CA 19-9 in Evaluation of adnexal mass: retrospective cohort analysis and review of the literature

Abstract

Objective

The aim of this study was to estimate the diagnostic accuracy of serum marker CA 19-9 levels in the triage of adnexal masses.

Methods

This retrospective cohort study was carried out in patients referred to the Gynecology Department at Carmel Medical Center due to adnexal masses. All patients underwent preoperative measurements of serum CA 125 and CA 19-9 and surgery with histopathologically confirmed diagnosis.

Results

Between January 2005 and December 2012, 503 patients with adnexal masses were evaluated with serum tumor markers. Combination of CA 19-9 with CA 125, compared with CA 125 levels alone, suggested a nonsignificant effect on sensitivity (86.9% vs. 88.9%, respectively, p = 0.54) or specificity (79.5% vs. 73.5%, p = 0.1) in differentiating malignant from benign adnexal masses. CA 19-9 was not helpful in detecting mucinous histological types or borderline tumors. Mean CA 19-9 levels were higher in metastatic cases compared with primary ovarian malignancy (488.7 ± 1,457 vs. 46.3 ± 149.8 U/mL, respectively, p = 0.001). In mature cystic teratomas, mean CA 19-9 levels were higher and CA 125 levels were lower than in ovarian carcinoma (p = 0.049 and p = 0.0012, respectively).

Conclusions

The combination of the tumor markers CA 19-9 and CA 125 did not contribute significantly to the detection of malignant adnexal masses compared with CA 125 alone. As our results suggest that higher CA 19-9 levels could be helpful in differentiating metastatic tumors from primary ovarian malignancy; this issue should be investigated in large well-designed prospective cohort trials.

Keywords

Cancer antigen 19-9 Ovarian cancer Ovarian mass Ovarian neoplasm Sensitivity and specificity

Introduction

Adnexal mass is a common gynecological finding, demonstrated in up to 7.8% of premenopausal and 2.5% of postmenopausal women (1, 2), and there is a 5% 10% lifetime risk for women to undergo surgical evaluation for an adnexal mass (3). The main concern of the managing physician is to exclude malignancy. Definitive diagnosis of ovarian cancer requires a histological sample, which is usually obtained by an invasive procedure. However, this approach often results in performance of surgical procedures in women with benign masses. While in postmenopausal women, 30% of complex adnexal masses are malignant (3), in premenopausal women, ovarian cancer is rare. Thus, accurate preoperative assessment of adnexal masses is important for patient counseling, choosing the optimal surgical procedure and avoiding unnecessary invasive procedure.

At present, combination characteristics are used to assess the risk of malignancy in patients presenting with adnexal masses. These include patient's age, menopausal status, gynecological examination, imaging modalities (mainly ultrasonography) and tumor markers. Tumor marker CA 125, a high-molecular-weight mucin protein (MUC16) that is recognized by the OC125 monoclonal antibody, has been the focus of most investigations and is the most extensively used, alone and in combination with other markers. Initial studies showed that serum levels of this antigen were elevated in approximately 80% of women with epithelial ovarian cancer (4). However, subsequent research has demonstrated both lower sensitivity and lower specificity for early-stage cancer detection (5, 6). A meta-analysis of 49 cohort studies and 2 case-control studies found that, at a threshold of 35 U/mL, CA 125 measurements had an overall sensitivity of 78.7% and a specificity of 77.9% (7). Elevated serum CA 125 levels are also associated with a variety of common benign gynecological conditions, including uterine leiomyomas, pelvic inflammatory disease, endometriosis, pregnancy and even menstruation and ovulation, which explains the low specificity, especially in premenopausal women.

Given the suboptimal accuracy of CA 125 alone in evaluation of adnexal mass, other serum tumor markers have been suggested alone and in combination with CA 125 by different investigators (8). Combining CA 125 with other markers has been shown to increase sensitivity by 5%-10%; however, specificity was reduced (8).

CA 19-9 is a monosialoganglioside, with an assay that was been demonstrated to yield high specificity and sensitivity for diagnosis of gastrointestinal adenocarcinomas, especially those of the pancreas (9). Since elevated levels of this biomarker have been reported in ovarian cancer patients, especially in mucinous histological types (10), measurement of CA 19-9 has been proposed to be of some clinical value in combination with CA 125 as a marker for serological monitoring of ovarian cancer (11). Accordingly, in some institutions, CA 19-9 has been incorporated as a tumor marker for evaluation of patients with adnexal masses. However, later studies have shown that CA 19-9 levels were not helpful in differentiating benign from malignant adnexal masses (12-14). Moreover, its levels were shown to be high in several benign ovarian findings, especially mature cystic teratomas (15) and endometriomas (16), and even in nongynecological conditions such as rheumatoid arthritis (17).

