ISSUES IN GYNECOLOGIC DISEASES AND DISORDERS
| CURRENT MANAGEMENT OF ENDOMETRIAL HYPERPLASIA AND CANCER —William T. Creasman, MD,
J. Marion Sims Professor, Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston
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| Classification of endometrial hyperplasia: before mid-1980s, architectural pattern used to determine likelihood of
progression to carcinoma; currently, cytologic atypia most useful for predicting likelihood of progression to carcinoma;
data show complex atypia associated with greatest incidence of progression to carcinoma; dilation and curettage
(D and C) should be performed if endometrial biopsy displays atypical hyperplasia; coexistent underlying
endometrial adenocarcinoma in 30% to 40% of patients with atypical hyperplasia
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| Management of patients with endometrial hyperplasia: simple or complex but without atypia—medical management
with progestin, oral contraceptives (OCs), or ovulation induction; D and C can be done in patient with simple hyperplasia
only, but not mandated; resample endometrium in 3 to 6 mo; majority of patients should show clearance;
atypical hyperplasia in patient who desires fertility—medical management treatment of choice with follow-up in 3 to
6 mo; hysterectomy last option; speaker recommends continuous administration of progestin (increase dosage until
patient amenorrheic); nonatypical hyperplasia with fertility preservation—treat medically; atypical hyperplasia with
no fertility preservation—speaker considers hysterectomy reasonable option
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| Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) and gynecologic cancers: significant relationship,
particularly with endometrial cancer; HNPCC accounts for 1% to 5% of colon cancers; lifetime risk of developing
endometrial cancer 30% to 60%; ≈10-fold increased risk of developing ovarian cancer; time between development
of gynecologic cancer and colon cancer relatively long, but can occur simultaneously; prophylactic hysterectomy
and bilateral salpingo-oophorectomy (BSO) reasonable in patients finished with childbearing; intense surveillance
recommended (colonoscopy every 1 to 3 yr from 25 yr of age); data show improved survival; surveillance of gynecologic
cancer—transvaginal ultrasonography (US) or endometrial biopsy suggested for patient 25 to 35 yr of age,
even though no data showing impact on survival
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| Detection of endometrial disease: ≈20% of postmenopausal bleeding attributed to cancer; amount of bleeding—data
show no difference in number of days and amount of bleeding and diagnosis of cancer; 1 day of spotting may be enough
to warrant evaluation; transvaginal US—prospective randomized study looking at different hormone replacement
therapy (HRT) regimens and mean thickness of endometrium showed 3.8 mm in placebo arm, 11.7 mm in estrogen-
only arm, and ≈6.0 mm in estrogen and progesterone arm; one patient with carcinoma in placebo arm; endometrial
thickness in high-risk histotypes—data show 17% of patients had endometrial stripe ≤5 mm; endometrial stripe indistinct
in 17%, illustrating significant chance of missing disease using cutoff of 5 mm in high-risk patients; no general
agreement on what cutoff indicates need for further evaluation; speaker does not rely heavily on endometrial thickness
in considering further evaluation; sensitivity of hysteroscopy—data showed diagnosis of polyp 50% of time, hyperplasia
50% of time, and cancer 20% of time
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| Evaluation of perimenopausal bleeding: common misconception that any bleeding during perimenopausal period due
to menopause; normal bleeding pattern becomes lighter and lighter and farther and farther apart; endometrial
biopsy—if normal and bleeding stops, observe patient; sensitivity of endometrial biopsy 90%; if patient continues
to bleed, perform second biopsy; if second biopsy normal, perform hysteroscopy and D and C
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| Characteristics of patient with endometrial cancer: obese, nulliparous, white, usually 50 to 70 yr of age, has well-
differentiated, superficially invasive cancer limited to uterus; good prognosis with hysterectomy; characteristics of
patient with grade 3 (papillary serous) endometrial cancer—thin, multiparous, black, same age range as typical patient,
but has poorly differentiated, deeply invasive disease and often has extrauterine disease; poor prognosis;
probably represents 20% to 25% of patients with endometrial cancer
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| Prognostic factors: histologic differentiation—generally better prognosis with well-differentiated than poorly differentiated
cancer; myometrial invasion—greater chance of having deep myometrial invasion with grade 3 lesion than
grade 1 lesion; cell type and histologic differentiation must be included in pathologist’s report; stage—rough estimate
on tumor volume (most important prognostic factor for any cancer); peritoneal cytology—controversy surrounding
significance; speaker thinks important; shown to be independent risk factor; adnexal involvement, lymph node metastasis,
and other extrauterine spread; OCs can significantly decrease risk for endometrial cancer
