Benign and Malignant Diseases of the Endometrium

NORMAL ANATOMY T2-weighted magnetic resonance imaging sequences In premenopausal women, three distinct zones are visible within the uterine corpus on T2-weighted images: the outer myometrium, the inner myometrium or junctional zone, and the endometrial complex (Fig. 1A). The outer myometrium is of intermediate signal intensity on T2-weighted images. The inner myometrium or junctional zone forms a well-defined band of low signal intensity and normally measures from 2–8 mm in maximum thickness (1). The cause of this low signal on T2-weighted sequences likely is multifactorial, and a number of hypotheses have been put forth. For example, the inner fibers of the myometrium are arranged in a more compact, organized manner, parallel to the basal layer of the endometrium, in contrast to the outer fibers of the myometrium, which are arranged more randomly (2). In addition, studies have shown that the fibers of the inner myometrium have a higher nuclear-to-cytoplasm ratio and a lower water content compared with the fibers of the outer layer (3,4). The contrast between the outer myometrium and junctional zone typically becomes less marked in the postmenopausal uterus as the myometrial signal intensity progressively decreases.FIG. 1.: Normal uterine anatomy in a premenopausal woman. A: Sagittal T2W FSE image depicting zonal anatomy. Central high-signal-intensity stripe (E) represents the endometrium. Hypointense zone immediately subjacent represents the junctional zone (JZ) or inner myometrium (white arrowheads). Band of low signal intensity within the cervix (Cx) represents the fibrous stroma. The outer myometrium is of intermediate signal intensity. B: Transverse SGE postgadolinium image obtained during the early phase shows greater enhancement of the inner myometrium (white arrows). Note that the endometrium remains hypointense. C: Sagittal SGE postgadolinium image obtained during the delayed phase shows homogeneous enhancement of the myometrium. The endometrium (white arrowheads) shows enhancement and appears minimally hyperintense relative to the myometrium. This enhancement pattern is seen most commonly during the proliferative phase of the menstrual cycle.The endometrium and fluid within the endometrial cavity correspond to the central high-signal-intensity stripe on T2-weighted magnetic resonance (MR) images. The endometrial thickness varies widely, depending on both the phase of the menstrual cycle and the age of the patient. The endometrial complex is thinnest during menstruation, but it increases progressively during the proliferative phase and continues to increase during the secretory phase, as a result of both estrogen and progesterone stimulation (5,6). The thickness of the endometrial complex varies considerably, typically ranging from 3–6 mm in the proliferative phase and from 5–13 mm in the secretory phase. The endometrial complex in the postmenopausal patient (not receiving exogenous hormones) should not exceed 5 mm (3,7,8). Postmenopausal women taking tamoxifen prophylaxis typically show widening of the endometrial complex. Conversely, the endometrium becomes thin in women taking oral contraceptives (average 2 mm) and shows little temporal variation. T1-weighted magnetic resonance imaging sequences T1-weighted images are used to evaluate the uterine contour because of the high inherent contrast between fat and the uterine soft tissue. T1-weighted images are not suitable for evaluating the internal anatomy because the uterus is of uniformly low signal intensity on these images. However, during the mid-secretory phase of the menstrual cycle, the endometrium may be of slightly greater intensity than the myometrium (9,10). T1-weighted images also are needed to diagnose the presence of hematometra. Postcontrast magnetic resonance imaging sequences The enhancement pattern of the uterus, and particularly the endometrium, also depends on the hormonal status of the patient. During the proliferative phase, there is early enhancement of a thin subendometrial layer (Fig. 1B), followed by enhancement of the remaining myometrium (Fig. 1C). This pattern also is observed in postmenopausal women (Fig. 2) (11). The junctional zone demonstrates early enhancement during the menstrual period (11). On the other hand, the secretory phase is characterized by early enhancement of the outer myometrium. The endometrium shows little enhancement on dynamic imaging but demonstrates significant delayed enhancement, becoming isointense or hyperintense relative to the myometrium. In some patients, delayed postcontrast