Adnexal mass: Role of serum biomarkers in diagnosing epithelial carcinoma of the ovary, fallopian tube, or peritoneum

INTRODUCTION — Epithelial ovarian cancer (EOC) is the collective term used to describe primary ovarian malignancies of serous, endometrioid, clear cell, and mucinous histologies. While the pathogenesis and clinical behavior may differ, management strategies are generally similar. The high-grade serous carcinoma histology is shared as well between primary malignancies of the fallopian tube and peritoneum, and thus these two latter malignancies are often grouped collectively with primary epithelial ovarian cancer.

Biologic markers (commonly termed "biomarkers") that are used to aid in the diagnosis of EOC are an active area of investigation, and have been identified in serum, urine, ovarian cyst fluid, ascites, and other body fluids. In this topic review, the term biomarkers will refer specifically to serum biomarkers.

Use of serum biomarkers for the diagnosis of EOC in patients who have an adnexal mass is reviewed here. Related topics are discussed separately, including:

●Screening in asymptomatic patients with no adnexal mass (see "Screening for ovarian cancer")

●Patients with symptoms of EOC but no adnexal mass (see "Early detection of epithelial ovarian cancer: Role of symptom recognition")

●General principles of the evaluation of an adnexal mass (see "Approach to the patient with an adnexal mass" and "Adnexal mass: Ultrasound categorization")

●Diagnosis of EOC (see "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis")

●Treatment of EOC and posttreatment surveillance (see "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging" and "Cancer of the ovary, fallopian tube, and peritoneum: Surgical cytoreduction", section on 'Predicting feasibility of cytoreduction' and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer")

●Nonepithelial ovarian cancer histologies (germ cell tumors, sex cord-stromal tumors) (see "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis" and "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults")

DEFINITIONS — The general definition of a biomarker is any indicator of disease; a tumor maker is a biomarker specific for malignancy.

The United States National Institutes of Health defines a biomarker as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to a therapeutic intervention" [1]. For EOC, this may include abnormal findings on physical examination, imaging studies, or laboratory tests (including serum biomarkers).

BACKGROUND — Serum biomarkers may aid in the diagnosis of EOC by helping to distinguish malignant from benign disease, thus helping to prevent unnecessary surgery and improve rates of early detection. This is particularly important as EOC presents several diagnostic challenges:

●While symptoms of EOC are usually present, they are often nonspecific. (See "Early detection of epithelial ovarian cancer: Role of symptom recognition".)

●It can be difficult to differentiate between benign and malignant adnexal masses on imaging. (See "Approach to the patient with an adnexal mass", section on 'Assessing the risk of malignancy'.)

●Definitive diagnosis of EOC requires histopathologic examination (typically surgical removal of an ovary or fallopian tube or biopsies of the peritoneum). (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Diagnosis'.)

●Most EOCs are diagnosed at a late stage. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Clinical presentation'.)

●EOC is associated with poor prognosis (table 1). (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Prognosis'.)

However, no biomarker can distinguish between the various EOC subtypes (ie, ovarian, fallopian tube, and peritoneal) and no serum biomarker is both highly sensitive and specific for the diagnosis of EOC. Combining serum markers or using multimodality strategies may improve detection of malignancy. (See 'Biomarkers' below and 'Biomarker panels for patients undergoing surgery' below.)

Clinicians use all the available information (eg, patient symptoms, imaging findings, serum biomarker testing, menopausal status, risk factors) to arrive at the degree of clinical suspicion that a mass is malignant and to decide whether the patient should undergo diagnostic surgery or continued surveillance, and whether referral to a gynecologic oncologist is appropriate. This is discussed in detail separately. (See "Approach to the patient with an adnexal mass".)

BIOMARKERS

Cancer antigen 125 — Cancer antigen 125 (CA 125), the most widely used biomarker for EOC, is approved by the US Food and Drug Administration (FDA) for monitoring response to therapy in patients with known EOC. CA 125 is also used off-label for evaluation of an adnexal mass and may be used alone or in combination with other serum biomarkers and/or pelvic ultrasound [2]. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Evaluation after adjuvant chemotherapy' and "Approach to the patient with an adnexal mass", section on 'Role of tumor markers and multimodal tests' and 'Biomarker panels for patients undergoing surgery' below.)