None of the national guidelines, including those of the American College of Obstetricians and Gynecologists (ACOG), the Society of Gynecologic Oncologists (SGO) and National Institute for Health and Clinical Excellence (NICE), have included CA 19-9 measurement as an adjunct in the triage of patients with adnexal masses (18, 19). Nevertheless, in many institutions, CA 19-9 is still sparingly used as a preoperative tumor marker in the investigation of a patient with an ovarian mass.

Thus, the objective of this study was to assess the added value of CA 19-9 measurement as a preoperative tumor marker in the evaluation of patients with ovarian masses.

Materials and Methods

Data from all cases referred to the Gynecology Department at Carmel Medical Center with a diagnosis of adnexal mass, between January 2005 and December 2012, were retrospectively obtained from the computerized database of the hospital charts and the pathological registry. All patients underwent a tertiary transvaginal or transabdominal sonography, and only cases with preoperative measurement of serum CA 125 and CA 19-9 levels (drawn as part of regular clinical practice) were included in the study. Oophorectomy, cystectomy or hysterectomy with unilateral or bilateral salpingo-oophorectomy were performed as treatment modality according to age and menopausal status, fertility considerations, physical examination and sonographic findings. Cases were excluded from the study if the final histological type of the adnexal finding was not documented. The reports were reviewed, and the retrieved parameters included patient's age and histological type. The latter was then divided into 6 categories: benign, borderline, primary ovarian malignancy, tumor metastatic to the ovary, granulosa or germ cell tumor.

All serum marker measurements were performed in the Clinical Biochemistry Laboratory of Carmel Medical Center, by electrochemiluminescence immunoassay on a Roche Cobas e analyzer (Roche Diagnostics, Mannheim, Germany). Serum CA 125 of <35 U/mL and CA 19-9 of <37 U/mL were taken as within the normal range. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), and odds ratio were calculated for each tumor marker and for their combination in evaluation of benign vs. malignant adnexal masses. A separate examination of CA 19-9 and CA 125 values was made in borderline tumors, mature cystic teratomas with or without malignant transformation, endometriomas and mucinous findings.

The study was approved by the local institutional review board committee for human subjects. Since data acquisition was performed retrospectively, informed consent from the patients whose samples were used in the study was not obtained.

Statistical Analysis

Data were analyzed using SPSS software (SPSS Inc., Chicago, IL, USA). Continuous variables were presented as means ± SD and were tested by Student's t-test. Categorical data were expressed as numbers and compared using Fisher's exact test and Z-test calculator for 2-population proportions, when appropriate. A p value <0.05 was considered statistically significant for all comparisons.

Results

Five hundred and three women aged 18-88 years, referred to our institution due to adnexal masses, were identified and included in the study. Benign pathology was diagnosed in 268 of the cases (53.3%), 182 of the histology reports (36.2%) were malignant and 17 (3.4%) metastatic, including 13 cases of gastrointestinal origin (none of which were of pancreatic source), 3 cases of metastatic breast carcinoma and 1 case of sarcoma of unknown origin. The remaining cases included 28 (5.6%) borderline tumors, 7 (1.4%) granulosa cell tumors and 1 case of germ cell tumor.

Mean preoperative serum CA 125 and CA 19-9 levels were 306.4 ± 869 U/mL and 55.5 ± 313.5 U/mL, respectively. CA 19-9 levels were elevated above 37 U/mL in 77 cases (15.3%). Using the Spearman rank correlation test, no correlation was found between the 2 markers (data not shown). Table I presents mean tumor marker levels by each pathology outcome.

Table I

CA 125 and CA 19-9 levels according to the pathology outcome

Pathology	No.	CA 125 (U/mL)	Elevated CA 125, No. (%)	CA 19-9 (U/mL)	Elevated CA 19-9, No. (%)
Benign finding	268	41 ± 168.9	55 (20.5)	34.3 ± 157.4	30 (11.2)
Ovarian malignancy	182	769.9 ± 1,309	161 (88.5)	46.3 ± 149.8	35 (19.2)
Metastatic spread	17	103.9 ± 84.9	12 (70.6)	488.7 ± 1,457.3	6 (35.3)
Borderline tumor	28	40.8 ± 46	12 (42.9)	66.9 ± 223.8	5 (17.9)
Granulosa cell tumor	7	12.9 ± 6.6	0	14.8 ± 17.8	1 (14.3)
Germ cell tumor	1	106.6	1 (100)	6.5	0

Values are means ± standard deviations, unless noted otherwise.

