Neville F. Hacker
Cancer of the endometrium is the most common gynecologic malignancy in the United States. For 2007, it is estimated that there will be more than 39,000 new cases and 7400 deaths. It is the fourth most common malignancy found in American women after breast, colorectal, and lung cancer and is predominantly a disease of affluent, obese, postmenopausal women of low parity.
Epidemiology and Etiology
The median age for endometrial cancer is about 58 years. The risk factors associated with the development of carcinoma of the endometrium are listed in Box 41-1. Any factor that increases the exposure to unopposed estrogen increases the risk for endometrial cancer. If the proliferative effects of estrogen are not counteracted by a progestin, endometrial hyperplasia and possibly adenocarcinoma can result.
BOX 41-1 Risk Factors for Endometrial Cancer
• Obesity
• Nulliparity
• Late menopause
• Diabetes mellitus
• Hypertension
• Family history of breast, colon, or ovarian cancer (HNPCC syndrome)
• Chronic unopposed estrogen stimulation
• Chronic tamoxifen use
HNPCC—hereditary nonpolyposis colon cancer syndrome.
Obesity results in an increased extraovarian aromatization of androstenedione to estrone. Androstenedione is secreted by the adrenal glands, whereas the increased peripheral conversion occurs predominantly in fat depots but also in the liver, kidneys, and skeletal muscles. Granulosa-theca cell tumors of the ovary produce estrogen, and up to 15% of patients with these tumors have an associated endometrial cancer.
Unopposed estrogenic stimulation from anovulatory cycles occurs in patients who have polycystic ovarian syndrome (Stein-Leventhal syndrome) and in patients with a late menopause. In postmenopausal women taking estrogen replacement without a progestin for menopausal symptoms, the risk for cancer developing appears to be both dose and duration dependent. This increased risk varies from 2-fold to 14-fold compared with nonusers. The addition of progestin in a cyclic fashion for 10 to 14 days of the month or in a continuous fashion daily throughout the month eliminates this increased risk. Women taking tamoxifen for breast cancer have a twofold to threefold increased risk for endometrial cancer. Young women who use oral contraceptives have been shown to have a lower incidence of subsequent endometrial cancer.
About 5% of endometrial cancers occur in women with the hereditary nonpolyposis colon cancer syndrome (HNPCC), which is caused by germ line mutations in the DNA repair genes. Women with the HNPCC syndrome have about a 40% risk for developing endometrial cancer, usually before the menopause.
Screening of Asymptomatic Women
Population screening for endometrial cancer is not feasible because there is no simple method of cancer detection available. However, screening may be justified for high-risk women, including those with a family history of HNPCC syndrome, those with polycystic ovarian disease, and any woman with an intact uterus taking unopposed estrogen. Only about 50% of women with endometrial cancer will have malignant cells on a Papanicolaou smear.
Since the 1990s, transvaginal ultrasonography has been increasingly used for endometrial evaluation. Almost all women with endometrial hyperplasia or carcinoma will have an endometrial thickness of 5 mm or more. Tamoxifen produces a confusing ultrasonic image, which leads to frequent false-positive reports.
Symptoms
The most common symptom of endometrial cancer is abnormal vaginal bleeding, which is present in 90% of patients. Postmenopausal bleeding is always abnormal and must be investigated. The most common conditions associated with postmenopausal bleeding are listed in Table 41-1. In the premenopausal patient, especially after age 35 years, menorrhagia or intermenstrual bleeding may signal an endometrial malignancy.
TABLE 41-1 ETIOLOGY OF POSTMENOPAUSAL BLEEDING
|
Factor |
Approximate Percentage |
|
Exogenous estrogens |
30 |
|
Atrophic endometritis, vaginitis |
30 |
|
Endometrial cancer |
15 |
|
Endometrial or cervical polyps |
10 |
|
Endometrial hyperplasia |
5 |
|
Miscellaneous (e.g., cervical cancer, uterine sarcoma, urethral caruncle, trauma) |
10 |
Signs
The general physical examination may reveal obesity, hypertension, and the stigmata of diabetes mellitus. Evidence of metastatic disease is unusual at initial presentation, but the chest should be examined for any effusion and the abdomen carefully palpated and percussed to exclude ascites, hepatomegaly, or evidence of upper abdominal masses.
