Elsevier

Gynecologic Oncology

Volume 145, Issue 1, April 2017, Pages 200-207
Gynecologic Oncology

Review Article
Molecular approaches for classifying endometrial carcinoma

https://doi.org/10.1016/j.ygyno.2016.12.015Get rights and content

Highlights

  • Histological classification of EC has some issues that can be subjected to debate.

  • Molecular classification separates EC into 4 categories with different prognosis.

  • EC is a heterogeneous disease even at a molecular level.

  • POLE-mutated and MSI might be more sensitive to immunotherapy with anti-PD1/PDL1 antibodies.

  • CN-low and -high might be less sensitive to anti-PD1/PDL1 antibodies and combinations could be more promising.

Abstract

Endometrial carcinoma is the most common cancer of the female genital tract. This review article discusses the usefulness of molecular techniques to classify endometrial carcinoma. Any proposal for molecular classification of neoplasms should integrate morphological features of the tumors. For that reason, we start with the current histological classification of endometrial carcinoma, by discussing the correlation between genotype and phenotype, and the most significant recent improvements. Then, we comment on some of the possible flaws of this classification, by discussing also the value of molecular pathology in improving them, including interobserver variation in pathologic interpretation of high grade tumors. Third, we discuss the importance of applying TCGA molecular approach to clinical practice. We also comment on the impact of intratumor heterogeneity in classification, and finally, we will discuss briefly, the usefulness of TCGA classification in tailoring immunotherapy in endometrial cancer patients. We suggest combining pathologic classification and the surrogate TCGA molecular classification for high-grade endometrial carcinomas, as an option to improve assessment of prognosis.

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)

  • T. Miyatake et al.

    B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration

    Gynecol. Oncol.

    (2007)
  • A. Yeramian et al.

    Endometrial carcinoma: molecular alterations involved in tumor development and progression

    Oncogene

    (2013)
  • X. Matias-Guiu et al.

    Molecular pathology of endometrial carcinoma

    Histopathology

    (2013)
  • R.J. Kurman et al.

    WHO Classification of Tumors of the Female Reproductive Organs. WHO Classification of tumors

    (2014)
  • C.A. Hamilton et al.

    Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers

    Br. J. Cancer

    (2006)
  • Cancer Genome Atlas Research N et al.

    Integrated genomic characterization of endometrial carcinoma

    Nature

    (2013)
  • O. Fadare et al.

    Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases

    Am. J. Cancer Res.

    (2013)
  • O. Fadare et al.

    Frequent expression of napsin A in clear cell carcinoma of the endometrium: potential diagnostic utility

    Am. J. Surg. Pathol.

    (2014)
  • O. Fadare et al.

    Diagnostic utility of hepatocyte nuclear factor 1-beta immunoreactivity in endometrial carcinomas: lack of specificity for endometrial clear cell carcinoma

    Appl. Immunohistochem. Mol. Morphol.

    (2012)
  • C.E. Pocrnich et al.

    Neuroendocrine carcinoma of the endometrium: a clinicopathologic study of 25 cases

    Am. J. Surg. Pathol.

    (2016)
  • L. Coenegrachts et al.

    Mutation profile and clinical outcome of mixed endometrioid-serous endometrial carcinomas are different from that of pure endometrioid or serous carcinomas

    Virchows Arch.

    (2015)
  • M.A. Castilla et al.

    Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma

    J. Pathol.

    (2011)
  • C.B. Gilks et al.

    Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma

    Am. J. Surg. Pathol.

    (2013)
  • M.K. McConechy et al.

    Use of mutation profiles to refine the classification of endometrial carcinomas

    J. Pathol.

    (2012)
  • D.N. Church et al.

    Prognostic significance of POLE proofreading mutations in endometrial cancer

    J. Natl. Cancer Inst.

    (2015)
  • E. Stelloo et al.

    Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts

    Clin. Cancer Res.

    (2016)
  • A. Talhouk et al.

    A clinically applicable molecular-based classification for endometrial cancers

    Br. J. Cancer

    (2015)
  • A. Talhouk et al.

    Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment

    Gynecol. Oncol.

    (2016)
  • 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).

    View full text