Carcinoma of the endometrium is the most common female pelvic malignancy and the fourth most common cancer in females, after breast, bowel, and lung carcinomas. In 1995, an estimated 32,800 new cases of endometrial carcinoma and 5,900 related deaths will occur in the United States . The relatively low mortality for this cancer is probably due to the fact that in 80% of cases, the disease is diagnosed when it is confined to the uterus.
Uterine CarcinomasUterine SarcomasReferences
Carcinoma of the endometrium is the most common female pelvic malignancy and the fourth most common cancer in females, after breast, bowel, and lung carcinomas. In 1995, an estimated 32,800 new cases of endometrial carcinoma and 5,900 related deaths will occur in the United States . The relatively low mortality for this cancer is probably due to the fact that in 80% of cases, the disease is diagnosed when it is confined to the uterus. The recent rise in the incidence of endometrial carcinoma may be related to the decreased incidence of cervical carcinoma, prolonged life expectancy, and earlier diagnosis. This disease occurs mostly (75%) in postmenopausal women (mean age, 60 years), and only 4% of women with endometrial cancer are younger than age 40 at diagnosis [1,2]. Tumors of the uterine corpus include adenocarcinomas and their variants and sarcomas.
Several lines of epidemiologic and clinicopathologic evidence support the hypothesis that there are two pathogenetic forms of endometrial carcinoma [3,4], designated type I (estrogen related) and type II (estrogen independent)(Table 1). The estrogen-related carcinomas are better differentiated and usually grade 1 and stage I. The estrogen-independent carcinomas are often poorly differentiated, present at an advanced stage, occur in older patients (mean age, 66 years), and are rarely associated with endometrial hyperplasia. Unfavorable subtypes, such as serous carcinoma, adenosquamous carcinoma, and clear-cell carcinoma, appear to be estrogen independent.
|Characteristic||Type I||Type II|
|Menopausal status||Pre- and perimenopausal||Postmenopausal|
Clinical evidence indicates that conditions resulting in hyperestrinism predispose patients to endometrial carcinoma. Obesity increases the risk 3- to 10-fold, depending on the degree of weight excess (Table 2). Adipose tissue contains aromatase enzymes that convert the adrenal-derived androstenedione to estrone, which can be converted to estradiol (a more potent estrogen), resulting in endometrial proliferation, hyperplasia, and potentially carcinoma. Polycystic ovarian syndrome, characterized by obesity, anovulation, abnormal bleeding or amenorrhea, hirsutism, and polycystic ovaries, increases the risk of endometrial carcinoma secondary to anovulation. Anovulation results in prolonged periods of estrogen exposure unopposed by a progestational agent. Infertility also is associated with this carcinoma, probably related to anovulation with the resultant unopposed estrogen effect. Use of iatrogenic unopposed contraceptives is another recognized predisposing factor. Other possible factors, such as hypertension and diabetes, are unconfirmed and probably do not independently influence risk .
|10-21 lb overweight||2|
|21-50 lb overweight||3|
|> 50 lb overweight||10|
|Menopausal estrogen use||4.5-13.9|
|Sequential oral contraceptives||Unknown|
|Nulliparity||2× that of a woman with one child 3× that of a woman with five children|
|Early menarche (< 12 years)||1.6-2.4|
|Polycystic ovarian syndrome||Unknown|
Hyperplasia is an important characteristic that correlates with low tumor grade and lack of myometrial invasion. Hyperplasia is rated according to the degree of cytologic atypia and is divided into three types: simple, which progresses to carcinoma in 1% of cases; complex, which has a progression rate of 3%; and atypical hyperplasia, which carries a risk of malignant transformation of 10% to 30%.
The role of tamoxifen in endometrial carcinoma has become a focus of concern. Indeed, in view of the widespread use of tamoxifen as adjuvant therapy for breast cancer, reports of an increased risk of endometrial cancer in users vs nonusers of tamoxifen are worrisome . The findings of some studies suggested not only an increased risk of endometrial cancer in all tamoxifen users (relative risk, 1.3; 95% CI, 0.7 to 2.4) but also an even greater risk for women who had used the drug for longer than 2 years (relative risk, 2.3; 95% CI, 0.9 to 5.9)[7,8]. Other studies  have confirmed this finding, showing that the frequency of endometrial cancers increases significantly along with relative risk (6.4) if tamoxifen is used for longer than 2 years . Women receiving tamoxifen also show an increase in benign proliferative lesions of the endometrium, endometrial thickening, and Papanicolaou smears with a higher proportion of endometrial cells with nuclear atypia . Tamoxifen is thought to exert these and other effects on the uterus by its partial estrogenic agonist action .
The National Cancer Institute's breast cancer prevention trial is an ongoing landmark study to determine whether tamoxifen prevents breast cancer in women at increased risk of this disease. However, in light of the previous data, the National Cancer Institute is changing the protocol to increase the surveillance for endometrial cancer through endometrial aspiration and yearly pelvic examinations . Of the 4,000 women in the trial, 25 who had taken tamoxifen have been diagnosed with endometrial cancer; of these 25 patients, 5 have died of their disease .
