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Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses. Discrimination of benign from malignant disease
Volume 159 Number 2
antimicrobial agents during pregnancy. Rev Infect Dis 1985;7:287-313. 12. Garite TJ, Keegan KA, Freeman RK, Nageotte MP. A randomized trial of ritodrine tocolysis versus expectant management in patients with premature rupture of membranes at 25 to 30 weeks of gestation. AM J OBSTET GYNECOL 1987; 157:388-93. 13. Morales WJ. The effect of chorioamnionitis on the developmental outcome of preterm infants at one year. Obstet Gynecol 1987;70:183-6.
New cervical catheter for managing PROM
14. Quinn PA, Bauty J, Taylor J, Hannah W. Chorioamnionitis: Its association with pregnancy outcome and microbial infection. AM j 0BSTET GYNECOL 1987;156:37987. 15. Yeast JD, Garite TR. The role of cervical cerclage in the management of preterm premature rupture of the membranes. AM j 0BSTET GYNECOL 1988; 158:106-10.
Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: Discrimination of benign from malignant disease George D. Malkasian, Jr., MD,a Robert C. Knapp, MD," Philip T. Lavin, PhD," Vincent R. Zurawski, Jr., PhD," Karl C. Podratz, MD,a C. Robert Stanhope, MD,a Rodrique Mortel, MD,C Jonathan S. Berek, MD,d Robert C. Bast, Jr., MD; and Roy E. Ritts, MD' Rochester, Minnesota, Boston, Massachusetts, Hershey, Pennsylvania, Los Angeles, California, and Durham, North Carolina CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels >65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels >65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels >65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%. (AM J OssTET GYNECOL 1988;159:341-6.)
Key words: CA I25 levels, benign and malignant ovarian disease, premenopausal, postmenopausal
From the Department of Obstetrics and Gynecology, Mayo Clinic and Mayo Foundation"; Brigham and Women's Hospital, Harvard Medical School, and the Gynecologic Oncology Laboratories, Dana Farber Cancer Institute'; the Hershey Medical Center, Pennsylvania State University'; the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Los Angeles, School of Medicine and Jonsson Comprehensive Cancer Center'-; the Department of Medicine, Duke University Medical Center; and the Department of Immunology, Mayo Clinic and Mayo Foundation/ Received for publication July 6, 1987; revised January 25, 1988; accepted February 19, 1988. Reprint requests: George D. Malkasian, Jr., MD, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905.
In I986, according to the American Cancer Society, approximately I9,000 new cases of ovarian cancer were diagnosed in the United States and II ,3 75 women died of this disease. Less than 25% of ovarian cancers have been diagnosed before spread of tumor cells beyond the ovary-an obvious indictment of our ability to detect the condition in its earliest stages. Even when a palpable pelvic mass has been found, it has been difficult to determine whether the mass was malignant or benign before exploratory laparotomy. Patients often undergo surgical exploration, are 341
342
Malkasian et al.
August 1988 Am J Obstet Gynecol
Table II. Characteristics of 68 patients with cancer
Table I. Characteristics of 90 patients with benign neoplasms Age (yr) Median Range Menopausal status Premenopausal Postmenopausal Histologic type (primary and secondary diagnoses) Benign neoplastic cyst Fibroids Functional cysts Pelvic inflammatory disease Stage I endometriosis Stage II endometriosis Stage III endometriosis Benign nonovarian cyst CA 125 assay value Median Range <35.0 U/ml 2:35.0 U/ml 2:65.0 U/ml 2:100.0 U/ml
43.5 15-88 56 34
(62.2%) (37.8%)
59 21 10
(65.6%) (23.3%) (11.1 %) (8.9%) (2.2%) (12.2%) (8.9%) (1.1%)
8
2
11 8
1
14.8 0.0-2221.6 72 18
7
4
(80.0%) (20.0%) (7.8%) (4.4%)
Age (yr) Median Range Menopausal status Premenopausal Postmenopausal Histologic type Serous Adenocarcinoma Mucinous Mixed Non<~varian pelvic malignannes Endometrioid Metastatic to ovary Borderline Clear cell Endodermal sinus Dysgerminoma Stage at initial diagnosis (60 patients) I II
III
IV
found to have widespread carcinoma, and are referred for a second operation at a center that specializes in cytoreductive procedures. Elevation of a reliable serum marker for gynecologic malignancy in conjunction with suspicious history, physical, and laboratory findings might prompt the referral of such patients for a definitive operation at the time of initial exploration, eliminating the morbidity and expense of a second procedure. Recently, an immunoradiometric assay that uses a papillary serous adenocarcinoma cell line has been developed to detect CA 125,' a tumor-associated antigen that is shed into serum or ascites from patients with a variety of malignancies including epithelial ovarian, fallopian tube, endometrial, and endocervical carcinomas? Approximately 80% of patients with advanced epithelial ovarian cancer will have CA 125 values >35 U I ml in serum.' The assay has not been effective in detecting mucinous or borderline neoplasms. Recently, Einhorn et al.,< in a study of 100 women undergoing diagnostic laparotomy because of palpable ovarian masses, noted that all 11 patients with frankly malignant, nonmucinous ovarian carcinoma had CA 125 levels >35 Ulml. Among 14 patients with CA 125 values >65 U I ml and a palpable pelvic mass, 13 had some form of gynecologic malignancy. The authors suggested that these results would allow theCA 125 assay to be used as a diagnostic adjunct for discriminating benign from malignant pelvic masses. Our present study confirms and extends this observation to consider the significance of an elevated serum CA 125 level in premenopausal and postmenopausal patients with pelvic masses.
