiguous sections.
+
[[File:Tumor to serosa slices.jpg|thumb|In order to determine the myometrial invasion, sample the entire distance from the uterine cavity to the serosa, as seen on this uterine cross-section, with two contiguous slices inked blue at the contiguity so that the glass slides can be apposed to measure tumor invasion.]]
 +
:*Measure tumor '''thickness''' and entire thickness of the wall, at the location of greatest percentage of tumor relative to wall thickness.
 +
:*Include 2 '''full-thickness sections''' (1 anterior and 1 posterior) at locations with seemingly greatest invasion. It may need multiple contiguous sections.
 
:*Remaining sections can be superficial to include tumor and inner myometrium, such as from lower uterine segment to fundus to maintain orientation.
 
:*Remaining sections can be superficial to include tumor and inner myometrium, such as from lower uterine segment to fundus to maintain orientation.
 
:*If possible, include 1 section with interface between tumor and normal.
 
:*If possible, include 1 section with interface between tumor and normal.
*Sections of any additional pathology, such as leiomyomas, polyps in their entirety.
+
 
*1 section of uninvolved endometrium if present.
+
*Sections of any '''additional pathology''', such as leiomyomas, polyps in their entirety.
*Inspect serosa for implants and submit sections if grossly detected.
+
*1 section of '''uninvolved''' endometrium if present.
*For serous carcinomas, submit the entire ovary and fallopian tube:
+
*Inspect '''serosa''' for implants and submit sections if grossly detected.
 +
*For '''serous''' carcinomas, submit the entire ovary and fallopian tube:
 +
 
 
:*Ovary, serially sectioned perpendicular to long axis.
 
:*Ovary, serially sectioned perpendicular to long axis.
 
:*SEE-FIM protocol for fallopian tubes:
 
:*SEE-FIM protocol for fallopian tubes:
 
::*Remove the distal 2 cm (fimbriae) and section it parallel to the long axis.
 
::*Remove the distal 2 cm (fimbriae) and section it parallel to the long axis.
 
::Section the remainder of the tube transversely at 2-3 mm intervals.
 
::Section the remainder of the tube transversely at 2-3 mm intervals.
 +
 
*For all other cancer types, submit adnexa as follows:
 
*For all other cancer types, submit adnexa as follows:
:*2 representative sections of each ovary.
+
 
:*Entire fimbriae (longitudinally sectioned) and 2 representative cross-sections on each side.
+
:*'''Ovaries''': 2 representative sections of each.
*'''[[Lymph node]]s
+
:*'''Fallopian tubes:''' Entire fimbriae (longitudinally sectioned) and 2 representative cross-sections on each side.
:*Size < 2 mm: submit intact.
+
 
:*Size > 2 mm: serially section perpendicular to the long axis in 2 mm intervals.
+
*'''[[Lymph node]]s'''
 +
 
 +
:*Size '''smaller''' than 2 mm: submit intact.
 +
:*Size '''larger''' than 2 mm: serially section perpendicular to the long axis in 2 mm intervals.
 
::*If no gross tumor, submit entirely.
 
::*If no gross tumor, submit entirely.
 
::*If grossly positive, submit 1-2 representative sections showing the greatest tumor dimension and extranodal fat.
 
::*If grossly positive, submit 1-2 representative sections showing the greatest tumor dimension and extranodal fat.
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===Diagnosis===
 
===Diagnosis===
<gallery mode=packed heights=200>
+
<gallery mode="packed" heights="200">
File:Pie chart of relative incidences of endometrial carcinoma.png|Relative incidences of endometrial carcinomas by histopathology, being endometrioid in a majority of cases.<ref>{{cite journal|last1=Mendivil|first1=Alberto|last2=Schuler|first2=Kevin M.|last3=Gehrig|first3=Paola A.|title=Non-Endometrioid Adenocarcinoma of the Uterine Corpus: A Review of Selected Histological Subtypes|journal=Cancer Control|volume=16|issue=1|year=2009|pages=46–52|issn=1073-2748|doi=10.1177/107327480901600107}}</ref>
+
File:Pie chart of relative incidences of endometrial carcinoma.png|Relative incidences of endometrial carcinomas by histopathology, being '''endometrioid''' in a majority of cases.<ref>{{cite journal|last1=Mendivil|first1=Alberto|last2=Schuler|first2=Kevin M.|last3=Gehrig|first3=Paola A.|title=Non-Endometrioid Adenocarcinoma of the Uterine Corpus: A Review of Selected Histological Subtypes|journal=Cancer Control|volume=16|issue=1|year=2009|pages=46–52|issn=1073-2748|doi=10.1177/107327480901600107}}</ref> Endometrioid carcinoma has patterns reminiscent of normal endometrium, with many new glands formed from columnar epithelium with some abnormal nuclei:
 