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| Clinical staging: data on extent of disease in patients thought to have stage 1 clinical disease (limited to uterus)
showed almost one quarter had disease outside corpus; 11% of patients had metastasis to pelvic and periaortic
lymph nodes singly or in combination; grade and depth of invasion and pelvic node metastasis—data show one third
of grade 3 deep invasions metastasize to pelvic lymph nodes; about one quarter of grade 3 deep invasions metastasize
to periaortic area; data show high margin of error in staging classification obtained from endometrial biopsy;
surgical staging valuable in establishing correct classification (grade) and level of metastasis; debatable how many
lymph nodes should be removed; data show survival affected by removal of >11 nodes; surgical management of all
grades of endometrial cancer—peritoneal cytology, total abdominal hysterectomy, BSO, bilateral pelvic, and para-
aortic lymphadenectomy
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| Postoperative irradiation: data show no impact on recurrence of grade 1 or grade 2 disease (local or distant) with external
irradiation; with grade 3, external irradiation decreased local and distant recurrences; speaker’s approach—
surgery only if disease grade 1, 2, or 3 and with superficial invasion; all patients surgically staged; reasonable to consider
pelvic irradiation for mid to deep invasion, but lack of supporting data; most common site of recurrence not vagina,
but distant; postoperative irradiation has diminished role in treatment of endometrial cancer
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| APPROACH TO THE PATIENT WITH MENOPAUSAL BLEEDING —James C. Heaps, MD, Assistant Clinical
Professor of Obstetrics and Gynecology and Gynecologic Oncology, David Geffen School of Medicine at the University
of California, Los Angeles
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| Introduction: menopause—time in woman’s life when menses and estrogen production stop; characterized by lack
of estrogen and elevated gonadotropins (follicle-stimulating hormone); average age at menopause 51 yr;
climacteric—time of waxing and waning ovarian function before menopause; perimenopausal—defined as any
woman 45 yr of age but not yet menopausal; menopausal symptoms (eg, vasomotor symptoms, vaginal dryness,
bladder dysfunction, menstrual irregularities) may be present; perimenopausal years characterized by shorter menstrual
cycles or irregular bleeding (anovulatory bleeding); vasomotor symptoms most common immediately before
or during menses
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| Menopausal bleeding: significant concern worthy of work-up and investigation; malignancy must be ruled out; not uncommon
to go 6 or 8 mo without menses, experience symptoms of menopause, and have spontaneous ovulation;
transvaginal US may show follicular cyst with no ovulation due to lack of luteinizing hormone surge; history of improved
sleep and breast tenderness, followed by bleeding, indicates some physiologic estrogen production
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 | Possible causes of vaginal bleeding: common neoplasms—endometrial cancer, cervical cancer, vaginal cancer, tubal
or ovarian cancer, bladder cancer, colon cancer, cancer metastatic to genital tract, and benign neoplasms, eg,
fibroids, polyps; infection—cervicitis, vaginitis, endometritis, and salpingitis; inflammation can mask malignant
cells; consider possibility of cancer with low index of suspicion for infection or if condition does not resolve after
appropriate therapy; tuberculosis—peritoneal or disseminated tuberculosis not uncommon in genital tract and
presents with bleeding; vaginal ulcer—secondary to uterine or vaginal prolapse; atrophy—vaginal or cervical;
atrophic endometrium—rare; consider polyp or submucous fibroid; thickened lining on US and atrophic endometrium
on biopsy pathognomonic for polyp; atrophic urethritis and atrophic cystitis; trauma—pessaries, foreign
objects, intercourse, and hemorrhoids
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| Medication history: hormones, corticosteroids, androgens, tamoxifen (can cause endometrial polyps, endometrial
carcinoma, and hyperplasia), chemotherapeutic agents, anticoagulants; over-the-counter (OTC) estrogen and soy
products—ask patient about use of OTC herbal menopause supplements (eg, Estroven [herbal blend]) and soy
products; educate patient that if they take enough to alter hot flushes and night sweats, they should undergo routine
Papanicolaou (Pap) test; educate all patients about importance of routine Pap tests
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| Physical examination: bimanual pelvic examination—inspect vulva, vagina, vaginal walls, vaginal fornices, cervix,
urethra, and anus (look for internal and external hemorrhoids); lift up cervix and feel cul-de-sac for pelvic nodularity;
feel for adnexal masses; perform rectal examination and test for occult blood with guaiac test; perform abdominal
examination and assess lymph nodes (supraclavicular, inguinal, and axillary); Pap test
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| Diagnostic modalities: endometrial biopsy—perform if endometrial cancer suspected; transvaginal US useful in assessing
adnexa and uterine lining; endocervical curettage—recommended if cervix larger than normal or excessive