On pelvic examination, the external genitalia are usually normal. The vagina and cervix are also usually normal but should be carefully inspected and palpated for evidence of involvement. A patulous cervical os or a firm, expanded cervix may indicate extension of disease from the corpus to the cervix. The uterus may be of normal size or enlarged, depending on the extent of the disease and the presence or absence of other uterine conditions, such as adenomyosis or fibroids. The adnexa should be carefully palpated for evidence of extrauterine metastases or an ovarian neoplasm. A granulosa cell tumor or an endometrioid ovarian carcinoma may occasionally coexist with endometrial cancer.
Diagnosis
Any woman who presents with postmenopausal bleeding should have a transvaginal ultrasound. If the endometrial thickness is greater than 5 mm, endometrial evaluation is necessary. Outpatient techniques for endometrial sampling include the use of the Kevorkian curette, Vabra aspirator, Gravlee jet washer, and Pipelle cannula. These techniques have a diagnostic accuracy of about 90%. If the endometrial biopsy reveals endometrial cancer, definitive treatment can be arranged. If the endometrial biopsy is negative for cancer or reveals endometrial hyperplasia, a hysteroscopy and fractional dilation and curettage should be performed under general anesthesia. Specimens from the endometrium and endocervix should be submitted separately for histologic evaluation to determine whether the tumor has extended to the endocervix.
In a premenopausal patient with high-risk factors and abnormal uterine bleeding, the endometrium must be sampled. Failure to respond to medical management or a suspicious transvaginal ultrasound is another indication for hysteroscopy and uterine curettage. A grossly obvious lesion of the cervix or vagina should be biopsied directly.
STAGING
The International Federation of Gynecology and Obstetrics (FIGO) changed from a clinical to a surgical staging system for endometrial cancer in 1988. The new surgical staging, based on pathologic confirmation of the extent of spread, is shown in Table 41-2.
TABLE 41-2 International Federation of Gynecology and Obstetrics (FIGO) STAGING OF ENDOMETRIAL CARCINOMA (1988)
|
Stage Ia |
Tumor limited to endometrium |
|
Stage Ib |
Invasion through less than half of the myometrium |
|
Stage Ic |
Invasion equal to or more than half of the myometrium |
|
Stage IIa |
Endocervical glandular involvement only |
|
Stage IIb |
Cervical stroma invasion |
|
Stage IIIa |
Tumor invades serosa or adnexa or both, or positive peritoneal cytologic findings, or both |
|
Stage IIIb |
Vaginal metastases |
|
Stage IIIc |
Metastases to pelvic or para-aortic lymph nodes, or both |
|
Stage IVa |
Tumor invasion of bladder or bowel mucosa, or both |
|
Stage IVb |
Distant metastases including intraabdominal or inguinal lymph nodes, or both |
|
Histologic grade does not change the stage |
|
|
Grade 1 |
Well differentiated |
|
Grade 2 |
Moderately differentiated |
|
Grade 3 |
Poorly differentiated |
Preoperative Investigations
In addition to a thorough physical examination, blood studies should include a complete blood count, determinations of hepatic enzymes, serum electrolytes, blood urea nitrogen, serum creatinine, and a coagulation profile. A routine urinalysis should be performed. The only radiologic study necessary is a chest x-ray. Additional radiographic procedures, including abdominopelvic computed tomography or magnetic resonance imaging, may be performed, particularly for poorly differentiated cancers, to look for metastatic disease.
