ARTICLE
Auteur(s) : Bin
Li, Xiao-guang Li, Ling-ying Wu, Wen-hua Zhang, Shu-min Li,
Cheng Min, Ju-zhen Gao
Department of Gynecologic Oncology, Cancer Hospital, Peking
Union Medical College, Chinese Academy of Medical Science, Beijing
100021, China
The presence of lymph node metastases has a major impact on the
prognosis of women with endometrial cancer. Assessment of lymph
node status has become the standard of care in the surgical staging
of patients with endometrial cancer, and plays a crucial role in
decision making for further adjuvant therapies. However, the
appropriate criterion for node status assessment has not been
established. Most surgeons employ either complete or selective
pelvic and paraaortic lymphadenectomy as their staging procedure.
The incidence of lymph node metastasis in patients with clinical
stage and endometrial carcinoma is approximately 10% [1]. This
means that 9 in 10 patients would not benefit from node
resection but would only experience the complications of surgery.In
an effort to assess node status more accurately, and to avoid
operative injury, the sentinel lymph node (SLN) has been
successfully applied to the treatment of breast cancer and
cutaneous melanoma. In the case of gynecological malignancies, the
SLN procedure seems to be feasible in vulvar and cervical cancer.
In contrast, few studies have examined use of the SLN procedure in
endometrial cancer. The aim of the present study is to examine the
feasibility of SLN detection using blue dye lymph mapping for
patients with endometrial cancer.
Materials and methods
Patients characteristics
From September 2004 to March 2005, 20 patients with endometrial
cancer who underwent surgical treatment in our institution were
included in this study. The patients were required to sign an
informed consent. The median age was 5 years (range, 33-65
years). Eighteen patients had endometrioid adenocarcinoma and 2 had
squamous carcinoma. Seven cases were in histology grade 1, 8 in
grade 2, and 5 in grade 3. According to the Federation of
International Gynecology and Obstetrics (FIGO1988) surgical staging
system, 3 patients were in stage a, 4 in stage b, 3 in stage c, 5
in stage a, 2 in stage b, 1 in stage IIIa and 2 in stage IIIc. None
of the patients had computer tomography or magnetic resonance
immaging evidence of lymph node involvement.
Surgery
Six patients (30%) underwent total hysterectomy and bilateral
salpingo-oophorectomy, 10 (50%) underwent subradical hysterectomy
and 4 (20%) underwent radical hysterectomy. During surgery, seventy
patients (85%) underwent pelvic lymphadenectomy, 3 patients (15%)
lymph node biopsy, and 4 patients (20%) underwent paraaortic lymph
node biopsy.
Lymphatic mapping and sentinel lymph node identification
At the time of explorative laparotomy and after obtaining
abdominal-pelvic washings for cytological analysis, the uterus was
exposed and fallopian tubes were occluded with hemoclips. Gauzes
were used to protect peripheral tissues from being dyed. 1%
methylene were injected into the subserosal myometrium of corpus
uteri using a five-milliliter volumes syringe with 22 G needle
( (figure 1) ). In the
first two cases, the injection sites were the most superior
portion, the anterior midline and the posterior midline of the
fundus. Two milliliters methylene blue was totally injected into
the 3 sites above-mentioned. Initial subserosal injection
produced a blue “flush” across the surface of the uterus could been
seen, but no dye uptake nodes were found. For the subsequent
18 patients, we added 2 milliliters dye injected into the
bilateral uterus isthmus. Local compression and electronic
coagulation were used to prevent dye spillage. The retroperitoneal
spaces were opened right after dye injection to expose the lymph
drainage region. Blue lymphatic channels were dissected in an
effort to identify the dye-contained lymph nodes (SLN), these nodes
were removed and forward to pathology as individual specimens for
routine HE staining examination. The number and position of the SLN
were recorded carefully. After this procedure, the formerly planned
surgery was performed.
Results
During the injection of methylene blue, blue “flash” firstly
happened on the uterus surface and then the blue dye diffused to
the infundibulopelvic ligaments. When dye was injected into the
uterus isthmus, distinctly blue lymph channels emerged in the
parametrical tissues. The large-carliber lymphatic channnels were
paralleled uterine vessels and the petty channnels were
reticulated. The blue dyed lymph channels were also seen on the
surface of the round ligments.
No SLNs were found in the first 5 patients (25%). In 2 of
the 5 patients, methylene blue was not injected into the
uterus isthmus. In the other 3 patients, the dye spillage
happened. Thereafter, locally pressing and electronic coagulation
were used to help preventing dye spillage. SLNs were successfully
identified in the sequential 15 patients (75%). In 4 patients
(27%), SLNs distributed in unilateral pelvis, and for the other 11
patients (73%), SLNs were found in bilateral pelvis. A total of
71 SLNs with a mean number of 4.7 (range, 1-10) were
identified from all pelvic sites. The SLN locations included,
obturator in 29 (41%), interiliac in 16 (26%), external in 13
(18%), common iliac in 11 (15%) and inguinal in 2 (3%). No
dye-containing paraaortic nodes were found. Of twenty patients, a
total of 585 nodes were removed, with a mean number of 29.3
nodes (range, 14-55) for each case. Two patients (10%) had nodal
metastases, and they all had at least one SLN found to be positive.