Since only 7 cases of granulosa cell tumor and 1 case of germ cell tumor were reported, these cases were omitted from the statistical analysis. In addition, the borderline tumor group was analyzed separately because of its unique nature. In the remaining 467 cases, 268 benign and 199 malignant (primary ovarian and metastatic) cases were demonstrated (Tab. II). Mean CA 125 levels in the malignant group were 730.3 ± 1282.8 U/mL, higher than in the benign group (p<0.0001), while mean CA 19-9 levels did not significantly differ between the malignant (84.4 ± 454.4 U/mL) and benign groups (p = 0.09). Combination of both markers did not exhibit any significant effect on malignancy diagnosis, compared with CA 125 alone. Of note, in the 239 cases with normal CA 125 level, which included 26 malignancies, elevated CA 19-9 was found in 20 cases. Of these, 16 cases were benign and 4 malignant (15.4% sensitivity and 20% PPV for malignancy), with varying pathology (Tab. III). Mean CA 19-9 levels did not differ significantly between the 26 malignant (33.97 ± 89.9 U/mL) and 213 benign (19.95 ± 54.2 U/mL) cases with normal CA 125 levels (p = 0.25).

Table II

Analysis of CA 125 and CA 19-9 levels in malignant vs. benign cases

	CA 125, ≥35 IU/mL	CA 125,<35 IU/mL	CA 19-9, ≥37 IU/mL	CA 19-9, <37 IU/mL	Abnormal CA 125 and/or CA 19-9	Normal markers	p Value^*
Malignant	173	26	41	158	177	22
Benign	55	213	30	238	71	197
Sensitivity	86.9%		20.6%		88.9%		0.54
Specificity	79.5%		88.8%		73.5%		0.10
PPV	75.9%		57.7%		71.4%		0.27
NPV	89.1%		60.1%		90.0%		0.77
RR (95% CI)	6.97 (4.8-10.1)		1.45 (1.2-1.8)		7.1 (4.7-10.6)

PPV = positive predictive value; NPV = negative predictive value; RR = relative risk; CI = confidence interval.

The p value is for combination of both markers vs. CA 125 alone.

Table III

Pathology of malignant cases with abnormal CA 19-9 and normal CA 125 levels

	CA 125 (U/mL)	CA 19-9 (U/mL)
Mucinous tumor, intestinal type, areas of borderline tumor, areas of carcinoma in situ and numerous foci of microinvasion	17.2	37.3
Serous papillary adenocarcinoma of ovary	25	44.9
Squamous cell carcinoma (from mature teratoma)	17	115
Invasive adenocarcinoma of colon	23.9	460

Out of 199 malignant cases, 182 primary ovarian malignant tumors were found and 17 cases of metastatic spread to the ovary (Tab. IV). Significantly higher mean CA 125 and lower mean CA 19-9 levels (Tab. I) were observed in primary ovarian malignant tumors compared with the metastatic group (p = 0.038 and p = 0.001, respectively).

Table IV

Analysis of elevated CA 125 and CA 19-9 incidence in primary ovarian malignant tumors vs. metastatic cases

	CA 125			CA 19-9
	≥35 IU/mL	<35 IU/mL	Sensitivity	≥37 IU/mL	<37 IU/mL	Sensitivity
Primary ovarian tumors	161	21	88.5%	35	147	19.2%
Metastatic tumors	12	5	70.6%	6	11	35.3%
p Value		0.052			0.125

Combined analysis of the 28 borderline tumors with benign cases is presented in Table V. Mean CA 125 and CA 19-9 levels (Tab. I) did not differ between borderline and benign groups (p = 0.99 and p = 0.32, respectively). In the 16 serous and 12 mucinous borderline tumors, elevated CA 19-9 was observed in 3 serous and 2 mucinous histotypes (p = 0.64). No significant differences were found between mean CA 19-9 levels in serous (30.9 ± 60.6 U/mL) vs. mucinous (113.5 ± 337.5 U/mL) borderline tumors (p = 0.34).

Table V

Analysis of elevated CA 125 and CA 19-9 incidence in borderline tumors vs. benign cases

	CA 125 ≥35 IU/mL	CA 125 <35 IU/mL	CA 19-9 ≥37 IU/mL	CA 19-9 <37 IU/mL
Borderline	12	18	5	23
Benign	55	213	30	238
Sensitivity	42.9%		17.9%
Specificity	79.5%		88.8%
PPV	17.9%		14.3%
NPV	92.2%		91.2%
RR (95% CI)	2.3 (1.2-4.5)		1.62 (0.7-3.9)

PPV = positive predictive value; NPV = negative predictive value; RR = relative risk; CI = confidence interval.

Fifty mucinous histotype cases were found overall, including 30 benign mucinous cystadenomas/cystadenofibromas, 12 borderline tumors, 5 cases of primary ovarian mucinous adenocarcinomas and 3 adenocarcinomas of colon. CA 19-9 was elevated in 10 of these cases (20%): 4 benign, 2 borderline tumors, 2 ovarian and 2 metastatic tumors. This proportion was not statistically significant compared with the rest of the cases. Mean CA 19-9 levels in the mucinous group (100.2 ± 273.9 U/mL) did not differ from the rest of the cases (p = 0.33). Also, CA 19-9 levels in the 8 mucinous malignant histotypes (373.26 ± 466.98 U/mL) were not significantly different from the rest of the malignant cases (p = 0.08).

