Gershenson, David M. MD1; Sun, Charlotte C. DrPH1; Lu, Karen H. MD1; Coleman, Robert L. MD1; Sood, Anil K. MD1; Malpica, Anais MD2; Deavers, Michael T. MD2; Silva, Elvio G. MD2; Bodurka, Diane C. MD1
Although several studies have shown that histologic grade is one of the most important prognostic factors in epithelial ovarian cancer, no universal grading system exists.1–5 In the early 1990s, to develop a simpler, more reproducible, more clinically meaningful grading system, our group designed and refined a two-tier grading system—low-grade and high-grade—for invasive serous carcinoma of the ovary. After more than a decade of clinical use, the details of this proposed two-tier grading system were recently published.6 With only one exception, all of the serous carcinomas considered low-grade using our system corresponded to grade 1 tumor according to the Shimizu–Silverberg and the International Federation of Gynecology and Obstetrics (FIGO) grading systems, and most of the high-grade tumors corresponded to grade 2 and 3 tumors in those systems.4,5,7,8 The validity of this two-tier grading system is currently being tested in a multi-institutional study.
At approximately the same time that the two-tier grading system was evolving at The University of Texas M.D. Anderson Cancer Center, investigators at Johns Hopkins University described a variant of serous tumor of low malignant potential (borderline tumor), the so-called micropapillary serous carcinoma,9,10 which they subclassified as noninvasive or invasive.9 Although some investigators recommended that micropapillary serous carcinoma be categorized separately from typical serous tumor of low malignant potential, most who had carefully studied it favored retaining it as a variant within the category of serous tumors of low malignant potential.10,11–13 Since then, the nomenclature has been further refined; noninvasive micropapillary serous carcinoma has been considered a variant of serous tumor of low malignant potential, whereas invasive micropapillary serous carcinoma seems to be considered synonymous with low-grade serous carcinoma.14–16
Over the past few years, the low-grade–high-grade model and terminology have gained increasing acceptance in molecular studies of serous tumors of low malignant potential and invasive serous ovarian tumors.15–22 The findings of these studies and others suggest that the pathogenesis of low-grade serous carcinomas and serous tumors of low malignant potential involves similar genes and pathways and is distinct from that of high-grade serous carcinomas.15–24
Our clinical observations seem to be consistent with others' molecular and genomic investigations. Approximately 60% of low-grade serous carcinomas of the ovary also contain areas of serous tumor of low malignant potential compared with only 2% of high-grade serous carcinomas.6 Furthermore, among patients with serous tumors of low malignant potential who relapse, approximately 75% of the recurrences are low-grade serous carcinoma.25 Because of the emerging molecular and clinical information suggesting the unique nature of low-grade serous carcinoma of the ovary and its apparent close relationship to ovarian tumors of low malignant potential, it is important for obstetrician–gynecologists to be informed of this entity to better counsel their patients and to optimize referral and treatment planning. The purpose of this study was to analyze the clinical behavior of stage II-IV low-grade serous carcinoma of the ovary in patients seen at our institution and who underwent standard therapy consisting of primary surgical cytoreduction followed by platinum-based chemotherapy.
MATERIALS AND METHODS
All patients diagnosed with stage II, III, or IV low-grade serous carcinoma of the ovary seen at M.D. Anderson Cancer Center from 1978 to 2003 were identified using databases from the Departments of Gynecologic Oncology and Pathology, and their medical records were reviewed. Eligibility criteria included the following: 1) stage II-IV low-grade serous carcinoma, and 2) treatment with primary surgery followed by platinum-based chemotherapy. One hundred twelve such patients were identified and comprise the study population. This study was approved by M.D. Anderson's institutional review board.
