Bethesda Handbook of Clinical Oncology, 2nd Edition
Christina M. Annunziata*
Michael J. Birrer†
*Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
†Department of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, Maryland
- Endometrial cancer is the most common pelvic gynecologic malignancy in women (6% of all cancers in women).
- In 2002, 39,300 new cases were diagnosed (the incidence of endometrial cancer was 22 cases per 100,000 population in the 1980s and has been constant since then).
- An estimated 6,400 deaths due to this malignancy are predicted yearly (accounting for 2% of all cancer deaths).
- The mortality rate has continued to decline since 1989, likely because of increased awareness of symptoms (abnormal vaginal bleeding).
- Mortality is twice as high in African American women than in white women. However, the incidence is 1.4 times higher in white women than in African American women.
- Peak incidence is in the sixth and seventh decades of life (5% of cases are diagnosed before the age of 40; 20% to 25% of patients are diagnosed before menopause).
- Endogenous estrogen excess
- Polycystic ovary disease
- Anovulatory menstrual cycles
- Obesity: being overweight by more than 20 to 50 lb increases the risk threefold and being overweight by more than 50 lb increases the risk 10-fold
- Granulosa cell tumor of the ovary (or other estrogen-secreting tumors)
- Advanced liver disease
- Endogenous prolonged estrogen exposure: early menarche and late menopause; menopause in women older than 52 years increases the risk by 2.4-fold.
- Irregular menses, infertility, and nulliparity: nulliparous women have twice the risk of developing uterine cancer compared to women with one child and thrice the risk when compared to women who give birth to five or more children
- Exogenous unopposed estrogen sources, including tamoxifen (TAM), a weak estrogen that increases the relative risk (RR) of developing endometrial cancer to 2.3
- Type 2 diabetes mellitus (DM), possibly related to the effects of hyperinsulinemia
- Family history: history of endometrial cancer in a first-degree relative increases the risk by threefold, and history of a colorectal cancer in a first-degree relative increases the risk of an endometrial cancer by twofold
- Personal history of breast, ovarian, or colorectal cancer; personal or family history consistent with hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch II syndrome).
- Oral contraceptives: There is a 50% decrease in RR when oral contraceptives are used for at least 12 months. This protection lasts for at least 10 years after discontinuation.
- Cigarette smoking: There appears to be a modest protective role of cigarette smoking. However, this is strongly outweighed by the significant increased risk of lung cancer and other major health hazards.
DIAGNOSIS AND SCREENING
- Routine screening for endometrial cancer is not required in asymptomatic women.
- Women taking TAM should have a gynecologic evaluation according to the same guidelines as for women who are not taking this drug. Endometrial biopsy should be done when the patient is symptomatic (vaginal bleeding or spotting).
SIGNS AND SYMPTOMS
- Abnormal vaginal bleeding is a common symptom of endometrial cancer (seen in approximately 90% of cases). Premenopausal women with prolonged and/or heavy menses, or intermenstrual spotting, should undergo endometrial biopsy. All postmenopausal women with vaginal bleeding should be evaluated for endometrial cancer (20% of these patients will ultimately be diagnosed with the malignancy). Biopsy is also recommended in women taking estrogen therapy for menopausal symptoms who may have withdrawal bleeding.
- Asymptomatic patients with abnormal glandular tissue on Papanicolaou smear should be evaluated for endometrial cancer (approximately 10% of uterine cancer cases are detected by a Papanicolaou smear). Papanicolaou smear, however, is not an adequate tool for detection of endometrial malignancy.
- Palpable, locally advanced tumor detected on pelvic examination is suggestive of endometrial cancer.
- Signs and symptoms of advanced disease (manifestation in <10% of cases) include bowel obstruction, jaundice, ascites, pain.
- Endocervical curettage and outpatient endometrial biopsy is a common procedure.
- Papanicolaou smear is of limited value (see previous text).
- Fractional curettage under anesthesia is a method that involves scraping of the endocervical canal, followed by the walls of the uterus in a set sequence. It is the standard procedure for the diagnosis of endometrial cancer that is used in symptomatic women with negative or inadequate endometrial biopsy.
