Ovarian Cancer

Epidemiology

Incidence: 22,000 new cases in U.S. in 2010
1. Lifetime Risk: 1 in 70 (1.4%)
2. Age adjusted risk: overall 12.5 cases per 100,000 women
  1. Age under 20 years: 0.7 per 100,000 women
  2. Age 20 to 50 years: 6.6 per 100,000 women
  3. Age 50 to 64 years: 26.9 per 100,000 women
  4. Age over 64 years: 48.6 to 55.6 per 100,000 women
Mortality: 14,000 deaths in U.S. in 2010
1. Accounts for 3% of cancer deaths in women
2. Fifth most common cause of cancer death in women (lung, Breast, colon, Pancreas are more common)
3. Five year survival <50% (even lower in black women)

Risk Factors

Age over 40 years (most occur over age 50 years)
1. Exception: Germ Cell Tumors (5% of cases) are most common age 20-30 years
Nulliparity
Estrogen Replacement Therapy for more than 5 years
Endometriosis
Family History
1. Up to 90% of Ovarian Cancer patients have no Family History of Ovarian Cancer
2. See Hereditary Ovarian Cancer Syndromes below (e.g. BRCA, Lynch Syndrome)
3. Accounts for up to 12% of Ovarian Cancer cases
4. Ovarian Cancer (2 to 20 fold increased risk)
  1. One affected first degree relative: 3 fold risk
  2. Two or more relatives affected: 40% risk
  3. Site-specific Ovarian Cancer Syndrome represents another Genetic Syndrome
5. Endometrial Cancer (Uterine Cancer)
Past Medical History

Risk Factors
Hereditary Ovarian Cancer Syndromes

Breast Cancer (Ashkenazi Jewish patients have a 10 fold increased risk of BRCA)
1. Breast-Ovarian Cancer Syndrome
2. BRCA1 and BRCA2 account for 10% of Ovarian Cancers
3. BRCA1 confers 44% lifetime risk of Ovarian Cancer and typically present in the mid-40s
4. BRCA2 confers 18% lifetime risk of Ovarian Cancer and typically presents in the mid-60s
Colon Cancer (and other intestinal tumors)
1. Hereditary Nonpolyposis Colorectal Cancer (Lynch II syndrome)
  1. Confers 10-12% lifetime Ovarian Cancer risk
  2. Associated with non-polyposis Colorectal Cancer
  3. Also associated with upper GI cancer, urinary tract cancer, Endometrial Cancer
2. MUTYH-Associated Polyposis (Small Bowel and colon)
3. Peutz-Jeghers Syndrome
  1. Stomach and intestinal polyps with onset as teens
PTEN Hamartoma Syndrome
1. Also associated with Thyroid and Breast Cancer

Pathophysiology
Ovarian Cancer types

Epithelial cell (over 85% of all overian cancers, most patients are over age 50)
1. Subtypes
  1. Serous (40% of all Ovarian Cancers)
  2. Mucinous (25% of all Ovarian Cancers)
  3. Endometrioid (20% of all Ovarian Cancers)
Stromal cell
1. Subtypes
  1. Granulosa-theca cell
  2. Sertoli-Leydig (androblastoma)
Germ cell (5% of cases, typically age 20-30 years old)
1. Subtypes
  1. Endodermal sinus
  2. Embryonal
  3. Mature (commonly benign such as Dermoid Cysts)
Krukenburg tumor
1. Metastasis to ovary from Breast or Gastrointestinal Tract