File:Histopathology of low-grade (FIGO grade 1) endometrial endometrioid adenocarcinoma.png|'''Endometrioid adenocarcinoma'''<ref>{{cite journal|last1=Stewart|first1=Colin J.R.|last2=Crum|first2=Christopher P.|last3=McCluggage|first3=W. Glenn|last4=Park|first4=Kay J.|last5=Rutgers|first5=Joanne K.|last6=Oliva|first6=Esther|last7=Malpica|first7=Anais|last8=Parkash|first8=Vinita|last9=Matias-Guiu|first9=Xavier|last10=Ronnett|first10=Brigitte M.|title=Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S75–S92|issn=0277-1691|doi=10.1097/PGP.0000000000000553}}<br>- "Figures - available via license: Creative Commons Attribution 4.0 International"</ref>, with low-grade being distinguished from hyperplasia with atypia by the presence of glandular crowding with endometrial stromal exclusion, and significant cribriform, confluent glandular, labyrinthine, papillary/villoglandular, or non-squamous solid architecture.<ref name="RabbanGilks2019">{{cite journal|last1=Rabban|first1=Joseph T.|last2=Gilks|first2=C. Blake|last3=Malpica|first3=Anais|last4=Matias-Guiu|first4=Xavier|last5=Mittal|first5=Khush|last6=Mutter|first6=George L.|last7=Oliva|first7=Esther|last8=Parkash|first8=Vinita|last9=Ronnett|first9=Brigitte M.|last10=Staats|first10=Paul|last11=Stewart|first11=Colin J.R.|last12=McCluggage|first12=W. Glenn|title=Issues in the Differential Diagnosis of Uterine Low-grade Endometrioid Carcinoma, Including Mixed Endometrial Carcinomas|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S25–S39|issn=0277-1691|doi=10.1097/PGP.0000000000000512}}</ref>
 
File:Histopathology of low-grade (FIGO grade 1) endometrial endometrioid adenocarcinoma.png|'''Endometrioid adenocarcinoma'''<ref>{{cite journal|last1=Stewart|first1=Colin J.R.|last2=Crum|first2=Christopher P.|last3=McCluggage|first3=W. Glenn|last4=Park|first4=Kay J.|last5=Rutgers|first5=Joanne K.|last6=Oliva|first6=Esther|last7=Malpica|first7=Anais|last8=Parkash|first8=Vinita|last9=Matias-Guiu|first9=Xavier|last10=Ronnett|first10=Brigitte M.|title=Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S75–S92|issn=0277-1691|doi=10.1097/PGP.0000000000000553}}<br>- "Figures - available via license: Creative Commons Attribution 4.0 International"</ref>, with low-grade being distinguished from hyperplasia with atypia by the presence of glandular crowding with endometrial stromal exclusion, and significant cribriform, confluent glandular, labyrinthine, papillary/villoglandular, or non-squamous solid architecture.<ref name="RabbanGilks2019">{{cite journal|last1=Rabban|first1=Joseph T.|last2=Gilks|first2=C. Blake|last3=Malpica|first3=Anais|last4=Matias-Guiu|first4=Xavier|last5=Mittal|first5=Khush|last6=Mutter|first6=George L.|last7=Oliva|first7=Esther|last8=Parkash|first8=Vinita|last9=Ronnett|first9=Brigitte M.|last10=Staats|first10=Paul|last11=Stewart|first11=Colin J.R.|last12=McCluggage|first12=W. Glenn|title=Issues in the Differential Diagnosis of Uterine Low-grade Endometrioid Carcinoma, Including Mixed Endometrial Carcinomas|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S25–S39|issn=0277-1691|doi=10.1097/PGP.0000000000000512}}</ref>
File:Histopathology of complex hyperplasia with atypia.jpg|'''Complex hyperplasia with atypia''' for comparison: Sparse intervening stroma.<ref>{{cite journal|last1=Rao|first1=Shalinee|last2=Sundaram|first2=Sandhya|last3=Narasimhan|first3=Raghavan|title=Biological behavior of preneoplastic conditions of the endometrium: A retrospective 16-year study in south India|journal=Indian Journal of Medical and Paediatric Oncology|volume=30|issue=4|year=2009|pages=131|issn=0971-5851|doi=10.4103/0971-5851.65335}}<br>- [https://www.researchgate.net/figure/Closely-packed-endometrial-glands-with-sparse-intervening-stroma-and-stratification-of_fig2_46256480 Figure- available via license: Creative Commons Attribution 2.0 Generic]</ref>
+
File:Histopathology of endometrial intraepithelial neoplasia (EIN).jpg|'''Endometrial intraepithelial neoplasia''' ('''EIN'''), for comparison, also showing gland crowding and atypia compared to normal endometrium, but without invasion.<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=1543-2165|doi=10.5858/arpa.2012-0709-RA}}</ref>
 
File:Histopathology of serous carcinoma of uterus.jpg|'''Papillary serous carcinoma''' of uterus, with characteristic discohesiveness of cells (like falling apart) around fibrovascular cores.{{MH}}
 
File:Histopathology of serous carcinoma of uterus.jpg|'''Papillary serous carcinoma''' of uterus, with characteristic discohesiveness of cells (like falling apart) around fibrovascular cores.{{MH}}
 
File:Histopathology of papillary serous carcinoma of the endometrium.jpg|'''Papillary serous carcinoma''' of uterus, in this case showing both papillary and micropapillary architecture.<ref name=Murali2019/>
 
File:Histopathology of papillary serous carcinoma of the endometrium.jpg|'''Papillary serous carcinoma''' of uterus, in this case showing both papillary and micropapillary architecture.<ref name=Murali2019/>
Line 52: Line 62:
 
File:Histopathology of clear cell carcinoma of the endometrium with solid architecture.png|'''Clear cell carcinoma''' of the endometrium with '''solid''' architecture.<ref name=Murali2019/>
 
File:Histopathology of clear cell carcinoma of the endometrium with solid architecture.png|'''Clear cell carcinoma''' of the endometrium with '''solid''' architecture.<ref name=Murali2019/>
 
File:Histopathology of dedifferantiated carcinoma of the endometrium.png|'''Dedifferantiated carcinoma''', a tumor that contains a component of undifferentiated endometrial carcinoma (UEC) and a component of conventional, usually lower-grade, endometrioid adenocarcinoma.<ref name=Murali2019/>
 