images may simulate T2-weighted MR images, with a high-signal-intensity endometrium, low-signal-intensity junctional zone, and an intermediate signal intensity outer myometrium. The contrast difference, however, is considerably less marked than on the T2-weighted images, and in most patients the junctional zone and outer myometrium become isointense on delayed contrast-enhanced images.FIG. 2.: Normal uterine anatomy in a postmenopausal woman. A: Sagittal T2W FSE image shows the endometrium to be thin and hyperintense (white arrowheads). B: Sagittal SGE postgadolinium image obtained during the early phase demonstrates the hypointense endometrium (black arrowheads) and a thin layer of subendometrial enhancement (black arrow) immediately subjacent.TECHNIQUE Patient preparation The objective of patient preparation is to obtain the best possible image quality while making the examination as comfortable as possible for the patient. To minimize motion artifacts induced by bowel peristaltism, patients are advised to fast from 6–8 hours before the procedure. In addition, patients are given glucagon 1 mg or hyoscine-N-butylbromide (Buscopan) 40 mg intramuscularly to further reduce bowel peristaltism (12). An empty urinary bladder minimizes ghosting artifact from patient motion. In addition, an empty urinary bladder maintains the uterus in a more caudal position in the pelvis, away from small bowel loops. When claustrophobia is a concern, prone scanning or intravenous sedation may be helpful. Surface coils Imaging of the endometrium should be performed using the smallest possible field of view (20–24 cm), thin sections of 4–5 mm, and the largest possible matrix size appropriate to each individual sequence. To achieve these high-resolution images, patients are ideally scanned using a dedicated phased-array pelvic multicoil, which greatly improves the signal-to-noise ratio (13,14). Although not used in routine clinical practice, endovaginal coils or endocavitary coils placed directly into the endometrial cavity can depict the anatomy of the endometrium in greater detail (15). Magnetic resonance imaging pulse sequences Pulse sequences used to image the endometrium include T2-weighted, precontrast fat-suppressed T1-weighted, and dynamic contrast-enhanced sequences. Following a single-shot fast spin-echo (SSFSE) T2-weighted localizer in the sagittal plane, fast spin-echo T2-weighted images are acquired in the transverse, sagittal, and coronal oblique (short-axis) planes. The short-axis coronal oblique is particularly valuable for staging endometrial carcinoma because it allows assessment of the depth of myometrial invasion in two orthogonal planes. Typical imaging parameters for the fast spin-echo T2-weighted MR images include TR/TE 4,000–7,500/102 milliseconds (repetition time/echo time), 20–24 cm field of view, four signals acquired, 512 × 256 matrix, echo train length of 16, bandwidth of 32, and a 4-mm section thickness with a 1-mm intersection gap. SSFSE sequences, as they are currently implemented, are not well suited for imaging the endometrium and particularly should not be used for staging endometrial carcinoma. The role of breath-hold fast spin-echo T2-weighted sequences in imaging endometrial pathology is still being evaluated. T1-weighted sequences in the transverse plane without fat suppression are used primarily to detect lymph node metastases in patients with documented uterine malignancies. Coverage should extend cranially to include the renal hila. T1-weighted spin-echo images are performed with the following parameters: TR/TE 600/9 milliseconds, 20–24 cm field of view, two signals acquired, 256 ×160 matrix, and 5-mm section thickness with a 2-mm gap. Respiratory ordered phase encoding to minimize breathing motion artifacts typically is applied. Alternatively, a breath-hold T1-weighted two-dimensional spoiled gradient echo (SGE) sequence may be obtained as follows: TR/TE 250/4.2 milliseconds, 20–24 cm field of view, one signal acquired, 256 × 160 matrix, and 5-mm section thickness with a 2-mm gap. Contrast-enhanced sequences are mandatory when evaluating endometrial pathology. They accurately distinguish between a hematometra and true endometrial pathology. In addition, they improve the detection and characterization of endometrial pathology, particularly endometrial polyps. Contrast-enhanced sequences also are helpful for endometrial carcinoma staging. Dynamic contrast-enhanced sequences using a gadolinium chelate typically are acquired in the sagittal or coronal oblique plane. Dynamic scanning is performed using a fat-suppressed