Ovarian Cancer

Overview

Ovarian cancer is a type of cancer that begins in the ovaries, the female reproductive organs responsible for producing eggs (ova) and hormones such as estrogen and progesterone. Despite accounting for only about 3% of cancers in women, ovarian cancer causes more deaths than any other cancer of the female reproductive system. This high mortality rate is largely due to the fact that ovarian cancer often goes undetected until it has spread within the pelvis and abdomen, making it more difficult to treat.

The ovaries are small, almond-shaped organs located on either side of the uterus. Each ovary is about the size of a walnut and contains thousands of eggs that can potentially be released during a woman's reproductive years. The ovaries are also part of the endocrine system, producing hormones that regulate menstruation, pregnancy, and other bodily functions.

Ovarian cancer was traditionally thought to begin in the ovaries themselves, but recent evidence suggests that many ovarian cancers may actually originate in the fallopian tubes and spread to the ovaries. This discovery has important implications for both prevention and early detection strategies. The disease affects approximately 1 in 78 women during their lifetime, with the median age at diagnosis being 63 years.

The prognosis for ovarian cancer varies significantly depending on the stage at diagnosis. When detected early and confined to the ovary, the 5-year survival rate is over 90%. However, only about 20% of ovarian cancers are found at this early stage. For advanced disease that has spread beyond the pelvis, the 5-year survival rate drops to about 30%. This stark difference underscores the critical importance of awareness, early detection, and ongoing research into better screening methods.

Symptoms

Ovarian cancer has been called the "silent killer" because symptoms often don't appear until the disease is advanced. However, research has shown that women with ovarian cancer do experience symptoms, even in early stages, but these symptoms are often vague and easily attributed to other conditions.

Additional Common Symptoms

• Pelvic or abdominal pain: Persistent discomfort that doesn't improve with usual remedies
• Urinary symptoms: Urgency or frequency of urination without infection
• Changes in bowel habits: Constipation or diarrhea
• Unexplained weight loss: Losing weight without trying
• Fatigue: Extreme tiredness that doesn't improve with rest
• Back pain: Particularly lower back pain
• Menstrual changes: Irregular periods or postmenopausal bleeding
• Pain during intercourse: New onset dyspareunia
• Abdominal swelling: Increase in abdominal girth
• Indigestion or heartburn: Persistent digestive issues

The Importance of Symptom Persistence

What distinguishes ovarian cancer symptoms from benign conditions is their persistence and progression. Symptoms that:

• Occur more than 12 times per month
• Are new within the past year
• Don't resolve with usual interventions
• Progressively worsen over time

Should prompt medical evaluation, especially in women over 50 or with risk factors.

Causes

The exact cause of ovarian cancer is not fully understood, but researchers have identified several factors that contribute to its development. Like other cancers, ovarian cancer results from genetic mutations that cause cells to grow and multiply uncontrollably.

Cellular Origins

Recent research has revolutionized our understanding of where ovarian cancers originate:

Fallopian Tube Origin Theory

• Many high-grade serous ovarian cancers may start in the fallopian tubes
• Precancerous cells (serous tubal intraepithelial carcinoma) found in tubes
• These cells may shed and implant on the ovary surface
• Explains why removing fallopian tubes reduces ovarian cancer risk

Ovarian Surface Epithelium

• Traditional theory: cancer arises from the ovary's outer layer
• Repeated ovulation causes trauma and repair cycles
• Each repair cycle increases mutation risk
• May explain why factors reducing ovulation lower risk

Genetic Mutations

Hereditary Mutations

• BRCA1 and BRCA2: Account for 10-15% of ovarian cancers
  • BRCA1: 35-70% lifetime risk of ovarian cancer
  • BRCA2: 10-30% lifetime risk of ovarian cancer
• Lynch syndrome: 10-12% lifetime risk
• Other genes: RAD51C, RAD51D, BRIP1, PALB2

