eMedicine Specialties > Radiology > Obstetrics/Gynecology
Endometrium, Carcinoma
Updated: Jan 12, 2010
Introduction
Background
Carcinoma of the endometrium is among the most common female pelvic malignancies and may develop in normal, atrophic, or hyperplastic endometrium. Most of the cancers are detected at an early stage, with the tumor confined to the uterine corpus in 75% of patients. The prognosis generally is favorable.1,2,3,4,5,6,7,8
Images of endometrioid carcinoma are provided below:
A 76-year-old woman with poorly differentiated endometrial adenocarcinoma. Sagittal transvaginal ultrasound image of the uterus shows a central mass replacing the endometrial stripe, with hyperechoic and hypoechoic regions.
A 76-year-old woman with poorly differentiated endometrial adenocarcinoma. CT image shows a relatively hypoattenuated mass in the region of the endometrial cavity. Diffuse myometrial thinning is evident. Surgical pathology revealed approximately 4.0 cm of pedunculated endometrial tumor associated with only superficial myometrial invasion (limited to inner one third).
An 83-year-old woman with moderately differentiated endometrioid endometrial adenocarcinoma. Axial T1-weighted MR image of the uterus shows a multilobulated, low signal intensity, polypoid tumor arising from the right side of the endometrium and surrounded by fluid. The fluid markedly distending the endometrial cavity is hyperintense on T1- and T2-weighted images, consistent with hematometra. Examination under anesthesia revealed significant benign stenosis of the atrophic cervix. Dilatation and curettage confirmed the fluid to be old blood and established the diagnosis of endometrial malignancy. Note that the marked myometrial thinning, due to both the elderly age and the marked distension of the uterine cavity, limits the assessment of myometrial invasion.
Multiple risk factors associated with endometrial cancer include conditions associated with disorders of menstruation, increased perimenopausal bleeding, menopause after age 52 years, long time period between menarche and menopause, estrogen replacement therapy, tamoxifen therapy for breast cancer, endometrial hyperplasia, obesity, nulliparity, diabetes mellitus, and hypertension. Genetic predisposition appears to play a role, since risk factors also include a family history of endometrial or breast cancer and a personal history of ovarian or breast cancer.
Recent studies
- Alcazar and Galvan evaluated the role of 3-dimensional power Doppler angiography (3D-PDA) to discriminate between benign and malignant endometrial disease in women with postmenopausal bleeding and thickened endometrium. Histologic diagnoses were endometrial cancer (44 cases), hyperplasia (13 cases), polyp (23 cases), cystic atrophy (14 cases), and submucous myoma (5 cases). Endometrial volume, VI, and vascularity-flow index were significantly higher in malignant conditions. Receiver operating characteristic analysis revealed that VI was the best parameter for the prediction of endometrial cancer.9
- Signorelli et al performed a retrospective study to determine the diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in detecting nodal metastases in patients with high-risk endometrial cancer. Pelvic node metastases were found at histopathologic analysis in 9 of the 37 patients (24.3%). Patient-based sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 77.8%, 100.0%, 100.0%, 93.1% and 94.4%, respectively. Nodal lesion site-based sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 66.7%, 99.4%, 90.9%, 97.2% and 96.8%, respectively.10
- Khoury-Collado et al described sentinel lymph node (SLN) detection rates in endometrial cancer and estimated how many cases are needed to achieve greater than 90% SLN detection. Lymph node mapping was performed using blue-dye injection into the cervix; blue-dye injection in the uterine fundus; and cervical injection of technetium-99m. The study included 115 patients with endometrial cancer. The cervix was the only site of injection in 82 cases (71%); a combined cervical and fundal injection was performed in 33 cases (29%). Overall, SLN detection was achieved in 98 (85%) cases. In the initial 27 months of the study, an SLN was identified in 50 of 64 cases (78%), with 2 false negatives. In the subsequent 15 months, successful mapping was achieved in 48 of 51 cases (94%), with no false negatives. When examining an individual provider's performance, after the first 30 cases, the rate of successful mapping significantly increased from 77% to 94%.11
- Hoekstra et al performed a retrospective review of 85 patients who underwent surgical staging with lymph node dissection to determine the clinicopathologic characteristics, nodal distribution, and postoperative treatment of patients with FIGO stage IIIC endometrial carcinoma and to determine patterns of recurrence and survival. At median follow-up of 50 months, 5-year overall survival (OS) was 61.3%; recurrence-free survival (RFS), 58.0%; and disease-specific survival (DSS), 71.9%. Age, non-endometrioid histology, and more than 50% invasion were significantly associated with OS; and age and non-endometrioid histology were associated with RFS. Disease recurred in 21 patients (24.7%): 15 distant, 4 abdominal, 1 para-aortic, and 1 pelvic. Disease recurred outside the field of radiation in all patients.12
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Women's Health Center. Also, see eMedicine's patient education articles Cervical Cancer and Menopause.