In one of the 2 patients, 5 metastatatic nodes were
located in the bilateral obturator and external iliac area, and 1
of 5 was SLN. The other patients had only one metastatatic SLN. No
false-negative SLNs were found in our study. No metastatic
paraaortic nodes were found.
The SLNs procedures prolonged the operation time for 20 to 30
minutes. The urine of patients were blue for 24 hours after
surgery. No adverse reactions were attributed to the study.
Discussion
The concept of the “sentinel node” was first introduced by Cabanas
in 1977 [2], it was assumed that the SLN would be initially
involved for being the first node receiving lymphatic drainage from
primary tumor. The pathological status of this specific node should
therefore reflect the overall status of the entire lymphatic basin.
Thus, a patient with pathologic negative SLN might receive a SLN
biopsy instead of a systemic lymphadenectomy, which can cause
complications. Intraoperative lymphatic mapping and SLN biopsy have
been widely employed in the treatment of cutaneous melanoma and
breast cancer patients [3, 4]. In the case of gynecologic
malignancies, the feasibility of this technique has been examined
in patients with vulvar cancer and cervical cancer with encouraging
results [5]. In contrast, only few studies have addressed the value
of SLN in the endometrial cancer.
In the preliminary studies of SLN identification in endometrial
cancer (table 1( Table 1 )), various
techniques have been employed, raising several concerns [6-10]. The
first issue is the choice of tracers. The tracers may include a
blue dye (isosulfan blue [6] or patent blue V [8-10]), a
radiocolloid (99mTc sulfur colloid [8, 9] or
99mTc-labeled phytate [7]), or a combination of both [8,
9]. The second issue is the choice of injection sites. Three
injection sites, subserosal intraoperative myometrial, pericervical
and preoperative intrauterine under hysteroscopic guidance, have
been previously used to detect SLN in patients with endometrial
cancer [6-10]. The third issue is the procedure of SLN
identification. Laparotomic or laparoscopic identification of SLN
has been performed in several studies. Despite the differences
observed with these various techniques, the results were globally
encouraging. Several recent studies showed the detection rates of
SLN ranged from 82 to 94% and no false negativity found [7-10],
except for a early research from Burke et al. [6] in which the
detection rates of SLN was 67% and one false- negative case was
reported.
In the present study, methylene blue was selected as the dye
tracer, not only for its excellent safety, but also for its
definite effect in the SLN identification in cervical cancer [11].
For endometrial cancer, the injection of tracer was a crucial step
of SLN procedure. In a preliminary study, Barrager et al. [8]
injected tracer percervically. The drainage of tracer didn’t
reflect the anatomical lymphatic drainage of the whole corpus
uteri. Niikura et al. [7] and Raspagliesi et al. [9] injected
tracer under hysteroscopic, it yielded a definite SLN detection
rates, but it also took the risk of cancer cell disseminating into
the abdominal cavity, especially for the patients with permeated
lesion or cervical involvement [12]. Subserosal intraoperative
myometrial injection of tracer is a direct and convenient
technique, the blue dye diffusion could mimick the natural lymph
drainage of corpus uteri. This technique was firstly used by Burke
et al. [6]. In the study, the low SLN detection rate might be
attributed to the method of dye injection. Some blue dye which was
injected in the fundus couldn’t reach the pelvic nodes through the
lower corpus. In our study, methylene blue was injected into corpus
fundus in two cases, no blue dyed lymph nodes were found. For the
next 18 patients, we injected a part of dye into the lower
corpus and got SLNs identified in 15 cases except 3 cases
with dye spillage. The dye spillage was finally avoided by locally
coagulation or compression. Due to the early failures, the SLN
detection rate was 75%. This reflects the natural learning curve in
mastering this technique.
According to classical handbooks, the patterns of lymph drainage
from corpus uteri are complicated, three lymphatic pathways have
been described. First, the lymphatic drainage may reach the common
iliac lymph nodes via the hypogastric or obturator regions. Second,
the lymph drainage may reach inguinal lymph nodes along the round
ligaments. Third, the lymphatics may travel with the ovarian
vessels directly to the paraaortic lymph nodes. In the present
study, 71 SLNs were widely scattered in the pelvis. The SLNs
were frequently located in the hypogastric or obturator regions. A
few SLNs were located in the inguinal region, and no paraaortic
SLNs were detected. These findings confirmed that the two of three
lymphatic pathways aforementioned really exist. In a recent study,
Jobo et al. [13] found that lymphatic metastases occurred more
frequently via the hypogastric and obturator regions, while direct
para-aortic spread was rarely observed. Mariani et al. [14] also
suggested that the pelvic lymph nodes would be initially involved
when nodal metastases were present, and the isolated involvement of
para-aortic lymph nodes occurred in only 1 to 6% of cases.