Acquired Mutations

• TP53: Tumor suppressor gene mutated in most high-grade serous cancers
• KRAS, BRAF: Common in low-grade serous cancers
• ARID1A, PIK3CA: Found in endometrioid and clear cell types
• HER2: Overexpressed in some ovarian cancers

Hormonal Factors

Hormones play a significant role in ovarian cancer development:

• Estrogen exposure: Lifetime exposure influences risk
• Ovulation: Each ovulation causes minor trauma to ovarian surface
• Gonadotropins: High levels may stimulate ovarian cells
• Androgens: May promote certain ovarian cancer types

Inflammatory Factors

• Endometriosis increases risk, especially for clear cell and endometrioid types
• Pelvic inflammatory disease may contribute
• Talc use historically linked to inflammation (contaminated with asbestos)

Risk Factors

Understanding risk factors for ovarian cancer is crucial for identifying women who may benefit from enhanced surveillance or preventive measures. Risk factors can be broadly categorized into those that increase risk and those that are protective.

Risk Assessment Tools

Several models help estimate ovarian cancer risk:

• BRCAPRO: Estimates probability of BRCA mutations
• Tyrer-Cuzick model: Incorporates multiple risk factors
• NCCN guidelines: Define high-risk criteria for genetic testing

High-Risk Categories

Women considered at high risk include those with:

• Known genetic mutations (BRCA1/2, Lynch syndrome)
• Strong family history (multiple affected relatives)
• Personal history of breast cancer before age 50
• Ashkenazi Jewish ancestry with family history
• Risk assessment models showing >5% lifetime risk

Types of Ovarian Cancer

Ovarian cancers are classified based on the type of cell where they originate. Each type has different characteristics, prognoses, and treatment approaches.

Epithelial Ovarian Cancer

Accounts for 90% of ovarian cancers, arising from the surface epithelium of the ovary or fallopian tube.

High-Grade Serous Carcinoma (HGSC)

• Most common type (70% of epithelial cancers)
• Often originates in fallopian tubes
• Usually diagnosed at advanced stage
• TP53 mutations in >95% of cases
• Responds well to platinum chemotherapy initially
• BRCA mutations in 15-20% of cases

Low-Grade Serous Carcinoma

• Less than 5% of epithelial cancers
• Younger age at diagnosis
• Slow-growing but chemotherapy-resistant
• KRAS or BRAF mutations common
• Better prognosis than high-grade

Endometrioid Carcinoma

• 10% of epithelial cancers
• Associated with endometriosis
• Often diagnosed at early stage
• May occur with endometrial cancer
• Generally good prognosis

Clear Cell Carcinoma

• 10% of epithelial cancers
• Associated with endometriosis
• More common in Asian populations
• Resistant to standard chemotherapy
• Risk of blood clots

Mucinous Carcinoma

• 3% of epithelial cancers
• Can be large at diagnosis
• Important to rule out metastasis from GI tract
• Chemotherapy-resistant if advanced

Germ Cell Tumors

5% of ovarian cancers, arising from egg-producing cells:

• Dysgerminoma: Most common, similar to testicular seminoma
• Yolk sac tumor: Produces AFP, common in young women
• Immature teratoma: Contains immature tissue elements
• Choriocarcinoma: Produces hCG, highly malignant
• Usually affect younger women (teens and 20s)
• Generally have excellent prognosis with treatment

Sex Cord-Stromal Tumors

5% of ovarian cancers, arising from connective tissue cells:

• Granulosa cell tumors: Produce estrogen, can recur late
• Sertoli-Leydig cell tumors: May produce androgens
• Fibroma/thecoma: Usually benign
• Often produce hormones causing symptoms
• Generally have good prognosis

Borderline Ovarian Tumors

Also called low malignant potential tumors:

• 10-15% of epithelial ovarian tumors
• Abnormal cells that don't invade surrounding tissue
• Excellent prognosis (>95% cure rate)
• Can recur, rarely progress to cancer
• Fertility-sparing surgery often possible

Diagnosis

Diagnosing ovarian cancer can be challenging because symptoms are often vague and there is no effective screening test for the general population. A combination of clinical evaluation, imaging, blood tests, and ultimately tissue diagnosis is required.