Grade (47 patients) Well differentiated Moderately differentiated Poorly differentiated CA 125 assay value Median Range <35.0 U/ml 2:35.0 U/ml 2:65.0 U/ml 2:100.0 U/ml
63.5 16-96 10 58
(14.7%) (85.3%)
24 12 10 5 4
(36.8%) (17.6%) (17.6%) (7.4%) (7.4%)
4 3 3 1 1 1
(7.4%) (4.4%) (4.4%) (1.5%) (1.5%) (1.5%)
14 6 37 3
(23.3%) (10.0%) (61.5%) (5.0%)
9 19 19
(19.1%) (40.4%) (40.4%)
297.3 6.8-10,000.0 15 53 51 50
(22.1%) (77.9%) (75.0%) (73.5%)
Material and methods
A total of 172 subjects had blood samples drawn before operation. Among the institutions participating in the study, the Mayo Clinic contributed 100 cases, Brigham and Women's Hospital/Dana Farber Cancer Institute 60, Pennsylvania State University 11, and University of California, Los Angeles, 1. To be eligible for this study the patients must have had a palpable pelvic mass and be scheduled for diagnostic surgery. There was to be no verified ovarian carcinoma before operation. Pathology reports were to document the diagnosis of a pelvic mass after oepration, and the sample for the preoperative CA 125 assay was to be drawn within 1 week before the operation. In the 172 subjects who had blood drawn before operation, eligibility was reviewed and 14 exclusions were made for the following reasons: ovarian cancer verified before surgery, 11 cases; no preoperative blood assay within 1 week before operation, three cases. The remaining 158 cases were eligible for evaluation. The population consisted of 90 subjects with benign neoplasms (Table I) and 68 patients with cancer (Table II). The malignant neoplasms included 4 nonovarian
CA 125 discrimination of benign versus malignant disease
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343
Table III. CA 125 assay characteristics of 90 patients with benign neoplasms Age (yr) Histology group
Sample size (n)
Median
Benign neoplastic cyst Fibroid Stage II endometriosis Functional cyst Stage III endometriosis Pelvic inflammatory disease Stage I endt;~metriosis Benign nonovarian cyst
59 21 11 10 8 8 2 1
Overall
90*
I
CA 125 assay (Uiml)
I
Range
Median
47.0 46.0 29.0 36.0 43.0 44.0 40.0 54.0
15-88 26-84 19-49 22-50 27-71 38-57 30-50 54.0
14.50 17.54 31.60 25.85 53.79 7.96 9.95 11.77
0.00-2221.60 5.30-58.50 6.20-454.81 3.95-74.58 30.49-102.30 4.16-44.62 7.91-12.00 11.77
44.0
15-88
14.80
0.00-2221.60
Range
*Some patients had more than one type of benign lesion.
Table IV. CA 125 assay characteristics for 68 patients with cancer Age (yr)
I
CA 125 assay (U I ml)
Histology group
Sample size
Median
Serous cystadenocarcinoma Unclassified adenocarcinoma Mucinous cystadenocarcinoma Mixed histologic epithelial adenocarcinoma Nonovarian pelvic malignancy Endometrioid adenocarcinoma Metastatic to ovary Borderline ovarian cancer Endodermal sinus Clear cell cystadenocarcinoma Dysgerminoma of ovary
24 13 12 5
62.0 70.0 58.0 63.0
35-77 47-80 44-79 54-69
445.95 246.09 28.17 413.70
5 4 3 3 1 1 1
71.0 57.5 75.0 74.0 16.0 67.0 71.0
64-96 49-70 63-77 70-77 16 67 71
14.31 540.75 293.40 21.43 3,002.00 9.00 14.31
Overall
68
63.5
16-96
297.30
pelvic malignancies, 3 tumors metastatic to the ovary, 1 dysgerminoma, 1 endodermal sinus tumor, and 59 primary epithelial ovarian carcinomas. Among the 59 primary epithelial cancers, 3 were borderline and 56 frankly malignant. Blood was drawn without anticoagulation. Serum was separated, frozen, and stored at -70° C. TheCA 125 immunoradiometric assay was performed at the Dana Farber Institute without knowledge of clinical data. The kits were provided by Centocor (Malvern, Penn.). The operative reports were subsequently reviewed; staging of cancer and of endometriosis was performed by each investigator and reviewed by one of the authors. Staging of endometriosis was performed according to the Kistner classification.' Results
CA 125 values for the entire study population. CA 125 values for the 90 patients with benign conditions and for the 68 patients with cancer are presented in Tables I to IV. Several differences were noted between the two groups. Those with malignancies were signif-
Median
Range
I
Range
6.80-10,000.00 117.00-1,239.30 12.70-574.00 21.70-4,105.40 7.54-307.30 157.20-671.91 185.05-817.80 12.70-27.10 3,002.00 9.00 14.31 6.80-10,000.00
Table V. 95% Confidence intervals for sensitivity and specificity in patients with cancer (n = 68) Ca 125 assay cutoff value (U/ml)
%
35 50 65 100
78 76 75 74
Sensitivity
I
n
Lower limit(%)
upper limit(%)
53/68 52/68 51168 50/68
66 64 63 62
88 86 85 84
icantly older, were more frequently postmenopausal, and had a higher median value of serum CA 125. Patients with benign pelvic masses had CA 125levels >35 U /ml in 20% of cases but >65 U /ml in only 8%. Patients with pelvic malignancies had CA 125 levels >35 U/ml in 78% of cases and >65 U/ml in 75%. Among the patients with benign lesions, the largest number with CA 125 levels > 35 U I ml had endometriosis in stage II or stage Ill. No patients with stage I endometriosis had levels >35 U /ml, while 4 of 11 with stage II and 7 of
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August 1988 Am J Obstet Gynecol
Table VIII. 95% Confidence intervals for sensitivity and specificity in premenopausal patients with benign neoplasms (n = 56)
Table VI. 95% Confidence intervals for sensitivity and specificity in patients with benign neoplasms (n = 90)
n
Lower limit(%)
Upper limit(%)
Ca 125 assay cutoff value (Uiml)
%
72/90 82/90 83/90 86/90
69 82 85 88
88 96 97 99
35 50 65 100
73 88 89 95
Specificity
CA 125 assay cutoff value (Uiml)
%
35 50 65 100
80 91 92 96
I
Table VII. 95% Confidence intervals for sensitivity and specificity in premenopausal patients with cancer (n = 10) Ca 125 assay cutoff value (Uiml)
Sensitivity
%
35 50 65 100
60 60 60 60
I
n
6/10 6/10
6/10
6/10
Specificity
l
n
41156 49/56 50156
53/56
Lower limit(%)
Upper limit(%)
58 77 78 85
83 95 96 98
Table IX. 95% Confidence intervals for sensitivity and specificity in postmenopausal patients with cancer (n = 58)
Lower limit(%)
Upper limit(%)
Ca 125 assay cutoff value (Uiml)
%
25 25 25 25
88 88 88 88
35 50 65 100
81 79 78 76
8 with stage III had serum levels >35 Ulml. In all21 patients with endometriosis, three had levels > 100 Ulml. Of the patients with fibroids 3 of 21 had levels >35 Ulml and no levels were >65 Ulml. For patients with malignant lesions, elevation of CA 125 levels was seen most frequently with unclassified adenocarcinomas, serous cystadenocarcinomas, endometrioid adenocarcinomas, carcinomas with mixed histologic features, and tumors that were metastatic to the ovary. Values of CA 125 were only occasionally elevated in cases of mucinous neoplasms, with values >35 Ulml in 2 of9 stage I and 3 of 3 stage III cases. One endodermal sinus tumor was associated with a substantial increase in CA 125 to 3002 U lml. No elevation of CA 125 was seen in three borderline tumors, a clear cell cystadenocarcinoma, or a dysgerminoma. No statistically significant correlation was observed between CA 125 values and tumor stage. By stage, 4 of 14 stage I, 6 of 6 stage II, 37 of 37 stage III, and 2 of 3 stage IV lesions were associated with serum levels of CA 125 > 35 U lml, and 3, 6, 35, and 2, respectively by stage, had levels > 100 U I ml. The median levels by stage were: stage I, 21.5 Ulml; stage II, 187.8 Ulml; stage III, 572 Ulml; stage IV, 170.2 Ulml. Our primary objective was to determine whether preoperative CA 125 values could discriminate benign from malignant pelvic masses. The sensitivity (proportion of cancer patients with a positive assay) and specificity (proportion of benign cases with a negative assay) were computed from a range of CA 125 thresholds between 10 and 1000 U I ml. For the study population
