Ovarian Cancer

Primary Author: Grenache, David G., PhD.

  • Key Points
  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Use of Tumor Markers in Pelvic Masses: Cancer Antigen 125 (CA-125) and Human Epididymis Protein (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

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

Screening

Diagnosis

  • Most ovarian tumors are epithelial and secrete CA-125 and HE4
    • In ~50% of patients, these markers do not increase early enough to be useful for detecting early stage ovarian cancer (NCCN 2014)
    • In small number of tumors, markers are not expressed
  • Increased survival rates associated with optimal surgical debulking in initial tumor surgery
    • Best performed at earlier stages
  • ACOG (2011) recommends referral to a gynecologic oncologist in the following cases
    • Premenopausal women with CA-125 levels >200 U/mL
    • Postmenopausal women with CA-125 levels >35 U/mL

Monitoring

  • Useful in monitoring therapy and for recurrence if CA-125 and/or HE4 level is initially elevated
  • Rising 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 adnexal mass patients into high- or low-risk epithelial ovarian cancer groups
    • Can be used to triage patients for appropriate referral
    • 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
    • HE4 in combination with CA-125 appears more sensitive than CA-125 alone

Postmenopausal

  • Useful in differential diagnosis of pelvic mass
  • Decreased false-positive rate if both tests are performed
  • CA-125 >65 U/mL highly suggestive of malignancy
  • ROMA – see above (Premenopausal)

Indications for Testing

  • Individual with suspected ovarian cancer

Laboratory Testing

  • Biomarkers
    • Epithelial cell tumors
      • Beta-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 tumors
      • CA-125 – frequently normal (not useful if normal)
      • Inhibin – alpha and beta (beta usually higher than alpha)
        • Total inhibin – highly sensitive
      • Estradiol – often elevated
    • Germ cell tumors
      • CA-125 – not useful (usually normal)
      • Beta-hCG – elevated
      • Alpha fetoprotein (AFP) – elevated
      • Neuron-specific enolase (NSE) – elevated
      • Lactate dehydrogenase (LD) – 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
        • HGSC
          • (+) p53, WT-1, p16, ER
        • LGSC
          • (+) WT-1, ER
      • Mucinous
        • (+) CK 7, CK 20 (weak, focal), CDX2 (weak, focal), SMAD4, DPC4
        • (-) ER, WT-1 (not diffusely positive), beta-catenin-1, p16
      • Endometrioid
        • (+) ER, PR (nuclear), beta-catenin-1, vimentin, CK 7
        • (+) p53 in some high-grade endometrioid – most lack p53, p16
        • (-) WT-1 (not diffusely positive), calretinin, inhibin, CK 20, CEA (monoclonal or polyclonal)
      • Clear cell
        • (+) HNFI-beta, beta-catenin-1
        • (-) 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, beta-hCG
  • Molecular testing based on histology
    • High-grade serous carcinoma (HGSC) – BRCA1 or BRCA2 gene mutations common
      • BRCA1 and BRCA2 testing is recommended for all of these patients (NCCN, 2014)
    • Low-grade serous carcinoma (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

Imaging Studies

  • Ultrasound
    • Transvaginal sonography (TVS) followed by CT/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
  • Beta-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

 Differential Diagnosis

  • Routine screening in general population is not currently recommended by any professional society
  • 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 35, or 5-10 years before earliest age of diagnosis of ovarian cancer in family
        • See NCCN Genetic/Familial High-Risk Assessment (Breast and Ovarian Oncology) 2014 screening 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 (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 (National Cancer Institute)
    • Symptoms in women with any of the following (Ovarian/Breast Ca) node 1191

      Based on family history (in asymptomatic patient) (Ovarian/Breast Ca) node 913

    • For individuals with a family history of a known pathogenic mutation previously identified in a relative – perform targeted mutation testing
  • 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
    • Alpha fetoprotein (AFP), beta-hCG, lactate dehydrogenase (LD)
      • Expect decrease after surgery
      • Increasing levels may signal recurrence

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.

 Epidemiology

  • Incidence
    • Ovarian cancer – ~22,000 new cases and >14,000 deaths annually (NCCN, 2014)
      • Epithelial subtype – 40/100,000 for postmenopausal women
      • ~90% of malignant tumors
    • 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

 Genetics

  • TP53 gene mutations
    • Present in ~50-80% of ovarian carcinomas
    • Correlates with high-grade and advanced state
    • High-grade serous carcinomas are the most common tumor in this group
  • KRAS gene mutations
    • Characteristic of both low-grade serous and mucinous carcinomas
  • BRAF gene mutations
    • Typical of low-grade serous carcinomas
  • FOXL2 gene mutation c.402C>T
    • Present in 97% of granulosa cell tumors in adults and 10% of juvenile tumors

