Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma

Summary

Ovarian surface epithelial carcinomas are routinely subclassified by pathologists based on tumor cell type and grade. It is controversial whether cell type or grade is superior in predicting patient response to treatment or survival, in patients stratified by stage of disease. The aim of this study was to uniformly apply updated criteria for cell-type and grade assignment to a series of 575 cases of ovarian surface epithelial carcinoma. All patients were optimally surgically debulked, with no macroscopic residual disease after primary surgery. Slides from these cases were reviewed by a single pathologist, who was blinded to patient outcomes. In 50 cases, 2 additional pathologists reviewed the slides independently to determine interobserver variation in assessment of cell type and grade. The distribution of tumor stage was as follows: stage I—233 cases, stage II—246 cases, stage III—96 cases. The most common cell type encountered was serous carcinoma (229/575, 40%), followed by clear cell (149/575, 26%), endometrioid (139/575, 24%), and mucinous (36/575, 6%). Serous carcinomas were significantly more likely to present with advanced stage disease (76/229 [33.2%] were stage III, and 82% of all stage III tumors were serous), whereas all nonserous cell types were stage I or II at diagnosis in greater than 90% of cases. Both FIGO grade and Silverberg grade stratified patients into groups with significantly different risks of relapse and survival, but the Silverberg grading system was a more powerful prognosticator. In multivariate analysis, stage was the most powerful prognostic indicator (P < .0001), followed by tumor cell type (P = .015), but grade was not of independent significance. Interobserver variation in assignment of cell type was very good (κ = 0.77) with moderate reproducibility in assignment of Silverberg grade (κ = 0.40) and minimal reproducibility in assignment of FIGO grade (κ = 0.27). Thus, in this series of cases of ovarian surface epithelial carcinomas with no macroscopic residual disease after primary debulking surgery, assignment of tumor cell type was both more reproducible and provided superior prognostic information compared with assignment of tumor grade. As tumor cell type also correlates with underlying molecular abnormalities and may predict response to chemotherapy, this suggests that tumor cell type could be used to guide treatment decisions for patients with ovarian surface epithelial carcinoma.

Introduction

Ovarian surface epithelial carcinoma (OSEC) is the most lethal gynecologic malignancy in the Western world, with an overall 5-year survival of approximately 40% [1]. The most important prognostic factors are tumor stage at diagnosis and resectability, with most patients presenting with advanced stage, incompletely resectable disease [1]. OSEC is routinely subclassified based on tumor cell type. In the case of borderline tumors (tumors of low malignant potential), tumors of different cell types show dramatic differences in stage at presentation and patient outcome, and a recent consensus conference strongly endorsed the view that it is not appropriate to group cases of different cell types for research purposes, because of these inherent differences [2]. The clinical relevance of cell type for carcinomas remains uncertain. Recent textbooks of gynecologic pathology or oncology consistently describe the different cell types and point out differences between tumors of these cell types with respect to stage or grade at presentation, but then group carcinomas of different cell types together when discussing treatment, concluding, for example, that “with few exceptions, the clinical presentation, treatment, and results of treatment are similar for all (cell) types of tumor” within the group of OSEC [3]. Increasingly, it is appreciated that tumor cell type correlates with epidemiological risk factors, BRCA1 or 2 mutation status, differences in gene expression profile and genetic events during oncogenesis, and response to treatment [4], [5], [6], [7], [8], [9]. A recent National Cancer Institute sponsored “State of the Science” conference on ovarian cancer concluded that trials of alternative therapies for clear cell and mucinous carcinoma should be initiated, based on existing evidence that these tumor cell types respond poorly to conventional chemotherapy [10]. Thus, cell type has the potential to convey information about underlying molecular abnormalities and to guide treatment so that the ability to reproducibly assess this variable is important.

Grading of ovarian cancer is also done routinely and but has not been done uniformly, or according to defined criteria, until recently (reviewed in Ref. [11]). The WHO, FIGO, and GOG grading systems for OSEC differ in that the FIGO grading system is based on architectural pattern, whereas WHO and GOG grading systems require consideration of both architectural and cytologic features, but lack defined criteria. Shimizu et al [12], [13] have proposed and tested a more defined grading system for ovarian carcinoma that is based on the widely used Nottingham grading system for breast carcinoma and is applicable to OSEC of all cell types. Two other groups have independently proposed 2-tier grading systems for serous carcinomas [14], [15]. These 2-tier grading systems mirror the underlying molecular pathways in serous carcinoma, with the high-grade tumors and low-grade tumors arising independently (ie, high-grade serous carcinomas do not arise through progression of lower grade tumors) [5], [15], [16], [17], [18].

Our objective was to assess the prognostic significance and reproducibility of cell-type and grade assignment, comparing different grading systems. We chose to look at a defined subset of patients with OSEC, specifically those patients with no macroscopically visible residual disease after surgery. This is a group of patients with a relatively favorable prognosis (>60% 5-year survival), in contrast to the very poor outcome for patients with ovarian carcinoma who are left with macroscopic residual disease after debulking surgery [19]. This case selection strategy can be anticipated to include relatively more cases of tumors of histologic cell types that more commonly present at early stage, such as clear cell and mucinous carcinoma, improving the ability to characterize these subsets.