Evaluation
Findings that may prompt further Ovarian Cancer screening

Universal Ovarian Cancer screening is not recommended in typical/normal risk, asymptomatic women by USPTF
1. Screening asymptomatic non-high risk women does not reduce mortality
2. High False Positive Rates associated with screening tools (CA-125, Transvaginal Ultrasound, bimanual exam)
3. Grossman (2018) JAMA 319(6): 588-94 [PubMed]
Family History suggestive of a cancer syndrome (BRCA1, BRCA2 or Lynch II) - see above
1. Breast Cancer: Bilateral, pre-Menopause or inrences a male relative (BRCA)
2. Ovarian Cancer in two or more first or second degree relatives (BRCA)
3. Colon Cancer or Endometrial Cancer (ask about Lynch II cluster)
Symptoms
1. At least one of the following 6 symptoms for more than 12 days per month for less than a year
  1. Pelvic Pain
  2. Abdominal Pain
  3. Increased abdominal size
  4. Abdominal Bloating
  5. Difficulty eating
  6. Early satiety
2. Efficacy
  1. Test Sensitivity: 56% in early Ovarian Cancer (and 79.5% in later stage disease)
  2. Test Specificity: 86% if younger than 50 years old, 90% if older than 50 years old
Associated paraneoplastic syndrome and other specific presentations
1. Subacute cerebellar degeneration
2. Leser-Trelat Sign
  1. New onset multiple Seborrheic Keratoses
3. Trousseau Syndrome
  1. Venous Thromboembolism (unprovoked, recurrent or migratory)
4. Hormonal presentations related to sex cord-stromal tumors
Exam
1. Abdominal mass or Adnexal Mass on bimanual rectovaginal examination
  1. See Adnexal Mass for differential diagnosis
  2. Ovary >10 cm, irregularity or nodularity should prompt further evaluation
  3. Palpable ovary 3-5 years after Menopause should also undergo further evaluation
    1. Ovaries should become non-palpable after Menopause
2. Inguinal Lymphadenopathy (although retroperitoneal involvement is more common)
3. Sister Mary Joseph Nodule (periumbilical deep Subcutaneous Nodule associated with metastases)
References
1. Goff (2007) Cancer 109(2): 221-7 [PubMed]
2. Roett (2009) Am Fam Physician 80(6): 609-18 [PubMed]

Imaging

Transvaginal Ultrasound
1. See Pelvic Ultrasound Ovarian Mass Findings
2. Indication: First line evaluation of Adnexal Mass
3. Test Sensitivity: 86-94%
4. Test Specificity: 94-96%
5. Findings on Ultrasound suggestive of Ovarian Cancer (esp if persistent >1-3 months)
  1. Ovarian volume >20 ml premenopause, non-pregnant (>10 ml Postmenopause)
  2. Increased cyst size
  3. Increased cyst wall thickness
  4. Intracystic papillary formations
  5. Intracystic solid areas
  6. Intracystic septation (complex cyst)
CT Abdomen and CT Pelvis
1. Indication: Preoperative evaluation of Adnexal Mass; monitoring post-treatment
2. Test Sensitivity: 90%
3. Test Specificity: 75%
MRI Abdomen and Pelvis
1. Indication: Further characterize indeterminate Adnexal Mass
2. Test Sensitivity: 91%
3. Test Specificity: 88%
PET Scan Abdomen and Pelvis
1. Indication: Ovarian Cancer metastases or recurrence if implants are not detectable on CT imaging alone
2. Test Sensitivity: 67%
3. Test Specificity: 79%
References
1. Funt (2002) Radiol Clin North Am 40(3): 591-608 [PubMed]

Labs
Marker for Diagnosis of Epithelial Cell Tumors (>85% of Ovarian Cancer)

CA-125 Radioimmunoassay
1. Low Test Specificity and low Test Sensitivity (especially in early disease and pre-Menopause)
  1. Test Sensitivity 79% (74 to 83%), Test Specificity 82% (76 to 85%), LR+ 4.4, LR- 0.25
2. Indications to refer to gynecologic oncology
  1. Premenopause: CA-125 >200 units/ml
  2. Post-Menopause: CA-125>35 units/ml (any elevation above normal after Menopause)
Human Epididymis Protein 4 (HE4)
1. Glycoprotein present in up to one third of ovarian tumors not expressing CA-125
2. Test Sensitivity 76% (72 to 80%), Test Specificity 93% (90 to 96%), LR+ 11.9, LR- 0.25
3. When performed with CA-125 improves Test Sensitivity to 83.8% and Specificity to 98.5%
ROMA Test
1. Consider in planned gynecologic surgery to risk stratify for surgery by gynecologic oncology
2. Do NOT use to screen for Ovarian Cancer in primary care
3. Values >=1.31 premenopause, >=2.77 post-Menopause are associated with a high likelihood of malignancy
4. Test Sensitivity 85% (81 to 88%), Test Specificity 82% (77 to 86%), LR+ 4.8, LR- 0.18
References
1. Bryce (2023) Am Fam Physician 107(3): 303-4 [PubMed]