Most studies confirm that tamoxifen may cause potentially malignant changes in the endometrium in postmenopausal women . Consequently, transvaginal ultrasonography can be used to identify women with thickened endometrium who should undergo endometrial sampling for microscopic analysis, but at present, this is quite controversial .
Interestingly, tamoxifen has been used with some success to treat patients with endometrial cancer. Tamoxifen and its metabolite 4-hydroxytamoxifen stimulate some endometrial carcinoma cell lines but inhibit others, as well as some primary cultures of human endometrial carcinoma cells [9,14]. Nevertheless, the possible connection between tamoxifen and endometrial cancer is being sought.
Although mass screening for endometrial cancer is impractical, screening of high-risk subgroups is justified. These groups include postmenopausal women receiving exogenous estrogens, particularly if they are obese, underwent menopause after age 50, or have coexistent polycystic ovarian disease or a family history of breast, endometrial, or ovarian carcinoma. There is consistent evidence that a family history of breast cancer is associated with a two- to threefold increased risk of breast cancer and that a positive family history of ovarian cancer increases the risk of breast cancer by nearly 50% [15-18]. One other high-risk group also bears mention: women with a family history of hereditary nonpolyposis colorectal cancer, which confers an increased risk of cancer, especially colorectal cancer. It has been recommended that colorectal cancer control programs be expanded to include endometrial cancer, the most common extracolonic cancer observed in hereditary nonpolyposis colorectal cancer families .
Approximately 50% of women with endometrial carcinoma have a positive Papanicolaou smear. Endometrial tissue on a Papanicolaou smear, whether the tissue is normal or abnormal, implies endometrial pathology, but the accuracy of the test for endometrial cancer is poor (25%). Fractional dilatation and curettage provides the maximum amount of tissue from the endometrial cavity, and its accuracy is 90%. All patients suspected of having endometrial carcinoma should undergo an endocervical curettage and an endometrial biopsy. However, if sampling techniques fail to provide sufficient diagnostic information, dilatation and curettage is mandatory. A diagnosis of endometrial hyperplasia on endometrial biopsy does not obviate the need for fractional curettage [5,19].
Abnormal vaginal bleeding occurs in 90% of patients, usually in the form of unusual peri- or postmenopausal bleeding. Signs and symptoms of more advanced disease include pelvic pain and leukorrhea. Physical examination commonly reveals an obese, hypertensive, postmenopausal woman, although 35% of patients are not obese. Abdominal examination is usually unremarkable, except in advanced cases, in which ascites or an enlarged uterus may be present. Occasionally, a hematometra will present as a large, smooth, midline mass arising from the pelvis. On pelvic examination, it is important to inspect and carefully palpate the genital area and perform a rectovaginal examination to evaluate the fallopian tubes, cul-de-sac, and ovaries.
Usually, carcinoma of the endometrium is easily diagnosed. Occasionally, however, a well-differentiated carcinoma may be confused with atypical hyperplasia. The main feature that helps to differentiate them is an infiltrating cellular or glandular pattern that produces a desmoplastic reaction in the stroma.
Adenocarcinomas are usually classified into three grades, depending on the degree of architectural differentiation of the tumor.
Grade I: In well-differentiated lesions, the cells are rather uniform, and a gland-like pattern is maintained. Mitoses are present but are not very helpful in identifying neoplastic potential. Approximately 70% to 75% of adenocarcinomas are well-differentiated lesions.
Grade II: In this moderately differentiated carcinoma, the proliferation of epithelial cells is more pronounced, and the lumina of the glands are often almost completely obliterated.
Grade III: Grade III adenocarcinomas are poorly differentiated lesions in which the glandular pattern is essentially eliminated by overgrowth of the epithelium .
Variants of Adenocarcinoma
Most endometrial carcinomas are pure adenocarcinomas (Table 3). Adenoacanthoma indicates the presence of benign squamous epithelium within an adenocarcinoma. This is not unusual and carries no prognostic importance. Adenosquamous carcinoma is a truly mixed neoplasia in which the squamous element is malignant. However, it is the degree of differentiation of the adenocarcinoma and not the malignant squamous component that determines the prognosis. Five-year survival rates, grade for grade, are similar for adenocarcinoma, adenoacanthoma, and adenosquamous carcinoma.
Serous carcinoma (papillary serous)
Mixed types of carcinoma
Uterine papillary serous carcinoma is similar in its clinical behavior to ovarian papillary serous carcinoma. More than 50% of patients with stage I uterine papillary serous carcinoma suffer a relapse outside the pelvis in the abdomen. Uterine papillary serous carcinoma, for which treatment remains unknown, must be distinguished from papillary (villoglandular) endometrioid carcinoma, which may respond to hormone therapy. Papillary serous carcinoma of the uterus is a virulent subtype of adenocarcinoma of the endometrium characterized by a poor prognosis, a high relapse rate, a propensity for transperitoneal seeding, and the frequent finding of more advanced disease at initial laparotomy .
The need for aggressive treatment of this disease has long been recognized. Surgery, including a thorough staging laparotomy, followed by adjuvant therapy, is considered by many to be the initial step in management. What constitutes optimal adjuvant therapy, however, remains unresolved. Both radiation and chemotherapy have been tried as adjuvant therapy, with varying results.