Although histopathologic review of all cases had been performed at the time of original diagnosis and/or presentation to M.D. Anderson Cancer Center, all slides were re-reviewed by one of the three pathologists (A.M., M.T.D., E.G.S.) for this study. Excluded from this study were cases of nonserous histotypes, serous tumors of low malignant potential, high-grade serous carcinomas, primary peritoneal low-grade serous carcinomas, stage I low-grade serous carcinomas of the ovary, and stage II-IV low-grade serous carcinomas of the ovary not treated with standard therapy consisting of surgery followed by platinum-based chemotherapy. We based confirmation of a low-grade serous carcinoma on three criteria: 1) frank destructive invasion of the ovarian stroma (to differentiate low-grade serous carcinomas from serous tumors of low malignant potential), 2) relatively uniform round to oval nuclei with mild to moderate atypia and evenly distributed chromatin, and 3) no more than 12 mitoses per 10 high-power fields.6 The tumor was presumed to be adequately sampled if a minimum of 1 section per centimeter of tumor diameter was available for pathologic review.26
Patient demographics were abstracted from the medical records. All patients underwent primary surgery, and operative reports were reviewed, if available. The following information was abstracted from the medical records: age; race; serum CA 125 at diagnosis; date and type of primary surgery; stage of disease based on criteria of FIGO; sites of metastatic disease; residual disease; type of platinum-based chemotherapy; clinical status at completion of primary chemotherapy; disease status at the date of contact; date of last contact or death; and, if applicable, clinical response to primary chemotherapy, findings of second-look surgery, and date of disease progression.
Clinical response to therapy was also determined for patients who had undergone computed tomography (CT) showing measurable disease after primary surgery and before beginning chemotherapy and who had also undergone repeat imaging after completion of chemotherapy. A complete response was defined as having no evidence of tumor and normal serum CA 125 level. Partial response was defined as having a 50% or greater decrease in the size of all measurable lesions. Progressive disease was defined as having a 25% or greater increase in any measurable lesion or the appearance of any new lesion. Stable disease was defined as having a change in measurable disease too small to be considered either a partial response or progressive disease and having no new lesions for at least 8 weeks.
Second-look findings were classified as microscopically negative (all cytologic washings and tissue biopsies negative), microscopically positive (no evidence of macroscopic disease but tissue biopsies or cytologic washings positive), or macroscopically positive (obvious evidence of macroscopic tumor).
Statistical analyses were performed using SPSS 12.0 software (SPSS, Cook County, Chicago, IL). Progression-free survival and overall survival times were calculated from the date of primary surgery to the date of disease progression or recurrence or the date of last contact or death, respectively. Progression-free survival and overall survival times were estimated using the method of Kaplan and Meier.27 The log-rank test was used to compare differences between survival curves. For the 112 eligible patients, the effects of six clinicopathologic variables were evaluated by using univariable and multivariable Cox proportional hazards regression analysis. P values of <.05 were considered statistically significant.
Review of database records identified 112 eligible patients. Mean follow-up time was 71 months (range, 11–315 months). The median and mean ages at diagnosis were 43 and 45 years, respectively (range 14–79 years.). The majority of the patients were white (85%) and had stage III disease (90%). Preoperative serum CA 125 was elevated (more than 35 U/mL) in 48 (86%) of the 56 patients for whom information was available. The median preoperative serum CA 125 level was 133 U/mL, with a range of 12–10,000 U/mL. The patient characteristics at initial diagnosis are summarized in Table 1.
All patients underwent primary surgery; 21(19%) underwent theirs at M.D. Anderson Cancer Center, and 81% had their initial surgery elsewhere. The most common initial surgical procedure consisted of abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy (61%). Of the 92 patients for whom information on residual disease was available, the majority (82%) had residual disease of 2 cm or less. The most common sites of extraovarian disease were the omentum (83%), fallopian tubes (63%), pelvic peritoneum (49%), and uterus (46%).
The majority (55%) of patients received postoperative chemotherapy consisting of paclitaxel and a platinum drug—either cisplatin or carboplatin. Chemotherapy regimens administered postoperatively are summarized in Table 2. The median number of primary chemotherapy cycles was 6 (range, 2–16 cycles).
Of the 107 patients for whom clinical information was available at the completion of primary chemotherapy, 56 (52%) were clinically disease-free based on the following examinations, tests, or record statements: abdominopelvic CT plus serum CA 125 (29 patients), abdominopelvic CT plus other tests (7), physical examination only (3), serum CA 125 only (2), physical examination plus serum CA 125 (6), physical examination plus chest X-ray (1), and a statement in the medical record about being clinically disease-free but without details (8). Fifty-one patients (48%) had persistent disease based on the following examinations, tests, or record statements: CT plus other tests (25), physical examination only (6), serum CA 125 only (2), physical examination plus serum CA 125 (2), and a statement in the medical record about having persistent disease but without details (16).
