Grading Uterine Endometrioid Carcinoma: A Proposal That Binary Is Best

S ince the institution of standardized grading of endometrioid endometrial adenocarcinoma (EEC) in the early 1980s, the FIGO grading system has been based on a 3-tier structure, dividing tumors into grade 1 (G1), grade 2 (G2), and grade 3 (G3) using somewhat arbitrary cutoffs of <5% solid growth, 5% to 50% solid growth, and >50% solid growth, respectively.1 In the 1980s, an additional nuclear grade component was included, whereby the presence of “high-grade” nuclei in association with architecture of a lower grade led to the elevation of the overall tumor grade to the next highest level. Despite a general trend within pathology to revert to binary grading systems (for example, in the urothelial tract and uterine cervix), the 3-tier system in EEC has remained in use. This is somewhat surprising when one considers the substantial volume of literature available that casts doubt on the added value of an intermediate grade in the gradation of EEC. Currently, >52,000 new cases of endometrial carcinoma are diagnosed annually in the United States, and there are >8500 deaths per year. The vast majority of cases of EEC are limited to the uterus at the time of diagnosis, and EEC-related mortality is concentrated in the <30% of patients who present with regional and metastatic disease and in patients with high-grade histology. In keeping with this finding, classification and regression tree statistical analysis has demonstrated that after tumor stage, the next most informative prognostic division in EEC is between high-grade (G3) and low-grade (G1/G2) tumors.4,5 Although it is reported that there is a small but statistically significant difference in survival of up to 5% between clinically low-stage G1 and G2 EEC,6,7 this has not been consistently demonstrated.4,8,9 Therefore, the key consideration in tumor grading at hysterectomy should be in identifying the presence of G3 EEC and any other highgrade components that may adversely affect patient prognosis and not in trying to differentiate between G1 and G2 EEC. For any pathologic grading system to be successful it must have the following key characteristics: efficacy, reproducibility, practicality, and clinical relevance. In the setting of EEC, efficacy can be defined as allowing the greatest proportion of tumors to segregate to the subcategory that most accurately assesses their prognostic risk. Although no prognostic grading system is perfect, the aim is to apply the greatest fit possible between the tumor population and our grading system. In the context of our proposed change from a 3-tier to a 2-tier EEC grading system, the key challenge is how to manage the intermediate grade group. Over the last 20 years, numerous studies4,7–10 have assessed the current FIGO system in terms of efficacy, practicality, and reproducibility and compared it with alternative binary grading systems, all of which combined percentage of solid growth with additional pathologic factors such as presence of necrosis,8,10 pattern of myometrial invasion,8 mitotic count, nuclear atypia, and lymphovascular invasion.10 Every one of these studies has demonstrated that the proposed novel binary grading system is both prognostic and comparable to the 3-tier FIGO system. These studies demonstrated 2 key features of EEC. First, EEC divides readily into 2 main low-risk and high-risk prognostic groups on the basis of a number of factors associated with increased tumor aggressiveness; the different grading systems show only slight disagreement over the distribution of a small number of cases in the gray zone between the 2 main prognostic groups. The second major feature of EEC demonstrated is that the assessment of proportion of solid growth represents a good foundation for the assessment of grade in EEC. All of the studies mentioned above also addressed the issue of grade reproducibility and compared the reproducibility of the novel systems with FIGO, and in some cases with a binary FIGO system, derived by combining G1 and G2 into 1 low-grade group.4,7,10,11 Although the resultant k value in each case varies, a pattern is apparent from these studies; in each individual case, the new grading system is equal to or marginally superior to the current 3-tier FIGO system in terms of interobserver variability k score, but the binary FIGO system, when assessed, consistently exceeds the 3-tier FIGO system. The overall range of k values for interobserver variability for binary FIGO is 0.48 to 0.71. It should be noted, however, that most of these studies From the Departments of *Pathology; wSurgery, Gynecology Service, Memorial Sloan Kettering Cancer Center; and zWeill Cornell Medical College, New York, NY. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Robert A. Soslow, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: gynbreast@mskcc.org). Copyright r 2014 by Lippincott Williams & Wilkins SPECIAL ARTICLE