Pathophysiology
The most frequent risk factor contributing to the development of endometrial cancer is protracted exposure to endogenous or exogenous estrogen that is unopposed by progesterone. Overexposure to endogenous estrogen has been reported in patients with chronic anovulation (eg, secondary to Stein-Leventhal syndrome). Overexposure to estrogen may be the result of an estrogen-producing neoplasm (eg, granulosa or theca cell tumor of the ovary). There may be an association with increased peripheral conversion of androstenedione to estrone in the adipose tissue of obese women.
Tamoxifen is a nonsteroidal drug that has a therapeutic antiestrogen effect on the breast and an estrogenic effect on the endometrium of postmenopausal women. Patients with breast cancer on prolonged tamoxifen therapy are reported to have increased risk of developing endometrial polyps, hyperplasia, and cancer.
In estrogen-related conditions, endometrial cancer most likely progresses from endometrial hyperplasia, tends to be well differentiated, and is associated with a generally favorable prognosis. In other conditions with unknown cause, the cancer typically develops de novo in the setting of an atrophic or inert endometrium, tends to have more aggressive or undifferentiated cell types, and usually has a poorer prognosis than do the estrogen-related endometrial cancers.
Endometrial cancer usually arises from the glandular component of the endometrium in the upper uterus. It may grow in a focal circumscribed pattern presenting as a friable mass protruding into the endometrial cavity. The cancer may be diffuse, involving multiple regions of the endometrium or the whole endometrial surface. It can occasionally arise within an endometrial polyp.
Spread of the disease occurs initially within the endometrium and/or myometrium, as well as from the fundus toward the isthmic portion of the uterus and the cervix. Progression beyond the uterus occurs through lymphatic pathways into pelvic and abdominal lymph nodes. The cancer eventually may metastasize hematogenously to the lungs and, in decreasing frequency, to the liver, brain, or bones. Transmural or transtubal tumor spread into the peritoneal cavity occurs with more aggressive cancers.
The rate of extrauterine tumor spread and lymph node metastasis increases with the depth of myometrial invasion, the degree of endocervical extension, and the presence of poor prognostic histologic factors. Approximately one half of patients with metastatic lymphadenopathy in the pelvis also have metastasis to the para-aortic lymph nodes. Solitary para-aortic lymph node metastasis rarely occurs.
Histopathologic types
Endometrioid adenocarcinoma is the histologic prototype and the most common form of endometrial carcinoma, occurring in as many as 75-80% of affected patients. Tumors vary from well differentiated to undifferentiated and are graded from 1-3 based on architectural and cytologic features. The most aggressive and least differentiated cell types are categorized as grade 3. Well-differentiated tumors occur most commonly and include a low-grade endometrioid cell type, which is usually associated with estrogen-related endometrial hyperplasia. It tends to occur in younger perimenopausal patients. Variants of endometrioid adenocarcinoma, including villoglandular or papillary carcinoma, secretory carcinoma, ciliated carcinoma, and adenocarcinoma with squamous differentiation, also occur.