Adjuvant whole abdominopelvic irradiation may be considered in the management of uterine papillary serous carcinoma . Patients who stand to benefit most have early disease by surgical staging with or without positive peritoneal cytologic findings . However, a review of the literature indicates that radiotherapy results in a 55% survival rate of only 55%, with follow-up ranging from 3 to 9 months [21-26]. Chemotherapeutic combinations with cisplatin (Platinol), doxorubicin (Adriamycin, Rubex), and cyclophosphamide (Cytoxan, Neosar) have also been used but have produced only some single, temporary responses. In short, systemic cisplatin-based combination chemotherapy appears to be of limited value for uterine papillary serous carcinoma [22-27].
Mucinous adenocarcinoma accounts for fewer than 1% of all endometrial carcinomas. However, it is usually associated with a good prognosis, because most cases are stage I. A primary intestinal malignancy with uterine metastasis should be ruled out in the presence of this histologic variant.
Mesonephroid carcinoma is similar to clear-cell carcinoma arising in the ovaries and the clear-cell carcinoma of children exposed to diethylstilbestrol (DES), although no association with DES has been described for the mesonephroid neoplasm. This uncommon lesion accounts for 2% to 3% of all adenocarcinomas of the endometrium and tends to be deeply invasive, with a poor prognosis at the time of discovery .
Undifferentiated carcinoma has no glandular, squamous, or sarcomatous differentiation and has a poor prognosis. Some of these tumors are small-cell carcinomas, and most of them contain epithelial antigens detected by immunologic stains.
Squamous-cell carcinoma is diagnosed only if there is no coexisting adenocarcinoma and no connection between the tumor and the squamous epithelium of the cervix. Only 23 cases of squamous-cell endometrial cancer have been reported to date.
Cancers of an identical cell type may be discovered simultaneously in the endometrium and ovaries. Usually, in such cases, the area that has the largest tumor mass and most advanced stage is designated the primary site. The prognosis depends on the grade and extension of the neoplasia at diagnosis [2,4].
In approximately 20% of cases, endometrial carcinoma is detected while the patient is still asymptomatic. An atypical Papanicolaou smear suggests an adenocarcinoma. When atypical glandular cells are seen on the Papanicolaou smear, the risk that an adenocarcinoma will be found is approximately 20%, but this risk increases to nearly 50% in women older than age 60. Postmenopausal bleeding is the presenting symptom in 90% of women. Endometrial carcinoma must be considered in any woman older than age 40 who has abnormal uterine bleeding and in younger women in whom abnormal bleeding is associated with infertility or anovulation. In these cases, cytologic evaluation of vaginal smears may be useful but cannot replace biopsy or fractional curettage for diagnosis in high-risk patients . Currently, there is no recognized screening program for this disease. Tumor spread may be by direct extension to adjacent structures, transtubal passage of exfoliated cells, or lymphatic or hematogenous dissemination [19,29].
Staging and Prognosis
Since 1988, staging has incorporated surgical information, such as extension, grade, depth, and uterine-wall invasion, and peritoneal cytology (Table 4).
|Ia||1, 2, 3||Tumor limited to endometrium|
|Ib||1, 2, 3||Invasion to 50% or less of myometrium|
|Ic||1, 2, 3||Invasion > 50% of myometrium|
|IIa||1, 2, 3||Endocervical glandular involvement only|
|IIb||1, 2, 3||Cervical stroma invasion|
|IIIa||1, 2, 3||Tumor invasion of serosa and/or adnexae, and/or positive peritoneal cytology|
|IIIb||1, 2, 3||Vaginal metastases|
|IIIc||1, 2, 3||Metastases to pelvic and/or para-aortic lymph nodes|
|IVa||1, 2, 3||Tumor invasion of bladder and/or bowel mucosa|
|IVb||1, 2, 3||Distant metastases, including intra-abdominal and/or inguinal lymph node|
Pretreatment evaluation should also include an intravenous pyelogram and barium enema to rule out coexistent gastrointestinal and urologic disease. The routine use of computed tomography (CT) or magnetic resonance imaging (MRI) of the pelvis is not advocated. However, in select cases, these studies may help to plan radiotherapy. The distribution of patients by stage and their respective 5-year survival rates are presented in Table 5.
|Stage||Percent at diagnosis||Percent survival at 5 yr|
Staging, including grade, is the most important prognostic factor. Other factors that may influence prognosis include age and vascular space invasion, which occurs in 15% of adenocarcinomas. The risk of pelvic-node metastasis is increased fourfold if the vascular space has been invaded. Receptor status (estrogen and progesterone) is important, and its level is inversely proportional to tumor grade, stage, and depth of invasion.
Histologic tumor grade, steroid receptor content, in vitro responsiveness to hormones, data on ploidy or DNA replicating activity obtained by flow cytometry, and fraction of cells in S phase are commonly used indicators of prognosis and responsiveness to therapy . Tumor grade/stage and invasiveness correlate with the expression of several oncogenes, particularly fms, neu, fos, myb, erb-B, and myc and the augmented production of growth factors, transforming growth factor (TGF)-alpha, TGF-beta, and epidermal growth factor receptor. The clinical course of the disease and response to treatment can be followed by analysis of markers recognized by monoclonal antibodies .
