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).

Tabs Content

Clinical Overview

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 High-risk factors – family history of ovarian cancer, Lynch syndrome, or linkage to BRCA1 and BRCA2 genotypes
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
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

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
- High-risk factors – family history of ovarian cancer, Lynch syndrome, or linkage to BRCA1 and BRCA2 genotypes

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

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

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)
  - Total inhibin – highly sensitive
- 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) (testing for HNF1β not offered at ARUP Laboratories), 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

Abdominal pain
- Appendicitis
- Cholecystitis
- Peptic ulcer disease
- Other gastrointestinal malignancies – gastric, pancreatic, gallbladder
- Uterine fibroids
- Irritable bowel syndrome
- Metastatic disease from other tumors
- Pelvic inflammatory disease
- Endometriosis
- Diverticulitis
- Inflammatory bowel disease (IBD)
Abdominal girth enlargement
- Pregnancy
- Polycystic ovarian syndrome
- Uterine cancer
- Ovarian cysts
- Primary lymphoma – B-cell lymphoma
- Uterine fibroids
- Cirrhosis with ascites
- Metastatic disease from other tumors
Genitourinary symptoms
- Uterine fibroids
- Endometriosis
- Pregnancy
- Urinary retention
- Polycystic kidney disease
Endocrine symptoms
- Adrenal tumors
- Pregnancy

Screening

Routine screening in general population is not currently recommended by the USPSTF (2018) or ACOG (2017)
Trials of screening
- Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial [PLCO] (Buys, 2011)
  - Multimodality screening does not reduce ovarian cancer mortality and can lead to health issues
  - No statistical difference in survival rates between screened and unscreened groups
- United Kingdom Collaborative Trial of Ovarian Cancer Screening [UKCTOCS] – ongoing
  - Evaluating multimodality screening (CA 125 and TVS)
  - Preliminary results indicate multimodality screening has greater specificity and positive predictive value than TVS alone
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
  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
- Epithelial tumors – exclusively female
- Germ cell tumors (gestational trophoblastic or testicular) and granulosa cell tumors occur in both sexes (M<F)

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

Hereditary gene mutations

Hereditary Gene Mutations
Gene Symbol	Inheritance	Cancer Association
ATM	AD, AR	Breast, possible increased risk for colorectal (AD) Ataxia telangiectasia (AR)
BARD1	AD	Breast, neuroblastoma
BRCA1	AD	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate; hereditary breast and ovarian cancer (HBOC) syndrome
BRCA2	AD, AR	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate, gallbladder, gastric, melanoma; HBOC syndrome (AD) Fanconi anemia, complementation group J (AR)
BRIP1	AD, AR	Ovarian, possible increased risk for breast (AD) Fanconi anemia, complementation group J (AR)
CDH1	AD	Gastric, breast, prostate
CHEK2	AD	Breast, colorectal, prostate
EPCAM	AD	Colorectal, ovarian; Lynch syndrome
MEN1	AD	Glucagonomas, gastrinomas, VIPomas, thymic, bronchial, gastric, breast; multiple endocrine neoplasia type 1 (MEN1)
MLH1	AD, AR	Ovarian, colorectal, endometrial, gastric, bladder, kidney; Lynch syndrome (AD) Constitutional mismatch repair deficiency (AR)
MSH2	AD, AR	Ovarian, colorectal, endometrium, gastric, bladder, kidney; Lynch syndrome (AD) Constitutional mismatch repair deficiency (AR)
MSH6	AD, AR	Ovarian, colorectal, endometrium, gastric, bladder, kidney; Lynch syndrome (AD) Constitutional mismatch repair deficiency (AR)
MUTYH	AD, AR	Colorectal, MUTYH-associated polyposis (MAP) (AR) Possible increased risk for gastric, breast, duodenal, endometrium (AD)
NBN	AD, AR	Breast, possible increased risk for ovarian (AD) Nijmegen breakage syndrome (AR)
PALB2	AD, AR	Breast, pancreatic, possible increased risk for ovarian (AD) Fanconi anemia, complementation group N (AR)
PTEN	AD	Breast, thyroid, endometrial, colorectal; PTEN hamartoma tumor syndrome/Cowden syndrome
RAD51C	AD, AR	Ovarian, possible increased risk for breast (AD) Fanconi anemia, complementation group O (AR)
RAD51D	AD	Ovarian, possible increased risk for breast
STK11	AD	Breast, colorectal, stomach, pancreatic, ovarian; Peutz-Jeghers syndrome
TP53	AD	Breast, ovarian, brain, soft tissue and osteosarcomas, gastrointestinal, leukemia, lymphoma, adrenocortical carcinoma; Li Fraumeni syndrome
AD, autosomal dominant; AR, autosomal recessive