●Gene and protein – The gene for CA 125 is called MUC16 [3]. The CA 125 antigen is a large transmembrane glycoprotein derived from both coelomic (pericardium, pleura, peritoneum) and müllerian (fallopian tube, endometrial, endocervical) epithelia [4,5]. The antigen complex contains two major domains, A and B. A portion of the extracellular domain includes repeat sequences that bind the OC125 and M11 monoclonal antibodies.

●Assays – There are dozens of CA 125 assays in use, and while they each have different test performance, for practical purposes, they are considered clinically equivalent [6-8].

The two assays most used in clinical practice include CA 125 (which reacts with OC125) and CA 125 II (which utilizes both the OC125 and M11 moieties [9]). While CA 125 II may be more specific, there are no data to support the superiority of one test over the other, and both assays are widely accepted [10]. However, clinicians should avoid comparing values from different assays; thus, serial tests should be done with the same assay, which usually means using the same laboratory.

Normal values vary (eg, CA 125: ≤35 units/mL, CA 125 II: <20 units/mL), and absolute cutoffs remain clinically arbitrary, particularly for premenopausal patients. This is discussed in detail below.

●Diagnostic performance and limitations – The diagnostic performance of CA 125 is limited and has a low sensitivity and a low overall specificity. In a meta-analysis including 77 studies assessing the diagnostic performance of CA 125 for preoperative identification of an adnexal mass suspicious for ovarian malignancy, an elevated CA 125 (defined as >35 units/mL) had a sensitivity of 78 percent and a specificity of 78 percent [11]. This may result from one or more of the following:

•CA 125 is not consistently produced by some histologic types of EOC, including mucinous, clear cell, and mixed müllerian ovarian tumors [4,12].

•CA 125 may be affected by disease stage. The diagnostic performance may be lower in early-stage compared with late-stage disease with studies reporting a wide range of sensitivities (stage I: range 25 to 75 percent; stage II: 61 to 96 percent) [13,14].

•CA 125 is associated with many conditions other than EOC (eg, fibroids, endometriosis, functional ovarian cysts), which are common in reproductive-age patients (table 2 and figure 1).

•CA 125 levels also vary with other factors including:

-Premenopausal status – Sensitivity and specificity are particularly low in premenopausal patients. In a meta-analysis including six studies evaluating the performance of CA 125 in patients with an adnexal mass and defining an elevated CA 125 as >35 units/mL, premenopausal compared with postmenopausal patients had lower sensitivities (50 to 74 versus 69 to 87 percent) and specificities (69 to 78 versus 81 to 93 percent) [15].

Based on the poor diagnostic performance of CA 125 in premenopausal patients with an adnexal mass, higher CA 125 thresholds (eg, >200 units/mL) for suspicion of malignancy have been proposed [16]. This is discussed in detail elsewhere. (See "Approach to the patient with an adnexal mass", section on 'When to refer to a gynecologic oncologist'.)

-Higher body mass index (BMI) – Lower CA 125 levels may be seen in patients with obesity (BMI ≥30 kg/m²) [17].

-Prior hysterectomy – Lower CA 125 levels may be seen in patients with prior hysterectomy [17].

-Cigarette smoking – Smoking may affect CA 125 levels. In the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial including over 25,000 females, in those without ovarian cancer, an elevated CA 125 level (defined as ≥35 units/mL) was more likely in patients with a history of cigarette smoking [17]. By contrast, mean CA 125 levels were lower in current smokers.

-Menstruation – CA 125 values vary (though slightly) with the menstrual cycle, with values increasing during menses [18]. While this increase is likely to be clinically insignificant, serial blood for testing should ideally be obtained during the first half of the cycle, or at least at the same time of the cycle, to minimize physiologic fluctuations.

The use of CA 125 for screening for ovarian cancer in asymptomatic patients is reviewed separately. (See "Screening for ovarian cancer", section on 'Cancer antigen 125 (CA 125)'.)

