Advanced Drug Delivery Reviews 61 (2009) 890–895

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Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Endometrial Cancer—current state of the art therapies and unmet clinical needs: The
role of surgery and preoperative radiographic assessment☆
Jessica Hunn, Mark K. Dodson, Joel Webb, Andrew P. Soisson ⁎
University of Utah, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 30N, 1900E, Suite 2B200, Salt Lake City, Utah 84132, USA

a r t i c l e i n f o a b s t r a c t

Article history: Endometrial carcinoma is the fourth most common cancer among women in the United States. Surgical
Received 6 November 2008 pathologic staging has been the standard of care since 1988, which consists of analysis of collected peritoneal fluid,
Accepted 28 April 2009 hysterectomy/oophorectomy, and pelvic and para-aortic lymphadenectomy. In 2005, it was further recom-
Available online 5 May 2009
mended that essentially all women with endometrial cancer who choose to undergo surgery have pelvic and para-
aortic lymph node analysis. Despite this recommendation, there still remains controversy as to whether all
Keywords:
patients with endometrial cancer should undergo full lymph node dissection. In this review, we assess the
Endometrial carcinoma
Lymphadenectomy
evidence surrounding this controversy and conclude that women with endometrial cancer should undergo
Lymph nodes complete lymphadenectomy at the time of surgery. Furthermore, we evaluate the evidence regarding
laparoscopic surgical staging as a safe and effective alternative to the more invasive traditional laparotomy.
Finally, for those patients who a gynecologic oncologist is not readily available to perform a complete lymph node
dissection, we evaluate the various imaging studies and their utility as preoperative triage modalities.
© 2009 Published by Elsevier B.V.

Contents

1. Surgical treatment of endometrial carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890

1.1. Description of current surgical practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
1.2. Technique of hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
1.3. Rationale and technique of lymph node sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
1.4. Laparoscopic hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
1.5. Sentinel lymph node dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
2. Preoperative evaluation of women with endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
2.2. Methods for the prediction of myometrial invasion in the preoperative and intraoperative setting . . . . . . . . . . . . . . . . . . 893
2.2.1. Sonographic determination of myometrial invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
2.2.2. MRI scanning for myometrial invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
2.3. Preoperative radiographic assessment of lymphatic metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894

1. Surgical treatment of endometrial carcinoma
1.1. Description of current surgical practices
Staging of women with endometrial cancer is done through surgical
procedures that have been mandated since 1988 [1]. Clinical staging was
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “The Role
of Gene- and Drug Delivery in Women’s Health—Unmet Clinical Needs and Future
Opportunities”.
⁎ Corresponding author. Tel.: +1 801 587 4002.
E-mail address: Andrew.soisson@hci.utah.edu (A.P. Soisson).
abandoned when gynecologic oncology group (GOG) protocol #33
revealed that approximately 22% of women with clinical stage I cancer
will be up-staged at surgery [2]. By 1988 the GOG and the Society of
Gynecologic Oncologists (SGO) recommended that surgical assessment
should consist of analysis of collected peritoneal fluid (pelvic washings),
hysterectomy/oophorectomy, and pelvic + para-aortic lymphadenect-
omy or lymph node sampling when certain histo-pathologic factors
were present. These factors included unusual histology such as
papillary-serous tumors, poorly differentiated cancers, and deep
myometrial invasion. Since the most common area of tumor spread
beyond the uterus is metastases to the pelvic and para-aortic lymph
nodes, algorithms were established to guide surgeons regarding

0169-409X/$ – see front matter © 2009 Published by Elsevier B.V.

doi:10.1016/j.addr.2009.04.015
 J. Hunn et al. / Advanced Drug Delivery Reviews 61 (2009) 890–895
appropriate indications for lymph node assessment [3]. According to
National Comprehensive Cancer Network (NCCN) guidelines, surgical
removal of these lymph nodes was recommended because palpation
and gross assessment is inaccurate [4,5]. In addition, surgical removal of
lymphatic metastases may be therapeutic; Kilgore et al. analyzed 649
women with endometrial cancer and showed a significant survival
advantage in those who underwent lymph node assessment versus
those that did not [6].