File:Histopathology of dedifferantiated carcinoma of the endometrium.png|'''Dedifferantiated carcinoma''', a tumor that contains a component of undifferentiated endometrial carcinoma (UEC) and a component of conventional, usually lower-grade, endometrioid adenocarcinoma.<ref name=Murali2019/>
File:Histopathology of carcinosarcoma of the endometrium.png|'''Carcinosarcoma''' of the endometrium.<ref name=Murali2019/>
+
File:Histopathology of carcinosarcoma of the endometrium.png|'''Carcinosarcoma''' of the endometrium, with carcinoma in addition to sarcoma (seen here as atypical fibrovascular cores).<ref name=Murali2019/>
 
</gallery>
 
</gallery>
  
 
===Endometrioid adenocarcinoma===
 
===Endometrioid adenocarcinoma===
For endometrioid adenocarcinoma, perform '''grading''':<ref name="SoslowTornos2019">{{cite journal|last1=Soslow|first1=Robert A.|last2=Tornos|first2=Carmen|last3=Park|first3=Kay J.|last4=Malpica|first4=Anais|last5=Matias-Guiu|first5=Xavier|last6=Oliva|first6=Esther|last7=Parkash|first7=Vinita|last8=Carlson|first8=Joseph|last9=McCluggage|first9=W. Glenn|last10=Gilks|first10=C. Blake|title=Endometrial Carcinoma Diagnosis|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S64–S74|issn=0277-1691|doi=10.1097/PGP.0000000000000518}}</ref>
+
For endometrioid adenocarcinoma, perform '''architectural grading''':<ref name="SoslowTornos2019">{{cite journal|last1=Soslow|first1=Robert A.|last2=Tornos|first2=Carmen|last3=Park|first3=Kay J.|last4=Malpica|first4=Anais|last5=Matias-Guiu|first5=Xavier|last6=Oliva|first6=Esther|last7=Parkash|first7=Vinita|last8=Carlson|first8=Joseph|last9=McCluggage|first9=W. Glenn|last10=Gilks|first10=C. Blake|title=Endometrial Carcinoma Diagnosis|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S64–S74|issn=0277-1691|doi=10.1097/PGP.0000000000000518}}</ref>
 +
 
 
*'''Grade 1: ≤5%''' solid non-glandular, non-squamous growth
 
*'''Grade 1: ≤5%''' solid non-glandular, non-squamous growth
 
*'''Grade 2: >5% and ≤50%''' solid non-glandular, non-squamous growth
 
*'''Grade 2: >5% and ≤50%''' solid non-glandular, non-squamous growth
 
*'''Grade 3: >50%''' solid non-glandular, non-squamous growth
 
*'''Grade 3: >50%''' solid non-glandular, non-squamous growth
  
<gallery mode=packed heights=200>
+
<gallery mode="packed" heights="200">
 
File:Histopathology of low-grade (FIGO grade 1) endometrial endometrioid adenocarcinoma.png|'''Grade 1'''<ref>{{cite journal|last1=Stewart|first1=Colin J.R.|last2=Crum|first2=Christopher P.|last3=McCluggage|first3=W. Glenn|last4=Park|first4=Kay J.|last5=Rutgers|first5=Joanne K.|last6=Oliva|first6=Esther|last7=Malpica|first7=Anais|last8=Parkash|first8=Vinita|last9=Matias-Guiu|first9=Xavier|last10=Ronnett|first10=Brigitte M.|title=Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S75–S92|issn=0277-1691|doi=10.1097/PGP.0000000000000553}}<br>- "Figures - available via license: Creative Commons Attribution 4.0 International"</ref>
 
File:Histopathology of low-grade (FIGO grade 1) endometrial endometrioid adenocarcinoma.png|'''Grade 1'''<ref>{{cite journal|last1=Stewart|first1=Colin J.R.|last2=Crum|first2=Christopher P.|last3=McCluggage|first3=W. Glenn|last4=Park|first4=Kay J.|last5=Rutgers|first5=Joanne K.|last6=Oliva|first6=Esther|last7=Malpica|first7=Anais|last8=Parkash|first8=Vinita|last9=Matias-Guiu|first9=Xavier|last10=Ronnett|first10=Brigitte M.|title=Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites|journal=International Journal of Gynecological Pathology|volume=38|year=2019|pages=S75–S92|issn=0277-1691|doi=10.1097/PGP.0000000000000553}}<br>- "Figures - available via license: Creative Commons Attribution 4.0 International"</ref>
 
File:Histopathology of grade 2 endometrioid endometrial adenocarcinoma with mucinous differentiation, low magnification.jpg|'''Grade 2''' (with mucinous differentiation)<ref group=notes>Mucinous endometrioid adenocarcinoma is an altered differentiation / metaplasia with intracytoplasmic mucin (intraluminal mucin pooling does not qualify).<br>- {{cite web|url=http://www.pathologyoutlines.com/topic/uterusendometrioid.html|title=Uterus - Carcinoma - Endometrioid carcinoma|author=Aarti Sharma, M.D., Ricardo R. Lastra, M.D.|website=PathologyOutlines}} Topic Completed: 3 September 2020. Minor changes: 21 September 2020</ref>
 
File:Histopathology of grade 2 endometrioid endometrial adenocarcinoma with mucinous differentiation, low magnification.jpg|'''Grade 2''' (with mucinous differentiation)<ref group=notes>Mucinous endometrioid adenocarcinoma is an altered differentiation / metaplasia with intracytoplasmic mucin (intraluminal mucin pooling does not qualify).<br>- {{cite web|url=http://www.pathologyoutlines.com/topic/uterusendometrioid.html|title=Uterus - Carcinoma - Endometrioid carcinoma|author=Aarti Sharma, M.D., Ricardo R. Lastra, M.D.|website=PathologyOutlines}} Topic Completed: 3 September 2020. Minor changes: 21 September 2020</ref>
Line 68: Line 79:
 