Human epididymis protein 4 — Human epididymis protein 4 (HE4) is approved by the FDA for monitoring of recurrent or progressive disease in patients with EOC [19], and may be particularly useful in detecting disease recurrence in patients with a nonelevated CA 125 levels at time of diagnosis [20].

In patients with EOC, HE4 may also have prognostic implications. In a cohort study with over 300 patients (mean age 62 years) with newly diagnosed EOC undergoing surgical management, a preoperative HE4 >277 pM was associated with increased mortality (adjusted hazard ratio 1.9, 95% CI 1.1-3.3), particularly in patients with serous histology [21].

●Gene and protein – HE4 is an antigen derived from human epididymis protein, a product of the WFDC2 gene that is overexpressed in patients with serous and endometrioid ovarian carcinoma [22,23].

●Assays – The laboratory reference range of HE4 is ≤150 pM; this value represents the upper 95^th percentile for both premenopausal and postmenopausal patients.

●Limitations – Serum HE4 may be affected by pregnancy and age. In the absence of EOC, median HE4 levels have been reported to be lower in pregnant compared with nonpregnant patients and in premenopausal compared with postmenopausal patients [24].

Its use may also be limited when used alongside ultrasound and CA 125. In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) nested cohort study including postmenopausal patients with an adnexal mass, the use of HE4 provided little additional value in diagnosing EOC when used alongside both ultrasound and CA 125 [25].

HE4 is also used for the evaluation of an adnexal mass as a component of the Risk of Malignancy Algorithm (ROMA) and serum Overa tests. (See 'Biomarker panels for patients undergoing surgery' below.)

Carcinoembryonic antigen — Carcinoembryonic antigen (CEA) is a protein normally found in embryonic or fetal tissue. Serum levels disappear almost completely after birth, but small amounts may be present in the colon. In adults, CEA may be elevated in malignancies that produce the protein, particularly mucinous cancers associated with the gastrointestinal tract or ovary.

●Assays – Individual laboratory assays vary slightly, but the typical upper limit of normal for CEA in nonsmokers is 3.8 micrograms per liter (mcg/L). For smokers, the upper limit of normal is 5.5 mcg/L [26].

●Limitations – CEA may also be elevated in patients without EOC and any of the following [27]:

•Malignancy (eg, gastrointestinal [particularly colon], breast, pancreas, thyroid, and lung carcinoma).

•Benign conditions (eg, mucinous cystadenoma of the ovary or appendix, cholecystitis, liver cirrhosis, diverticulitis, inflammatory bowel disease, pancreatitis, pulmonary infections).

•Pseudomyxoma peritonei, whether the cause is of a benign or malignant etiology.

•Cigarette smoking.

The ratio of CA 125 to CEA has diagnostic implications. In a retrospective study including 640 patients undergoing evaluation for a pelvic mass, when CEA levels were >5 ng/mL, 68 percent were found to have nonovarian malignancies. In those with a CA 125/CEA ratio >25, a primary ovarian cancer was found in 82 percent of patients [28].

Cancer antigen 19-9 — Cancer antigen 19-9 (CA 19-9) is a mucin protein that may be elevated in EOC but is used sparingly in ovarian cancer management [29]. More commonly, CA 19-9 is used to monitor disease response to therapy or detect cancer recurrence in patients with a documented gastric cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, or adenocarcinoma of the ampulla of Vater.

Other — Many biomarkers for EOC are under investigation [30]. The following serum markers have been reported to be potentially useful: osteopontin [31,32], mesothelin [33], lysophosphatidic acid (LPA) [34], haptoglobin [35], transthyretin [36], apolipoprotein A1 [36], serum C-reactive protein [37], and OVX1 [38].

BIOMARKER PANELS FOR PATIENTS UNDERGOING SURGERY — OVA1, Overa, and the Risk of Malignancy Algorithm (ROMA) are biomarker panels approved by the US Food and Drug Administration (FDA) to assess the likelihood of malignancy in patients in whom surgery for an adnexal mass is planned [39-41]. Test availability and expense may factor into which test is most appropriate for each clinical situation.

In the absence of data regarding the use of OVA1, Overa, and ROMA in the initial evaluation of an adnexal mass, we do not recommend use of these tests alone to decide whether to proceed with surgical exploration for an adnexal mass. These tests have also not been studied for ovarian cancer screening.

