Wednesday, December 6, 2023
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
Nurses - 1.00 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology)
This activity was developed for obstetrician/gynecologist physicians, gynecologic oncologist physicians, obstetrician/gynecologist nurses, and nurse practitioners.
Adnexal masses (pelvic masses of the ovary, fallopian tube, or surrounding tissues) in pre- and postmenopausal women are a common problem and can result in serious health complications if not properly assessed, diagnosed, and treated. An undiagnosed and untreated malignancy, such as ovarian cancer, can have life-ending effects and likely requires aggressive treatment with cytoreductive surgery or comprehensive surgical staging. The goal of the primary evaluation of an adnexal mass is to identify acute conditions, determine if a mass is malignant before surgery, and, if the risk is high for malignancy, to refer the patient to a gynecologic oncologist.
The methods for assessing patients with adnexal masses for risk of malignancy are well defined, yet use and performance vary. While pelvic ultrasound is used in the initial assessment, the test can be impacted by multiple factors. Serum biomarkers and risk algorithms also have utility in determining risk for malignancy before surgery. CA125 is commonly used for the initial risk assessment, but has limited sensitivity, particularly in early-stage disease and in the presence of other conditions. CA125, along with another biomarker for ovarian cancer, human epididymis 4 (HE4), are individually indicated for monitoring response to therapy. CA125 and HE4 are synergistic and are more sensitive and specific when combined with a higher probability of accurately determining risk for malignancy. Guidelines also suggest the added use of biomarker and multimodal algorithms for the initial preoperative malignancy risk assessment.
For optimal outcomes, it is imperative that adnexal masses are properly assessed, diagnosed, and treated, which may include referring the patient to a specialist. Knowing when to refer the patient and determining whether the patient is at low or high risk of malignancy saves valuable time and resources.
This educational article will review clinical recommendations and evidence to assist the clinician in their decision-making with patients with adnexal masses, primarily focusing on ovarian cancer. Clinical recommendations specify that a patient with a high risk of malignancy should be referred to a gynecologic oncologist for better outcomes, while referral to a specialist for a patient at low risk of a malignant mass is unnecessary.
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CME / CE Released: 12/15/2021; Reviewed and Renewed: 5/17/2023
Valid for credit through: 5/17/2024, 11:59 PM EST
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This CME activity was developed to be distributed on Medscape.org
Since the initial release of this program, an additional relevant study has been published. This information has been appended to the end of the activity.
The incidence of a pelvic mass arising in a female is difficult to estimate as many patients are asymptomatic. In the United States, there is a 5%–10% lifetime risk that a woman will undergo surgery for a suspected ovarian neoplasm, resulting in 200,000 to 300,000 women undergoing surgery annually for a pelvic mass.[1,2] Of these women undergoing surgery, 9%–20% will ultimately be diagnosed with a malignancy. The cumulative lifetime risk for developing ovarian cancer is 1 in 78 with 70% of epithelial ovarian cancer (EOC) being diagnosed after the age of 55 years (the median age of onset is 63 years).[3] Contemporary opinions regarding the origin of ovarian cancer suggest that these cancers arise from the fallopian tube and not truly the ovary.[4] For purposes of this paper, the term EOC includes fallopian tube, primary peritoneal, and ovarian cancers. In 2020, approximately 21,750 diagnoses of EOC will occur and an estimated 13,940 women will succumb to this disease.[5] While nonspecific symptoms can occur in early disease, the majority of EOCs (80%) are diagnosed at a late stage as many women only experience symptoms in the presence of widespread metastatic disease. There are currently no effective screening methods for the early detection of EOC.