</gallery>
 
</gallery>
  
===Staging===
+
:{{Moderate-begin}}Also perform '''nuclear grading:'''{{Moderate-end}}
If possible, perform '''staging''' by the FIGO system:<ref>{{cite web |title=Stage Information for Endometrial Cancer |url=http://www.cancer.gov/cancertopics/pdq/treatment/endometrial/HealthProfessional/page3 |publisher=National Cancer Institute |access-date=23 April 2014 |url-status=live |archive-url=https://web.archive.org/web/20140406044240/http://www.cancer.gov/cancertopics/pdq/treatment/endometrial/HealthProfessional/page3 |archive-date=6 April 2014  |date=January 1980 }}</ref><ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK525981/|title=Endometrial Cancer|author=Murray J. Casey; Garth K. Summers; David Crotzer.|website=StatPearls, National Center for Biotechnology Information}} Last Update: July 13, 2020</ref>
+
<gallery mode="packed" heights="200">
 +
File:Histopathology of endometrioid cancer, grade 1, nuclear grade 1.jpg|'''Nuclear grade 1''': Oval, mildly enlarged nucleus with evenly distributed chromatin.{{MH}}<ref name="pmid22496699">{{cite journal| author=Nofech-Mozes S, Ismiil N, Dubé V, Saad RS, Ghorab Z, Grin A | display-authors=etal| title=Interobserver agreement for endometrial cancer characteristics evaluated on biopsy material. | journal=Obstet Gynecol Int | year= 2012 | volume= 2012 | issue= | pages= 414086 | pmid=22496699 | doi=10.1155/2012/414086 | pmc=3306930 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22496699  }} </ref>
 +
File:Histopathology of endometrioid cancer, grade 1, nuclear grade 2.jpg|'''Nuclear grade 2''': Intermediate features.{{MH}}<ref name="pmid22496699"/>
 +
</gallery>
 +
*'''Nuclear grade 3''': Markedly enlarged and pleomorphic nuclei, with coarse chromatin and distinct nucleoli.<ref name="pmid22496699"/>
 +
 
 +
====FIGO grading====
 +
Perform FIGO grading in case of endometrioid or mucinous carcinomas. FIGO classification is architectural grading as above, but that the presence of grade 3 nuclear atypia in an architectural pattern grade I tumor '''raises the grade by one point''':<ref name=who5th>{{cite book | author=World Health Organization. Classification of Tumours Editorial Board | author2=International Agency for Research on Cancer | author3=World Health Organization | title=Female genital tumours | publication-place=Lyon, France | date=2020 | isbn=978-92-832-4504-9 | oclc=1199943903 | language=nl}}</ref><ref name="pmid26715172">{{cite journal| author=Malpica A| title=How to approach the many faces of endometrioid carcinoma. | journal=Mod Pathol | year= 2016 | volume= 29 Suppl 1 | issue=  | pages= S29-44 | pmid=26715172 | doi=10.1038/modpathol.2015.142 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26715172  }} </ref>
 +
*'''FIGO grade 1: ≤5%''' solid non-glandular, non-squamous growth
 +
*'''FIGO grade 2''':
 +
:*'''>5% and ≤50%''' solid non-glandular, non-squamous growth
 +
:or
 +
:*'''≤5%''' solid non-glandular, non-squamous growth '''and''' markedly enlarged and pleomorphic nuclei, with coarse chromatin and distinct nucleoli (in these cases, also consider a serous carcinoma of glandular variant)
 +
*'''FIGO grade 3: >50%''' solid non-glandular, non-squamous growth
  
[[File:Histopathology of grade 2 endometrioid endometrial cancer with myometrial invasion.jpg|thumb|For biopsies, at least look for myometrial invasion (pictured).]]
+
===Bimodal grading===
 +
It is recommended to classify FIGO grade 1 and 2 tumors as low-grade, and grade 3 tumors as high-grade.<ref name=who5th/>
  
 +
===Staging===
 +
Preferably, stage by '''both the AJCC TNM system and the FIGO system''':<ref>{{AJCC-8}}</ref>
 +
The following system is for uterine carcinoma and carcinosarcoma (but a separate staging system is used for sarcomas).
 
{| class="wikitable"
 
{| class="wikitable"
!Stage
+
! T Category !! FIGO Stage !! T Criteria
!Description
+
|-
 +
| TX ||  || Primary tumor cannot be assessed
 
|-
 
|-
|IA
+
| T0 ||  || No evidence of primary tumor
|Tumor is confined to the uterus with less than half myometrial invasion
 
 
|-
 
|-
|IB
+
| T1 || I || Tumor confined to the corpus uteri, including endocervical glandular involvement
|Tumor is confined to the uterus with more than half myometrial invasion
 
 
|-
 
|-
|II
+
| T1a || IA || Tumor limited to the endometrium or invading less than half the myometrium
|Tumor involves the uterus and the cervical stroma
 
 
|-
 
|-
|IIIA
+
| T1b || IB || Tumor invading one half or more of the myometrium
|Tumor invades serosa or adnexa
 
 
|-
 
|-
|IIIB
+
| T2 || II || Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement.
|Vaginal and/or parametrial involvement
 
 
|-
 
|-
|IIIC1
+
| T3 || III || Tumor involving serosa, adnexa, vagina, or parametrium
|Pelvic lymph node involvement
 
