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Preoperative Value of CA 125 as a Reflection of Tumor Grade in Epithelial Ovarian Cancer
GYNECOLOGIC ONCOLOGY ARTICLE NO.
63, 166–172 (1996)
0301
Preoperative Value of CA 125 as a Reflection of Tumor Grade in Epithelial Ovarian Cancer IGOR BUT, M.D., M.SC.,*
AND
BORUT GORISˇEK, M.D., PH.D.†
*Division of Gynecologic Oncology and †Department of Gynecology and Obstetrics, Maribor Teaching Hospital, Ljubljanska 5, 2000 Maribor, Slovenia Received September 11, 1995
A retrospective study of 60 patients with invasive epithelial ovarian cancer was conducted. The significance of preoperative serum CA 125 level with respect to tumor grade and tumor stage was determined. Tumor grade bears a strong influence on the preoperative CA 125 level; the correlation is high and statistically significant (r Å 0.74, P õ 0.01). The influence of FIGO stage on preoperative CA 125 level is also significant (r Å 0.51, P õ 0.01), but the results of the multivariate analysis show that the influence of tumor grade on preoperative CA 125 level is stronger (P õ 0.01). It is believed that tumor grade is the decisive factor dictating the level of CA 125 in a certain stage of the disease and so influences the preoperative CA 125 level. It is also believed that low preoperative antigen levels of well-differentiated ovarian carcinomas in FIGO stage I are the cause of poor sensitivity of the CA 125 test, thus limiting its applicability for screening purposes. q 1996 Academic Press, Inc.
INTRODUCTION
Histogenetically, primary epithelial ovarian cancers belong to the group of cancers of the germinative, coelomic epithelium. Among ovarian cancers they hold the majority (90%), their characteristic traits being histologic pleomorphism and heterogeneity. Ovarian cancer is detected relatively late, so 70% of the cancers are already in stage III or IV when the diagnosis is set. Hence the mortality rate, the highest among gynecologic malignant growths and exceeding the total mortality rate of cervical and endometrial cancer [1]. Despite the progress in diagnosis and treatment, the 5-year survival rate has not improved essentially in the past 30 years and amounts to 35% for all stages [2–4]. All the reasons stated, as well as the high prevalence of the disease during postmenopause and in women who are related to ovarian cancer patients, dictate the discovery of a method that would facilitate the early diagnosis of this serious disease, for early diagnosis is the only basis for successful treatment. Cancer is a disease of the cell and it is the task of researchers to define the qualitative as well as quantitative differences between a normal cell and a neoplastic cell. These findings
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METHODS
Ours is a retrospective study extending over the period between January 1990 and December 1994 and including 60 patients with primary invasive ovarian carcinoma. Patients with nonepithelial malignant growth as well as those with secondary or borderline epithelial cancer were excluded from the study. The control group consisted of 45 patients with benign epithelial ovarian tumor. Preoperative serum CA 125 levels were determined by means of an enzyme immunoassay (Cobas Core CA 125 II EIA, Roche Diagnostic Systems). All patients were operated (total abdominal hysterectomy, bilateral adnexectomy, omentectomy, lymphadenectomy). A pathologist examined the surgical specimens and determined the histologic type and tumor grade according to WHO provisions. On the basis of the operative record, histologic findings of operative spec-
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0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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would then serve as a basis for diagnosis, treatment, and prophylaxis. In 1981, Bast discovered the tumor marker CA 125 on the surface of cells changed by cancer [5–7]. It is a tumor-associated antigen identifiable in serum by means of the highly specific murine monoclonal antibody IgG1 OC 125 in more than 80% of ovarian cancer patients and in only 1% of healthy women [8–13]. According to the same authors, the preoperative marker level reflects the quantity of the tumor mass and, thus, also the stage of disease. For more than 5 years, the preoperative serum level of tumor marker CA 125 is being determined at our Department of Gynecology. At first the findings merely served as rough orientation in making the distinction between a benign and a malignant adnexal mass or as a reference when following the success of therapy and, thus, also the course of disease. But we noticed that apart from the stage of the disease, the tumor grade also may exert an influence on the preoperative CA 125 level. Hence ensues our study, which presupposes that in epithelial ovarian cancer the preoperative serum CA 125 value is in inverse proportion to tumor grade in the sense that the higher the preoperative antigen values, the less the cancer is differentiated.
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TABLE 1 Analysis of Preoperative CA 125 Levels with Respect to Histologic Type CA 125 sensitivity (ú35 U/ml)
Ca 125 (U/ml) Histologic type
No. (%)
Mean
25th percentile
Median
75th percentile
FIGO stage I
FIGO stages I–IV
Serous Mucinous Other types
39 (65.) 10 (16.6) 11 (18.4)
275.6 28.7 181.4
92.5 4.5 32.1
262.0 19.9 192.5
500.0 34.6 265.9
50.0% 12.5% 50.0%
89.7% 30.0% 82.0%
217.2 U/ml (25th percentile Å 46.4 U/ml, median Å 140.4 U/ml, 75th percentile Å 396.9 U/ml). The control group consisted of 45 patients with benign epithelial tumor. The average age of the patients was 54.8 years (SD Å 7.4). The youngest was 37, the oldest 77. The mean CA 125 value in the control group was 9.9 U/ml (25th percentile Å 3.4 U/ ml, median Å 6.8 U/ml; 75th percentile Å 14.6 U/ml).
imens and biopsy, as well as cytologic findings of ascites or abdominal lavage, respectively, staging of the cancers was carried out according to FIGO [14, 15]. After surgery, the patients received chemotherapy according to a scheme; some had radiation therapy at the Institute of Oncology in Ljubljana. Statistical analysis was performed using the statistical package Statistica for Windows (StatSoft Inc.) on a personal computer. Correlations between variables (CA 125, tumor grade, FIGO stage) were assessed by Pearson’s correlation coefficient (r). In a multiple linear regression model, the combined effect of the two variables (FIGO clinical stage, tumor grade) on preoperative CA 125 level was analyzed. Comparison of means was achieved by the Student t test, requiring P õ 0.05 for statistical significance.
