Ovarian Cancer

Key Points

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 epithelia (ovary, fallopian tube, peritoneum, pericardium, colon, 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 sensitivity 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 (see table below)
OVARIAN CANCER

Screening

  • Not currently recommended for general population screening (UKCTOCS 2009, PLCO trial 2011)
  • In patients with high-risk factors, may be used in conjunction with transvaginal ultrasound and bimanual pelvic examination

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 2011)
    • 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 more specific – its use alone or in combination with CA-125 is not recommended to rule out malignancy

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
  • Recent studies, using the Risk of Ovarian Malignancy Algorithm (ROMA) that combine CA-125 and HE4 concentrations to calculate risk, have produced conflicting reports
    • HE4 in combination with CA-125 appears more sensitive than CA-125 alone

Diagnosis

Indications for Testing

  • Patient 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
    • Genetic biomarkers
      • Consider BRCA1 and BRCA2 testing in patients with
        • Family history of ovarian cancer
        • Family members with both breast and ovarian cancer (at least one of each type)
  • Molecular genetics
    • High-grade serous carcinoma (HGSC) – BRCA1 or BRCA2 test result frequently positive
    • Low-grade serous carcinoma (LGSC) – BRAF or KRAS mutations
    • Mucinous – KRAS mutations frequent
    • Endometrioid – beta-catenin (CTN NB1) and PTEN mutations common
    • Clear cell – lack BRCA1 or BRCA2
    • Transitional cell
      • If lacking Brenner component – BRCA1 or BRCA2 frequently positive
    • Granulosa cell – FOXL2 mutation

Histology

  • Surgical biopsy to determine if ovarian mass is malignant (with planned surgical debulking if malignant)
    • Avoid percutaneous biopsy as it 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

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 deregulation in serous subtype
    • Associated with poor prognosis in patients with incomplete response to platinum-based therapy
  • Beta-catenin-1 deregulation 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 – only in 10% of patients
    • Correlates with poor survival
  • MMP-9
    • Associated with poor prognosis

 Differential Diagnosis

Screening

  • Routine screening in general population is not currently recommended by any professional society
    • Ongoing trials to evaluate multimodality screening (CA-125 and TVS)
    • Completed trial
    • CA-125
      • 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) 2011 screening guidelines (subscription required)  
          • 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

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, beta-hCG, LD
      • Expect decrease after surgery
      • Increasing levels may signal recurrence

Clinical Background

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 
      • Epithelial subtype – 40/100,000 for postmenopausal women
    • Age
      • 50-60 years – 26.9/100,000
      • 65-74 years – 48.6/100,000
      • >75 years – 57/100,000
  • Age – 63 years (median)
  • Sex

 Genetics

  • p53 mutations
    • Present in ~50-80% of ovarian carcinomas
    • Correlate with high-grade and advanced state
    • High-grade serous carcinomas are the most common tumor in this group
  • KRAS mutations
    • Characteristic of both low-grade serous and mucinous carcinomas
  • BRAF mutations
    • Typical of low-grade serous carcinomas
  • FOXL2 mutation c.402C>T
    • Present in 97% of granulosa cell tumors in adults and 10% of juvenile tumors

 Risk Factors

  • Increased risk associated with
    • Family history of breast or ovarian cancer
      • Genetic predisposition identified in only 5% of cases
      • Genetic syndromes
    • Nulliparity
    • Older age at first birth (≥35 years)
    • Early menarche
    • Hormone therapy
  • 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
      • Teratoma
      • Embryonal
      • Choriocarcinoma
    • Metastases to ovaries
      • Krukenberg tumor

 Clinical Presentation

  • Epithelial cell tumors
    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
    Stromal cell tumors
    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
    Germ Cell Tumors
    • Frequently asymptomatic
    • Abdominal pain, increasing girth (predominant symptoms)
    • Postmenopausal vaginal bleeding

Prevention

  • In patients with known BRCA1 or BRCA2 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Cancer Antigen 125 0080462
Method: Quantitative Electrochemiluminescent Immunoassay

Do not use as a single diagnostic test – adjunct test for evaluation of ovarian mass

Monitor (if initially elevated) epithelial cell tumor – combine with HE4 testing for fewer false positives

Adjunct test for distinguishing benign from malignant pelvic mass, particularly in postmenopausal women

Also useful for early detection of ovarian cancer in high-risk hereditary syndromes (eg, BRCA1 and BRCA2)

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

Do not use as a single diagnostic test – adjunct test for evaluation of ovarian mass

Monitor (if initially elevated) epithelial cell tumor – combine with CA-125 testing for fewer false positives

Not recommended for screening general population for ovarian cancer

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

 
Inhibin B 0070413
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Evaluate suspected granulosa cell tumor

Monitor mucinous subtype tumor – combine with CA-125 testing

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

Evaluate suspected granulosa cell tumor

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

Evaluate suspected germ cell tumor

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

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

Evaluate suspected germ cell tumor

   
Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Evaluate suspected germ cell tumor

Use for problematic ovarian tumor identification

   
Beta-hCG, Quantitative (Tumor Marker) 0070029
Method: Quantitative Electrochemiluminescent Immunoassay
Evaluate suspected germ cell tumor

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

Result not interpretable as a tumor marker in pregnant females

 
p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and resulted by ARUP

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

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
p16 by Immunohistochemistry 2004064
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of ovarian cancer

Stained and resulted by ARUP

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

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
CDX2 by Immunohistochemistry 2003821
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
Beta-Catenin-1 by Immunohistochemistry 2003454
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
Vimentin by Immunohistochemistry 2004181
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
Calretinin by Immunohistochemistry 2003490
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
Inhibin by Immunohistochemistry 2003969
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
Cancer Antigen 125 by Immunohistochemistry 2003478
Method: Immunohistochemistry

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

   
Smad4 by Immunohistochemistry 2006403
Method: Immunohistochemistry

Stained and returned to client pathologist; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
EGFR Mutation Detection by Pyrosequencing 2002440
Method: Polymerase Chain Reaction/Pyrosequencing

Prognostication in ovarian cancer

HER2/neu Quantitative by ELISA 2004672
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Prognostication in ovarian cancer

KRAS Mutation Detection 0040248
Method: Polymerase Chain Reaction/Pyrosequencing

Prognostication in ovarian cancer

PTEN-Related Disorders (PTEN) Deletion/Duplication 2002726
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Prognostication in ovarian cancer

Solid Tumor Mutation Panel by Next Generation Sequencing 2007991
Method: Massively Parallel Sequencing

Prognostication in ovarian cancer