OVA1 — OVA1 (also referred to as the multivariate index assay) is a test that includes five serum biomarkers: two are up-regulated (cancer antigen [CA] 125 II, beta 2 microglobulin) and three down-regulated (transferrin, transthyretin [pre-albumin], apolipoprotein A1) [4,42-45].

OVA1 is performed exclusively through Quest Diagnostics, which is available in over 130 countries worldwide. The proprietary OvaCalc software combines the values for each assay and uses the OVA1 algorithm to generate an ovarian malignancy risk index score. The numeric result varies based on menopausal status, as determined either by clinician report or serum follicle stimulating hormone level. (See "Clinical manifestations and diagnosis of menopause".)

The score ranges from 0 to 10 is interpreted as follows [46]:

●Premenopausal patients:

•Low probability of malignancy: OVA1 <5

•High probability of malignancy: OVA1 ≥5

●Postmenopausal patients:

•Low probability of malignancy: OVA1 <4.4

•High probability of malignancy: OVA1 ≥4.4

In a prospective series including 494 patients scheduled for surgery for an adnexal mass and enrolled by general gynecologists, the sensitivity of OVA1 for EOC, when combined with clinical assessment, was 96 percent; OVA1 correctly predicted ovarian malignancy in 92 percent of patients with early-stage disease and had a negative predictive value of almost 97 percent [47]. Risk of malignancy also increases with rising OVA 1 scores. In an analysis of 1110 patients with an adnexal mass, the likelihood for malignancy was higher for patients with higher OVA scores and those with a high-risk versus low-risk ovarian imaging score [48].

As with many immunoassays, there may be interference if triglyceride levels exceed 4.5 g/L or rheumatoid factor levels ≥250 international units/mL. This information is provided primarily to assist laboratories with assay interpretation only. There is no need to routinely test for these interferents; however, if such levels are known to be elevated, OVA1 should not be ordered.

Overa — Overa (initially known as OVA2) is a second-generation multivariate index assay that utilizes different biomarkers (ie, CA 125 II, human epididymis protein 4 (HE4), apolipoprotein A1, follicle-stimulating hormone, and transferrin) to improve the relatively low specificity of OVA1 [40,49]. While the indications for use are the same as OVA1, because follicle-stimulating hormone is part of the panel, determining menopausal status is not required.

The test result is calculated using the same proprietary software (ie, OvaCalc) as OVA1 (see 'OVA1' above); the score ranges from 0 to 10 and has the following clinical interpretation:

●Low risk of malignancy <5

●High risk of malignancy ≥5

In a prospective series including 493 banked serum patient samples from the OVA500 trial, Overa had a sensitivity and specificity of 91 and 69 percent, respectively; the negative and positive predictive values were 97 and 30 percent, respectively [49]. In addition, when combined with clinician assessment, Overa detected 75 percent of malignancies that were missed by clinician assessment alone. As with OVA1, the combination of imaging and Overa improves the preoperative assessment of an adnexal mass [50]. This is discussed in more detail below. (See 'Comparison of methods' below.)

Risk of Malignancy Algorithm — The Risk of Malignancy Algorithm (ROMA) uses CA 125 and HE4; results are determined by two separate logistic regression algorithms, depending on menopausal status (as determined by clinician report) [51]. The algorithms are not proprietary and may be determined with a calculator, through websites, or on smartphone applications, though none have been validated for use in the United States; ROMA is available internationally.

The score is interpreted as follows:

●Premenopausal patients – High risk of malignancy ≥13.1 percent

●Postmenopausal patients – High risk of malignancy ≥27.7 percent

ROMA was initially validated in a prospective multi-institutional study including 531 patients with a pelvic mass and scheduled for surgery; ROMA correctly classified patients at high risk for EOC in 92 percent of postmenopausal patients and 76 percent of premenopausal patients [51]. To validate this model in a lower risk population, the ROMA investigators performed a second prospective multi-institutional study including 472 patients (ovarian cancer incidence: 10 percent) [52]. In this low-risk cohort, sensitivity and specificity of ROMA in postmenopausal patients were 92 and 76 percent; in premenopausal patients, sensitivity and specificity were 100 and 74 percent, respectively.