Thirty-three cases of mature cystic teratomas (MCTs) were noted, 9 of which (27.3%) demonstrated elevated CA 19-9 levels – not significant compared with the study group (p = 0.055). Mean MCT CA 19-9 levels (127.8 ± 415.8 U/mL) did not differ from the rest of the study group (p = 0.21), but were significantly higher than in primary ovarian malignant tumors (p = 0.049). Mean CA 125 levels (19.7 ± 26.8 U/mL) in MCT cases were found to be significantly lower than in primary ovarian malignant tumors (p = 0.0012).

The pathological report noted 3 cases of malignant transformation of MCT, with mean CA 19-9 level of 93.3 ± 77.9 U/mL, which was not different from benign MCT CA 19-9 levels (p = 0.89).

In addition, CA 19-9 levels were high in 8 of 23 endometrioma cases (34.7%) – a statistically significant proportion compared with the rest of the cases (p = 0.013). However, mean CA 19-9 levels in this group (47.3 ± 54.5 U/mL) did not differ from the rest of the study group (p = 0.9), or from ovarian malignancy in particular (p = 0.97). Mean CA 125 levels (106.1 ± 124.2 U/mL) in endometriosis were found to be significantly lower than in primary ovarian malignant tumors (p = 0.0012), but higher than in MCTs (p = 0.003).

Finally, 5 cases of extremely high CA 19-9 levels (above 1,000 U/mL) were demonstrated (Tab. VI), with varying pathology. Four of these cases also exhibited increased CA 125 levels, except 1 case of borderline mucinous tumor.

Table VI

Pathology of cases with CA 19-9 levels above 1,000 U/mL

	CA 125 (U/mL)	CA 19-9 (U/mL)
Serous papillary adenocarcinoma of ovary	6,000	1,117
Mucinous cystadenoma, with foci of mucinous borderline tumor	26.6	1,181
Ovarian mucinous adenocarcinoma	176	1,333
Benign mature cystic teratoma	151	2,342
Krukenberg tumor	240	6,076

Discussion and Review of the Literature

CA 19-9 and Malignancy

CA 19-9, a monoclonal antibody reacting with sialylated lacto-N-fucopentaose 11 (20), was originally raised against a human colon carcinoma cell line SW 116 (21). Initial studies showed that at serum concentrations above 37 U/mL, CA 19-9 levels had high specificity (98.5%) and high sensitivity (up to 79%) for patients with gastrointestinal adenocarcinomas, especially those originating from the pancreas (9). When examined immunohistochemically, CA 19-9 has been shown to occur in association with ovarian adenocarcinomas, with mucinous histological types reacting much more frequently than serous (22). In 1983, elevated CA 19-9 was demonstrated in the serum of ovarian cancer patients, and thus was proposed to be of some clinical value in combination with CA 125 as a marker for serological monitoring of ovarian cancer (11). Previous reports have found elevated CA 19-9 levels in 41.7%-48.8% of ovarian cancer patients (10, 23). Gadducci et al evaluated 90 patients with epithelial ovarian cancer and 254 patients with benign ovarian pathology, and showed that combination of serum CA 125 and CA 19-9 had a significantly higher sensitivity (93.2% vs. 81.1%; p = 0.03) and a slightly lowered specificity (78.9% vs. 86.0%; p = 0.46) than CA 125 assay alone in the differential diagnosis of ovarian masses in patients above 50 years of age (24). However, more recent studies have shown that CA 19-9 levels were not statistically significant in the differentiation of benign and malignant of adnexal masses (12-14). A study that evaluated preoperative CA 19-9 in 186 patients who were subsequently surgically treated for adnexal masses, demonstrated sensitivity of 18.4% and specificity of 93% (14). Similar estimations were suggested in our study (sensitivity of 20.6% and specificity of 88.8%).

The usefulness of CA 125 for predicting malignancy of adnexal mass in our study (sensitivity of 86.9%, specificity of 79.5%, PPV of 75.9% and NPV of 89.1%) also approximated the findings reported by other larger studies. Combination of both markers did not exhibit a significant effect on the performance of CA 125 alone. Therefore, in our opinion, and consistent with several previous studies, preoperative CA 19-9 levels have no meaningful value in predicting whether a suspected adnexal finding is benign or malignant.

CA 19-9 and metastases

An interesting finding demonstrated in our analysis was significantly higher mean CA 19-9 levels in metastatic cases compared with the primary ovarian malignancy group. While a few studies have noted increased CA 19-9 levels in nongynecological malignancies metastasizing to the ovaries (25, 26), surprisingly very scarce data are to be found in the professional literature regarding the ability of serum CA 19-9 levels to differentiate between primary and metastatic ovarian tumors. Several studies, using immunohistochemistry, showed that CA 19-9 is not a useful discriminatory parameter in differentiating between primary and metastatic ovarian carcinomas (22, 27, 28). As our results suggest that CA 19-9 serum levels can be helpful in differentiating metastatic from primary ovarian malignancy, this matter should be investigated in larger, prospective studies.