Conversely in some other studies, the para-aortic SLNs have been
definitely detected. Burke et al. [6] found that the paraaortic
SLNs were all located between the levels of the renal vessels and
the origin of the inferior mesenteric artery, no SLNs were
identified in the lower paraaortic region. Therefore, the authors
suggested that there might be some lymphatic pathways traveling
through the infundibulopelvic ligament directly to the paraaortic
lymph nodes. In our study, the dye diffused rapidly to the upper
paraaortic area through some large-carliber lymphatic channels
along with the infundibulopelvic ligament. The lymphatic channels
were often seen traversing both the pelvic and paraaortic areas
without leading into a blue-dyed SLN. Burke et al. [6] presumed
that some of these channels empty directly into the cisterna chili,
the thoracic duct, and then the systemic circulation. This would
provide a shortcut for dissemination that bypasses the
retroperitoneal lymph nodes.
According to the FIGO 1988 surgical staging system of
endometrial cancer, the presence of retroperitoneal lymph node
involvement is classified into stage IIIc, thereby it is considered
as a critical prognosis factor and plays a crucial role in decision
making for further adjuvant therapies. Thus lymphadenectomy has
been recommended as an important procedure in the staging surgery
of endometrial cancer. However, the appropriate criteria for node
status assessment have not been established. Two types of surgery
have been employed for node status assessment including the
randomized node sampling and systemic lymphadenectomy. Because of
the complicated lymph drainage of corpus uteri, the systemic
lymphadenectomy usually involves a wider region. The Gynecologic
Oncology Group (GOG) suggested that all the paraaortic and pelvic
lymph nodes should be removed, including the nodes located in the
region between the inferior mesenteric and renal artery. But for
most patients without lymph nodes metastasis, it seems unnecessary
to undergo such a radical surgery. Furthermore a significant number
of patients with obesity or other comorbidities would barely endure
such surgery. Although randomized sampling can decrease surgical
morbidity, sampling is not always accurate because only 10% of
metastatic nodes are enlarged. How to target some special nodes for
sampling is the key point of surgery. The SLN procedure is
undoubtedly an ideal alternative of randomized sampling. Our study
proved the feasibility of SLN identification in endometrial cancer.
A mean number of 4.7 SLNs compared with 29.3 lymph nodes
totally removed, the extension of node resection would be limited
if the SLN biopsy is performed. The present study initially showed
that SLN might be predictive for node metastasis in patients with
endometrial cancer. The clinical validity of this SLN detection
procedure needs to be evaluated in subsequent studies.
Table 1 Sentinel lymph node (SLN) identification in
endometrial cancer: studies
|
Author
|
No. patients
|
Tracer
|
Site of injection
|
Surgery
|
Mean of SLN
|
Distribution of SLN
|
SLN detection rate (%)
|
No.SLN(+)
|
False negative rate (%)
|
|
Burke [6] 1996
|
15
|
Isosulfan
|
- subserosal myometrium
- of corpus uteri
|
Laparotomy
|
—
|
- Para-aortic,
- common iliac, pelvic
|
67
|
4
|
25
|
|
Niikura [7] 2004
|
28
|
99m-Tc-label phytate
|
- intrauterine under
- hysteroscopic guidance
|
Laparotomy
|
3.1
|
- Para-aortic,
- external iliac, obturator
|
82
|
1
|
0
|
|
Barranger [8] 2004
|
17
|
- Patent blue,
- 99m-Tc sulfur colloid
|
pericervical
|
laparoscopy
|
2.6
|
External iliac, interiliac obturator, common iliac
|
94
|
2
|
0
|
|
Raspagliesi [9] 2004
|
18
|
- Patent blue,
- 99m-Tc sulfur colloid
|
- preoperative intrauterine
- under hysteroscopic guidance
|
Laparotomy
|
3
|
- Para-aortic,
- common iliac, interiliac, external iliac, obturator.
|
94
|
0
|
0
|
|
Holub [10] 2004
|
25
|
Patent blue
|
- subserosal myometrium
- of corpus uteri and pericervical
|
laparoscopy
|
2.1
|
obturator, interiliac, common iliac
|
84
|
2
|
0
|
|
20
|
methylene blue
|
- subserosal myometrium
- of corpus uteri and bilateral isthmus.
|
Laparotomy
|
4.7
|
obturator, interiliac, external iliac, common iliac, inguinal
|
75
|
2
|
0
|
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