Therefore, during the time period of 1988 to 2005 there were well-
recognized clinical algorithms that could be used by surgeons to
indicate when retroperitoneal lymph node assessment should be
performed [7]. However, these algorithms that are described above,
were often confusing and somewhat inaccurate. Thus, in 2005 the
American College of Obstetrics and Gynecology and the Society of
Gynecologic Oncologists recommended that essentially all women
with endometrial cancer who choose to undergo surgery have pelvic
and para-aortic lymph node analysis [8]. As recently as 2004, less than
30% of women with endometrial cancer were undergoing lymph node
assessment at the time of surgery [9]. Chan and colleagues, using data
from the Surveillance and End Results (SEER) program showed that
only one third of women with endometrial cancer underwent lymph
node assessment in the United States from 1988–2001. Also, in this
analysis, they compared women who did not have lymph node
sampling with those that did and showed that complete surgical
staging is associated with improved survival in stage I grade III and
more advanced cancers [10]. Therefore, the “standard of care” for the
surgical treatment of endometrial cancer since 2005 is to include
retroperitoneal lymph node assessment in the great majority of cases.
1.2. Technique of hysterectomy
While total abdominal hysterectomy has been the standard
surgical approach, laparoscopic assisted vaginal hysterectomy
(LAVH) and bilateral salpingo-oophorectomy (BSO) and total laparo-
scopic hysterectomy (TLH) and BSO are gaining more acceptance in
the treatment of endometrial cancer in recent years. A simple vaginal
hysterectomy and BSO should generally be avoided because a
thorough evaluation of the pelvis, abdomen and lymph nodes cannot
truly be undertaken. This operation should be reserved for high-risk
surgical patients who cannot tolerate abdominal or laparoscopic
surgery. For abdominal hysterectomy, a mid-line vertical incision is
recommended. A Pfannenstiel incision may not allow adequate
exposure for examination of the upper abdomen and evaluation of
the para-aortic retroperitoneal lymph nodes. An alternative to the
vertical incision might be a transverse, muscle-dividing or tendon-
dividing incision (Maylard or Cherney). After the abdomen is opened
through an appropriate incision or with laparoscopic exposure,
peritoneal washings should be collected in sterile normal saline
solution. Next, a thorough exploration of the abdomen and pelvis
should be completed including examining the colic gutters, liver,
diaphragm, spleen, omentum, para-aortic lymph nodes and an
evaluation of the bowel. Biopsy of any suspicious lesion should be
performed. The laparoscopic technique should mirror the same steps
performed in the open cases.
Following the careful examination of the abdomen and pelvis, an
extra-fascial hysterectomy should be performed with careful attention
to remove the entire uterus and cervix. A bilateral salpingo-
oophorectomy should be performed in most cases. This is to ensure
exclusion of adnexal metastasis or the possibility of a synchronous
primary tumor [11]. Furthermore, removal of the ovaries eliminates a
source of estrogen production that stimulates the growth of many
endometrial cancers. After the specimen is removed we believe it
should be evaluated grossly by the surgeon before being sent to
pathology. For complete staging we advocate the performance of a
pelvic and para-aortic lymph node dissection. Despite recommenda-
tions by the American College of Obstetricians and Gynecologists
891
(ACOG) and the SGO, there still remains some controversy as to
whether all patients with endometrial cancer should undergo full
lymph node dissection or whether patients can be stratified into low-
risk and high-risk groups. The following section will address this
controversy and carefully evaluate the issues surrounding the lymph
node dissection.
1.3. Rationale and technique of lymph node sampling
The presence of extra-uterine disease is one of the most important
prognostic indicators for endometrial cancer and metastases to the
retroperitoneal lymph nodes is a common site of extra-uterine disease
[12,13]. Complete lymph node dissection helps appropriately guide
adjuvant radiation and decreases the amount of unnecessary treatment.
Despite the known importance of pelvic and para-aortic lymph node
dissection, there is continued controversy surrounding the best surgical
management for staging and therapeutic lymphadenectomy in women
with low grade and early stage endometrial cancer. The debate
surrounding the management of low-risk endometrial cancer centers
on the question of whether lymphadenectomy is even required. If
lymphadenectomy is performed, there is debate over a complete versus
selective lymphadenectomy. Lastly, there is also controversy as to the
anatomical extent of lymphadenectomy, particularly concerning the
para-aortic lymph nodes.