Initial Evaluation

Medical History and Physical Examination

• Detailed symptom history and duration
• Family history of cancer (especially ovarian, breast, colorectal)
• Reproductive history (pregnancies, contraceptive use, infertility)
• Pelvic examination to feel for masses or abnormalities
• Abdominal examination for distension, fluid, masses
• Lymph node examination

Blood Tests

Tumor Markers

• CA-125:
  • Elevated in 80% of advanced epithelial ovarian cancers
  • Less reliable in early-stage disease (50% sensitivity)
  • Can be elevated in benign conditions
  • More specific in postmenopausal women
• HE4: More specific than CA-125, especially in premenopausal women
• ROMA score: Combines CA-125, HE4, and menopausal status
• CEA, CA 19-9: May suggest GI origin if elevated
• AFP, hCG, LDH: For suspected germ cell tumors
• Inhibin, estradiol: For suspected sex cord-stromal tumors

Imaging Studies

Transvaginal Ultrasound

• First-line imaging for pelvic masses
• Evaluates size, complexity, blood flow
• Distinguishes cystic from solid components
• Color Doppler assesses vascularity

CT Scan

• Chest, abdomen, and pelvis for staging
• Detects metastases, lymph nodes, ascites
• Helps surgical planning
• Not ideal for characterizing ovarian masses

MRI

• Better soft tissue characterization than CT
• Helpful for indeterminate masses
• Evaluates local invasion
• Diffusion-weighted imaging improves accuracy

PET/CT

• Not routine for initial diagnosis
• May help in recurrent disease
• Detects metabolically active disease

Tissue Diagnosis

Surgery is Usually Required

Unlike many cancers, ovarian cancer is typically diagnosed during surgery rather than by biopsy:

• Risk of tumor spillage with biopsy
• Surgery provides staging information
• Allows for treatment (debulking) at same time

Exceptions for Biopsy

• Suspected metastatic disease to ovary
• Patient not surgical candidate
• Neoadjuvant chemotherapy planned
• Image-guided biopsy of omental cake or ascites

Genetic Testing

Recommended for all women with epithelial ovarian cancer:

• BRCA1/2 testing at minimum
• Multi-gene panel testing increasingly common
• Tumor testing for homologous recombination deficiency
• Microsatellite instability testing
• Results impact treatment and family screening

Differential Diagnosis

Conditions that can mimic ovarian cancer:

• Benign ovarian cysts and tumors
• Endometriosis/endometriomas
• Pelvic inflammatory disease
• Metastatic cancer from other sites
• Fibroids
• Gastrointestinal tumors

Staging

Ovarian cancer staging is crucial for treatment planning and prognosis. The FIGO (International Federation of Gynecology and Obstetrics) staging system is used worldwide, updated in 2014 to better reflect prognosis.

FIGO Staging System

Surgical Staging Procedures

Comprehensive surgical staging includes:

• Careful inspection of all peritoneal surfaces
• Peritoneal washings or ascites sampling
• Total abdominal hysterectomy and bilateral salpingo-oophorectomy
• Omentectomy
• Pelvic and para-aortic lymph node dissection
• Random peritoneal biopsies
• Biopsy of any suspicious areas

Grade Classification

• Grade 1: Well differentiated
• Grade 2: Moderately differentiated
• Grade 3: Poorly differentiated or undifferentiated

Prognostic Factors

Beyond stage, factors affecting prognosis include:

• Histologic type: Clear cell and mucinous have worse prognosis
• Grade: Higher grade associated with worse outcomes
• Residual disease: Amount of tumor remaining after surgery
• CA-125 levels: Normalization after treatment
• Performance status: Overall health and function
• BRCA status: BRCA-mutated cancers often respond better to treatment

