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Ovarian Cancer
Celeste Straight, MD
Susan Zweizig, MD
image BASICS
There are >22,000 new cases of ovarian cancer annually, and >15,000 women will die of their disease, making this the most lethal of gynecologic cancers.
DESCRIPTION
Malignancy that arises from the epithelium (90%), stroma, or germ cells of the ovary; also, tumors metastatic to the ovary; histologic types include the following:
  • Epithelial
    • Serous (tubal epithelium)
    • Mucinous (cervical and GI mucinous epithelium)
    • Endometrioid (endometrial epithelium)
    • Clear cell (mesonephroid)
    • Brenner (transitional cell epithelium)
    • Carcinosarcoma
  • Stromal
    • Granulosa cell tumor
    • Theca cell tumor
    • Sertoli-Leydig cell tumors
    • Gynandroblastoma
    • Lipid cell tumor
  • Germ cell
    • Teratoma (immature)
    • Dysgerminoma
    • Embryonal carcinoma
    • Gonadoblastoma
    • Endodermal sinus tumor
    • Embryonal carcinoma
    • Choriocarcinoma
  • Metastatic disease from the following:
    • Breast
    • Endometrium
    • Lymphoma
    • GI tract (Krukenberg tumor)
    • Primary peritoneal
  • System(s) affected: GI, reproductive, endocrine, metabolic
EPIDEMIOLOGY
Incidence
  • 21,990 new cases/year in the United States; 15,460 deaths/year
  • Leading cause of gynecologic cancer death in women; mortality from ovarian cancer has decreased only slightly during the past 4 decades (1)[A].
  • 75% diagnosed at advanced stage
  • Predominant age
    • Epithelial: mid-50s
    • Germ cell malignancies: usually observed in patients <20 years of age
Prevalence
Lifetime risk for general population: 1 in 70 women develop ovarian cancer.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Malignant transformation of the ovarian epithelium from repeated trauma during ovulation may lead to this change. Many of these cancers originate in the distal fallopian tube.
  • Most ovarian cancer (75%) presents as advanced disease. Metastatic disease may develop at the same time as the primary tumor (1).
Genetics
  • Hereditary breast/ovarian cancer syndrome: earlyonset breast or ovarian cancer, autosomal dominant transmission, usually associated with BRCA-1 or BRCA-2 mutation
  • Lynch II syndrome: autosomal dominant inheritance; increased risk for colorectal, endometrial, stomach, small bowel, breast, pancreas, and ovarian cancers; defect in mismatch repair genes
RISK FACTORS
  • 90% of ovarian cancer is sporadic and not inherited, but family history is the most significant risk factor. Multiple relatives with breast or ovarian cancer increases risk: Refer these patients for genetic counseling. Individuals in families with familial cancer syndromes have 20-60% risk of developing ovarian cancer.
  • Nulligravidity (or infertility), early menarche, late menopause, endometriosis
  • Environmental (talc, smoking, obesity)
GENERAL PREVENTION
For epithelial cancer, frequency of ovulation appears to be important. The following factors are protective (1)[A]:
  • Use of oral contraceptives: 5 years of use decreases risk by 20%; 15 years by 50%.
    • The progestin component of oral contraceptive preparations (OCPs) may protect against ovarian cancer by regulating apoptosis of the ovarian epithelium (2)[A].
  • Multiparity
  • Breastfeeding
  • Tubal ligation or hysterectomy
  • Recent studies have shown no clear association exists between ovarian cancer and use of ovulationinduction agents such as clomiphene, but more long-term studies are necessary.
  • NSAIDs and acetaminophen use have been shown to reduce risk of ovarian cancer.
  • Recommendations for high-risk (family history of a hereditary ovarian cancer syndrome) population
    • Women should undergo pelvic examinations, CA-125 level measurement, and transvaginal US every 6 to 12 months beginning at age 25 to 35 years.
    • Women with family histories of ovarian cancer or premenopausal breast cancer should be referred for genetic counseling.
    • Prophylactic oophorectomy is advised for mutation carriers after childbearing is completed or by age 35 years.
      • Risk of primary peritoneal carcinoma is 1% after prophylactic oophorectomy.
  • Screening: No effective screening exists for ovarian cancer (1)[A].
    • Routine use of CA-125 and transvaginal US for screening in women of average risk is discouraged. Annual pelvic examinations are recommended, particularly in postmenopausal women. An adnexal mass in a premenarchal female or a palpable adnexa in a postmenopausal female warrants further evaluation.
COMMONLY ASSOCIATED CONDITIONS
  • Ascites
  • Pleural effusion
  • Decrease of serum albumin
  • Breast carcinoma
  • Bowel obstruction
  • Carcinomatosis
image DIAGNOSIS
PHYSICAL EXAM
  • Ascites
  • Cul-de-sac and/or pelvic nodularity
  • Pelvic mass
  • Pleural effusion
  • Omental mass
  • Cachexia
  • Adenopathy
  • Hirsutism in androgen-secreting germ cell tumors
DIFFERENTIAL DIAGNOSIS
  • GI, fallopian, or endometrial malignancies
  • Irritable bowel syndrome
  • Colitis
  • Hepatic failure with ascites
  • Diverticulitis
  • Pelvic kidney
  • Tubo-ovarian abscess or hydrosalpinx
  • Uterine fibroids
  • Endometriomas
  • Physiologic cysts
  • Benign or borderline neoplasms
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Obtain only with confirmed or suspected disease.
  • CA-125 (not specific for ovarian cancer, not to be used for screening)
  • Liver function tests (LFTs) to rule out hepatic disease
  • CBC
  • Urinalysis
  • Serum albumin
  • Carcinoembryonic antigen (CEA) if GI primary suspected
  • If nonepithelial tumor suspected: chorionic gonadotropin (&bgr;-hCG [dysgerminoma, choriocarcinoma, embryonal carcinoma]), &agr;-fetoprotein (endodermal sinus tumor, embryonal carcinoma), lactate dehydrogenase (LDH [dysgerminoma]), or inhibin (granulosa cell tumor)
  • Pelvic US
  • CXR
  • Abdominopelvic CT scan with contrast material
P.747

