Ovarian cancer is the deadliest gynecologic cancer and the fifth leading cause of cancer-related death for women in the United States. It is most frequently diagnosed among women age 55 to 64 years.¹ In 2022, 19,880 new cases of ovarian cancer were diagnosed and 12,810 women died from ovarian cancer.¹ Early detection of ovarian cancer is clinically important as metastasis is common and prognosis is directly dependent on stage at time of diagnosis. When detected at an early stage, the 5-year survival rate is greater than 90%. However, 80% of ovarian cancer cases are detected at an advanced stage when the 5-year relative survival rate is 30%.¹ The majority of patients with undetected ovarian cancer will initially present in a primary care setting. The ability to properly assess the risk for an ovarian malignancy can improve early diagnosis and appropriate referral to a gynecologic oncology specialist, which is paramount to improve survival rates. This article describes assessment and referral considerations for clinicians in a primary care setting when a pelvic or adnexal mass has been detected.

Clinical detection

Clinical detection of ovarian cancer is challenging. Early stages are asymptomatic, and all screening methods have proven to be ineffective. Risk factors have been identified (Table 1).² Yet ovarian cancer can occur in any woman even in the absence of risk factors.

Symptoms in advanced stages are nonspecific and can be generalized to other conditions. No strategy for early detection of ovarian cancer is currently recommended.³ Most women are diagnosed after symptom onset. Clinicians should consider ovarian cancer on a differential diagnosis if signs or symptoms outlined in Table 2 are of new onset and manifest for more than 12 days in a month.^3,4

The presence of a pelvic or adnexal mass identified through physical exam or as an incidental finding on imaging for another reason is of potential concern. Pelvic and adnexal masses are common and statistically likely to be of benign origin, but clinical evaluation is warranted to rule out potential malignancy.³ The initial physical examination should include palpation of cervical, supraclavicular, axillary, and groin lymph nodes; pulmonary auscultation; abdominal palpation and auscultation; pelvic examination with visual inspection of the perineum, cervix, and vagina and bimanual palpation; and a rectovaginal examination if indicated.⁵ The presence of a palpable pelvic mass that is irregular, firm, fixed, nodular, bilateral, or associated with ascites or abdominal distention is concerning for malignancy.⁵ A nutritional status assessment also should be conducted. Clinicians should obtain a comprehensive family cancer history and refer for genetic counseling as indicated.⁶ It is important to note that primary treatment for suspected ovarian malignancy should never be delayed while awaiting genetic counseling.

Transvaginal ultrasound is recommended for initial diagnostic evaluation when a mass is identified on a pelvic exam.³ Characteristics for concern on adnexal imaging are listed in Table 3.⁵ If first-line imaging is indeterminate or indicates concern for metastatic disease, clinicians should use further diagnostic imaging. Contrast-enhanced computed tomography (CT) of the abdomen and pelvis may be helpful in evaluating metastasis, but it is not intended to detect or characterize a mass and should not be used as a front-line modality.⁵ If CT is unavailable, a chest x-ray for women with respiratory symptoms may be helpful for evaluation of the thorax.⁷ In maximal-sourced settings, pelvic magnetic resonance imaging with contrast is recommended when first-line imaging is indeterminate.⁷ Diagnostic laboratory workup includes a complete blood count, a blood chemistry including liver function tests, and serum cancer antigen 125 (CA125) in the postmenopausal patient.⁶ If indicated from nutritional status, serum protein, albumin, and transferrin may be appropriate.⁶

The definitive diagnosis for ovarian cancer occurs through histologic exam, often following surgery. Biopsies are generally avoided due to risk of spillage and seeding of malignant cells.⁸ When high clinician suspicion for a malignant or borderline ovarian tumor occurs, referral to a gynecologic oncology specialist is recommended. Five-year survival rates are highest when initial surgical intervention and staging is performed by an experienced gynecologic oncologist as compared to a general gynecologist.⁹ However, research indicates less than 50% of patients with confirmed ovarian cancer had initial surgical management performed by a gynecologic oncologist. Location can be a barrier to care, especially in areas geographically distant from tertiary academic centers, which account for 73% of gynecologic oncology practice.¹⁰ Other identified barriers to access include under-developed referral networks and insurance-based disparities. A significant number of community health centers are unaffiliated with specialty care centers and at risk for treatment delays when referrals are indicated.¹¹ Medicare Advantage plans do not include access to a gynecologic oncologist as a network adequacy standard, while Medicaid and commercial plans are under no legal requirement to provide in-network access to a gynecologic oncologist.¹¹ The Centers for Disease Control and Prevention (CDC) has identified access to subspecialty care for ovarian cancer as a priority to improve ovarian cancer survival. Recommended mitigation strategies for patient, provider, and system level factors are outlined in the CDCs Toolkit to Increase Receipt of Ovarian Cancer Care from a Gynecologic Oncologist, available online.¹²