The key component in the management of a woman with a pelvic mass relates to the proper preoperative assessment for the risk of malignancy; only 1 in 6 women undergoing surgical evaluation of a pelvic mass will be diagnosed with EOC.[2,6] Cytoreductive surgeries and extensive surgical staging are the hallmarks of surgical management for women with EOC.[7-9] Unfortunately, less than half of women with EOC are initially operated on and cared for by gynecologic oncologists in centers that are experienced in the surgical and oncological management of this disease.[6,10-13] Women with an accurate preoperative determination of high risk of malignancy can be referred to a specialty-trained gynecologic oncologist at an appropriate referral center.[14] Multiple studies have demonstrated that women who are operated on by surgeons specializing in, and facilities equipped for, the management of EOC have decreased morbidity and increased overall survival.[12,13,15-17] Thus, an exact method for assessing the likelihood that a pelvic mass is malignant is critical for the efficient triage of women at high risk for malignancy. A successful triage tool allows women at low risk for cancer to remain in their community for treatment with their primary gynecologist and support network.[18]
Pelvic ultrasound (US). US evaluation of pelvic masses can be limited by subjective interpretation of imaging studies. Multiple publications examining the performance parameters of pelvic US to assess malignancy risk report sensitivities of 86%–94%, specificities of 94%–96%, and positive predictive values (PPVs) of 35%–40%.[19-22] The characteristics that are worrisome for malignancy on imaging include cystic solid lesions, multiple thick septations, papillary excrescences, mural nodules, positive doppler flow, and ascites. Researchers have suggested the use of CA125 and US to assist in the diagnosis of complex pelvic masses to stratify the risk of EOC.[23-25] However, the PPV for the diagnosis of ovarian malignancy is low and ranges from 10%–21%, yet the current standard for diagnosing EOC includes US and the measurement of serum CA125.[26]
Review of American College of Obstetricians and Gynecologists (ACOG) Practice Guidelines. ACOG and the Society of Gynecologic Oncology have developed criteria for referring women with an adnexal mass to a gynecologic oncologist. Risk factors include: 1) postmenopausal women with an elevated CA125 or premenopausal women with a very elevated CA125 and/or US findings suggestive of malignancy, ascites, a nodular or fixed pelvic mass, or evidence of abdominal or distant metastasis; 2) premenopausal or postmenopausal women with an elevated score on a formal risk assessment test, such as the Risk of Ovarian Malignancy Algorithm (ROMA), multivariate index assay, Risk of Malignancy Index (RMI), or one of the US-based scoring systems.[20]
CA125. Serum CA125 measurement is the most well studied and commonly used biomarker for the evaluation and monitoring of women with a pelvic mass,[27] yet it is not a good screening tool or an ideal marker for initial risk assessment. In women with advanced stage disease, CA125 is elevated in 80% of cases; however, in early-stage disease, CA125 is only elevated in less than half of cases, resulting in decreased sensitivity.[28-29] The sensitivity of using CA125 to predict EOC in women with a pelvic mass ranges from 43%–81%. Unfortunately, the specificity of CA125 alone is limited by the fact that serum concentrations can be elevated in benign gynecologic conditions (ie, endometriosis, pelvic inflammatory disease, and benign ovarian neoplasms) and other non-gynecologic medical conditions (ie, congestive heart failure, cirrhosis, infections, and inflammatory disorders) and can vary according to menstrual cycle timing and menopausal status.[14, 28-31] This lack of specificity and unreliable PPV explains the use of CA125 as an isolated, predictive test.[32]
Human Epididymis Protein 4 (HE4). It has been documented that HE4, a biomarker with known utility in assessing EOC, is less frequently elevated than CA125 in benign ovarian neoplasms.[33] The biological function of HE4 is unknown, and because it is not falsely elevated in benign conditions, it complements CA125 by improving specificity (Figures 1 and 2).[30,34-35] A 2008 study looked at enhancing the sensitivity and specificity of CA125 by assessing it in combination with other biomarkers. Serum and urine samples from women with adnexal masses were compared to pathology results.[36] Logistic regression models with cross-validation were performed to obtain sensitivities for the markers and combinations thereof. Of the study patients, 233 of 259 were included in the analysis: 67 EOC and 166 benign ovarian neoplasms. HE4 as a single marker and in combination with CA125 had the highest sensitivity, 72.9% (specificity 95%) and 76.4% (specificity 95%), respectively. Therefore, the study demonstrated that CA125 and HE4 complemented each other and performed better than either marker alone.[36] The addition of CA125 to HE4 enables the detection of malignancies in patients with tumors that do not express CA125. Equally important, HE4 has been shown to have greater sensitivity in patients with early-stage disease compared with CA125.[36]
Risk of malignancy index (RMI). The RMI provides a quantitative risk assessment of malignant disease in patients with pelvic masses.[24] Jacobs et al developed the RMI by incorporating menopausal status, US characteristics, and serum CA125 levels to estimate a woman’s risk for EOC.[37] This approach allows the RMI a level of discrimination between benign and malignant disease greater than could be achieved by the individual criteria alone. The RMI is intended to provide a quantitative assessment for the risk of malignancy. Its preoperative use for selecting patients for specialist management would be expected to correctly classify approximately 90% of patients. In validation studies, the reported preoperative sensitivity and specificity of identifying EOC ranged between 71.0%–88.5% and 74.3%–97.0%, respectively.[14,38] To simulate a typical clinical scenario, the RMI was examined in a diverse population, allowing for variations in sonography and differences in CA125 assays, to validate it in a representative setting. When the RMI cut point was >200 for the detection of EOC and low-malignant potential (LMP) tumors in patients with a pelvic mass, the RMI algorithm achieved a sensitivity of 85.4% and a specificity of 96.9%.[37] The use of pelvic US increases user and site variability and involves expertise and equipment complexity, which reduces the reproducibility of the RMI score. Often, pelvic US reports fail to measure or comment on the mass’s architectural features making it difficult, if not impossible, to calculate an RMI score.
