Novelties in treatment planning

The role of myometrial invasion in stage I disease has been updated in the 2009 revision of FIGO staging [2]:

• Prognosis for tumor confined to endometrium (former IA) or tumor invading the inner half of the myometrium (former IB) is comparable.
• Former FIGO stage IA and IB have been merged, thus reducing the subgroups of stage I to IA (EC confined to endometrium or invading the inner half of the myometrium) and IB (EC invading the outer half of the myometrium).

Prognosis of EC patients depends on multiple different factors, most of which not included in the FIGO staging:

• Clinical: age of the patient, size of the tumor, lymphovascular spaces invasion.
• Histological: type and grade.
• Molecular: mutations and alterations of TP53, PI3K, KRAS, ERBB, FGFR and others have been investigated [3].

Sentinel lymph node mapping has been proposed to assess lymph nodal status.

• Lymph nodal involvement, related to deep invasion (>50%) of the myometrium, grade (G3) or non-endometrioid histologies, is the strongest predictor of recurrence.
• Lymphadenectomy may be beneficial in EC with intermediate-high risk of recurrence.
• Sentinel lymph node mapping represents an innovative technique to identify lymph node metastases, while reducing the surgical morbidity (lymphoedema, lymphocysts) associated with systematic lymphadenectomy.
• Some centres, thanking the advent of the sentinel node mapping during surgery, do not perform routinely MR for pre-operative staging.

Minimally invasive surgery, including robotic assisted surgery, has been introduced:

• Fewer moderate-to-severe postoperative adverse events and a lower frequency of hospitalisations < 2 days than laparotomy.
• Cervical stromal invasion should be considered during surgical planning both in open and minimally invasive approaches since is may require radical hysterectomy instead of total hysterectomy (performed in patients with stage I).

Novelties in imaging evaluation

Ultrasound

Transvaginal ultrasound (TVUS) is usually part of the gynecological examination and is commonly the first imaging evaluation. TVUS performed in a referral center might be the only imaging modality for evaluation of local extent and the patient may complete the pre-operative staging with a CT scan.

TVUS main points:

• A dedicated vaginal probe using high frequencies and a small field of view allows good local evaluation.
• An endometrial thickness of 5 mm is commonly indicated as the normal cut-off value in post-menopausal women [3], but in the presence of bleeding this cut-off value may be lowered to 3 mm [4].
• Three-dimensional TVUS (3D-TVUS) is a novel technique which acquires US images that may be reconstructed in any desired plane, to better depict myometrial invasion in the uterine corners [5]. However 3D-TVUS has not yet proved superior to conventional 2D-TVUS in the assessment of myometrial involvement and identification of cervical infiltration [6].

MRI

MR with paramagnetic contrast agent is considered an accurate imaging technique for local staging because the tumoral tissue, the endometrium and the myometrium show different MR signals.

Guidelines of the European Society of Uro-genital Radiology (ESUR) have suggested in 2009 a dedicated MR protocol for accurate local staging of endometrial carcinoma [7] (Fig. 2).

Fig. 2: ESUR Suggested MR imaging protocol for staging endometrial cancer.

After publication of the abovementioned guidelines, many advances in knowledge of EC behavior and in imaging technology have been achieved.

3T scanners

Overall the accuracy of preoperative evaluation of depth of myometrial infiltration has been reported equivalent to that of 1.5 T MR [8].

Diffusion-Weighted Imaging (DWI)

DWI, which was not included in the abovementioned 2009 ESUR guidelines, is now widely used as an adjunct to T2w and dynamic imaging in routine clinical practice [9].

• DWI is a helpful tool in detecting EC when endometrial biopsy is technically impossible, due to cervical stenosis, as well as when histopathologic results are inconclusive, because ADC values are significantly lower in cancer than normal endometrium or benign polyps [10].
• It is also under consideration if the combination of T2w images and DWI may be superior to dynamic contrast-enhanced MR. This could be a valid alternative for local staging in patients that cannot receive contrast medium.

Reduced FOV for DWI imaging may improve the local staging accuracy of MRI in the assessment of the depth of myometrial invasion [11].

• New sequences (FOCUS) allow acquisition of a small FOV, excluding possible sources of artifacts that are outside the region of interest.
• Severe geometric distortion at air-tissue interfaces around the uterus, ovaries and rectum, can be minimized on reduced FOV DW imaging.
• For patients with coexisting adenomyosis, it can be a helpful alternative diagnostic tool to 3D DCE MRI.
• It cannot substitute the traditional large FOV DWI sequence since it only evaluates local tumor extent and would miss lymph node metastases, peritoneal dissemination and/or bone metastases.

IntraVoxel Incoherent Motion (IVIM)

• DWI signal and ADC values can be influenced not only by molecular proton diffusion, but also by microcirculation or blood perfusion: the molecular motion in the capillary network can indeed be viewed as “pseudodiffusion” since capillary networks lack a defined spatial orientation.
• By using IVIM-based perfusion MRI, microcirculation or perfusion effects can be distinguished from true tissue diffusion: IVIM MRI can be considered as an extension of DWI that enables the simultaneous acquisition of both microcirculatory and diffusivity information and therefore can provide both measurements without the requirement of a further co-registration processing step. 

