Grading systems for ovarian serous carcinomas include the FIGO system which is based solely on architecture 1
, the WHO grading system based on cytological and architectural features 15
and the Silverberg-Shimizu grading which takes into account architectural and nuclear features and mitotic activity. 11
More recently, a two-tier grading system that divides serous carcinomas into low and high-grade has been proposed. 6, 12
This grading system is primarily based on nuclear grade with mitotic activity used as a secondary feature. In contrast to the three tier system, the two-tier grading system has a molecular genetic underpinning. This is important because it provides biologic support rather than being based entirely on morphologic criteria.3, 10
Using the two-tier system, the majority of serous carcinomas can be classified into either low or high-grade, but there are occasional tumors with nuclear features that are intermediate between conventional low-grade and high-grade. The current study provides clinical and molecular genetic evidence that tumors with grade 2 nuclei are more closely related to high-grade rather than low-grade serous carcinomas. Specifically, the aggressive behavior of the tumors, the high proportion of TP53
mutations (90%) and the absence of KRAS, BRAF, ERBB2 mutations are similar to tumors with grade 3 nuclei as compared to tumors with grade 1 nuclei.
The results of this study have important clinical implications because the architectural features such as solid growth pattern (poorly differentiated), papillary (moderately differentiated) or micropapillary/macropapillary (well-differentiated) may overlap. The findings in the present study support those in our previous study in which we showed that serous carcinomas with micropapillary features and grade 3 nuclei were similar to conventional high-grade carcinomas based on absence of KRAS
Thus, nuclear grade 2/3 versus grade 1 is the major microscopic feature that distinguishes low from high-grade serous carcinomas. As there were only eleven cases in this study, more cases are needed to corroborate our conclusion.
We found that the mitotic activity ranged widely among the 11 carcinomas with grade 2 nuclei (). There were seven tumors with mitotic counts below 12 mitoses/10 HPFs, a cutoff proposed to distinguish low-grade versus high-grade serous carcinomas in a previous study. 6
Thus, mitotic activity should be used as an ancillary feature in the two-tier grading system. In fact, we believe the proposed mitotic count cut point of 12 mitotic figures/10 HPFs should be revised. In our experience low grade serous carcinomas almost never have mitotic counts greater than 5 mitotic figures/10 HPFs. A larger study will be necessary to come up with firm guidelines.
In conclusion, we analyzed a series of ovarian serous carcinomas with grade 2 nuclei to delineate their clinicopathologic and molecular genetic relationship to low- and high-grade serous carcinomas. All the tumors were high stage and clinically aggressive. Mutations of KRAS
which characterize most low-grade serous carcinomas were not identified in any of them. In contrast, 10 (90%) of 11 tumors contained non-synonymous TP53
mutations characteristic of high-grade serous carcinoma. The clinical and morphologic data in this study showing close similarity between ovarian serous carcinomas with grade 2 nuclei and those with grade 3 nuclei together with our recent report showing that subclassification of high-grade serous carcinoma into moderately and poorly differentiated serous carcinomas is not relevant 16
provide strong support for the use of a two-tier grading system for ovarian serous carcinomas.