Owing to the high prevalence of gynecological malignancies worldwide, it is of utmost importance to detect these malignancies early, thus reducing their morbidity and mortality rates. Imaging plays a significant role not only in detection but also, owing to the new functional techniques including perfusion MRI, in staging and directing treatment planes. In this article we review the different perfusion techniques used in endometrial, cervical and ovarian malignancies and the importance and potential benefits for their use. The importance of early and proper diagnosis of gynecologic malignancies lies in the fact that they contribute to a large number of female mortality and morbidity in the United States.
Abbreviations: MRI: Magnetic Resonance Imaging; DCE-MRI: Dynamic Contrast Enhanced MRI; MVD: Microvessel Density; VEGF: Vascular Endothelial Growth Factor; IAUGC: Initial Area Under the Gadolinium Concentration-Time Curve; TAH-BSO: Total Abdominal Hysterectomy and Bilateral Salpingo-Oophorectomy; ESUR: European Society of Urogenital Radiology; FIGO: International Federation of Gynecology and Obstetrics; SI: Signal-Intensity Curve
In 2006, 41,200 new uterine body cancer case was diagnosed, 20,180 ovarian cancer case, and 9,710 cervical cancer case [1,2]. Diagnostic imaging plays an important role in diagnosing and staging gynecologic neoplasms and thus helps in treatment decision-making. Recent advances in MRI such as increased field strength, development of parallel imaging [3,4], and the use of novel methods of rapid data acquisition have markedly improved image quality in body MRI applications . MRI plays a pivotal role, owing to its good soft tissue resolution that allows accurate topographic assessment of the tumor (size, location, extension and nodal involvement) .
Unfortunately, conventional T1 and T2 sequences cannot provide adequate information about the tumor’s microenvironment. Also, owing to the similar morphological appearance, conventional imaging has a limited value in assessing tumor’s response to therapy and differentiating between residual /recurrent disease and post-treatment fibrosis [5,6]. Recently, the advancement of contrast enhanced Magnetic Resonance Imaging (MRI) has lead to offering an in vivo functional examination, where information on the structure and function of the tumor microvasculature can be provided
. Many studies now support the use of functional MRI in
assessment of tumor response to therapy with promising results, particularly in cervical cancer . DCE-MRI has the ability to
noninvasively assess tumor perfusion and capillary permeability and thus assessing the anti angiogenic response of tumor tissue after therapy, which allows evaluation of treatment response earlier than using the conventional methods of assessing tumor size .
The early predictability of tumor response after therapy provides a golden opportunity to quickly change failed treatment regimens, limiting the related side effects and high costs and instituting these regimens with more successful ones [5,9]. Dynamic contrast enhanced MRI (DCE-MRI) is performed by acquisition of multiple sequential images before, during and after the passage of contrast material through a specific area of interest . As the contrast material passes through a certain area, its paramagnetic effect increases the signal intensity; the degree of enhancement depends on various factors. In the early phase of enhancement (vascular phase), blood flow, vascular density, capillary permeability, and capillary surface area play a major role, while later in the interstitial phase, by extra vascular space volume .
This gives an idea about tumor microvascularity through variations in tissue enhancement over time. It has been shown that the more intense the enhancement of a tissue is, the more it is rich in vascularity. The rate of enhancement of a tissue (as demonstrated by the rate of wash-in and wash-out) is directly proportional to the expression of angiogenic factors such as micro vessel density (MVD) and vascular endothelial growth factor (VEGF) . So, variation in contrast enhancement is the result of
variation in tumor histopathological features. Aggressive tumors
mostly show rapid and intense enhancement and washout, due
to high vascularity and strong expression of VEGF . The use of
post therapy DCE-MRI in cervical and endometrial cancer may
be able to predict which patients are at risk of early recurrence
and therefore super select patients suitable for more aggressive
surgery . In general, DCE perfusion MRI is very safe. Besides
the general MRI risks and contraindications, IV infusion of
a gadolinium- based contrast agent is done at a fairly rapid
injection rate, so it is contraindicated in patients with renal
Five-year survival rates of patients diagnosed with ovarian
cancer decrease from 90% in stage I to 30-40% in stage III and IV
[12,13]. This dramatic decrease makes it of utmost importance
to diagnose malignant ovarian masses as early as possible. DCE
MRI is a non-invasive method that allows detection of ovarian
malignancy early. Several studies were made proving its ability to
differentiate between benign, borderline and high-grade ovarian
tumors as well as its ability to differentiate between ovarian
masses and pedunculated subserous uterine fibroid [7,14-16].