Application of IVIM in EC:

• EC has low perfusion and high diffusion IVIM characteristics with promising potential for early non-invasive diagnosis, hence proving potentially useful for tissue differentiation [12].
• IVIM parameters have also been tested as imaging markers of MSI status (Micro-Satellite Instability), defined as a germline mutation of mismatch repair system (DNA polymerase) that leads to a higher risk to develop EC [13].

CT

• CT is widely recognized as helpful in assessing distant metastases.
• Low sensitivity (83%) and specificity (42%) in detecting and evaluating myometrial involvement, as well as in assessing cervical stromal invasion.
• Dual-energy CT evaluation of deep myometrial invasion has been suggested, with promising results on images reconstructed at 50 keV.

PET/CT

• More sensitive than CT or MR imaging for detection of nodal metastases.
• In patients for whom biopsy demonstrates high-risk histology, PET/CT may be used to identify unsuspected distant disease that would obviate the morbidity of a surgical staging.
• A significant percentage of lymph nodes still go undetected by PET/CT.

PET/MR

MR imaging and PET are complementary in the initial staging of EC:

• MR is more accurate for evaluation of local extent of the tumor;
• PET is more accurate for distant metastases.

Lesions detected on PET or DWI can be precisely localized and characterized on the conventional MR sequences, thereby allowing for improved sensitivity without a loss of specificity.

Imaging keypoints according to stage.

2009 FIGO stages are summarized in Fig. 3.

Fig. 3: 2009 FIGO staging of endometrial cancer.

Stage I

TVUS:

• Myometrial invasion appears as an iso-hyperechoic tissue compared to the surrounding myometrium. Although myometrial invasion can often be well-appreciated, sometimes it can only be presumed according to an irregular aspect of the endomyometrial junction (Fig. 4).
• Subjective assessment of myometrial invasion may be as good as or better than objective measurement techniques (Gordon’s and Karlsson’s approaches).

Fig. 4: A 52-year-old woman with endometrioid adenocarcinoma (stage IA). Transvaginal ultrasound shows the endometrial cancer invading < 50% of the myometrium.

MRI:

MRI discriminates the degree of myometrial infiltration with a sensitivity of 87% [14].

• In stage IA, either the low T2 signal of the junctional zone, representing the limit between endometrium and myometrium, is normal and a complete sub-endometrial enhancement on T1 contrast imaging is present, or there is a disruption of the low T2-w signal junctional zone with <50% invasion of the myometrium (Fig. 5).

Fig. 5: A 51-year-old woman with endometrioid adenocarcinoma invading < 50% of the myometrium. Sagittal T2-w MRI (a) shows an intermediate-signal intensity tumour with disruption of the low signal junctional zone but the extent of myometrial invasion is unclear. Corresponding axial DWI image (b) shows an area of high signal intensity within the endometrial tumour invading only the inner myometrium (arrow).

• In stage IB tumours, disruption or irregularity of the low T2-w signal junctional zone and/or of sub-endometrial enhancement in post-contrast T1 images with myometrial invasion >50% can be demonstrated (Fig. 6). Dynamic axial T1 images after intravenous injection of paramagnetic contrast agent with a timing between 90 and 150s are helpful for an optimal evaluation of myometrial invasion, especially in post-menopausal women (Fig. 7).

Fig. 6: A 66-year-old woman with endometrioid adenocarcinoma, grade 3. Sagittal T2-weighted image shows an intermediate-signal intensity endometrial tumour invading > 50% of the myometrium (a), with disruption of the low T2 signal junctional zone (white asterisk) and preservation of the low signal band of the outer myometrium (black arrowhead). Sagittal post contrast CT (b) in the same patient, performed for evaluation of distant metastases, does not discriminate the extent of myometrial infiltration.

Fig. 7: A 75-year-old woman with endometrioid carcinoma. Paracoronal post-gadoliunium T1-w subtracted dynamic images at 0 s (a), 60s (b) and 90s (c) help the evaluation of deep myometrial invasion in a post-menopausal patient.

DWI sequences could help radiologists to assess myometrial invasion, alone or in combination with T2w images (Fig. 8 , Fig. 9) [15]. This might be particularly helpful in cases of tumours extending to the cornua, myometrial compression from a polypoid tumor, leiomyomas, or adenomyosis, where anatomic details on morphologic images could be confusing, or in patients with relative contraindications to gadolinium-based contrast agents.

Fig. 8: A 67-year-old patient with endometrioid carcinoma of the uterus, grade 2. Axial T2-weighted-DWI fused image shows an overlap of high DWI signal intensity and thicker uterine wall in the right side of the uterus. This makes the detection of tumour depth easier and more confident.