Pattern of Spread

Understanding how ovarian cancer spreads helps with staging and treatment:

• Direct extension: To adjacent pelvic organs
• Peritoneal seeding: Most common route; follows peritoneal fluid circulation
• Lymphatic spread: To pelvic and para-aortic nodes
• Hematogenous spread: Less common; to liver, lungs, bones

Treatment Options

Treatment for ovarian cancer typically involves a combination of surgery and chemotherapy. The specific approach depends on the cancer stage, type, patient's overall health, and fertility desires.

Surgery

Primary Debulking Surgery

The goal is complete removal of all visible tumor (optimal cytoreduction):

• Standard procedures:
  • Total abdominal hysterectomy
  • Bilateral salpingo-oophorectomy
  • Omentectomy
  • Lymph node dissection
  • Removal of all visible disease
• Additional procedures as needed:
  • Bowel resection
  • Diaphragm stripping
  • Splenectomy
  • Liver resection
  • Peritonectomy
• Outcomes:
  • R0: No gross residual disease (best outcome)
  • R1: Residual disease ≤1 cm
  • R2: Residual disease >1 cm

Fertility-Sparing Surgery

For select young women with early-stage disease:

• Unilateral salpingo-oophorectomy
• Comprehensive staging
• Preservation of uterus and contralateral ovary
• Close follow-up required
• Complete surgery after childbearing

Interval Debulking Surgery

• After 3-4 cycles of neoadjuvant chemotherapy
• For patients not initially resectable
• Similar survival to primary surgery in appropriate patients

Chemotherapy

First-line Chemotherapy

Maintenance Therapy

• PARP inhibitors:
  • Olaparib: For BRCA-mutated or HRD-positive cancers
  • Niraparib: Approved regardless of BRCA status
  • Rucaparib: For BRCA-mutated cancers
• Bevacizumab: Anti-angiogenic therapy
• Combination: Olaparib + bevacizumab for HRD-positive

Treatment by Stage

Early Stage (I-II)

• Comprehensive surgical staging
• Adjuvant chemotherapy for:
  • Stage IC or II
  • High-grade tumors
  • Clear cell or carcinosarcoma histology
• 3-6 cycles of chemotherapy typically

Advanced Stage (III-IV)

• Primary debulking surgery if resectable
• Neoadjuvant chemotherapy if not initially resectable
• 6 cycles of combination chemotherapy
• Maintenance therapy based on molecular features

Recurrent Disease Treatment

Platinum-Sensitive Recurrence (>6 months)

• Platinum-based combination chemotherapy
• Consider secondary cytoreduction
• Add bevacizumab if not used previously
• PARP inhibitor maintenance

Platinum-Resistant Recurrence (<6 months)

• Single-agent chemotherapy (pegylated liposomal doxorubicin, topotecan, gemcitabine)
• Bevacizumab combination
• Clinical trials
• Focus on quality of life

Targeted and Immunotherapy

• PARP inhibitors: Exploit homologous recombination deficiency
• Anti-angiogenic agents: Bevacizumab, pazopanib
• Immunotherapy: Limited role currently; trials ongoing
• Folate receptor alpha antibodies: Mirvetuximab soravtansine

Supportive Care

• Management of chemotherapy side effects
• Nutritional support
• Pain and symptom management
• Psychological support and counseling
• Genetic counseling for families
• Fertility preservation counseling
• Palliative care integration

Prevention

While there's no guaranteed way to prevent ovarian cancer, several strategies can significantly reduce risk, especially for high-risk women.

