Ovarian Cancer

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the U.S. and the fifth most common cause of cancer mortality in U.S. women. Useful biomarkers include cancer antigen 125 (CA 125) and human epididymis protein 4 (HE4).

Key Points

Tumor Markers

Markers used in pelvic masses – CA 125 and HE4

Biology

  • CA 125 – glycoprotein antigen expressed in tissue derived from coelomic epithelial cells (ovary, fallopian tube, peritoneum, pericardium, colorectal, kidney, stomach)
    • Frequency of elevation correlates with clinically detected stage of cancer, tumor burden, and type of tumor
  • HE4 – secreted protein expressed in most epithelial ovarian tumors
    • Marker of relapse
    • Improves specificity of CA 125 if used in conjunction

Uses

  • Tumor markers in ovarian cancer and pelvic masses
  • In general, the combination of CA 125 and HE4 provides the highest sensitivity and specificity
Ovarian Cancer

Screening

  • The U.S. Preventive Services Task Force (USPSTF) and the American Academy of Family Physicians (AAFP) recommend against screening asymptomatic women for ovarian cancer (USPSTF, 2018; Choosing Wisely, 2018)
  • In patients with high-risk factors, CA 125 may be used in conjunction with transvaginal ultrasound and bimanual pelvic examination

Diagnosis

  • Most ovarian tumors are epithelial and secrete CA 125 and HE4
    • These markers do not increase early enough to be useful for detecting early stage ovarian cancer (National Comprehensive Cancer Network [NCCN], 2018)
    • In small number of tumors, markers are not expressed
  • Increased survival rates are associated with optimal surgical debulking in initial tumor surgery
    • Best performed at earlier stages
  • Tumor marker panels (American College of Obstetricians and Gynecologists [ACOG], 2017)
    • Insufficient data to recommend for or against use for evaluation of ovarian cancer
  • Recommendations for CA 125 assessment (ACOG, 2017)
    • Cutoffs for referral for ovarian cancer evaluation have poor sensitivity and specificity
    • Mathematical models using rates of change have better positive predictive value
    • Neither cutoffs nor serial CA 125 assessment found to reduce ovarian cancer mortality

Monitoring

  • Markers are useful in monitoring therapy and monitoring for recurrence if CA 125 and/or HE4 level is initially elevated
  • Increasing levels accurately predict relapse
Pelvic Mass

Premenopausal

  • Cannot use markers to differentiate benign from malignant mass
    • False elevations of CA 125 occur in many benign gynecologic diseases (eg, endometriosis)
    • HE4 is more specific – its use alone or in combination with CA 125 is not recommended to rule out malignancy
  • Risk of Ovarian Malignancy Algorithm (ROMA) is useful for assessment of cancer risk in adnexal mass, particularly epithelial cell ovarian cancer
    • Combines CA 125 and HE4, together with menopausal status, to classify patients with adnexal mass into high- or low-risk epithelial ovarian cancer group
    • Can be used to triage patients for appropriate referral
    • Should not be used without an independent clinical radiological evaluation – not intended to be a screening test or to determine whether a patient should proceed to surgery
    • HE4 in combination with CA 125 appears more sensitive than CA 125 alone
  • OVA1 Plus is an alternative to ROMA for preoperative risk stratification for patients with an adnexal mass
    • Combines CA 125, Apo A1, Beta-2 microglobulin, transferrin, and prealbumin into a proprietary multivariate index assay
    • Can be used to triage patients for appropriate referral
    • Should not be used without an independent clinical radiologic evaluation
    • Published studies so far indicate that OVA1 Plus has a slightly lower positive predictive value, and slightly higher negative predictive value, versus ROMA.

