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Cited by 295Endometrial and Cervical Cancer TreatmentsNeuroendocrine Tumor Research AdvancesCervical Cancer and HPV Research

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High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations

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Murali, Rajmohan, Davidson, Ben, Fadare, Oluwole, Carlson, Joseph A., Crum, Christopher P., Gilks, C. Blake, Irving, Julie A., Malpica, Anais, Matias-Guiu, Xavier, McCluggage, W. Glenn, Mittal, Khush, Oliva, Esther, Parkash, Vinita, Rutgers, Joanne K. L., Staats, Paul N., Stewart, Colin J. R., Tornos, Carmen, Soslow, Robert A.·2019·International Journal of Gynecological Pathology
DOI 10.1097/pgp.0000000000000491PMC PMC6296248
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Abstract

This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors’ review of the literature followed by discussions at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed “dedifferentiated carcinoma”) is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.

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Figures

FIG. 1 FIGO grade 3 endometrioid carcinoma. Solid architecture (A), glandular architecture with high nuclear grade (B).
FIG. 1 FIGO grade 3 endometrioid carcinoma. Solid architecture (A), glandular architecture with high nuclear grade (B).CC BY · PubMed Central
FIG. 2 Serous carcinoma. Typical papillary and micropapillary architecture (A), glandular serous carcinoma recognized by highly atypical nuclei and high nuclear:cytoplasmic ratios (B), intraepithelial serous carcinoma involving atrophic endometrial polyp (C).
FIG. 2 Serous carcinoma. Typical papillary and micropapillary architecture (A), glandular serous carcinoma recognized by highly atypical nuclei and high nuclear:cytoplasmic ratios (B), intraepithelial serous carcinoma involving atrophic endometrial polyp (C).CC BY · PubMed Central
FIG. 3 Diagnostically difficult endometrial carcinoma. This tumor presented in a 45-yr-old woman with atypical endometrial hyperplasia. Sequencing revealed a POLE mutation, but no TP53 mutation. The final diagnosis was high-grade endometrioid carcinoma; the presence of a POLE mutation is prognostically favorable.
FIG. 3 Diagnostically difficult endometrial carcinoma. This tumor presented in a 45-yr-old woman with atypical endometrial hyperplasia. Sequencing revealed a POLE mutation, but no TP53 mutation. The final diagnosis was high-grade endometrioid carcinoma; the presence of a POLE mutation is prognostically favorable.CC BY · PubMed Central
BOX 1 Distinction of FIGO Grade 3 Endometrioid Carcinoma and Serous Carcinoma
BOX 1 Distinction of FIGO Grade 3 Endometrioid Carcinoma and Serous CarcinomaCC BY · PubMed Central
FIG. 4 Immunohistochemistry useful in distinction of serous carcinoma and high-grade endometrioid carcinoma. (A) p53 overexpression (aberrant) may be seen in high-grade endometrioid carcinoma and serous carcinoma. (B) Null p53 phenotype (aberrant) may be seen in high-grade endometrioid carcinoma and serous carcinoma. Note positive internal control. (C) Wild-type p53 expression, not seen in serous carcinoma. (D) Loss of MLH1 expression (aberrant), not seen in serous carcinoma. (E) Geographic loss of ARID1A expression (left), not seen in most serous carcinomas.
FIG. 4 Immunohistochemistry useful in distinction of serous carcinoma and high-grade endometrioid carcinoma. (A) p53 overexpression (aberrant) may be seen in high-grade endometrioid carcinoma and serous carcinoma. (B) Null p53 phenotype (aberrant) may be seen in high-grade endometrioid carcinoma and serous carcinoma. Note positive internal control. (C) Wild-type p53 expression, not seen in serous carcinoma. (D) Loss of MLH1 expression (aberrant), not seen in serous carcinoma. (E) Geographic loss of ARID1A expression (left), not seen in most serous carcinomas.CC BY · PubMed Central
FIG. 5 Clear cell carcinoma. Papillary architecture (A), tubulocystic architecture (B), solid architecture (C).
FIG. 5 Clear cell carcinoma. Papillary architecture (A), tubulocystic architecture (B), solid architecture (C).CC BY · PubMed Central
FIG. 6 Immunohistochemistry in clear cell carcinoma. Hepatocyte nuclear factor 1-beta (HNF1B) is frequently expressed in clear cell carcinoma (A), as is Napsin A (B). A significant minority of endometrial clear cell carcinomas can display aberrant p53 staining (C).
FIG. 6 Immunohistochemistry in clear cell carcinoma. Hepatocyte nuclear factor 1-beta (HNF1B) is frequently expressed in clear cell carcinoma (A), as is Napsin A (B). A significant minority of endometrial clear cell carcinomas can display aberrant p53 staining (C).CC BY · PubMed Central
FIG. 7 Mixed clear cell and endometrioid carcinoma. Note stark difference in cell shape, nuclear features and growth patterns.
FIG. 7 Mixed clear cell and endometrioid carcinoma. Note stark difference in cell shape, nuclear features and growth patterns.CC BY · PubMed Central
FIG. 8 Clear cell carcinoma versus serous carcinoma. (A) Mixed serous and clear cell carcinoma. Serous carcinoma with overtly pleomorphic nuclei, stratification, tumor cell budding and slit-like spaces is found at the top of the image. (B) High-grade endometrial carcinoma displaying morphologic features overlapping those of clear cell carcinoma and serous carcinoma. The high mitotic index and nuclear pleomorphism are most characteristic of serous carcinoma.
FIG. 8 Clear cell carcinoma versus serous carcinoma. (A) Mixed serous and clear cell carcinoma. Serous carcinoma with overtly pleomorphic nuclei, stratification, tumor cell budding and slit-like spaces is found at the top of the image. (B) High-grade endometrial carcinoma displaying morphologic features overlapping those of clear cell carcinoma and serous carcinoma. The high mitotic index and nuclear pleomorphism are most characteristic of serous carcinoma.CC BY · PubMed Central
BOX 2 Clear Cell Carcinoma
BOX 2 Clear Cell CarcinomaCC BY · PubMed Central
FIG. 9 Undifferentiated and dedifferentiated carcinoma. (A) Prototypical undifferentiated carcinoma. (B) Dedifferentiated carcinoma. (C) Undifferentiated carcinoma containing rhabdoid cells in a myxoid matrix. (D) Undifferentiated carcinoma containing monomorphic and pleomorphic cells. (E) Undifferentiated carcinoma containing multinucleate giant cells. This pattern corresponds to the “giant cell carcinoma” of Scully and is unrelated to other types of undifferentiated carcinomas discussed herein.
FIG. 9 Undifferentiated and dedifferentiated carcinoma. (A) Prototypical undifferentiated carcinoma. (B) Dedifferentiated carcinoma. (C) Undifferentiated carcinoma containing rhabdoid cells in a myxoid matrix. (D) Undifferentiated carcinoma containing monomorphic and pleomorphic cells. (E) Undifferentiated carcinoma containing multinucleate giant cells. This pattern corresponds to the “giant cell carcinoma” of Scully and is unrelated to other types of undifferentiated carcinomas discussed herein.CC BY · PubMed Central
FIG. 10 Immunohistochemistry in undifferentiated carcinoma of monomorphic type. (A) Focally intense labeling with CK18 in the absence of PAX 8 expression (latter not shown). (B) Loss of BRG-1 (SMARCA4) expression.
FIG. 10 Immunohistochemistry in undifferentiated carcinoma of monomorphic type. (A) Focally intense labeling with CK18 in the absence of PAX 8 expression (latter not shown). (B) Loss of BRG-1 (SMARCA4) expression.CC BY · PubMed Central
BOX 3 Undifferentiated and Dedifferentiated Carcinoma
BOX 3 Undifferentiated and Dedifferentiated CarcinomaCC BY · PubMed Central
FIG. 11 Carcinosarcoma. (A and B) Examples of homologous carcinosarcoma. (C and D) Examples of carcinosarcoma with heterologous elements, with cartilaginous differentiation (C) and rhabdomyoblastic differentiation (D).
FIG. 11 Carcinosarcoma. (A and B) Examples of homologous carcinosarcoma. (C and D) Examples of carcinosarcoma with heterologous elements, with cartilaginous differentiation (C) and rhabdomyoblastic differentiation (D).CC BY · PubMed Central
BOX 4 Undifferentiated and Dedifferentiated Carcinoma
BOX 4 Undifferentiated and Dedifferentiated CarcinomaCC BY · PubMed Central