two-dimensional SGE sequence, in three sequential acquisitions, after intravenous contrast administration. A preinjection run confirms the accuracy of the slice locations and facilitates quantitative and qualitative assessment of contrast enhancement. Once the dynamic run is completed, a delayed acquisition in a plane perpendicular to the dynamic run is obtained. The dynamic run can be performed using the following imaging parameters: TR 250 milliseconds, min TE, 20–24 cm field of view, one signal acquired, 256 × 160 matrix, and 5-mm section thickness without an intersection gap. Three-dimensional fast gradient-echo sequences currently are being evaluated and eventually may replace two-dimensional fast gradient-echo sequences for dynamic imaging of the female pelvis. ENDOMETRIAL HYPERPLASIA Clinical and histopathologic considerations Endometrial hyperplasia is a common sequela of unopposed estrogen or sequential estrogen-progesterone hormone replacement therapy in postmenopausal women (16,17). Chronic local hyperestradiolemia in the uterus has been considered the main factor in the development of hyperplastic lesions in the endometrium (18). Less commonly, endometrial hyperplasia may be seen in premenopausal women, in association with polycystic ovary disease, obesity, and persistent anovulatory cycles. It also may be encountered with estrogen-producing tumors, such as granulosa cell tumors and thecomas (19). Patients typically present with abnormal uterine bleeding. In postmenopausal women, endometrial hyperplasia can mimic endometrial carcinoma both clinically and on imaging. Endometrial hyperplasia presents with excessive proliferation of endometrial glands with an increase in the ratio of glands to stroma (20). Endometrial hyperplasia can be broadly classified into three categories: (1) simple hyperplasia without cellular atypia consisting of cystically dilated glands with increased interglandular stroma; (2) complex hyperplasia characterized by crowded and irregularly branched glands with minimal stroma; and (3) atypical hyperplasia (intraendometrial neoplasia) showing atypical epithelial cells with a high risk of malignancy (21,22). The incidence of malignant degeneration in patients with atypical hyperplasia ranges from 25–33%. The risk of malignant degeneration in patients without cellular atypia is low (20,23). Patients with atypical hyperplasia at endometrial sampling typically are treated with hysterectomy, because of the high incidence of malignant degeneration. Patients with simple or complex hyperplasia usually undergo a trial of progesterone therapy with follow-up endovaginal sonography (EVS) and/or endometrial sampling to document a decrease in the endometrial thickness. Recent studies show that continuous combined hormone replacement therapy containing estradiol and norethisterone may reverse preexisting hyperplasia (22). Magnetic resonance imaging Magnetic resonance imaging (MRI) plays no role in the routine evaluation of patients with suspected endometrial hyperplasia. It should be used as a problem-solving modality for patients with indeterminate findings on EVS in whom hysterosonography or endometrial sampling is not possible. In this setting, MRI can document the thickness of the endometrium and exclude the presence of pseudothickening on EVS due to a vertically oriented uterus or concomitant adenomyosis. In some cases, MRI can differentiate diffuse causes of endometrial thickening, such as hyperplasia and carcinoma from thickening caused by an endometrial polyp. Nevertheless, it is important to keep in mind that the imaging appearance of endometrial hyperplasia is not specific and overlaps with that of stage 1A endometrial carcinoma, cystic atrophy, and endometrial polyps. On MRI, the maximal thickness of the normal postmenopausal endometrium on T2-weighted images has been proposed to be 4 mm. However, up to 6 mm may be acceptable in patients on some hormonal replacement regimens (10,24). Compared with the vast body of sonographic literature, there is a relative paucity of data in the MRI literature on the maximal endometrial thickness for distinguishing the normal versus the abnormal endometrium. On MRI, endometrial hyperplasia presents as diffuse or, less commonly, localized thickening of the endometrial complex (Fig. 3A) (25). The endomyometrial border remains well defined. The signal intensity is isointense or slightly hypointense relative to the normal endometrium on T2-weighted sequences. Endometrial hyperplasia, like the normal endometrium, is hypointense relative to the myometrium during the early postcontrast