Pathologic Features
About 75% of endometrial cancers are endometrioid adenocarcinomas. When squamous elements are present, the tumor is called an adenocarcinoma with squamous differentiation. Such tumors are graded on the glandular component of the lesion. Less often, clear cell, squamous, or serous carcinomas occur, and all carry a worse prognosis.
Invasive adenocarcinoma of the endometrium demonstrates proliferative glandular formation with minimal or no intervening stroma. Tumor grade is determined by both the degree of abnormality of the glandular architecture and the degree of nuclear atypia. A lesion that is well differentiated (grade 1) forms a glandular pattern similar to normal endometrial glands (Figure 41-1). A moderately well-differentiated lesion (grade 2) has glandular structures admixed with papillary, and occasionally solid, areas of tumor. In a poorly differentiated lesion (grade 3), the glandular structures have become predominantly solid with a relative paucity of identifiable endometrial glands (Figure 41-2).
FIGURE 41-1 Well-differentiated endometrial adenocarcinoma (histologic study). Note the back-to-back glands with minimal intervening stroma and the gland-within-gland pattern.
FIGURE 41-2 Poorly differentiated endometrial adenocarcinoma (histologic study). Note the predominantly solid nature of the tumor with minimal gland formation.
Pattern of Spread
Endometrial cancer spreads by (1) direct extension, (2) exfoliation of cells that are shed through the fallopian tubes, (3) lymphatic dissemination, and (4) hematogenous dissemination.
The most common route of spread is direct extension of the tumor to adjacent structures. The tumor may invade through the myometrium and eventually penetrate the serosa. It may also grow downward and involve the cervix. Although uncommon, progressive growth may eventually involve the vagina, parametrium, rectum, or bladder.
Exfoliated cells may pass through the fallopian tubes and implant on the ovaries, the visceral or parietal peritoneum, or the omentum.
Lymphatic spread occurs most commonly in patients with deep myometrial penetration. Spread mainly occurs to the pelvic lymph nodes and subsequently to the para-aortic lymph nodes, although simultaneous spread to both nodal groups may occur. In stage I endometrial cancer, the overall incidence of pelvic lymph node metastases is about 12%, and para-aortic metastases occur in about 8% of cases. In patients with deeply invasive, poorly differentiated stage I adenocarcinomas, however, pelvic lymph node metastases occur in up to 40% of cases. Lymphatic spread is also responsible for vaginal vault recurrences.
Hematogenous dissemination is less common, but it results in parenchymal metastases, particularly in the lungs, liver, or both.
Treatment
STAGE I
Surgery
An exploratory laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy is performed on all patients, unless there are absolute medical contraindications (Figure 41-3). On opening the abdomen, peritoneal washings are taken with normal saline for cytologic evaluation. About 15% of patients with disease confined to the corpus have positive peritoneal cytology.Retroperitoneal spaces should be opened and evaluated, and any enlarged pelvic or para-aortic lymph nodes should be resected. Formal surgical staging, including at least pelvic lymphadenectomy, should be performed on high-risk patients, including those with serous, clear cell, or grade 3 histology; outer-half myometrial invasion; or cervical extension. Laparoscopic surgery, including laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy, with or without laparoscopic lymph node dissection, is being increasingly used, particularly for obese patients, and those with grade 1 or 2 cancers.
FIGURE 41-3 Specimen from a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The uterus has been opened to reveal an exophytic carcinoma on the posterior wall of the corpus.
Radiation Therapy
With the advent of surgical staging, less reliance has been placed on adjuvant radiation therapy in the management of patients with endometrial cancer.
Recommendations are as follows (Figure 41-4).
1. Patients with grade 1 or 2 endometrioid carcinomas confined to the inner half of the myometrium may be followed without adjuvant therapy (i.e., stage Ia or Ib, grade 1 or 2).
2. Patients with high-risk carcinomas with negative pelvic nodes (i.e., any stage Ic cancer; any grade 3, clear cell, or serous cancer; or any stage II cancer) may have vault brachytherapy (without external-beam pelvic radiation).