Clinical response to primary chemotherapy was evaluable in 10 (9%) of the 112 patients (15% of 65 patients with gross residual disease); 4 had a complete clinical response, 4 had a partial clinical response, and 2 had progressive disease, for an overall response rate of 80%. Forty-two (38%) of the 112 patients underwent second-look surgery after primary chemotherapy; sufficient information regarding surgicopathologic findings was available in 39 of them. Two (5%) had microscopically negative findings, 13 (33%) had microscopically positive findings, and 24 (62%) had macroscopically positive disease.
The median progression-free survival time for all the patients was 19.5 months, and the median overall survival time was 81.8 months. Excluding the 6 patients with stage II disease, the median overall survival time for the 106 with stage III or IV disease was 81.3 months.
Despite the good overall survival time of this cohort, 10 (9%) patients survived only 24 months or less, two of whom died of other causes. Of the other 8 patients, 6 had progressive disease during primary chemotherapy or persistent disease at completion of primary chemotherapy. In addition, 7 of the 8 had intestinal obstruction in the weeks before death.
The log-rank test was used to compare Kaplan Meier survival curves for both progression-free survival and overall survival times for the following variables: age (less than 45 years compared with more than 45 years), preoperative serum CA 125 (less than 35 U/mL compared with more than 35 U/mL), preoperative serum CA 125 (less than median CA 125 [133 U/mL] compared with more than median CA 125), FIGO stage (II compared with III compared with IV), residual disease status (no gross residual compared with less than 2 cm compared with more than 2 cm), residual disease status (no gross residual compared with any gross residual), type of chemotherapy (taxane-based compared with non–taxane-based), status at completion of primary chemotherapy (no clinical evidence of disease compared with persistent disease), and second-look surgery findings (microscopically negative compared with microscopically positive compared with macroscopically positive). Statistically significant variables with regard to progression-free survival time included FIGO stage (median, 19.7 months for stage III compared with 14.4 months for stage IV, P=.003; median, 19.5 months for stage II compared with 14.4 months for stage IV, P=.02), and status at completion of primary chemotherapy (median, 26 months for clinically disease-free compared with 14.5 months for persistent disease, P<.001). For overall survival time, the only two variables that attained statistical significance were FIGO stage (median 83.6 months for stage III compared with 31.4 months for stage IV, P=.007) and status at completion of chemotherapy (median, 102.9 months for clinically disease-free compared with 47 months for persistent disease, P<.001).
When analyzed in a univariable analysis (Table 3), stage IV disease and persistent disease at the completion of primary chemotherapy were associated with decreased overall survival time. After adjusting for both of these covariates in a multivariable analysis, persistent disease after primary chemotherapy was the only variable associated with shorter overall survival time (hazard ratio [HR] 3.46; 95% confidence interval[CI] 2.00–5.97, P<.001).
In a similar analysis using the Cox proportional hazards model, FIGO stage IV disease (HR 6.9, 95% CI 1.9–23.4, P=.004) and persistent disease at the completion of primary chemotherapy (HR 2.36, 95% CI 1.57–3.54, P < .001) were significantly associated with decreased progression-free survival time. In addition, clinical variables such as residual disease (none compared with any) (HR 1.41, 95% CI 0.87–2.29, P=.17), taxane-based chemotherapy (non–taxane-based regimen compared with taxane-based regimen) (HR 1.42, 95% CI 0.95–2.12, P=.09), and age (younger than 45 years compared with older than 45 years) (HR 0.71, 95% CI 0.48–1.05, P=.08) were included in a multivariable Cox model. After adjusting for these variables, persistent disease after primary chemotherapy (HR 2.64, 95% CI 1.55–4.19, P<.001) and taxane-based chemotherapy (HR 2.20, 95% CI 1.30–3.71, P=.003) were associated with shorter progression-free survival time, but age older than 45 years was associated with longer progression-free survival time (HR .56, 95% CI 0.33–0.94, P=.03).
At the time of analysis, 35 patients (31%) were alive: 10 (9%) alive disease-free, 23 (21%) alive with disease, and 2 (2%) alive with uncertain disease status. Seventy-seven (69%) patients had died: 67 (60%) had died of their disease, 8 (7%) died of other causes, and 2 (2%) died of unknown causes.