Tumor Grade There were 22 (36.7%) well-differentiated, 21 (35.0%) moderately differentiated, and 17 (28.3%) poorly differentiated types of cancer. There was a statistically significant difference in CA 125 values between G1 tumors and control group (t Å 4.50; P õ 0.01), between G2 and G1 tumors (t Å 4.45; P õ 0.01), as well as between G3 and G2 tumors (t Å 3.79; P õ 0.01). Mean and percentile as well as the sensitivity of the CA 125 test in individual degrees of tumor differentiation are shown in Table 2. The correlation between tumor grade and preoperative serum CA 125 value was r Å 0.74, meaning a real significant correlation (P õ 0.01). Graphically the correlation is depicted by a regression curve in Fig. 1.
RESULTS
In the 5-year period, 60 patients with primary invasive ovarian carcinoma were included in our analysis. The average age of our patients was 59.0 years (SD, 12.8 years). The youngest patient was 29 and the oldest 84 years old. Twothirds of our cancer cases (n Å 41 or 68.3%) were discovered during postmenopause. The most frequent type of cancer was the serous type (n Å 39 or 65.0%), followed by the mucinous type (n Å 10 or 16.6%), endometrioid type (n Å 6 or 10.0%), unclassified type (n Å 4 or 6.7%), and a single case of undifferentiated cancer (n Å 1 or 1.7%). The CA 125 values (mean and percentile) and sensitivity of the test with respect to histologic type are shown in Table 1. The mean serum CA 125 value in all 60 patients amounted to
Tumor Stage Ovarian carcinoma FIGO stage I was detected in 14 patients (23.3%), stage II in 9 patients (15%), stage III in 23 patients (38.3%), and stage IV in 14 patients (23.3%). There was a significant difference in CA 125 values between FIGO stage I and control group (t Å 3.99; P õ 0.01) and between stages II and I (t Å 3.95; P õ 0.01). The difference between
TABLE 2 CA 125 Level and the Degree of Cancer Differentiation CA 125 (U/ml) Tumor grade
No. (%)
Mean
25th percentile
Median
75th percentile
Sensitivity (ú35 U/ml)
Significance
G1 G2 G3
22 (36.7) 21 (35.0) 17 (28.3)
64.5 222.2 408.8
9.6 111.6 321.1
45.1 218.2 500.0
85.0 280.6 500.0
54.5% 85.7% 100.0%
Ca:G1, P õ 0.01 G:G2, P õ 0.01 G2:G3, P õ 0.01
a
C, control group.
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FIG. 1.
Relationship between preoperative CA 125 level and tumor grade.
CA 125 values of stages III and II (t Å 0.95; P Å 0.35), stages IV and III (t Å 0.09; P Å 0.93), as well as between those CA 125 values of stages IV and II (t Å 0.87; P Å 0.39) was statistically insignificant. Mean and percentile as well as the sensitivity of the test in individual FIGO stages are shown in Table 3. We studied the influence of stage on the preoperative antigen CA 125 value and found that the correlation of both parameters was good and significant (r Å 0.51, P õ 0.01). The correlation is best described by the regression curve shown in Fig. 2. Relationship between Tumor Stage and Tumor Grade Stages I and II, denoting limited disease, were established in 23 cases of ovarian cancer (38.3%). Among them welldifferentiated cases prevailed, (65.2%), followed by moderately (21.7%) and poorly (13.1%) differentiated ones. Stages
III and IV, denoting advanced disease, were detected in 37 cases (61.7%). Among these, moderately differentiated types were prevailing (43.3%), followed by poorly (37.8%) and well-differentiated ones (18.9%) (Fig. 3). The correlation between tumor stage and tumor grade was good and statistically significant (r Å 0.44; P õ 0.01). Relationship between CA 125 and tumor stage with respect to tumor grade. The correlation between both parameters was good and statistically significant in well-differentiated tumors (r Å 0.63; P õ 0.01), but there was no correlation between both parameters in moderate (r Å 0.19; P Å 0.42), and also in poor differentiated tumors (r Å 0.26; P Å 0.31). In well-differentiated cancers there was no statistically significant difference in CA 125 values between FIGO stage II and stage I (t Å 1.62; P Å 0.12), FIGO stage III and stage II (t Å 0.77; P Å 0.48), and also between stage IV and III cancers (t Å 0.82, P Å 0.45); but there was a significant
TABLE 3 Analysis of Preoperative CA 125 Levels with Respect to FIGO Stage CA 125 (U/ml)
FIGO stage I II III IV a
No. (%)
Mean
25th percentile
Median
75th percentile
Sensitivity (ú35 U/ml)
14 9 2 14
29.3 220.0 289.8 284.0
7.1 79.2 82.8 123.8
18.1 192.5 290.5 259.0
34.6 254.3 500.0 428.6
28.6% 88.9% 91.3% 100.0%
(23.3) (15.0) (38.3) (23.3)
C, control group.
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Significance (P) Ca:I, P õ I:I, P õ II:III, P Å III:IV, P Å
0.01 0.01 0.35 0.93
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FIG. 2.
Relationship between preoperative CA 125 level and FIGO stage.
difference in CA 125 values between FIGO stage IV and stage I (t Å 3.19; P õ 0.01) and also between stage III and stage I cancers (t Å 3.42; P õ 0.01). In moderately differentiated (G2) cancers there was no significant difference in preoperative CA 125 values between stages II and II (t Å 0.5, P Å 0.30) and between stages IV and III (t Å 0.65; P Å 0.26). In poorly differentiated (G3) stage II, III, and IV cancers, the CA 125 values also did not differ statistically significantly. Relationship between CA 125 level and tumor grade with respect to tumor stage. A significant correlation also exists between CA 125 values and tumor grade in individual stages according to FIGO. Thus, the correlation between both parameters was statistically significant in stage II (r Å 0.92;
FIG. 3.
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P õ 0.01), stage III (r Å 0.58; P õ 0.01), stage IV (r Å 0.71; P õ 0.01), and statistically insignificant in stage I according to FIGO (r Å 0.33; P Å 0.26). Within the frame of individual stages, the correlation of CA 125 and tumor grade can also be expressed by means of regression curves, as shown in Fig. 4. The results of the stepwise multiple regression with the independent variables tumor stage and tumor grade and the dependent variable preoperative CA 125 level are shown in Table 4. DISCUSSION
Comment on Our CA 125 Assay In the graphs and the tables, as one can see, the highest CA 125 value amounted to 500 U/ml. It does not mean that
Distribution of the different degrees of tumor differentiation in limited (stages I and II) and advanced (stages III and IV) disease.