Risk of Ovarian Malignancy Algorithm (ROMA). The ROMA score considers only the patient’s menopausal status in combination with serum CA125 and HE4 levels and does not incorporate imaging.[32] Multiple studies have shown the effectiveness of ROMA for assessing the risk of malignancy in women with pelvic masses (Table 1).[39-45]
The ROMA score was developed based on the pivotal 2008 study that examined CA125 and HE4. When combining premenopausal and postmenopausal groups for the detection of invasive EOC alone, the ROMA score achieved a sensitivity of 93.8% at a set specificity of 75%.[18] This algorithm successfully classified women of all ages and menopausal status into high- and low-risk groups with 93.8% of EOC correctly predicted as high-risk. There were no cancers missed when detecting EOC in only the premenopausal patients.
| Title | Study Design | Sample Size | Results | Conclusions |
|---|---|---|---|---|
| Moore RG, et al.[35] | Prospective, Multicenter | 472 | In postmenopausal women, ROMA had a sensitivity of 92.3% and a specificity of 76.0%. In premenopausal women, ROMA had a sensitivity of 100% and specificity of 74.2% for detecting ovarian cancer. When considering all women together, ROMA had a sensitivity of 93.8%, a specificity of 74.9%, and a NPV of 99.0%. | The use of the serum biomarkers CA125 and HE4 with ROMA has a high sensitivity for the prediction of ovarian cancer in women with a pelvic mass. These findings support the use of ROMA as a tool for the triage of women with an adnexal mass to gynecologic oncologists. |
| Moore RG, et al.[36] | Prospective, Multicenter | 457 | ROMA had a sensitivity of 94.3% and RMI had a sensitivity of 84.6% for distinguishing benign from malignant ovarian cells (P = 0.0029). In patients with stage I and II disease, ROMA achieved a sensitivity of 85.3% compared with 64.7% for RMI (P < 0.0001). | The dual marker algorithm utilizing CA125 and HE4 to calculate a ROMA value achieves a significantly higher sensitivity for identifying women with EOC than does RMI. |
| Moore RG, et al.[37] | Prospective, Multicenter | 461 | In detecting ovarian cancer, ICRA had a sensitivity of 85.4%, a specificity of 84.3%, and a NPV of 97.8% in detecting ovarian cancer. Adding ROMA produced significant improvement with a sensitivity of 93.8%, a specificity of 67.2%, and a NPV of 98.8%. Examination of all malignancies (ovarian and non-ovarian) provided a sensitivity of 89.7% for ROMA + ICRA in comparison to 77.9% for ICRA alone. | Adjunctive use of ROMA with clinical assessment improves the stratification of women with a pelvic mass into low and high risk groups for ovarian cancer. The combination is particularly effective in ruling out malignant disease. |
| Grenache DG, et al.[38] | Prospective | 146 | The sensitivity of a MIA and ROMA was 97% and 87%, respectively (P = 0.25). ROMA was more specific (83%) than the MIA (55%) (P < 0.0001). The NPVs for ROMA (98.4%) and the MIA (96.0%) were similar. | A MIA and ROMA have similar performance characteristics, with the MIA having non-significant greater diagnostic sensitivity and ROMA having greater diagnostic specificity. |
| Lokich E, et al.[39] | Retrospective, Single center | 498 | The sensitivity of using ROMA in conjunction with clinical judgment for detecting malignancy was 100% with a specificity of 47.7% and a NPV of 100%. When including LMP tumors the sensitivity was 99.1%. For stage I–IV, ROMA alone had a sensitivity of 95.3%. | ROMA in conjunction with clinical assessment can safely identify women for conservative management. |
| Abdalla N, et al.[40] | Prospective, Single center | 302 | ROMA performed significantly better than CA125 in the differentiation of all malignancies and differentiation of stage I FIGO malignancies from nonmalignant pathologies (P = 0.043 and P = 0.025, respectively). AUC was higher for ROMA and HE4 than CA125 in both pre- and post-menopausal women. | ROMA was more useful than CA125 alone for determining malignant adnexal tumors. |
| Shen F, et al.[41] | Prospective, Multicenter | 684 | With ROMA, the sensitivities and specificities were 85.6% and 81.7% for all patients, 85.7% and 81.5% for premenopausal women, and 85.6% and 83.9% for postmenopausal women, respectively, for pelvic mass malignancy. The AUC of ROMA was significantly better than that of CA125 (P < 0.0001) or HE4 (P = 0.0003) or for all malignant diseases compared to benign. | ROMA is useful in the distinction of ovarian cancers from benign disease, especially in premenopausal women. |
