Ovarian Cancer

Primary Author: Grenache, David G., PhD.

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 Not currently recommended for general population screening (United Kingdom Collaborative Trial of Ovarian Cancer Screening [UKTOCS], 2009; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO], 2014) In patients with high-risk factors, 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 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)

Ovarian Cancer

Screening

Not currently recommended for general population screening (United Kingdom Collaborative Trial of Ovarian Cancer Screening [UKTOCS], 2009; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO], 2014)
In patients with high-risk factors, 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
- 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

Abdominal pain
- Appendicitis
- Cholecystitis
- Peptic ulcer disease
- Other gastrointestinal malignancies – gastric, pancreatic, gallbladder
- Uterine fibroids
- Irritable bowel disease
- Metastatic disease from other tumors
- Pelvic inflammatory disease
- Endometriosis
- Diverticulitis
- Inflammatory bowel disease
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

Routine screening in general population is not currently recommended by any professional society
- Ongoing trials to evaluate multimodality screening (CA-125 and TVS)
  - European Randomized Trial of Ovarian Cancer Screening (ERTOCS)
  - United Kingdom Collaborative Trial of Ovarian Cancer Screening [UKTOCS], 2009
    - Multimodality screen shows significantly greater specificity and positive predictive value than TVS alone
- Completed trial
  - Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO], 2014
    - 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
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
  Symptoms in women with any of the following
  
  Breast cancer diagnosed by 45 yrs
  
  Ovarian cancer
  
  Two primary breast cancers, first diagnosed by 50 yrs
  
  Breast cancer diagnosed by 50 yrs with ≥1 family members with breast cancer
  
  Triple negative breast cancer diagnosed by 60 yrs
  
  Breast cancer at any age with ≥1 family members with breast cancer diagnosed by 50 yrs
  
  Breast cancer diagnosed at any age with ≥2 family members from the same side diagnosed with breast cancer at any age
  
  Breast cancer at any age with ≥1 family members with ovarian cancer
  
  Breast cancer diagnosed at any age with ≥2 family members with pancreatic or prostate cancer
  
  Breast cancer diagnosed at any age and male family member with breast cancer
  
  Breast cancer at any age and Ashkenazi Jewish ancestry
  Based on family history (in asymptomatic patient) (Ovarian/Breast Ca) node 913
  Based on family history (in asymptomatic patient)
  
  For women with no Ashkenazi Jewish ancestry and family history of any of the following on the same side of the family
  Two first-degree relatives diagnosed with breast cancer, one diagnosed at 50 yrs or younger
  
  Three or more first-degree or second-degree relatives diagnosed with breast cancer regardless of their age
  
  A combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person)
  
  A first-degree relative with bilateral breast cancer
  
  A combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis
  
  A first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis
  
  Breast cancer diagnosed in a male relative
  
  For women with Ashkenazi Jewish ancestry and family history of any of the following
  First-degree relative diagnosed with breast or ovarian cancer
  
  Two second-degree relatives on the same side of the family diagnosed with breast or ovarian cancer
- 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
- Epithelial tumors – exclusively female
- Germ cell tumors (gestational trophoblastic or testicular) and granulosa cell tumors occur in both sexes (M<F)

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

Hereditary gene mutations

Gene Symbol	Inheritance	Cancer Association
ATM	AD	Breast
BARD1	AD	Breast, neuroblastoma
BRCA1	AD	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate
BRCA2	AD	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate, gallbladder, gastric, melanoma
BRIP1	AD	Breast, ovarian
CDH1	AD	Gastric, breast, prostate
CHEK2	AD	Breast, colorectal, prostate
EPCAM	AD	Colorectal, ovarian
MEN1	AD	Glucagonomas, gastrinomas, VIPomas, thymic, bronchial, gastric, breast
MLH1	AD	Ovarian, colorectal, endometrial, bladder, kidney
MSH2	AD	Ovarian, colorectal, endometrium, bladder, kidney
MSH6	AD	Ovarian, colorectal , endometrium, bladder, kidney
MUTYH	AR, AD	Colorectal (AR), gastric, breast, duodenal, endometrium (AD)
NBN	AD	Breast, ovarian
PALB2	AD	Breast, pancreatic
PTEN	AD	Thyroid, breast, endometrial
RAD51C	AD	Breast, ovarian
RAD51D	AD	Breast, ovarian
STK11	AD	Colorectal, pancreatic, breast, ovarian
TP53	AD	Breast, ovarian, brain, soft tissue and osteosarcomas, gastrointestinal, leukemia, lymphoma, adrenocortical carcinoma
AD = autosomal dominant; AR = autosomal recessive

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

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

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

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)

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

Recommended Use

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

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

Recommended Use

Use for assessment of cancer risk, particularly epithelial cell ovarian cancer, in pre- and post-menopausal women who present with an adnexal mass

Can be used to triage patients for appropriate referral

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

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

Recommended Use

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

Recommended Use

Evaluate suspected granulosa cell tumor

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 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

Recommended Use

Preferred first-tier genetic test for confirmation of hereditary breast and ovarian cancer (HBOC) syndrome

Highest detection rate for HBOC syndrome but also highest likelihood of identifying variants of unknown 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

Clinical sensitivity – unknown

Analytical sensitivity and specificity of sequencing – 99% and 96%, respectively

Analytical sensitivity and specificity of CGH – 99%

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

Recommended Use

Acceptable first-tier genetic test for confirmation of HBOC

Only the BRCA1 and BRCA2 genes are assayed

Clinical sensitivity – ~20-60% sensitivity for HBOC syndrome

Analytical sensitivity and specificity of sequencing – 99% and 96%, respectively

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

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 resulted by ARUP

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

Cancer Antigen 125 by Immunohistochemistry 2003478
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

Distinguish ovarian cancer from breast 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

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

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