Ovarian Cancer

Indications for Testing

Patient with suspected ovarian cancer

Laboratory Testing

Biomarkers
- Epithelial cell tumors
  - βhCG – consider this test in premenopausal females to rule out pregnancy
  - CA 125
    - Not recommended for initial diagnostic testing (although levels >65 U/mL are suspicious for ovarian cancer)
    - Recommended use for differential diagnosis of suspicious pelvic mass in postmenopausal females
      - Combining with HE4 decreases false positives
  - Inhibin complements CA 125 – performs best in mucinous subtype
  - Other markers currently available are not generally as useful
- Granulosa-theca tumors
  - CA 125 – frequently normal
  - Inhibin – α and β (β usually higher than α); total inhibin is highly sensitive
  - Estradiol – often elevated
- Germ cell tumors
  - CA 125 – not useful
  - βhCG – elevated
  - Alpha fetoprotein (AFP) – elevated
  - Neuron-specific enolase (NSE) – elevated
  - Lactate dehydrogenase (LD) – elevated
- Genetic biomarkers
  - Consider BRCA1 and BRCA2 testing in patients with
    - Family history of ovarian cancer
    - Family members with both breast and ovarian cancer (at least one of each type)
  - FOXL2 testing – if suspicion of granulosa cell tumor or problematic ovarian tumor identification
Molecular genetics
- High-grade serous (HGSC) – BRCA1 or BRCA2 frequently positive
- Low-grade serous (LGSC) – BRAF or KRAS mutations
- Mucinous – KRAS mutations frequent
- Endometrioid – β catenin (CTN NB1) and PTEN mutations common
- Clear cell – lack BRCA1 or BRCA2
- Transitional cell
  - If lacking Brenner component – BRCA1 or BRCA2 frequently positive
- Granulosa cell – FOXL2

Histology

Surgical biopsy to determine if ovarian mass is malignant (with planned surgical debulking if malignant)
- Avoid percutaneous biopsy as it can cause tumor spillage into the pelvis
- All tumors require histologic confirmation for diagnosis
Immunohistochemistry
- Epithelial
  - Serous
    - HGSC
      - (+) p53, WT-1, p16, ER
    - LGSC
      - (+) WT-1, ER
  - Mucinous
    - (+) CK 7, CK 20 (weak, focal), CDX2 (weak, focal), SMAD4, DPC4
    - (-) ER, WT-1 (not diffusely positive), beta-catenin-1, p16
  - Endometrioid
    - (+) ER, PR (nuclear), beta-catenin-1, vimentin, CK 7
    - (+) p53 in some high-grade endometrioid, but most lack p53, p16
    - (-) WT-1 (not diffusely positive), calretinin, inhibin, CK 20, CEA (monoclonal or polyclonal)
  - Clear cell
    - (+) HNFI-β, 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, βhCG

Imaging Studies

Ultrasound
- Transvaginal sonography (TVS) followed by CT/MRI if suspicious TVS findings

Prognosis

p53 overexpression correlates with poor survival, propensity for recurrence and distant recurrence
RAS deregulation in serous subtype associated with poor prognosis in patients with incomplete response to platinum-based therapy
Beta-catenin-1 deregulation in serous subtype associated with poor prognosis in patients with incomplete response to platinum-based therapy
EGFR overexpression associated with platinum resistance and poor prognosis
HER2 expression correlates with poor survival (only 10% display this)
MMP-9 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)
  - Multimodality screen shows significantly greater specificity and positive predictive value than TVS alone
- Completed trial
  - Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) – multimodality screening does not reduce ovarian cancer mortality and can lead to health issues; no statistical difference in survival rates between screened and not-screened groups
- CA 125
  - BRCA – ovarian cancer risk >50%
    - If patient chooses not to undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy, begin screening at age 35 or 5-10 years before earliest age of diagnosis of ovarian cancer in family
      - See NCCN Genetic/Familial High-Risk Assessment (Breast and Ovarian Oncology) 2011 screening guidelines (subscription required)
      - Concurrent TVS (preferably day 1-10 of menstrual cycle in premenopausal women) and CA 125 (preferably after day 5 of menstrual cycle in premenopausal women) every 6 months
  - 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