Newer studies are now emerging to prove its ability to predict
early response to therapy . DCE MRI in cases of ovarian cancer is done using a T1-weighted gradient-echo sequence
that is acquired so that the solid ovarian tumor tissue (i.e., solid
portion, papillary projections, or thickened irregular septa) and
the uterus are seen in a single image. After gadolinium injection,
images are obtained at five-second intervals for two minutes,
beginning immediately after the bolus injection. Followed by
post contrast axial and sagittal T1- weighted gradient-echo
images with breathhold [14,16].
Ovarian tumor detection and characterization:According to the enhancement pattern of the solid component
within an adnexal mass, DCE MRI is able to differentiate between
benign, borderline and malignant ovarian neoplasms. The
more malignant lesions exhibit earlier and greater maximum
enhancement. This variation of enhancement is attributed to
the fact that malignant lesions have immature microvasculature
with defective pericyte layer and over expression of VEGF
receptors (VEGFR-2) [7,15,16]. DCE MRI can be performed by
either qualitative or quantitative analyses.
In qualitative analysis, three curves are seen in the early
phase of enhancement (<2min), all are in comparison to the
enhancement dynamics of the myometrium: [7,15,16].
Type 1 curve: gradual enhancement never exceeding
the enhancement of the myometrium, this is the benign
curve (Figure 1).
Type 2 curves: early enhancement exceeding that of the
myometrium followed by a plateau (Figure 2).
Type 3 curves: early and late enhancement exceeding
that of the myometrium, this is specific to invasive
malignancies (Figure 3).
The importance of DCE MRI in ovarian cancer cases lies
in its ability to differentiate between borderline and invasive
malignancies. Since both are morphologically similar, so
conventional MRI won’t be of help. Patients with borderline
ovarian tumors are young and usually want to preserve their
fertility. And so, correct preoperative diagnosis and complete
staging may give them the chance to do conservative surgeries
[14,17,18]. Moreover, preoperative MRI suggesting borderline
pathology was shown to help pathologists when intraoperative
histology is required [14,19].
Differentiating ovarian tumors from pedunculated
subserous fibroids:Solid pelvic masses are sometimes very confusing, and when large, it is often impossible to
determine their exact tissue of origin. Of special interest is
the differentiation between ovarian fibromas and subserous
uterine fibroids. Both are morphologically similar, however, it is
important not to misdiagnose or confuse them owing to their
different management options.
Both usually present as a T2-weighted solid homogenous or
heterogeneous hypo intense mass with regular outlines . DCE
MRI easily differentiates between both, where ovarian fibromas
show a type 1 curve (Benign curve) and subserous pedunculated
fibroids show a type 2 curve (paralleling the myometrium)
[7,16] (Figure 4).
Predicting response to treatment:Using quantitative DCE
analysis,(within the region of interest),the following parameters
can be calculated; the volume transfer constant (K trans), the rate constant (kep), the fractional volume of the extra vascular
extracellular space (ve), the fractional plasma volume (vp) and
the initial area under the gadolinium concentration-time curve (IAUGC) [5,20]. Sala et al. [21,22] investigated the response
of neo adjuvant chemotherapyin 22 patients with advanced
primary ovarian cancer using both DWI and DCE-MR. In the
primary ovarian lesion, responders showed a significantly larger
increase in the ADC and in V (e) parameter of DCE as a result
of the cytotoxic effect of platinum-based chemotherapy, but no
significant changes were found in omental or peritoneal deposits.
The authors suggest the use of ADC and V (e) parameters as
response markers to platinum-based therapy .
Predicting recurrent disease:In patients with
asymptomatic residual disease after chemotherapy, Mitchell et
al.  found that relapsed patients who eventually developed
clinically progressive disease showed higher percent change of
the enhancing fraction of the tumor 4-8 weeks post-baseline.
Authors suggested that DCE MRI was able to predict relapse
early. They also suggested that there is a positive relationship
between the circulating tumor angiogenesis biomarkers (soluble
vascular endothelial growth factor receptor-1 and -2) and the K
trans, as well as a negative relationship between them and Vp
[10,22]. This has the advantage of predicting chemo-resistance
and therefore providing individualized patient treatment,
reducing unnecessary costs and side effects .
Endometrial cancer is staged using the International
Federation of Gynecology and Obstetrics (FIGO) system .