Risk-Reducing Surgery

Prophylactic Bilateral Salpingo-oophorectomy (PBSO)

• Removes ovaries and fallopian tubes preventively
• Reduces ovarian cancer risk by 80-90% in BRCA carriers
• Also reduces breast cancer risk by 50% if premenopausal
• Recommended timing:
  • BRCA1: By age 35-40
  • BRCA2: By age 40-45
  • After completion of childbearing
• Includes careful pathologic examination (SEE-FIM protocol)

Opportunistic Salpingectomy

• Removal of fallopian tubes during other pelvic surgery
• Preserves ovarian function
• May reduce ovarian cancer risk by 65%
• Recommended for women undergoing:
  • Hysterectomy for benign disease
  • Sterilization procedures

Medications

Oral Contraceptives

• 5 years of use reduces risk by 50%
• Protection persists for decades after stopping
• Benefits outweigh small increased risk of breast cancer
• Particularly beneficial for BRCA mutation carriers

Aspirin

• Regular use may reduce risk by 20-30%
• Most benefit with daily low-dose aspirin
• Consider risks vs. benefits with physician

Lifestyle Modifications

Reproductive Factors

• Pregnancy: Each full-term pregnancy reduces risk
• Breastfeeding: Longer duration provides more protection
• Tubal ligation: Reduces risk by disrupting path to ovaries

Diet and Exercise

• Maintain healthy body weight
• Regular physical activity
• Diet rich in vegetables and low in animal fat
• Limited evidence for specific dietary supplements

Screening and Early Detection

Current Limitations

• No effective screening for general population
• CA-125 and ultrasound have high false-positive rates
• Large trials (PLCO, UKCTOCS) show no mortality benefit
• Risk of unnecessary surgery from false positives

High-Risk Surveillance

For women at high genetic risk who decline or delay surgery:

• Consider enrollment in research protocols
• Every 6 months starting at age 30-35:
  • Transvaginal ultrasound
  • CA-125 blood test
• Limited effectiveness; surgery remains gold standard

Genetic Counseling and Testing

• Identify high-risk individuals
• Test for hereditary cancer syndromes
• Cascade testing of family members
• Personalized risk assessment
• Discussion of prevention options

Future Directions

Research into prevention includes:

• Better understanding of fallopian tube origins
• Biomarkers for early detection
• Preventive vaccines
• Improved risk assessment models
• Novel chemoprevention agents

When to See a Doctor

Early detection of ovarian cancer can be challenging, but prompt medical attention for concerning symptoms is crucial.

Seek Medical Evaluation For:

• Persistent bloating: Daily for more than 2-3 weeks
• Pelvic or abdominal pain: That doesn't resolve with usual measures
• Difficulty eating or feeling full quickly: New onset and persistent
• Urinary symptoms: Urgency or frequency without infection
• Changes in bowel habits: Lasting more than a few days
• Unexplained weight loss: Especially with abdominal symptoms
• Abnormal vaginal bleeding: Especially after menopause

Important Considerations

High-Risk Individuals Should Discuss:

• Genetic testing if family history suggests hereditary cancer
• Risk-reducing surgery options and timing
• Enhanced surveillance protocols
• Chemoprevention strategies
• Family planning considerations

During Treatment - Contact Your Team For:

• Fever >100.4°F (38°C)
• Severe nausea/vomiting preventing fluid intake
• Signs of infection at surgical sites
• Shortness of breath or chest pain
• Severe abdominal pain or distension
• Inability to have bowel movement for >3 days
• New or worsening symptoms

Follow-up Care

After treatment, regular follow-up is essential:

• Physical exam every 3-4 months for 2 years
• Then every 6 months for 3 years
• Annual visits thereafter
• CA-125 monitoring if initially elevated
• Imaging as clinically indicated
• Report new symptoms promptly

Genetic Counseling Referral Criteria

Consider genetic counseling if you have:

• Personal history of ovarian cancer
• Family history of ovarian cancer at any age
• Family history of breast cancer <50 years
• Male breast cancer in family
• Multiple cancers in one person
• Ashkenazi Jewish ancestry with cancer history

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