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Preoperative CA 125 Level
FIG. 4. Correlation of CA 125 level and tumor grade within the frame of individual stages: regression curves.
there were no higher CA 125 values, but it does mean that serum antigen values greater than 500.0 U/ml were given only descriptive (ú500.0 U/ml). Because this study was retrospective, we were unable to get more precise CA 125 values by further serum dilution; however, none of the CA 125 values in well-differentiated and only some of the CA 125 values (9.5%) in moderately differentiated cancers exceeded this above-mentioned border at 500.0 U/ml. In contrast, nearly two-thirds (64.7%) of CA 125 values in poorly differentiated cancers (serous types and undifferentiated type) were higher than 500.0 U/ml. Because the objective of this study was preoperative serum CA 125 analysis and not the follow-up, according to our opinion and that of the statistician, this fixed CA 125 value at 500.0 U/ml did not essentially hinder our analysis. From the literature, using a cutoff level of 35 U/ml, there is a high correlation (r Å 0.81) between preoperative serum levels and immunohistochemical detection of CA 125 in tumor tissue [16]. We have not assessed the presence of CA 125 antigen by immunohistochemical techniques on carcinomatous tissues because, according to Breitenecker et al., no relationship could be detected between histologic grade (the main topic of our study) and intensity of the reaction [16].
Most authors connect the high marker level in serum with a large quantity of tumor mass and an unfavorable prognosis. As a rule, in patients in the late phase of the disease, preoperative CA 125 values are higher than those in patients with early-phase cancer, where the tumor mass is smaller [8–13]. The authors share the opinion that tumor grade bears no influence on the preoperative marker CA 125 level. The connection is merely apparent and as such the result of the fact that poorly differentiated cancers are in a higher stage of the disease while the well-differentiated ones are in the early phase of the disease, and the CA 125 level is a reflection of the quantity of tumor mass [8–10]. But in literature other observations can also be found. Some authors believe that a connection between tumor grade and serum CA 125 level does exist, but they devote no special attention to it. Among these authors Vergote and Boermer [17] have an exceptional position, for they believe that the relationship between tumor grade and serum CA 125 value is in inverse ratio in the sense that: the less the tumor is differentiated, the higher the serum antigen values. At the same time Vergote and Boermer [17] state that in poorly differentiated cancers, the quantity of tumor mass is not responsible for increased CA 125 values, for there is no significant correlation between the degree of tumor differentiation and tumor burden (P Å 0.40). CA 125 Level and FIGO Stage When we analyzed our relatively small group of patients we found that in the higher stages of the disease, higher serum values of the tumor antigen studied were present (r Å 0.51, P õ 0.01). Another way of presenting this relatively strong connection between the quantity of tumor mass and the preoperative CA 125 level was calculating the statistically significant difference in CA 125 values among FIGO stages. If the preoperative CA 125 level really reflected the quantity of tumor mass, a statistically significant difference in CA 125 values between individual FIGO stages should exist. We verified this statistical significance and the results were surprising. The CA 125 values among individual stages did not differ significantly, e.g., CA 125 values in stage II
TABLE 4 Regression Summary for Dependent Variable CA 125 Level R 2 Å 0.584 P õ 00000
R Å 0.764 F (2, 57) Å 40.008
Intercept Grade Stage
R2
R 2 Ch
b
SE b
B
SE B
t (57)
P level
0.542 0.584
0.542 0.042
0.635 0.228
0.095 0.095
0168.97 147.75 39.34
47.84 22.17 16.44
03.53 6.66 2.39
0.0008 1.156E-08 0.0208
CA 125 Å 0168.97 / 147.75∗grade / 39.34∗stage
Equation
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Adjusted R 2 Å 0.569 SEE Å 123.44
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did not differ significantly from those in stage III or IV. The only statistically significant difference in CA 125 values found was between stage I on one side and stage II, III, or IV on the other. We believe that this significant difference in CA 125 values was because of the two factors. First, we should not forget the connection between the augmented serum CA 125 level and peritoneal reaction, e.g., peritoneal irritation caused by spreading of ovarian carcinoma. Such a peritoneal reaction can be observed in the cases of pelvic endometriosis and pelvic inflammatory disease (PID), the two main factors causing the false positivity of the CA 125 test. Second, according to our opinion, this was the consequence of unequal distribution of tumor grade in individual FIGO stages, which is a consequence of different histologic types of ovarian cancer present in individual FIGO stages (serous carcinomas tend to be high grade and high stage in contrast to mucinous carcinomas, which tend to be low grade and low stage). So, the correlation of both tumor stage and tumor grade was statistically significant (P õ 0.01). CA 125 Level and Tumor Grade During our clinical work it was noticed that apart from the stage of the disease, the tumor grade also exerts an important influence on the preoperative CA 125 in the following sense the higher the preoperative antigen values the less the cancer is differentiated. In our results this relationship is confirmed and described by the statistically significant and important correlation demonstrated in Fig. 1. Thus, we join the opinion of previously mentioned authors Vergote and Boermer. There was also a statistically significant difference in CA 125 values between different degrees of tumor differentiation; e.g., CA 125 values differ significantly between G1 and G2 and also between G2 and G3. There were two interesting observations: First, the CA 125 values of equally mature tumors did not differ statistically significantly among stages; e.g., the CA 125 values in G2 and G3 carcinomas (the same histologic type) stage II did not differ significantly from the same-grade, stage III or IV carcinomas. Second, the results showed that CA 125 values in poorly, moderately, and well-differentiated tumors within the same stage differ significantly. Statistically significant was also the correlation between both parameters (tumor grade and CA 125) in stages II, III, and IV of the disease. In stage I the correlation was implied but, due to the small number of moderately and poorly differentiated tumors, statistically insignificant. The relationship of both parameters in individual stages is shown by regression curves in Fig. 4. The question arises which of the two parameters has the predominating influence on serum CA 125 values: Is it the stage of disease as some authors maintain, or is it tumor grade according to our hypothesis? The results of
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the multivariate regression analysis show the predominant influence of tumor grade over tumor stage on preoperative CA 125 level (for the results, see the regression summary in Table 4). As opposed to the other authors exposing the predominating influence of the stage of disease on serum CA 125 value, we conclude on the basis of our findings that tumor grade is the factor bearing the predominating influence on the preoperative level of the studied antigen in serum. We share the opinion that CA 125 is the tumor marker reflecting the degree of dedifferentiation of serous ovarian carcinoma. CA 125 Level and Histologic Type of Ovarian Carcinoma In the first-stage, mucinous carcinomas were prevalent (57.1% of all stage I cancers); they were exclusively well differentiated with low preoperative CA 125 levels and also low CA 125 sensitivity (Table 1). In stages III and IV serous carcinomas were in majority (75.9% of all stage III and IV cancers), they were mainly dedifferentiated (G2 and G3 in 89.3%) with high preoperative CA 125 levels and high sensitivity of the assay. There were also a few serous carcinomas in first FIGO stage. They were exclusively well differentiated, the preoperative CA 125 levels exceeded the border at 35 U/ml only in 50% (Table 1). Based on our data we believe that good differentiation of ovarian carcinomas in the first stage of disease is the cause of low preoperative CA 125 values and of poor sensitivity of the CA 125 test, thus limiting its applicability for screening purposes. Estimation on a larger study group is, however, needed. Many questions arise regarding CA 125: What are the possible reasons? Why are the levels of CA 125 higher, the less differentiated the tumor? Is it DNA aneuploidy possibly reason for that? Does the normalization of the CA 125 values after therapy mean that the least differentiated cells are destroyed, leaving better differentiated, chemotherapy-resistant cancer cells? Is there also a correlation between serum CA 125 levels and histologic grade of residual lesions detected at second-look surgery? Further studies are needed. We have no convincing data and, so, no real answers, to the abovementioned questions yet. CONCLUSIONS
The relationship between tumor grade and serum CA 125 level is an inverse ratio: the higher the preoperative CA 125 values, the less the tumor is differentiated. There is no statistically significant difference between CA 125 values of equally mature tumors. The CA 125 values among individual stages do not difference statistically significantly, which is the result of a more even distribution of tumor differentiation within the individual stage. Tumor grade is the decisive factor dictating the level of CA 125 in a certain stage of the disease.