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

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

Recommended Use

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

Limitations

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

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

Recommended Use

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

Limitations

Not useful in cancer screening

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

Recommended Use

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

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

Total Inhibin, Serum 2014109
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Aid in detection and monitoring of granulosa cell tumors of the ovary

Inhibin B 0070413
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

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

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

Recommended Use

Suitable for measurement of estradiol in adult premenopausal women

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

Recommended Use

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

Recommended Use

Use as a tumor marker for evaluation of neuroendocrine tumors

Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Recommended Use

Evaluate suspected germ cell tumor

Use for problematic ovarian tumor identification

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

Recommended Use

Evaluate suspected germ cell tumor

Limitations

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

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

Recommended Use

Preferred first-tier genetic test to diagnose a hereditary cancer syndrome related to breast and ovarian cancer, if a known variant has NOT been previously identified in the family

When a relative has a previously identified pathogenic variant, see familial mutation targeted sequencing test

Highest detection rate for a hereditary syndrome related to breast and/or ovarian cancer, but also highest likelihood of identifying variants of uncertain significance

Genes tested – ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53

Refer to Additional Technical Information document for further content

Limitations

Deep intronic and regulatory variants, 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 variant), 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

Recommended Use

Preferred first-tier genetic test to confirm HBOC syndrome (BRCA1 and BRCA2 genes only)

When a relative has a previously identified pathogenic BRCA1 or BRCA2 variant, see familial mutation targeted sequencing test

Up to 99% sensitivity for BRCA1 and BRCA2 variants

~20-60% sensitivity for hereditary breast and ovarian cancers, in general

Limitations

Deep intronic and regulatory variants will not be detected

Breakpoints for large deletions/duplications will not be determined

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

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

Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing 2011954
Method: Polymerase Chain Reaction/ Sequencing

Recommended Use

Acceptable first-tier genetic test to confirm HBOC syndrome

Up to 90% sensitivity for BRCA1 and BRCA2 variants

~20-60% sensitivity for hereditary breast and ovarian cancers, in general

When a relative has a previously identified pathogenic BRCA1 or BRCA2 variant, see familial mutation targeted sequencing test

Limitations

Deep intronic and regulatory variants will not be detected

Breakpoints for large deletions/duplications will not be determined

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and resulted by ARUP

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

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

p16 by Immunohistochemistry 2004064
Method: Immunohistochemistry

Recommended Use

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

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and resulted by ARUP

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

Recommended Use

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

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

CDX2 by Immunohistochemistry 2003821
Method: Immunohistochemistry

Recommended Use

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

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

Vimentin by Immunohistochemistry 2004181
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

Calretinin by Immunohistochemistry 2003490
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

Inhibin by Immunohistochemistry 2003969
Method: Immunohistochemistry

Recommended Use

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

Recommended Use

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

Recommended Use

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

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist; consultation available if needed

Smad4 by Immunohistochemistry 2006403
Method: Immunohistochemistry

Recommended Use

Stained and returned to client pathologist; consultation available if needed

PAX8 by Immunohistochemistry 2010787
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist for interpretation; consultation available if required

PD-L1 by Immunohistochemistry 2011158
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of ovarian cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