The argument against performing lymphadenectomy is that the
morbidity of the procedure may be significant, especially in untrained
hands, and there is no significant clear-cut survival advantage in
patients with low-risk cancer. Historically, the decision to stage low
grade endometrial cancer has been stratified by associated risk factors
(high tumor grade and high-risk histologic subtypes) and intra-
operative assessment of depth of myometrial invasion. Mariani et al.
[14] from the Mayo Clinic, extensively studied and analyzed their
extensive surgical experience and concluded that lymph node
dissection does not benefit women with low-risk disease. This group
includes tumors that are grade I or II with less than 50% myometrial
invasion (stage IA and IB) and tumor less than 2 cm in size. However, it
is obvious that definitive grade and stage cannot be determined
without removing the uterus and awaiting permanent pathologic
evaluation, or relying inefficient and inaccurate frozen section. Mayo
Clinic surgeons have the distinct advantage of very rapid and accurate
frozen section evaluation on essentially all resected tumors which aids
their intraoperative decision making. However, most institutions do
enjoy this type of service. Another large retrospective study at Duke
University showed that, while pelvic and para-aortic lymph node
dissection showed survival improvement in women with poorly
differentiated tumors, those with grade 1 or 2 tumors did not have a
significant improvement in survival when lymph node dissection was
performed when they analyzed SEER data [12]. Furthermore, Chan
et al. did not find survival benefits in stage 1, grade 1 disease when
lymphadenectomy was performed [15]. Finally, two studies were
published in 2006 in the Journal of Cancer Surgery addressing this
topic. The first reported that absolute and relative survival estimates at
5 years was 85.0 and 93.7% in those with low grade disease who did
not undergo lymphadenectomy compared to 88.2 and 93.9% in those
with lymphadenectomy. In addition, the rate of recurrence was 8.5% in
those who did not undergo lymphadenectomy compared to 5.6% in
those who underwent the procedure. These differences were not
statistically significant indicating that omission of the lymphadenect-
omy in low-risk patients was acceptable [16]. The second study
evaluated the incidence of complications associated with retro-
peritoneal lymph node analysis and found that some postoperative
morbidities and complications were increased by the addition of the
lymphadenectomy. These complications included the amount of blood
loss during operation, percentage of transfusion requirements and
incidence of postoperative morbidities [17]. However, it is important
to note that performing a complete pelvic and para-aortic lymph node
892 J. Hunn et al. / Advanced Drug Delivery Reviews 61 (2009) 890–895
dissection does not impose added risk for the patient when completed
by trained gynecologic oncologists [26,27].
Despite the argument that lymphadenectomy can be omitted in
low-risk endometrial cancer, lymph node metastasis remains the most
common extra-uterine site of spread in endometrial cancer. In a
prospective GOG trial, Creasman and colleagues noted that the risk of
nodal metastasis in 621 women with stages I and II endometrial
cancer was 11% [3]. This is significant given that patients with stage I
disease have a 90% five year survival when no nodal metastasis are
identified. However, survival rates are only 50% if nodal disease is
present [18,19]. While rare, the identification of nodal metastasis in
low-risk disease allows these patients to be treated in clinical trials
providing the potential to one day identify a regimen which will afford
a survival advantage in this group of patients. The proponents of
universal pelvic and para-aortic lymph node dissection argue that it is
not just overall survival that is important when deciding who should
undergo the procedure. Other important benefits are the decrease
incidence of over treatment and improved cost efficiency. Barakat
et al. at Memorial-Sloan Kettering presented their 12-year experience
as the management of endometrial cancer evolved. They found that as
their institution adopted universal lymph node dissection as the
standard of care, the amount of postoperative whole pelvic radiation
therapy decreased [20]. This resulted from the ability to guide
adjuvant therapy based on known disease rather than treating
based on factors such as grade and depth of myometrial invasion
[20]. Another study that looked specifically at cost-effectiveness of
surgical staging on grade 1 endometrial cancer patients found that
staging all patients was the most cost-effective strategy and decreases
the use of postoperative radiation therapy [21].