aROMA = Risk of Ovarian Malignancy Algorithm; NPV = negative predictive value; RMI = Risk of Malignancy Index; EOC = epithelial ovarian cancer; ICRA = initial risk assessment; MIA = multivariate index assay; LMP = low malignant potential; FIGO = International Federation of Gynecology and Obstetrics; AUC = area under the curve
In a 2011 national validation trial, ROMA achieved a high sensitivity for the detection of EOC vs benign disease (Table 2).[39] In that same study, all premenopausal women with EOC were accurately classified into the high-risk group providing a sensitivity of 100%. Pre- and postmenopausal women with early-stage EOC were correctly classified into the high-risk group (9 of 12 EOC patients) providing a sensitivity of 75%.[39]
| EOC vs Benign | Premenopausal Women | Early Stages of Malignancy | |
|---|---|---|---|
| ROMA | % (95% CI) | % (95% CI) | % (95% CI) |
| Sensitivity | 92.3 (79.1-98.4) | 100 (66.4-100) | 75 (42.8-94.5) |
| Specificity | 76.0 (68.4-82.6) | 74.2 (68.1-79.7) | 74.9 (70.3-79.2) |
| NPV | 97.4 (92.7-99.5) | 100 (97.9-100) | 99.0 (97.0-99.8) |
aROMA = Risk of Ovarian Malignancy Algorithm; EOC = epithelial ovarian cancer; CI = confidence interval; NPV = negative predictive value
ROMA vs RMI. One study compared the ROMA score to RMI in predicting EOC risk in women with a pelvic mass.[40] All 457 study participants (123 EOCs, 22 LMP tumors, 312 benign disease; 212 premenopausal and 245 postmenopausal) had imaging (ie, US, computed tomography [CT], magnetic resonance imaging [MRI]) and serum CA125 and HE4 determined prior to surgery for the pelvic mass. The ROMA score had a sensitivity of 94.3% compared to RMI sensitivity of 84.6% for distinguishing benign conditions from EOC (P=0.0029) at a set specificity of 75%. The ROMA score outperformed RMI for all stages of EOC patients, and importantly, in patients with stage I and II disease, the ROMA score achieved a sensitivity of 85.3% compared with 64.7% for RMI (P<0.0001).[40] The ROMA score achieved a significantly higher sensitivity for identifying women with EOC than did RMI and outperformed RMI for all stages of EOC. In another direct comparison, ROMA achieved greater sensitivity (94%) than the RMI (75%) at 75% specificity.[6] In a prospective study by Richards et al, investigators found that RMI was inferior to ROMA.[46]
ROMA and Initial Clinical Risk Assessment (ICRA). Adjunctive use of ROMA with ICRA improves the stratification of women with a pelvic mass into low- and high-risk groups for EOC (Figure 3).[41] In a prospective, multi-center study comparing ROMA to ICRA, ICRA had a sensitivity of 85.4% and a negative predictive value (NPV) of 97.8%. By adding ROMA, sensitivity improved to 93.8% with a NPV of 98.8% and allowed for the detection of 13 additional malignancies initially missed by ICRA alone.[41] The inclusion of ROMA as part of the initial workup of women diagnosed with a pelvic mass significantly improved the stratification of women into low- and high-risk groups for malignancy, allowing for effective triage of these patients. ROMA plus ICRA was evaluated in a retrospective cohort study through a prospective tumor board process in women diagnosed with a pelvic mass who had either surgical or conservative management.[43] When combining ROMA and ICRA, the tumor board was able to safely recommend conservative management in 187 (37.4%) women who otherwise would have undergone surgery.[42,43] ROMA achieved a sensitivity of 92.3% in postmenopausal women and 76.5% in premenopausal women, successfully classifying 93.8% of EOC as high-risk; this was a similar sensitivity and specificity of 95% and 65%, respectively, as found in an earlier study.[39] The use of ROMA with ICRA provided a high sensitivity analysis resulting in no invasive EOC being assigned to the low-risk group or missed and, equally important, 37% of the patients were able to avoid the risks associated with an unnecessary surgery.[43]
Comparing the tumor board recommendations using ROMA and ICRA to the performance characteristics of the ICRA reported in the ROMA submission to the US Food and Drug Administration (FDA) shows that the performance characteristics of the 2 trials were similar and validates the previously reported trial that used ROMA to stratify patients into risk groups.[18,26,39,46]
The use of a ROMA score has also been independently validated in multiple multisite trials around the world and aids in the triage of female patients to gynecologic oncologists.[18,31,32,43] For transparency, and to allow for independent validation, the ROMA score was published.
