Ovarian Cancer

Key Points

Use of Tumor Markers in Pelvic Masses: CA 125 and HE4

Biology

• CA 125 – glycoprotein antigen expressed in tissues derived from coelomic epithelia (ovary, fallopian tube, peritoneum, pericardium, colon, kidney, stomach)
• HE4 – secreted protein expressed in most epithelial ovarian tumors

Uses

• In general, the combination of CA 125 and HE4 provides the highest sensitivity and specificity
• Tumor markers in pelvic masses (see table below)

Diagnosis

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 as a single initial diagnostic test (although results >65 U/mL are highly suggestive of malignancy)
      • Recommended use for differential diagnosis of suspicious pelvic mass in postmenopausal females
    • HE4 – combining with CA 125 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

Screening

Monitoring

Clinical Background

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
  • Type 
    • Epithelial – 40/100,000 for postmenopausal females (CDC 2006, ACS 2008, NCI-SEER Data 2007)
    • Stromal – 1/100,000
  • Age
    • 50-60 years – 26.9/100,000
    • 65-74 years – 48.6/100,000
    • >75 years – 57/100,000
• Age – 63 years (median)
• 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
  • Present in ~50-80% of ovarian carcinomas
  • Correlate with high-grade and advanced state
  • High-grade serous carcinomas are the most common tumor in this group
• KRAS mutations
  • Characteristic of both low-grade serous and mucinous carcinomas
• BRAF mutations
  • 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

  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

  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

  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

Indications for Laboratory Testing

• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
EGFR Mutation Detection by Pyrosequencing 2002440 Method: Polymerase Chain Reaction/Pyrosequencing	Detects mutations in EGFR exons 18, 19, 20, and 21
HER2/neu Quantitative by ELISA 2004672 Method: Quantitative Enzyme-Linked Immunosorbent Assay
KRAS Mutation Detection 0040248 Method: Polymerase Chain Reaction/Pyrosequencing
PTEN-Related Disorders (PTEN) Deletion/Duplication 2002726 Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification
Solid Tumor Mutation Panel by Next Generation Sequencing 2007991 Method: Massively Parallel Sequencing	Prognosis/treatment of individuals with solid tumor cancers at initial diagnosis or with refractory disease