CA 19-9 and borderline ovarian tumors

Borderline ovarian tumors (BOTs) account for 10%-20% of ovarian epithelial tumors (29). BOTs differ from benign findings by an increased mitotic index and the presence of nuclear atypia, but unlike malignant forms, BOTs lack stromal invasion (30). These tumors have a favorable prognosis, with a 10-year survival rate higher than 95% (31). Limited studies have evaluated CA 19-9 levels in BOTs. In 1996, a retrospective study of 101 BOT patients suggested that CA 19-9 has clinical value in screening for BOTs, since its levels were found to be positive in 51.5% of serous tumor cases and 44.7% of mucinous tumors (32). Additional studies reported on elevated CA 19-9 rates in 8%-27% of serous and 30.4%-65% of mucinous BOTs (33, 34). When retrospectively comparing 50 women a BOT and 50 individuals with benign adnexal mass, the sensitivity of CA 19-9 was shown to be 40%, specificity 66%, PPV 54%, NPV 52%, while the risk of malignancy index (35) was more accurate in discriminating between BOTs and benign adnexal masses (36).

Regarding tumor histology, it has been suggested that CA 19-9 levels are higher in mucinous tumors compared with serous (37, 38). In addition, it has been shown that endocervical-like mucinous BOTs exhibit higher CA 19-9 levels vs. intestinal-type tumors (39). In another 50 BOT patients, a significant relation was found between elevated CA 19-9 and cytology positivity, and in serous BOTs between abnormal CA 19-9 and recurrence (40). In addition, since abnormal levels of CA 19-9 were found more frequently in stages IB-IIIC than in stage IA, a prognostic role for this marker has been suggested (41). Finally, as the marker levels tended to normalize after surgical tumor excision, a role of CA 19-9 in the follow-up of patients with a borderline mucinous histology has been proposed (38).

In our study, low sensitivity and PPV of CA 19-9 were demonstrated in differentiating BOTs from benign adnexal masses (17.9% and 14.3%, respectively), with relatively high specificity and NPV (88.8% and 91.2%, respectively). Likewise, no significant differences were found between mean CA 125 and CA 19-9 levels in borderline and benign groups. Finally, CA 19-9 was not found useful in distinguishing between serous and mucinous borderline tumors.

CA 19-9 and mucinous histotypes

Several studies have demonstrated elevated serum CA 19-9 levels in epithelial neoplasms of mucinous type and in benign mucinous ovarian findings (42-44). However, in our study this marker was not found to be useful in distinguishing between mucinous and nonmucinous malignancies, or between overall mucinous histotypes and the rest of the cases. These findings are supported by other studies (13).

CA 19-9 and benign findings

Increased CA 19-9 levels may be misleading in the context of diagnostics. For example, a CA 19-9 level of 2,880 U/mL was reported in 60-year-old woman presenting with ascites, eventually diagnosed with benign ruptured ovarian cyst (45). Significant increases in serum CA 19-9 were reported following torsion of ovarian adenofibroma (46), in benign mucinous ovarian cystadenoma (3,170 U/mL) (44) and in a case of appendiceal mucocele mimicking an adnexal complex mass (47).

In our study we found 5 cases with CA 19-9 levels above 1,000 U/mL, including 1 MCT, 1 borderline tumor, 1 metastatic tumor and 2 ovarian adenocarcinoma cases – serous and mucinous. Highest values were demonstrated in Krukenberg tumor (6,076 U/mL), and in MCT (2,342 U/mL), implying that even extremely high CA 19-9 levels are not enough to rule out a benign diagnosis.

CA 19-9 and MCTs

MCTs are common benign neoplasms, accounting for 10%-20% of all ovarian tumors (48). CA 19-9 has been immunohistochemically demonstrated in the bronchial mucosa and glands of MCT, and was shown to be secreted into the cystic cavity of the lesion (49). Several studies have noted that serum CA 19-9 levels have the highest positivity rate in ovarian MCTs, compared with other tumor markers including CA 125, CA 15-3, carcinoembryogenic antigen, alpha-fetoprotein and sialyl Tn antigen (15, 50-52). Several studies found increased CA 19-9 levels in 37.4%-39.6% of MCT cases (15, 50, 51, 53), with up to 78% in 1 prospective trial (54). CA 19-9 levels showed significant correlations with tumor size (50-52, 55), presence of adhesions (55) or fat component (56) and were significantly higher in cases of bilaterally occurring MCTs (15, 52). A recent retrospective study of 322 women by Cho et al aimed to determine whether CA 19-9 is a useful marker in discrimination of MCT from ovarian carcinomas (56). They showed that the incidence of CA 19-9 elevation was not different between the 2 groups, but the mean value of CA 19-9 was higher in those with ovarian malignancy. Futagami et al examined whether CA 19-9 can predict malignant transformation in MCTs (57). This retrospective analysis of 2 cases of MCT with malignant transformation and 76 cases of benign MCT showed that CA 19-9 can be elevated in both malignant and benign cases, while serum squamous cell carcinoma level may serve as indicator of malignancy.