Medical Reviewers

Bayrak-Toydemir, Pinar, MD, PhD, Medical Director, Molecular Genetics and Genomics at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Best, Hunter, PhD, Medical Director, Molecular Genetics and Genomics; Co-Scientific Director, NGS and Biocomputing; Director, High Complexity Platforms-NGS, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Genzen, Jonathan R., MD, PhD, Laboratory Section Chief, Clinical Chemistry, and Medical Director, Automated Core Laboratory, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Jarboe, Elke, MD, Staff Pathologist, Surgical Pathology and Cytopathology at ARUP Laboratories; Assistant Professor of Anatomic Pathology, Adjunct Assistant Professor, Obstetrics/Gynecology, University of Utah

McMillin, Gwendolyn A., PhD, Medical Director, Toxicology, and Medical Director, Pharmacogenetics, at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Miller, Christine E., MS, LCGC, Genetic Counselor, Molecular Genetics at ARUP Laboratories; Faculty, Graduate Program in Genetic Counseling, University of Utah

Samowitz, Wade S., MD, Medical Director, Anatomic Pathology, at ARUP Laboratories; Professor of Anatomic Pathology, University of Utah

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology and Automated Core Laboratory at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

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
Protocol for the Examination of Specimens From Patients With Primary Tumors of the Ovary or Fallopian Tube. Based on AJCC/UICC TNM, 7th ed., and FIGO 2014. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Published: Jan 2016; Accessed: Jul 2018]
BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. U.S. Preventive Services Task Force. Rockville, MD [Release Date: Dec 2013; Accessed: Jul 2018]
NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2019. National Comprehensive Cancer Network. Fort Washington, PA [Released: Jul 2018; Accessed: Jul 2018]
NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2018. National Comprehensive Cancer Network. Fort Washington, PA [Released: Mar 2018; Accessed: Jul 2018]
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
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
Breast Cancer Risk Assessment Tool. National Cancer Institute. Bethesda, MD [Accessed: Jul 2018]
American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Committee Opinion No. 716: The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer in Women at Average Risk. Obstet Gynecol. 2017; 130(3): e146-e149. PubMed
Ray-Coquard I, Morice P, Lorusso D, Prat J, Oaknin A, Pautier P, Colombo N, ESMO Guidelines Committee. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; PubMed
US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Davidson KW, Doubeni CA, Epling JW, Kemper AR, Krist AH, Kurth AE, Landefeld S, Mangione CM, Phipps MG, Silverstein M, Simon MA, Tseng C. Screening for Ovarian Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018; 319(6): 588-594. PubMed
American Academy of Family Physicians. Choosing Wisely - Twenty Things Physicians and Patients Should Question. American Board of Internal Medicine (ABIM) Foundation. Philadelphia, PA [Updated: Aug 2018; Accessed: Aug 2018]

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

United Kingdom Collaborative Trial of Ovarian Cancer Screening. University College London. London, United Kingdom. [Updated: 2017; Accessed: Nov 2017]

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

Homicsko K, Coukos G. Targeting Programmed Cell Death 1 in Ovarian Cancer. J Clin Oncol. 2015; 33(34): 3987-9. 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

Xiang L, Kong B. PAX8 is a novel marker for differentiating between various types of tumor, particularly ovarian epithelial carcinomas. Oncol Lett. 2013; 5(3): 735-738. PubMed

Yang M, Xie X, Ding Y. SALL4 is a marker of poor prognosis in serous ovarian carcinoma promoting invasion and metastasis. Oncol Rep. 2016; 35(3): 1796-806. PubMed

Educational Videos

Last Update: August 2018


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	Grenache D. Ovarian Cancer. ARUP Consult^©. Retrieved September 19, 2018, from: https://arupconsult.com/content/ovarian-cancer

Ovarian Cancer

Key Points

Tumor Markers

Biology

Uses

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Imaging Studies

Prognosis

Differential Diagnosis

Screening

Indications for testing in individuals with any of the following

Monitoring

Background

Epidemiology

Familial Genetics

Hereditary gene mutations

Risk Factors

Pathophysiology

Clinical Presentation

Prevention

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

References from the ARUP Institute for Clinical and Experimental Pathology^®