Labs
Diagnosis of germ cell tumors (younger patients)

Germ cell tumors
1. Beta hCG
2. Serum Alpha-fetoprotein
Sex-cord stromal tumors
1. Inhibin A-B
Other biomarkers used
1. Neuron-sepcific enolase
2. Lactate Dehydrogenase

Labs
Other supportive labs

Complete Blood Count
Comprehensive metabolic panel including Serum Calcium

Staging

Stage I: Ovary only (25% of Ovarian Cancer diagnosis)
1. Stage IA: One ovary involved
2. Stage IB: Both ovaries involved
3. Stage IC: Stage IA or IB with below:
  1. Tumor on surface of ovary or
  2. Ovarian capsule ruptured or
  3. Malignant Ascites or
  4. Peritoneal cytology positive
Stage II: Pelvic Extension
1. Stage IIA: Spread to Uterus or fallopian tubes
2. Stage IIB: Spread to other pelvic tissues
3. Stage IIC: Stage IIA or IIB with below
  1. Tumor on surface of ovary or
  2. Ovarian capsule ruptured or
  3. Malignant Ascites or
  4. Peritoneal cytology positive
Stage III: Peritoneal implants
1. Stage IIIA: Microscopic seeding to peritoneum
2. Stage IIIB: Abdominal peritoneal implants <2 cm
3. Stage IIIC: Abdominal implants >2cm or positive nodes
Stage IV: Distant Metastasis

Management
Surgical resection

First-line tool for staging and debulking
1. May be curative in early disease
Standard resection
1. Protocol
  1. Total abdominal Hysterectomy
  2. Bilateral salping-oopherectomy
  3. Pelvic and para-aortic Lymph Node resection
  4. Omentum resection
  5. Appendectomy (in mucinous Ovarian Cancer)
2. Efficacy: Radical surgical resection improves survival
  1. Benefit most significant in carcinomatosis
  2. Cliby (2006) Obstet Gynecol 107:77-85 [PubMed]
Fertility-sparing procedures
1. Indications
  1. Stage I Ovarian Cancer in age 30-50 years
  2. Low malignant potential tumors
  3. Germ cell tumors
  4. Sex cord-stromal tumors
2. Protocol
  1. Unilateral salpingo-oophorectomy
  2. Consider later total Hysterectomy and contralateral salpingoopherectomy
  3. Adjuvant Chemotherapy in these lower risk cases only if residual disease post-resection

Management
Adjuvant Chemotherapy

Indications
1. Stage II-IV Ovarian Cancer (not typically for Stage I or ovary-confined disease)
Typically administered every 3 weeksfor 6 cycles (70% respond)
Medications: Protocols combine Platinum with Taxane
1. Platinum Agents
  1. Cisplatin
    1. Significant Nausea and Vomiting
    2. Significant nephrotoxicity and neurotoxicity
    3. Administered over 24 hours with IV fluids
  2. Carboplatin
    1. Equivalent efficacy to Cisplatin
    2. Much less toxicity than with Cisplatin
    3. Can be administered outpatient over 3 hours
2. Taxane Agents
  1. Paclitaxel (Taxol)
    1. Arthralgias and myalgias may be significant
    2. Risk of Peripheral Neuropathy
  2. Docetaxel
    1. Significant Neutropenia and nadir fever
    2. Less risk of adverse effects seen with Taxol
    3. May be preferred in pre-existing Neuropathy
Intravenous (all 3 protocols with similar efficacy)
1. Protocol 1: Cisplatin and Paclitaxel (Taxol)
2. Protocol 2: Carboplatin and Paclitaxel
3. Protocol 3: Carboplatin and Docetaxel
Intraperitoneal (Regional) Chemotherapy
1. Cisplatin is currently being used
2. Carboplatin appears safe but efficacy not proven
Current protocol recommended by NCI
1. Cisplatin and Taxol Intraperitoneal and IV
2. Armstrong (2006) NEJM 354:34-43 [PubMed]
References
1. Markman (2003) Hematol Oncol Clin North Am 17:957 [PubMed]