Another dilemma of neglecting lymph node dissection in grade 1
tumors is the unreliability of preoperative tumor grade or intraopera-
tive tumor stage. Studies have shown that 30% of preoperative grade 1
tumors have a higher grade on review of final pathology [22,23].
Furthermore, intraoperative assessment of positive lymph node
metastasis by palpation and visualization is highly inaccurate
[23,24]. Less than 10% of patients with metastasis have grossly
positive disease and less than one third of metastatic nodes are
abnormal on palpation [25]. Universally performing lymph node
dissection on all patients with endometrial cancer negates the need to
use inaccurate preoperative and intraoperative methods for deter-
mining the appropriate procedure. Therefore, while there is no
absolute survival advantage with lymphadenectomy for early stage/
low grade disease, we feel that lymph node assessment should be
performed in the majority of women with endometrial cancer if the
surgeon has undergone appropriate training in these techniques.
Lastly, controversy remains regarding the anatomic extent of retro-
peritoneal lymph node dissection in women with endometrial carcinoma.
Para-aortic nodal involvement is known to be more common when pelvic
nodal metastasis is present. In patients with positive pelvic nodes 40–57%
will also have para-aortic metastasis [14,25]. However positive para-aortic
node metastasis have been found without the presence of pelvic node
disease [28]. The results of GOG #33 found that 35% of para-aortic nodal
metastases occurred with negative pelvic nodes [2]. Another study found
that 11% of para-aortic node metastases occurred with negative pelvic
nodes [29]. Given these findings and the overall incidence of para-aortic
metastasis, the dissection should include, in our opinion, para-aortic
nodes, at least to the level of the inferior mesenteric artery (IMA). This
approach more accurately defines the extent of disease and aids in
strategizing adjuvant therapies. There has been recent debate as to
whether para-aortic dissection to the IMA is extensive enough. There have
been studies that report extension of disease by a direct route from the
corpus to the para-aortic node area by lymphatic channels via the gonadal
vessels [14,30,31]. Mariani et al. found 77% of para-aortic lymphatic spread
was above the IMA [14,25]. A smaller series found 64% of patients with
para-aortic disease had positive nodes above the IMA [29]. Mariani
concluded that limiting dissection to the IMA will potentially miss 38–46%
of patients with positive para-aortic nodes and extending the full
dissection to the renal vessels is necessary for the assessment and
determination of treatment [14,25]. Regardless, most gynecologic
oncologists currently extend the para-aortic dissection to the IMA only.
One argument given for this approach is the extremely poor prognosis in
patients with high para-aortic nodal metastasis.
1.4. Laparoscopic hysterectomy
Laparoscopy for gynecologic malignancy was reported for endome-
trial cancer in 1992 by Childers [32]. Laparoscopy offers the significant
advantage of being minimally invasive with shorter recovery time. The
literature contains many small studies comparing total laparoscopic
hysterectomy (TLH) or laparoscopic assisted vaginal hysterectomy
(LAVH) and abdominal hysterectomy in the treatment of endometrial
cancer. There are no large randomized controlled trials published to
date. The small studies and series have, however, uniformly found that
both TLH and LAVH are acceptable and safe alternatives for hyster-
ectomy, BSO and complete lymph node dissection for early stage
endometrial cancer. With laparoscopy there is noted to be a slightly
longer operating time, but less blood loss, surgical complications and
decreased hospital stay with shorter recovery time [33–37]. Other
studies have compared TLH and abdominal hysterectomy for obese
women with endometrial cancer [38,39]. Mean operating time and
blood loss were similar in both groups. Hospital stay was significantly
shorter in the TLH group and wound infections were significantly less in
this group as well. Recurrence and survival were similar in both groups.
Given these results and the apparent advantages of TLH over TAH,
laparoscopic treatment of early stage endometrial cancer appears to be
an advantageous approach for obese women.