In a subsequent meta-analysis including 11 studies evaluating patients with a pelvic mass, the overall sensitivity and specificity of ROMA for EOC were 89 and 83 percent, respectively [53]. For diagnosis of early-stage EOC, the sensitivity and specificity were lower (81 and 76 percent, respectively). Sensitivity and specificity also varied by menopausal status (postmenopausal patients: 93 and 79 percent, respectively; premenopausal patients: 82 percent for both).

Risk of Malignancy Index — The risk of malignancy index (RMI) is a multimodal approach that combines pelvic ultrasound ("U"), menopausal status ("M"), and serum CA 125 into an index score ("I"; I = U x M x CA 125) to predict the risk of ovarian cancer in patients with an adnexal mass [54].

RMI is primarily used in the United Kingdom, and the calculation for RMI is included in the United Kingdom National Institute for Health and Clinical Excellence (NICE) guidelines; all patients with an RMI index score of ≥250 are referred to a specialist [55,56]:

●"U" – The ultrasound result is scored 1 point for each of the following characteristics: multilocular cyst, solid areas, metastases, ascites, and bilateral masses. U = 0 for an ultrasound score of 0 points, U = 1 for an ultrasound score of 1 point, and U = 3 for an ultrasound score of 2 to 5 points.

●"M" – Menopausal status is scored as 1 = premenopausal and 3 = postmenopausal. "Postmenopausal" is defined as no menses for more than one year or a patient over 50 years of age who has had a hysterectomy.

●CA 125 – Serum CA 125 is measured in units/mL.

A number of modifications to the RMI have since been proposed (the versions are referred to as RMI I through IV), which involve assigning different values to each variable [54,57-61]. As an example, in the RMI II, the score for "M" is 1 for premenopausal status and 4 for postmenopausal status, and the "U" score is expressed as 1 or 4. In a systematic review including 109 studies evaluating RMI I through IV, compared with 79 other ovarian cancer prediction scoring systems, RMI I and II (using a cutoff score of 200) had the best diagnostic performance (RMI I: sensitivity 78 and specificity 87 percent; RMI II: sensitivity 79 and specificity 81 percent) [61]. Similar results were reported in a meta-analysis of 66 studies, with the only notable difference being that the specificity of RMI II was 89 percent [15].

An advantage of the RMI system over other serum biomarker tests is that it combines the three most important clinical elements in predicting the malignant risk of an ovarian tumor. Conversely, the challenge for the RMI is that the formula includes the actual CA 125 value (rather than assigning a point value to different ranges of CA 125 levels). This can be problematic in early-stage cancers and in premenopausal patients, in whom the CA 125 level is often misleading.

ADNEX model — The Assessment of Different Neoplasias in the Adnexa (ADNEX) model is unique in that it is intended to predict not only whether an adnexal mass is malignant, but also identify other outcomes: benign, borderline, stage I invasive, stage II to IV invasive, and secondary metastatic adnexal tumors [62]. The results are reported as a percent risk of malignancy.

The ADNEX model combines three clinical and six ultrasound predictors:

●Age

●Serum CA 125

●Type of center (ie, oncology centers [defined as tertiary referral centers with a specific gynecologic oncology unit], other hospitals)

●Ultrasound features:

•Maximum diameter of lesion

•Proportion of solid tissue (maximum diameter of the largest solid component divided by the maximum diameter of the lesion)

•>10 cyst locules

•Number of papillary projections (0, 1, 2, 3, >3)

•Acoustic shadows

•Ascites

The model is available at www.iotagroup.org/adnexmodel/.

The ADNEX model was evaluated in an observational study using clinical and ultrasound data from the International Ovarian Tumour Analysis (IOTA) group (3507 patients; the "development" set) and validated on data from 24 centers in 10 countries (2403 patients; the "validation" set); serum CA 125 was missing in 31 percent of patients, for whom the value was imputed [62]. For patients in the validation set, when a threshold for probability of malignancy was set at 10 percent, the ADNEX model had a sensitivity of 97 percent and specificity of 71 percent. Specificity decreased if a lower malignancy risk threshold was used (eg, for a malignancy risk of 5 percent, specificity was 59 percent).