3. Patients with one positive pelvic node should receive external pelvic radiation.
4. Patients with multiple positive pelvic nodes or proven positive para-aortic nodes should receive extended-field radiation (i.e., pelvic and para-aortic).
5. For patients with adnexal or omental metastases, chemotherapy with carboplatin and paclitaxel (Taxol) should be given.
FIGURE 41-4 Algorithm for the treatment of stage I and occult stage II endometrial cancer. BSO, bilateral salpingo-oophorectomy; PA, para-aortic; RT, radiation therapy; TAH, total abdominal hysterectomy.
In patients medically unfit for surgery, radiation therapy alone may be employed. A combination of intracavitary plus external-beam radiation is used. The overall 5-year survival rate is about 20% lower than for patients treated with hysterectomy.
Hormonal Therapy
Endometrial cancer occasionally occurs in women younger than 40 years. These tumors are usually early-stage and low-grade, and there is frequently a desire to preserve fertility. High-dose medroxyprogesterone acetate (200 mg twice daily) for 3 to 6 months will reverse the changes in about two thirds of patients, but recurrences are common, so careful monitoring is essential.
STAGE II
If the cervix is grossly normal and involvement is detected only on the histologic evaluation of the endocervical curettage material (occult stage II disease), treatment may be the same as for stage I disease (i.e., total abdominal hysterectomy, bilateral salpingo-oophorectomy, surgical staging, and tailored postoperative radiotherapy).
Alternatively, regardless of the size of the cervix, primary radical hysterectomy, bilateral salpingo-oophorectomy, together with pelvic and para-aortic lymphadenectomy, may be performed. If the lymph nodes are negative, no brachytherapy is required. If positive, postoperative external-beam pelvic or extended-field radiation is required.
ADVANCED STAGES
For advanced disease, treatment is individualized. The uterus, tubes, and ovaries should be removed, if possible, for palliation of bleeding and other pelvic symptoms. If gross disease is present in the upper abdomen, tumor metastases that are readily removable, such as an omental “cake,” should be extirpated in an attempt to improve the patient’s quality of life by temporarily decreasing abdominal discomfort and ascites. In addition, patients with advanced disease also require chemotherapy, radiation therapy, or both, as shown in Figure 41-4.
Chemotherapy
There is increasing evidence for the use of chemotherapy in patients with advanced endometrial cancer. The combination of cisplatin and doxorubicin has been studied recently and may be used alone or in combination with radiation therapy, as shown in Figure 41-4.
RECURRENT DISEASE
Seventy-five percent of recurrences develop within 2 years of treatment. If recurrent disease is detected, the patient should undergo a complete physical examination and metastatic workup. Careful follow-up is particularly important for patients treated without adjuvant therapy. Most recurrences in these patients are at the vaginal vault, and 70% to 80% of isolated vault recurrences can be salvaged by radiation therapy.
Metastases in other sites, such as the upper abdomen, lungs, or liver, are treated initially with high-dose progestins or antiestrogens. About one third of recurrent endometrial carcinomas contain estrogen and progesterone receptors, with the more well-differentiated tumors more likely to contain such receptors. As with breast cancer, the likelihood of a patient responding to progestin treatment is increased in patients whose tumor contains estrogen and progesterone receptors. About 80% of such patients respond to progestin therapy, compared with fewer than 10% of patients whose tumor is receptor negative.
Medroxyprogesterone acetate (Provera, 50 mg 3 times daily; Depo-Provera, 400 mg intramuscularly weekly) or megestrol acetate (Megace), 80 mg twice daily, may be given. If disease progresses while the patient is receiving progestins, chemotherapy may be offered. The combination of carboplatin and paclitaxel (Taxol) gives a response rate of about 50%.
Prognosis
Prognosis is dependent on several variables, including uterine size, histologic type, grade of tumor, depth of myometrial penetration, status of lymph nodes, status of peritoneal cytologic features, and presence or absence of occult adnexal or upper abdominal metastases. Serous and clear cell endometrial carcinomas have a particularly bad prognosis, and both of these histologic types are prone to early dissemination. Five-year survival rates for these tumor types are less than 50%, even for patients with stage I disease.
