Ovarian Cancer

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

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
    • 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
  • 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 (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

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