Presurgical identification of malignancy remains difficult, especially in lower-sourced settings, with premenopausal women, and in early stages of the disease. Many of the guidelines for care have been based on maximally sourced settings with imaging conducted by experienced ultrasonographers in specialty care centers. This level of experience is not available in all settings. When used in conjunction with imaging, serum biomarkers may assist the primary care clinician with categorizing the mass for risk of malignancy.

CA125

Serum cancer antigen 125 is the most frequently used tumor marker for the early assessment for ovarian malignancy. Despite widespread use, challenges are seen with the reliance on CA125 for early detection. CA125 has a low sensitivity and specificity for the detection of ovarian cancer. Elevated CA125 levels occur in less than 50% of early-stage ovarian cancer and 75% to 80% of advanced-stage ovarian cancer.⁵ CA125 elevation varies widely based on histology. CA125 is overexpressed in serous epithelial ovarian cancer, which accounts for 70% of ovarian malignancies.¹³ However, many other histologic subtypes of ovarian cancer can occur. Some of the less common ovarian cancers, malignant germ cell tumors, malignant sex cord-stromal tumors, clear cell carcinomas, undifferentiated carcinomas, and or mucinous carcinomas rarely exhibit CA125 elevation.^5,13 Menopause has a significant impact on baseline CA125 expression. The levels of CA125 are substantially higher in premenopausal women as compared to postmenopausal women.⁵ Many common benign conditions also elevate CA125, including endometriosis, uterine leiomyomas, pelvic inflammatory disease, systemic lupus erythematosus, inflammatory bowel disease, pregnancy, and use of hormone therapy for menopausal symptom management.^5,9

The reliance on CA125 for early ovarian cancer detection is especially concerning given the ethnic disparities in clinical performance. Emerging evidence indicates that race is the biggest predictor of CA125 levels.¹⁴¹⁸ Several studies indicate that CA125 levels vary based on ethnicity. African American and Asian women display CA125 levels 13% to 24% lower than White women, while women with Jewish ancestries have higher CA125 elevations than other women with the same histologic ovarian cancer type.¹⁴¹⁸ Clinicians should use caution when interpreting CA125 levels to establish oncology referral need, especially if the threshold is not individualized.

HE4

Human epididymis protein (HE4) is another frequently used biomarker for the risk assessment of ovarian malignancy. Unlike CA125, HE4 levels are not affected by pregnancy, menstrual cycle, hormone treatment, or endometriosis.⁹ HE4 levels may be elevated, however, in current smokers or in patients using oral contraceptives. When added to diagnostic workup, HE4 with CA125 outperforms CA125 alone for early-stage detection. The addition of HE4 to prediction algorithms has significantly improved referral patterns, decreasing the number of benign referrals to a gynecologic oncology setting and increasing the number of malignant referrals to specialty care.¹⁹ Similar to CA125, HE4 expression varies based on histology type and increases in HE4 have not been observed in all types of ovarian cancer.¹³ HE4 frequently appears in clinical guidelines but is not as widely recommended as CA125, leading to variable levels of insurance coverage or the need for prior authorization.

Multivariate index assays

One of the challenges of presurgical risk assessment for ovarian cancer is the potential for a number of different biomarker patterns based on histologic subtype. A single biomarker is unlikely to adequately assess the risk for all women suspected of ovarian malignancy. OVA1 was the first FDA-approved multivariate assay of seven biomarkers selected to target all histologic expressions of ovarian cancer: apolipoprotein, beta-2 microglobulin, prealbumin, transferrin, follicle-stimulating hormone, HE4, and CA125. It was developed for the nongynecologic oncologist to predict risk of malignancy and is ideal for use in low-resourced settings and geographically remote areas. This send-out laboratory test uses a proprietary testing kit from a single blood draw, with a turnaround time of 72 hours. It is accepted on many commercial, Medicare, and Medicaid plans.

