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Two-tier grading system for ovarian epithelial cancer: has its time arrived?

In this issue of the American Journal of Surgical Pathology, Malpica and associates validate a two-tier system for grading ovarian serous carcinoma based primarily on the assessment of nuclear atypia. Their study demonstrates that the system is easy to learn and shows excellent agreement among both gynecologic and general surgical pathologists at different institutions. The most commonly used grading system in the past was that of the International Federation of Gynecology and Obstetrics (FIGO). The FIGO grade is a three-tier system based on tumor architecture that divides neoplasms according to the ratio of glandular or papillary structures to solid growth. As currently applied to ovarian epithelial cancer by the Gynecologic Oncology Group, grade 1 tumors contain 5% or less solid areas, grade 2 neoplasms from 6% to 50%, and grade 3 tumors greater than 50%. The unpublished grading system of the Gynecologic Oncology Group is widely used and eclectic; both architectural and nuclear features are assessed. The criteria vary according to the histologic type of ovarian neoplasm, and the validity of the grading system has never been tested. Silverberg most recently reviewed the subject of grading of ovarian epithelial carcinoma in separate articles published in both gynecologic oncology and pathology journals. Although three or four-tier grading systems in various forms have been in vogue for grading ovarian epithelial malignancy for many decades, these systems do not currently provide optimal benefit to clinicians, who often have only 2 main therapeutic options. It is essential that information derived from pathologic examination facilitate future translational research that can lead to an improved clinical outlook for patients with ovarian cancer. To reach this goal requires refinement of classification and grading systems at appropriate intervals of time. Development of optimal systems may require sophisticated statistical methodology to correlate surgical pathologic observations with survival and molecular data. Recent evidence has demonstrated 2 distinct molecular pathways in the development of serous carcinoma with differing clinicopathologic features and survival. Low-grade serous carcinomas typically arise from low malignant potential (borderline) tumors and have a survival advantage, whereas high-grade tumors arise for the most part de novo and have a considerably worse prognosis. A recent study demonstrated that serous neoplasms of low malignant potential and low-grade serous carcinoma have KRAS and BRAF mutations in 60% of cases and p53 mutations in less than 10% of cases, whereas high-grade serous carcinomas are characterized by p53 mutations in over 50% of cases and lack KRAS and BRAF mutations. Another study found that BRAF mutations were limited to low-grade serous tumors; however, 12% of high-grade tumors had KRAS mutations. Using a two-tier grading system based primarily on the degree of nuclear atypia and secondarily on mitotic rate, a prior study from the University of Texas M.D. Anderson Cancer Center (MDACC) showed excellent correlation between