Stage I and Stage II Occult: All medically fit patients should undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy. The adnexa should be removed, as they may be the site of microscopic metastases and patients with endometrial carcinoma may have synchronous ovarian cancer. Peritoneal washings are taken from the pelvis, paracolic gutters, and subdiaphragmatic region. The excised uterus is opened and the depth of myometrial penetration and presence or absence of cervical involvement is determined by clinical observation and/or microscopic frozen section. In the absence of gross residual intraperitoneal tumor, pelvic and para-aortic lymph nodes should be sampled only if any of the following is noted: a grade 3 lesion; adenosquamous, clear cell, or serous carcinoma; myometrial invasion greater than 50%; or cervical extension. Lymph nodes need not be sampled for tumors limited to the endometrium, regardless of grade, because fewer than 1% of patients with these lesions have disease that has spread to pelvic or para-aortic lymph nodes.
Adjuvant radiation has not been shown to improve survival but can reduce the chance of a pelvic recurrence. Patients with a grade 1 lesion confined to the inner third of the myometrium have a 96% 5-year survival rate, and adjuvant radiation does not improve on this. Patients with superficially invasive grade 2 carcinoma may be treated with intravaginal radiation (colpostats, 55 to 60 Gy), which has been shown to reduce the vaginal recurrence rate from 14% to 1.7%. Patients with grade 3 disease, invasion of more than one third of the myometrium, cervical extension, positive lymph nodes, or extrauterine pelvic disease should receive external pelvic irradiation with a dose of 45 to 50 Gy or a dome cylinder or cesium applicator to the vaginal cuff. Patients with extrapelvic disease should be considered for systemic therapy.
Stage II endometrial carcinoma can be confused with stage IB adenocarcinoma of the cervix. In this situation, it is helpful to note that patients with endometrial cancer more frequently are obese, are elderly, and have a bulky uterus, whereas patients with cervical carcinoma are younger, have a normal-sized corpus, and have a bulky cervix. Pelvic lymph nodes are involved in one third of patients with stage II endometrial cancer.
Two therapeutic approaches are currently in use for stage II endometrial carcinoma: (1) radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymphadenectomy or (2) preoperative external pelvic irradiation and intracavitary radium or cesium, followed in 6 weeks by total hysterectomy and bilateral salpingo-oophorectomy.
Stage III: Clinical stage III disease is uncommon, and treatment should be individualized. Rates of 5-year survival vary in this heterogeneous population. Parametrial involvement, determined surgically, carries an overall 5-year survival rate of 40%. Patients with adnexal involvement alone have a survival rate of 80%, as opposed to a rate of 15% if other extrauterine structures are involved.
Adjuvant therapy is of unproven value in stage III disease. Abdominal recurrence is common (80%), but the abdomen is rarely the sole site of recurrence. Accordingly, whole abdominal irradiation is not warranted [2,16,27,28].
Stage IV: The treatment of stage IV disease is designed primarily for palliation. Surgery is palliative, but if tumor is removed, estrogen-receptor and progesterone-receptor assays should be obtained. In stage IVA disease, irradiation (45 to 50 Gy) of the whole pelvis, and, if technically feasible, brachytherapy, is a reasonable approach. In patients with stage IVB lesions, a similar dose of external radiotherapy may be helpful.
Endometrial Cancer Diagnosed After Hysterectomy
This situation is best avoided by routinely opening the excised uterus in the operating room so that the adnexa can be removed and appropriate staging performed. Grade 1 lesions with involvement of less than one half of the myometrium require no further treatment. In the event of a grade 3 lesion or a grade 2 lesion with extension to the outer third of the myometrium or to the cervix, a re-laparotomy should be performed, with the removal of adnexa, surgical staging, and appropriate postoperative irradiation. All other cases should undergo external pelvic irradiation .
Treatment of Recurrent Disease
Patients with recurrent disease have an anticipated survival of up to 12 months. Half of the recurrences have a distant component and three fourths, a local component. About 80% of recurrences will occur within 3 years of initial treatment. The patient with an isolated vaginal recurrence may benefit from surgery and/or irradiation; others may benefit from systemic therapy (hormones, chemotherapeutic agents , or biological agents).
Hormonal Therapy: Recurrent or metastatic endometrial carcinoma is usually treated initially with a hormonal agent such as a progestational agent or an antiestrogen (tamoxifen). Progestational agents have been the mainstay of treatment of endometrial cancer.
Responses are short and are seen primarily in better differentiated tumors. Some studies have shown significant antitumor activity for gonadotropin-releasing hormone (GnRH) analogs like leuprolide (Lupron) or goserelin (Zoladex). Response rates range from 15% to 40% [26,31]. However, recent trials have reported lower response rates for such treatment, probably due to more stringent response criteria and a smaller number of patients with well-differentiated carcinomas.