Since the condition is predominantly treated surgically, staging
according to the revised FIGO classification is mainly surgical
. Surgery is used to initially treat patients as well as to
identify patients who need further therapy according various
factors, the most important of which is the depth of myometrial
invasion, because it directly correlated with tumor grade,
cervical involvement and the presence of lymph node metastasis
[25-27]. The incidence of loco-regional lymph node metastases
increases from 3% with superficial myometrial invasion (stage
IA) to 46% with deep myometrial invasion (stage IB) [24,25].
Evaluation of the depth of myometrial invasion remains
inaccurate in many cases by gross inspection at surgery or at
frozen-section analysis [25,28,29]. The standard treatment
of low-risk patients is total abdominal hysterectomy and
bilateral salpingo-oophorectomy (TAH-BSO), with lymph node
sampling of suspicious lymph nodes only. On the contrary,
in high-risk patients, TAH-BSO as well as radical lymph node
dissection should be made. This requires a specialized center
with gynecologic-oncology surgeon . Over-treating low risk
patients results in increasing their morbidity, Furthermore,
the recent introduction of laparoscopic techniques offers an
alternative approach for these patients [25,30,31].
Accordingly preoperative MRI may play an important role
owing to its ability to accurately detect the depth of myometrial
invasion as well as the local and distant spread of endometrial
tumors . DCE MRI in cases of endometrial carcinoma is done using a 3DT1-weighted gradient- echo sequence. Images
are taken before contrast medium injection and then at sagittal
oblique planes at 1 min, and 2 min after injection and at axial
oblique plane 3 min after injection .
A. Tumor detection: Endometrial cancers can be seen
as a slowly enhancing area as compared to the enhancement
of the surrounding myometrium . So in the early phase of
enhancement, a hypointense area is seen as compared to the
myometrium, whereas later, an increase in the signal intensity
is noted, which could be seen as a hypointense area (in 70% of
patients), isointense area (in 20%) or a hyper intense area (in
10% of cases) [6,7]. Unfortunately, there are no specific imaging
findings to differentiate endometrial cancer from endometrial
hyperplasia or endometrial polyps, so MRI plays a limited role in
Some studies suggest that Diffusion weighted imaging and
ADC value would be of help, where ADC value of carcinoma (0.88-
0.98 × 10-3 mm2/s) is significantly lower than of endometrial
polyps (1.27-1.58 × 10-3 mm2/s) and of normal endometrium
(1.53 × 10-3 mm2/s) . To date, the standard of care is as
follows; following presentation, the initial examination of choice
is TVUS. Abnormally thick endometrium (≤ 5 mm) warrants
endometrial sampling . After histopathological confirmation
of endometrial carcinoma, MRI is recommended for proper
B. Tumor staging:DCE MRI plays a vital role in staging of
endometrial cancer. Based on the FIGO system, it is important to
determine the depth of the myometrial invasion and differentiate
correctly between stages 1A (<50% myometrial invasion)
and stage 1B (>50%). More than 50% myometrial invasion is
associated with higher relapse rate, especially when combined
with high tumor grade and histological subtype (28,49). The
incidence of presence of metastatic lymph nodes increases from 2.4% in low risk patients to 9% in intermediate risk patients
and to 24% in high risks ones . In order to adequately assess
the myometrial extension on conventional T2W images, the
junctional zone has to be seen clearly. However, sometimes this is not the case. As hormones affect the junctional zone, it is not
clearly visualized in post-menopausal women; in these cases
assessment with combined DCE MRI and DWI is important 
(Figures 5 & 6).
It has been pointed out that at 50-120 seconds after
contrast administration, the contrast between the hypointense
endometrial tumor and the enhancing myometrium is maximum
allowing for easy detection and accurate assessment of deep
myometrial invasion. Delayed enhancement at 3-4 minutes is the
best for assessing cervical stromal invasion (FIGO II) . DCE
MRI was shown to be useful if cervical extension is suspected
because of the poorly vascularized cervical stroma .
C. Predicting response to treatment:The presence of
hypoxia as a result of changes in tumor micovasculature and
consequently changes in tumor perfusion one of the risk factors
associated with resistance to treatment [1,20]. Theoretically
speaking, the ability to measure the extent of hypoxia is of value
in predicting response to therapy and to identify the patients
who may benefit from additional therapeutic measures , but
studies are lacking .