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We believe that good differentiation of ovarian carcinomas in FIGO stage I is the cause of poor sensitivity of the CA 125 test, thus limiting its applicability for screening purposes.
14.
15.
REFERENCES 16. 1. Tortolero-Luna. Epidemiology and screening of ovarian cancer, in Update on epithelial ovarian cancer (D. M. Gershenson, Ed.), Obstet. Gynecol. Clin. North Am. 21, 1–23 (1994). 2. Barber, H. Ovarian carcinoma: Etiology, diagnosis and treatment, 3rd ed., Springer-Verlag, New York, pp. 2–3 (1993). 3. Burghardt, E., Lahousen, M., Stettner, H., and Petru, E. Results: Calculating survival rates, in Surgical gynecologic oncology (E. Burghardt, Ed.), Thieme, Stuttgart, New York, pp. 474–487 (1993). 4. Baker, V. V. Molecular biology and genetics of epithelial ovarian cancer, in Update on epithelial ovarian cancer (D. M. Gershenson, Ed.), Obstet. Gynecol. Clin. North. Am. 21, 25–40 (1994). 5. Bast, R. C., Jacobs, I., and Berchuck, A. Malignant transformation of ovarian epithelium, J. Natl. Cancer. Inst. 84, 556–558 (1992). 6. Bast, R. C., Feeney, M., Lazarus, H.,and Knapp, R. C. Reactivity of a monoclonal antibody with human ovarian carcinoma, J. Clin. Invest. 68, 1331–1337 (1981). 7. Kabawat, S. E., Bast, R. C., Welch, W. R., and Knapp, R. C. Immunopathologic characterization of a monoclonal antibody that recognizes common surface antigens of human ovarian tumors of serous, endometrioid, and clear cell types, Am. J. Clin. Pathol. 79, 98–104 (1983). 8. Brioschi, P. A., and Irion, O. Serum CA 125 in epithelial ovarian cancer: A longitudinal study, Br. J. Obstet. Gynaecol. 94, 193–207 (1987). 9. Welander, C. E. What do CA 125 and other antigens tell us about ovarian cancer biology, Acta Obstet. Gynecol. Scand. 71, 85–93 (1992). 10. Tholander, B., Taube, A., and Lindgren, A. Pretreatment serum levels of CA 125, carcinoembryonic antigen, tissue polypeptide antigen and placental alkaline phosphatase in patients with ovarian carcinoma: Influence of histological type, grade of differentiation and clinical stage of disease, Gynecol. Oncol. 39, 26–33 (1990).
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12. Patsner, B., and Mann, W. J. The value of preoperative serum CA 125 levels in patients with a pelvic mass, Am. J. Obstet. Gynecol. 159, 873–876 (1988).
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preoperative serum CA 125 levels in patients with early stage ovarian carcinoma, Gynecol. Oncol. 30, 7–14 (1988). International Federation of Gynecology and Obstetrics (FIGO). Changes in gynecologic cancer staging by the International Federation of Gynecology and Obstetrics, Am. J. Obstet. Gynecol. 162, 610 (1990). Creasman, W. T. New gynecologic cancer staging, Obstet. Gynecol. 75, 287–288 (1990). Breitenecker, G., Neunteufel, W., Bieglmayer, C., Koelbl, H., and Schieder, K. Comparison between tissue and serum content of CA 125, CA 19-9, and carcinoembryonic antigen in ovarian tumors, Int. J. Gynecol. Pathol. 8, 97–102 (1989). Vergote, I. B., and Boermer, O. P. Evaluations of serum CA 125 levels in the monitoring of ovarian cancer, Am. J. Obstet. Gynecol. 157, 88– 92 (1987). Patsner, B., and Day, T. G. Predictive value of CA 125 levels in advanced ovarian cancer, Am. J. Obstet. Gynecol. 156, 440–441 (1987). Hempling, R. E. Tumor markers in epithelial ovarian cancer: Clinical applications, in Update on epithelial ovarian cancer (D. M. Gershenson, Ed.), Obstet. Gynecol. Clin. North. Am. 21, 41–61 (1994). Malkasian, G. D., Knapp, R. C., and Lavin, P. T. Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: Discrimination of benign from malignant disease, Am. J. Obstet. Gynecol. 2, 341–346 (1988). Westhoff, C., Gollub, E., Patel, J., and Bast, R. The CA 125 levels in menopausal women, Obstet. Gynecol. 76, 428–431 (1990). Malkasian, G. D., and Melton, J. Prognostic significance of histologic classification and grading of epithelial malignancies of the ovary, Am. J. Obstet. Gynecol. 149, 274–284 (1984). Sevelda, P., Schemper, M., and Spona, J., CA 125 as an independent prognostic factor for survival in patients with epithelial ovarian cancer, Am. J. Obstet. Gynecol. 161, 1213–1216 (1989). Malkasian, G. D. Editorial, Gynecol. Oncol. 44, 205–206 (1992). Makar, A., Kristensen, G. B., and Kaern, J. Prognostic value of preand postoperative serum CA 125 levels in ovarian cancer: New aspects and multivariate analysis, Obstet. Gynecol. 79, 1002–1010 (1992). Bast, R. C., Niloff, J. M., and Klug, T. L. Monitoring human ovarian carcinoma with a combination of CA 125, CA 19-9 and carcinoembryonic antigen, Am. J. Obstet. Gynecol. 149, 553–559 (1984). Buller, R. E., and Berman, M. L. CA 125 regression: A model for ovarian cancer response, Am. J. Obstet. Gynecol. 165, 360–367 (1991). Niloff, J. M., Knapp, R. C., and Bast, R. C. The CA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer, Am. J. Obstet. Gynecol. 155, 56–60 (1986). But, I. Preoperativna analiza CA 125 pri invazivnem ovarijskem karcinomu: Magistrskanaloga. Medicinska fakulteta Univerza v Ljubljani, Ljubljana (1994).