Postmenopausal

  • CA 125 and HE4 are useful in differential diagnosis of pelvic mass
  • Decreased false-positive rate if both tests are performed
  • CA 125 >65 U/mL is highly suggestive of malignancy
  • ROMA – see Premenopausal section above
  • OVA1 Plus – see Premenopausal section above

Diagnosis

Indications for Testing

  • Increase in abdominal size or bloating
  • Pelvic or abdominal pain
  • Early satiety
  • Adnexal mass on imaging or bimanual exam

Laboratory Testing

  • Epithelial cell tumors
    • Beta-hCG (β-hCG) – consider this test in premenopausal females to rule out pregnancy
    • CA 125
      • Not recommended as a single initial diagnostic test (although results >65 U/mL are highly suggestive of malignancy)
      • Recommended differential diagnosis of suspicious pelvic mass in postmenopausal females
    • HE4 – combining with CA 125 decreases false positives
    • Inhibin – complements CA 125
      • Best performance in mucinous subtype
    • Other markers currently available are not generally as useful
  • Granulosa-theca cell tumors
    • CA 125 – frequently normal (not useful if normal)
    • Inhibin – A and B (B usually higher than A)
    • Estradiol – often elevated
  • Germ cell tumors
    • CA 125 – not useful (usually normal)
    • β-hCG – elevated
    • Alpha fetoprotein (AFP) – elevated
    • Neuron-specific enolase (NSE) – elevated
    • Lactate dehydrogenase (LDH) – elevated

Histology

  • Surgical biopsy to determine if ovarian mass is malignant (with planned surgical debulking if malignant)
    • Avoid percutaneous biopsy – can cause tumor spillage into the pelvis
    • All tumors require histologic confirmation for diagnosis
  • Immunohistochemistry
    • Epithelial
      • Serous
        • High-grade serous carcinoma (HGSC)
          • (+) p53, Wilms tumor (WT-1), p16, estrogen receptor (ER)
        • Low-grade serous carcinoma (LGSC)
          • (+) WT-1, ER
        • (+) SALL4, PAX8
      • Mucinous
        • (+) CK 7, CK 20 (weak, focal), CDX2 (weak, focal), PAX8, SMAD4, DPC4 (testing for DPC4 not offered at ARUP Laboratories)
        • (-) ER, WT-1 (not diffusely positive), beta-catenin-1 (β-catenin-1), p16
      • Endometrioid
        • (+) ER, progesterone receptor (PR) (nuclear), β-catenin-1, vimentin, CK 7, PAX8
        • (+) p53 in some high-grade endometrioid – most lack p53, p16
        • (-) WT-1 (not diffusely positive), calretinin, inhibin, CK 20, carcinoembryonic antigen (CEA) (monoclonal or polyclonal)
      • Clear cell
        • (+) HNF1-beta (HNF1β), β-catenin-1, PAX8
        • (-) ER, WT-1 – typically lack p53 unless high grade
      • Transitional cell
        • (+) WT-1, ER, p53
        • (-) p53 – typically lack p53 unless high grade
    • Granulosa/Sertoli – (+) inhibin, WT-1, calretinin
    • Germ cell – (+) CA 125, inhibin, AFP, β-hCG
  • Molecular testing based on histology
    • HGSC – BRCA1 or BRCA2 gene mutations common
    • LGSC – BRAF or KRAS gene mutations
    • Mucinous – KRAS gene mutations common
    • Endometrioid – CTNNB1 and PTEN gene mutations common
    • Clear cell – lacks BRCA1 or BRCA2 gene mutations
    • Transitional cell
      • If lacking Brenner component – BRCA1 or BRCA2 gene mutations common
    • Granulosa cell – FOXL2 gene mutations (test not offered at ARUP Laboratories)

Imaging Studies

  • Ultrasound
    • Transvaginal sonography (TVS) followed by computed tomography (CT)/magnetic resonance imaging (MRI) if suspicious TVS findings

Prognosis

  • p53 overexpression
    • Correlates with poor survival, propensity for recurrence, and distant recurrence
  • RAS dysregulation in serous subtype
    • Associated with poor prognosis in patients with incomplete response to platinum-based therapy
  • β-catenin-1 dysregulation in serous subtype
    • Associated with poor prognosis in patients with incomplete response to platinum-based therapy
  • EGFR overexpression
    • Associated with platinum resistance and poor prognosis
  • HER2 expression – in only 10% of patients
    • Correlates with poor survival
  • MMP-9 overexpression
    • Associated with poor prognosis
  • SALL4 overexpression
    • Associated with poor prognosis
  • PD-L1 overexpression
    • Associated with poor prognosis

