Review ArticleMolecular approaches for classifying endometrial carcinoma☆
Section snippets
Pathologic classification of endometrial carcinoma
EC is heterogeneous from the pathologic viewpoint. There are different histological types, with different microscopical features, pathogenesis, behaviour and prognosis. WHO has recently updated the pathologic classification of EC [4]. Nine different subtypes are recognized (Table 1), but EEC and serous carcinoma (SC) account for the vast majority of them.
EECs are estrogen-related carcinomas, which occur in perimenopausal patients, and are preceded by precursor lesions (endometrial
Flaws of the pathologic classification of endometrial carcinoma
Although the current histological classification is good for tumor stratification, in our opinion, there are some issues that can be subjected to debate, which can lead to possible future improvements. Some of these areas of improvement may benefit from advances in understanding of the molecular alterations involved in the different types of tumor. Some of these points are:
- 1.
Better definition of mucinous carcinoma, with possible inclusion as a variant of EEC. This is an unusual type of tumor.
TCGA molecular classification
The Cancer Genome Atlas Research Network (TCGA) performed an integrating genomic, transcriptomic and proteomic characterization of EC, based on array and sequencing technologies in 373 cases [6]. Exome sequence analysis revealed four groups of tumors. Group 1, with EEC with somatic inactivating mutations in POLE exonuclease and very high mutation rates (hypermutated) (7%), associated with good prognosis. Group 2 and group 3 both showing similar progression-free survival rates. Group 2 included
Impact of intratumor heterogeneity in pathologic and molecular classification
Endometrial Carcinoma shows intratumor heterogeneity, with different neoplastic cell components within the same tumor, with different morphologic and molecular features [26]. There is a wide spectrum of heterogeneous tumors, ranging from EEC with subtle variations in cytological or architectural patterns, to mixed tumors composed of two different histological types in the same tumor (for example mixed EEC-SC). Tumor heterogeneity may have an important clinical impact, since it can be a
Tailoring immunotherapy based on molecular classification of endometrial carcinoma
Application of TCGA surrogate classification to high-grade EC may help in deciding the use of immunotherapy in these patients. POLE-mutated and microsatellite unstable tumors show higher mutation rates in comparison with the other two groups [6], [27], and also a higher number of tumor infiltrating lymphocytes (TILs) [27] (Fig. 2). These two features seems to be related as higher mutation rates may generate more neo-antigens to which the T-cell receptor (TCR) repertoire of the patient is
Conclusion
In summary, integration of molecular classification into pathologic diagnosis may be important to improve assessment of prognosis and clinical management of patients with EC. We suggest combining pathologic classification and the surrogate TCGA molecular classification for high-grade EC, as an option to improve assessment of prognosis in EC patients.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
References (56)
Two pathogenetic types of endometrial carcinoma
Gynecol. Oncol.
(1983)- et al.
Utility of alpha-methylacyl-coenzyme-A racemase (p504s) immunohistochemistry in distinguishing endometrial clear cell carcinomas from serous and endometrioid carcinomas
Hum. Pathol.
(2013) - et al.
Molecular genetic heterogeneity in undifferentiated endometrial carcinomas
Mod. Pathol.
(2016) Endometrial carcinomas with ambiguous features
Semin. Diagn. Pathol.
(2010)- et al.
Practical issues in the diagnosis of serous carcinoma of the endometrium
Mod. Pathol.
(2016) - et al.
POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium
Gynecol. Oncol.
(2014) - et al.
Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations
Mod. Pathol.
(2015) - et al.
Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative
Mod. Pathol.
(2015) - et al.
Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer
Gynecol. Oncol.
(2009) - et al.
Polymerase epsilon (POLE) ultra-mutated tumors induce robust tumor-specific CD4 + T cell responses in endometrial cancer patients
Gynecol. Oncol.
(2015)
B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration
Gynecol. Oncol.
Endometrial carcinoma: molecular alterations involved in tumor development and progression
Oncogene
Molecular pathology of endometrial carcinoma
Histopathology
WHO Classification of Tumors of the Female Reproductive Organs. WHO Classification of tumors
Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers
Br. J. Cancer
Integrated genomic characterization of endometrial carcinoma
Nature
Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases
Am. J. Cancer Res.
Frequent expression of napsin A in clear cell carcinoma of the endometrium: potential diagnostic utility
Am. J. Surg. Pathol.
Diagnostic utility of hepatocyte nuclear factor 1-beta immunoreactivity in endometrial carcinomas: lack of specificity for endometrial clear cell carcinoma
Appl. Immunohistochem. Mol. Morphol.
Neuroendocrine carcinoma of the endometrium: a clinicopathologic study of 25 cases
Am. J. Surg. Pathol.
Mutation profile and clinical outcome of mixed endometrioid-serous endometrial carcinomas are different from that of pure endometrioid or serous carcinomas
Virchows Arch.
Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma
J. Pathol.
Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma
Am. J. Surg. Pathol.
Use of mutation profiles to refine the classification of endometrial carcinomas
J. Pathol.
Prognostic significance of POLE proofreading mutations in endometrial cancer
J. Natl. Cancer Inst.
Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts
Clin. Cancer Res.
A clinically applicable molecular-based classification for endometrial cancers
Br. J. Cancer
Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment
Gynecol. Oncol.
Cited by (0)
- ☆
Supported by grants, Fundació La Marató de TV3 (2/C2013), Fundación Asociación Española contra el Cancer (GCEIO 2010), and from the Spanish Ministry of Economy and Competitiveness, co-financed by FEDER funds from the European Union (“Una manera de hacer Europa”) (PI13/01701, RD12/0036/0013), and the Autonomous Government of Catalonia (2014SGR138).