Hereditary gene mutations (Ovarian/Breast Ca) node 1139

Risk Factors

  • Increased risk associated with
    • Family history of breast or ovarian cancer (hereditary breast or ovarian cancer [HBOC])
      • 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 the Müllerian epithelium on the ovarian surface or Müllerian inclusion cysts in the ovarian cortex
    • Some high-grade serous carcinomas likely represent spread from a primary tumor arising in the distal fallopian tube
  • Often spreads early to the contiguous peritoneal mesothelium
    • Spread follows the flow of peritoneal fluid
  • Types
    • Epithelial (85-95%)
      • WHO classification of epithelial tumors
        • Serous
        • Mucinous
        • Endometrioid
        • Clear cell
        • Transitional cell and squamous types (rare)
    • Stromal (5-8%)
      • Granulosa-theca
      • Sertoli-Leydig
    • Germ cell (3-5%)
      • Dysgerminoma
      • Endodermal sinus
      • Immature teratoma
      • Embryonal
    • Metastasis to ovaries
      • Krukenberg tumor

Clinical Presentation

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
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Cancer Antigen 125 0080462
Method: Quantitative Electrochemiluminescent Immunoassay

Limitations 

Not recommended for screening general population for ovarian cancer

Elevated in other gynecological conditions

Higher rate of false positives than HE4

Patients with confirmed ovarian carcinoma may have pretreatment CA-125 value in the same range as healthy individuals

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

Human Epididymis Protein 4 (HE4) 2003020
Method: Quantitative Enzyme Immunoassay

Limitations 

Not recommended for screening general population for ovarian cancer

Not recommended for monitoring patients with known mucinous or germ cell subtype

Risk of Ovarian Malignancy Algorithm 2012618
Method: Quantitative Enzyme Immunoassay, Electrochemiluminescent Immunoassay

Limitations 

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

Inhibin B 0070413
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Estradiol, Adult Premenopausal Female, Serum or Plasma 0070045
Method: Quantitative Chemiluminescent Immunoassay

Alpha Fetoprotein, Serum (Tumor Marker) 0080428
Method: Quantitative Chemiluminescent Immunoassay

Neuron Specific Enolase 0098198
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Beta-hCG, Quantitative (Tumor Marker) 0070029
Method: Quantitative Electrochemiluminescent Immunoassay

Limitations 

Cannot be interpreted as absolute evidence of the 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

Breast and Ovarian Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 20 Genes 2012026
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations 

Deep intronic and regulatory mutaitons, breakpoints for large deletions/duplications, sequence changes in EPCAM (exons 11-15 of CHEK2 will not be evaluated with the exception of the c.1100delC mutation), and deletions/duplications (exon 1 in CDH1, MSH2, and RAD51D; exons 4,6, 7 in STK11; exon 8 in PTEN; exon 12 in ATM) will not be determined or evaluated

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing and Deletion/Duplication 2011949
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Rare diagnostic errors can occur due to primer or probe site mutations

Regulatory region mutations and deep intronic mutations will not be detected

Genes causing HBOC syndrome, other than BRCA1 and BRCA2, are not tested

Deletion/duplication breakpoints will not be determined

p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry

Wilms Tumor (WT-1), N-terminus by Immunohistochemistry 2004184
Method: Immunohistochemistry

p16 by Immunohistochemistry 2004064
Method: Immunohistochemistry

Estrogen/Progesterone Receptor with Interpretation by Immunohistochemistry 0049210
Method: Immunohistochemistry

Cytokeratin 7 (CK 7) by Immunohistochemistry 2003854
Method: Immunohistochemistry

Cytokeratin 20 (CK 20) by Immunohistochemistry 2003848
Method: Immunohistochemistry

CDX2 by Immunohistochemistry 2003821
Method: Immunohistochemistry

Beta-Catenin-1 by Immunohistochemistry 2003454
Method: Immunohistochemistry

Vimentin by Immunohistochemistry 2004181
Method: Immunohistochemistry

Calretinin by Immunohistochemistry 2003490
Method: Immunohistochemistry

Inhibin by Immunohistochemistry 2003969
Method: Immunohistochemistry

Carcinoembryonic Antigen, Monoclonal (CEA M) by Immunohistochemistry 2003824
Method: Immunohistochemistry

Carcinoembryonic Antigen, Polyclonal (CEA P) by Immunohistochemistry 2003827
Method: Immunohistochemistry

Cancer Antigen 125 by Immunohistochemistry 2003478
Method: Immunohistochemistry

Sal-like 4 (SALL4) by Immunohistochemistry 2005432
Method: Immunohistochemistry

Smad4 by Immunohistochemistry 2006403
Method: Immunohistochemistry

PAX8 by Immunohistochemistry 2010787
Method: Immunohistochemistry

PD-L1 by Immunohistochemistry 2011158
Method: Immunohistochemistry

Guidelines

American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Committee Opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer. Obstet Gynecol. 2011; 117(3): 742-6. PubMed

BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. U.S. Preventive Services Task Force. Rockville, MD [Accessed: Nov 2015]

