eMedicine Specialties > Obstetrics and Gynecology > Gynecologic Oncology

Uterine Cancer

William E Winter III, MD, Director of Gynecology Tumor Board, Assistant Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brooke Army Medical Center
Jim A Gosewehr, MD, Consulting Staff, Northwest Cancer Specialists, PC, Portland, Oregon
Contributor Information and Disclosures

Updated: May 19, 2006

Introduction

Invasive neoplasms of the female pelvic organs account for almost 15% of all cancers in women. In 2005, approximately 80,000 women in the United States were predicted to receive a diagnosis of pelvic gynecologic malignancy.

The most common of these malignancies is uterine cancer, specifically, endometrial cancer. Endometrial cancer is the fourth most common cancer in women, following breast, lung, and colorectal cancer, in that order. However, it is only the eighth most common cause of cancer deaths because it is usually detected in early stages.

Of the 40,880 cases of uterine cancer predicted for 2005, only 7,310 cancer deaths were predicted for the year. Ovarian cancer accounts for the largest number and highest frequency of cancer deaths from pelvic gynecologic malignancies, with 22,220 new cases and 16,210 deaths predicted for 2005.

History of the Procedure

Cancer of the uterine corpus is the most common pelvic gynecologic malignancy in the United States and in most developed countries with access to sufficient health care. Approximately 95% of these malignancies are carcinomas of the endometrium. The most common symptom in up to 90% of women is postmenopausal (PMP) bleeding. Most women recognize the need for prompt evaluation, although only 10-20% of women with PMP vaginal bleeding have a gynecologic malignancy. Because of this prompt evaluation, 70-75% of women are diagnosed with surgical stage I disease.

Currently, no screening tests for cancer of the uterus are recommended for asymptomatic women. No evidence suggests that routine endometrial sampling or transvaginal sonography to evaluate the endometrial stripe in asymptomatic women has a role in early detection of uterine cancer, even in women who take tamoxifen after breast cancer. The early detection, presenting symptoms, and higher survival rate make it unlikely that screening will have a successful impact on earlier detection and increased survival rate.

Sixty percent of endometrial carcinomas are adenocarcinomas. Other histologic subtypes include adenosquamous, clear cell, and papillary serous carcinomas. Sarcomas make up about 4% of uterine corpus malignancies, including carcinosarcomas or mixed homologous müllerian tumors (48-50%), leiomyosarcomas ([LMS] 38-40%), and endometrial stromal sarcomas ([EES] 8-10%). The remaining sarcomas are made up of heterologous tumors—tumors that contain histologic components foreign to the uterus, such as rhabdomyosarcomas, osteosarcomas, and chondrosarcomas. This article discusses endometrial cancer but briefly addresses uterine sarcomas.

Problem

Uterine cancer is defined as any invasive neoplasm of the uterine corpus.

Frequency

Approximately 40,880 women were predicted to develop this form of malignancy in 2005 in the United States. After doubling in the early 1970s, the incidence of uterine cancer has remained fairly constant. In 2005, 7,310 deaths were predicted.

Endometrial cancer is primarily a disease of postmenopausal women. The average age at diagnosis is approximately 60 years. Women diagnosed with endometrial cancer when they are younger than 40 years make up only 5% of the total cases. These women invariably have specific risk factors such as morbid obesity, chronic anovulation, and hereditary syndromes. Endometrial cancer is more common in white women when compared to black women.

Uterine sarcomas, regardless of the histologic subtype, are more common in black women. LMS tends to occur more often in women aged 30-50 years, as compared to carcinosarcomas and EES, which have much higher incidence in women older than 50 years.

Etiology

• Risk factors for endometrial cancer
  • Obesity (relative risk of 2-11) - Relative risk of 3.0 in women 21-50 lb overweight and 10 in women more than 50 lb overweight
  • Nulliparity (relative risk of 2-3)
  • Late menopause, ie, occurring in women older than 52 years (relative risk of 2.4)
  • Exogenous unopposed estrogen (relative risk of 1.6-12)
  • Tamoxifen (relative risk of 1.7-2.5)
  • Diabetes (relative risk of 1.3-2.7)
  • Hypertension (relative risk of 1.2-2.1)
  • High dietary fat consumption
  • Radiation therapy (relative risk of 8)
• Miscellaneous risk factors
  • Risk factors for uterine LMS include early menarche, late menopause, African American race, and a history of induced abortions.
  • Women with a history of pelvic radiation are at greatest risk for carcinosarcomas and, to a lesser extent, LMS.
  • Nulliparous women are at greater risk for both types of sarcomas.
• Factors that reduce risk
  • Protective effects are noted with combination oral contraceptives. Past or current use of oral contraceptives prevents about 2000 cases of endometrial cancer each year. For these patients, the relative risk for developing endometrial cancer is approximately 0.5.
  • Although smoking decreases the risk of endometrial cancer, the increased risk of lung cancer and other major morbidities far outweighs this benefit.
  • While unopposed estrogens have an adverse effect in terms of risk, progestins have a well-known protective effect on the endometrium even when administered in combination with estrogen replacement. The other risks of combined hormone replacement therapy (eg, myocardial infarction, stroke, breast cancer) are an entirely separate discussion.