Five-year survival rates for each stage of endometrioid endometrial cancer are presented in Table 41-3.
TABLE 41-3 SURVIVAL FOR ENDOMETRIAL CANCER BY FIGO STAGE (N = 5694)
|
Stage |
No. of Patients |
Five-Year Survival (%) |
|
Ia |
1063 |
91.1 |
|
Ib |
2735 |
89.7 |
|
Ic |
1219 |
81.3 |
|
IIa |
364 |
78.7 |
|
IIb |
426 |
71.4 |
|
IIIa |
484 |
60.4 |
|
IIIb |
73 |
30.2 |
|
IIIc |
293 |
52.1 |
|
IVa |
47 |
14.6 |
|
IVb |
160 |
17.0 |
Data from the Annual Report on the Results of Treatment in Gynecological Cancer. Patients treated 1996-1998. J Epidemiol Biostat 83:79-118, 2003.
Follow-Up
Follow-up examinations should be performed every 3 months for 2 years, every 6 months for 3 years, and then annually. It is important to take a vault Papanicolaou smear on patients who have not had radiation therapy.
Uterine Sarcomas
Uterine sarcomas account for about 3% of uterine cancers. They arise from the stromal components of the uterus, either the endometrial stroma or the mesenchymal and myometrial tissues. As a group, sarcomas tend to be more advanced at the time of diagnosis, are more likely to disseminate hematogenously, and have much lower 2- and 5-year survival rates.
CLASSIFICATION
A classification system for uterine sarcomas is presented in Table 41-4.
TABLE 41-4 CLASSIFICATION OF UTERINE SARCOMAS
|
Type |
Homologous |
Heterologous |
|
Pure |
Leiomyosarcoma Endometrial stromal sarcoma Endometrial sarcoma |
Rhabdomyosarcoma Chondrosarcoma Osteosarcoma Liposarcoma |
|
Mixed |
Carcinosarcoma |
Malignant mixed mesodermal tumor |
Uterine sarcomas can be classified as either pure, in which the only malignant tissue is of mesenchymal origin, or mixed, in which malignant mesenchymal and malignant epithelial tissues are present. They may also be classified as homologous, implying that the tissue that is malignant is normally present in the uterus (e.g., endometrial stroma, smooth muscle), or heterologous, implying that the tissue that is malignant is not normally present in the uterus (e.g., bone or cartilage). Most pure uterine sarcomas are leiomyosarcomas and endometrial stromal sarcomas.
LEIOMYOSARCOMA
Leiomyosarcomas may be associated with a benign leiomyoma of the uterus, but the risk for malignant transformation in a benign fibroid is less than 1%. The histologic criteria for distinguishing leiomyosarcomas from leiomyomas are the mitotic count (usually greater than 10 per 10 high-power fields), the presence or absence of coagulative necrosis, and the presence or absence of cellular atypia.
Clinically, the mean age of patients with leiomyosarcoma is about 55 years. Patients with this disease may present with pelvic pain, abnormal uterine bleeding, or a pelvic or lower abdominal mass. A sensation of pressure on the bladder or rectum may also be noted.
Most cases are not diagnosed preoperatively but are discovered at the time of exploratory surgery for a probable fibroid. Curettings are usually normal. If a known fibroid uterus appears to be rapidly enlarging, especially postmenopausally, malignancy should be suspected.
The treatment of a uterine leiomyosarcoma consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy. Adjuvant pelvic radiation appears to decrease local pelvic recurrence but does not prolong survival because most patients die with distant metastases.
Response rates to chemotherapy are very low.
ENDOMETRIAL STROMAL TUMORS
The three types of stromal tumors are (1) endometrial stromal nodule; (2) endometrial stromal sarcoma, previously known as endolymphatic stromal myosis; and (3) high-grade endometrial sarcoma. The first of these, the stromal nodule, is a rare benign condition. There are typically three or fewer mitoses per 10 high-power fields. A hysterectomy is curative.