Follow-Up Tests & Special Considerations
Disorders that may alter lab results: CA-125 may be elevated from gynecologic causes (e.g., menses, pregnancy, endometriosis, peritonitis, myomas, pelvic inflammatory disease) and with ascites, pleural effusion, congestive heart failure (CHF), pancreatitis, systemic lupus erythematosus (SLE), or liver disease.
  • Patients with ovarian cancer need current mammography.
  • Barium enema or colonoscopy if a colon primary is suspected
Diagnostic Procedures/Other
  • Endometrial biopsy if abnormal bleeding present
  • Surgery is necessary for definitive diagnosis.
  • Paracentesis if patient with symptomatic ascites and not an operative candidate
Test Interpretation
Epithelial ovarian cancer commonly involves the peritoneal surfaces of the abdomen and pelvis, especially the cul-de-sac, paracolic gutters, and diaphragmatic surfaces.
image TREATMENT
MEDICATION
First Line
  • After surgery, most patients will require chemotherapy or adjuvant therapy. Stage 1a, grade 1 and most stage 1b, grade 1 tumors do not require adjuvant therapy. Patients with clear cell carcinomas, grade 3 tumors, or tumors staged 1c or worse do require adjuvant therapy. Patients should be encouraged to participate in clinical trials whenever possible.
  • Paclitaxel (Taxol) or docetaxel are recommended in combination with platinum-based therapy (carboplatin or cisplatin) as the first-line treatment of epithelial ovarian cancer.
  • Intraperitoneal (IP) chemotherapy in combination with IV chemotherapy improves survival in advanced ovarian cancer. IP chemotherapy is associated with more toxicity (4)[A].
  • Germ cell cancers: bleomycin, etoposide, platinum agent
  • Contraindications: poor functional status, excessive toxicity, hypersensitivity
  • Precautions: All regimens cause bone marrow suppression. Cisplatin is associated with ototoxicity, renal toxicity, and peripheral neuropathy. Taxol can cause neutropenia and neuropathy.
  • Antiemetic: ondansetron (Zofran), dronabinol (Marinol), metoclopramide (Reglan), prochlorperazine (Compazine), promethazine (Phenergan)
Second Line
  • Liposomal doxorubicin
  • Carboplatin/gemcitabine
  • Topotecan
  • Etoposide
  • Bevacizumab
  • Cyclophosphamide
  • Tamoxifen may be used in recurrent disease when chemotherapy is not appropriate (5)[A].
ADDITIONAL THERAPIES
Some patients with advanced disease and poor functional status and/or extreme tumor burden are managed with preoperative chemotherapy (neoadjuvant treatment) followed by interval cytoreductive surgery. These patients receive more chemotherapy after tumor debulking.
SURGERY/OTHER PROCEDURES
  • Surgical exploration with staging and debulking is critical. Maximal cytoreduction of tumor burden enhances effectiveness of adjuvant therapy and is associated with longer survival.
  • For epithelial malignancies, careful staging, tumor excision/debulking includes the following:
    • Cytologic evaluation of peritoneal fluid (or washings from peritoneal lavage)
    • Bilateral salpingo-oophorectomy with hysterectomy and tumor reductive surgery
    • Excision of omentum
    • Inspection and palpation of peritoneal surfaces
    • Cytologic smear of right hemidiaphragmatic surface
    • Biopsy of adhesions or any suspicious areas
    • Biopsy of paracolic recesses, pelvic sidewalls, posterior cul-de-sac, and bladder peritoneum
    • Pelvic and para-aortic lymph node biopsies
  • Germ cell cancers (less likely to be bilateral): salpingo-oophorectomy (unilateral if only one ovary involved) in young patient
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Physical exam every 3 months for the first 2 years after diagnosis; every 6 months until 5 years and then annually thereafter
  • If CA-125 elevated at diagnosis, follow levels after treatment to detect recurrence (is often elevated 2 to 5 months before clinical detection of relapse).
  • Germ cell/sex-cord stromal cancer: physical exam and tumor markers every 3 months for the first 2 years after diagnosis
    • Tumor markers for sex-cord stromal cancers should be checked every 6 months for 10 years, as recurrences can occur remote from initial diagnosis.
  • CT scan of chest, abdomen, and pelvis and/or PET scan when recurrence suspected
  • Screening with CXR, MRI, CT, or PET not recommended; insufficient data to support (6)[B]
PROGNOSIS
  • Recurrence rates
    • Early-stage disease: 25%
    • Advanced disease: >80%
  • 5-year survival rates for ovarian cancer based on International Federation of Gynecology and Obstetrics (FIGO) data
  • For most recent FIGO staging criteria, see “References” (7)[A].