Sensitivity
l
n
Lower limit(%)
upper limit(%)
47/58 46/58 45/58 44/58
67 64 63 61
90 88 87 86
composed of 68 cancers and 90 benign neoplasms, the sensitivity and specificity were computed for a range of cutoffs as illustrated in Tables V and VI. The sensitivity remained between 75% and 78% for cutoffs below 100 U I ml, while the specificity was ""91% for cutoffs above 50 U I ml. For a 65-unit cutoff the 95% two-sided confidence intervals were 63% and 85% for sensitivity and 85% and 97% for specificity. The 95% two-sided confidence intervals for the 35, 50, 65, and 100 U I ml unit thresholds are displayed in Tables V and VI. CA 125 values for nonmucinous, frankly malignant epithelial ovarian cancer. In other reports theCA 125 assay has exhibited optimal sensitivity when detecting nonmucinous, frankly malignant primary epithelial ovarian cancers. When a cutoff of 65 U I ml was chosen to discriminate benign from malignant lesions, the exclusion of nonovarian and metastatic lesions did not alter the sensitivity of 75%. If nonepithelial and borderline tumors were also excluded, the sensitivity increased to 80%, and if mucinous tumors were further eliminated, the sensitivity became 91%. Thus an exclusion of borderline, nonovarian, nonepithelial, and mucinous tumors resulted in a 16% increase in apparent sensitivity. CA 125 values for premenopausal and postmenopausal patients. The series included 66 premenopausal and 92 postmenopausal patients. Among the postmenopausal patients a CA 125 value of 65 U I ml discriminated benign from malignant lesions with a specificity of 97% and a sensitivity of 78% (Tables VII and VIII). In premenopausal patients a similar cutoff pro-
Volume 159 Number 2
duced a specificity of 89% and a sensJtlVlty of 60% (Tables IX and X). The prevalence of malignancy in the premenopausal group of 15% (10/66) was significantly less than the 63% (58/92) observed in the postmenopausal group (p < 0.0001, Fisher's exact test). Given a prevalence of 15%, in the premenopausal group the predictive value of a positive test was 49% and that of a negative test was 93%. With a prevalence of 63% in the postmenopausal group, the predictive value of a CA 125 level in excess of 65 U /ml was 98% and the predictive value of a negative assay was 72%. Comment
Our present study confirms and extends an earlier report that CA 125 might prove useful for discriminating benign from malignant pelvic masses.< Values of CA 125 in excess of 65 U I ml distinguished malignant from benign disease with a specificity of 92% and a sensitivity of 75% when both premenopausal and postmenopausal patients were considered together. Greater specificity and sensitivity were observed in postmenopausal subjects where the specificity of the assay was 97% and the sensitivity 78%. Application of theCA 125 assay might differ in premenopausal and postmenopausal patients. Given the substantial prevalence of malignancy in the postmenopausal population, the sensitivity of an assay would have to approach 100% in order to preclude surgical exploration once a palpable adnexal pelvic mass has been detected. However, a test with high specificity used in conjunction with highly suspicious clinical and laboratory findings might prompt appropriate referral of patients who are likely to require cytoreductive operations. Aggressive surgical cytoreduction is thought to be an important initial step in the effective management of epithelial ovarian cancer and is best done as the initial operation, thus allowing prompt adjunctive therapy. Our present data, together with those of Einhorn eta!.,< suggest that postmenopausal patients with a pelvic mass and a CA 125level >65 U /ml should undergo exploration by a surgical oncologist. Nonovarian tumors may also be encountered. Elevations of serum CA 125 levels have been observed with endometrial, fallopian tube, and endocervical adenocarcinomas as well as with nongynecologic neoplasms that can present as a pelvic mass! In premenopausal patients with a pelvic mass, extremely high sensitivity would be required if assay results were to be used to argue against exploration in a patient with a persistent pelvic mass. In the present study, as in previous reports, CA 125 levels have not been frequently elevated in patients with borderline or mucinous neoplasms. Exclusion ofthese cases improves the apparent sensitivity of the assay substantially, but this is oflittle value to the clinician who seeks to remove
CA 125 discrimination of benign versus malignant disease
345
Table X. 95% Confidence intervals for sensitivity and specificity in postmenopausal patients with benign neoplasms (n = 34) Ca 125 assay cutoff value (Uiml)
35
50 65
100
Specificity
% 91
97 97 97
I
n
Lower limit(%)
31/34 33/34 33/34 33/34
91 91 91
75
Upper limit(%)
98
100
100
100
malignant tumors of all grades and histologic features. Several tests that detect mucinous ovarian tumors have been reported, and these might be elevated in combination with CA 125 for identifying mucinous ovarian malignancies. Although borderline tumors express CA 125 in tissue sections, serum CA 125levels are not often elevated. Whether this relates to a lack of antigen secretion, minimal antigen shedding, little tissue necrosis, or effective compartmentalization of antigen remains to be determined. An assay specific for the presence of malignancy might aid the clinician in deciding when to perform exploration in selected premenopausal patients. In the case of CA 125, a specificity of 89% would, however, prompt premature exploration in a substantial number of patients with benign disease. False-positive values have been observed most frequently in patients with benign cysts and severe endometriosis; this is consistent with earlier reports. 6 -9 In other studies elevated CA 125 levels have been associated with menstruation, 10 pelvic inflammatory disease, and adenomyosis." Recent data suggest that use of assays in combination can increase substantially the apparent specificity of CA 125 as an indicator for gynecologic malignancy. Several ovarian tumor-associated antigens have been defined with monoclonal antibodies. Assays have been developed for TAG 72 and CA 15-3. TAG 72 is a carbohydrate determinant associated with a high-molecular-weight glycoprotein recognized by the monoclonal antibody B72.3.' 1- 13 Elevated antigen levels are found in serum from patients with breast, lung, and colo rectal carcinoma as well as ovarian carcinoma. The CA 15-3 assay is a doubledeterminant radioimmunometric assay that utilizes two antibodies directed against different epitopes on a high-molecular-weight glycoprotein 14- 17 that is often associated with breast, lung, and prostate cancers in addition to epithelial ovarian carcinomas. When a panel of sera from patients with ovarian cancer was examined, CA 125 levels were elevated in 82%. Among the CA 125-positive sera either TAG 72 orCA 15-3levels were also elevated in 83%_17 A panel of false-positive CA 125 sera were chosen from 4947 patients with be-
)
346
Malkasian et al.
