Issues in Gynecologic Disease

Educational Objectives

The goal of this program is to increase the rate of early detection of ovarian cancer and improve the management of women with endometriosis. After hearing and assimilating this program, the clinician will be better able to:

Review methods of measuring test efficacy and determine how they apply to disease screening.

Recognize early symptoms of ovarian cancer and identify women who should undergo screening for ovarian can­cer.

List current and promising ovarian cancer screening tests and distinguish them by levels of efficacy.

Discuss the efficacy of surgical interventions for endometriosis.

Determine the appropriate medical therapy for patients with endometriosis.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Leiserowitz was recorded at Women’s Health Conference, sponsored by the University of California, Davis, Health Sys­tem Office of Continuing Medical Education and Women’s Center for Health, held June 15-19, 2008, in Monterey, CA. Dr. Murphy was recorded at Clinical Approaches to Obstetrics and Gynecology, sponsored by the Medical College of Georgia, Division of Continuing Education and School of Medicine, and held June 27-29, 2008, in Savannah, GA. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Early Detection of Ovarian Cancer

Gary S. Leiserowitz, MD, Professor and Chief, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Davis, School of Medicine, Sacramento

General considerations: ovarian cancer most deadly of gynecologic cancers; most patients present with advanced disease; 5-yr survival for advanced disease, 30% to 40% (stable for last 10-20 yr); 5-yr survival for stage I disease, 80% to 90%; 5-yr survival rates significantly worse than those for endometrial and cervical cancers; barriers to early detection  —  lack of specific symptoms (eg, bleeding); lack of a long latent phase; lack of successful screening programs (eg, Papanicolaou [Pap] test); goal is early detection (when disease confined to ovary)

Screening: desirable because of high morbidity and mortality; at present time, unrealistic goal; principles of dis­ease screening  —  most effective for most important diseases and when diagnosis and therapy available; disease must have latent or early phase; test must be safe and acceptable, as well as reliable and valid; costs should match benefits

Diagnostic value of tests (and associated terminology): sensitivity  —  likelihood that test identifies disease; specificity  — ability of test to identify healthy people; positive predictive value (PPV)  —  patients with disease have positive test; negative predictive value (NPV)  —  healthy people have negative test; prevalence of disease in population  —  necessary for PPV and NPV (but not needed for sensitivity and specificity); since prevalence of ovar­ian cancer low (»30 in 100  000 women), presents challenge for developing successful screening test; eg, assuming screening test 80% sensitive and 99% specific (which in most other situations would be acceptable), only 2.3% of women would have ovarian cancer among 100 abnormal serum cancer antigen 125 (CA-125) tests; however, in sit­uation with higher prevalence (eg, screening BRCA 1 or 2 carriers), that same 80% sensitive and 99% specific test would have PPV approaching 30%; acceptable PPV »10% (eg, mammography); specificity must be high if preva­lence low (test must be almost 100% accurate)

Symptoms: disease often thought silent until advanced stages; increasing evidence of symptoms even with early-stage disease; symptoms (mostly abdominal) reported by 95% of 1700 women surveyed who had history of ovarian cancer; only 11% of women with stage I, and 3% of women with advanced stage disease, reported no symptoms before diagnosis; symptoms commonly ignored by patients; delay in diagnosis common; diagnoses to exclude  —  depression, stress, irritable bowel syndrome (IBS), and gastritis; contribute to delay in diagnosis; often patient sent for colonoscopy, but pelvic examination not performed (Goff, 2000); patients with ovarian cancer more likely to present with symptoms £6 mo before diagnosis (Smith, 2005); pelvic examination, pelvic imaging, and CA-125 warranted for patient with persistent symptoms (eg, pain, abdominal bloating)

Costs of screening: based on 1998 figures; 43 million women in United States >45 yr of age; cost of pelvic ultraso­nography (US) and CA-125 $14 billion annually; costs $500  000 to identify one case of early-stage ovarian cancer; costs driven by low PPV and expense of surgery; combining tests increases specificity and reduces false positives

Pelvic examination: provides opportunity to detect asymptomatic disease; important for evaluating abdominal com­plaints (detection of ovarian mass); 7 cm³ (approximately size of tennis ball) smallest mass detectable on pelvic ex­amination