Differential Diagnosis

Screening

  • Routine screening in general population is not currently recommended by the USPSTF (2018) or ACOG (2017)
  • Trials of screening
  • Screening for specific syndromes
    • BRCA – ovarian cancer risk >50%
      • If patient chooses not to undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy, begin screening at age 30
        • See NCCN Genetic/Familial High-Risk Assessment (Breast and Ovarian Cancer) 2018 guidelines
        • Concurrent TVS and CA 125 – every 6 months
          • TVS – preferably day 1-10 of menstrual cycle in premenopausal women
          • CA 125 – preferably after day 5 of menstrual cycle in premenopausal women
    • Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) – ovarian cancer risk 10%
      • TVS – beginning at 30-35 years (for endometrial cancer screening)
      • CA 125 – unproven efficacy due to inadequate trials
  • Hereditary breast and ovarian cancer (HBOC) genetic testing recommendations, based on personal and family history (NCCN, 2018)
    • Indications for testing in individuals with any of the following (NCCN, 2018)
      • Breast cancer or high-grade prostate cancer diagnosed at any age and Ashkenazi Jewish ancestry
      • Breast cancer diagnosed by 50 years
      • Triple-negative breast cancer diagnosed by 60 years
      • Two breast cancer primaries diagnosed at any age
      • Breast cancer diagnosed at any age and one or more close blood relatives with breast cancer diagnosed by 50 years, invasive ovarian cancer, male breast cancer, pancreatic cancer, or high-grade or metastatic prostate cancer
      • Breast cancer diagnosed at any age and two or more close blood relatives with breast cancer at any age
      • Ovarian cancer, pancreatic cancer, or metastatic prostate cancer diagnosis at any age
  • Indications for testing in asymptomatic patient with either of the following
    • One or more first- or second-degree relatives with breast cancer diagnosed by 45 years, ovarian cancer, male breast cancer, pancreatic cancer, metastatic prostate cancer, two or more breast cancer primaries in the same family member, or two or more family members with breast cancer primaries on the same side of the family with at least one diagnosed by 50 years
    • Personal and/or family history on the same side of the family with three or more diagnoses of
      • Breast cancer, sarcoma, adrenocortical carcinoma, brain tumor, leukemia
      • Colon cancer, endometrial cancer, thyroid cancer, kidney cancer, dermatologic manifestations, macrocephaly, hamartomatous polyps of gastrointestinal tract
      • Lobular breast cancer, diffuse gastric cancer
      • Breast cancer, gastrointestinal cancer or hamartomatous polyps, ovarian sex chord tumors, pancreatic cancer, testicular sertoli cell tumors, or childhood skin pigmentation
    • Perform targeted mutation testing in women with
      • Known pathogenic or likely pathogenic variant in a cancer susceptibility gene within the family
      • Known pathogenic or likely pathogenic variant in a cancer susceptibility gene found on tumor testing

Monitoring

  • Epithelial
    • CA 125
      • Assess patient response to chemotherapy, detect early relapse, and predict prognosis
        • Absolute serum value of CA 125 before third cycle of chemotherapy – most important factor for predicting progression at 12 months
      • Suggested monitoring – every 2-4 months for the first 2 years
        • Persistent postoperative elevation suggests poor prognosis
    • HE4
      • Relatively new marker in ovarian cancer monitoring
      • Useful because not all patients with ovarian cancer have elevated CA 125 levels
      • May be complementary when used with CA 125 for monitoring
      • ≥25% change is considered significant
    • Inhibin – most useful in monitoring of mucinous subtype tumors
    • Other emerging markers, such as osteopontin, show promise but cannot be recommended
  • Stromal tumors (including granulosa, granulosa-theca, and Sertoli-Leydig tumors)
    • Inhibin levels – increased levels parallel tumor recurrence
  • Germ cell
    • AFP, β-hCG, LDH
      • Expect decrease after surgery
      • Increasing levels may signal recurrence

Background

Epidemiology

  • Incidence
    • Ovarian cancer – estimated 22,240 new cases and >14,000 deaths annually in the U.S. (NCCN, 2018)
      • Epithelial subtype – ~90% of malignant tumors (NCCN, 2018)
    • Incidence increases with age
      • 50-54 years – 20.4/100,000
      • 65-69 years – 38/100,000
      • 75-80 years – 48/100,000
  • Age – median is 63 years
    • 90% of women with ovarian cancer are >40 years
  • Sex