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Preoperative Value of CA 125 as a Reflection of Tumor Grade in Epithelial Ovarian Cancer IGOR BUT, M.D., M.SC.,*
AND
BORUT GORISˇEK, M.D., PH.D.†
*Division of Gynecologic Oncology and †Department of Gynecology and Obstetrics, Maribor Teaching Hospital, Ljubljanska 5, 2000 Maribor, Slovenia Received September 11, 1995
A retrospective study of 60 patients with invasive epithelial ovarian cancer was conducted. The significance of preoperative serum CA 125 level with respect to tumor grade and tumor stage was determined. Tumor grade bears a strong influence on the preoperative CA 125 level; the correlation is high and statistically significant (r Å 0.74, P õ 0.01). The influence of FIGO stage on preoperative CA 125 level is also significant (r Å 0.51, P õ 0.01), but the results of the multivariate analysis show that the influence of tumor grade on preoperative CA 125 level is stronger (P õ 0.01). It is believed that tumor grade is the decisive factor dictating the level of CA 125 in a certain stage of the disease and so influences the preoperative CA 125 level. It is also believed that low preoperative antigen levels of well-differentiated ovarian carcinomas in FIGO stage I are the cause of poor sensitivity of the CA 125 test, thus limiting its applicability for screening purposes. q 1996 Academic Press, Inc.
INTRODUCTION
Histogenetically, primary epithelial ovarian cancers belong to the group of cancers of the germinative, coelomic epithelium. Among ovarian cancers they hold the majority (90%), their characteristic traits being histologic pleomorphism and heterogeneity. Ovarian cancer is detected relatively late, so 70% of the cancers are already in stage III or IV when the diagnosis is set. Hence the mortality rate, the highest among gynecologic malignant growths and exceeding the total mortality rate of cervical and endometrial cancer [1]. Despite the progress in diagnosis and treatment, the 5-year survival rate has not improved essentially in the past 30 years and amounts to 35% for all stages [2–4]. All the reasons stated, as well as the high prevalence of the disease during postmenopause and in women who are related to ovarian cancer patients, dictate the discovery of a method that would facilitate the early diagnosis of this serious disease, for early diagnosis is the only basis for successful treatment. Cancer is a disease of the cell and it is the task of researchers to define the qualitative as well as quantitative differences between a normal cell and a neoplastic cell. These findings
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METHODS
Ours is a retrospective study extending over the period between January 1990 and December 1994 and including 60 patients with primary invasive ovarian carcinoma. Patients with nonepithelial malignant growth as well as those with secondary or borderline epithelial cancer were excluded from the study. The control group consisted of 45 patients with benign epithelial ovarian tumor. Preoperative serum CA 125 levels were determined by means of an enzyme immunoassay (Cobas Core CA 125 II EIA, Roche Diagnostic Systems). All patients were operated (total abdominal hysterectomy, bilateral adnexectomy, omentectomy, lymphadenectomy). A pathologist examined the surgical specimens and determined the histologic type and tumor grade according to WHO provisions. On the basis of the operative record, histologic findings of operative spec-
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would then serve as a basis for diagnosis, treatment, and prophylaxis. In 1981, Bast discovered the tumor marker CA 125 on the surface of cells changed by cancer [5–7]. It is a tumor-associated antigen identifiable in serum by means of the highly specific murine monoclonal antibody IgG1 OC 125 in more than 80% of ovarian cancer patients and in only 1% of healthy women [8–13]. According to the same authors, the preoperative marker level reflects the quantity of the tumor mass and, thus, also the stage of disease. For more than 5 years, the preoperative serum level of tumor marker CA 125 is being determined at our Department of Gynecology. At first the findings merely served as rough orientation in making the distinction between a benign and a malignant adnexal mass or as a reference when following the success of therapy and, thus, also the course of disease. But we noticed that apart from the stage of the disease, the tumor grade also may exert an influence on the preoperative CA 125 level. Hence ensues our study, which presupposes that in epithelial ovarian cancer the preoperative serum CA 125 value is in inverse proportion to tumor grade in the sense that the higher the preoperative antigen values, the less the cancer is differentiated.
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TABLE 1 Analysis of Preoperative CA 125 Levels with Respect to Histologic Type CA 125 sensitivity (ú35 U/ml)
Ca 125 (U/ml) Histologic type
No. (%)
Mean
25th percentile
Median
75th percentile
FIGO stage I
FIGO stages I–IV
Serous Mucinous Other types
39 (65.) 10 (16.6) 11 (18.4)
275.6 28.7 181.4
92.5 4.5 32.1
262.0 19.9 192.5
500.0 34.6 265.9
50.0% 12.5% 50.0%
89.7% 30.0% 82.0%
217.2 U/ml (25th percentile Å 46.4 U/ml, median Å 140.4 U/ml, 75th percentile Å 396.9 U/ml). The control group consisted of 45 patients with benign epithelial tumor. The average age of the patients was 54.8 years (SD Å 7.4). The youngest was 37, the oldest 77. The mean CA 125 value in the control group was 9.9 U/ml (25th percentile Å 3.4 U/ ml, median Å 6.8 U/ml; 75th percentile Å 14.6 U/ml).
imens and biopsy, as well as cytologic findings of ascites or abdominal lavage, respectively, staging of the cancers was carried out according to FIGO [14, 15]. After surgery, the patients received chemotherapy according to a scheme; some had radiation therapy at the Institute of Oncology in Ljubljana. Statistical analysis was performed using the statistical package Statistica for Windows (StatSoft Inc.) on a personal computer. Correlations between variables (CA 125, tumor grade, FIGO stage) were assessed by Pearson’s correlation coefficient (r). In a multiple linear regression model, the combined effect of the two variables (FIGO clinical stage, tumor grade) on preoperative CA 125 level was analyzed. Comparison of means was achieved by the Student t test, requiring P õ 0.05 for statistical significance.