In view of the factors that predict a response to progestational agents, it can be argued that patients with progesterone-receptor-positive tumors should be given first-line treatment with medroxy progesterone acetate. If the receptor status is unknown but the original tumor is well differentiated or the interval from initial diagnosis to recurrence is more than 1 year, the treatment of choice is hormonal. Because at least 3 months must elapse before the results of hormonal therapy can be evaluated, the selected patients must have a life expectancy of at least 4 months. There is no obvious dose response with progestins, and oral therapy appears as effective as parenteral therapy. Patients with grade 3 tumors have a response rate of 10% or less. Attempts to identify patients more likely to respond to hormonal therapy have met with limited success, but data suggest that tumors with positive progestin receptors are more likely to respond to hormonal therapy (Table 6). GnRH agonists also may be of benefit [32,33].
|Cressman et al||4||0||1||8|
|Martin et al||13||1||0||6|
|Benrad et al||6||2||1||5|
|Ehrlich et al||7||1||1||15|
|Schwartz and Naftolin||1||0||7||4|
|Total||37 (89%)||4 (11%)||10 (19%)||38 (81%)|
Other factors that suggest an increased likelihood of response to hormonal therapy are a long disease-free interval, exceeding 2 to 3 years, and low-grade tumors. In summary, because of their low toxicity, hormones should be used initially in patients with recurrent endometrial cancer, particularly patients with positive receptors. Therapy should be started with megestrol acetate (Megace), 40 mg orally two to four times daily, and continued until progression occurs. If the patient had an initial response to progestins, then tamoxifen, 20 mg given orally twice daily until further progression, should be considered.
Adjuvant hormonal therapy with progestational agents in endometrial cancer is attractive but unproven. Such therapy is usually guided by the pathogenetic type of disease and morphology of tumor, ie, well-differentiated endometrial cancers usually have high levels of hormone receptors in relation to steroid hormones and seem to be more sensitive to hormonal therapy. Cytoplasmic receptors to progesterone are estrogen-dependent proteins which increase in number with administration of estrogen or tamoxifen.
For patients whose profile indicates a decreased likelihood of response to progestins (negative receptor status, poor condition, undifferentiated tumor) or when the tumor load does not allow delay to await the results of hormonal manipulation, the use of cytotoxic drugs can be considered as initial therapy.
Chemotherapy: Patients in whom hormonal therapy fails may be considered for chemotherapy with palliative intent . Responses have been identified in the literature for cisplatin, doxorubicin, carboplatin (Paraplatin), cyclophosphamide, and hexamethylmelamine (altretamine, Hexalen)(Table 7). Response rates with combination chemotherapy range from 20% to 50%. Most of the responses are partial, with a median duration of 4 to 8 months and a median survival of less than 12 months.
There is no survival benefit to combination chemotherapy over single-agent cisplatin [2,34,35]. Still, it is not entirely certain that combinations are more effective than single agents. Combinations including both doxorubicin and cisplatin seem to improve the initial likelihood of a response. In general, if a response is obtained, chemotherapy is continued until progression or intolerable toxicity occurs. The addition of a progestin to chemotherapy does not appear to enhance the response. The most frequently used combination is cyclophosphamide, 500 mg/m²; doxorubicin, 50 mg/m²; and cisplatin, 50 mg/m². Single-agent cisplatin or carboplatin would be reasonable and less toxic alternatives in this patient population . Doxorubicin, could be reserved for hormone- and platinum-resistant tumors .
Studies at M D. Anderson on cisplatin, doxorubicin, and cyclophosphamide treatment of metastatic or recurrent endometrial cancer have shown an overall response rate of 45%, a complete remission rate of 14%, and a median response duration of 4 to 8 months.
Anecdotally, patients with tumors refractory to hormonal therapy and chemotherapy may respond to a combination of alpha interferon (IFN-alfa), 13-cis-retinoic acid, and alpha-tocopherol . Interferons are known to modulate the expression of receptors for estrogen (ER), progesterone (PR), and epidermal growth factor (EGFR) in women with endometrial cancer . However, no significant improvement in survival was reported in one study by Scambia and associates. The role of adjuvant systemic therapy remains to be adequately explored but is thus far unproven.
Finally, there is currently considerable interest in the activity of the natural product paclitaxel (Taxol) not only in ovarian cancer but also in endometrial cancer. Taxol has a unique mechanism of cytotoxicity that involves the polymerization of microtubules. Another taxane of interest is docetaxel (Taxotere). Recently, the Gynecologic Oncology Group has reported the results of a phase II study of paclitaxel in endometrial cancer. The objective response rate was 35% with a 15% complete response rate (Ball HG, personal communication, September, 1995).
Uterine sarcomas are rare heterogeneous tumors that account for 3% of uterine malignant neoplasms in white women, 10% of uterine malignancies in black women. These tumors are not estrogen dependent and appear at a median age of 60 years. Prior radiation therapy to the pelvis has been implicated in the genesis of uterine sarcomas, but this is unproven. The incidence of uterine sarcomas is 1.7 per 100,000 women. Carcinosarcoma is the most common uterine sarcoma, followed by leiomyosarcoma and endometrial stromal sarcoma. These neoplasms are frequently associated with obesity, diabetes, and hypertension [16,25,41,42]. The peak age of incidence for carcinosarcoma (mixed mllerian tumor) is 55 to 65 years of age, whereas it is 45 to 55 years of age for leiomyosarcoma and endometrial stromal sarcoma .
