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Original Article
Reclassification of Serous Ovarian Carcinoma
by a 2-Tier System
A Gynecologic Oncology Group Study
Diane C. Bodurka, MD1; Michael T. Deavers, MD1; Chunqiao Tian, PhD2; Charlotte C. Sun, DrPH, MPH1;
Anais Malpica, MD1; Robert L. Coleman, MD1; Karen H. Lu, MD1; Anil K. Sood, MD1; Michael J. Birrer, MD, PhD3;
Robert Ozols, MD4; Rebecca Baergen, MD5; Robert E. Emerson, MD6; Margaret Steinhoff, MD7;
Behnaz Behmaram, MD8; Golnar Rasty, MD9; and David M. Gershenson, MD1
BACKGROUND: A study was undertaken to use the 2-tier system to reclassify the grade of serous ovarian tumors
previously classified using the International Federation of Gynecology and Obstetrics (FIGO) 3-tier system and determine the progression-free survival (PFS) and overall survival (OS) of patients treated on Gynecologic Oncology
Group (GOG) Protocol 158. METHODS: The authors retrospectively reviewed demographic, pathologic, and survival
data of 290 patients with stage III serous ovarian carcinoma treated with surgery and chemotherapy on GOG Protocol 158, a cooperative multicenter group trial. A blinded pathology review was performed by a panel of 6 gynecologic
pathologists to verify histology and regrade tumors using the 2-tier system. The association of tumor grade with PFS
and OS was assessed. RESULTS: Of 241 cases, both systems demonstrated substantial agreement when combining
FIGO grades 2 and 3 (overall agreement, 95%; kappa statistic, 0.68). By using the 2-tier system, patients with lowgrade versus high-grade tumors had significantly longer PFS (45.0 vs 19.8 months, respectively; P ¼.01). By using
FIGO criteria, median PFS for patients with grade 1, 2, and 3 tumors was 37.5, 19.8, and 20.1 months, respectively
(P ¼.07). There was no difference in clinical outcome in patients with grade 2 or 3 tumors in multivariate analysis.
Woman with high-grade versus low-grade tumors demonstrated significantly higher risk of death (hazard ratio, 2.43;
95% confidence interval, 1.17-5.04; P ¼.02). CONCLUSIONS: Women with high-grade versus low-grade serous carcinoma of the ovary are 2 distinct patient populations. Adoption of the 2-tier grading system provides a simple yet preC 2011 American Cancer Society.
cise framework for predicting clinical outcomes. Cancer 2012;118:3087-94. V
KEYWORDS: ovarian cancer, serous histology, 2-tier grading system, FIGO grading.
Corresponding author: Diane C. Bodurka, MD, University of Texas, MD Anderson Cancer Center, Department of Gynecologic Oncology, 1155 Herman Pressler,
Unit 1362, Houston, TX 77030; Fax: (713) 792-7586; [email protected]
1
The University of Texas MD Anderson Cancer Center, Houston Texas; 2Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute,
Buffalo, New York; 3Massachusetts General Hospital, Boston, Massachusetts; 4Fox Chase Cancer Center, Philadelphia, Pennsylvania; 5New York-Presbyterian Hospital, Weill-Cornell Medical Center, New York, New York; 6Indiana University School of Medicine, Indianapolis, Indiana; 7Women and Infants Hospital, Providence,
Rhode Island; 8Medical College of Wisconsin, Milwaukee, Wisconsin; 9University Health Network, Toronto, Ontario, Canada
Chunqiao Tian’s current address: Precision Therapeutics, Inc., Pittsburgh, Pennsylvania
The following Gynecologic Oncology Group member institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center,
Abington Memorial Hospital, University of Rochester Medical Center, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical
School, Emory University Clinic, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group P.C., University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, Georgetown University Hospital, University of Cincinnati, University of North Carolina School of Medicine, University of Texas Southwestern Medical Center at Dallas, Indiana University School of Medicine, Wake Forest
University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St.