Epithelial
- CA125
  - Assess patient response to chemotherapy, detect early relapse and prediction of prognosis
    - Absolute serum value of CA 125 before third cycle of chemotherapy is most important factor for predicting progression at 12 months
  - Suggested monitoring is every 2-4 months for the first 2 years
    - Persistent post-operative elevation suggests poor prognosis
- HE4
  - Product of WFDC2 (HE4) gene that is overexpressed in patients with ovarian cancer
  - 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, βhCG, 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 by type
- Epithelial – 40/100,000 for postmenopausal females (CDC 2006, ACS 2008, NCI-SEER Data 2007)
- Stromal – 1/100,000
Incidence – increases with age
- 50-60 years – 26.9/100,000
- 65-74 years – 48.6/100,000
- >75 years – 57/100,000
Age – median is 63 years
Sex
- Epithelial tumors – exclusively female
- Germ cell tumors (gestational trophoblastic or testicular) and granulosa cell tumors occur in both sexes (F>M)

Genetics

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

Risk Factors

Increased risk associated with
- Family history of breast or ovarian cancer
  - Genetic predisposition identified in only 5% of cases
  - Genetic syndromes
    - Associated with BRCA1, BRCA2 and Lynch Syndrome II
    - Higher probability of BRCA mutations in Ashkenazi Jews
- Nulliparity
- Older age at first birth (≥35 years)
- Early menarche
- Hormone therapy
Decreased risk (30-60%) associated with
- Oral contraceptive use
- Pregnancy and first birth at young age (≤25 years)
- Multiparity
- Lactation (>18 months)
- History of tubal ligation/hysterectomy
- Early menopause/late menarche

Pathophysiology

Malignant transformation of the Müllerian epithelium on the ovarian surface or Müllerian inclusion cysts in the ovarian cortex
- Some high-grade serous carcinomas likely represent spread from a primary tumor arising in the distal fallopian tube
Often spreads early to the contiguous peritoneal mesothelium
- Spread follows the flow of peritoneal fluid
Types
- Epithelial (85-95%)
  - WHO classification of epithelial tumors
    - Serous
    - Mucinous
    - Endometrioid
    - Clear cell
    - Transitional cell and squamous types (rare)
- Stromal (5-8%)
  - Granulosa-theca
  - Sertoli Leydig
- Germ cell (3-5%)
  - Dysgerminoma
  - Endodermal sinus
  - Teratoma
  - Embryonal
  - Choriocarcinoma
- Metastases to ovaries – Krukenberg tumor

Clinical Presentation

Epithelial cell tumors
- 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 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

Test name: Cancer Antigen 125

ARUP #: 0080462

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

Do not use to diagnose ovarian cancer

Monitor patient response to treatment

Adjunct in distinguishing benign from malignant pelvic masses, 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 general population screening for ovarian cancer

Elevated in other gynecological conditions

Combine with HE4 testing to reduce false positives

Test name: Human Epididymis Protein 4 (HE4)

ARUP #: 2003020

Methodology: Quantitative Enzyme Immunoassay

Use:

Testing and monitoring for epithelial cell tumors in combination with CA 125 testing

Test name: Total Inhibin

ARUP #: 2002550

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Test for granulosa cell tumors

Monitor mucinous subtype tumors with concurrent CA 125 measurements

Test name: Estradiol, Adult Premenopausal Female, Serum or Plasma

ARUP #: 0070045

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Test for granulosa cell tumors

Test name: Alpha Fetoprotein, Serum (Tumor Marker)

ARUP #: 0080428

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Test and monitor for germ cell tumors

Test name: Neuron Specific Enolase

ARUP #: 0098198

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Test for germ cell tumors

Test name: Lactate Dehydrogenase, Serum or Plasma

ARUP #: 0020006

Methodology: Quantitative Enzymatic

Use:

Test for germ cell tumors or use for problematic ovarian tumor identification

Test name: Beta-hCG, Quantitative (Tumor Marker)

ARUP #: 0070029

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

Rule out pregnancy

Test for germ cell tumors

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

Test name: p53 Tissue Assay, Paraffin

ARUP #: 0049250

Methodology: Immunohistochemistry

Use: