Epidemiology

Endometrial cancer is the most common gynaecological malignancy in industrialised countries . Incidence differs between rural and urban populations and across countries, indicating that lifestyle has an effect . Excess weight alone is estimated to cause around 50% of all endometrial cancer cases in Europe and the USA .

Peak incidence is around 65 years, 90% of the cases being diagnosed in postmenopausal women, and most women seeking care owing to postmenopausal bleeding (PMB). Prognosis depends on patient age, histological type, grade, tumour size, depth of myometrial invasion, the presence of cervical stroma invasion, and lymph-node metastases . Most women are diagnosed at stage I, in which prognosis is generally good, and the 5-year survival is 88% . The prognosis is worse for women with high-risk cancer (i.e. deep myometrial invasion, cervical stroma invasion, or high-grade disease — see below for an explanation), as these women are at increased risk of lymph-node metastases.

Endometrial cancer histology and classification

Epithelial carcinomas of the uterus are subdivided into two histological subtypes: type 1 (endometroid adenocarcinomas) and type 2 (non-endometroid tumours). Endometroid adenocarcinomas account for 90% of the tumours. They are further subdivided according to histological grade: grade I are well differentiated, grade II are moderately differentiated and grade III are poorly differentiated. Type 2 (non-endometroid tumours) include serous or seropapillary, clear cell and carcinosarcomas. Type 1 endometrial carcinomas are associated with oestrogen excess and obesity. They often arise from atypical hyperplasia, occur in the early postmenopausal period, are generally low grade, diagnosed at an early stage, and generally have a good prognosis. Type 2 endometrial cancer, on the other hand, has no association with oestrogen excess or atypical hyperplasia, and is, by definition, a high-grade tumour (see below). Diagnosis is often made at higher stages, and prognosis is poor. The non-endometroid tumours and the grade 3 endometroid tumours are classified as high-grade tumours, as they have a more aggressive biological behaviour with a higher risk of locally advanced disease at the time of diagnosis than the low-grade tumours (grade 1 and 2 endometroid adenocarcinomas). On the basis of histological type and local extension of the disease, endometrial cancer can be classified as high-risk endometrial cancer (high grade or ≥ stage IB) and low risk (low grade and stage IA) endometrial cancer.

Endometrial cancer staging

The International Federation of Gynecology and Obstetrics (FIGO) classification system is most often used to stage endometrial carcinoma ( Table 1 ), and the staging remains surgical as the treatment is most often surgical. The new FIGO classification system requires systematic pelvic and para-aortic lymphadenectomy in addition to total hysterectomy and bilateral salpingoophorectomy for proper staging. The recommendation to carry out systematic pelvic and para-aortic lymphadenectomy is based on non-randomised studies that suggest a survival benefit . In a more recent Cochrane Review , including two randomised-controlled trials , pelvic lymphadenectomy was found to provide no benefit in overall or recurrence-free survival for women with early endometrial cancer. The investigators concluded that pelvic lymphadenectomy cannot be recommended as a routine procedure for therapeutic purposes in women with stage I endometrial cancer outside of a clinical trial, as it may be associated with unnecessary morbidity. On the basis of these studies , several centres suggest systematic lymphadenectomy only for high-risk endometrial cancer, enabling low-risk cases to be treated with simple hysterectomy and bilateral salpingo-oophoprectomy at regional hospitals. This would offer the possibility of only referring high-risk cases to tertiary gynaecology centres for more radical surgery with proper staging. A reliable preoperative identification of high-risk patients is therefore important.

Several studies have shown that intra-operative gross examination or frozen section can detect deep myometrial invasion with high accuracy . Preoperative diagnostic techniques, however, are favourable so that healthcare resources can be optimised and surgery tailored to avoid unnecessary morbidity.

The role of imaging in the preoperative work up of endometrial cancer

Imaging has several potential roles, such as tumour staging, treatment planning, assessing treatment response, and complications, as well as detecting recurrent disease. In this review, we focus on the use of imaging in the preoperative work up. In order for imaging to work optimally, it is important that the sonographer, the radiologist, and the other members of the multidisciplinary team understand the treatment options, diagnostic performance, advantages, and limitations of each imaging modality. According to the National Cancer Network guidelines for uterine neoplasms (version 2013), only chest imaging is mandatory. Magnetic resonance I (MRI) is suggested in cases with suspected or gross cervical involvement. Positron emission tomography (PET), computed tomography or MRI is recommended only where extrauterine spread is suspected ( http://www.nccn.org ). No consensus has been reached or recommendation made for using imaging to assess local extension of disease to identify high-risk cases, and the clinical routines vary between countries and hospitals. Some centres use only preoperative grade for their risk stratification. On the basis of this strategy, 70–75% will be low risk based on grade alone; however, around 40–45% of these women will be considered high risk according to surgical staging , and will thus need either re-staging with systematic lymph-node dissection or additional radiotherapy and possibly chemotherapy. It is potentially beneficial to identify high-risk endometrial cancer before surgery. It is also advantageous to recognise cervical stromal invasion before surgery, as these women should either undergo radical (instead of total) hysterectomy or radiotherapy complemented by total hysterectomy, in combination with bilateral salpingo-oophoprectomy and systematic lymph-node dissection. Additionally, in stage IV disease, imaging would be helpful to depict local extension of the disease, to determine if the tumour is resectable, and if additional colorectal and urological expertise is needed.

Both transvaginal ultrasound and MRI are imaging modalities that can be used to identify women with high-risk cancer. It therefore enables women with endometrial cancer to be triaged to more radical surgery if they are considered to be at high risk, thereby avoiding over-treatment in low-risk cases. The primary aim of this review is to present the role of ultrasound and MRI to assess the local tumour extension in women with endometrial cancer. The secondary goal is to briefly present the role of positron emission tomography combined with computed tomography (PET-CT) and computed tomography, imaging modalities that are primarily used to detect lymph node and distant metastasis.

Examination technique and the use of different ultrasound modalities in the assessment

To properly assess all aspects related to tumour evaluation in women with endometrial cancer, a high-end ultrasound system should preferentially be used, with a two-dimensional or three dimensional 3–5 to 9–10 MHz transvaginal transducer. In some women with endometrial cancer, the image quality is simply too poor for any assessment, even for a skilled examiner using high-end ultrasound equipment. Poor image quality is often related to adiposity, which is a common finding in women with endometrial cancer. The examination should preferentially be carried out transvaginally complemented by transabdominal examination in the case of a large uterus, when extrauterine disease is suspected, or both. In cases of vaginal stenosis, transrectal ultrasound provides an attractive alternative, as the image quality is similar to that of the transvaginal route. The women should be examined in the lithotomy position with an empty bladder. The transvaginal probe is introduced slowly into the sagittal plane, first focusing the assessment on the uterine cervix to evaluate subjectively the presence or absence of cervical stromal invasion. The tumour extension in relation to the internal cervical orifice should be established. In cases in which the tumour is seen at the point of the internal orifice, one can gently use the probe to push at the cervix to see whether the tumour is sliding and only bulging down into the cervical canal, or if it is truly invading (no sliding) into the cervical stroma. One can also look for vessels entering the tumour at the region of the inner cervical orifice, suggesting invasive growth. In cases of gross cervical invasion, one should also look for parametrial invasion. In tumours with the greatest dimensions at the isthmus region, it can be challenging to determine if the primarity of the tumour is the cervix or the endometrium. This is of high clinical importance, as a cervical cancer with deep stromal invasion or parametrial invasion should not primarily be treated surgically.

After assessing the cervix, the probe is introduced deeper into the vagina to visualise the whole uterine body. The image is then magnified until the uterine body fills at least two-thirds of the screen. The uterine body is then scanned slowly in the sagittal plane from cornu to cornu, and in the transverse plane from the cervix to the fundus, to subjectively assess if the tumour is invading deeply (≥50%) into the myometrium at any point. It is sometimes difficult to delineate the tumour, especially when diffusely infiltrating. Saline-infusion sonography can be used in selected cases to better visualise the tumour and to evaluate the extension of the tumour. It is not, however, recommended as a standard procedure, as it has not been shown to significantly improve the assessment of myometrial invasion , and it still remains debatable if saline infusion may spread malignant cells through the fallopian tubes . Even though saline infusion at hysteroscopy or hydrosonography may increase the number of women with positive peritoneal cytology, the prognosis does not seem to be affected . Moreover, the presence of positive cytology is no longer considered using the new FIGO classification system .

After assessing cervical and myometrial invasion, the tumour size should be measured, and the ultrasound morphology described . The International Endometrial Tumour analysis proposed a classification system for the assessment of endometrial grayscale and vascular morphology . It has been shown that the grayscale and vascular sonomorphological appearance of endometrial cancer is significantly associated with endometrial tumour stage, grade and size . High-risk endometrial cancer more often has a mixed or hypoechoic echogenicity, a higher colour score, and multiple vessels with multifocal origin, whereas less advanced tumours are more often hyperechoic, have no or low colour score, and a single or multiple vessels with a focal origin ( Fig. 1 ) . It is, therefore, of clinical importance to describe the tumour greyscale echogenicity (e.g. hyperechoic, isoechoic, hyperechoic or mixed), vascular morphology (e.g. single vessel, multiple vessels focal origin, multiple vessels multifocal origin, or scattered vessels), and colour score (e.g. no, little, moderate, or abundant colour, such as vascularisation, inside the endometrium at colour or power Doppler ultrasound examination) .

(a) Low-risk endometrial cancer (<50% myometrial invasion, no cervical stroma invasion, and moderately or well-differentiated endometroid tumour). Ultrasound characteristics: hyperechoic echogenicity, single or multiple vessels with focal origin, and no or sparse vascularisation; (b) high-risk endometrial cancer (>50% myometrial invasion or cervical stroma invasion or poorly differentiated endometroid tumour or non-endometroid histology). Ultrasound characteristics: mixed or hypoechoic echogenicity, moderate or high colour score and multiple vessels with multifocal origin.

The size and extension of the tumour can also be expressed by measuring the tumour. This can be expressed as; tumour size in three dimensions, tumour–uterine anterioposterior diameter ratio, and minimal tumour free margin ( Fig. 2 ). In the sagittal plane, the endometrial thickness is measured at the point of the maximal thickness, and the tumour–uterine anterio–posterior diameter ratio are measured at the point where the deepest myometrial invasion is found. In cases in which myometrial invasion is not suspected, the tumour–uterine anterio–posterior diameter ratio is calculated by measuring endometrial thickness and dividing it by the uterine anterio–posterior diameter. The minimal tumour-free margin is measured in any plane where the smallest distance from the tumour to the serosa is observed. This can be achieved with the use of both two-dimensional or three-dimensional ultrasound . It is also possible to measure the three-dimensional tumour volume and the three-dimensional tumour–uterine volume, but the three-dimensional volume measurements does not seem to confer any advantage over two-dimensional measurements or over subjective ultrasound assessment . In a recent prospective study including 60 women, the three-dimensional volume contrast-imaging technique was shown be a useful tool for delineating the tumour . The technique makes it possible to assess slices of tissue, of variable thickness, in any plane within the volume. This technique reduces artifacts and noise, and improves the contrast resolution, which might facilitate the demarcation of the lesion. Future studies will show if three-dimensional volume contrast-imaging adds to the certainty of the examiner and improves assessment of cervical and myometrial invasion in women with endometrial cancer.

(a). Tumour diameters longitudinal section: anterio–posterior (AP) diameter, cervico-fundal (CF) diameter; (b) tumour diameters, transversal section: lateral-lateral (LL) tumour diameter; (c) tumour measurements: A, uterine AP diameter; B, tumour AP diameter; C, minimal tumour-free margin. B/A, tumour/uterine AP ratio.

It is also important to assess the adnexal regions to exclude the possibility of a hormone-producing ovarian tumour, such as granulosa cell tumours ( Fig. 3 ), or the presence of tumour spread outside the uterus. In cases of advanced disease with concurrent adnexal lesions, it is important to establish the tumour primarity (i.e. primary ovarian cancer with uterine spread or primary endometrial cancer with ovarian metastasis), to tailor treatment. Where disease has disseminated, an ultrasound-guided tru-cut biopsy is a simple, quick, minimally invasive technique that will establish the tumour primarity in most cases . If disseminated disease is suspected, MRI, computed tomography, or PET-CT should be carried out. It is also possible to use ultrasound to assess bulky pelvic or para-aortic lymph nodes, omental cake and other types of disseminated disease , but the method has not been prospectively validated in large-scale studies.

Don’t forget to assess the ovaries, to rule out the presence of a hormone-producing tumour (e.g. a Granulosa cell tumour). Ultrasound features include solid tumour, with ‘Swiss cheese’ pattern and rich vascularisation.

Diagnostic accuracy of ultrasound

Examination technique and the use of different ultrasound modalities in the assessment

To properly assess all aspects related to tumour evaluation in women with endometrial cancer, a high-end ultrasound system should preferentially be used, with a two-dimensional or three dimensional 3–5 to 9–10 MHz transvaginal transducer. In some women with endometrial cancer, the image quality is simply too poor for any assessment, even for a skilled examiner using high-end ultrasound equipment. Poor image quality is often related to adiposity, which is a common finding in women with endometrial cancer. The examination should preferentially be carried out transvaginally complemented by transabdominal examination in the case of a large uterus, when extrauterine disease is suspected, or both. In cases of vaginal stenosis, transrectal ultrasound provides an attractive alternative, as the image quality is similar to that of the transvaginal route. The women should be examined in the lithotomy position with an empty bladder. The transvaginal probe is introduced slowly into the sagittal plane, first focusing the assessment on the uterine cervix to evaluate subjectively the presence or absence of cervical stromal invasion. The tumour extension in relation to the internal cervical orifice should be established. In cases in which the tumour is seen at the point of the internal orifice, one can gently use the probe to push at the cervix to see whether the tumour is sliding and only bulging down into the cervical canal, or if it is truly invading (no sliding) into the cervical stroma. One can also look for vessels entering the tumour at the region of the inner cervical orifice, suggesting invasive growth. In cases of gross cervical invasion, one should also look for parametrial invasion. In tumours with the greatest dimensions at the isthmus region, it can be challenging to determine if the primarity of the tumour is the cervix or the endometrium. This is of high clinical importance, as a cervical cancer with deep stromal invasion or parametrial invasion should not primarily be treated surgically.

After assessing the cervix, the probe is introduced deeper into the vagina to visualise the whole uterine body. The image is then magnified until the uterine body fills at least two-thirds of the screen. The uterine body is then scanned slowly in the sagittal plane from cornu to cornu, and in the transverse plane from the cervix to the fundus, to subjectively assess if the tumour is invading deeply (≥50%) into the myometrium at any point. It is sometimes difficult to delineate the tumour, especially when diffusely infiltrating. Saline-infusion sonography can be used in selected cases to better visualise the tumour and to evaluate the extension of the tumour. It is not, however, recommended as a standard procedure, as it has not been shown to significantly improve the assessment of myometrial invasion , and it still remains debatable if saline infusion may spread malignant cells through the fallopian tubes . Even though saline infusion at hysteroscopy or hydrosonography may increase the number of women with positive peritoneal cytology, the prognosis does not seem to be affected . Moreover, the presence of positive cytology is no longer considered using the new FIGO classification system .

After assessing cervical and myometrial invasion, the tumour size should be measured, and the ultrasound morphology described . The International Endometrial Tumour analysis proposed a classification system for the assessment of endometrial grayscale and vascular morphology . It has been shown that the grayscale and vascular sonomorphological appearance of endometrial cancer is significantly associated with endometrial tumour stage, grade and size . High-risk endometrial cancer more often has a mixed or hypoechoic echogenicity, a higher colour score, and multiple vessels with multifocal origin, whereas less advanced tumours are more often hyperechoic, have no or low colour score, and a single or multiple vessels with a focal origin ( Fig. 1 ) . It is, therefore, of clinical importance to describe the tumour greyscale echogenicity (e.g. hyperechoic, isoechoic, hyperechoic or mixed), vascular morphology (e.g. single vessel, multiple vessels focal origin, multiple vessels multifocal origin, or scattered vessels), and colour score (e.g. no, little, moderate, or abundant colour, such as vascularisation, inside the endometrium at colour or power Doppler ultrasound examination) .

(a) Low-risk endometrial cancer (<50% myometrial invasion, no cervical stroma invasion, and moderately or well-differentiated endometroid tumour). Ultrasound characteristics: hyperechoic echogenicity, single or multiple vessels with focal origin, and no or sparse vascularisation; (b) high-risk endometrial cancer (>50% myometrial invasion or cervical stroma invasion or poorly differentiated endometroid tumour or non-endometroid histology). Ultrasound characteristics: mixed or hypoechoic echogenicity, moderate or high colour score and multiple vessels with multifocal origin.

The size and extension of the tumour can also be expressed by measuring the tumour. This can be expressed as; tumour size in three dimensions, tumour–uterine anterioposterior diameter ratio, and minimal tumour free margin ( Fig. 2 ). In the sagittal plane, the endometrial thickness is measured at the point of the maximal thickness, and the tumour–uterine anterio–posterior diameter ratio are measured at the point where the deepest myometrial invasion is found. In cases in which myometrial invasion is not suspected, the tumour–uterine anterio–posterior diameter ratio is calculated by measuring endometrial thickness and dividing it by the uterine anterio–posterior diameter. The minimal tumour-free margin is measured in any plane where the smallest distance from the tumour to the serosa is observed. This can be achieved with the use of both two-dimensional or three-dimensional ultrasound . It is also possible to measure the three-dimensional tumour volume and the three-dimensional tumour–uterine volume, but the three-dimensional volume measurements does not seem to confer any advantage over two-dimensional measurements or over subjective ultrasound assessment . In a recent prospective study including 60 women, the three-dimensional volume contrast-imaging technique was shown be a useful tool for delineating the tumour . The technique makes it possible to assess slices of tissue, of variable thickness, in any plane within the volume. This technique reduces artifacts and noise, and improves the contrast resolution, which might facilitate the demarcation of the lesion. Future studies will show if three-dimensional volume contrast-imaging adds to the certainty of the examiner and improves assessment of cervical and myometrial invasion in women with endometrial cancer.

(a). Tumour diameters longitudinal section: anterio–posterior (AP) diameter, cervico-fundal (CF) diameter; (b) tumour diameters, transversal section: lateral-lateral (LL) tumour diameter; (c) tumour measurements: A, uterine AP diameter; B, tumour AP diameter; C, minimal tumour-free margin. B/A, tumour/uterine AP ratio.

It is also important to assess the adnexal regions to exclude the possibility of a hormone-producing ovarian tumour, such as granulosa cell tumours ( Fig. 3 ), or the presence of tumour spread outside the uterus. In cases of advanced disease with concurrent adnexal lesions, it is important to establish the tumour primarity (i.e. primary ovarian cancer with uterine spread or primary endometrial cancer with ovarian metastasis), to tailor treatment. Where disease has disseminated, an ultrasound-guided tru-cut biopsy is a simple, quick, minimally invasive technique that will establish the tumour primarity in most cases . If disseminated disease is suspected, MRI, computed tomography, or PET-CT should be carried out. It is also possible to use ultrasound to assess bulky pelvic or para-aortic lymph nodes, omental cake and other types of disseminated disease , but the method has not been prospectively validated in large-scale studies.

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