In addition to the short-term advantages of laparoscopic hyster-
ectomy, survival and recurrence need to be fully ascertained. Again, no
randomized controlled trials have been completed, but many retro-
spective studies have been undertaken. Gil-Moreno et al. reviewed the
literature regarding survival after LAVH compared to the conventional
abdominal approach for early stage endometrial carcinoma. Impor-
tantly, survival and prognosis were not affected by the laparoscopic
approach [33]. They also found that laparoscopic surgical staging is
both feasible and is associated with lower perioperative morbidity and
shorter hospital stay compared to TAH. Another study evaluated 69
patients to assess the safety, recurrence, and long-term outcome. They
found overall survival and disease-free survival were similar in both
the LAVH and TAH groups indicating the feasibility and safety of the
laparoscopic approach [40]. Similarly, a 2004 study found that TLH
compared to TAH also showed that prognosis was not worsened by the
laparoscopic approach [39]. Barakat and colleagues reported their
experience evaluating 1312 patients between 1993 and 2004. The use
of the laparoscopic technique had increased over time and there was
no negative effect on overall survival when laparoscopy was used [20].
Clearly, laparoscopic hysterectomy and laparoscopic retroperitoneal
dissection is an acceptable treatment for women with endometrial
cancer and may become the standard surgical procedure.
1.5. Sentinel lymph node dissection
Alternative approaches to retroperitoneal exploration for women
with endometrial cancer to detect lymphatic metastases are a
combination of radiographic modalities and limited surgical exploration
such as sentinel node biopsy (SLN). This modality is attractive because it
is a less invasive technique to identify lymph node metastasis and thus
might result in decreased morbidity. This approach has been applied to
the staging and treatment of malignancies of various organs and other
malignancies [41]. The sentinel lymph node is defined as the lymph
node with the highest possibility of involvement from the primary
tumor [42]. According to the lymphatic mapping hypothesis, if the
sentinel node is negative, then non-sentinel nodes are expected to be
 J. Hunn et al. / Advanced Drug Delivery Reviews 61 (2009) 890–895
negative [42]. In terms of gynecologic malignancies, vulvar carcinoma
has been the most thoroughly and successfully studied and the SLN
dissection will likely become “standard of care”. On the other hand, the
utility and feasibility of SLN mapping in endometrial cancer has not been
studied extensively, but several studies have been published examining
this concept [41,43,44].
In 1996, Burke and colleagues at M. D. Anderson Cancer Center
published their results of a pilot study [43]. They looked at the feasibility
of lymphatic mapping by injecting isosulfan blue dye at the uterine
fundus. They found that lymphatic mapping was feasible and could
identify targets for selective nodal biopsy. They acknowledge however,
that the lymphatic drainage of the uterus was complex and further
developments were needed to enable sentinel lymph node mapping to
replace random lymph node sampling [43]. Endometrial sentinel lymph
node mapping by preoperative lymphoscintigraphy and intraoperative
gamma probes was studied several years later by Niikura et al. in Japan
[41]. They used a radioisotope that was injected into the endometrium
hysteroscopically prior to the surgery. In the 28 patients studied, the
detection rate for at least one SLN was 82%. Of the 23 patients with SLNs
identified, one had a SLN positive for metastases and subsequent
lymphadenectomy confirmed further lymph node metastases. The 22
patients with negative SLNs had all negative lymph nodes on
subsequent lymphadenopathy. This resulted in a sensitivity and
specificity of 100%. Niikura and colleagues concluded that this technique
was useful in identifying sentinel nodes in endometrial cancer, and
yielded better results than simple injection of blue dye into the fundus of
the uterus. A study recently published in Gynecologic Oncology compared
cervical and hysteroscopic injection of Technetium 99m radiocolloid in
the identification of SLN in endometrial cancer [44]. Perrone and
colleagues evaluated 54 women with endometrial cancer and divided
them into the cervical injection group and the hysteroscopic injection
group. They found a SLN detection rate of 70% in the cervical injection
group and 65% in the hysteroscopic group. However, para-aortic SLN
were only identified in the hysteroscopy group.
While study results regarding SLN mapping in endometrial cancer
are promising, further studies are needed to determine the best
technique and whether it is applicable to all patients. Considering the
observation that retroperitoneal exploration in the hand of well-
trained gynecologic oncologists is associated with low morbidity, it
may be hard to justify this technique. The primary reason that SLN
biopsy has gained popularity in breast and vulvar cancer is that it
reduces the incidence of limb edema compared to complete dissec-
tion. This event is rare with pelvic lymph node sampling [45].