In our study we found increased levels of CA 19-9 in 27.3% of MCT cases, with mean levels not differing from the rest of the cases or from the 3 cases of MCTs with malignant transformation. When comparing marker measurements in MCTs vs. primary ovarian malignant cases, the former yielded significantly higher levels of CA 19-9 and lower levels of CA 125. Hence, as was already suggested in the study by Cho et al (56), when an adnexal mass is demonstrated by ultrasound, and serum CA 19-9 is elevated, lower CA 125 levels can support a diagnosis of an MCT.

CA 19-9 and endometriosis

Several cases of endometriosis with extremely elevated CA 19-9 levels were reported (up to 7,604 IU/mL) (34, 35). One study even proposed CA 19-9 as a useful marker for determining the severity of endometriosis (36). Comparing 101 women with endometriosis and 22 without endometriosis, this retrospective work showed that mean serum CA 19-9 levels in patients at all stages of endometriosis were significantly higher than those in patients without endometriosis – elevated in 38.9% of cases – and that serum CA 19-9 levels significantly correlated with the Revised American Fertility Society classification scores.

In the 23 cases of endometriomas found in our study, the incidence of elevated CA 19-9 was 34.7%, comparable with previous reports. This percentage was significantly higher compared with the rest of the cases (p = 0.013), but the mean levels of this marker did not differ either from the rest of the cases in general or from the primary ovarian tumor group in particular. The finding that CA 19-9 can be significantly elevated in benign ovarian findings, such as endometriomas and MCTs, further supports the fact that elevated CA 19-9 has limited value in pointing out malignant tumors.

In summary, the combination of CA 19-9 with CA 125 did not exhibit clinical significance in distinguishing between benign and malignant adnexal masses compared to CA 125 alone. Likewise, CA 19-9 measurement was not useful in distinguishing mucinous findings or borderline tumors, or in distinguishing between MCTs and teratomas with malignant transformation. As our results imply that CA 19-9 levels could be helpful in differentiating metastatic tumors from primary ovarian malignancy, this subject should be further investigated in large well-designed prospective cohort trials.

Footnotes

Financial support: No grants or funding have been received for this study.

Conflict of interest: None of the authors have any conflicts of interest to declare.

References

Borgfeldt

Andolf

Transvaginal sonographic ovarian findings in a random sample of women 25-40 years old. Ultrasound Obstet Gynecol 1999;13(5):345–350

Castillo

Alcázar

Jurado

Natural history of sonographically detected simple unilocular adnexal cysts in asymptomatic postmenopausal women. Gynecol Oncol 2004;92(3):965–969

National Institutes of Health Consensus Development Conference Statement. Ovarian cancer: screening, treatment, and follow-up Gynecol Oncol 1994;553 Pt 2:S4–7S14

Bast

Jr Klug

St John

A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 1983;309(15):883–887

Jacobs

Bast

Jr The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod 1989;4(1):1–12

Woolas

Jacobs

Elevation of multiple serum markers in patients with stage I ovarian cancer. J Natl Cancer Inst 1993;85(21):1748–1751

Dodge

Covens

Lacchetti

Gynecology Cancer Disease Site Group Management of a suspicious adnexal mass: a clinical practice guideline. Curr Oncol 2012;19(4):e244–e257

Bast

Jr Badgwell

New tumor markers: CA 125 and beyond. Int J Gynecol Cancer 2005;15Suppl 3:274–281

Del Villano

Brennan

Brock

Radioimmunometric assay for a monoclonal antibody-defined tumor marker, CA 19-9. Clin Chem 1983;29(3):549–552

10.

Yabushita

Sawaguchi

Hieda

Clinical usefulness of sialyl SSEA-1 antigen as tumor marker for ovarian cancer as compared with CA 125, CA 19-9, TPA, IAP, CEA and ferritin. Nihon Sanka Fujinka Gakkai Zasshi 1989;41(2):217–224 PubMed

11.

Canney

Wilkinson

James

Moore

CA 19-9 as a marker for ovarian cancer: alone and in comparison with CA 125. Br J Cancer 1985;52(1):131–133

12.

Gramellini

Rutolo

Verrotti

Piantelli

Fieni

Vadora

[Sonographic characterization, Doppler ultrasonography and tumor markers in the diagnosis of malignancy of ovarian masses] [article in Italian]. Minerva Ginecol 2001;53(1):1–11

13.