- Available data on transvaginal ultrasound suggest a correlation between endometrial stripe thickness, as seen on ultrasound, and subsequent risk of endometrial cancer. Less than a 4 to 5 mm “cutoff” of endometrial stripe has been used as a diagnostic criterion; however, occasional cases of endometrial cancer could still be missed. Therefore, there is no general agreement on the cutoff thickness of endometrial stripe for recommending endometrial biopsy. Patients taking TAM have thicker endometrium than their counterparts who do not take TAM.
- Endometrioid (75% to 80%)
- Uterine papillary serous (5% to 10%)
- Clear cell (1% to 5%)
- Mucinous (1%)
- Squamous cell (<1%)
- Mixed mesodermal (10%)
Endometrial carcinoma may also be divided into two types (I and II) according to its dependence on estrogen:
- Type I (estrogen related): It is the more common type of endometrial carcinoma, is associated with DM and obesity, and tends to have better prognosis [more differentiated; more favorable histologic subtypes such as endometrioid, mucinous, and secretory carcinoma; higher incidence of superficial invasion, lower grade, and lower stage; higher progesterone receptor (PgR) levels; and younger patients].
- Type II (unrelated to estrogen stimulation and endometrial hyperplasia): This type is less common; it usually has a short duration of symptoms, poor differentiation, deep myometrial invasion, poor prognosis, and more aggressive histology (serous, clear cell).
- Adenomatous hyperplasia is an estrogen-dependent lesion, which could be seen along with type I but not type II endometrial carcinoma.
- Physical examination
- Chest x-ray (CXR)
- Urinary imaging studies (i.v. pyelogram or renal scan), cystoscopy, and proctoscopy (very rarely done)
- Routine blood and urine studies
- Routine age-appropriate health maintenance; if HNPCC is suspected, colonoscopy should be performed before planning treatment
- Evaluation of specific symptoms or physical examination findings, as indicated
- Routine use of ultrasound, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) are NOT recommended, and bone scan rarely adds useful information.
- Staging for endometrial carcinoma is surgical (see Table 18.1) and is based on information from hysterectomy, bilateral salpingo-oophorectomy (BSO), peritoneal cytology, and pelvic and periaortic lymph node (LN) dissection.
- Endometrial cancer distribution by stage is as follows:
- Stage I: 73%
- Stage II: 12%
- Stage III: 12%
- Stage IV: 3%.
TABLE 18.1. Staging for endometrial cancer: 1988
FIGO, Federation Internationale de Gynecogie et d'Obstetrique.
From DiSaia PJ, Creasman WT. Clinical gynecologic oncology, 5th ed. St. Louis: Mosby, 1997:140–141, with permission.
Stage IA G123
Tumor limited to endometrium
Stage IB G123
Invasion to >50% of the myometrium
Stage IC G123
Invasion to <50% of the myometrium
Stage IIA G123
Endocervical glandular involvement only
Stage IIB G123
Cervical stromal invasion
Stage IIIA G123
Tumor invades serosa and/or adnexa, and/or positive peritoneal cytology
Stage IIIB G123
Stage IIIC G123
Metastases to pelvic and/or paraaortic lymph nodes
Stage IVA G123
Tumor invasion of bladder and/or bowel mucosa
Distant metastases including intraabdominal and/or inguinal lymph nodes
Histopathology: Degree of differentiation
Cases of carcinoma of the corpus should be classified (or graded) according to the degree of histologic differentiation, as follows:
G1: 5% of a nonsquamous or nonmorular solid growth pattern
G2: 6% of 50% of a nonsquamous or nonmorular solid growth pattern
G3: >50% of a nonsquamous or nonmorular solid growth pattern
Notes on pathologic gradings
1. Notable nuclear atypia, inappropriate for the architectural grade, raises the grade of a grade 1 or grade 2 tumor by 1.
2. In serious adenocarcinomas, clear cell adenocarcinomas, and squamous cell carcinomas nuclear grading takes precedence.
3. Adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular component.
Rules related to staging
1. Because corpus cancer is now staged surgically, procedures previously used for determination of stages are no longer applicable, such as the findings from fractional dilation and curettage to differentiate between stage I and II.
2. It is appreciated that there may be a small number of patients with corpus cancer who will be treated primarily with radiation therapy. If that is the case, the clinical staging adopted by FIGO in 1971 should still apply, but designation of that staging system would be noted.