Tumor Grade There were 22 (36.7%) well-differentiated, 21 (35.0%) moderately differentiated, and 17 (28.3%) poorly differentiated types of cancer. There was a statistically significant difference in CA 125 values between G1 tumors and control group (t Å 4.50; P õ 0.01), between G2 and G1 tumors (t Å 4.45; P õ 0.01), as well as between G3 and G2 tumors (t Å 3.79; P õ 0.01). Mean and percentile as well as the sensitivity of the CA 125 test in individual degrees of tumor differentiation are shown in Table 2. The correlation between tumor grade and preoperative serum CA 125 value was r Å 0.74, meaning a real significant correlation (P õ 0.01). Graphically the correlation is depicted by a regression curve in Fig. 1.
RESULTS
In the 5-year period, 60 patients with primary invasive ovarian carcinoma were included in our analysis. The average age of our patients was 59.0 years (SD, 12.8 years). The youngest patient was 29 and the oldest 84 years old. Twothirds of our cancer cases (n Å 41 or 68.3%) were discovered during postmenopause. The most frequent type of cancer was the serous type (n Å 39 or 65.0%), followed by the mucinous type (n Å 10 or 16.6%), endometrioid type (n Å 6 or 10.0%), unclassified type (n Å 4 or 6.7%), and a single case of undifferentiated cancer (n Å 1 or 1.7%). The CA 125 values (mean and percentile) and sensitivity of the test with respect to histologic type are shown in Table 1. The mean serum CA 125 value in all 60 patients amounted to
Tumor Stage Ovarian carcinoma FIGO stage I was detected in 14 patients (23.3%), stage II in 9 patients (15%), stage III in 23 patients (38.3%), and stage IV in 14 patients (23.3%). There was a significant difference in CA 125 values between FIGO stage I and control group (t Å 3.99; P õ 0.01) and between stages II and I (t Å 3.95; P õ 0.01). The difference between
TABLE 2 CA 125 Level and the Degree of Cancer Differentiation CA 125 (U/ml) Tumor grade
No. (%)
Mean
25th percentile
Median
75th percentile
Sensitivity (ú35 U/ml)
Significance
G1 G2 G3
22 (36.7) 21 (35.0) 17 (28.3)
64.5 222.2 408.8
9.6 111.6 321.1
45.1 218.2 500.0
85.0 280.6 500.0
54.5% 85.7% 100.0%
Ca:G1, P õ 0.01 G:G2, P õ 0.01 G2:G3, P õ 0.01
a
C, control group.
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FIG. 1.
Relationship between preoperative CA 125 level and tumor grade.
CA 125 values of stages III and II (t Å 0.95; P Å 0.35), stages IV and III (t Å 0.09; P Å 0.93), as well as between those CA 125 values of stages IV and II (t Å 0.87; P Å 0.39) was statistically insignificant. Mean and percentile as well as the sensitivity of the test in individual FIGO stages are shown in Table 3. We studied the influence of stage on the preoperative antigen CA 125 value and found that the correlation of both parameters was good and significant (r Å 0.51, P õ 0.01). The correlation is best described by the regression curve shown in Fig. 2. Relationship between Tumor Stage and Tumor Grade Stages I and II, denoting limited disease, were established in 23 cases of ovarian cancer (38.3%). Among them welldifferentiated cases prevailed, (65.2%), followed by moderately (21.7%) and poorly (13.1%) differentiated ones. Stages
III and IV, denoting advanced disease, were detected in 37 cases (61.7%). Among these, moderately differentiated types were prevailing (43.3%), followed by poorly (37.8%) and well-differentiated ones (18.9%) (Fig. 3). The correlation between tumor stage and tumor grade was good and statistically significant (r Å 0.44; P õ 0.01). Relationship between CA 125 and tumor stage with respect to tumor grade. The correlation between both parameters was good and statistically significant in well-differentiated tumors (r Å 0.63; P õ 0.01), but there was no correlation between both parameters in moderate (r Å 0.19; P Å 0.42), and also in poor differentiated tumors (r Å 0.26; P Å 0.31). In well-differentiated cancers there was no statistically significant difference in CA 125 values between FIGO stage II and stage I (t Å 1.62; P Å 0.12), FIGO stage III and stage II (t Å 0.77; P Å 0.48), and also between stage IV and III cancers (t Å 0.82, P Å 0.45); but there was a significant
TABLE 3 Analysis of Preoperative CA 125 Levels with Respect to FIGO Stage CA 125 (U/ml)
FIGO stage I II III IV a
No. (%)
Mean
25th percentile
Median
75th percentile
Sensitivity (ú35 U/ml)
14 9 2 14
29.3 220.0 289.8 284.0
7.1 79.2 82.8 123.8
18.1 192.5 290.5 259.0
34.6 254.3 500.0 428.6
28.6% 88.9% 91.3% 100.0%
(23.3) (15.0) (38.3) (23.3)
C, control group.
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Significance (P) Ca:I, P õ I:I, P õ II:III, P Å III:IV, P Å
0.01 0.01 0.35 0.93
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FIG. 2.
Relationship between preoperative CA 125 level and FIGO stage.
difference in CA 125 values between FIGO stage IV and stage I (t Å 3.19; P õ 0.01) and also between stage III and stage I cancers (t Å 3.42; P õ 0.01). In moderately differentiated (G2) cancers there was no significant difference in preoperative CA 125 values between stages II and II (t Å 0.5, P Å 0.30) and between stages IV and III (t Å 0.65; P Å 0.26). In poorly differentiated (G3) stage II, III, and IV cancers, the CA 125 values also did not differ statistically significantly. Relationship between CA 125 level and tumor grade with respect to tumor stage. A significant correlation also exists between CA 125 values and tumor grade in individual stages according to FIGO. Thus, the correlation between both parameters was statistically significant in stage II (r Å 0.92;
FIG. 3.