Kelly

Archbold

Price

Cardwell

McCluggage

Serum CA 19.9 levels are commonly elevated in primary ovarian mucinous tumours but cannot be used to predict the histological subtype. J Clin Pathol 2010;63(2):169–173

14.

Bozkurt

Yumru

Aral

Evaluation of the importance of the serum levels of CA-125, CA 15-3, CA-19-9, carcinoembryonic antigen and alpha fetoprotein for distinguishing benign and malignant adnexal masses and contribution of different test combinations to diagnostic accuracy. Eur J Gynaecol Oncol 2013; 34(6):540–544

15.

Dede

Gungor

Yenen

Alanbay

Duru

Hasimi

CA 19-9 may have clinical significance in mature cystic teratomas of the ovary. Int J Gynecol Cancer 2006;16(1):189–193.

16.

Harada

Kubota

Aso

Usefulness of CA 19-9 versus CA 125 for the diagnosis of endometriosis. Fertil Steril 2002;78(4):733–739

17.

Bergamaschi

Morato

Bazzo

Tumor markers are elevated in patients with rheumatoid arthritis and do not indicate presence of cancer. Int J Rheum Dis 2012;15(2):179–182.

18.

American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Committee opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer Obstet Gynecol 2011;117(3):742–746

19.

Redman

Duffy

Bromham

Francis

Guideline Development Group Recognition and initial management of ovarian cancer: summary of NICE guidance. BMJ 2011;342(1):d2073

20.

Magnani

Nilsson

Brockhaus

A monoclonal antibody-defined antigen associated with gastrointestinal cancer is a ganglioside containing sialylated lacto-N-fucopentaose II. J Biol Chem 1982;257(23):14365–14369

21.

Koprowski

Steplewski

Mitchell

Herlyn

Fuhrer

Colorectal carcinoma antigens detected by hybridoma antibodies. Somatic Cell Genet 1979;5(6):957–971

22.

Charpin

Bhan

Zurawski

Jr Scully RE. Carcinoembryonic antigen (CEA) and carbohydrate determinant 19-9 (CA 19-9) localization in 121 primary and metastatic ovarian tumors: an immunohistochemical study with the use of monoclonal antibodies. Int J Gynecol Pathol 1982;1(3):231–245.

23.

Kataoka

Yakushiji

[A study of localizations and serum data; four tumor markers (CA 125, CA 19-9, CEA and TPA) in ovarian cancers] [article in Japanese]. Nihon Gan Chiryo Gakkai Shi 1990;25(1):47–54 PubMed

24.

Gadducci

Ferdeghini

Prontera

The concomitant determination of different tumor markers in patients with epithelial ovarian cancer and benign ovarian masses: relevance for differential diagnosis. Gynecol Oncol 1992;44(2):147–154

25.

Turan

Aykan

Koc

Analysis of metastatic ovarian tumors from extragenital primary sites. Tumori 2006;92(6):491–495

26.

Saito

Koide

Miyagawa

Pseudo-Meigs syndrome caused by sigmoid colon cancer metastasis to the ovary. Am J Surg 2012;203(1):e1–e3

27.

Lagendijk

Mullink

Van Diest

Meijer

Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry: differential diagnosis between colonic and ovarian carcinomas as primary sites. Hum Pathol 1998;29(5):491–497

28.

Raspollini

Amunni

Villanucci

Baroni

Taddei

Utility of CDX-2 in distinguishing between primary and secondary (intestinal) mucinous ovarian carcinoma: an immunohistochemical comparison of 43 cases. Appl Immunohistochem Mol Morphol 2004;12(2):127–131

29.

Bostwick

Tazelaar

Ballon

Hendrickson

Kempson

Ovarian epithelial tumors of borderline malignancy: a clinical and pathologic study of 109 cases. Cancer 1986;58(9):2052–2065

30.

Prat

Serous borderline tumors of the ovary. Adv Clin Path 1997;1(2):97–102.

31.

Zanetta

Rota

Chiari

Bonazzi

Bratina

Mangioni

Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study. J Clin Oncol 2001;19(10):2658–2664.

32.

Tamakoshi

Kikkawa

Shibata

Clinical value of CA 125, CA 19-9, CEA, CA 72-4, and TPA in borderline ovarian tumor. Gynecol Oncol 1996;62(1):67–72

33.

Benito

Lubrano

Arencibia

Serous and mucinous borderline ovarian tumors: are there real differences between these two entities?

Eur J Obstet Gynecol Reprod Biol 2010;153(2):188–192

34.

Gotlieb

Soriano

Achiron

CA 125 measurement and ultrasonography in borderline tumors of the ovary. Am J Obstet Gynecol 2000;183(3):541–546

35.