Familial Genetics

  • BRCA1 and BRCA2 testing is recommended for all patients with history of ovarian cancer (NCCN, 2018)
  • TP53 gene mutations (Li-Fraumeni syndrome)
    • Present in ~50-80% of ovarian carcinomas
    • Correlate with high grade and advanced state
    • High-grade serous carcinomas are the most common tumors in this group
 

Risk Factors

  • Increased risk associated with
    • Family history of breast or ovarian cancer (hereditary breast or ovarian cancer)
      • Associated with BRCA1, BRCA2, and Lynch Syndrome II
        • Higher probability of BRCA1 and BRCA2 gene mutations in Ashkenazi Jews
        • 10-15% of ovarian cancers are caused by BRCA1 or BRCA2 mutations
    • Nulliparity
    • Older age at first birth (≥35 years)
    • Early menarche
    • Hormone therapy
    • Pelvic inflammatory disease (PID), in vitro stimulation may increase risk
  • Decreased risk (30-60%) associated with
    • Oral contraceptive use
    • Pregnancy and first birth at young age (≤25 years)
    • Multiparity
    • Lactation (>18 months)
    • History of tubal ligation/hysterectomy
    • Early menopause/late menarche

Pathophysiology

  • Malignant transformation of Müllerian epithelium on ovarian surface or Müllerian inclusion cysts in ovarian cortex
    • Some high-grade serous carcinomas likely represent spread from a primary tumor arising in distal fallopian tube
  • Often spreads early to contiguous peritoneal mesothelium
    • Spread follows flow of peritoneal fluid
  • Types
    • Epithelial
    • Stromal
    • Germ cell
    • Metastases
    • Miscellaneous

Clinical Presentation

  • Epithelial cell tumors
    • Symptoms – usually nonspecific; most patients present with stage III or IV disease
    • Abdominal symptoms
      • Abdominal fullness
      • Dyspepsia
      • Early satiety
      • Bloating
      • Pelvic pain
    • Physical findings
      • Ascites
      • Pleural effusions
      • Umbilical mass (Sister Mary Joseph nodule)
      • Ovarian mass
    • Unusual findings
      • Seborrheic keratoses (Leser-Trélat sign)
      • Migratory superficial thrombophlebitis (Trousseau sign)
      • Subacute cerebellar degeneration (paraneoplastic syndrome)
      • Palmar fasciitis
      • Dermatomyositis
  • Stromal cell tumors
    • Granulosa-theca
      • Juvenile
        • Suspect this tumor in females <20 years with adnexal mass
        • Precocious sexual development in prepubertal female
        • Rare virilization
        • Abdominal pain (predominant symptom)
      • Adult
        • Abdominal pain, increasing girth (predominant symptoms)
        • Premenopausal – hyperestrogenism, menstrual irregularities
        • Postmenopausal – abnormal uterine bleeding, breast tenderness
    • Sertoli-Leydig – virilization common
  • Germ cell tumors
    • Frequently asymptomatic
    • Abdominal pain, increasing girth (predominant symptoms)
    • Postmenopausal vaginal bleeding

Prevention

In patients with known BRCA1 or BRCA2 gene mutation who have completed childbearing, bilateral salpingo-oophorectomy dramatically reduces risk for tubo-ovarian cancer

  • Small risk will still exist for primary peritoneal serous carcinoma

ARUP Lab Tests

Evaluate and monitor ovarian cancer, usually epithelial subtype

Monitoring requires elevated pretreatment value of CA 125

Combination with HE4 may enhance sensitivity

Not recommended for monitoring breast cancer or germ cell tumors

Not a stand-alone test for ovarian cancer screening or diagnosis

Not useful in cancer screening

Individuals with confirmed ovarian carcinoma may have pretreatment CA 125 values in the same range as healthy individuals

May be elevated in patients with nonmalignant disease

Test values for CA 125 are not interchangeable between different laboratories or test platforms – sequential monitoring should be performed at the same laboratory

Use with CA 125 to monitor ovarian cancer, usually epithelial subtype, posttherapy if pretreatment level was elevated

Not recommended for monitoring mucinous or germ cell ovarian cancer

Not a stand-alone test for ovarian cancer screening or diagnosis

Not useful in cancer screening

Assess risk of ovarian cancer in women who present with an adnexal mass.