OVA1 has a high sensitivity for the detection of ovarian cancer (96%) and accuracy with predicting absence of malignancy, with a negative predictive value of 98%.²⁰ It performs well (91.3%) in the assessment of early-stage ovarian cancer compared to CA125 (65.7%) and outperforms CA125 in the detection of ovarian cancer in premenopausal women (46% vs 91%). It also outperforms CA125 and HE4 in detecting ovarian cancer in African American women.²¹ The use of OVA1 has improved referral patterns of the patient with an adnexal mass. Elevated OVA1 scores are more likely to be referred to a gynecologic oncologist, whereas low-risk scores are more likely to have care managed in a general gynecology setting.²²

Two other multivariate assays are now FDA approved. The Centers for Medicare and Medicaid Services website has information on all three tests, including a summary of evidence on prognostic performance.²³

When to refer or retain the patient with an adnexal mass

In general, clinicians should refer all patients with an identified adnexal mass and:
Postmenopausal with CA125 elevation over 30 U/mL, ultrasound suggestive of malignancy, ascites, nodular or fixed pelvic mass, or evidence of metastasis⁵
Premenopausal with CA125 elevation greater than 200 U/mL, ultrasound suggestive of malignancy, ascites, nodular or fixed pelvic mass, or evidence of metastasis⁵
Pre- or postmenopausal with elevated score on the OVA1 multivariate assay formal risk assessment⁵

Referral to a gynecologic oncologist may not be appropriate or necessary in cases with low risk for malignancy.⁵ Expectant management is appropriate when imaging suggests the mass is benign.⁵ No ideal follow-up interval has been recommended for a benign adnexal mass. It may be prudent to conduct short interval imaging in 1 to 3 months as evidence indicates that malignant growth is likely to be identified by 7 months.⁵ After a mass is determined to be stable, interval imaging may occur on an annual basis depending on characteristics of the mass.⁵

Implications for practice

Primary care remains the most likely point of entry for a patient with an undetected ovarian malignancy. Providers should be attentive to any patient reporting abdominal or pelvic pain, bloating or abdominal distension, and gastrointestinal concerns. Women with ovarian cancer experience these symptoms more frequently than the general population. The initial evaluation should include a comprehensive family cancer history, a focused abdominal and pelvic exam, and an assessment of nutritional status. Transvaginal ultrasound is the first-line imaging modality for evaluation of an identified or suspected adnexal mass. The gold standard for diagnosis is a histologic exam by an experienced gynecologic oncologist. The evidence is clear that patients with suspected ovarian cancer who are referred to gynecologic oncology experience better outcomes and improved survivability, but access to subspecialty care remains a barrier and many primary care clinicians serve patients vulnerable to delays in diagnosis and treatment. Telehealth is not an appropriate option for the patient with an adnexal mass who needs expert imaging and specialty surgery for diagnosis, staging, and treatment. The ability to rapidly refine presurgical malignancy risk prediction is paramount to identifying the need for specialty care against expectant local management. Clinicians should use extreme caution, with reliance on CA125 in premenopausal women, women with conditions that elevate the serum levels, and in non-White populations. The Ova1 multivariate assay offers superior risk assessment for ovarian cancer in premenopausal women, in early-stage cancers, and in non-White populations and is an affordable option for determining malignancy risk in settings where access to gynecologic oncology is scarce. The Box provides additional resources for building referral networks, holding crucial conversations with patients, conducting high-risk cancer assessments, and online resources for patients.

Womens Healthcare. 2023;11(3):10-14,31. doi: 10.51256/WHC062310

References

¹ US Department of Health and Human Services, National Institutes of Health. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: ovarian cancer. https://seer.cancer.gov/statfacts/html/ovary.html.

² Centers for Disease Control and Prevention. Division of Cancer Prevention and Control. What are the risk factors for ovarian cancer? August 31, 2022. https://www.cdc.gov/cancer/ovarian/basic_info/risk_factors.htm.

³ American College of Obstetricians and Gynecologists. Committee Opinion no. 716. The role of the obstetriciangynecologist in the early detection of epithelial ovarian cancer in women at average risk. Obstet Gynecol. 2017;130(3):e146-e149.