 
|-
 
|-
|IIIC2
+
| T3a || IIIA || Tumor involving the serosa and/or adnexa (direct extension or metastasis)
|Para-aortic lymph node involvement, with or without pelvic node involvement
 
 
|-
 
|-
|IVA
+
| T3b || IIIB || Vaginal involvement (direct extension or metastasis) or parametrial involvement
|Tumor invades bladder mucosa and/or bowel mucosa
 
 
|-
 
|-
|IVB
+
| T4 || IVA || Tumor invading the bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)
|Distant metastases including abdominal metastases and/or inguinal lymph nodes
+
|}
 +
{| class="wikitable"
 +
! N Category !! FIGO Stage !! N Criteria
 +
|-
 +
| NX ||  || Regional lymph nodes cannot be assessed
 +
|-
 +
| N0 ||  || No regional lymph node metastasis
 +
|-
 +
| N0(i+) ||  || Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm
 +
|-
 +
| N1 || IIIC1 || Regional lymph node metastasis to pelvic lymph nodes
 +
|-
 +
| N1mi || IIIC1 || Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to pelvic lymph nodes
 +
|-
 +
| N1a || IIIC1 || Regional lymph node metastasis (greater than 2.0 mm in diameter) to pelvic lymph nodes
 +
|-
 +
| N2 || IIIC2 || Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes
 +
|-
 +
| N2mi || IIIC2 || Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes
 +
|-
 +
| N2a || IIIC2 || Regional lymph node metastasis (greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes
 +
|}
 +
The suffix ('''sn''') is added to the N category when metastasis is identified only by sentinel lymph node biopsy.
 +
{| class="wikitable"
 +
! M Category !! FIGO Stage !! M Criteria
 +
|-
 +
| M0 ||  || No distant metastasis
 +
|-
 +
| M1 || IVB || Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone). (It excludes metastasis to pelvic or para-aortic lymph nodes, vagina, uterine serosa, or adnexa).
 +
|}
 +
;AJCC Prognostic Stage Groups
 +
{| class="wikitable"
 +
! When T is… !! And N is… !! And M is… !! Then the stage group is…
 +
|-
 +
| T1 || N0 || M0 || I
 +
|-
 +
| T1a || N0 || M0 || IA
 +
|-
 +
| T1b || N0 || M0 || IB
 +
|-
 +
| T2 || N0 || M0 || II
 +
|-
 +
| T3 || N0 || M0 || III
 +
|-
 +
| T3a || N0 || M0 || IIIA
 +
|-
 +
| T3b || N0 || M0 || IIIB
 +
|-
 +
| T1-T3 || N1/N1mi/N1a || M0 || IIIC1
 +
|-
 +
| T1-T3 || N2/N2mi/N2a || M0 || IIIC2
 +
|-
 +
| T4 || Any N || M0 || IVA
 +
|-
 +
| Any T || Any N || M1 || IVB
 +
|}
 +
<gallery mode=packed heights=220>
 +
File:Calculation of myometrial invasion.jpg|thumb|Calculation of myometrial invasion: The dotted lines show the position of the endometrial/myometrial junction (EMJ), and the line where the tumor would invade half of the myometrium (50 % MI). The arrows show the absolute depth of invasion (a) and tumor-free distance (b) measurements. Invasion as a percentage is calculated as:<br>a / (a+b)
 +
File:Histopathology of grade 2 endometrioid endometrial cancer with myometrial invasion.jpg|For biopsies, just look for absence or presence of myometrial invasion (pictured).
 +
File:Histopathology of endometrial cancer with lymphovascular invasion.jpg|Generally look for '''lymphovascular invasion''' (pictured) as well.
 +
</gallery>
 +
 
 +
===Further workup===
 +
Generally perform the following molecular testing on endometrial carcinomas:<ref>{{Danbury}}</ref>
 +
*'''Mismatch repair (MMR)''' genes (MLH-1, PMS-2, MSH-2 and MSH-6) on all cancer types and grades. If MLH1 is lost, test for MLH1 promotor methylation.
 +
*'''ER/PR and p53''' for all high grade carcinomas regardless of stage.
 +
*'''HER2''' on all high grade carcinomas, or only on serous carcinomas, or those that are stage III or IV or recurrent.
 +
 
 +
For '''MMR genes''', {{IHC of MMR}}
 +
 
 +
{|class=wikitable
 +
|
 +
[[File:Patterns of p53 expression.png|right|420px]]
 +
This image shows different patterns of '''p53 expression''' in endometrial cancers on [[immunohistochemistry]], whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying p53 mutation:<ref>{{cite journal| author=Köbel M, Ronnett BM, Singh N, Soslow RA, Gilks CB, McCluggage WG| title=Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility. | journal=Int J Gynecol Pathol | year= 2019 | volume= 38 Suppl 1 | issue=  | pages= S123-S131 | pmid=29517499 | doi=10.1097/PGP.0000000000000488 | pmc=6127005 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29517499  }}<br>- "This is an open access article distributed under the Creative Commons Attribution License 4.0"</ref>
 +
*'''Wild-type''', upper left: Endometrial endometrioid carcinoma showing normal wild-type pattern of p53 expression with variable proportion of tumor cell nuclei staining with variable intensity. Note, this wild-type pattern should not be reported as “positive,” because this is ambiguous reporting language.
 +
*'''Overexpression''', upper right: Endometrial endometrioid carcinoma, grade 3, with overexpression, showing strong staining in virtually all tumor cell nuclei, much stronger compared with the internal control of fibroblasts in the center. Note, there is some cytoplasmic background indicating that this staining is quite strong but this should not be interpreted as abnormal cytoplasmic pattern.
 +
*'''Complete absence''', lower left: Endometrial serous carcinoma showing complete absence of p53 expression with internal control showing moderate to strong but variable staining. Note, wild-type pattern in normal atrophic glands at 12 and 6 o’clock.
 +
*'''Both cytoplasmic and nuclear''', lower right: Endometrial endometrioid carcinoma showing cytoplasmic p53 expression with internal control (stroma and normal endometrial glands) showing nuclear wild-type pattern. The cytoplasmic pattern is accompanied by nuclear staining of similar intensity.
 
