How to Best Classify Endometrial Cancers?

This article refers to two original articles. The second article can be found here.

Judith Michels

Classically, endometrial cancers were classified in hormone-dependant type I and -independent type II tumours. In general, endometrioid adenocarcinomas are often preceded by endometrial hyperplasia and are considered as type I cancers whereas serous and mixed cell adenocarcinomas derive from intraepithelial carcinomas arising in atrophic endometrium and are considered as type II cancers. (1) The type II cancers are less common (10%) and more aggressive (40% of deaths from this disease). (2) Two recent articles postulate that high-grade endometrioid cancers have similar features than serous type II cancers and should be reclassified. (3, 4)

In a pooled analysis of data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium, a total of 14,069 patients with endometrial tumours were grouped and compared with 35,312 controls for the associated risk factors (3). They were defined as type I (n=12,853) (i.e. endometrioid cancer n=7,246; adenocarcinoma not otherwise specified n=4,830; adenocarcinoma with squamous differentiation n=777) and type II (n=854) (i.e. serous n=508 and mixed cell carcinoma n=346) endometrial cancers. Clear cell (n=196) and mucinous (n=166) histology were considered separately.

The mean age of patients was lowest in endometrioid cancers and adenocarcinoma with squamous differentiation (61.9 and 61.8; standard deviation (SD) 9.5 and 8.8 respectively) and highest in serous cancers (66.5; SD 8). Increasing body mass index (BMI) and diabetes were positively associated with risk for endometrial cancer whereas increasing age at menarche, parity, use of oral contraception (OC), smoking and pack-years of smoking was inversely associated with risk. Unexpectedly the two groups were similar for parity, OC use, age at menarche, diabetes and cigarette smoking.

Only high BMI was significantly associated with type I tumours (Odds ratio (OR) per 2 kg/m2 increase was 1.2 (95%CI, 1.19-1.21) in type I and 1.12 (95%CI, 1.09-1.14) in type II cancers, p<0.0001). Low-grade (grade ≤2; n=3,630) and high-grade (grade 3; n=519) endometrioid cancers were differently associated with the increase of BMI risk factor (OR per 2 kg/m2 increase was 1.23 (95%CI, 1.21-1.25) in low-grade and 1.16 (95%CI, 1.12-1.20) in high-grade cancers, p<0.0001). Interestingly the risk factor patterns were similar for high grade endometrioid and type II tumours.

In conclusion type II tumours have similar risk factors than type I tumours and may not be totally oestrogen independent. Finally it would be useful to distinguish the more aggressive high-grade endometrioid subtype from the low-grade presentation, rather to stick to the type I/II classification.

In a genomic characterisation of endometrial tumours, 373 (i.e. low and high-grade endometrioid n=307, serous n=66 (53), mixed (13) cases) carcinomas were analysed on a genomic, transcriptomic and proteomic multiplatform. (4) The median follow-up of the cohort was 32 months. An unsupervised hierarchical clustering pooled the tumors into fours clusters.

Serous histology and 25% of high-grade endometrioid carcinomas were grouped in a ‘serous-like’ cluster and showed to be the most genetically instable (i.e. extensive copy number alterations) and PT53 mutated (90%). Moreover PIK3CA mutations (42%) and ERBB2 amplifications (27%) were frequent in this subgroup of patients. Endometrioid tumors were associated with microsatellite instability in 40%, low genome alteration, high DNA methylation changes, frequent mutations in PTEN (84%), PIK3CA, KRAS, ARID1A and rare mutation in p53 gene. The patients grouped in the ‘serous-like’ cluster had worse progression-free survival compared to endometroid tumours (p<0.003).
The general conclusion of this article is that a genomic characterisation of endometrial tumours may help for the management of these patients.

Discussion questions:

Is it time to consider genomic-based classification in endometrial tumours?
Are basal-like breast, serous endometrial and high-grade serous ovarian cancers a similar disease?


  1. Hecht JL, Mutter GL. Molecular and pathologic aspects of endometrial carcinogenesis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006, 24(29): 4783-4791.
  2. Moore KN, Fader AN. Uterine papillary serous carcinoma. Clinical obstetrics and gynecology 2011, 54(2): 278-291.
  3. Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, et al. Type I and II Endometrial Cancers: Have They Different Risk Factors? Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013, 31(20): 2607-2618.
  4. Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013, 497(7447): 67-73.

The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.

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