Natural History and Clinical Presentation
Generally, uterine sarcomas are characterized by an aggressive growth pattern with early hematogenous spread and lymphatic dissemination in about 35% of patients with disease clinically confined to the uterus. Overall survival is poor, in the range of 1 to 2 years after diagnosis. The 5-year survival for stage 1 tumors is 50% but falls to 20% for leiomyosarcoma if there is any spread beyond the uterus and to approximately 16% for endometrial stromal sarcoma (ESS) irrespective of stage. However, low-grade leiomyosarcomas, ESS, and endolymphatic stromal myosis are associated with better cure and survival rates. Prognosis depends on the extent of extrauterine spread and the number of mitotic cells per 10 high-power fields. In the case of leiomyosarcoma, more than 10 mitotic cells constitute a very aggressive, high-grade tumor, whereas fewer than five mitotic cells usually indicate a benign tumor. Cases with 5 to 10 mitotic cells per 10 high-power fields and significant cellular atypia are considered high grade.
Abnormal uterine bleeding is the most frequent presenting symptom for all histologic types and occurs in at least 80% of patients. Pelvic pain is present in about one third of patients with sarcoma. Other less common presentations include uterine enlargement, prolapsed neoplasm, and malodorous discharge. Because of this aggressive and nonspecific clinical picture, the early diagnosis of uterine sarcomas is rare. However, if the diagnosis of a sarcoma is made prior to a hysterectomy, more appropriate treatment planning can be done if a CT scan or MRI of the pelvis is obtained. The diagnostic yield of Papanicolaou smear is 46% for endometrial stromal sarcoma and 22% for leiomyosarcoma, whereas with endometrial biopsy it is 91% for mixed mesodermal sarcoma. Like endometrial carcinomas, uterine sarcomas infiltrate the myometrium.
Staging: No accepted staging system exists for uterine sarcomas because of their rarity. Usually, a modified staging based on the system developed by the International Federation of Gynecology and Obstetrics (FIGO) for endometrial cancer is used (Table 8)[25,27,43].
|I||Sarcoma is confined to the corpus|
|II||Sarcoma is confined to the corpus and cervix|
|III||Sarcoma has spread outside the uterus but is confined to the true pelvis|
|IV||Sarcoma has spread outside the true pelvis|
Pathology: Uterine sarcomas are classified as pure sarcomas if they contain only one recognizable element and mixed sarcomas if they contain at least two elements (Table 9). These elements may be homologous, when tissue is native to the uterus (eg, smooth muscle, endometrial stroma, vessels) or heterologous, when its components are tissues foreign to the uterus (bone, cartilage, striated muscle, fat).
|Pure||Leiomyosarcoma Stromal sarcoma||Rhabdomyosarcoma Chondrosarcoma Osteosarcoma Liposarcoma|
|Mixed||Mixed mesodermal tumor||Mixed mesodermal tumor|
Carcinosarcomas and adenosarcomas belong to a group of mixed tumors. Carcinosarcoma contains histologically malignant epithelial and nonepithelial elements. An adenosarcoma is characterized by a benign epithelial component and a malignant stroma. In the current classification system, these are referred to as “malignant mixed mesodermal tumor” or “malignant mixed mllerian tumor [42,44].”
The only treatment of any proven curative value for uterine sarcomas is surgical excision with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Random biopsies of retroperitoneal lymph nodes rarely yield clinically useful information. In stage I patients, the average survival rate is 45% at 2 years . Although radiation therapy is often administered, its value is controversial as it seems to reduce pelvic recurrence without influencing overall survival. There is a high incidence of distant failure, particularly in the lungs and upper abdomen .
Systemic chemotherapy is part of the integrated treatment of uterine sarcomas. Chemotherapy recommendations vary according to histologic subtype, even though there are no well-controlled series for any histologic type owing to the rarity of these tumors. The most active agents are doxorubicin, cisplatin, and ifosfamide. Unfortunately, most responses are partial and short duration. Adjuvant chemotherapy after hysterectomy is an attractive concept; however, neither survival nor progression-free interval are prolonged by currently available adjuvant chemotherapy . The potential value of hormonal agents in the management of uterine sarcomas awaits further evaluation, although there have been anecdotal reports of responses to progestins or GnRH agonists [16,45].
As mentioned above, chemotherapy recommendations vary according to histologic subtype (Table 10). The most frequently used combinations are doxorubicin, dacarbazine (DTIC-Dome), dactinomycin (Cosmegen), and cyclophosphamide or cyclophosphamide, vincristine (Oncovin), doxorubicin, and dacarbazine. A partial response follows chemotherapy in 20% to 30% and a complete response in 10% to 15%, but there is no improvement in survival. In leiomyosarcoma, the recommended treatment is doxorubicin (50 to 90 mg/m²) as a single agent, with dose escalation as tolerated. The addition of dacarbazine adds little in terms of response but more in terms of toxicity. The addition of other drugs (cyclophosphamide, cisplatin, vincristine, dactinomycin, or ifosfamide [Ifex]) does not appear to contribute to response or survival but, again, increases toxicity. In any case, the dose of doxorubicin should not be reduced in order to add other drugs.
|Agent||Response rate (%) for tumor type|
For carcinosarcoma and mixed mesodermal tumor, the drug of choice is ifosfamide (1.2 to 1.5 g/m²/d for 5 days ) or cisplatin (50 to 75 mg/m²)[45,48-52]. There is no evidence that combining these two drugs results in a higher response rate, and the combination is clearly more toxic. Carboplatin has not been tested but may be used in patients with renal compromise or poor performance status [41-43]. However, patients who receive prior pelvic radiation may develop greater myelosuppression. Hematopoietins may be considered to allow the maintenance of dose intensity .