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P õ 0.01), stage III (r Å 0.58; P õ 0.01), stage IV (r Å 0.71; P õ 0.01), and statistically insignificant in stage I according to FIGO (r Å 0.33; P Å 0.26). Within the frame of individual stages, the correlation of CA 125 and tumor grade can also be expressed by means of regression curves, as shown in Fig. 4. The results of the stepwise multiple regression with the independent variables tumor stage and tumor grade and the dependent variable preoperative CA 125 level are shown in Table 4. DISCUSSION
Comment on Our CA 125 Assay In the graphs and the tables, as one can see, the highest CA 125 value amounted to 500 U/ml. It does not mean that
Distribution of the different degrees of tumor differentiation in limited (stages I and II) and advanced (stages III and IV) disease.
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Preoperative CA 125 Level
FIG. 4. Correlation of CA 125 level and tumor grade within the frame of individual stages: regression curves.
there were no higher CA 125 values, but it does mean that serum antigen values greater than 500.0 U/ml were given only descriptive (ú500.0 U/ml). Because this study was retrospective, we were unable to get more precise CA 125 values by further serum dilution; however, none of the CA 125 values in well-differentiated and only some of the CA 125 values (9.5%) in moderately differentiated cancers exceeded this above-mentioned border at 500.0 U/ml. In contrast, nearly two-thirds (64.7%) of CA 125 values in poorly differentiated cancers (serous types and undifferentiated type) were higher than 500.0 U/ml. Because the objective of this study was preoperative serum CA 125 analysis and not the follow-up, according to our opinion and that of the statistician, this fixed CA 125 value at 500.0 U/ml did not essentially hinder our analysis. From the literature, using a cutoff level of 35 U/ml, there is a high correlation (r Å 0.81) between preoperative serum levels and immunohistochemical detection of CA 125 in tumor tissue [16]. We have not assessed the presence of CA 125 antigen by immunohistochemical techniques on carcinomatous tissues because, according to Breitenecker et al., no relationship could be detected between histologic grade (the main topic of our study) and intensity of the reaction [16].
Most authors connect the high marker level in serum with a large quantity of tumor mass and an unfavorable prognosis. As a rule, in patients in the late phase of the disease, preoperative CA 125 values are higher than those in patients with early-phase cancer, where the tumor mass is smaller [8–13]. The authors share the opinion that tumor grade bears no influence on the preoperative marker CA 125 level. The connection is merely apparent and as such the result of the fact that poorly differentiated cancers are in a higher stage of the disease while the well-differentiated ones are in the early phase of the disease, and the CA 125 level is a reflection of the quantity of tumor mass [8–10]. But in literature other observations can also be found. Some authors believe that a connection between tumor grade and serum CA 125 level does exist, but they devote no special attention to it. Among these authors Vergote and Boermer [17] have an exceptional position, for they believe that the relationship between tumor grade and serum CA 125 value is in inverse ratio in the sense that: the less the tumor is differentiated, the higher the serum antigen values. At the same time Vergote and Boermer [17] state that in poorly differentiated cancers, the quantity of tumor mass is not responsible for increased CA 125 values, for there is no significant correlation between the degree of tumor differentiation and tumor burden (P Å 0.40). CA 125 Level and FIGO Stage When we analyzed our relatively small group of patients we found that in the higher stages of the disease, higher serum values of the tumor antigen studied were present (r Å 0.51, P õ 0.01). Another way of presenting this relatively strong connection between the quantity of tumor mass and the preoperative CA 125 level was calculating the statistically significant difference in CA 125 values among FIGO stages. If the preoperative CA 125 level really reflected the quantity of tumor mass, a statistically significant difference in CA 125 values between individual FIGO stages should exist. We verified this statistical significance and the results were surprising. The CA 125 values among individual stages did not differ significantly, e.g., CA 125 values in stage II
TABLE 4 Regression Summary for Dependent Variable CA 125 Level R 2 Å 0.584 P õ 00000
R Å 0.764 F (2, 57) Å 40.008
Intercept Grade Stage
R2
R 2 Ch
b
SE b
B
SE B
t (57)
P level
0.542 0.584
0.542 0.042
0.635 0.228
0.095 0.095
0168.97 147.75 39.34
47.84 22.17 16.44
03.53 6.66 2.39
0.0008 1.156E-08 0.0208
CA 125 Å 0168.97 / 147.75∗grade / 39.34∗stage
Equation
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Adjusted R 2 Å 0.569 SEE Å 123.44
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did not differ significantly from those in stage III or IV. The only statistically significant difference in CA 125 values found was between stage I on one side and stage II, III, or IV on the other. We believe that this significant difference in CA 125 values was because of the two factors. First, we should not forget the connection between the augmented serum CA 125 level and peritoneal reaction, e.g., peritoneal irritation caused by spreading of ovarian carcinoma. Such a peritoneal reaction can be observed in the cases of pelvic endometriosis and pelvic inflammatory disease (PID), the two main factors causing the false positivity of the CA 125 test. Second, according to our opinion, this was the consequence of unequal distribution of tumor grade in individual FIGO stages, which is a consequence of different histologic types of ovarian cancer present in individual FIGO stages (serous carcinomas tend to be high grade and high stage in contrast to mucinous carcinomas, which tend to be low grade and low stage). So, the correlation of both tumor stage and tumor grade was statistically significant (P õ 0.01). CA 125 Level and Tumor Grade During our clinical work it was noticed that apart from the stage of the disease, the tumor grade also exerts an important influence on the preoperative CA 125 in the following sense the higher the preoperative antigen values the less the cancer is differentiated. In our results this relationship is confirmed and described by the statistically significant and important correlation demonstrated in Fig. 1. Thus, we join the opinion of previously mentioned authors Vergote and Boermer. There was also a statistically significant difference in CA 125 values between different degrees of tumor differentiation; e.g., CA 125 values differ significantly between G1 and G2 and also between G2 and G3. There were