2. Preoperative evaluation of women with endometrial cancer
2.1. Introduction
Endometrial carcinoma is the fourth most common cancer among
women in the United States. The vast majority of these individuals
develop their malignancy after age 50 while in the post-menopausal
state. Most seek medical attention when they develop vaginal bleeding.
Thus, most are diagnosed with early stage disease and prognosis is
usually favorable with the vast majority being cured of their malignancy
(83%) [2,3]. For such women, primary radiation and/or the use of
chemotherapeutic agents or anti-estrogen compounds are less likely to
be curative compared to surgery [2–4]. Therefore, surgery has become
the most common treatment modality and is considered the “standard
of care” for treatment. Surgical goals consist of removal of the tumor
(hysterectomy) and surgical staging to characterize the risk of
recurrence and the need for postoperative radiation. We agree with
the ACOG and SGO 2005 bulletin that recommends all women undergo
surgical staging for endometrial cancer. Unfortunately, not all surgeons
who care for women with endometrial cancer have training in these
types of surgical techniques and thus, care is often compromised as the
presence of extra-uterine spread is not properly assessed. While ideally
893
all women with endometrial cancer would be managed surgically by
gynecologic oncologists this is not the case throughout the United States.
For a number of reasons, some justified and others not, many
endometrial cancer patients receive their care by general obstetrician
gynecologist or general surgeons. In these cases many physicians use
preoperative radiographic evaluations to determine if a patient should
be referred to a gynecologic oncologist. One of the major factors given for
not referring patients for care by a gynecologic oncologist is the long
distance to travel to one of these specialists. Prior to 2005, there is an
entire body of literature devoted to the development of radiographic
studies which would more accurately identify patients with deep
myometrial invasion, nodal metastasis and other metastatic disease
which would be more appropriately managed by a gynecologic
oncologist. We will review this literature focusing on the ability to
accurately determine the depth of myometrial invasion and predict the
likelihood of retroperitoneal lymph node metastases.
2.2. Methods for the prediction of myometrial invasion in the preoperative
and intraoperative setting
2.2.1. Sonographic determination of myometrial invasion
Ultrasound appears to be reasonably accurate for the prediction of the
presence or absence of deep myometrial invasion in women with
endometrial cancer. Ruangvutilert evaluated 111 women with endome-
trial cancer using transvaginal ultrasound (TVUS) and showed that it had a
sensitivity of 69.4% for predicting deep myometrial invasion in the
preoperative setting [46]. Takac [47] compared ultrasound with saline
infusion of the endometrial cavity (SIUS) with TVUS to assess myometrial
invasion and showed that the accuracy of TVUS was 86% and was
improved to 96.4% with saline infusion. The risk of spread of malignant
cells during saline infusion is controversial and for the most part is
unknown, though more recent data say it does not affect prognosis.
2.2.2. MRI scanning for myometrial invasion
MRI scanning appears to be the most accurate radiographic modality
for assessing preoperative myometrial invasion especially when newer
techniques incorporating new contrast agents (biopolymers) are used
and this appears to be the radiographic modality that is most accurate.
Conventional MRI scanning has been extensively evaluated in the
preoperative setting and can be used for the accurate prediction of
myometrial invasion, cervical involvement and lymphatic metastases.
Multiple investigators have shown that MRI scanning has a sensitivity of
83–87% for predicting the depth of myometrial invasion utilizing studies
with sufficient number of patients [48–51]. The accuracy of MRI has
slowly improved with the utilization of better technology and the
incorporation of better radiographic detected contrast agents. For
instance, Torricelli et al. [52] assessed 3T MRI for the detection of
myometrial invasion in 43 women with endometrial cancer and
demonstrated a sensitivity of 83% for predicting deep myometrial
invasion. Nakao et al. [53] used T2-weighted or dynamic MRI without
contrast agents in 116 women with endometrial cancer and showed that
this type of MRI had a positive predictive value of 94% for predicting
myometrial invasion. Nasi et al. [54] and associates compared FSE T2-
weighted MRI with gadolinium-enhanced FMPSGR MRI in 45 patients
and showed that using gadolinium improved the sensitivity of MRI from
81 to 92%. Finally, Rockall et al. [55] compared T2-weighted MRI with
dynamic gadolinium-enhance MRI in 96 patients and showed that both
types of MRI had over a 90% sensitivity for predicting myometrial
invasion and a 66% (T2-weighted) and 73% (gadolinium-enhanced)
sensitivity for predicting lymphatic metastases.