For this study, we attempted to select a homogeneous group of patients who presented with metastatic low-grade serous carcinoma of the ovary and were treated with primary cytoreductive surgery followed by platinum-based chemotherapy. The principal findings of this study indicate that patients with low-grade serous carcinoma of the ovary are young at diagnosis and have a prolonged overall survival.
In our experience, low-grade serous carcinomas are much less common than high-grade serous carcinomas; however, their true incidence remains unclear. Some indication of the incidence of low-grade serous carcinomas may be found by surveying recent publications of phase III chemotherapy trials for grade 1 tumors, acknowledging that a small proportion of these tumors may be cell types other than serous. In four phase III studies of the Gynecologic Oncology Group—two of optimally cytoreduced patients and two of suboptimally cytoreduced patients—the percent of grade 1 tumors ranged from 6% to 12%; of 2,254 total patients in these four studies, only 206 (9%) had grade 1 tumors.28–31
It seems that invasive micropapillary serous carcinoma described by investigators at Johns Hopkins is a type of low-grade serous carcinoma as defined by the two-tier grading system.9,10,15,16,32 A picture has emerged over the past few years implicating a continuum in the pathogenesis of serous tumors of low malignant potential and low-grade serous carcinomas that is distinct from that of high-grade serous carcinomas.15–22,33 Singer and colleagues17 observed K-ras mutations in approximately 50% of serous tumors of low malignant potential and low-grade serous carcinomas (invasive micropapillary serous carcinomas) and a progressive increase in the degree of allelic imbalance compared with no K-ras mutations and a high degree of allelic imbalance in high-grade serous carcinomas. Subsequent studies confirmed those previous observations and further demonstrated that either BRAF or K-ras mutations occurred in 68% of low-grade serous carcinomas and in 61% of serous tumors of low malignant potential but in none of the 72 high-grade serous carcinomas.16 Furthermore, none of the low-grade tumors contained mutations in both K-ras and BRAF.
In a immunohistochemical study of mitogen-activated protein kinase, which is regulated by upstream kinases, including K-ras and BRAF, there was a significantly lower frequency of expression of active mitogen-activated protein kinase in high-grade serous carcinomas of the ovary than in low-grade serous carcinomas and serous tumors of low malignant potential.19 The molecular similarities between serous tumors of low malignant potential and low-grade serous carcinomas and their distinction from high-grade serous carcinomas were further confirmed by a study of p53 mutation analysis and immunohistochemical staining.20 In that study, p53 mutations were found in one of 12 (8.3%) low-grade serous carcinomas, two of 25 (8%) serous tumors of low malignant potential, and 30 of 59 (51%) of high-grade serous carcinomas.
Moreover, genomic profiling studies have also suggested segregating low-grade serous tumors—serous tumors of low malignant potential and low-grade serous carcinomas—and high-grade serous carcinomas.22–24 Using a 6,500-feature cDNA microarray, Jazaeri and associates23 compared the molecular profiles of four low-grade serous carcinomas with eight grade 3 serous carcinomas. They identified 99 genes whose expression profiles were significantly different between low-grade and high-grade serous carcinomas, with a number of oncogenes of interest located on 20q13. Meinhold-Heerlein et al24 used oligonucleotide arrays and comparative genomic hybridization to profile serous tumors of low malignant potential and serous carcinomas of varying grade. They observed a striking similarity between serous tumors of low malignant potential and grade 1 (ie, low-grade tumors) serous carcinomas and a significant difference compared with grade 2 and 3 (ie, high-grade tumors) serous carcinomas in a number of genes, including p21/WAF1, STAT-1-, and STAT-3/JAK-1/2-induced gene expression. Also, in microdissected serous tumors of low malignant potential, low-grade serous carcinomas, and high-grade serous carcinomas, Bonome et al22 used gene expression profiles to show that serous tumors of low malignant potential are distinct from high-grade serous carcinomas but similar to low-grade serous carcinomas. In particular, in low malignant potential tumors and low-grade carcinomas, pathways present in high-grade tumors (ie, cell cycle progression, cellular proliferation, and chromosomal instability) were absent.