Pathophysiology

• Direct/local spread accounts for the majority of local extension beyond the uterus.
• Lymphatic spread accounts for spread to pelvic, para-aortic, and, rarely, inguinal lymph nodes.
• Hematologic spread is responsible for metastases to the lungs, liver, bone, and brain (rare).
• Peritoneal/transtubal spread results in intraperitoneal implants, particularly with uterine papillary serous carcinoma (UPSC), similar to the pattern observed in ovarian cancer.

Adenocarcinoma of the endometrium, the most common histology, is usually preceded by adenomatous hyperplasia with atypia. If left untreated, simple and complex endometrial hyperplasia with atypia progress to adenocarcinoma in 8% and 29% of cases, respectively. Without atypia, simple and complex hyperplasia progress to cancer in only 1% and 3% of cases, respectively.

Endometrial adenocarcinoma is histologically characterized by cribriform glands (or glandular crowding) with little, if any, stromal tissue between the glands. Nuclear atypia, variation in gland size, and increased mitoses are common in adenocarcinoma. Well-differentiated tumors may be confused with complex hyperplasia with atypia histologically. Likewise, poorly differentiated tumors might be confused with sarcomas histologically. The differentiation of endometrial cancers is one of the most important prognostic factors. Grade 1, 2, and 3 tumors make up approximately 45%, 35%, and 20%, respectively, of adenocarcinomas of the endometrium. The 5-year survival rate of clinical stage I cancers is 94%, 88%, and 79% for grade 1, 2, and 3 tumors, respectively. The degree of histologic differentiation of adenocarcinoma of the endometrium as defined by the International Federation of Gynecology and Obstetrics (FIGO) is as follows:

• FIGO grade 1 - Five percent or less of solid/nonglandular areas
• FIGO grade 2 - Six percent to 50% of solid/nonglandular areas
• FIGO grade 3 - More than 50% of solid/nonglandular areas

Less histologic differentiation is associated with higher incidence of deep (ie, greater than one half) myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival rates.

Histological variants

Other histologic variants of endometrial carcinoma exist. Some tumors have more than one histologic variant. An element of malignant squamous differentiation occurs in 5-6% of endometrial cancers. These tumors are adenosquamous carcinomas. When corrected for grade, however, the presence of squamous components has not been demonstrated to cause a significant difference in prognosis compared to pure adenocarcinomas.

UPSC is an aggressive variant of endometrial cancer found in 5% of cases. A higher incidence of deep myometrial invasion, lymphvascular space involvement, lymph node metastases, extrauterine disease, and positive peritoneal cytology and implants is characteristic. Even with surgical stage I cancer, the 5-year survival rate is 60%. UPSC resembles papillary serous carcinoma of the ovary histologically. Although adjuvant chemotherapy is helpful, UPSC does not have the same duration of response to cytotoxic agents (eg, paclitaxel, carboplatin) as its ovarian counterpart. Often, elements of clear cell carcinoma are associated with UPSC.

Clear cell carcinoma is another variant of endometrial carcinoma characterized by its aggressive behavior. It makes up about 3-6% of all endometrial carcinomas. The 5-year survival rate associated with these tumors is 45-60%. Nuclear grade adds no prognostic information in terms of survival.

In regards to uterine sarcomas, specifically LMS, the histopathologic diagnosis can be unclear until the time of definitive surgery. Diagnosis of LMS is believed to depend on the number of mitoses (or mitotic count) and the degree of cellular atypia. The diagnosis of LMS versus leiomyoma and leiomyoma with high mitotic activity or uncertain malignant potential is based on the metastatic potential of the tumor. The mitotic count and cellular atypia correlates to this metastatic potential.

Although controversy continues to exist regarding the diagnosis of LMS, several studies support the theory that if the mitotic count is less than 5 per 10 high-powered fields (HPF), the tumor is a leiomyoma with negligible metastatic potential regardless of the presence of any cellular atypia. Likewise, the tumor has a high metastatic potential and is considered an LMS, regardless of the degree of cellular atypia, if the mitotic count is greater than 10 per 10 HPF. Some believe that mitotic count alone is not a good indicator of metastatic potential.