Uterine serous papillary carcinoma constitutes 5-10% of endometrial carcinomas, occurs in women older than those seen with the endometrioid prototype, and commonly arises in atrophic endometrium. This type of carcinoma is aggressive, with a predilection for early deep myometrial and vascular invasion that frequently is associated with early extrauterine spread and, in some patients, with transtubal peritoneal dissemination.
Additional aggressive tumors include clear cell carcinoma, constituting 3-5% of endometrial carcinomas, and the less common undifferentiated carcinomas. Similar to the serous papillary variety, clear cell carcinoma and undifferentiated carcinoma tend to occur in older women, have dismal prognoses, and are usually unrelated to protracted unopposed exposure to estrogen.
Miscellaneous rare endometrial carcinomas include mucinous adenocarcinoma, squamous cell carcinoma, mixed cell type carcinoma, postmenopausal-occurring choriocarcinoma, endodermal sinus tumor, small cell carcinoma, and metastatic carcinoma
Frequency
United States
Cancer of the endometrium is the most common genital malignancy in the United States and ranks as the fourth most common malignancy in women after breast, bronchopulmonary, and colorectal cancers. Approximately 1 in 100 women may develop the disease in the United States.13
International
Worldwide, cancer of the endometrium ranks as the third most common genital malignancy after cancers of the cervix and ovary. The estimated total number of new cases of cancer of the corpus uteri is 142,000 per year worldwide or 3.7% of cancers in women.
Reported global cancer statistics show the incidence to be highest in North America, followed by Europe and temperate South America. The increased prevalence of the disease in the United States relative to other gynecologic cancers is influenced by the earlier diagnosis and decreasing incidence of cervical cancer, prolonged life expectancy, and dietary factors (perhaps related to increased obesity). The incidence of endometrial carcinoma is low in southern and eastern Asia, as well as in most of Africa.
Mortality/Morbidity
Endometrial carcinoma usually has a favorable prognosis. Good survival rates, 84% in the United States and 72% in Europe, have been reported. However, worldwide, approximately 42,000 deaths occur annually from cancer of the corpus uteri, which represents 1.9% of cancer deaths in women.
Race
The prevalence and survival rates of endometrial carcinoma appear to be higher in whites than in blacks. A review of the Gynecologic Oncology Group database showed a relatively higher number of African American patients were older than 70 years at the time of diagnosis and had more aggressive histologic cell types and more advanced local and metastatic disease.14
Age
Endometrial carcinoma is primarily a disease of menopausal and postmenopausal women, with the peak incidence in women aged 55-65 years. Approximately 75% of patients are aged 50 years and older, and 5% are younger than 40 years. Endometrial carcinoma is rare in patients younger than age 30 years.
Anatomy
The endometrium is the mucosal lining of the uterine cavity. It consists of a columnar surface epithelium overlying a stroma of round to ovoid cells intermixed with glands and a characteristic vascular system. The glands open into the surface epithelium and are surrounded by a network of fibrillar elements.
The thickness and sonographic appearance of the normal endometrium vary with the menstrual cycle. Endometrial thickness, as reported in the ultrasound (US) literature, is measured on a midline sagittal image of the uterus and is a summation of the anteroposterior (AP) width of both the anterior and posterior endometrial layers, exclusive of possible intracavitary content.
During menses, the endometrium is thin, patchy, and not clearly delineated. In the proliferative phase, the endometrial stripe develops a multilayered sonographic appearance; the wider inner portion of the proliferative endometrium is hypoechoic, and the outer portion is relatively hyperechoic. In the secretory phase, the endometrial stripe thickens to a mean of 14-16 mm in AP width and becomes diffusely hyperechoic secondary to accumulation of mucus and glycogen in the increasingly tortuous glands.
The endometrium progressively atrophies following menopause. The rate at which this process occurs is influenced by the variable presence of adrenal sources of genital hormones and by the degree of ovarian activity. Many authorities will report as abnormal measurements of 5 mm or greater in postmenopausal patients not on hormone replacement therapy (HRT). Some will allow as great as 8-mm thickness if the patient is on HRT. Others will limit the AP measurement, even in that group, to up to 5 mm.