two interesting observations: First, the CA 125 values of equally mature tumors did not differ statistically significantly among stages; e.g., the CA 125 values in G2 and G3 carcinomas (the same histologic type) stage II did not differ significantly from the same-grade, stage III or IV carcinomas. Second, the results showed that CA 125 values in poorly, moderately, and well-differentiated tumors within the same stage differ significantly. Statistically significant was also the correlation between both parameters (tumor grade and CA 125) in stages II, III, and IV of the disease. In stage I the correlation was implied but, due to the small number of moderately and poorly differentiated tumors, statistically insignificant. The relationship of both parameters in individual stages is shown by regression curves in Fig. 4. The question arises which of the two parameters has the predominating influence on serum CA 125 values: Is it the stage of disease as some authors maintain, or is it tumor grade according to our hypothesis? The results of
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the multivariate regression analysis show the predominant influence of tumor grade over tumor stage on preoperative CA 125 level (for the results, see the regression summary in Table 4). As opposed to the other authors exposing the predominating influence of the stage of disease on serum CA 125 value, we conclude on the basis of our findings that tumor grade is the factor bearing the predominating influence on the preoperative level of the studied antigen in serum. We share the opinion that CA 125 is the tumor marker reflecting the degree of dedifferentiation of serous ovarian carcinoma. CA 125 Level and Histologic Type of Ovarian Carcinoma In the first-stage, mucinous carcinomas were prevalent (57.1% of all stage I cancers); they were exclusively well differentiated with low preoperative CA 125 levels and also low CA 125 sensitivity (Table 1). In stages III and IV serous carcinomas were in majority (75.9% of all stage III and IV cancers), they were mainly dedifferentiated (G2 and G3 in 89.3%) with high preoperative CA 125 levels and high sensitivity of the assay. There were also a few serous carcinomas in first FIGO stage. They were exclusively well differentiated, the preoperative CA 125 levels exceeded the border at 35 U/ml only in 50% (Table 1). Based on our data we believe that good differentiation of ovarian carcinomas in the first stage of disease is the cause of low preoperative CA 125 values and of poor sensitivity of the CA 125 test, thus limiting its applicability for screening purposes. Estimation on a larger study group is, however, needed. Many questions arise regarding CA 125: What are the possible reasons? Why are the levels of CA 125 higher, the less differentiated the tumor? Is it DNA aneuploidy possibly reason for that? Does the normalization of the CA 125 values after therapy mean that the least differentiated cells are destroyed, leaving better differentiated, chemotherapy-resistant cancer cells? Is there also a correlation between serum CA 125 levels and histologic grade of residual lesions detected at second-look surgery? Further studies are needed. We have no convincing data and, so, no real answers, to the abovementioned questions yet. CONCLUSIONS
The relationship between tumor grade and serum CA 125 level is an inverse ratio: the higher the preoperative CA 125 values, the less the tumor is differentiated. There is no statistically significant difference between CA 125 values of equally mature tumors. The CA 125 values among individual stages do not difference statistically significantly, which is the result of a more even distribution of tumor differentiation within the individual stage. Tumor grade is the decisive factor dictating the level of CA 125 in a certain stage of the disease.
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We believe that good differentiation of ovarian carcinomas in FIGO stage I is the cause of poor sensitivity of the CA 125 test, thus limiting its applicability for screening purposes.
14.
15.
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preoperative serum CA 125 levels in patients with early stage ovarian carcinoma, Gynecol. Oncol. 30, 7–14 (1988). International Federation of Gynecology and Obstetrics (FIGO). Changes in gynecologic cancer staging by the International Federation of Gynecology and Obstetrics, Am. J. Obstet. Gynecol. 162, 610 (1990). Creasman, W. T. New gynecologic cancer staging, Obstet. Gynecol. 75, 287–288 (1990). Breitenecker, G., Neunteufel, W., Bieglmayer, C., Koelbl, H., and Schieder, K. Comparison between tissue and serum content of CA 125, CA 19-9, and carcinoembryonic antigen in ovarian tumors, Int. J. Gynecol. Pathol. 8, 97–102 (1989). Vergote, I. B., and Boermer, O. P. Evaluations of serum CA 125 levels in the monitoring of ovarian cancer, Am. J. Obstet. Gynecol. 157, 88– 92 (1987). Patsner, B., and Day, T. G. Predictive value of CA 125 levels in advanced ovarian cancer, Am. J. Obstet. Gynecol. 156, 440–441 (1987). Hempling, R. E. Tumor markers in epithelial ovarian cancer: Clinical applications, in Update on epithelial ovarian cancer (D. M. Gershenson, Ed.), Obstet. Gynecol. Clin. North. Am. 21, 41–61 (1994). Malkasian, G. D., Knapp, R. C., and Lavin, P. T. Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: Discrimination of benign from malignant disease, Am. J. Obstet. Gynecol. 2, 341–346 (1988). Westhoff, C., Gollub, E., Patel, J., and Bast, R. The CA 125 levels in menopausal women, Obstet. Gynecol. 76, 428–431 (1990). Malkasian, G. D., and Melton, J. Prognostic significance of histologic classification and grading of epithelial malignancies of the ovary, Am. J. Obstet. Gynecol. 149, 274–284 (1984). Sevelda, P., Schemper, M., and Spona, J., CA 125 as an independent prognostic factor for survival in patients with epithelial ovarian cancer, Am. J. Obstet. Gynecol. 161, 1213–1216 (1989). Malkasian, G. D. Editorial, Gynecol. Oncol. 44, 205–206 (1992). Makar, A., Kristensen, G. B., and Kaern, J. Prognostic value of preand postoperative serum CA 125 levels in ovarian cancer: New aspects and multivariate analysis, Obstet. Gynecol. 79, 1002–1010 (1992). Bast, R. C., Niloff, J. M., and Klug, T. L. Monitoring human ovarian carcinoma with a combination of CA 125, CA 19-9 and carcinoembryonic antigen, Am. J. Obstet. Gynecol. 149, 553–559 (1984). Buller, R. E., and Berman, M. L. CA 125 regression: A model for ovarian cancer response, Am. J. Obstet. Gynecol. 165, 360–367 (1991). Niloff, J. M., Knapp, R. C., and Bast, R. C. The CA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer, Am. J. Obstet. Gynecol. 155, 56–60 (1986). But, I. Preoperativna analiza CA 125 pri invazivnem ovarijskem karcinomu: Magistrskanaloga. Medicinska fakulteta Univerza v Ljubljani, Ljubljana (1994).
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