nign disease who had been thoroughly evaluated at the Mayo Clinic. In this group of sera, TAG 72 or CA 15-3 levels were elevated in only 5% of cases. Use of assays in combination has been applied prospectively to two groups of patients with pelvic masses, and preliminary data indicate that specificity of the CA 125 assay can be significantly improved through the use of the three assays in combination. 18 From the current report, additional tests are advised in the premenopausal population to confirm or rule out ovarian malignancy. REFERENCES 1. Bast RC Jr, Klug TL, St. John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Eng! J Med 1983;309: 883-7. 2. Kabawat SE, Bast RC Jr, Chan AK, Welch WR, Knapp RC, Colvin RB. Tissue distribution of a coelomic epithelium related antigen recognized by the monoclonal antibody OC 125. Int J Gynecol Pathol 1983;2:275-85. 3. Bast RCJr, Knapp RC. The emerging role of monoclonal antibodies in the clinical management of epithelial ovarian carcinoma. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important advances in oncology. Philadelphia: JB Lippincott, 1987:39-53. 4. Einhorn N, Bast RCJr, Knapp RC, Tjernberg B, Zurawski VRJr. Preoperative evaluation of serum CA 125levels in patients with primary epithelial ovarian cancer. Obstet Gynecol 1986;67:414-6. 5. Kistner RW. Endometriosis and infertility. Clin Obstet Gynecol 1979;22:101. 6. Barbieri RL, Niloff JM, Bast RC Jr, Schaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations of CA125 in patients with advanced endometriosis. Fertil Steril 1986;45:630-4. 7. Malkasian GD Jr, Podratz KC, Stanhope CR, Ritts RE Jr, Zurawski VR Jr. CA 125 in gynecologic practice. AM J 0BSTET GYNECOL 1986;155:515-8.
August 1988 Am J Obstet Gynecol
8. Takahashi K, Kijima S, Yoshino K, Shibukawa T, Murao F, Kitao M. Differential diagnosis between uterine myoma and endometriosis using CA 125 as a new tumor marker of ovarian carcinoma. Asia Oceania J Obstet Gynaecol 1986;12:99-103. 9. Shimizu Y, Fujiwara H, Akagaki E, et al. Significance of CA 125 antigen levels in patients with ovarian cancer. Gran Kagaku Ryoho 1986;13:46-52. 10. Pittaway DE, Fayez JA. Serum CA-125 antigen levels increase during menses. AM J 0BSTET GYNECOL 1987; 156:75-6. 11. Colcher D, Horan H, Nuti P, SchlomJ. Differential binding to human mammary and non-mammary tumors of monoclonal antibodies reactive with carcinoembryonic antigens. Cancer Invest 1983; 1:127-38. 12. Johnston WW, Szapk CA, Lottich SC, Thor A, SchlomJ. Use of a monoclonal antibody (B72.3) as an immunocytochemical adjunct to diagnosis of adenocarcinomas in effusions. Cancer Res 1985;45:1894-900. 13. Thor A, Gorstein F, Ohuchi N, Szpak CA,Johnston WW, Schlom J. Tumor-associated glycoprotein (TAG-72) in ovarian carcinomas defined by monoclonal antibody B72.3. JNCI 1986;76:995-1006. 14. Hilkens J, Bulis F, Hilgers J, et al. Monoclonal antibodies against human milk-fat globule membranes detecting differentiation antigens of the mammary gland and its tumor. Int J Cancer 1984;34: 197-206. 15. Sekine H, Hayes DF, Keefe KA, et al. Measurement of DF3 and CA125 antigen levels in sera from patients with epithelial ovarian carcinoma. J Clin Oncol 1985;3:135563. 16. Friedman EL, Hayes DF, Kufe DW. Reactivity of monoclonal antibody DF3 with a high molecular weight antigen expressed in human ovarian carcinomas. Cancer Res 1986;46:5189-94. 17. Bast RC J r, Knauf S, Epenetos A, et al. Coordinate elevation of serum markers in ovarian cancer but not in benign disease. Hybridoma 1987;6:228. 18. Einhorn N, Zurawski VR, Knapp RC, Bast RC Jr. Preoperative elevation of CA 125, CA 72, and CA 15-3 in patients with mucinous epithelial ovarian cancer. Proc Am Assoc Cancer Res 1987;28:357.