Area under the receiver operating characteristic curves (AUC) were also calculated for various performance measures; for patients in the validation set, AUC was as follows: discrimination between benign versus malignant tumors (0.94), benign versus borderline (0.85), benign versus stage I ovarian cancer (0.92), benign versus stage II to IV cancer (0.99), benign versus secondary metastatic (0.95), borderline versus stage I cancer (0.75), and stage II to IV versus secondary metastatic (0.82).

The ADNEX model was also compared with the risk of malignancy index and is described below. (See 'Comparison of methods' below.)

While the ability of ADNEX to distinguish between a benign mass versus an early-stage ovarian cancer appears promising, the low specificity may result in unnecessary surgery for benign masses. (See 'Comparison of methods' below.)

COMPARISON OF METHODS — In patients with a pelvic mass suspicious for EOC, the Assessment of Different Neoplasias in the Adnexa (ADNEX) model compared with Risk of Malignancy Algorithm (ROMA) and Risk of Malignancy Index (RMI) appears to have higher sensitivity, but lower specificity, for diagnosing EOC. In a systematic review comparing the accuracy of ADNEX, ROMA, and RMI in both pre- and postmenopausal patients with a suspicious adnexal mass on imaging, the sensitivity was higher for ADNEX (95.5 and 97.6 percent) compared with ROMA (77.4 and 90.3 percent) and RMI (57.2 and 78.4 percent) [63]. Specificity was lower for ADNEX (77.8 and 55 percent) compared with ROMA (84.3 and 81.5 percent) and RMI (92.5 and 85.4 percent). Thus, the choice of test must be individualized and balance the risk of a missed diagnosis with that of unnecessary testing and surgery.

The efficacy of OVA1 compared with CA 125 or Overa, as well as ROMA compared with HE4 or CA 125 are discussed below:

●OVA1

•Versus CA 125 – For patients with an adnexal mass and scheduled for surgical management, OVA1 compared with CA 125 appears to have better sensitivity for diagnosis of EOC [47,64]. In a prospective series including 524 patients scheduled for surgery for an ovarian tumor, OVA1 compared with CA 125 II alone (with thresholds of >200 units/mL for premenopausal patients and >35 units/mL for postmenopausal patients) and clinician assessment (eg, history, physical examination, imaging, CA 125) had a higher sensitivity (93 versus 69 versus 75 percent) but a lower specificity (43 versus 84 versus 79 percent) for the diagnosis of ovarian malignancy [64]. OVA1 compared with CA 125 also had higher sensitivity when the results were stratified by menopausal status and stage, particularly in premenopausal patients.

A subsequent study evaluated the use of OVA1 compared with CA 125 as part of the American College of Obstetricians and Gynecologists (ACOG) referral criteria for detecting ovarian cancer (see "Approach to the patient with an adnexal mass", section on 'When to refer to a gynecologic oncologist'). Use of OVA1 rather than CA 125 was associated with an increase in sensitivity (94 versus 77 percent) but a decrease in specificity (35 versus 68 percent) [65]. For premenopausal patients, use of OVA1 rather than CA 125 increased the sensitivity further (91 versus 58 percent). In a follow-up study evaluating the impact of OVA1 on patient referral, OVA1 did not lead to an increase in the number of patients referred to a gynecologic oncologist, but rather enriched the referred cohort by including 90 percent of the cancers [66].

Based on pooled data from the two prospective studies [47,64], the sensitivity for detecting ovarian malignancy for OVA1 compared with CA 125 was the following: all ovarian malignancies (92 versus 71 percent); stage I (88 versus 57 percent); and premenopausal patients with stage I and II disease (86 versus 36 percent) [67]. OVA1 detected 78 percent of early-stage malignancies that were not detected by CA 125 and 68 percent of those not detected by the ACOG criteria.