CT does not depict the endometrium consistently and is not reliable for accurate evaluation of its thickness. Immediate postcontrast dynamic CT scans of the uterus often show central hypoattenuation that may be related to secretions in the cavity or a lag in contrast enhancement of the endometrium compared to myometrium; however, the endometrium is not visualized distinctly as separate from the myometrium, and accurate measurement of its thickness is not feasible. This is because the endometrium and myometrium have similar attenuation and cannot be distinguished either on CT scans obtained without intravenous contrast or on routine or delayed postcontrast CT scans.
MRI depicts the endometrium as a central zone of high signal intensity on T2-weighted images, while the myometrium is depicted at its inner aspect as a zone of low signal intensity (junctional zone) and at its outer aspect as a wider zone of intermediate signal intensity. On T1-weighted images, the endometrium has intermediate signal intensity similar to the myometrium; therefore, the endometrium is not visualized distinctly as separate from the myometrium.
As measured on MRI, endometrial thickness reportedly is almost always less than that measured on US. Endometrial thickness varies in menstruating women from 4 mm in the early proliferative phase to 13 mm in the late secretory phase. The upper limit of normal thickness in asymptomatic postmenopausal women has been suggested at 8 mm, regardless of hormonal therapy.
Presentation
Early endometrial cancer is usually asymptomatic. Eventually, 80% of patients present with vaginal bleeding, mostly postmenopausal. Ten percent of patients present with purulent vaginal discharge, which sometimes is tinged with blood.
In patients with endometrial cancer, 5% or fewer cases are diagnosed while the patient still is asymptomatic, with the cancer being discovered after a hysterectomy is performed for benign indications or during a diagnostic workup for abnormal Papanicolaou smear results. Pain and pelvic pressure are usually manifestations of advanced disease.
Although only 10-20% of postmenopausal vaginal bleeding is the result of gynecologic malignancy, the probability that it is caused by endometrial carcinoma progressively increases with age.
Preferred Examination
Medical procedures
Endometrial biopsy, usually using an aspiration-type curet or other device, is generally accepted as the first-step office procedure for the diagnosis of endometrial cancer and should be coupled with endocervical curettage. The procedure is definitive if results are positive for malignancy. The reported accuracy of the procedure is approximately 90%.
When endometrial sampling does not yield a conclusive histologic diagnosis and when adequate evaluation is precluded by cervical stenosis or by limited patient tolerance, traditional fractional curettage may be necessary because it provides the largest amount of endometrial tissue. This procedure is performed under anesthesia in the operating room. The procedure includes initial circumferential scraping of the endocervical canal and subsequent systemic curettage of the entire endometrial surface. Cervical and endometrial specimens are evaluated separately to determine if endometrial cancer invaded the cervix and to allow detection of occult endocervical cancer.
Endometrial curettage may be falsely negative in 2-6% of cases because the endometrium is sampled randomly and incompletely. Some clinicians advocate hysteroscopy with biopsy as the preferred procedure following negative biopsy results, because this allows the surgeon to perform the biopsy directly on focal abnormalities that may be missed during curettage. Other clinicians caution against the use of hysteroscopy unless absolutely necessary, since cancer cells may be pushed through the fallopian tubes into the peritoneal cavity.
The thickness of the endometrial stripe, as measured by US, has been advocated as a factor in determining the need for dilatation and curettage. Although considerable overlap exists in the endometrial thickness and appearance between the various benign and malignant histologic types, several reports suggest that the presence of a thin stripe is usually associated with atrophic endometrium and may indicate that a histologic diagnosis is not necessary.
Granberg et al reported that if a cutoff of 5-mm was used to define the thickness of the normal endometrial stripe in symptomatic postmenopausal patients, approximately 70% of patients with vaginal bleeding could have avoided curettage.15 A multicenter study reported by Karlsson et al revealed that dilatation and curettage found cancer in 2 of 88 patients with a 5-mm stripe, while cancer was detected in none of 518 women with a stripe of 4-mm or less; therefore, the authors concluded that a 4-mm cutoff may be more appropriate. Women on estrogen replacement therapy typically may have endometrial stripe thickness measuring up to 8-10 mm.16
No consensus has been reached regarding the cutoff for the US measurement of endometrial thickness that definitively eliminates the need for histologic evaluation of patients with abnormal uterine bleeding. In addition, many clinicians still prefer endometrial sampling as the initial diagnostic procedure used in evaluating symptomatic postmenopausal patients.