Endometrial stromal sarcoma is a low-grade lesion. Histologically, there is minimal to no cellular atypia, with usually fewer than five mitoses per 10 high-power fields. There is always evidence of vascular channel invasion. These patients usually present with abnormal vaginal bleeding and often with pelvic pain.
Most patients are cured with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Local and distant recurrences may occur even 10 to 20 years later and require reexploration and resection of disease. Prolonged survival is possible after resection of recurrent disease, and response to progestins is good. Pelvic disease may respond to radiation therapy.
High-grade endometrial sarcoma generally causes abnormal uterine bleeding, and more than half of patients are premenopausal. The diagnosis can often be made by endometrial biopsy or uterine curettage.Histologically, there are 10 or more mitoses per 10 high-power fields, and the lesion is composed of very poorly differentiated cells. Aggressive myometrial invasion occurs, and hematogenous spread is common at the time of diagnosis.
The treatment of high-grade endometrial sarcoma is total abdominal hysterectomy and bilateral salpingo-oophorectomy. A thorough exploration of the peritoneal cavity and retroperitoneum should be made for evidence of metastases. Postoperative pelvic irradiation improves local control but does not improve survival. In patients with metastatic disease, progestogens or chemotherapy may be offered. The best chemotherapeutic agents are cisplatin, doxorubicin, and ifosfamide, but the prognosis is poor.
MALIGNANT MIXED MESODERMAL TUMORS
Malignant mixed mesodermal tumors or carcinosarcomas account for about 40% of uterine sarcomas. Most patients are postmenopausal and present with vaginal bleeding or discharge. About one third of patients have tumor growing through the cervix into the vagina as a polypoid mass. Up to 50% of patients with this lesion have evidence of metastatic disease at the time of diagnosis if surgically staged. The tumors aggressively invade the myometrium and disseminate through the lymphatics and the bloodstream.
The primary treatment of malignant mixed mesodermal tumors or carcinosarcomas is total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. Patients with negative nodes should receive vault brachytherapy, and patients with positive nodes should receive external-beam pelvic or extended-field radiation. Adjuvant chemotherapy may improve the prognosis.
Prognosis
The prognosis for uterine leiomyosarcomas and endometrial sarcomas is poor because of the propensity for hematogenous dissemination. The overall 5-year survival rate is about 35%. Patients with endometrial stromal sarcomas have a good prognosis, whereas patients with stage I or II carcinosarcomas have a 5-year survival of about 70% if treated with surgical staging and adjuvant radiation and chemotherapy.
SUGGESTED READING
Aalders J.G., Thomas G. Endometrial cancer—revisiting the importance of pelvic and paraaortic lymph nodes. Gynecol Oncol. 2007;104:222-231.
Hacker N.F. Endometrial cancer. In Berek J.S., Hacker N.F., editors: Practical Gynecologic Oncology, 5th ed, Philadelphia: Lippincott Williams & Wilkins, 2009.
Leath C.A.III, Huh W.K., Hyde J., et al. A multi-institutional review of outcomes of endometrial stromal sarcoma. Gynecol Oncol. 2007;105:630-634.
Lee N.K., Cheung M.K., Shin J.Y., et al. Prognostic factors for uterine cancer in reproductive-aged women. Obstet Gynecol. 2007;109:655-662.
Parazzini F., La Vecchi C., Bocciolone L., Franceschi S. The epidemiology of endometrial cancer. Gynecol Oncol. 1991;41:1-16.
Prat J., Gallardo A., Cuatrecasas M., Catasus L. Endometrial carcinoma: Pathology and genetics. Pathology. 2007;39:1-7.
Secord A.A., Havrilesky L.J., Bae-Jump V., et al. The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer. Gynecol Oncol. 2007;107:285-291.