Carcinosarcomas or homologous mixed müllerian tumors (MMT) typically have an endometrioid carcinoma, usually a higher grade, and an undifferentiated spindle cell sarcoma. The sarcomatous portion of the tumor may exhibit an ESS pattern, if differentiated. MMTs are termed heterologous only if identifiable extrauterine histology is demonstrated. MMTs are characterized by early extrauterine spread and lymph node metastases. Extrauterine disease and lymph node metastases are directly related to depth of myometrial invasion and the presence of cervical disease. The presence of heterologous elements does not seem to affect prognosis in terms of the initial extent of disease. New evidence points to a substantial expression of c-kit receptors in MMTs.

ESS can be divided into 2 categories: low-grade ESS (LGESS) and high-grade ESS (HGESS). LGESS is characterized by fewer than 5-10 mitoses per 10 HPF and minimal cellular atypia. These tumors can have a recurrence rate of up to 50% but demonstrate indolent growth and late recurrences. HGESS have a greater mitotic count and degree of cellular atypia. Risk of recurrence in both LGESS and HGESS is determined not only by histological characteristics but also by surgical stage and extent of disease. Interestingly, some authors believe that true HGESS does not exist.

Presentation

Other presenting symptoms may include purulent genital discharge, pain, weight loss, and a change in bladder or bowel habits. These are symptoms of advanced disease. Fortunately, most cases of endometrial cancer are diagnosed prior to this clinical presentation because of the recognition of PMP bleeding as a possible early symptom of cancer. Less than 5% of the cases of endometrial cancer are diagnosed incidentally when the patient is asymptomatic. The finding of atypical glandular cells on Papanicolaou test (Pap smear) in a woman after menopause is strongly suggestive of uterine malignancy.

Uterine sarcomas can present in a similar fashion to endometrial carcinomas. LMS may present in women early in the sixth decade of life with irregular menses or PMP bleeding. Other symptoms include pain, pelvic pressure, and a rapidly enlarging pelvic mass. Unfortunately, the diagnosis is rarely made prior to definitive surgery. ESS usually presents with PMP bleeding, pelvic pain, and an enlarging mass. Like MMT, ESS typically presents in the seventh decade of life. Irregular and PMP bleeding are the most common symptoms of MMT also. Weight loss, anorexia, and change in bowel or bladder habits are signs of advanced disease all cases of uterine cancer.

Indications

The 2 mainstays of primary treatment in endometrial cancer and uterine sarcomas are surgery and radiotherapy. Chemotherapy plays a role in adjuvant therapy for high-grade uterine sarcomas, in addition to recurrent or metastatic endometrial cancer and adjuvant therapy for UPSC. Hormonal therapy also has a role in adjuvant therapy in receptor-positive endometrial cancers. Details regarding all of these therapies are discussed later in this article.

Knowledge of the surgicopathologic, as well as clinical, staging of cancer of the uterine corpus (FIGO 1988) is crucial in developing an appropriate management plan for endometrial cancer and uterine sarcomas. The staging classification is as follows (see Pathophysiology for a discussion of grading classification):

Table 1. Staging of Cancer of the Uterine Corpus

Open table in new window

*Tumor confined to the uterine corpus

Most endometrial cancers are diagnosed as stage I tumors. In fact, most endometrial cancer can be cured with surgery alone, and relatively few patients need adjuvant radiotherapy. In the past, surgery and radiation therapy were both used as primary therapy. Now, survival rates with surgery are known to be 15-20% better than with primary radiation therapy. Thus, primary radiation therapy is reserved only for patients who are poor surgical candidates or for those with unresectable disease.

Like endometrial cancer, primary surgical therapy is the first step in treatment of uterine sarcomas. In fact, these tumors are often found at the time of surgery for benign indications such as uterine leiomyomata and dysfunctional uterine bleeding, or they are found postoperatively. Approximately 1 of every 2000 women older than 40 years who are undergoing a hysterectomy for uterine leiomyomata have LMS on final pathologic diagnosis.

Relevant Anatomy

See Images 3-5 for relevant surgical anatomy.

Contraindications

Reserve primary radiation therapy for those patients who are poor surgical candidates or for those with unresectable disease. Although the survival rate with primary radiation alone is 15-20% less than with surgery, the morbidity and mortality from surgical therapy in some patients may outweigh the benefits gained in terms of survival and recurrence.

References

• Cancer and Tumors Center
• Women's Health Center
• Cervical Cancer Overview
• Cervical Cancer Causes
• Cervical Cancer Symptoms
• Cervical Cancer Treatment
• Vaginal Bleeding Overview