|}
 
|}
  
 
===Microscopy report===
 
===Microscopy report===
 
Example:
 
Example:
{|class=wikitable
+
{| class="wikitable"
 
| (Endometrium, polypectomy:)<br> Endometrial adenocarcinoma, endometrioid type, FIGO grade 2, with mucinous differentiation. Carcinoma focally invades myometrial smooth muscle.
 
| (Endometrium, polypectomy:)<br> Endometrial adenocarcinoma, endometrioid type, FIGO grade 2, with mucinous differentiation. Carcinoma focally invades myometrial smooth muscle.
  
<gallery mode=packed>
+
<gallery mode="packed">
 
File:Histopathology of grade 2 endometrioid endometrial adenocarcinoma with mucinous differentiation, low magnification.jpg
 
File:Histopathology of grade 2 endometrioid endometrial adenocarcinoma with mucinous differentiation, low magnification.jpg
 
File:Histopathology of grade 2 endometrioid endometrial adenocarcinoma with mucinous differentiation, high magnification.jpg
 
File:Histopathology of grade 2 endometrioid endometrial adenocarcinoma with mucinous differentiation, high magnification.jpg
Line 116: Line 214:
 
</gallery>
 
</gallery>
 
|}
 
|}
 +
{{CAP}}
 
{{Bottom}}
 
{{Bottom}}
 +
<references />

Latest revision as of 19:51, 26 September 2022

Author: Mikael Häggström [note 1]

Presentations

Gross processing

Gross pathology of extensive endometrial adenocarcinoma (endometrioid type).

A regular hysterectomy grossing is performed, but with the following sampling and additions:[1]

  • 2 longitudinal sections through ecto/endocervix (1 anterior and 1 posterior).
  • 2 longitudinal sections through upper endocervix/lower uterine segment (1 anterior and 1 posterior), contiguous with sections taken from cervix.
  • Tumor:
  • Measure greatest dimension of tumor.
  • If tumor is smaller than 3 cm, submit entirely.
  • If tumor is larger than 3 cm, submit 1 per cm.
In order to determine the myometrial invasion, sample the entire distance from the uterine cavity to the serosa, as seen on this uterine cross-section, with two contiguous slices inked blue at the contiguity so that the glass slides can be apposed to measure tumor invasion.
  • Measure tumor thickness and entire thickness of the wall, at the location of greatest percentage of tumor relative to wall thickness.
  • Include 2 full-thickness sections (1 anterior and 1 posterior) at locations with seemingly greatest invasion. It may need multiple contiguous sections.
  • Remaining sections can be superficial to include tumor and inner myometrium, such as from lower uterine segment to fundus to maintain orientation.
  • If possible, include 1 section with interface between tumor and normal.
  • Sections of any additional pathology, such as leiomyomas, polyps in their entirety.
  • 1 section of uninvolved endometrium if present.
  • Inspect serosa for implants and submit sections if grossly detected.
  • For serous carcinomas, submit the entire ovary and fallopian tube:
  • Ovary, serially sectioned perpendicular to long axis.
  • SEE-FIM protocol for fallopian tubes:
  • Remove the distal 2 cm (fimbriae) and section it parallel to the long axis.
Section the remainder of the tube transversely at 2-3 mm intervals.
  • For all other cancer types, submit adnexa as follows:
  • Ovaries: 2 representative sections of each.
  • Fallopian tubes: Entire fimbriae (longitudinally sectioned) and 2 representative cross-sections on each side.
  • Size smaller than 2 mm: submit intact.
  • Size larger than 2 mm: serially section perpendicular to the long axis in 2 mm intervals.
  • If no gross tumor, submit entirely.
  • If grossly positive, submit 1-2 representative sections showing the greatest tumor dimension and extranodal fat.

Microscopic evaluation

Diagnosis

Endometrioid adenocarcinoma

For endometrioid adenocarcinoma, perform architectural grading:[7]

  • Grade 1: ≤5% solid non-glandular, non-squamous growth
  • Grade 2: >5% and ≤50% solid non-glandular, non-squamous growth
  • Grade 3: >50% solid non-glandular, non-squamous growth
(Also perform nuclear grading:)
  • Nuclear grade 3: Markedly enlarged and pleomorphic nuclei, with coarse chromatin and distinct nucleoli.[9]

FIGO grading

Perform FIGO grading in case of endometrioid or mucinous carcinomas. FIGO classification is architectural grading as above, but that the presence of grade 3 nuclear atypia in an architectural pattern grade I tumor raises the grade by one point:[10][11]

  • FIGO grade 1: ≤5% solid non-glandular, non-squamous growth
  • FIGO grade 2:
  • >5% and ≤50% solid non-glandular, non-squamous growth
or
  • ≤5% solid non-glandular, non-squamous growth and markedly enlarged and pleomorphic nuclei, with coarse chromatin and distinct nucleoli (in these cases, also consider a serous carcinoma of glandular variant)
  • FIGO grade 3: >50% solid non-glandular, non-squamous growth

Bimodal grading

It is recommended to classify FIGO grade 1 and 2 tumors as low-grade, and grade 3 tumors as high-grade.[10]

Staging

Preferably, stage by both the AJCC TNM system and the FIGO system:[12] The following system is for uterine carcinoma and carcinosarcoma (but a separate staging system is used for sarcomas).