Bound volumes available to subscribers Bound volumes of the AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY are available to subscribers (only) for the 1988 issues from the Publisher, at a cost of $54.00 ($77 .00 international) for Vol. 158 (January-June) and Vol. 159 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the JoURNAL name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146-3318, USA; phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular JOURNAL subscription.
antimicrobial agents during pregnancy. Rev Infect Dis 1985;7:287-313. 12. Garite TJ, Keegan KA, Freeman RK, Nageotte MP. A randomized trial of ritodrine tocolysis versus expectant management in patients with premature rupture of membranes at 25 to 30 weeks of gestation. AM J OBSTET GYNECOL 1987; 157:388-93. 13. Morales WJ. The effect of chorioamnionitis on the developmental outcome of preterm infants at one year. Obstet Gynecol 1987;70:183-6.
New cervical catheter for managing PROM
14. Quinn PA, Bauty J, Taylor J, Hannah W. Chorioamnionitis: Its association with pregnancy outcome and microbial infection. AM j 0BSTET GYNECOL 1987;156:37987. 15. Yeast JD, Garite TR. The role of cervical cerclage in the management of preterm premature rupture of the membranes. AM j 0BSTET GYNECOL 1988; 158:106-10.
Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: Discrimination of benign from malignant disease George D. Malkasian, Jr., MD,a Robert C. Knapp, MD," Philip T. Lavin, PhD," Vincent R. Zurawski, Jr., PhD," Karl C. Podratz, MD,a C. Robert Stanhope, MD,a Rodrique Mortel, MD,C Jonathan S. Berek, MD,d Robert C. Bast, Jr., MD; and Roy E. Ritts, MD' Rochester, Minnesota, Boston, Massachusetts, Hershey, Pennsylvania, Los Angeles, California, and Durham, North Carolina CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels >65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels >65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels >65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%. (AM J OssTET GYNECOL 1988;159:341-6.)
Key words: CA I25 levels, benign and malignant ovarian disease, premenopausal, postmenopausal
From the Department of Obstetrics and Gynecology, Mayo Clinic and Mayo Foundation"; Brigham and Women's Hospital, Harvard Medical School, and the Gynecologic Oncology Laboratories, Dana Farber Cancer Institute'; the Hershey Medical Center, Pennsylvania State University'; the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Los Angeles, School of Medicine and Jonsson Comprehensive Cancer Center'-; the Department of Medicine, Duke University Medical Center; and the Department of Immunology, Mayo Clinic and Mayo Foundation/ Received for publication July 6, 1987; revised January 25, 1988; accepted February 19, 1988. Reprint requests: George D. Malkasian, Jr., MD, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905.
In I986, according to the American Cancer Society, approximately I9,000 new cases of ovarian cancer were diagnosed in the United States and II ,3 75 women died of this disease. Less than 25% of ovarian cancers have been diagnosed before spread of tumor cells beyond the ovary-an obvious indictment of our ability to detect the condition in its earliest stages. Even when a palpable pelvic mass has been found, it has been difficult to determine whether the mass was malignant or benign before exploratory laparotomy. Patients often undergo surgical exploration, are 341
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Malkasian et al.
August 1988 Am J Obstet Gynecol
Table II. Characteristics of 68 patients with cancer
Table I. Characteristics of 90 patients with benign neoplasms Age (yr) Median Range Menopausal status Premenopausal Postmenopausal Histologic type (primary and secondary diagnoses) Benign neoplastic cyst Fibroids Functional cysts Pelvic inflammatory disease Stage I endometriosis Stage II endometriosis Stage III endometriosis Benign nonovarian cyst CA 125 assay value Median Range <35.0 U/ml 2:35.0 U/ml 2:65.0 U/ml 2:100.0 U/ml
43.5 15-88 56 34
(62.2%) (37.8%)
59 21 10
(65.6%) (23.3%) (11.1 %) (8.9%) (2.2%) (12.2%) (8.9%) (1.1%)
8
2
11 8
1
14.8 0.0-2221.6 72 18
7
4
(80.0%) (20.0%) (7.8%) (4.4%)
Age (yr) Median Range Menopausal status Premenopausal Postmenopausal Histologic type Serous Adenocarcinoma Mucinous Mixed Non<~varian pelvic malignannes Endometrioid Metastatic to ovary Borderline Clear cell Endodermal sinus Dysgerminoma Stage at initial diagnosis (60 patients) I II
III
IV
found to have widespread carcinoma, and are referred for a second operation at a center that specializes in cytoreductive procedures. Elevation of a reliable serum marker for gynecologic malignancy in conjunction with suspicious history, physical, and laboratory findings might prompt the referral of such patients for a definitive operation at the time of initial exploration, eliminating the morbidity and expense of a second procedure. Recently, an immunoradiometric assay that uses a papillary serous adenocarcinoma cell line has been developed to detect CA 125,' a tumor-associated antigen that is shed into serum or ascites from patients with a variety of malignancies including epithelial ovarian, fallopian tube, endometrial, and endocervical carcinomas? Approximately 80% of patients with advanced epithelial ovarian cancer will have CA 125 values >35 U I ml in serum.' The assay has not been effective in detecting mucinous or borderline neoplasms. Recently, Einhorn et al.,< in a study of 100 women undergoing diagnostic laparotomy because of palpable ovarian masses, noted that all 11 patients with frankly malignant, nonmucinous ovarian carcinoma had CA 125 levels >35 Ulml. Among 14 patients with CA 125 values >65 U I ml and a palpable pelvic mass, 13 had some form of gynecologic malignancy. The authors suggested that these results would allow theCA 125 assay to be used as a diagnostic adjunct for discriminating benign from malignant pelvic masses. Our present study confirms and extends this observation to consider the significance of an elevated serum CA 125 level in premenopausal and postmenopausal patients with pelvic masses.