CA-125 assay: convenient, cost modest, minimal expertise needed to perform, and better accepted by patients; glyco­protein surface antigen associated with most ovarian cancers; found on cell surface of abdominal structures; not very specific or sensitive (CA-125 elevated in only 50% of stage I disease); many benign causes of elevated CA-125; false-positive rate in postmenopausal women »2%, with few having ovarian cancer; conditions associated with elevated CA-125  —menstruation, first trimester pregnancy, endometriosis, adenomyosis, uterine myomas, hep­atitis, and other liver diseases; Food and Drug Administration (FDA)-approved test; serial collections of serum tested for CA-125 show rising levels occasionally precede diagnosis by £18 mo; single measurement insensitive; serial measurements may be more sensitive

Promising advances in screening: ovarian cancer serum panel  —  combination of 6 protein markers; high likelihood of ovarian cancer with positive panel; high sensitivity (95%) and specificity; PPV approaches 99%; prospective clinical trial needed to confirm results; glycomics analysis  —  glycans attached to glycoproteins altered in cancer cells; can be analyzed separately; 15 novel peaks noted on mass spectrometry, making up finger-printing profile; test performance superior to CA-125 assay; canine scent detection  —  recent study demonstrated trained dogs can use breath samples to distinguish healthy control subjects from those with lung and breast cancer; preliminary work suggests ovarian cancer may also be detected via exhaled volatile biomarkers

Ultrasonography: theorized useful because malignancy results in early ovarian enlargement before metastasis; transabdominal  —large study of 5500 women, 16  000 images; of 326 women undergoing surgery, 5 had stage I dis­ease (3 with low malignant potential (LMP) tumors (indolent tumors); 4 had metastatic cancer; sensitivity 100%; acceptable specificity, but PPV only 1%; transvaginal  —  review of 5 large studies; 13 of 22 patients had stage I dis­ease; LMP tumors seen in 7 of 13 patients, 1 granulosa tumor; 5 of 13 tumors invasive; PPV 3.1%; 32 surgeries per­formed for each cancer discovered (Karlan 1994); University of Kentucky study (van Nagell 2000)  —  morphology index used; subjects underwent secondary screening with CA-125; 180 patients underwent surgery (primary ovar­ian cancer in 17 patients); stage I disease in 11 of 17 patients; PPV 9.4%; 3 LMP and 1 granulosa cell tumor; 4 women diagnosed with ovarian cancer £1 yr after having negative screening test

Prostate, Lung, Colon, and Ovarian Cancer Trial (PLCO; Buys et al, 2005): combination screening; 78  000 women randomized to cancer screening vs routine care; 39  000 women randomized to screening with combination annual serial CA-125 and transvaginal US; 28 000 women received  ³1 test; abnormal transvaginal US in 4.7%; PPV 1% (slightly better for CA-125; »23% if both tests abnormal)

High-risk women: defined genetic mutation (eg, BRCA 1 or 2); strong family history of breast and/or ovarian can­cers; personal history of early-onset breast cancer plus one first-degree or second-degree family member with breast or ovarian cancer; disease prevalence highest in BRCA carriers; lifetime risk »40% to 60%; breast cancer risk by 70 yr of age »80% in carriers; ovarian cancer risk »40% to 50% for BRCA 1 carrier, 16% to 25% for BRCA 2 carriers; cancers occur approximately one decade earlier than nonmutation cancers; screening in high-risk women not shown more beneficial than screening in general population; screening can cause high false-positive rate, high rate of surgeries, and increased patient/clinician anxiety; management of high-risk patients  —  based on expert opin­ion only, no science to support; ovarian suppression with oral contraceptives shown to decrease risk by »50%; che­moprophylaxis with tamoxifen for patients with breast cancer; genetic counseling and testing; consider risk-reducing surgery; use of hormone replacement therapy (HRT) unanswered question; risk-reducing bilateral sal­pingo-oophorectomy (does not prevent primary peritoneal cancer), prophylactic hysterectomy, and risk-reducing bilateral mastectomy

Current Management of Endometriosis

Ana A. Murphy, MD, Greenblatt Professor and Chair, Department of Obstetrics and Gynecology, Medical Col­lege of Georgia, Augusta