Fig. 9: Images of a 56-year-old woman with biopsy proven endometrial cancer: multiparametric study: T2WI (a). FOCUS DWI images of b = 1000 s/mm2 (b and c). Perfusion map T2WI on sagittal plane (d) shows endometrial lesion confined to the endometrial cavity. FOCUS DWI images show tumor lesion in higher spatial resolution with a definite clear border, less artifacts, and image blurring.

Stage II

TVUS:

• Iso-hyperechoic endometrial thickening of the cervical canal may suggest cervical involvement by EC which may extend deeper into the cervical stroma (Fig. 10).
• Assessment of cervical invasion can be difficult as prominent pathologic tissues may sometimes protrude through the internal uterine ostium into the cervical canal with no infiltration of the endocervical glandular epithelium, in which case a slight pressure with the probe may be helpful.
• The distance from the outer cervical os to the lower tumor margin is the only parameter that might have the potential to predict cervical invasion.

Fig. 10: A 61-year-old women with endometrioid adenocarcinoma, grade 2. TVUS shows an exophytic isoechoic lesion extending to the cervix, as confirmed by post-surgical pathology.

MRI discriminates the degree of infiltration of the cervical stroma and vaginal walls with a sensitivity of 80% and, in addition, it can help in the assessment of parametrial infiltration (Fig. 11).

Fig. 11: A 54-year-old women with EC. Sagittal (a) and axial (b) T2-w images show infiltration of the cervical stroma, without extension to the parametria, staging this tumour as II.

The use of dynamic contrast MRI could help distinguish between stromal invasion and polypoid tumor protruding into the endocervix [9]. If delayed phase images show tumor protrusion and normal enhancement of the cervical mucosa, stromal invasion can be excluded.

Stage III

TVUS can be used to diagnose metastatic disease to the ovaries with a sensitivity and specificity of subjective evaluation of grey-scale and Doppler ultrasound findings of 84-91% and 94-100%, respectively, when used by experienced ultrasound examiners.

MR

• In stage IIIA, it shows invasion of the serosa with disruption of low T2-w signal uterine serosa ( Fig. 12 ) and/or adnexa (Fig. 13) with irregularity to the uterine contour.

Fig. 12: A 67-year-old woman with EC stage IIIA. MR sagittal T2-w image depicting the endometrial lesion of the posterior uterine wall extending to the internal orifice without cervical involvement. There is a disruption of the junctional zone (arrowhead) indicating myometrial invasion, and disruption of the hypointense line contouring the myometrium on the outer side of the uterus (arrow), indicating serosal invasion. Collaterally there is a submucosal leiomyoma (asterisk).

Fig. 13: A 54-year-old EC patient with deep myometrial infiltration and serosal involvement. Coronal (a) and sagittal (b) MR images show a small mass in the right ovary (arrows) with solid components of the same signal intensity as the EC, representing ovarian involvement.

• In stage IIIB, MR shows thickening of the vaginal wall and a high T2-w signal tumour infiltrating the low signal vaginal wall, or irregular intensity of the parametria (Fig. 14), respectively. Also in these cases, DWI improves the depiction of extrauterine metastatic deposits into the parametrium or vagina.

Fig. 14: A 57-year-old woman with EC stage IIIB. Para-axial T2-w MR image (a) shows the endometrial carcinoma extending to the left parametrium (arrow). The tumour infiltrates the cervix through the internal uterine ostium leading to a retrodilation of the cavity which appears occupied by fluid (asterisk). In the same patient, the axial CT image shows the mass invading the left parametrium (b); collaterally there is a centimetric leiomyoma of the left wall of the uterus.

• In stage IIIC, MR shows pelvic or para-aortic lymphadenopathies (Fig. 15). Lin et al. reported good results in differentiating metastatic and benign lymph nodes with 3T-MRI, combining ADC values, relative ADC values, and size criteria [15]. Further studies of 1.5-T MR images reported conflicting results [16].

Fig. 15: A 46-year-old woman with EC grade 3. TVUS image (a) shows an endometrial mass of 4.79 cm (measure in yellow) invading < 50% of the myometrium. Despite a superficial myometrial invasion, CT images at staging (b) showed pelvic and lombo-aortic lymphoadenopathies (arrow), that were confirmed at surgery.

Stage IV

On T2-weighted images, extension of tumor directly into the normally hyperintense vescical or rectal mucosa is indicative of endometrial tumor invasion, however, the sole disruption of the hypointense muscularis layer does not indicate stage IV disease because it cannot be visualized at subsequent cystoscopy or sigmoidoscopy. Similarly, bullous edema, which appears as thickening of the high-signal-intensity mucosal layer, is not indicative of mucosal invasion.

• Stage IVA: MR may clearly depict disruption of the low T2-w signal of the bladder or rectal wall through the whole thickness of the wall, and/or intraluminal bladder mass (Fig. 16).
• Stage IVB: malignant ascites with peritoneal deposits, para-aortic lymphadenopathy above the renal vessels or inguinal node metastases can be demonstrated.

Fig. 16: A 57-year-old woman with EC stage IVA. Coronal T2-weighted MR image showing a slightly hypointense tissue extending from the left parametrium to focally disrupt the urinary bladder wall on the left side (arrow).