Radiologic procedures
US is the modality of choice for the initial imaging evaluation of female pelvic organs. US is widely available in many regions of the world, is relatively inexpensive, is noninvasive, and does not use ionizing radiation. Typical examinations include transabdominal sonography (TAS) and transvaginal sonography (TVS), which are supplemented by color Doppler imaging as needed.17
TAS is performed through subcutaneous fat and abdominal wall muscles and uses the full urinary bladder as an acoustic window. TAS transducers, needed in most patients to penetrate the abdominal wall and adequately visualize pelvic organs, have lower frequency and resolution than TVS probes.
TVS has the advantage of using high-frequency transducers that are placed close to the regions of interest and produce high-resolution images of significantly better quality than transabdominal images. While both TAS and TVS allow visualization of the endometrium, exquisitely finer endometrial details are possible to depict transvaginally rather than transabdominally.
TVS is clinically established as the preferred technique for evaluation of endometrial disorders and is especially useful in the workup of abnormal uterine bleeding. Hysterosonography can be used to identify the cause of endometrial stripe thickening in some patients. The procedure consists of TVS performed with sterile fluid placed within the endometrial cavity and may help show a thick endometrial stripe as secondary to diffuse or focal endometrial thickening, endometrial polyp, submucosal leiomyoma, or synechiae. This may help further diagnostic planning.
TVS is superior to CT and approaches MRI in its ability to depict endometrial carcinoma and to provide information regarding myometrial, cervical, and, perhaps, parametrial tumor invasion. However, US is unable to depict the entire intrapelvic or intra-abdominal anatomic regions adequately; therefore, US is not suitable for the comprehensive staging of endometrial carcinoma. US has significantly lower sensitivity than CT in detecting enlarged abdominal or pelvic lymph nodes and in depicting intraperitoneal, omental, or mesenteric metastases. In addition, US is inferior to CT in assessing pelvic sidewall extension and adjacent organ invasion.
CT and MRI are more accurate staging modalities than US. Both techniques allow survey of the entire pelvis, abdomen, thorax, and brain. CT is available more widely, is less costly than MRI, provides rapid image acquisition, and has high spatial resolution. The advantages of CT also include the availability of GI and intravenous (IV) contrast materials. Opacification of the GI tract with oral and rectal contrast facilitates optimal evaluation of the bowel and helps distinguish intraperitoneal and retroperitoneal masses from bowel. IV contrast injection improves evaluation of vascular structures and detection of mass lesions in parenchymatous organs. The recent advent of spiral/helical and multidetector technology has improved the multiplanar capability of CT.
The advantages of MRI include superior spatial and tissue contrast resolution, multiplanar capabilities, lack of exposure to ionizing radiation, and availability of noniodinated, nonnephrotoxic IV contrast material.
Preferred staging modality
Histopathologic features of the tumor and clinical findings at presentation influence the choice of imaging modality for preoperative staging of endometrial cancer. Kinkel et al18 provided clinical practice guidelines for staging based on a meta-analysis of the usefulness of MRI, CT, and US in imaging patients with endometrial cancer.
- Patients with grade 1 tumor, a clinically normal-sized uterus, and no clinical evidence of coexisting pelvic disease generally require no preoperative imaging because the risk for myometrial, cervical, or lymph node disease is low. If the clinical evaluation is inconclusive or coexisting pelvic disease is suggested, then US, CT, or MRI may be used for the initial imaging evaluation.
- In patients at risk for disease dissemination and lymph node involvement at presentation (because of tumor grade, histologic cell type, or clinical findings), CT or MRI of the abdomen and pelvis should be performed to determine the extent of tumor spread.