3. Ideally, width of the myometrium should be measured along with the width of tumor invasion.
- Histologic type
- Histologic differentiation
- Stage of disease: 5-year survival (%) distribution by stage is as follows: I: 86%; II: 66%; III: 44%; and IV: 16%
- Myometrial invasion
- Vascular space invasion (rate of disease recurrence seen is approximately 25%).
- Positive peritoneal cytology (rate of disease recurrence seen is approximately 15%)
- LN metastasis: involvement of pelvic LN or peritoneal metastases poses approximately 25% risk for disease recurrence, whereas metastasis to periaortic LN increases this risk to 40%
- Adnexal metastasis (approximately 15% recurrence risk)
- Tumor hormone–receptor status: the presence of estrogen receptor (ER)/PgR and their levels were found to be inversely proportional to histologic grade and was associated with a longer survival
- Tumor size: tumors larger than 2 cm have worse prognosis
- Molecular factors include deoxyribonucleic acid (DNA) ploidy and p53 overexpression (however, most studies are small and use different techniques and cutoff values; further standardization is needed before conclusions can be drawn).
- Endometrial hyperplasia:Total abdominal hysterectomy (TAH) or BSO is the treatment of choice for patients with persistent endometrial hyperplasia after the failure of adequate therapy with progestin.
- Endometrial carcinoma:Therapy should be individualized.
Low Risk: Stage IA, IB (or IC with Grade 1 Histology)
TAH/BSO (selected pelvic LN may be removed): This is considered adequate for patients with well-differentiated or moderately differentiated tumors, with negative peritoneal cytology (if no peritoneal fluid is found during surgery, peritoneal washing with normal saline should be done), with no vascular space invasion, and with less than 50% myometrial invasion.
Intermediate Risk: Stage II, Grade 1
- TAH/BSO combined with paraaortic and selective pelvic LN sampling or dissection:If there are no medical or technical contraindications (e.g., morbid obesity), this should be done in patients with
- tumors involving more than 50% of outer myometrium
- tumor presence in cervical isthmus
- adnexal and other extrauterine metastases
- serous, clear cell, undifferentiated, or squamous histology and
- LN enlargement (visible or palpable).
- Adjuvant (postoperative) total pelvic irradiation:This method is used for tumors with deep myometrial invasion, grade 2 or 3 histology, vascular space invasion, and/or cervical involvement. Radiation doses of 45 to 50 Gy of standard fractionation and daily treatments of multiple fields with small-bowel protection are applied.
- Low-risk patients who are not surgical candidates can be treated with radiation therapy alone; however, this may achieve a lower cure rate than surgery.
- Combined surgery and external radiation has a higher complication rate than either treatment alone (e.g., bowel complications, 4%). Therefore, special attention should be given to appropriate patient selection and choice of surgical techniques [e.g., fewer complications are seen with retroperitoneal approach, as well as with LN sampling versus LN dissection (trials comparing conventional TAH/BSO and pelvic and periaortic LN dissection versus laparoscopic pelvic and periaortic LN dissection, BSO, and vaginal hysterectomy are ongoing)].
- Pelvic surgery has an increased risk for thrombophlebitis in the pelvis and lower extremities; hence, low-dose heparin or Venodyne boots should be used in these patients.
- In case of papillary serous tumor histology, because of the higher rate of vaginal, pelvic, and upper abdominal recurrences seen with this histology, treatment recommendations include whole-abdominal irradiation for up to 30-Gy dose and additional treatments to reach a pelvic dose of 50 Gy. A vaginal cylinder or colpostats can be used to give an additional surface dose of 40-Gy radiation (a 5-year survival of 50% was documented with this approach).
High risk: Stage IB (or Beyond) Grade 3, Stage IC (or Beyond) Grade 2, or Any Stage III
- Hysterectomy, BSO, and periaortic LN sampling, followed by postoperative radiation:The radiation therapy is administered as an external beam to a dose of 45 to 50 Gy along with vaginal irradiation with vaginal cylinder or colpostats to bring the vaginal surface dose to 80 to 90 Gy (5-year disease-free survival of 80% and locoregional control of 90% were
seen with this treatment). Whole-abdominal radiation should be considered for high-risk patients with positive peritoneal washings or micrometastases in the upper abdomen.