Management
Ovarian Cancer Survivor

Gynecologic oncology
1. First 2 years: Visits every 2-4 months
2. Next 3 years: Visits every 3-6 months
3. After 5 years: Yearly (surveillance may be transitioned to primary care at this point)
Exams and labs for each visit
1. Pelvic exam
2. Surveillance of previously elevated markers (e.g. CA-125, HE-4)
Genetic Counseling
1. As indicated if referral not already made
2. Evaluate for risk of other hereditary cancers as well as determine risk in children
Additional measures as indicated
1. Other labs (e.g. Complete Blood Count, serum chemistry panel)
2. Imaging (CT, MRI, PET scan, Chest XRay)
References
1. Salani (2011) Am J Obstet Gynecol 204(6): 466-78 [PubMed]

Prognosis

Median survival: 32 months
Five year survival
1. Overall five year survival: 40-45%
2. Five year survival for advanced Ovarian Cancer: 17-20%
  1. Later stage Ovarian Cancer presentations account for 60% of cases
3. Stage 1: 92% five year survival for epithelial cell (95-96% for stromal or germ cell)
4. Stage 2: 73-78% five year survival for epithelial cell (78% for stromal or germ cell)
5. Stage 3: 39-59% five year survival for epithelial cell (65% for stromal or germ cell)
6. Stage 4: 17-28% five year survival for epithelial cell (35% for stromal or germ cell)
Predictors of better outcome
1. Low-grade, Stage I Epithelial cell tumor (typically in premenopausal women): 95-99% ten year survival
Predictors of worse outcome
1. Age >75 contrasted with age <45 (Hazard Ratio 2.8)
2. Residual tumor >1 cm (Hazard Ratio 1.72)
3. FIGO stage 4 versus stage 1 (Hazard Ratio 11.75)
4. Clear cell or mucinous cell tumors
References
1. Tingulstad (2003) Obstet Gynecol 101:885-91 [PubMed]

Prevention

Universal Ovarian Cancer screening is not recommended by USPTF, AAFP
1. High risk patients for Genetic Syndromes (see below) should be offered Genetic Counseling
2. Positive testing for high risk Genetic Syndromes should prompt screening protocol (see below)
Factors associated with a decreased risk of Ovarian Cancer development
1. More than one full-term pregnancy (risk decreases with each successive pregnancy)
2. Oral Contraceptive use (extended use of 4 years reduces risk of Ovarian Cancer by 50% in BRCA patients)
3. Surgeries that reduce uterine and ovarian Blood Flow (Hysterectomy, Tubal Ligation)
4. Late Menarche and early Menopause
5. Low Fat Diet
6. Avoid postmenopausal Hormone Replacement

Prevention
High Risk Patients (Hereditary Ovarian Cancer Syndromes - BRCA1, BRCA2, Lynch II)

Prophylactic Oophorectomy (preferred)
1. Oophorectomy at age 35 or when childbearing complete
2. Estrogen Replacement after oophorectomy (not if post-menopausal)
3. Efficacy
  1. Reduces Ovarian Cancer risk by 69-100%
  2. Peritoneal Primary papillary serous tumors may occur
Surveillance (alternative for those who forestall oophorectomy)
1. BRCA: Transvaginal Ultrasound and CA-125 every 6 months during days 1-10 of Menstrual Cycle
2. Lynch II: Transvaginal Ultrasound annually
3. Onset of screening
  1. Age 35 years or
  2. Start 5-10 years earlier than the earliest case in the family
4. Efficacy
  1. Test Sensitivity: 50-71%
  2. Test Specificity: 91%

References