Staging of cervical cancer is also based on FIGO criteria, but
in cervical cancer as opposed to endometrial cancer, the FIGO
criteria are CLINICAL, owing to the fact that cervical cancer is
most prevalent in developing countries with limited resources
. Clinical staging is somewhat misleading as compared to the
surgical staging with nearly 32% of cases with stage IB disease
and 65% with stage III disease being falsely staged. It is also
highly inaccurate in predicting tumor size, parametrial invasion,
pelvic sidewall invasion and lymph node metastasis, which are
important prognostic factors that preoperative MRI excels at
detecting [24,25]. It is important to distinguish early disease
(with no parametrial invasion; stage I and IIA), which can be
treated with surgery from advanced disease (with parametrial
invasion; stage IIB and higher), which should be treated by
chemo-radiotherapy . DCE MRI in cervical carcinoma cases is not routinely done, as T2W images clearly detect the tumor
as well as its extent . DCE MRI in cervical carcinoma cases
is done using a T1 turbo spin echo sequence in either the axial
or coronal planes. Five acquisitions are obtained, each lasting
for 30 seconds, starting after administering the whole dose of
contrast material .
Cervical tumor detection:Cervical masses are seen as well
defined T2 isointense areas within the T2 hypointense cervical
fibrous stroma, which if small, can be difficult to visualize .
Several studies suggested that DCE MRI does not add additional
information and its use is not encouraged [24,35]. However,
other studies suggest that it could be helpful when the tumor
is not visualized in T2W images, especially small tumors that
should be considered for trachelectomy. The tumor enhances
early (30 seconds) as compared to the cervical stroma, so
early acquisitions will show the cervical mass as an enhancing
area with surrounding non-enhancing stroma. However, late
acquisitions will not be able to show the tumor as both, the
tumor and the cervical stroma are enhancing [6-8].
Accordingly, DCE MRI should not be part of the routine MRI
protocol of cervical carcinoma, and its use should only be limited
to specific occasions; small tumors not seen on T2W images
and in post-treatment follow up , as recommended by the
European Society of Urogenital Radiology (ESUR) guidelines for
staging cervical carcinomas [24,34,36]. Other studies suggest
that DCE MRI also has a role is determining the exact endocervical
extent of the tumor as well as differentiating between cervical
and endometrial carcinomas .
It is not advised to measure the tumor on DCE MRI as the
enhancement of the surrounding normal stroma tends to
exaggerate measurements .
Predicting Response to treatment and predicting
recurrence:Internal areas of necrosis that are commonly seen
in large tumors seen as low enhancing areas, an indicator of
poor vascularity and hypoxia, are associated with poor response
to treatment. On the other hand, highly vascular tumors are
more radiosensitive , with lower rate of recurrence [10,37]
(Figure 7). So DCE MRI has the theoretical advantage of noninvasively
measuring tissue hypoxia, instead of using the
invasive polarographic electrode. It is believed that tumors that
respond well to early treatment show an increase in tumoral
enhancement and have a lower rate of recurrence .
Accordingly, tumors with persistent low perfusion
throughout treatment means poor treatment response and
hence poor prognosis [5,38,39]. Low perfusion can be measured
Quantitative analysis, where some studies postulated
low perfusion is the lower 10th percentile of the signalintensity
curve (SI 10%) [5,39], while other considered SI
15% is more specific [5,40].
Qualitative analysis, where low perfusion is less than
that of the normal cervical tissue . Still, DCE MRI is still
used as an investigational method and its evaluation in this
area is still ongoing [6,10].
Post-therapy DCE-MRI to differentiate post-treatment
fibrosis from recurrence:DCE MRI is able to differentiate
between post-radiation fibrosis and early recurrence according
to various studies . It is believed that if persistent enhancement
is present at the site of the cervical tumor or the surgical bed,
residual disease is likely with high risk of recurrence and poor
prognosis and adjunctive therapy should be advised [5,9,41]. In
a small study conducted by Boss et al. [5,42] done on patients
after radiotherapy, early enhancement at the original site of
the tumor (<6 seconds) was associated with poor prognosis
and denoted recurrence, whereas delayed enhancement (>6
seconds) was associated with good prognosis and was the result
of post-radiotherapy fibrosis. Still, these are all investigational
studies and more studies are needed in this field.
DCE MRI is a valuable problem-solving tool in gynecological
malignancies, which can answer a lot of questions guiding
gynecologists to less invasive therapeutic options, which could
preserve fertility in young women and decrease morbidity and
mortality rates in the elder group.