images (Fig. 3B) and becomes isointense or hyperintense relative to the adjacent myometrium on delayed contrast-enhanced images (Fig. 3C). However, at times it may remain slightly hypointense to the myometrium on delayed images. In addition, small hypointense foci representing cystic glandular dilations may be seen within the thickened endometrial complex on delayed sequences. This imaging appearance is nonspecific and overlaps with that of other endometrial disorders, including endometrial carcinoma and endometrial polyps.FIG. 3.: Endometrial hyperplasia. A: Sagittal T2W FSE image. The uterus is retroverted and shows the endometrium (E) to be diffusely thickened and hypointense. Sagittal SGE postgadolinium images obtained during the early (B) and late (C) phases show progressive enhancement of the thickened endometrial complex (E). Note that the junctional zone is intact. This imaging appearance is nonspecific, and differentiation with early endometrial carcinoma is not possible.ENDOMETRIAL POLYPS Clinical and histopathologic considerations Endometrial polyps are among the most common pathologic lesions of the uterine corpus. Although polyps usually are asymptomatic, they may result in postmenopausal bleeding if ulceration or necrosis occurs. Polyps are multiple in approximately 20% of cases. They can be broad based or pedunculated with a thin stalk. Endometrial polyps may occur in isolation or in the setting of endometrial hyperplasia or less commonly carcinoma (26). Polyps are a more frequent cause of abnormal endometrial thickening than either hyperplasia or carcinoma (27,28). The incidence of endometrial polyps is higher in postmenopausal women treated with tamoxifen than in untreated women (8–36% versus 0–10%), especially in patients with an endometrial thickness of 5 mm or greater (29,30). In the general population, endometrial polyps typically measure 0.5–3 cm in diameter and, microscopically, contain a mixture of three elements in varying degrees: (1) stroma of dense fibrous tissue, (2) thick-walled vascular channels, and (3) endometrial glands. Patients with postmenopausal bleeding and endometrial polyps usually undergo endometrial sampling and removal of the polyps for the following reasons: (1) alleviation of the symptoms of bleeding, (2) foci of atypical hyperplasia and/or carcinoma may be present at histopathology in benign-appearing polyps, and (3) endometrial polyps and carcinoma may coexist in the same patient (31). Magnetic resonance imaging Endometrial polyps are of intermediate signal intensity on T1-weighted images (32). On T2-weighted images, polyps present as masses that are slightly hypointense relative to the normal endometrium (Fig. 4A). However, polyps may be entirely isointense on T2-weighted sequences and present as diffuse or localized endometrial thickening. Large polyps frequently are heterogeneous in signal intensity (32,33). The presence of a central fibrous core and intratumoral cysts favors the diagnosis of a benign polyp (32,33). On T2-weighted sequences, the fibrous core is seen as a hypointense area within a polyp. Intratumoral cysts are well-defined cystic structures of variable size and are seen as high-signal-intensity foci on T2-weighted images (32,33). The presence of intratumoral cysts is nonspecific, however, and these cysts also may be encountered in endometrial carcinomas. Submucosal fibroids, focal hyperplasia, and endometrial carcinoma all may mimic a polyp at MRI. However, classic fibroids appear hypointense relative to the endometrium on T2-weighted sequence (Fig. 5) and, therefore, in combination with their myometrial origin are easy to differentiate from endometrial polyps.FIG. 4.: Endometrial polyp. A: Sagittal T2W FSE image. There is focal thickening of the endometrial complex with an area of hypointensity (white arrows) along the ventral endometrium. B: Sagittal SGE postgadolinium image obtained during the early phase shows a focal area of enhancement (white arrows) corresponding to the area of low signal on the T2W images. Note that the normal endometrium does not show enhancement on early contrast-enhanced images.FIG. 5.: Submucosal uterine fibroid. Sagittal T2W FSE image. There is a large hypointense submucosal fibroid (F) displacing the endometrium (white arrowheads).Adding gadolinium-enhanced sequences significantly improves the detection rate of endometrial polyps (34). Endometrial polyps show a variable degree of enhancement after gadolinium administration. Small polyps enhance early and are well delineated against the hypointense endometrial complex on early dynamic scans (Fig. 4B). In addition, a vascular stalk can frequently be identified during the arterial phase. On delayed images, polyps are slightly hypointense relative to the endometrium but remain isointense or hyperintense relative to the adjacent myometrium (25). Large polyps demonstrate a heterogeneous pattern of enhancement. However, the enhancement characteristics of polyps are not sufficiently specific to obviate the need for tissue sampling (32,33). TAMOXIFEN USE Clinical and histopathologic considerations Tamoxifen is an important adjunct in the treatment of breast cancer, particularly in the postmenopausal patient (35). Tamoxifen has an antiestrogen effect on the breast due to its cytoplasmic estrogen receptor binding capacity, but it has only a weak estrogenic effect on the uterus. This is demonstrated by increased expression of progesterone receptors in the endometrial stroma of tamoxifen users (36). Tamoxifen therapy is associated with a wide spectrum of endometrial pathology, including atrophy, proliferative change, hyperplasia, fibrocystic endometrial polyps, adenomyosis, cellular metaplasia, and carcinoma (29,37–39). In addition, tamoxifen has been found to cause increased uterine volume (40). Up to 50% of women receiving tamoxifen develop endometrial abnormalities within 6–36 months of treatment. Postmenopausal patients on tamoxifen have a significantly thicker endometrium than controls. In a series by Cohen at al. (41), the mean endometrial thickness in women receiving tamoxifen was 13 mm. This endometrial thickening decreases significantly 6 months after discontinuation of tamoxifen therapy (42). Endometrial cystic atrophy is frequently found at histopathology in patients receiving tamoxifen. The histologic findings include multiple cystic spaces lined by atrophic endometrium. The endometrial glands are dilated with a small amount of fibrous stroma. These cystic spaces may be situated within the endometrium or extend into the endometrial-myometrial junction to form subendometrial cysts (29). On imaging, these patients typically present with diffuse endometrial thickening that may be indistinguishable from hyperplasia. There is a significant increase in the incidence of endometrial hyperplasia in postmenopausal patients with breast cancer treated with tamoxifen. The incidence increases from 0–10% in the general (symptomatic and asymptomatic) female population to 1.3–20% in women receiving tamoxifen. Endometrial hyperplasia is classified according to the presence or absence of cytologic atypia. The difference is significant for prognosis, as patients with cytologic atypia have a higher risk of developing endometrial carcinoma (23% versus 2%) (23,43). Unfortunately, imaging cannot distinguish between hyperplasia with or without cellular atypia. The diagnosis of endometrial hyperplasia is established on the basis of microscopic findings of a morphologically abnormal proliferative-type endometrium. There must be an associated abnormal increase in endometrial volume (29). The incidence of endometrial polyps is higher in women treated with tamoxifen than in untreated women (8–36% versus 0–10%). Although these polyps may cause abnormal uterine bleeding, most women are asymptomatic. Tamoxifen-related polyps differ from polyps occurring in women not receiving tamoxifen. They tend to be larger (mean diameter, 5 cm) and usually are associated with higher proliferative activity (cystic glandular dilation), aberrant epithelial differentiation (metaplasia), stromal fibrosis, and focal periglandular stromal condensation (29,44). Tamoxifen therapy carries an increased risk (1.3- to 7.5-fold) of developing endometrial cancer (29). This risk increases with the duration of therapy and the cumulative tamoxifen dose. Tamoxifen-related endometrial cancers usually are high grade and more aggressive (45). However, the benefits of tamoxifen therapy outweigh the small increased risk of developing endometrial carcinoma (29). Other uterine changes include the growth of new leiomyomas or an increase in the size of previously existing ones. Tamoxifen also is associated with the development of adenomyosis in postmenopausal women. Imaging Endovaginal sonography and hysterosonography The American College of Radiology recommends EVS as the first-line imaging modality for evaluating the uterus in women undergoing tamoxifen therapy (46). In general, women undergoing tamoxifen treatment have a thicker endometrium than control subjects (9–13 mm versus 4.0–5.4 mm) (40,47). The most common sonographic pattern in patients on tamoxifen is a thickened endometrium with multiple