- Patients in whom cervical invasion is suggested clinically or in whom endocervical curettage was inconclusive benefit in particular from MRI, because MRI can depict cervical and myometrial invasion most accurately and is approximately equivalent to CT in detecting enlarged lymph nodes.
MRI, with its exquisite soft tissue contrast and multiplanar capability, is superior to US and CT in helping assess the depth of myometrial invasion, cervical invasion, and early parametrial invasion. MRI is approximately equivalent to CT in detecting enlarged lymph nodes, but CT is considerably superior to MRI in detecting and distinguishing intraperitoneal, omental, and mesenteric metastases from bowel.
Although MRI is superior to CT in evaluating myometrial and cervical invasion and is the best alternative for patients with significant contrast allergies or renal malfunction, CT is more sensitive than MRI in the overall detection of tumor spread outside the uterus. In addition, CT remains the imaging modality used most frequently in clinical practice for comprehensive preoperative evaluation of the extent of disease.
CT is clinically advocated in the evaluation of patients with poorly differentiated or high-grade tumor, serous papillary carcinoma, or clear cell carcinoma because of the high risk for advanced disease and metastatic lymphadenopathy at the time of presentation. CT also is advised for patients who have abnormal liver function test results, elevated serum cancer antigen 125 levels, clinical suggestion of advanced disease, or inconclusive clinical evaluation.
Limitations of Techniques
US is operator-dependent; it has relatively poor spatial and tissue contrast resolution compared with MRI and CT; its image quality is degraded by large body habitus; and visualization of portions of the pelvis and abdomen is precluded by bowel gas and bony structures. The transabdominal approach also is influenced by the degree of bladder filling and is impeded by the presence of surgical incision, dressings, drains, or skin lesions. Transvaginal probes have inherent limitations, including small field of view, short range of penetration of high-frequency transducers, and occasional patient intolerance or lack of acceptance of the transvaginal approach.
CT uses ionizing radiation and has inferior soft tissue contrast resolution, making it less capable than MRI of distinguishing between tumor and normal soft tissues in the uterine corpus and cervix. CT image quality is degraded by metallic prostheses, an extremely large body habitus, and patient or respiratory motion. The iodinated IV contrast available for CT is associated with a risk of significant allergic reactions (including fatal anaphylaxis), nephrotoxicity, and complications of contrast extravasation.
MRI is contraindicated in patients who have vital metallic biomedical devices or metallic objects in strategic anatomic regions. It is more costly and less readily available than CT and requires long image acquisition times. MRI image quality is degraded by artifacts related to respiratory motion and bowel peristalsis, which are likely to occur during the long image acquisition time. No effective GI contrast material is currently available for MRI. Claustrophobia deters some patients from undergoing MRI.
Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.
NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.
Differential Diagnoses
Cervix, Cancer
Leiomyoma, Uterus (Fibroid)
Other Problems to Be Considered
Endometrial hyperplasia
Endometrial polyp
Tamoxifen-related endometrial changes
Hematometra or pyometra
Endometrial sarcoma
Myometrial malignancy
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Further Reading
Related eMedicine topics
Endometrial Carcinoma
Premalignant Lesions of the Endometrium
Dysfunctional Uterine Bleeding
Uterus Carcinosarcoma
Uterus Stromal Tumors
Clinical guidelines
Systemic Therapy for Advanced or Recurrent Endometrial Cancer, and Advanced or Recurrent Uterine Papillary Serous Carcinoma
Initial Management of Abnormal Cervical Cytology (Pap Smear) and HPV Testing
Clinical studies
Levonorgestrel Intrauterine Device (IUD) to Treat Complex Atypical Hyperplasia (CAH) and Grade 1 Endometrioid Endometrial Carcinoma (G1EEC)
Temsirolimus With or Without Megestrol and Tamoxifen in Treating Patients With Advanced, Persistent, or Recurrent Endometrial Cancer
Keywords
carcinoma of the endometrium, cancer of the corpus uteri, epithelial tumors of the corpus uteri, corpus cancer, endometrial carcinoma, endometrial cancer