Epidemiology: incidence of visualized endometriosis »1.5 per 1000 women of reproductive age; prevalence un­known; when performing surgery for pelvic pain in adolescents and women with infertility, 50% of time endometri­osis found; percentage of women with endometriosis consistent worldwide

Etiology: theory of implantation  —  menstrual fragments become established in peritoneal cavity through retrograde menstruation; in vitro model suggests adhesion to mesothelium and invasion; women with müllerian anomalies as­sociated with obstruction almost always have severe endometriosis; aberrant gene expression in endometrium  —  most favored theory; aberrant genes and gene products believed responsible for difference between women with endometriosis and those without; matrix metalloproteinase (MMP) increases dissolution of peritoneal surfaces; in­creased MMP (present in peritoneal fluid) leads to increased capacity to invade; aromatase enzyme that converts androgens to estrogens; expressed in endometrium and endometriotic lesions, but not in normal endometrium; apoptosis (programmed cell death) way of eliminating “bad” cells; BCL2 (increased in women with endometriosis) increases survival of lesions on peritoneal surface (proendometriotic issue); other proposed etiologies  —  shed cells cause alterations in immune system; inherent dysfunction in immunity; coelomic metaplasia; vascular dissemina­tion occurs during dilation and curettage (D and C)

Symptoms: progressive dysmenorrhea; dyspareunia; chronic pelvic pain; infertility; less common symptoms  —  urgency; rectal bleeding (endometriosis invades bowel); hematuria; hemoptysis; intestinal obstruction; cutaneous nodules; catamenial chest pain; pneumothorax

Detection: history; clinical examination including rectovaginal (uterosacral ligaments and posterior cul de sac areas most dependent); US of pelvis; magnetic resonance imaging (MRI); rectal endoscopic sonography; operative visu­alization; operative palpation (using laparoscopic probe); laparoscopic diagnosis  —classic black implants; non­classic/atypical implants; infiltrating endometriosis; masked endometriosis; microscopic

Indications for surgical therapy: diagnosis, pain, and presence of adhesions, endometrioma, or deep nodular dis­ease; recurrence after surgical therapy; failure of medical therapy; trial looking at laser laparoscopy  —  shown su­perior to expectant management in pain relief at 3 and 6 mo (Sutton); follow-up study showed symptom relief continued at 1 yr in 90% of patients; second look at all symptomatic patients showed disease progression in 30%; 42% regressed or had static disease (Sutton)

Deeply infiltrating endometriosis: data show depth of penetration important in determining cause of pain; superfi­cial implants associated with little pain; increased pain with intermediate or deep infiltration; 55% of deep infiltra­tion found in pouch of Douglas and uterosacral ligaments (retrovaginal examination important to assess implants in those areas); superficial implants found most frequently in patients with infertility (Cornillie)

Surgical therapy: excisional surgery vs ablative surgery for ovarian endometrioma  —  excisional surgery associated with reduced rate of recurrence (40%) and pain; reduced recurrence rate of symptoms (eg, dysmenorrhea, dyspa­reunia, nonmenstrual pelvic pain); excisional surgery also associated with increased rate of spontaneous pregnancy in subfertile women (odds ratio [OR] 5.21); laparoscopic uterosacral nerve ablation (LUNA) vs surgical treatment  —  clinical trials showed no added benefit to LUNA; presacral neurectomy (PSN) combined with endo­metriosis treatment significantly better than endometriosis surgery alone; adverse events more common with PSN; infertility  —  trial (Marcoux) showed ablation beneficial if endometriosis minimal or mild; meta-analysis showed no treatment equivalent to surgery in minimal or mild disease; overall pregnancy rates do not differ whether surgery performed via laparoscopy or laparotomy (deficiencies may be present in meta-analysis)

Medical therapy for infertility: meta-analysis showed medical therapy not appropriate for treatment of infertility, except if patient has pain; ovulation induction (clomiphene or gonadotropins) with intrauterine insemination for maximum of 3 to 4 cycles; success reported with assisted reproductive technology; fertility and endometriosis  —  surgical treatment of minimal to mild endometriosis confers benefit (level I evidence); surgical treatment of moder­ate to severe endometriosis confers benefit (level III evidence); in vitro fertilization confers benefit (level II evi­dence)