Grade (47 patients) Well differentiated Moderately differentiated Poorly differentiated CA 125 assay value Median Range <35.0 U/ml 2:35.0 U/ml 2:65.0 U/ml 2:100.0 U/ml
63.5 16-96 10 58
(14.7%) (85.3%)
24 12 10 5 4
(36.8%) (17.6%) (17.6%) (7.4%) (7.4%)
4 3 3 1 1 1
(7.4%) (4.4%) (4.4%) (1.5%) (1.5%) (1.5%)
14 6 37 3
(23.3%) (10.0%) (61.5%) (5.0%)
9 19 19
(19.1%) (40.4%) (40.4%)
297.3 6.8-10,000.0 15 53 51 50
(22.1%) (77.9%) (75.0%) (73.5%)
Material and methods
A total of 172 subjects had blood samples drawn before operation. Among the institutions participating in the study, the Mayo Clinic contributed 100 cases, Brigham and Women's Hospital/Dana Farber Cancer Institute 60, Pennsylvania State University 11, and University of California, Los Angeles, 1. To be eligible for this study the patients must have had a palpable pelvic mass and be scheduled for diagnostic surgery. There was to be no verified ovarian carcinoma before operation. Pathology reports were to document the diagnosis of a pelvic mass after oepration, and the sample for the preoperative CA 125 assay was to be drawn within 1 week before the operation. In the 172 subjects who had blood drawn before operation, eligibility was reviewed and 14 exclusions were made for the following reasons: ovarian cancer verified before surgery, 11 cases; no preoperative blood assay within 1 week before operation, three cases. The remaining 158 cases were eligible for evaluation. The population consisted of 90 subjects with benign neoplasms (Table I) and 68 patients with cancer (Table II). The malignant neoplasms included 4 nonovarian
CA 125 discrimination of benign versus malignant disease
Volume 159 Number 2
343
Table III. CA 125 assay characteristics of 90 patients with benign neoplasms Age (yr) Histology group
Sample size (n)
Median
Benign neoplastic cyst Fibroid Stage II endometriosis Functional cyst Stage III endometriosis Pelvic inflammatory disease Stage I endt;~metriosis Benign nonovarian cyst
59 21 11 10 8 8 2 1
Overall
90*
I
CA 125 assay (Uiml)
I
Range
Median
47.0 46.0 29.0 36.0 43.0 44.0 40.0 54.0
15-88 26-84 19-49 22-50 27-71 38-57 30-50 54.0
14.50 17.54 31.60 25.85 53.79 7.96 9.95 11.77
0.00-2221.60 5.30-58.50 6.20-454.81 3.95-74.58 30.49-102.30 4.16-44.62 7.91-12.00 11.77
44.0
15-88
14.80
0.00-2221.60
Range
*Some patients had more than one type of benign lesion.
Table IV. CA 125 assay characteristics for 68 patients with cancer Age (yr)
I
CA 125 assay (U I ml)
Histology group
Sample size
Median
Serous cystadenocarcinoma Unclassified adenocarcinoma Mucinous cystadenocarcinoma Mixed histologic epithelial adenocarcinoma Nonovarian pelvic malignancy Endometrioid adenocarcinoma Metastatic to ovary Borderline ovarian cancer Endodermal sinus Clear cell cystadenocarcinoma Dysgerminoma of ovary
24 13 12 5
62.0 70.0 58.0 63.0
35-77 47-80 44-79 54-69
445.95 246.09 28.17 413.70
5 4 3 3 1 1 1
71.0 57.5 75.0 74.0 16.0 67.0 71.0
64-96 49-70 63-77 70-77 16 67 71
14.31 540.75 293.40 21.43 3,002.00 9.00 14.31
Overall
68
63.5
16-96
297.30
pelvic malignancies, 3 tumors metastatic to the ovary, 1 dysgerminoma, 1 endodermal sinus tumor, and 59 primary epithelial ovarian carcinomas. Among the 59 primary epithelial cancers, 3 were borderline and 56 frankly malignant. Blood was drawn without anticoagulation. Serum was separated, frozen, and stored at -70° C. TheCA 125 immunoradiometric assay was performed at the Dana Farber Institute without knowledge of clinical data. The kits were provided by Centocor (Malvern, Penn.). The operative reports were subsequently reviewed; staging of cancer and of endometriosis was performed by each investigator and reviewed by one of the authors. Staging of endometriosis was performed according to the Kistner classification.' Results
CA 125 values for the entire study population. CA 125 values for the 90 patients with benign conditions and for the 68 patients with cancer are presented in Tables I to IV. Several differences were noted between the two groups. Those with malignancies were signif-
Median
Range
I
Range
6.80-10,000.00 117.00-1,239.30 12.70-574.00 21.70-4,105.40 7.54-307.30 157.20-671.91 185.05-817.80 12.70-27.10 3,002.00 9.00 14.31 6.80-10,000.00
Table V. 95% Confidence intervals for sensitivity and specificity in patients with cancer (n = 68) Ca 125 assay cutoff value (U/ml)
%
35 50 65 100
78 76 75 74
Sensitivity
I
n
Lower limit(%)
upper limit(%)
53/68 52/68 51168 50/68
66 64 63 62
88 86 85 84
icantly older, were more frequently postmenopausal, and had a higher median value of serum CA 125. Patients with benign pelvic masses had CA 125levels >35 U /ml in 20% of cases but >65 U /ml in only 8%. Patients with pelvic malignancies had CA 125 levels >35 U/ml in 78% of cases and >65 U/ml in 75%. Among the patients with benign lesions, the largest number with CA 125 levels > 35 U I ml had endometriosis in stage II or stage Ill. No patients with stage I endometriosis had levels >35 U /ml, while 4 of 11 with stage II and 7 of
344
Malkasian et al.