2.3. Preoperative radiographic assessment of lymphatic metastases
The primary value for accurate preoperative radiographic staging for
women with endometrial cancer is that it could allow practitioners in
smaller community settings, who are not experienced in retroperitoneal
894 J. Hunn et al. / Advanced Drug Delivery Reviews 61 (2009) 890–895
exploration, to triage women with endometrial cancers to tertiary
centers with gynecologic oncology support. Selman in the UK, did a
META analysis to evaluate the accuracy of radiographic imaging to
predict lymphatic metastases and found that MRI and sentinel node
biopsy were more accurate than CT scanning [56]. Most studies that have
evaluated the accuracy of radiographic imaging in the preoperative
setting for the detection of extra-uterine disease have utilized MRI
scanning. However, more recent studies have begun to incorporate PET/
CT scanning, unfortunately, none of these modalities have been
extensively studied.
In GOG protocol #33 over 900 women with early stage endometrial
carcinoma underwent complete surgical staging that consisted of at
least pelvic lymph node sampling in addition to hysterectomy and
oophorectomy [2]. For the entire group of women approximately 7% had
retroperitoneal lymphatic metastases. Considering the relatively low
incidence of lymph node metastases in women with endometrial cancer,
there have been no studies with sufficient numbers of women have
undergone preoperative assessment of lymphatic involvement followed
by hysterectomy and retroperitoneal exploration to adequately evaluate
any radiographic modality for its ability to accurately predict retro-
peritoneal lymphatic involvement. More importantly, these studies are
underpowered to assess the false negative rate or the absence of nodal
metastases. For instance, Kitajima et al. [57] evaluated 40 women with
endometrial cancer who underwent FDG-PET//CT to evaluate the
presence or absence of lymphatic metastases followed by retro-
peritoneal exploration. In this study only 10 women had lymph node
metastases. They calculated that the sensitivity was only 53% for the
prediction of lymphatic metastases. Similarly, Horowitz and associates,
evaluated 20 women with endometrial cancer who underwent
complete surgical staging including retroperitoneal exploration. In this
study only three patients had lymphatic metastases and the sensitivity
of PET scanning was only 60% for the detection of lymph node
involvement [58]. Finally, Park et al. [59] and associates compared
PET/CT with MRI for accuracy in detecting retroperitoneal metastases in
53 women with endometrial cancer. For the prediction of nodal
involvement the sensitivity for MRI was 46% compared to 69% for
PET/CT. Thus, in all of these studies MRI or PET/CT would have a false
negative rate that is too high to allow practitioners to use these
modalities instead of surgical exploration to assess the presence or
absence of nodal involvement. It is our opinion that preoperative
assessment of myometrial invasion is most accurately predicted by MRI
scanning incorporating synthetic bioploymers. However, the preopera-
tive assessment of extra-uterine disease is limited and has not been
sufficiently studied. Additionally, current radiographic modalities such
as MRI and PET/CT are very expensive.
Our opinion remains that surgical staging for all patients is the most
appropriate management for endometrial cancer. However, the reality
remains that despite best efforts, there will be women who cannot be
treated by a gynecologic oncologist. As more extensive studies are
performed and radiographic technologies continue to improve, the
future may provide an accurate modality for preoperative assessment
which will allow for appropriate triage of patients. Thus, until extensive
studies can be accomplished it seems most reasonable to perform
surgical retroperitoneal lymph node assessment in the majority of cases
in order to obviate the need for preoperative radiographic evaluation. It
also appears, from our review that most women with endometrial
adenocarcinoma should be treated surgically and that these complex
surgeries should be performed by a gynecologic oncologist.
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