Luke’s Medical Center, SUNY Downstate Medical Center, University of Kentucky, Community Clinical Oncology Program, The Cleveland Clinic Foundation, Johns
Hopkins Oncology Center, State University of New York at Stony Brook, Eastern Pennsylvania GYN/ONC Center, P.C., Washington University School of Medicine,
Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical School, Fox Chase Cancer Center, Medical University
of South Carolina, Women’s Cancer Center, University of Oklahoma, University of Virginia Health Sciences Center, University of Chicago, Tacoma General Hospital,
Thomas Jefferson University Hospital, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, Gynecologic Oncology
Network, Oregon Health Sciences University, University of Southern California at Los Angeles, University of Miami School of Medicine, Stanford University Medical
Center, Eastern Virginia Medical School, University of Arizona Health Science Center, Mayo Clinic, and Long Island Jewish Medical Center.
DOI: 10.1002/cncr.26618, Received: June 29, 2011; Revised: August 25, 2011; Accepted: September 7, 2011, Published online November 9, 2011 in Wiley
Online Library (wileyonlinelibrary.com)
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June 15, 2012
3087
Original Article
Figure 1. Low-grade serous carcinoma of the ovary is characterized by relative uniformity of the cells and up to 12 mitoses
per 10 high-power fields. Courtesy of Anais Malpica, MD.
INTRODUCTION
Ovarian cancer remains the most lethal gynecologic
malignancy. Tumors of different histologies and grades
have traditionally been grouped together and studied as a
single disease entity. Recent developments, however, have
questioned the wisdom of this strategy, especially as it
applies to the treatment of women with serous carcinoma
of the ovary.
Both histologic type and grade of tumors have been
proven to be of prognostic significance for women with
ovarian cancer. Prognostic significance of histologic grade
has been complicated by the inclusion of all epithelial subtypes in the analyses within several studies.1-4 Nevertheless, no single system is universally used to grade these
tumors. Our group has chosen to focus solely upon the
grading of the most common histologic type, invasive serous carcinoma. We have developed and refined a simpler,
clinically meaningful, and reproducible 2-tier grading system in which serous ovarian carcinomas are classified as
low-grade or high-grade.5 This grading system is based
primarily on the assessment of nuclear atypia, with mitotic rate used as a secondary feature (Figs. 1 and 2).
Tumors with mild to moderate cytologic atypia are designated as low-grade, whereas tumors with marked cytologic atypia are designated as high-grade. Low-grade
tumors tend to have a lower mitotic rate (usually up to 12
mitoses per 10 high-power fields [HPFs]). In contrast,
high-grade tumors have conspicuous mitotic activity
(>12 mitoses per 10 HPFs) and multinucleated cells.5
3088
Figure 2. High-grade serous carcinoma of the ovary is characterized by pleomorphism; there is marked nuclear atypia
and >12 mitoses per 10 high-power fields. Courtesy of Anais
Malpica, MD.
We have used this system at our institution for more than
15 years, and it has been subsequently validated and
shown to have prognostic utility.6
Gershenson et al. described the clinical behavior of
112 patients with metastatic low-grade serous ovarian carcinoma.7 The data indicated that women with this type of
tumor are younger and survive longer than women with
high-grade tumors. Because the above study focused on
patients from a single institution, we proposed to test the
validity of the 2-tier grading system in a multi-institutional setting. We conducted an ancillary study of data
from Gynecologic Oncology Group (GOG) Protocol
158, a prospective study of women with advanced epithelial ovarian cancer.8 The purpose of our study was 2-fold:
1) to use the 2-tier grading system to reclassify the histologic grade of tumors from women with serous ovarian
carcinoma whose tumors had previously been classified
using the International Federation of Gynecology and
Obstetrics (FIGO) 3-tier system and 2) to determine the
progression-free survival (PFS) and overall survival (OS)
of patients treated on GOG 158 based upon reclassification of these tumors as low-grade or high-grade using the
2-tier system.9
MATERIALS AND METHODS
Before initiation of this study, institutional review board
approval was obtained at The University of Texas MD
Anderson Cancer Center. We retrospectively reviewed demographic, pathologic, and survival data of patients who
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June 15, 2012
Grading Serous Ovarian Cancer/Bodurka et al
participated in GOG Protocol 158, a cooperative multicenter prospective study of women with advanced epithelial ovarian cancer. Patients who underwent surgery with
no residual mass >1 cm were randomized to postoperative cisplatin/paclitaxel (arm I) or carboplatin/paclitaxel
(arm II). Our study focused on women with serous ovarian cancer treated with carboplatin/paclitaxel because of
the labor-intensive pathology review and available resources. All patients signed an approved informed consent.
