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 |
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Screening
|
Diagnosis
|
Monitoring
|
Pelvic Mass |
Premenopausal
|
Postmenopausal
|
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
- High-grade serous carcinoma (HGSC)
- 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
- Serous
- Granulosa/Sertoli – (+) inhibin, WT-1, calretinin
- Germ cell – (+) CA 125, inhibin, AFP, β-hCG
- Epithelial
- 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
- Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial [PLCO] (Buys, 2011)
- 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
- If patient chooses not to undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy, begin screening at age 30
- 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
- BRCA – ovarian cancer risk >50%
- 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
- Assess patient response to chemotherapy, detect early relapse, and predict 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
- CA 125
- 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
- AFP, β-hCG, LDH
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
- Ovarian cancer – estimated 22,240 new cases and >14,000 deaths annually in the U.S. (NCCN, 2018)
- 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
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
- Associated with BRCA1, BRCA2, and Lynch Syndrome II
- Nulliparity
- Older age at first birth (≥35 years)
- Early menarche
- Hormone therapy
- Pelvic inflammatory disease (PID), in vitro stimulation may increase risk
- Family history of breast or ovarian cancer (hereditary breast or ovarian cancer)
- 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
- Juvenile
- Sertoli-Leydig – virilization common
- Granulosa-theca
- 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 Laboratory 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
Quantitative Electrochemiluminescent Immunoassay
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
Quantitative Electrochemiluminescent Immunoassay
Assess risk of ovarian cancer in women who present with an adnexal mass.
Electrochemiluminescent Immunoassay (ECLIA)/Fixed-Rate-Time Nephelometry
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
Quantitative Electrochemiluminescent Immunoassay
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
Quantitative Enzyme-Linked Immunosorbent Assay
Suitable for measurement of estradiol in adult premenopausal women
Quantitative Chemiluminescent Immunoassay
Evaluate suspected germ cell tumor
Monitor germ cell tumor during treatment (if level initially elevated)
Quantitative Chemiluminescent Immunoassay
Use as a tumor marker for evaluation of neuroendocrine tumors
Quantitative Enzyme-Linked Immunosorbent Assay
Evaluate suspected germ cell tumor
Use for problematic ovarian tumor identification
Quantitative Enzymatic
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
Quantitative Electrochemiluminescent Immunoassay
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
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
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)
Massively Parallel Sequencing/Multiplex Ligation-dependent Probe Amplification
Aid in histologic diagnosis of ovarian cancer
Stained and resulted by ARUP
Immunohistochemistry
Immunohistochemistry
Aid in histologic diagnosis of ovarian cancer
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Predicts response to tyrosine kinase inhibitor (TKI) therapy
Polymerase Chain Reaction/Pyrosequencing
Prognostication in ovarian cancer
Quantitative Enzyme-Linked Immunosorbent Assay
Predicts response to anti-EGFR and MAPK pathway therapies in a variety of malignancies
Polymerase Chain Reaction/Pyrosequencing
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
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Refer to aruplab.com/bodyfluids for clinical indications and interpretive information
Quantitative Chemiluminescent Immunoassay
Test Fact Sheet(s)
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References
Choosing Wisely - Retest Interval - American Academy of Family Physicians - 20 Things
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NCCN - Ovarian Cancer
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