August 1988 Am J Obstet Gynecol
Table VIII. 95% Confidence intervals for sensitivity and specificity in premenopausal patients with benign neoplasms (n = 56)
Table VI. 95% Confidence intervals for sensitivity and specificity in patients with benign neoplasms (n = 90)
n
Lower limit(%)
Upper limit(%)
Ca 125 assay cutoff value (Uiml)
%
72/90 82/90 83/90 86/90
69 82 85 88
88 96 97 99
35 50 65 100
73 88 89 95
Specificity
CA 125 assay cutoff value (Uiml)
%
35 50 65 100
80 91 92 96
I
Table VII. 95% Confidence intervals for sensitivity and specificity in premenopausal patients with cancer (n = 10) Ca 125 assay cutoff value (Uiml)
Sensitivity
%
35 50 65 100
60 60 60 60
I
n
6/10 6/10
6/10
6/10
Specificity
l
n
41156 49/56 50156
53/56
Lower limit(%)
Upper limit(%)
58 77 78 85
83 95 96 98
Table IX. 95% Confidence intervals for sensitivity and specificity in postmenopausal patients with cancer (n = 58)
Lower limit(%)
Upper limit(%)
Ca 125 assay cutoff value (Uiml)
%
25 25 25 25
88 88 88 88
35 50 65 100
81 79 78 76
8 with stage III had serum levels >35 Ulml. In all21 patients with endometriosis, three had levels > 100 Ulml. Of the patients with fibroids 3 of 21 had levels >35 Ulml and no levels were >65 Ulml. For patients with malignant lesions, elevation of CA 125 levels was seen most frequently with unclassified adenocarcinomas, serous cystadenocarcinomas, endometrioid adenocarcinomas, carcinomas with mixed histologic features, and tumors that were metastatic to the ovary. Values of CA 125 were only occasionally elevated in cases of mucinous neoplasms, with values >35 Ulml in 2 of9 stage I and 3 of 3 stage III cases. One endodermal sinus tumor was associated with a substantial increase in CA 125 to 3002 U lml. No elevation of CA 125 was seen in three borderline tumors, a clear cell cystadenocarcinoma, or a dysgerminoma. No statistically significant correlation was observed between CA 125 values and tumor stage. By stage, 4 of 14 stage I, 6 of 6 stage II, 37 of 37 stage III, and 2 of 3 stage IV lesions were associated with serum levels of CA 125 > 35 U lml, and 3, 6, 35, and 2, respectively by stage, had levels > 100 U I ml. The median levels by stage were: stage I, 21.5 Ulml; stage II, 187.8 Ulml; stage III, 572 Ulml; stage IV, 170.2 Ulml. Our primary objective was to determine whether preoperative CA 125 values could discriminate benign from malignant pelvic masses. The sensitivity (proportion of cancer patients with a positive assay) and specificity (proportion of benign cases with a negative assay) were computed from a range of CA 125 thresholds between 10 and 1000 U I ml. For the study population
Sensitivity
l
n
Lower limit(%)
upper limit(%)
47/58 46/58 45/58 44/58
67 64 63 61
90 88 87 86
composed of 68 cancers and 90 benign neoplasms, the sensitivity and specificity were computed for a range of cutoffs as illustrated in Tables V and VI. The sensitivity remained between 75% and 78% for cutoffs below 100 U I ml, while the specificity was ""91% for cutoffs above 50 U I ml. For a 65-unit cutoff the 95% two-sided confidence intervals were 63% and 85% for sensitivity and 85% and 97% for specificity. The 95% two-sided confidence intervals for the 35, 50, 65, and 100 U I ml unit thresholds are displayed in Tables V and VI. CA 125 values for nonmucinous, frankly malignant epithelial ovarian cancer. In other reports theCA 125 assay has exhibited optimal sensitivity when detecting nonmucinous, frankly malignant primary epithelial ovarian cancers. When a cutoff of 65 U I ml was chosen to discriminate benign from malignant lesions, the exclusion of nonovarian and metastatic lesions did not alter the sensitivity of 75%. If nonepithelial and borderline tumors were also excluded, the sensitivity increased to 80%, and if mucinous tumors were further eliminated, the sensitivity became 91%. Thus an exclusion of borderline, nonovarian, nonepithelial, and mucinous tumors resulted in a 16% increase in apparent sensitivity. CA 125 values for premenopausal and postmenopausal patients. The series included 66 premenopausal and 92 postmenopausal patients. Among the postmenopausal patients a CA 125 value of 65 U I ml discriminated benign from malignant lesions with a specificity of 97% and a sensitivity of 78% (Tables VII and VIII). In premenopausal patients a similar cutoff pro-
Volume 159 Number 2
duced a specificity of 89% and a sensJtlVlty of 60% (Tables IX and X). The prevalence of malignancy in the premenopausal group of 15% (10/66) was significantly less than the 63% (58/92) observed in the postmenopausal group (p < 0.0001, Fisher's exact test). Given a prevalence of 15%, in the premenopausal group the predictive value of a positive test was 49% and that of a negative test was 93%. With a prevalence of 63% in the postmenopausal group, the predictive value of a CA 125 level in excess of 65 U /ml was 98% and the predictive value of a negative assay was 72%. Comment
Our present study confirms and extends an earlier report that CA 125 might prove useful for discriminating benign from malignant pelvic masses.< Values of CA 125 in excess of 65 U I ml distinguished malignant from benign disease with a specificity of 92% and a sensitivity of 75% when both premenopausal and postmenopausal patients were considered together. Greater specificity and sensitivity were observed in postmenopausal subjects where the specificity of the assay was 97% and the sensitivity 78%. Application of theCA 125 assay might differ in premenopausal and postmenopausal patients. Given the substantial prevalence of malignancy in the postmenopausal population, the sensitivity of an assay would have to approach 100% in order to preclude surgical exploration once a palpable adnexal pelvic mass has been detected. However, a test with high specificity used in conjunction with highly suspicious clinical and laboratory findings might prompt appropriate referral of patients who are likely to require cytoreductive operations. Aggressive surgical cytoreduction is thought to be an important initial step in the effective management of epithelial ovarian cancer and is best done as the initial operation, thus allowing prompt adjunctive therapy. Our present data, together with those of Einhorn eta!.,< suggest that postmenopausal patients with a pelvic mass and a CA 125level >65 U /ml should undergo exploration by a surgical oncologist. Nonovarian tumors may also be encountered. Elevations of serum CA 125 levels have been observed with endometrial, fallopian tube, and endocervical adenocarcinomas as well as with nongynecologic neoplasms that can present as a pelvic mass! In premenopausal patients with a pelvic mass, extremely high sensitivity would be required if assay results were to be used to argue against exploration in a patient with a persistent pelvic mass. In the present study, as in previous reports, CA 125 levels have not been frequently elevated in patients with borderline or mucinous neoplasms. Exclusion ofthese cases improves the apparent sensitivity of the assay substantially, but this is oflittle value to the clinician who seeks to remove