All pathology slides underwent central review by the
GOG Pathology Committee for confirmation of eligibility. In the present study, 2 to 23 hematoxylin and eosinstained slides of each primary ovarian tumor were reviewed
by a gynecologic pathologist (M.T.D.) in a blinded fashion to confirm the original histologic diagnosis and independently reclassify the tumors using the 2-tier system. To
strengthen the study, we expanded the group of reviewers
by adding 5 additional pathologists (R.B., R.E., M.S.,
B.B., and G.R.), who also reviewed cases in an independent, blinded fashion. Despite time constraints, the vast majority of slides were reviewed by a minimum of 4
pathologists. The final 2-tier grade was determined by the
grade agreed upon by the majority of reviewers. Pathologic
data were correlated with clinical variables and survival.
Patients were divided into 2 groups, low- and high-grade,
for analysis according to tumor grade. The primary endpoints were PFS and OS. PFS was calculated from the date
of study enrollment to the date of disease recurrence,
death, or last contact. OS was calculated from the date of
study enrollment to the date of death or last contact.
PFS and OS functions were estimated using the
Kaplan-Meier procedure.10 The log-rank test was used to
make comparisons based on tumor grade. A Cox proportional hazards model was used to confirm the independent
prognostic value of the tumor grade adjusted for age, performance status (PS), and residual disease.10 These covariates were included for adjustment based on the prognostic
variables identified by previous GOG studies.4 The Wilcoxon rank sums, Pearson chi-square, or the Fisher exact
test was used to assess associations between tumor grade
and patient clinicodemographic characteristics.11 Agreement between the 2-tier and FIGO grading systems was
evaluated using kappa statistics.11 Comparisons were
made between 2-tier low-grade versus FIGO grade 1
tumors and between 2-tier high-grade versus FIGO grade
2 and 3 tumors. All statistical tests were 2-tailed, with the
significance level set at a ¼ .05. Statistical analyses were
performed using Statistical Analysis Software version 9.1
(SAS Institute, Cary, NC).
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June 15, 2012
Table 1. Patient Characteristics, N ¼ 241
Characteristic
No. of Patients
%
8
52
82
68
31
3.3
21.6
34.0
28.2
12.9
108
115
18
44.8
47.7
7.5
69
172
28.6
71.4
16
102
123
6.6
42.3
51.0
21
220
8.7
91.3
Agea
<40 years
40-49 years
50-59 years
60-69 years
‡70 years
GOG performance status
0
1
2
Residual tumor
Microscopic
Gross, £1.0 cm
FIGO grade
1
2
3
MDACC grade
Low
High
Abbreviations: FIGO, Federation of Gynecology and Obstetrics; GOG, Gynecologic Oncology Group; MDACC, The University of Texas MD Anderson
Cancer Center.
a
Median years (range) ¼ 56.7 (21.8-81.9).
RESULTS
A total of 392 patients were enrolled on the carboplatin/
paclitaxel arm of GOG Protocol 158. Of these, 290
patients were diagnosed by GOG pathologists as having
serous carcinoma. Slides from 4 (1.4%) patients were not
available. The tumors of 11 patients were excluded because
of histologies other than serous ovarian cancer: 6 were borderline serous tumors, 2 were clear cell carcinoma, 2 were
adenocarcinoma not otherwise specified, and 1 was mucinous carcinoma. To ensure the homogeneity of the study
population, an additional 34 patients who did not complete the required chemotherapy were also excluded.
Therefore, a total of 241 patients were included in the final
analysis. Of the tumors of 241 patients, 15 were evaluated
by 3 reviewers using the 2-tier system, 190 by 4 reviewers,
and 36 by 5 reviewers. Therefore, the tumors of 226
(94%) patients were reviewed by a minimum of 4 pathologists. The reviewers showed high consistency in evaluation,
with full agreement in the tumors of 197 (82%) patients.
Patient characteristics are summarized in Table 1.