inflammation present; speaker performs 3-step process using (1) Pipelle device, (2) Kevorkian curette, (3) Pipelle
again; primary tests—blood tests, colonoscopy, and cystoscopy; order based on patient’s history and when appropriate
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| Endometrial biopsy: atrophic endometrium with thickness on US—discordant information; continue with work-up; if
transvaginal US results show insufficient tissue (and 18 mm sounded), polyp most likely present; polyps have
significant malignant transformation potential; remove through hysteroscopic resection, whether in endometrium
or cervix; proliferative endometrium—overweight patient at risk because of high level of unopposed
estrogen; prescribe progesterone and repeat biopsy to ensure proliferation halted; endometritis—treat inflammation
aggressively; follow up with US and repeat endometrial biopsy to ensure underlying carcinoma not cause of
infectious process; consider endometrial or cervical cancer if inflammation not resolved by treatment;
hyperplasia—simple or adenomatous; atypical hyperplasia characterized by atypical cells within hyperplastic
glands; estrogen and progesterone receptors found on endometrial glands; cells of atypical hyperplasia lose ability
to respond to estrogen and progesterone in normal way; atypical hyperplasia must be treated more aggressively
than hyperplasia with no atypia
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| Transvaginal US: endometrial thickness should be 5 mm in menopausal woman not on HRT; consider hyperplasia,
cancer, or polyp if endometrium >5 mm; fluid in endometrial cavity likely blood; serous fluid may indicate metaplastic
process
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| Risk factors for endometrial cancer: obesity, exogenous estrogen use, personal or family history of breast, ovarian,
colon, or endometrial cancer, late menopause, and nulliparity; women with perimenopausal anovulatory cycles or
chronic polycystic ovary syndrome at significant risk; screening endometrial biopsy recommended for women with
risk factors, regardless of presence of bleeding
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| Biopsy shows hyperplasia: reverse with progestin therapy; estrogen induces endometrial cells to make progesterone
receptors, causing progesterone to be more potent; progestin therapy can be administered cyclically or continuously,
with or without estrogen; repeat biopsy in 3 mo; atypical hyperplasia—cells no longer respond to estrogen
and progestin; about one third of women with atypical hyperplasia on endometrial biopsy have endometrial cancer;
hysterectomy treatment of choice; refer patient to gynecologic oncologist; endometrial cancer leading gynecologic
cancer in United States; 45,000 new cases annually; <5000 deaths annually; menopausal bleeding early sign; cure
rate >95% with stage 1 endometrial cancer
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Educational Objectives
| The goal of this program is to educate the listener about the management of patients with endometrial hyperplasia and
postmenopausal bleeding. After hearing and assimilating this program, the clinician will be better able to:
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| 1. State the criteria for classifying endometrial hyperplasia.
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| 2. Describe the genetic syndrome associated with gynecologic cancer and the suggested surveillance for women
at high risk.
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| 3. Identify women at high risk for endometrial cancer.
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| 4. Review causes of postmenopausal bleeding and evaluate patients presenting with menopausal bleeding.
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| 5. Recognize patients at risk for endometrial hyperplasia.
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Discussed on This Program
Medroxyprogesterone acetate [Amen, Curretab, Cycrin, Depo–Provera, Depo-subQ Provera, Hematrol, Provera]
Progesterone [Crinone, Prochieve, Progesterone In Oil, Prometrium]
Tamoxifen citrate [Nolvadex]
Suggested Reading
Atiomo WU et al: Evaluation of a one-stop clinic for the rapid assessment of post-menopausal bleeding. J Obstet Gynaecol
18:148, 1998; Chamber JT et al: Endometrial sampling: When?Where?Why?With what? Clin Obstet Gynecol
35:28, 1992; Chen S et al: Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296:1479,
2006; Kurman RJ et al: The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in
170 patients. Cancer 56:403, 1985; Lasmar RB et al: Validation of hysteroscopic view in cases of endometrial hyperplasia
and cancer in patients with abnormal uterine bleeding. J Minim Invasive Gynecol 13:409, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the faculty reported nothing to disclose.
Dr. Heaps was recorded at Office Gynecology/Women’s Health for Primary Care, sponsored by the David Geffen
School of Medicine at the University of California, Los Angeles, held July 27-30, 2006, in Anaheim, CA. Dr. Creasman
was recorded at the 37th Annual Ob/Gyn Spring Symposium, sponsored by the Medical University of South Carolina,
held March 27-29, 2006, in Charleston, SC. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
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