- Preoperative intracavitary radiation plus external-beam radiation:This method is a combination of preoperative intracavitary radiation (consisting of uterine tandem and vaginal colpostat insertions with a standard Fletcher applicator delivering 20 to 25 Gy to a point A) and external-beam radiation (dose of 40 to 45 Gy with standard fractionation delivered to multiple fields). In patients with extensive cervical involvement precluding initial hysterectomy, the external-beam radiation should be followed in 4 to 6 weeks by hysterectomy and BSO with periaortic LN sampling (this approach can provide 5-year disease-free survival of 70% to 80%).
- Adjuvant chemotherapy:This method is not routinely recommended because of insufficient data. It should be given only in the setting of a clinical trial.
Special Considerations for High-risk Patients
- Women with isolated ovarian metastasis form a subgroup with a relatively better prognosis. However, some believe that this represents double primary tumors rather than true metastasis from primary endometrial cancer. Five-year disease-free survival ranges between 60% and 82% (depending on the histologic grade of tumor and the depth of myometrial invasion). The pelvic radiation doses of 45 to 50 Gy are given in standard fractionation, with vaginal boost with cylinder or colpostats adding 30 to 35 Gy to the vaginal surface.
- If tumor extends to the pelvic wall, patients would be considered inoperable and should be treated with radiation.
- When parametrial extension is present, preoperative radiation (external and intracavitary) is applied.
- If the pelvic and/or paraaortic LNs are involved in the tumor, patients should be treated with extended-field radiation (encompassing pelvic and periaortic regions) by using 45- to 50-Gy doses, and they may be included as candidates for clinical trials on radiation and/or chemotherapy because they are at higher risk for recurrence (see previous text).
- Patients who are not candidates for either surgery or radiation are treated with progestational agents (see subsequent text).
Stage IV and Recurrent Disease
- Therapy recommendations depend on the sites of metastasis or recurrent disease and the disease-related symptoms. All patients should be considered for clinical trials.
- Pelvic exenteration:This method can be considered for patients with disease extending only to the bladder or rectum (tumor tissue should be checked for ER and PgR levels) and for isolated central recurrence after irradiation (some long-term survivals have been reported).
- Radiation(palliative): Radiation is applied for localized recurrences, for example, pelvic LN (external-beam radiation together with brachytherapy boost), paraaortic LN, or distant metastases.
- In isolated vaginal recurrence (if not previously given), irradiation may be curative.
- Hormonal therapy:This therapy produces responses in 15% to 30% of patients and is associated with improved survival (two times longer survival than those seen in nonresponders). On average, responses last for 1 year. Hormone-receptor levels and degree of tumor differentiation correlate well with responses.
Drugs and Regimens Most Frequently Used in Uterine Cancer
- Medroxyprogesterone acetate (Depo-Provera), 400 to 1,000 mg i.m. weekly for 6 weeks, and then monthly
- Oral medroxyprogesterone (Provera), approximately 150 mg PO daily
- Megestrol acetate (Megace), 40 to 80 mg PO four times daily
- Tamoxifen, 20 mg PO daily, with or without a progestin
- The use of aromatase inhibitors (e.g., anastrozole, letrozole) is under investigation for the treatment of endometrial carcinoma.
- No standard chemotherapeutic regimen is available.
- Chemotherapeutic use is restricted to stage IV or recurrent disease or to nonresponders to hormonal therapy.
- On average, duration of responses is around 4 months, and survival is for 9 months.
- The most active single agents are doxorubicin [35% to 40% odds ratio (OR)], cisplatin (36% OR), and paclitaxel (36% OR).
- Chemotherapy can be used in conjunction with hormonal therapy.
- Several combination regimens have been tried including carboplatin and paclitaxel; carboplatin, methotrexate, 5-fluorouracil, and medroxyprogesterone; melphalan, 5-fluorouracil, and medroxyprogesterone; cisplatin, doxorubicin, etoposide, and medroxyprogesterone; each regimen produced better response rates than historic controls, but no phase III studies have shown improvement in survival to date.
In patients with endometrial cancer, estrogen-replacement therapy remains controversial.
POSTTHERAPY SURVEILLANCE (SUGGESTED)
The following posttherapy surveillances have been suggested for endometrial cancer:
- Physical examination, CA125 measurement, and vaginal cytology every 3 to 6 months for 2 years, and then annually.
- Most recurrences are seen in the first 3 years after primary therapy.
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