T Category FIGO Stage T Criteria
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 I Tumor confined to the corpus uteri, including endocervical glandular involvement
T1a IA Tumor limited to the endometrium or invading less than half the myometrium
T1b IB Tumor invading one half or more of the myometrium
T2 II Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement.
T3 III Tumor involving serosa, adnexa, vagina, or parametrium
T3a IIIA Tumor involving the serosa and/or adnexa (direct extension or metastasis)
T3b IIIB Vaginal involvement (direct extension or metastasis) or parametrial involvement
T4 IVA Tumor invading the bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)
N Category FIGO Stage N Criteria
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N0(i+) Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm
N1 IIIC1 Regional lymph node metastasis to pelvic lymph nodes
N1mi IIIC1 Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to pelvic lymph nodes
N1a IIIC1 Regional lymph node metastasis (greater than 2.0 mm in diameter) to pelvic lymph nodes
N2 IIIC2 Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes
N2mi IIIC2 Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes
N2a IIIC2 Regional lymph node metastasis (greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes

The suffix (sn) is added to the N category when metastasis is identified only by sentinel lymph node biopsy.

M Category FIGO Stage M Criteria
M0 No distant metastasis
M1 IVB Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone). (It excludes metastasis to pelvic or para-aortic lymph nodes, vagina, uterine serosa, or adnexa).
AJCC Prognostic Stage Groups
When T is… And N is… And M is… Then the stage group is…
T1 N0 M0 I
T1a N0 M0 IA
T1b N0 M0 IB
T2 N0 M0 II
T3 N0 M0 III
T3a N0 M0 IIIA
T3b N0 M0 IIIB
T1-T3 N1/N1mi/N1a M0 IIIC1
T1-T3 N2/N2mi/N2a M0 IIIC2
T4 Any N M0 IVA
Any T Any N M1 IVB

Further workup

Generally perform the following molecular testing on endometrial carcinomas:[13]

  • Mismatch repair (MMR) genes (MLH-1, PMS-2, MSH-2 and MSH-6) on all cancer types and grades. If MLH1 is lost, test for MLH1 promotor methylation.
  • ER/PR and p53 for all high grade carcinomas regardless of stage.
  • HER2 on all high grade carcinomas, or only on serous carcinomas, or those that are stage III or IV or recurrent.

For MMR genes, scoring is as follows:[14]

Patterns of p53 expression.png

This image shows different patterns of p53 expression in endometrial cancers on immunohistochemistry, whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying p53 mutation:[15]

  • Wild-type, upper left: Endometrial endometrioid carcinoma showing normal wild-type pattern of p53 expression with variable proportion of tumor cell nuclei staining with variable intensity. Note, this wild-type pattern should not be reported as “positive,” because this is ambiguous reporting language.
  • Overexpression, upper right: Endometrial endometrioid carcinoma, grade 3, with overexpression, showing strong staining in virtually all tumor cell nuclei, much stronger compared with the internal control of fibroblasts in the center. Note, there is some cytoplasmic background indicating that this staining is quite strong but this should not be interpreted as abnormal cytoplasmic pattern.
  • Complete absence, lower left: Endometrial serous carcinoma showing complete absence of p53 expression with internal control showing moderate to strong but variable staining. Note, wild-type pattern in normal atrophic glands at 12 and 6 o’clock.
  • Both cytoplasmic and nuclear, lower right: Endometrial endometrioid carcinoma showing cytoplasmic p53 expression with internal control (stroma and normal endometrial glands) showing nuclear wild-type pattern. The cytoplasmic pattern is accompanied by nuclear staining of similar intensity.

Microscopy report

Example:

(Endometrium, polypectomy:)
Endometrial adenocarcinoma, endometrioid type, FIGO grade 2, with mucinous differentiation. Carcinoma focally invades myometrial smooth muscle.

For cancers, generally include a synoptic report, such as per College of American Pathologists (CAP) protocols at cap.org/protocols-and-guidelines.

Notes

  1. Mucinous endometrioid adenocarcinoma is an altered differentiation / metaplasia with intracytoplasmic mucin (intraluminal mucin pooling does not qualify).
    - Aarti Sharma, M.D., Ricardo R. Lastra, M.D.. Uterus - Carcinoma - Endometrioid carcinoma. PathologyOutlines. Topic Completed: 3 September 2020. Minor changes: 21 September 2020
  1. For a full list of contributors, see article history. Creators of images are attributed at the image description pages, seen by clicking on the images. See Patholines:Authorship for details.