CA 125 discrimination of benign versus malignant disease
345
Table X. 95% Confidence intervals for sensitivity and specificity in postmenopausal patients with benign neoplasms (n = 34) Ca 125 assay cutoff value (Uiml)
35
50 65
100
Specificity
% 91
97 97 97
I
n
Lower limit(%)
31/34 33/34 33/34 33/34
91 91 91
75
Upper limit(%)
98
100
100
100
malignant tumors of all grades and histologic features. Several tests that detect mucinous ovarian tumors have been reported, and these might be elevated in combination with CA 125 for identifying mucinous ovarian malignancies. Although borderline tumors express CA 125 in tissue sections, serum CA 125levels are not often elevated. Whether this relates to a lack of antigen secretion, minimal antigen shedding, little tissue necrosis, or effective compartmentalization of antigen remains to be determined. An assay specific for the presence of malignancy might aid the clinician in deciding when to perform exploration in selected premenopausal patients. In the case of CA 125, a specificity of 89% would, however, prompt premature exploration in a substantial number of patients with benign disease. False-positive values have been observed most frequently in patients with benign cysts and severe endometriosis; this is consistent with earlier reports. 6 -9 In other studies elevated CA 125 levels have been associated with menstruation, 10 pelvic inflammatory disease, and adenomyosis." Recent data suggest that use of assays in combination can increase substantially the apparent specificity of CA 125 as an indicator for gynecologic malignancy. Several ovarian tumor-associated antigens have been defined with monoclonal antibodies. Assays have been developed for TAG 72 and CA 15-3. TAG 72 is a carbohydrate determinant associated with a high-molecular-weight glycoprotein recognized by the monoclonal antibody B72.3.' 1- 13 Elevated antigen levels are found in serum from patients with breast, lung, and colo rectal carcinoma as well as ovarian carcinoma. The CA 15-3 assay is a doubledeterminant radioimmunometric assay that utilizes two antibodies directed against different epitopes on a high-molecular-weight glycoprotein 14- 17 that is often associated with breast, lung, and prostate cancers in addition to epithelial ovarian carcinomas. When a panel of sera from patients with ovarian cancer was examined, CA 125 levels were elevated in 82%. Among the CA 125-positive sera either TAG 72 orCA 15-3levels were also elevated in 83%_17 A panel of false-positive CA 125 sera were chosen from 4947 patients with be-
)
346
Malkasian et al.
nign disease who had been thoroughly evaluated at the Mayo Clinic. In this group of sera, TAG 72 or CA 15-3 levels were elevated in only 5% of cases. Use of assays in combination has been applied prospectively to two groups of patients with pelvic masses, and preliminary data indicate that specificity of the CA 125 assay can be significantly improved through the use of the three assays in combination. 18 From the current report, additional tests are advised in the premenopausal population to confirm or rule out ovarian malignancy. REFERENCES 1. Bast RC Jr, Klug TL, St. John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Eng! J Med 1983;309: 883-7. 2. Kabawat SE, Bast RC Jr, Chan AK, Welch WR, Knapp RC, Colvin RB. Tissue distribution of a coelomic epithelium related antigen recognized by the monoclonal antibody OC 125. Int J Gynecol Pathol 1983;2:275-85. 3. Bast RCJr, Knapp RC. The emerging role of monoclonal antibodies in the clinical management of epithelial ovarian carcinoma. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important advances in oncology. Philadelphia: JB Lippincott, 1987:39-53. 4. Einhorn N, Bast RCJr, Knapp RC, Tjernberg B, Zurawski VRJr. Preoperative evaluation of serum CA 125levels in patients with primary epithelial ovarian cancer. Obstet Gynecol 1986;67:414-6. 5. Kistner RW. Endometriosis and infertility. Clin Obstet Gynecol 1979;22:101. 6. Barbieri RL, Niloff JM, Bast RC Jr, Schaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations of CA125 in patients with advanced endometriosis. Fertil Steril 1986;45:630-4. 7. Malkasian GD Jr, Podratz KC, Stanhope CR, Ritts RE Jr, Zurawski VR Jr. CA 125 in gynecologic practice. AM J 0BSTET GYNECOL 1986;155:515-8.
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8. Takahashi K, Kijima S, Yoshino K, Shibukawa T, Murao F, Kitao M. Differential diagnosis between uterine myoma and endometriosis using CA 125 as a new tumor marker of ovarian carcinoma. Asia Oceania J Obstet Gynaecol 1986;12:99-103. 9. Shimizu Y, Fujiwara H, Akagaki E, et al. Significance of CA 125 antigen levels in patients with ovarian cancer. Gran Kagaku Ryoho 1986;13:46-52. 10. Pittaway DE, Fayez JA. Serum CA-125 antigen levels increase during menses. AM J 0BSTET GYNECOL 1987; 156:75-6. 11. Colcher D, Horan H, Nuti P, SchlomJ. Differential binding to human mammary and non-mammary tumors of monoclonal antibodies reactive with carcinoembryonic antigens. Cancer Invest 1983; 1:127-38. 12. Johnston WW, Szapk CA, Lottich SC, Thor A, SchlomJ. Use of a monoclonal antibody (B72.3) as an immunocytochemical adjunct to diagnosis of adenocarcinomas in effusions. Cancer Res 1985;45:1894-900. 13. Thor A, Gorstein F, Ohuchi N, Szpak CA,Johnston WW, Schlom J. Tumor-associated glycoprotein (TAG-72) in ovarian carcinomas defined by monoclonal antibody B72.3. JNCI 1986;76:995-1006. 14. Hilkens J, Bulis F, Hilgers J, et al. Monoclonal antibodies against human milk-fat globule membranes detecting differentiation antigens of the mammary gland and its tumor. Int J Cancer 1984;34: 197-206. 15. Sekine H, Hayes DF, Keefe KA, et al. Measurement of DF3 and CA125 antigen levels in sera from patients with epithelial ovarian carcinoma. J Clin Oncol 1985;3:135563. 16. Friedman EL, Hayes DF, Kufe DW. Reactivity of monoclonal antibody DF3 with a high molecular weight antigen expressed in human ovarian carcinomas. Cancer Res 1986;46:5189-94. 17. Bast RC J r, Knauf S, Epenetos A, et al. Coordinate elevation of serum markers in ovarian cancer but not in benign disease. Hybridoma 1987;6:228. 18. Einhorn N, Zurawski VR, Knapp RC, Bast RC Jr. Preoperative elevation of CA 125, CA 72, and CA 15-3 in patients with mucinous epithelial ovarian cancer. Proc Am Assoc Cancer Res 1987;28:357.
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