⁴ American Cancer Society. Ovarian Cancer Early Detection, Diagnosis and Staging. 2018. https://www.cancer.org/content/dam/CRC/PDF/Public/8775.00.pdf.

⁵ American College of Obstetricians and Gynecologists. Practice Bulletin no. 174. Evaluation and management of adnexal masses. Obstet Gynecol. 2016;128(5):e210-e226.

⁶ National Comprehensive Cancer Network (NCCN). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer: NCCN evidence blocks. NCCN Guidelines, 2023. https://www.nccn.org/professionals/physician_gls/pdf/ovarian_blocks.pdf.

⁷ Vanderpuye VD, Clemenceau JRV, Temin S, et al. Assessment of adult women with ovarian masses and treatment of epithelial ovarian cancer: ASCO Resource-Stratified Guideline. JCO Global Oncol, 2021;7:1032-1066.

⁸ May T, Oza A. Conservative management of adnexal masses. Lancet Oncol. 2019;20(3):326-327.

⁹ Vernooij F, Heintz P, Witteveen E, van der Graaf Y. The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review. Gynecol Oncol. 2007;105(3):801-812.

¹⁰ Ricci S, Tergas AI, Long Roche L, et al. Geographic disparities in the distribution of the U.S. gynecologic oncology workforce: a Society of Gynecologic Oncology study. Gynecol Oncol Rep. 2017;22:100-104.

¹¹ Bodurtha Smith AJ, Pena D, Ko E. Insurance-mediated disparities in gynecologic oncology care. Obstet Gynecol, 2022;139(2):305-312.

¹² Centers for Disease Control and Prevention. Toolkit to Increase Receipt of Ovarian Cancer Care from a Gynecologic Oncologist. US Department of Health and Human Services, 2021. https://www.cdc.gov/cancer/ovarian/gynecologic-oncologist/pdf/ovarian-cancer-toolkit-508.pdf.

¹³ Zang R, Siu MKY, Ngan HYS, Chan KKL. Molecular biomarkers for the early detection of ovarian cancer. Int J Mol Sci. 2022;23(19):12041.

¹⁴ Rius M, Fuste P, Ros C, et al. HE4 might be a more useful tumor biomarker to detect malignancy in patients with ovarian endometrioma when malignancy is suspected. J Int Med Res. 2021;49(9):3000605211047701.

¹⁵ Pauler DK, Menon U, McIntosh M, et al. Factors influencing serum CA125II levels in healthy postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2001;10(5):489-493.

¹⁶ Skates SJ, Mai P, Horick NK, et al. Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status. Cancer Prev Res (Phila). 2011;4(9):1401-1408.

¹⁷ Cramer DW, Vitonis AF, Welch WR, et al. Correlates of the preoperative level of CA125 at presentation of ovarian cancer. Gynecol Oncol. 2010;119(3):462-468.

¹⁸ Babic A, Cramer DW, Kelemen LE, et al. Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium. Cancer Causes Control. 2017;28(5):459-468.

¹⁹ Lof P, van de Vrie R, Korse CM, et al. Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital? Gynecol Oncol. 2022;166(2):284-291.

²⁰ Bristow RE, Smith A, Zhang Z, et al. Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay. Gynecol Oncol. 2013;128(2):252-259.

²¹ Dunton C, Bullock RG, Fritsche H. Multivariate index assay is superior to CA125 and HE4 testing in detection of ovarian malignancy in African-American women. Biomark Cancer. 2019;11:1179299X19853785.

²² Dunton CJ, Eskander RN, Bullock RG, Pappas T. Low-risk multivariate index assay scores, physician referral and surgical choices in women with adnexal masses. Curr Med Res Opin. 2020;36(12):2079-2083.

²³ Centers for Medicare and Medicaid Services. Multimarker Serum Tests Related to Ovarian Cancer Testing. https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38371&ver=12&=.

Web resources
^A pathlms.com/npwh/courses/53437

^B cdc.gov/cancer/ovarian/gynecologic-oncologist/pdf/ovarian-cancer-action-plan-v2-508.pdf

^C ascopubs.org/doi/pdf/10.1200/JCO.2017.75.2311

^D nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

^E cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer

Key words: adnexal mass, ovarian cancer, ovarian malignancy, CA125, HE4, OVA1, multivariate assay