In the case of endometrial stromal sarcoma, optimal therapy is undefined . However, frontline treatment with the single agent doxorubicin is suggested. If no response is noted, a trial of cisplatin or ifosfamide, as for carcinosarcoma, may be attempted. Low-grade sarcomas may respond to progestational agents or GnRH agonists. Yet, given the rarity of these tumors, inclusion of patients in clinical trials should be considered. No current role for chemotherapy has been defined in the adjuvant setting. Clearly, further studies are needed to identify additional active agents. Radiotherapy as safe treatment should be considered in patients who are considered inoperable and in whom parametrial metastases are present .
1. Wingo PA, Tong T: Cancer statistics, 1995. CA Cancer J Clin 45:8â30, 1995.
2. Park R, Grigsby P, Muss H, et al: Corpus: Epithelial tumors, in Hoskins WI, Perez C, Young RC (eds): Principles and Practice of Gynecologic Oncology, 1st ed, pp 663â693. Philadelphia, JB Lippincott, 1992.
3. Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 15:10â12, 1983.
4. Kurman RJ, Norris HJ: Endometrial carcinoma, in Kurman RJ (ed): Blaustein's Pathology of the Female Genital Tract, 3rd ed, pp 338â372. New York, Springer-Verlag, 1987.
5. Piver MS, Marchetti DL: Endometrial carcinoma, in Piver MS (ed): Manual of Gynecologic Oncology and Gynecology. Boston, Little, Brown & Co, 1989.
6. Seachrist L: Restating the risks of tamoxifen Science 263:910â911, 1994.
7. Sasiene P: Endometrial cancer during tamoxifen treatment. Lancet 23;343:1048, 1994.
8. Baum M, Odling-Smee W, Houghton J: Endometrial cancer during tamoxifen treatment. Lancet 343:1291, 1994.
9. Rayter Z, Sheperd J, Gazrt JC: Tamoxifen and endometrial lesions. Lancet 343:1124, 1993.
10. Love RR: Endometrial cancer in tamoxifen treated breast cancer patients. J Natl Cancer Inst 86:1025â1026, 1994.
11. Smigel K, Ulbrich S: Breast cancer prevention trial will resume (news). J Natl Cancer Inst 86:961â963, 1994.
12. Kedar RP, Bourne TH: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343:1318â1321, 1994.
13. Chambers JT, Chambers SK: Endometrial sampling: When, where, why, with what? Clin Obstet Gynecol 35:28â39, 1992.
14. Anzai Y, Holinka CF, Kuramato H: Stimulatory effect of 4-hydroxytamoxifen on proliferation of human endometrial adenocarcinoma cells (Ishikawa line). Cancer Res 49:2362â2365, 1989.
15. Parazzinni F, Lavecchlia C, Negri E: Family history of breast, ovarian, and endometrial cancer and risk of breast cancer. Int J Epidemiol 22:614â618, 1993.
16. Thompson WD, Schildkrant JM: Family history of gynecological cancers: Relationships to the incidence of breast cancer prior to age 55. Int J Epidemiol 20:595â602, 1991.
17. Kelsey JL, Fischer DB, Holford TR, et al: Exogenous estrogens and other factors in the epidemiology of breast cancer. J Natl Cancer Inst 67:327â333, 1981.
18. Watson P, Vasen HF: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96:516â520, 1994.
19. Hacker NF: Uterine cancer, in Berek JS, Hacker NF (eds): Practical Gynecologic Oncology, 1st ed, pp 285â326. Baltimore, Williams & Wilkins, 1989.
20. Mallipeddi P, Kapp DS: Long-term survival with adjuvant whole abdominopelvic irradiation for uterine papillary serous carcinoma. Cancer 71:3076â3081, 1993.
21. Christman JE, Kapp DS: Therapeutic approaches to uterine papillary serous carcinoma: A preliminary report. Gynecol Oncol 26:228â235, 1987.
22. Chambers JT, Merino M: Uterine papillary serous carcinoma. Obstet Gynecol 69:109â113, 1987.
23. Gallion HH, Van Nagell JR, et al: Stage 1 serous papillary carcinoma of endometrium. Cancer 63:2224â2228, 1989.
24. Walker AN, Mills SE: Serous papillary carcinoma of endometrium: A clinicopathologic study of 11 cases. Diagn Gynecol Obstet 4:261â267, 1982.
25. Sutton GP, Brill L: Malignant papillary lesions of the endometrium. Gynecol Oncol 27:294â304, 1987.
26. Frank AH, Tseng PC: Adjuvant whole abdominal radiation therapy in uterine papillary serous carcinoma. Cancer 68:1516â1519, 1991.
