Data for this Review were identified by searches of PubMed, references from relevant articles, and internet searches, with the search terms “endometrium”, “endometrial”, “uterus”, “uterine corpus”, and “cancer”, “carcinoma”, “adenocarcinoma”, “endometrial carcinoma”, or “endometrial adenocarcinoma”. Only articles published in English between January, 1983, and September, 2013, were included. The final reference list was generated on the basis of originality and relevance to this paper.
ReviewClassification of endometrial carcinoma: more than two types
Introduction
Endometrial cancer is the most common gynaecological malignant disease, and the fourth most common cancer in European and North American women, accounting for about 6% of new cancer cases and 3% of cancer deaths per year.1, 2 Incidence is steadily increasing;3 age-adjusted annual incidence was 24·3 per 100 000 women in the USA in 2006–10, and 19·4 per 100 000 in the UK in 2008.1, 3 Around 75% of patients with endometrial cancer are diagnosed in the early stages (International Federation of Gynecology and Obstetrics [FIGO] stages I or II), and 5-year overall survival is 74–91%.1, 4 For women with advanced stage III or IV disease, 5-year overall survival of 57–66% and 20–26%, respectively, has been reported.4
Traditionally, endometrial carcinomas have been classified as type I or type II, as defined by Bokhman,5 on the basis of clinical, endocrine, and epidemiological observations. Type I tumours were oestrogen dependent, and associated with endometrial hyperplasia, whereas type II tumours were oestrogen independent and associated with endometrial atrophy.5 Endometrial carcinoma is also classified according to histopathological characteristics,6 with the most common subtypes being endometrioid carcinoma, serous carcinoma, carcinosarcoma, and clear-cell carcinoma. Correlations have been noted between the subtypes in these two classification systems—type I cancers generally have endometrioid histology and most type II cancers are serous carcinomas—but these correlations are imperfect.
In the past decade it has become increasingly clear that endometrial cancer comprises a biologically, clinically, morphologically, and genetically heterogeneous group of tumours. Traditional classifications do not entirely take into account this heterogeneity and, being prognostic in nature, are limited in predicting response to therapy. A genomic classification of endometrial carcinoma has been proposed7 in an attempt to identify potential targets for treatment in different subgroups of the disease.
In this Review, we provide an overview of traditional and genomic classifications of endometrial carcinoma, and discuss their potential and their limitations. In view of the substantial morphological and molecular heterogeneity in endometrial cancer, we suggest that classification systems based on limited sets of parameters are insufficient for the development of effective individualised treatments. We propose a rationale for establishing an integrated classification system that incorporates molecular and histopathological features to define biologically and clinically relevant subsets of endometrial cancer.
Section snippets
Dualistic and histological classification
Bokhman5 proposed that endometrial cancers can be categorised into two pathogenetic types that are primarily based on clinical, metabolic, and endocrine characteristics (table 1).7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 Type I tumours were associated with oestrogen excess, obesity, hormone-receptor positivity, and endometrial hyperplasia, were moderately or highly differentiated, and had favourable outcomes; type II tumours were more common in non-obese women, arose in the absence of endocrine
Genetic alterations and molecular classification
Many studies have assessed genetic alterations in endometrial cancer, almost exclusively in endometrioid and serous carcinomas. Early research focused mainly on single candidate genes or pathways,9 but next-generation sequencing studies have provided insights into genome-wide genetic alterations in these tumours.
Towards an integrated classification system
In view of the substantial genetic and morphological heterogeneity in endometrial carcinomas, the current approach of histopathology-based classification requires refinement. We propose that an integrated classification system incorporating molecular and clinicopathological features would define biologically and clinically relevant subsets of endometrial cancer.
Most cancer taxonomies are prognostic, although some, such as lung cancer classifications, provide predictive information.59 In
Future challenges and opportunities
Next-generation sequencing studies have confirmed and expanded knowledge of recurrently altered signalling pathways in endometrial cancer, and have laid the foundations for rational design of genomics-based clinical trials. In view of the high mutation rates, patterns of epistatic interactions between known cancer genes in a subset of endometrioid carcinomas might differ from those in other epithelial malignant disease. Additionally, whether different mutations (eg, in PTEN, PIK3CA, PIK3R1, or
Conclusions
The results of next-generation sequencing studies have substantially broadened understanding of endometrial cancers. Nevertheless, detailed analyses of rare subtypes and clarification of the biological importance of novel mutations are required for translation of these insights into clinical benefit for patients. All information needed to define the optimum therapy for each patient is unlikely to be obtained from the analysis of somatic genetic aberrations, particularly because of the
Search strategy and selection criteria
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