•Versus Overa – For patients with an adnexal mass and scheduled for surgical management, Overa compared with OVA1 appears to have better test performance. Since OVA1 and Overa were evaluated using the same data set, performance comparisons between the two tests are valid. In a prospective series including 493 banked serum patient samples from the OVA500 trial, test sensitivity was similar between Overa and OVA1 (91 and 94 percent, respectively), while test specificity was higher for Overa than for OVA1 (69 and 54 percent, respectively) [49]. The negative predictive values for both Overa and OVA1 were 97 percent, while the positive predictive value for Overa was higher than OVA1 (40 versus 31 percent).

Using Overa, the sensitivity for early-stage malignancies (stage I, II) is 86 percent for all subjects and 89 percent for premenopausal patients, similar to OVA1 (91 percent for both) [47,49]. Overa detected 75 percent of malignancies that were missed by clinician assessment alone, compared with 83 percent for OVA1.

●ROMA

•Versus HE4 or CA 125 alone – ROMA appears to have similar diagnostic performance compared with either HE4 or CA 125 alone for the diagnosis of EOC. In a retrospective review of three studies comparing ROMA with HE4 and CA 125, while ROMA was the most sensitive (ROMA: 86 percent; HE4: 80 percent; CA 125: 84 percent) and HE4 was the most specific (ROMA: 84 percent; HE4: 94 percent; CA 125: 78 percent), these differences were not statistically significant [53]. An earlier study including 389 patients also found that the combination of HE4 and CA 125 (ROMA) did not improve the performance over the individual biomarkers alone [68].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian and fallopian tube disease".)

SUMMARY AND RECOMMENDATIONS

●Use of biomarkers – Use of serum biomarkers for the diagnosis of epithelial ovarian cancer (EOC) is an active area of investigation. (See 'Introduction' above.)

•Biomarkers or panels of biomarkers are generally used in combination with each other or with imaging to arrive at the degree of clinical suspicion that an adnexal mass is benign or malignant and whether referral to a gynecologic oncologist is appropriate. (See 'Background' above.)

•No biomarker can distinguish between the various EOC subtypes (ie, ovarian, fallopian tube, and peritoneal) and no serum biomarker is both highly sensitive and specific for the diagnosis of EOC. (See 'Background' above.)

●Serum biomarkers – Several biomarkers are commercially available, including cancer antigen 125 (CA 125), human epididymis protein 4 (HE4), carcinoembryonic antigen (CEA), and cancer antigen 19-9 (CA 19-9). (See 'Biomarkers' above.)

•CA 125 – CA 125 is approved for monitoring response to therapy in patients with known EOC; it is also the most used biomarker for the evaluation of adnexal masses for EOC, although it is not approved for this indication. CA 125 has a low sensitivity, particularly for early-stage ovarian cancer, and low specificity, particularly in premenopausal patients. (See 'Cancer antigen 125' above.)

•HE4 – HE4 is approved for monitoring for recurrent or progressive disease in patients with EOC and may be particularly useful in detecting disease recurrence in patients with a nonelevated CA 125 levels at time of diagnosis. (See 'Human epididymis protein 4' above.)

•CEA – CEA may be elevated in malignancies associated with the gastrointestinal tract or ovary; the ratio of CA 125 to CEA has diagnostic implications with higher levels being associated with primary ovarian malignancies. (See 'Carcinoembryonic antigen' above.)

•CA 19-9 – CA 19-9 may be elevated in EOC but is used sparingly in ovarian cancer management. (See 'Cancer antigen 19-9' above.)

●Biomarker panels – Commercially available biomarker panels, including OVA1, Overa, Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI), and the Assessment of Different Neoplasias in the Adnexa (ADNEX) model are used to assess the likelihood of malignancy in patients in whom surgery for an adnexal mass is planned. These tests should not be used alone to decide whether to proceed with surgical exploration for an adnexal mass. (See 'Biomarker panels for patients undergoing surgery' above.)

•The individual biomarkers used in each panel vary; test availability and expense may factor into which test is most appropriate for each clinical situation. (See 'Biomarker panels for patients undergoing surgery' above.)

•These tests have not been studied for ovarian cancer screening. (See 'Biomarker panels for patients undergoing surgery' above.)

ACKNOWLEDGEMENTS — The UpToDate editorial staff acknowledges Frederick R Ueland, MD, who contributed to earlier versions of this topic review.