The clinical observations that serous tumors of low malignant potential frequently coexist with low-grade serous carcinomas and that they frequently recur as low-grade serous carcinomas certainly lend support to the molecular findings.6,25 However, there is still no proof that all low-grade serous carcinomas arise from serous tumors of low malignant potential. The clinical picture is complicated by the fact that approximately 30% of serous tumors of low malignant potential are associated with either noninvasive or invasive peritoneal implants, and, in contrast to stage I disease, these are the tumors that are most likely to recur.34,35 In addition, if serous tumors of low malignant potential have the ability to progress to low-grade serous carcinomas, are both variants—typical serous tumors of low malignant potential and micropapillary type tumors—capable of doing so?
The findings of the present study seem to highlight clinical differences between low-grade serous carcinomas and epithelial ovarian cancer in general (approximately 90% of which are high-grade carcinomas). Although the age range for patients with low-grade serous carcinoma of the ovary is wide, the median age of 43 years in our study population is much younger than the average age, 63 years, of all women with epithelial ovarian cancer.36 In 2 large Gynecologic Oncology Group studies, the median age in the various arms of the studies was 59–60 years.28,29
In addition, the rate of bulky residual disease in our study population was somewhat low; of the 92 patients for whom we had information on residual disease at primary surgery, only 17 (18%) had residual tumor larger than 2 cm. The percentage of those patients achieving optimal residual disease status at completion of primary surgery in our study was significantly higher than in most reports of ovarian cancer in general.37 From previous studies, it seems that the proportion of patients achieving optimal cytoreductive surgery is higher for cases of serous tumors of low malignant potential than for those with invasive epithelial ovarian cancer.34,35 Whether a similar pattern is true of patients with low-grade serous carcinomas remains unclear.
Our data suggest that patients with metastatic low-grade serous carcinoma of the ovary have, on average, a significantly longer overall survival time than do all women with ovarian cancer. Even when the six patients with stage II disease were excluded, the remaining 106 women with stage III or IV disease had a median overall survival time of 81 months. In the Gynecologic Oncology Group 111 trial, patients with suboptimal disease (residual tumor larger than 1 cm) had median overall survival times of 24 and 38 months in the control and study arms, respectively, and in the Gynecologic Oncology Group 132 trial, median overall survival times in the three arms were 30 months, 26 months, and 26 months.28,29 For patients with optimal disease (residual tumor smaller than 1 cm), median overall survival times were 52 and 63 months in the control and study arms, respectively, in Gynecologic Oncology Group 114, and 49 and 57 months in the two arms of Gynecologic Oncology Group 158.30,31 As stated, all of these studies included at least a small proportion of patients with grade 1 tumors. However, 91% of the 2,254 patients in these four studies had grade 2 or 3 tumors, which generally corresponds to high-grade cancer, as demonstrated in our initial report on the two-tier grading system.6,28–31 As might be expected, the univariable Cox regression analysis demonstrated that stage IV disease and persistent disease at completion of chemotherapy were both significantly associated with a worse outcome.
The median progression-free survival time of 19.5 months observed in our study does not seem to be substantially different from the findings of several studies of advanced epithelial ovarian cancer in general. As shown by the univariable Cox regression analysis, stage IV and persistent disease at completion of chemotherapy were both associated with a worse progression-free survival time. Based on the relatively small number of patients evaluable for clinical response and the retrospective nature of this study, it is impossible to make any direct comparisons between our findings and those on cases of high-grade serous carcinoma or ovarian cancer in general. Although our overall experience suggests that low-grade serous carcinoma is not as responsive to conventional chemotherapy as high-grade serous carcinoma, a definitive answer will need to await further investigation. Future studies from our group on patients treated with neoadjuvant chemotherapy or those treated for recurrence should help elucidate the sensitivity of low-grade serous carcinomas to a variety of systemic agents.
The limitations of this study are those characteristic of any retrospective study of an uncommon tumor type, including incomplete data, a long study period, referral bias, other types of selection bias, inhomogeneous treatment, changing detection methods, and other confounding variables. However, the findings of early studies such as this are hypothesis generating and we hope will facilitate the development of future prospective clinical trials specifically focused on low-grade serous carcinomas.
In summary, our findings support those of previous clinical and translational studies from our group and others that low-grade serous carcinomas seem to have a clinical behavior distinct from high-grade serous carcinomas. Specifically, metastatic low-grade serous carcinoma of the ovary is characterized by young age at diagnosis and prolonged survival. In our opinion, the unique biologic and clinical behavior of low-grade serous carcinoma of the ovary warrants segregating patients with this diagnosis in future clinical trials.
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