Progestins: work by suppressing gonadotropin-releasing hormone (GnRH); patient becomes hypoestrogenic; direct effect on endometrium, with glandular atrophy; anti-inflammatory effect; side effects  —  spotting and breakthrough bleeding (if significant, addition of estrogen can help); depression (because of high dosage of progestin); breast tenderness; fluid retention; weight gain; bone loss

Danazol: first approved therapy for endometriosis; suppresses gonadotropin; binds to androgen and progesterone re­ceptors (antiprogestin and antiandrogen); inhibits steroidogenesis; displaces estradiol; decreases sex hormone-binding globulin; side effects  —  weight gain (69%), muscle cramps (52%), breast atrophy, hot flushes, mood swings, oily skin, depression, acne, hirsutism, and deepening of voice; shown effective in relieving pain, compared to placebo; laparoscopic scores improved; side effects more commonly reported in patients receiving danazol than placebo, limiting usefulness (Selak)

GnRH agonists and add-back therapy: GnRH down-regulates gonadotroph, leading to hypoestrogenism; various ways to administer add-back therapy, including use of bisphosphonates; side effects vary among treatments; more androgenic side effects with danazol and gestrinone; more hypoestrogenic symptoms with GnRH agonists; better control of endometriosis and hypoestrogenic symptoms using low-dose estrogen/progestin combination (little rea­son to use danazol); recurrence of endometriosis after GnRH agonist treatment  —  80% for severe disease; 7% for moderate disease, and <7% for mild

Aromatase inhibitors: inhibit peripheral aromatization and aberrant expression in endometriotic implant; effective for menopausal woman with endometriotic pelvic pain; letrozole and anastrozole options; speaker uses letrozole 2.5 mg or 5 mg daily for ovulation induction; no hypoestrogenism, hot flushes, or multiple gestations, as seen with clomiphene

Present and future medical therapy: asoprisnil  — progesterone agonist/antagonist with high degree of endometrial selec-tivity; levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena)  —  statistically significant reduction in recurrence of dysmenorrhea in LNG-IUS group, compared to control group receiving GnRH agonist; also, sigin­ificantly higher proportion of women in LNG-IUS group satisfied with treatment than in GnRH agonist group; pro­vides high level of progestin at level of endometrium and uterosacral ligaments without peripheral effects of progestin; can be used for menopausal patient; allows choice of estrogen formulation

Neoplastic transformation: monoclonality of endometriotic cysts; increased risk for ovarian cancer (endometrioid) with long history of endometriosis; high frequency of atypia in endometriosis associated with ovarian carcinoma; endometriosis and ovarian carcinoma show identical PTEN (tumor suppressor gene) mutations; low-magnitude risk observed consistent with view that ectopic and utopic endometrium undergo malignant transformation with similar frequency

Suggested Reading

Adamson GD et al: Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol 171:1488, 1994; Buys SS et al: Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial. Am J Ob­stet Gynecol 193:1630, 2005; Cornillie FJ et al: Deeply infiltrating pelvic endometriosis: histology and clinical sig­nificance. Fertil Steril 53:978, 1990; Goff BA et al: Ovarian carcinoma diagnosis. Cancer 89:2068, 2000; Karlan BY et al: The current status of ultrasound and color Doppler imaging in screening for ovarian cancer. Gynecol Oncol 55(3 Pt 2):S28, 1994; Leiserowitz GS et al: Glycomics analysis of serum: a potential new biomarker for ovarian cancer? Int J Gynecol Cancer 18:470, 2008; Marcoux S et al: Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 337:217, 1997; McCulloch M et al: Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers. Integr Cancer Ther 5:30, 2006; Selak V et al: Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2001;(4):CD000068, 2001; Smith LH et al: Ovarian cancer: Can we make the clinical diagnosis earlier? Cancer 104:1398, 2005; Sutton CJ et al: Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 62:696, 1997; Sut­ton CJ et al: Follow-up report on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain as­sociated with minimal to moderate endometriosis. Fertil Steril 68:1070, 1997; van Nagell JR Jr et al: The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecol Oncol 77:350, 2000.