Breast Cancer Risk Assessment Tool. National Cancer Institute. Bethesda, MD [Accessed: Apr 2016]

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. PubMed

NCCN Clinical Practice Guidelines in Oncology, Breast and Ovarian Cancer Genetic/Familial High-Risk Assessment: Breast and Ovarian . National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2016]

NCCN Clinical Practice Guidelines in Oncology, Ovarian Cancer. Epithelial Ovarian Cancer (including Fallopian Tube Cancer and Primary Peritoneal Cancer). National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

Protocol for the Examination of Specimens From Patients With Carcinoma of the Ovary or Fallopian Tube. Based on AJCC/UICC TNM, 7th ed., and FIGO Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

Salani R, Backes FJ, Fung MF, Holschneider CH, Parker LP, Bristow RE, Goff BA. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol. 2011; 204(6): 466-78. PubMed

Sturgeon CM, Duffy MJ, Stenman U, Lilja H, Brünner N, Chan DW, Babaian R, Bast RC, Dowell B, Esteva FJ, Haglund C, Harbeck N, Hayes DF, Holten-Andersen M, Klee GG, Lamerz R, Looijenga LH, Molina R, Nielsen HJ, Rittenhouse H, Semjonow A, Shih I, Sibley P, Sölétormos G, Stephan C, Sokoll L, Hoffman BR, Diamandis EP, National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008; 54(12): e11-79. PubMed

General References

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 J, Prorok PC, Gohagan JK, Berg CD, PLCO Project Team. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011; 305(22): 2295-303. PubMed

Clarke-Pearson DL. Clinical practice. Screening for ovarian cancer. N Engl J Med. 2009; 361(2): 170-7. PubMed

Gilks B, Prat J. Ovarian carcinoma pathology and genetics: recent advances. Hum Pathol. 2009; 40(9): 1213-23. PubMed

Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014; 384(9951): 1376-88. PubMed

Köbel M, Gilks B, Huntsman DG. Adult-type granulosa cell tumors and FOXL2 mutation. Cancer Res. 2009; 69(24): 9160-2. PubMed

Leung F, Diamandis EP, Kulasingam V. Ovarian cancer biomarkers: current state and future implications from high-throughput technologies. Adv Clin Chem. 2014; 66: 25-77. PubMed

Miller RE, Rustin GJ. How to follow-up patients with epithelial ovarian cancer. Curr Opin Oncol. 2010; 22(5): 498-502. PubMed

Moore RG, Maclaughlan S. Current clinical use of biomarkers for epithelial ovarian cancer. Curr Opin Oncol. 2010; 22(5): 492-7. PubMed

Robertson DM, Pruysers E, Jobling T. Inhibin as a diagnostic marker for ovarian cancer. Cancer Lett. 2007; 249(1): 14-7. PubMed

Roett MA, Evans P. Ovarian cancer: an overview. Am Fam Physician. 2009; 80(6): 609-16. PubMed

Schorge JO, Modesitt SC, Coleman RL, Cohn DE, Kauff ND, Duska LR, Herzog TJ. SGO White Paper on ovarian cancer: etiology, screening and surveillance. Gynecol Oncol. 2010; 119(1): 7-17. PubMed

Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King M, Swisher EM. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011; 108(44): 18032-7. PubMed

Zagouri F, Dimopoulos MA, Bournakis E, Papadimitriou CA. Molecular markers in epithelial ovarian cancer: their role in prognosis and therapy. Eur J Gynaecol Oncol. 2010; 31(3): 268-77. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Cho S, Sun Y, Soisson AP, Dodson MK, Peterson M, Jarboe EA, Kennedy AM, Janát-Amsbury MM. Characterization and evaluation of pre-clinical suitability of a syngeneic orthotopic mouse ovarian cancer model. Anticancer Res. 2013; 33(4): 1317-24. PubMed

Grenache DG, Heichman KA, Werner TL, Vucetic Z. Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass Clin Chim Acta. 2015; 438: 358-63. PubMed

Jarboe EA, Folkins AK, Drapkin R, Ince TA, Agoston ES, Crum CP. Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective. Histopathology. 2009; 55(5): 619. PubMed

Kushnir MM, Naessén T, Kirilovas D, Chaika A, Nosenko J, Mogilevkina I, Rockwood AL, Carlström K, Bergquist J. Steroid profiles in ovarian follicular fluid from regularly menstruating women and women after ovarian stimulation. Clin Chem. 2009; 55(3): 519-26. PubMed

Mongia SK, Rawlins ML, Owen WE, Roberts WL. Performance characteristics of seven automated CA 125 assays. Am J Clin Pathol. 2006; 125(6): 921-7. PubMed

Shaaban AM, Rezvani M, Elsayes KM, Baskin H, Mourad A, Foster BR, Jarboe EA, Menias CO. Ovarian malignant germ cell tumors: cellular classification and clinical and imaging features. Radiographics. 2014; 34(3): 777-801. PubMed

Medical Reviewers

Last Update: September 2016