By using the 2-tier system, 21 patients (8.7%) were confirmed as having low-grade serous carcinoma, and 220
(91.3%) were confirmed as having high-grade disease. Table 2 shows associations of tumors graded by the 2-tier
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Table 2. Comparison of the Outcomes Associated With the 2-Tier Versus the FIGO Grading System
Characteristic
Median age, y
P
MDACC Grade
Low
High
No. of Patients (%)
No. of Patients (%)
51.1
57.0
.03
13 (61.9)
8 (38.1)
95 (43.2)
125 (56.8)
.10
8 (38.1)
13 (61.9)
61 (27.7)
159 (72.3)
.62
13 (61.9)
7 (33.3)
1 (4.8)
3 (1.4)
95 (43.2)
122 (55.5)
<.001
Performance status
0
1 or 2
Tumor residual
Microscopic
Gross
FIGO grade
1
2
3
Abbreviations: FIGO, Federation of Gynecology and Obstetrics; MDACC, The University of Texas MD Anderson Cancer
Center.
Associations were assessed using Wilcoxon test (for age), or Pearson chi-square or Fisher exact test (for categorical
variables).
Table 3. Estimates of PFS and OS According to the 2-Tier and FIGO Grading Systemsa
Grade
No. of
Patients
PFS
OS
3 Year,
%
Median,
mo
P
3 Year,
%
Median,
mo
P
21
220
55.9
27.7
45.0
19.8
.01
90.5
67.6
126.2
53.8
.002
16
102
123
50.0
23.1
33.3
37.5
19.8
20.1
.07
87.5
66.1
69.9
113.8
52.7
58.2
.02
MDACC
Low
High
FIGO
1
2
3
Abbreviations: FIGO, Federation of Gynecology and Obstetrics; MDACC, The University of Texas MD Anderson Cancer
Center; OS, overall survival; PFS, progression-free survival.
a
Survival was estimated by Kaplan-Meier procedure, and survival functions were compared using log-rank test.
system with age, performance status, size of residual disease, and FIGO tumor grade.
When FIGO grades 2 and 3 were combined, the
overall agreement between the 2-tier and FIGO grading
systems (low-grade vs FIGO grade 1 and high-grade vs
FIGO grades 2 and 3) was 95% (230 of 241). The kappa
statistic for this relationship was 0.68 (95% confidence
interval [CI], 0.50-0.86), which was interpreted as substantial agreement. Of the 11 tumors graded differently
by the 2-tier and FIGO grading systems, 7 tumors were
originally characterized as FIGO grade 2 tumors, but were
reclassified as low-grade in the 2-tier system; 3 tumors
3090
were originally classified as FIGO grade 1 but were reclassified as high-grade carcinomas.
With a median follow-up of 53 months, 206
(85.5%) patients progressed, and 183 (75.9%) died. By
using the 2-tier system, patients with low-grade tumors
had significantly longer median PFS compared with
women with high-grade carcinomas (45.0 vs 19.8
months; P ¼ .01); median OS for patients with highgrade carcinomas was 53.8 months, whereas median OS
for patients with low-grade serous carcinomas was 126.2
months (P ¼ .002; Table 3, Fig. 3). With the 2-tier system, 3-year PFS was 55.9% for patients with low-grade
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Grading Serous Ovarian Cancer/Bodurka et al
Table 4. Comparison of Outcomes Associated With Tumor
Grade Adjusted for Key Variablesa
Grade
PFS
OS
HR
95% CI
P
HR
95% CI
P
1.0
1.71
0.98-2.99
.06
1.0
2.43
1.17-5.04
.02
1.0
1.73
1.36
0.92-3.24
0.73-2.53
.09
.34
1.0
2.57
2.07
1.16-5.68
0.94-4.57
.02
.07
MDACC
Low
High
FIGO
1
2
3
Abbreviations: CI, confidence interval; FIGO, Federation of Gynecology and
Obstetrics; HR, hazard ratio; MDACC, The University of Texas MD Anderson Cancer Center; OS, overall survival; PFS, progression-free survival.
a
HR estimated from Cox proportional hazards model adjusted for age
group, performance status, and amount of tumor residual.