In the original trials, CA125 was measured using the Abbott ARCHITECT platform and HE4 was measured using the Fujirebio enzyme immunoassay platform. Based on the pilot and prior validation trials, for premenopausal patients, a ROMA score of ≥ 13.1% is considered high risk for malignancy, and for postmenopausal patients a ROMA score of ≥ 27.7% is considered high risk for malignancy.[43]
It is important to understand that the ROMA cut points will vary depending on the platforms that are used to measure CA125 and HE4. When a ROMA test is ordered, the CA125 and HE4 levels are reported with the biomarker cut points for that platform along with the low- or high-risk ROMA score based on pre- and postmenopausal status. For clinicians who have CA125 and HE4 values and desire to calculate a ROMA score, a ROMA calculator specific to the FDA-approved method the laboratory is utilizing (ie, Fujirebio, Abbott, Roche) must be used. The University of Rochester Wilmot Cancer Center ROMA application (app) can also be downloaded from the app store by searching for "ROMA Calculator." The advantage of ROMA over other risk-assessment algorithms is that it does not require a specialty laboratory and can be performed in any hospital reference or independent laboratory.
Women with EOC have improved survival rates and outcomes and fewer complications when care is provided by the appropriate specialist in a high-volume healthcare facility. Women who present with an ovarian cyst or pelvic mass clearly benefit when treated by clinicians in institutions that specialize in the care and management of EOC when the risk of malignancy is high. When the risk of malignancy is low, the majority of women benefit from remaining in the care of their gynecologist. The ACOG Practice Bulletin recommends utilizing algorithmic scores to improve the accuracy of referrals. Compared to CA125 and ICRA, the ROMA score provides additional objective results that are more consistent and reproducible between centers and regions. By combining CA125, HE4, and menopausal status, the ROMA score can be used to successfully classify pre- and postmenopausal women into low- and high-risk groups, allowing for more accurate referrals to appropriate providers and centers of care. These findings support the use of an algorithmic score, like ROMA, as a clinical best practice for referring women with an adnexal mass.
Addendum
A cost-analysis comparison with and without ROMA assessment for the management of women with pelvic masses was conducted by Underkofler et al (2022). The objective was to evaluate whether the use of ROMA, alone or in combination with Initial Clinical Risk Assessment (ICRA), would provide a cost benefit when compared to the use of ICRA alone. A health-economic decision model was created, which quantified the clinical and cost differences between three different risk assessment methodologies.
Total healthcare costs were modeled for each methodology using the Medicare 2020 reimbursement rates.
A total of 461 patients with pelvic masses were included in the cost-analysis. From this cohort, 10.4% were diagnosed with EOC. Costs for patients with diagnoses of EOC, low malignant potential tumors, or benign disease using ROMA alone were 3.3% lower than those triaged with ICRA alone. Laboratory costs using ROMA increased by 55%. These increased lab costs were offset by decreases in laparotomy costs (3.1%) and laparoscopy costs (4%) when compared to ICRA. The combination of ROMA and ICRA lowered total healthcare costs by 3.9% when compared to ICRA alone. A 63% reduction in repeat surgeries due to false negative ICRAs was predicted by this health-economic decision model.
They concluded that triage of women with pelvic masses using the ROMA score lowered overall healthcare costs when compared to ICRA alone. The ROMA score resulted in fewer false negative results when compared to ICRA alone. ROMA also improved the rates of initial detection of malignancy and reduced the number of second surgical treatments in these women.[47]