Assess cancer risk, particularly epithelial cell ovarian cancer, in pre- and postmenopausal women with an adnexal mass

Combines CA 125 and HE4, together with menopausal status, to classify adnexal mass patients into high- or low-risk epithelial ovarian cancer groups

Not intended as a screening, stand-alone, or tumor-monitoring test

Tumor monitoring using HE4 and/or CA 125 test should be ordered separately

Should not be used without an independent clinical/radiological evaluation and is not intended to be a screening test or to determine whether a patient should proceed to surgery

Use to differentiate ovarian tumor with normal CA 125 as stromal or mucinous epithelial tumor

May be used for monitoring recurrence of stromal ovarian tumors

Suitable for measurement of estradiol in adult premenopausal women

Evaluate suspected germ cell tumor

Monitor germ cell tumor during treatment (if level initially elevated)

Use as a tumor marker for evaluation of neuroendocrine tumors

Evaluate suspected germ cell tumor

Use for problematic ovarian tumor identification

Evaluate suspected germ cell tumor

Cannot be interpreted as absolute evidence of presence or absence of malignant disease

Result not interpretable as a tumor marker in pregnant females

Results obtained with different test methods or kits cannot be used interchangeably

Recommended test to confirm a diagnosis of hereditary breast and/or ovarian cancer in individuals with a personal or family history of breast and/or ovarian cancer.

When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).

Refer to Test Fact Sheet for full list of genes tested

Refer to Test Fact Sheet for limitations

Recommended test to confirm hereditary breast and ovarian cancer (HBOC) syndrome (BRCA1 and BRCA2 genes only).

When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).

Refer to Test Fact Sheet for limitations

Acceptable test to confirm HBOC syndrome (BRCA1 and BRCA2 genes only).

When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).

Refer to Test Fact Sheet for limitations

Aid in histologic diagnosis of ovarian cancer

Stained and resulted by ARUP

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

Related Tests

Predicts response to tyrosine kinase inhibitor (TKI) therapy

Prognostication in ovarian cancer

Predicts response to anti-EGFR and MAPK pathway therapies in a variety of malignancies

Recommended test to confirm a diagnosis of a hereditary cancer syndrome with with personal or family history consistent with features of more than one cancer syndrome.

When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).

Refer to Test Fact Sheet Hereditary Cancer Panel document for list of genes tested

Refer to aruplab.com/bodyfluids for clinical indications and interpretive information

Medical Experts

Contributor
Contributor

Best

Hunter Best, PhD, FACMG
Associate Professor of Clinical Pathology, University of Utah
Scientific Director, NGS and Biocomputing; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories
Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical Laboratory, ARUP Laboratories
Contributor

McMillin

Gwendolyn A. McMillin, PhD
Professor of Clinical Pathology, University of Utah
Scientific Director, Mass Spectrometry Platform; Medical Director, Clinical Toxicology and Pharmacogenomics, ARUP Laboratories
Contributor
Contributor
Contributor

References

Additional Resources
  • 21642681

    Buys SS

    Partridge E

    Black A

    Johnson CC

    Lamerato L

    Isaacs C

    Reding DJ

    Greenlee RT

    Yokochi LA

    Kessel B

    Crawford D

    Church TR

    Andriole GL

    Weissfeld JL

    Fouad MN

    Chia D

    O'Brien B

    Ragard LR

    Clapp JD

    Rathmell JM

    Riley TL

    Hartge P

    Pinsky PF

    Zhu CS

    Izmirlian G

    Kramer BS

    Miller AB

    Xu JL

    Prorok PC

    Gohagan JK

    Berg CD

    PLCO Project Team

    JAMA

    2011
    305
    22
    2295-303
    PubMed
  • 25394175

    Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70–87. Reaffirmed with Addendum: Genetics in Medicine (2019) 21:2844.

    PubMed
  • Resources from the ARUP Institute for Clinical and Experimental Pathology®