Figure 3. (Top) Kaplan-Meier estimate of progression-free
survival by 2-tier grade is shown. NP, no disease progression;
P, progression of disease. (Bottom) Kaplan-Meier estimate of
overall survival by The University of Texas MD Anderson Cancer Center 2-tier grade is shown.
carcinomas and 27.7% for those with high-grade carcinomas. Furthermore, 3-year OS was 90.5% and 67.6%,
respectively, for those with low-grade versus high-grade
carcinomas (Table 3, Fig. 3). The independent prognostic
value of the 2-tier system was further evaluated by multivariate analysis. Adjusted for age, performance status, and
tumor residual, patients with tumors classified as highgrade using the 2-tier system were at increased risk for disease progression (hazard ratio [HR], 1.71; 95% CI, 0.982.99; P ¼ .06) and also for death (HR, 2.43; 95% CI,
1.17-5.04; P ¼ .02; Table 4).
Clinical outcome using the FIGO grading system
was also assessed. Median PFS for patients with FIGO
grade 1, 2, and 3 tumors was 37.5, 19.8, and 20.1
months, respectively (P ¼ .07). Median OS for FIGO
grade 1 was 113.8 months, whereas median OS was 52.7
and 58.2 months for FIGO grade 2 and 3 tumors, respectively (P ¼ .02; Table 3, Fig. 4). Three-year PFS was
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June 15, 2012
50.0%, 23.1%, and 33.3%, respectively, for FIGO grade
1, 2, and 3 tumors. Three-year OS was 87.5% for patients
with FIGO grade 1 tumors, 66.1% for those with grade 2
tumors, and 69.9% for those with grade 3 tumors. The
adjusted results from the multivariate analysis were essentially the same (Table 4).
Generally, patients with FIGO grade 2 and 3 tumors
had similar risk for poor prognosis. FIGO grade 2 and 3
tumors were associated with increased risk for disease progression and death when compared with FIGO grade 1
tumors. Importantly, median PFS, median OS, 3-year
PFS, and 3-year OS were all shorter for patients with
FIGO grade 2 tumors than for those with FIGO grade 3
tumors.
DISCUSSION
Our results demonstrate that serous carcinoma of the
ovary can be effectively classified as 2 clinically distinct tumor types and that the 2-tier grading system, compared
with the 3-tier FIGO grading system, offers a simpler yet
precise framework for predicting clinical outcomes.
Despite the prognostic value associated with histologic type and tumor grade, no single grading system is
universally used for serous carcinoma of the ovary, the
most common histologic subtype of ovarian cancer. Multiple studies have demonstrated that evaluation of histology and grade is subjective and lacks both intraobserver
and interobserver reliability.1,12 Bertelsen and Anderson
proposed 2 classification systems: 1 based on architectural
pattern and another based on the combination of nuclear
pleomorphism, mitotic count, and nucleocytoplasmic
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Original Article
Figure 4. (Top) Kaplan-Meier estimate of progression-free
survival is shown by Federation of Gynecology and Obstetrics (FIGO) grade. NP, no disease progression; P, progression
of disease. (Bottom) Kaplan-Meier estimate of overall survival
is shown by FIGO grade.
ratio.2 The rate of agreement between the 2 systems was
only 62%.
Subsequently, Shimizu and Silverberg designed a
schema based on architectural growth pattern, mitotic
count, and nuclear grade.3 Predictions of survival according to the Shimizu-Silverberg system did not correlate
well with those of the FIGO system, which is based primarily on the architectural structure of the tumor.3 Ishioka et al. further evaluated the utility of the ShimizuSilverberg system by directly comparing it to the FIGO
system as a prognostic indicator for ovarian cancer.13
Although the k value for the Shimizu-Silverberg grading
system showed more agreement among pathologists than
did the FIGO system, the majority of inconsistencies
among the 3 independent pathologists using the ShimizuSilverberg system were based on nuclear grade.