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Research works printed but not linked: 3

  1. Holmes, 2014, Napsin A: a sensitive immunohistochemical marker for uterine clear cell carcinoma, Mod Pathol, 27, 536
  2. O'Keefe, 2015, Napsin A has utility in the diagnosis of clear cell carcinoma in the ovary but may be less valuable in the endometrium, Mod Pathol, 28, 530
  3. DeLair, 2012, Endometrial clear cell carcinoma with and without aberrant p53 expression: a study of 16 cases, Mod Pathol, 25, 265A

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Metadata

Authors
Murali, R., Davidson, B., Fadare, O., Carlson, J. A., Crum, C. P., Gilks, C. B., Irving, J. A., Malpica, A., Matias-Guiu, X., McCluggage, W. G., Mittal, K., Oliva, E., Parkash, V., Rutgers, J. K. L., Staats, P. N., Stewart, C. J. R., Tornos, C., & Soslow, R. A.
Affiliations
Oslo University Hospital (NO)
Corresponding author
Soslow, Robert A.
ORCID
Venue
International Journal of Gynecological Pathology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-01
Volume
38
Issue
Supplement 1
Pages
S40-S63
ISSN
0277-1691 (ISSN-L)
DOI
10.1097/pgp.0000000000000491
PMC
PMC6296248
OpenAlex
W2904313334
Cited by
278
References
152
Citations by year
2026: 20 · 2025: 38 · 2024: 33 · 2023: 53 · 2022: 42 · 2021: 42 · 2020: 33 · 2019: 17
FWCI
3.71
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Gynecological Pathology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repositori ObertUDL (University of Lleida) (publishedVersion, other-oa)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, cc-by)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders
  • National Institutes of Health (CA008748)
  • National Cancer Institute (CA008748, P30CA008748)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
  • Health Sciences › Medicine › Oncology › Neuroendocrine Tumor Research Advances
  • Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
Keywords
high-grade endometrial cancer, endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, carcinosarcoma, immunohistochemistry, p53, p16, DNA mismatch repair, PTEN, ARID1A, Napsin A, AMACR, diagnostic criteria, overdiagnosis, SWI/SNF chromatin remodeling, E-cadherin
MeSH terms
Female, Humans, Immunohistochemistry, Societies, Medical, Biomarkers, Tumor, Endometrial Neoplasms, Practice Guidelines as Topic, Carcinoma, Endometrioid, Neoplasm Grading

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