Main page

References

  1. Nicole Cipriani (2020-06-22). Gross Pathology Manual - Uterus, Endometrial Cancer. The University of Chicago Department of Pathology.
  2. Mendivil, Alberto; Schuler, Kevin M.; Gehrig, Paola A. (2009). "Non-Endometrioid Adenocarcinoma of the Uterine Corpus: A Review of Selected Histological Subtypes ". Cancer Control 16 (1): 46–52. doi:10.1177/107327480901600107. ISSN 1073-2748. 
  3. Stewart, Colin J.R.; Crum, Christopher P.; McCluggage, W. Glenn; Park, Kay J.; Rutgers, Joanne K.; Oliva, Esther; Malpica, Anais; Parkash, Vinita; et al. (2019). "Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites ". International Journal of Gynecological Pathology 38: S75–S92. doi:10.1097/PGP.0000000000000553. ISSN 0277-1691. 
    - "Figures - available via license: Creative Commons Attribution 4.0 International"
  4. Rabban, Joseph T.; Gilks, C. Blake; Malpica, Anais; Matias-Guiu, Xavier; Mittal, Khush; Mutter, George L.; Oliva, Esther; Parkash, Vinita; et al. (2019). "Issues in the Differential Diagnosis of Uterine Low-grade Endometrioid Carcinoma, Including Mixed Endometrial Carcinomas ". International Journal of Gynecological Pathology 38: S25–S39. doi:10.1097/PGP.0000000000000512. ISSN 0277-1691. 
  5. 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 1543-2165. 
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 Rajmohan Murali, M.B.B.S., M.D., F.R.C.P.A., Ben Davidson, M.D., Ph.D., Oluwole Fadare, M.D., Joseph A. Carlson, M.D., Ph.D., Christopher P. Crum, M.D., C. Blake Gilks, M.D., Julie A. Irving, M.D., F.R.C.P.C., Anais Malpica, M.D., Xavier Matias-Guiu, M.D., Ph.D., W. Glenn McCluggage, F.R.C.Path., Khush Mittal, M.D., Esther Oliva, M.D., Vinita Parkash, M.D., Joanne K. L. Rutgers, M.D., Paul N. Staats, M.D., Colin J. R. Stewart, M.D., Carmen Tornos, M.D., and Robert A. Soslow, M.D. (2019). "High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations. ". Int J Gynecol Pathol 38 Suppl 1: S40-S63. doi:10.1097/PGP.0000000000000491. PMID 30550483. PMC: 6296248. Archived from the original. . 
    - "This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited."
  7. Soslow, Robert A.; Tornos, Carmen; Park, Kay J.; Malpica, Anais; Matias-Guiu, Xavier; Oliva, Esther; Parkash, Vinita; Carlson, Joseph; et al. (2019). "Endometrial Carcinoma Diagnosis ". International Journal of Gynecological Pathology 38: S64–S74. doi:10.1097/PGP.0000000000000518. ISSN 0277-1691. 
  8. Stewart, Colin J.R.; Crum, Christopher P.; McCluggage, W. Glenn; Park, Kay J.; Rutgers, Joanne K.; Oliva, Esther; Malpica, Anais; Parkash, Vinita; et al. (2019). "Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites ". International Journal of Gynecological Pathology 38: S75–S92. doi:10.1097/PGP.0000000000000553. ISSN 0277-1691. 
    - "Figures - available via license: Creative Commons Attribution 4.0 International"
  9. 9.0 9.1 9.2 Nofech-Mozes S, Ismiil N, Dubé V, Saad RS, Ghorab Z, Grin A (2012). "Interobserver agreement for endometrial cancer characteristics evaluated on biopsy material. ". Obstet Gynecol Int 2012: 414086. doi:10.1155/2012/414086. PMID 22496699. PMC: 3306930. Archived from the original. . 
  10. 10.0 10.1 World Health Organization. Classification of Tumours Editorial Board; International Agency for Research on Cancer; World Health Organization (2020) (in nl). Female genital tumours . Lyon, France. ISBN 978-92-832-4504-9. OCLC 1199943903. 
  11. Malpica A (2016). "How to approach the many faces of endometrioid carcinoma. ". Mod Pathol 29 Suppl 1: S29-44. doi:10.1038/modpathol.2015.142. PMID 26715172. Archived from the original. . 
  12. Amin, Mahul (2017). AJCC cancer staging manual (8 ed.). Switzerland: Springer. ISBN 978-3-319-40617-6. OCLC 961218414. 
    - For access, see the Secrets chapter of Patholines.
    - Copyright note: The AJCC, 8th Ed. is published by a company in Switzerland, and the tables presented therein are Public Domain because they consist of tabular information without literary or artistic innovation, and therefore do not fulfil the inclusion criterion of the Swiss Copyright Act (CopA) which applies to "literary and artistic intellectual creations with individual character" (see Federal Act on Copyright and Related Rights (Copyright Act, CopA) of 9 October 1992 (Status as of 1 January 2022)). edit
  13. Practice at Danbury Hospital, Danbury, Connecticut, New England.
  14. These cutoffs are used for both colorectal and endometrial cancers:
    - Sarode, Venetia R.; Robinson, Linda (2019). "Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies ". Archives of Pathology & Laboratory Medicine 143 (10): 1225–1233. doi:10.5858/arpa.2018-0201-OA. ISSN 0003-9985. 
    - Sarode VR, Robinson L (2019). "Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies. ". Arch Pathol Lab Med 143 (10): 1225-1233. doi:10.5858/arpa.2018-0201-OA. PMID 30917047. Archived from the original. . 
    - Lee JHS, Li JJX, Chow C, Chan RCK, Kwan JSH, Lau TS (2021). "Long-Term Survival and Clinicopathological Implications of DNA Mismatch Repair Status in Endometrioid Endometrial Cancers in Hong Kong Chinese Women. ". Biomedicines 9 (10). doi:10.3390/biomedicines9101385. PMID 34680502. PMC: 8533409. Archived from the original. . 
  15. Köbel M, Ronnett BM, Singh N, Soslow RA, Gilks CB, McCluggage WG (2019). "Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility. ". Int J Gynecol Pathol 38 Suppl 1: S123-S131. doi:10.1097/PGP.0000000000000488. PMID 29517499. PMC: 6127005. Archived from the original. . 
    - "This is an open access article distributed under the Creative Commons Attribution License 4.0"

Image sources