The above-described studies illustrate the importance of both histology and grade as prognostic indicators
for women with epithelial ovarian cancer. Whereas significant work has been performed on a general level, our
3092
group has focused solely on invasive serous carcinoma of
the ovary. We developed and refined a simple, clinically
meaningful, and reproducible 2-tier grading system by
classifying tumors as low-grade or high-grade. This system
has been used at our institution for more than 15 years;
tumors classified as low-grade using our system correspond extremely well with tumors classified as grade I by
the Shimizu-Silverberg and FIGO systems, and the majority of high-grade tumors correspond to grade 2 and 3
tumors in those systems. Grade 2 and 3 tumors are
grouped together because they both correspond with the
high-grade serous carcinoma category.5 In addition, interobserver and intraobserver variability have been assessed
among a group of 2 general surgical pathologists and 7 gynecologic pathologists using this system.6 Statistical analysis demonstrated an overall k statistic of 0.909 among the
observers, indicating virtually perfect agreement.
Most recently, Seidman et al. reported on the comparison of a new binary system versus the 2-tier grading
system for 113 cases of FIGO stage III serous carcinoma
of the ovary and peritoneum.14 The authors hypothesized
that a binary system would provide sufficient data for
treatment decisions and would be more reproducible
among pathologists. Although both systems are based on
nuclear grade, the binary system has a higher threshold of
nuclear size for diagnosing high-grade tumors.14 When
Seidman and colleagues compared their new binary system with the 2-tier system, the authors concluded that the
2-tier grading system appears more promising, because it
identifies a small but distinct group of serous tumors with
a favorable prognosis.14
There is a significant and growing body of literature
that provides molecular, genetic and clinical correlation
with the 2-tier grading system and reinforces the existence
of 2 distinct disease entities. DNA array studies by several
groups demonstrated differential gene expression based
upon a binary grading system.15-17 Studies focused upon
BRAF, KRAS, and p53 mutations provide further support
of unique genetic mutations among the 2 tumor
grades.18-20 Recent molecular, genetic and in vitro drug
resistance data also present additional evidence that subclassification of high-grade serous carcinoma into moderately-differentiated and poorly-differentiated categories is
not relevant.21 On the basis of these data, Vang et al. suggested that grade 2 and grade 3 serous tumors simply be
classified as high-grade serous carcinoma.21 Lastly, immunohistochemical comparisons between low-grade and
high-grade carcinomas reveal significantly different levels
of expression of a variety of proteins.22-24 Taken together,
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June 15, 2012
Grading Serous Ovarian Cancer/Bodurka et al
these data strongly suggest a unique underlying pathogenesis for low-grade and high-grade lesions.
With respect to clinical outcomes, Gershenson et al.
indicated that women with low-grade serous carcinoma of
the ovary are younger and have longer survival than
women with high-grade disease.7 The long OS of 81.8
months is similar to that of patients with low-grade
tumors described in the current study. Whereas the median PFS in the study by Gershenson et al. was less than
that reported in the current study (19.9 and 42.5 months,
respectively), the variance may be because of the smaller
number of patients with low-grade disease in the current
study and differences in chemotherapy regimens, disease
stage, and amount of post-treatment residual disease
reported in the 2 studies.7 Regardless of their distinctions,
both of these studies strongly suggest different clinical
courses for patients with low-grade and high-grade serous
ovarian cancer.
Winter et al. recently combined data from 6 GOG
protocols in an effort to identify factors predictive of poor
prognosis in a similarly treated population of women with
advanced epithelial ovarian cancer.4 The study sample
included 1895 patients treated by primary surgery followed by platinum and taxane-based chemotherapy.
Patient age, PS, tumor histology, and amount of residual
tumor were identified as independent predictors of prognosis.4 Although tumor grade was not found to predict
survival, tumors in this study were of all histologic subtypes. We believe that the wide variation in histology may
have diluted the influence of tumor grade on PFS and OS.
Because our study focused solely upon serous tumors and
controlled for histology, we have evaluated the influence
of tumor grade upon prognosis more rigorously.
Our data further reinforce the finding that distinguishing FIGO grade 2 tumors from FIGO grade 3
tumors is ambiguous at best. As shown in Table 4 and Figure 4, Top, the PFS event rate is lower among those classified as FIGO grade 3 when compared with FIGO grade 2.