Stage I

a 90%

b 86%

c 83%

Stage II

a 71%

b 66%

c 71%

Stage III

a 47%

b 42%

c 33%

Stage IV

19%

REFERENCES
1. Schorge JO, Modesitt SC, Coleman RL, et al. SGO white paper on ovarian cancer: etiology, screening and surveillance. Gynecol Oncol. 2010;119(1):7-17.
2. Beral V, Doll R, Hermon C, et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet. 2008;371(9609):303-314.
3. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer. 2007;109(2):221-227.
4. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43.
5. Orlando M, Costanzo MV, Chacon RD, et al. Randomized trial of combination chemotherapy (combo) versus monotherapy (mono) in relapsed ovarian carcinoma (ROC): a meta-analysis of published data. J Clin Oncol. 2007;25:5524.
6. Gadducci A, Cosio S, Zola P, et al. Surveillance procedures for patients treated for epithelial ovarian cancer: a review of the literature. Int J Gynecol Cancer. 2007;17(1):21-31.
7. Prat J. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124(1):1-5.
Additional Reading
&NA;
  • Salani R, Backes FJ, Fung MF, et al. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol. 2011;204(6):466-478.
  • Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol. 2003;21(6):1180-1189.
Codes
&NA;
ICD10
  • C56.9 Malignant neoplasm of unspecified ovary
  • C56.1 Malignant neoplasm of right ovary
  • C56.2 Malignant neoplasm of left ovary
Clinical Pearls
&NA;
  • Family history of ovarian cancer or early-onset breast cancer is the most significant risk factor for the development of ovarian cancer; yet, the vast majority of cases remain sporadic.
  • The diagnosis of ovarian cancer should be suspected in women with persistent bloating, upper abdominal discomfort, or GI symptoms of unknown etiology.
  • Surgery is the mainstay of diagnosis and treatment for ovarian cancer. Many patients benefit from adjuvant chemotherapy.
  • The prognosis of advanced ovarian cancer is poor and requires close follow-up by physical exam, tumor markers, and imaging when indicated.