cystic spaces. The differential for this appearance includes cystic atrophy, hyperplasia, polyps, subendometrial cysts, adenomyosis, and endometrial carcinoma, which frequently has a nonspecific appearance. Therefore, endometrial sampling is recommended in all women using tamoxifen and presenting with vaginal bleeding (48). In cases where EVS is nondiagnostic or is suggestive of an abnormality, hysterosonography can provide additional information, such as confirmation of the presence of polyps and subendometrial cysts. Several studies have shown discrepancies between a thickened endometrium on EVS and normal findings at endometrial biopsy (31,49,50). This most often occurs when endometrial thickening is the result of polyps, cystic atrophy, or adenomyosis. Magnetic resonance imaging The imaging appearance of the uterus in women undergoing tamoxifen varies on MRI. In a series of 35 postmenopausal patients with breast cancer undergoing tamoxifen treatment, Ascher et al. (51) noted two MRI patterns: (1) an endometrium with homogeneously high signal intensity on T2-weighted sequences (mean thickness, 0.5 cm) associated with contrast enhancement of the endometrial-myometrial interface and a nonenhancing lumen on gadolinium-enhanced images; and (2) an endometrium with heterogeneous signal intensity on T2-weighted sequences (Fig. 6A) (mean thickness, 1.8 cm) associated with enhancement of the endometrial-myometrial interface and lattice-like enhancement of the endometrial canal on gadolinium-enhanced images (Fig. 6B). The first pattern was most often associated with an atrophic or proliferative endometrium at histopathologic analysis, and the latter with polyps and/or cancer. Other imaging findings include subendometrial cysts, leiomyomas, and adenomyosis.FIG. 6.: Tamoxifen induced changes. A: Sagittal T2W FSE image. The endometrial complex is thickened (white arrows) in this patient with cystic atrophy. B: Sagittal SGE postgadolinium image obtained during the early phase shows contrast enhancement of the endometrial-myometrial interface and a nonenhancing lumen. Note small subendometrial cysts enhancement significantly improves the characterization of the endometrial an stalk is seen in of the polyps, the Although the role of MRI in this patient population currently is not well MRI can demonstrate both endometrial and myometrial pathology associated with tamoxifen MRI may be appropriate in patients with an or abnormal endovaginal are to undergo hysterosonography or endometrial sampling due to ENDOMETRIAL Endometrial may be or in and can cause which includes and The diagnosis usually is by and by commonly shows the It is to the on the endometrial cavity is by when the are seen as of tissue within the The cavity as such may be MRI has only a role to in the detection of uterine however, it may be helpful in the of the T2-weighted MR images show hypointense of fibrous tissue representing of the uterine (Fig. The of MRI is imaging the uterine cavity the which are not by It is for to the presence of endometrial in the of the uterine cavity may be in patients their and clinical A: Transverse T2W FSE image. The endometrial cavity (E) is with A hypointense (white arrowheads) is seen the endometrial B: SGE postgadolinium image obtained during early phase shows enhancement of the uterine (white arrowheads). Clinical and histopathologic considerations Endometrial carcinoma is the most common malignancy of the female and the most common cancer in women 1 in women may develop endometrial carcinoma. The age of diagnosis is The presenting in of patients is postmenopausal or bleeding, which often has been by endometrial biopsy or and to early most women present with stage disease, and the is risk include unopposed estrogen replacement endometrial hyperplasia, polycystic ovary and a antiestrogen has been shown to have a association with endometrial carcinoma (29). There also have been of endometrial carcinoma occurring in the of adenomyosis of endometrial are These from well to Other histologic include and carcinomas. Although the histologic is a the and have a than the of endometrial cannot be on the basis of imaging The by or endometrial carcinoma the myometrium and the invasion of the or bowel occurs. to lymph may occur without pelvic lymph node if the the the higher grade and greater than 50% myometrial invasion are associated with an increased incidence of pelvic and lymph node as well as and are most commonly to The most frequent of metastases is the also may occur on the of the the and staging is for

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