If the FIGO grading system were accurate, we would
expect the opposite outcomes, that is, higher rates of disease progression and shorter survival in patients with
FIGO grade 3 versus grade 2 disease. These seemingly
counterintuitive observations strongly suggest that the
FIGO grading system is not as clinically robust as we had
once thought and should be further scrutinized.
The potential preference for use of the 2-tier grading
system over the 3-tier system seems appropriate for several
important reasons. First, the 2-tier system has minimal
interobserver variability, demonstrated by the high level
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June 15, 2012
of agreement among the 6 participating pathologists. It is
simple, user-friendly, and highly reproducible, characteristics specifically identified as crucial to the development
of a universal grading system by all groups who have
attempted to do so. Second, it appears to be clinically
irrelevant to separate FIGO grade 2 and 3 tumors when
grading serous ovarian carcinomas (Tables 3 and 4). Examination of the Kaplan-Meier survival curves, FIGO
grade 2 and 3 survival curves and PFS point to poorer similar overall clinical outcomes in patients with FIGO grade
2 versus grade 3 tumors, even at the 5-year time period
(Fig. 4). We are currently in an era in which novel therapeutics are being investigated, and potentially significant
treatment advances may soon be based upon specific molecular and genetic tumor characteristics. Use of 2 categories rather than 3 to facilitate the study of low-grade
serous carcinoma by triaging patients with low-grade serous carcinoma to appropriate clinical trials is not without
possible errors. In the validation study, features that generated confusion in assignment of the grade in cases of
low-grade serous carcinoma included high nuclear:cytoplasmic ratio, slightly irregular chromatin pattern, presence of nucleoli, and presence of cases with cribriform or
solid architectural pattern. These histologic features are
associated with less differentiated tumors at other sites
and may have led to discrepant readings in the tumors
graded differently by the 2-tier and FIGO grading systems.6 It is prudent to question the benefit of using the
FIGO grading system in the face of repetitive inconsistencies and questionable clinical relevance.
Our study has several limitations. First, because no
single grading system is infallible, reclassification using a
2-tier system is not without possible errors. An atypical
clinical course should prompt the physician to question
the accuracy of the pathology report. Second, one might
argue that the results could be inaccurate because all 6
pathologists did not review every slide. However, as demonstrated previously, variability between observers is significantly less using the 2-tier grading system versus the 3tier system. Although not perfect, the k statistic among
the various observers was 0.909 in the validation study.6
To date, no studies have been published demonstrating
such a high correlation among observers using the 3-tier
grading system. Furthermore, the slides of 286 patients
were re-reviewed in this study, yielding 9% low-grade
tumors. Although larger numbers of low-grade tumors
might be more reassuring, the shorter median PFS and
OS in patients with FIGO grade 2 versus FIGO grade 3
tumors in our study, as well in the study by Winter et al.,
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indicate that there is no clinical justification to separate
these 2 grades.4 Lastly, although these findings apply to a
population of women with advanced, optimally cytoreduced serous ovarian cancer, we believe that these results
might also apply to patients with early-stage disease as
well as those with advanced suboptimally cytoreduced disease. Further study is warranted.
In conclusion, when compared with the FIGO grading system, the 2-tier grading system for serous carcinoma
of the ovary is a simple, yet precise, framework for predicting clinical outcomes. Use of the FIGO 3-tier grading system yields clinically ambiguous results. Our findings,
bolstered by the information from previous clinical and
molecular studies, clearly support the logic of separating
women with serous ovarian carcinoma into 2 clinically
distinct populations, low-grade and high-grade, in an
effort to develop more effective therapies.4-7,13-24 It is critical to acknowledge this clinicopathologic distinction as
we move toward more personalized care of women with
various subtypes of ovarian cancer. Utilization of the 2tier system will ultimately improve the efficiency of clinical trials by triaging patients with rare tumors to trials
solely evaluating those specific tumor types, thereby significantly impacting the standard of care for women with
this disease. The separation of patients with low-grade
and high-grade serous ovarian cancer is crucial, as our
patients deserve unique consideration of and treatment
for their specific histotypes.
FUNDING SOURCES
This study was supported by National Cancer Institute grants to
the Gynecologic Oncology Group Administrative Office (CA
27469) and Gynecologic Oncology Group Statistical and Data
Center (CA 37517).
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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