27. Greven K, Olds W: Isolated vaginal recurrences of endometrial adenocarcinoma and their management. Cancer 60:419â421, 1987.
28. Larson DM, Johnson KK: Prognostic significance of malignant cervical cytology in patients with endometrial cancer. Obstet Gynecol 84:399â403, 1994.
29. Berman ML, Berek JS: Uterine corpus, in Haskel C (ed): Cancer Treatment, 3rd ed, pp 338â350. Philadelphia, WB Saunders, 1990.
30. Thigpen JT, Vance R, Lambuth B, et al: Chemotherapy for advanced or recurrent gynecological cancer. Cancer 60:2104â2116, 1987.
31. Moore TD, Philips PH, Nerenstone SR, et al: Systemic treatment of advanced and recurrent endometrial carcinoma: Current status and future direction. J Clin Oncol 9:1071â1088, 1991.
32. Burke TW, Wolfson AH: Limited endometrial carcinoma: Adjuvant therapy. Semin Oncol 21:84â90, 1994.
33. Perl V, Schally AV, Comaru-Schally AM, et al: Use of D-Trp-6-LH-RH in endometrial adenocarcinoma. Proceedings from the XXII Congreso Chileno de Obstetrica y Ginecologia, Santiago, Chile 2:7, 1987.
34. De Saia PJ, Creasman WT (eds): Clinical Gynecologic Oncology, pp 167â213. St Louis, CV Mosby Co, 1989.
35. Martinez A, Schray M, Podratz K, et al: Postoperative whole abdominopelvic irradiation for patients with high risk endometrial cancer. Int J Radiat Oncol Biol Phys 17:371, 1989.
36. Burke TW, Munkarah A, Kavanagh JJ: Treatment of advanced or recurrent endometrial carcinoma with single agent carboplatin. Gynecol Oncol 51:397â400, 1993.
37. Vishnevsky AS, Tsyrlina EV, Sofroniy DF: Criteria of endometrial carcinoma sensitivity to hormone therapy: Pathogenetic type of the disease and the tumor reaction to tamoxifen. Eur J Gynaecol Oncol 14:139â143, 1993.
38. Kudelka AP, Freedman RS, Kavanagh JJ: Metastatic adenocarcinoma of the endometrium treated with 13-cis-retinoic acid plus interferon-alpha. Anticancer Drugs 4:335â337, 1993.
39. Muss HB: Chemotherapy of metastatic endometrial cancer. Semin Oncol 21:107â113, 1994.
40. Deppe G: Chemotherapy for endometrial cancer, in Deppe G (ed): Chemotherapy of Gynecologic Cancer, 2nd ed, pp 155â174. New York, Alan R Liss, 1990.
41. Thigpen JT: Chemotherapy of cancers of the female genital tract, in Perry MC (ed): The Chemotherapy Source Book, 1st ed, pp 1039â1067. Baltimore, Williams & Wilkins, 1992.
42. Neijt JP: Systemic treatment in disseminated endometrial cancer. Eur J Cancer 29:628â632, 1993.
43. Kudelka AP, Freedman RS, Edwards CL, et al: Verbal communication. January 1993.
44. Kavanagh JJ, Kudelka AP: Systemic therapy of gynecologic cancer. Curr Opin Oncol 5:891â899, 1993.
45. Ozols RF: Advances in the chemotherapy of gynecological malignancies. Hematol Oncol 10:43â51, 1992.
46. Sutton GP, Blessing JA, McGuire W, et al: Phase II trial of ifosfamide and mesna in leiomyosarcomas of the uterus. Gynecol Oncol 36:295, 1990.
47. Sutton GP, Blessing JA, Rosenheim N, et al: Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus. Am J Obstet Gynecol 161:309, 1989.
48. Hannigan E, Curtin J, Silverberg S, et al: Corpus: Mesenchymal tumors, in Hoskins WJ, Perez C, Young RC (eds): Principles and Practice of Gynecologic Oncology, 1st ed, pp 695â714. Philadelphia, JB Lippincott, 1992.
49. Zlovdek CH, Norris HJ: Mesenchymal tumors of the uterus, in Kurman RJ (ed): Blaustein's Pathology of the Female Genital Tract, 3rd Ed, pp 373â408. New York, Springer-Verlag, 1987.
50. Hoskins WJ, Perez C, Young RC: Gynecologic tumors, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 3rd ed, pp 1099â1161. Philadelphia, JB Lippincott, 1989.
51. Hacker NF, Moore JG (eds): Essentials of Obstetrics and Gynecology, 1st ed. Philadelphia, WB Saunders, 1986.
52. Gershenson DM, Kavanagh JJ, Copeland LJ, et al: Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus. J Clin Oncol 5:618, 1987.
53. Meden H, Meyer-Rath D, Schauer A: Endometrial stromal sarcoma of the uterus. Anticancer Drugs 2:35â37, 1991.
54. Omura GA, Blessing JA, Major F, et al: A randomized clinical trial of adjuvant Adriamycin in uterine sarcomas: A Gynecologic Oncology Group study. J Clin Oncol 3:1240, 1985.