Jacobs

Oram

Fairbanks

Turner

Frost

Grudzinskas

A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol 1990;97(10):922–929

36.

Alanbay

Akturk

Coksuer

Comparison of risk of malignancy index (RMI), CA 125, CA 19-9, ultrasound score, and menopausal status in borderline ovarian tumor. Gynecol Endocrinol 2012;28(6):478–482.

37.

Saygili

Uslu

Erten

Doğan

Borderline ovarian tumours: retrospective analysis of twenty-one cases. Eur J Gynaecol Oncol 1998;19(2):182–185

38.

Messalli

Grauso

Balbi

Napolitano

Seguino

Torella

Borderline ovarian tumors: features and controversial aspects. Eur J Obstet Gynecol Reprod Biol 2013;167(1):86–89

39.

Song

Choi

Lee

Endocervical-like versus intestinal-type mucinous borderline ovarian tumors: a large retrospective series focusing on the clinicopathologic characteristics. Gynecol Obstet Invest 2013;76(4):241–247

40.

Alanbay

Aktürk

Coksuer

Comparison of tumor markers and clinicopathological features in serous and mucinous borderline ovarian tumors. Eur J Gynaecol Oncol 2012;33(1):25–30

41.

Nomelini

da Silva

Tavares Murta

Murta

Parameters of blood count and tumor markers in patients with borderline ovarian tumors: a retrospective analysis and relation to staging. ISRN Oncol 2012;2012:947831.

42.

Dong

Cui

[Clinical value of serum CA 19-9, CA 125 and CP2 in mucinous ovarian tumor: a retrospective study of 273 patients] [article in Chinese]. Zhonghua Fu Chan Ke Za Zhi 2008;43(1):5–8

43.

Gadducci

Cosio

Carpi

Nicolini

Genazzani

Serum tumor markers in the management of ovarian, endometrial and cervical cancer. Biomed Pharmacother 2004;58(1):24–38.

44.

Ito

Komatsu

Takagi

Extremely high levels of CA 19-9 and CA 125 antigen in benign mucinous ovarian cystadenoma. Gynecol Oncol 1994;52(2):267–271

45.

Brain

Brown

Suvarna

Chapman

Markedly elevated CA 19-9 associated with benign ovarian cyst and ascites. BMJ Case Rep 2009;2009.

46.

Fujiwara

Moriya

Mikami

Significant increases in serum CA 125 and CA 19-9 following torsion from an adenofibroma of the ovary: a case report. Jpn J Clin Oncol 1994;24(2):116–119

47.

Scaffa

Di Bella

Tartaglia

Rotondi

Lup

Messalli

Surgical approach to appendiceal mucocele mimicking an adnexal complex mass: case report. Eur J Gynaecol Oncol 2007;28(6):503–505

48.

Ayhan

Bukulmez

Genc

Karamursel

Ayhan

Mature cystic teratomas of the ovary: case series from one institution over 34 years. Eur J Obstet Gynecol Reprod Biol 2000;88(2):153–157

49.

Ito

CA 19-9 in mature cystic teratoma. Tohoku J Exp Med 1994;172(2):133–138

50.

Emin

Tayfun

Cantekin

Ozlem

Umit

Leyla

Tumor markers in mature cystic teratomas of the ovary. Arch Gynecol Obstet 2009;279(2):145–147

51.

Var

Tonguc

Ugur

Altinbas

Tokmak

Tumor markers panel and tumor size of ovarian dermoid tumors in reproductive age. Bratisl Lek Listy 2012;113(2):95–98.

52.

Kataoka

Watanabe

Hoshiai

Retrospective evaluation of tumor markers in ovarian mature cystic teratoma and ovarian endometrioma. J Obstet Gynaecol Res 2012;38(8):1071–1076

53.

Frimer

Seagle

Chudnoff

Goldberg

Shahabi

Role of elevated cancer antigen 19-9 in women with mature cystic teratoma. Reprod Sci 2014;21(10):1307–1311

54.

Târcoveanu

Vasilescu

Georgescu

Laparoscopic approach to ovarian dermoid cysts. Chirurgia (Bucur) 2012; 107(4):461–468

55.

Ugur

Ozturk

Balat

Dikensoy

Teke

Aydin

Do high levels of CA 19-9 in women with mature cystic teratomas of the ovary warrant further evaluation?

Eur J Gynaecol Oncol 2012;33(2):207–210

56.

Cho

Kim

Jeon

Kim

CA 19-9 elevation in ovarian mature cystic teratoma: discrimination from ovarian cancer - CA 19-9 level in teratoma. Med Sci Monit 2013; 19:230–235

57.

Futagami

Yokoyama

Mizukami

Shigeto

Mizunuma

Can malignant transformation in mature cystic teratoma be preoperatively predicted?

Eur J Gynaecol Oncol 2012;33(6) 662–665