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1447
The Prognostic Significance of Vascular Invasion by
Endometrial Carcinoma
Yoshiki lnoue, M.D.
Koshiro Obata, M.D.
Kunio Abe, M.D.
Gen Ohmura, M.D.
Kunihiko Doh, M.D.
Tadaaki Yoshioka, M.D.
Hiroshi Hoshiai, M.D.
Kiichiro Noda, M.D.
Department of Obstetrics and Gynecology, Kinki
University School of Medicine, Osaka-Sayama,
Osaka, Japan.
BACKGROUND. Recently, invasion of vascular spaces by endometrial carcinoma
has received particular attention as a prognostic factor. The goal of the current
investigation was to re-examine the effect of vascular invasion on tumor recurrence
and survival in patients with endometrial carcinoma.
METHODS. Surgical specimens from 238 patients with endometrial carcinoma were
examined for the presence of vascular invasion by tumor cells. Vascular invasion
was compared with clinicopathologic features and postoperative survival. SuMval
curves by vascular invasion were evaluated by the Kaplan-Meier method.
RESULTS. In a histopathologic review of 238 cases of endometrial carcinoma, 82
neoplasms demonstrated vascular invasion. Vascular invasion significantly correlated with the extension of primary tumor, depth of myometrial invasion, and
histologic grade. Patients with lymph node metastasis had a significantly higher
incidence of vascular invasion. Survival at 5 years for patients with vascular invasion was 73.4%. This was significantly lower than the survival rate of 91.5% for
women without this finding ( P i 0,001). Among patients with lymph node metastasis, 80.2% of the patients with vascular invasion survived for 5 years compared
with 95.3% of the patients without vascular invasion ( P < 0.05). Ten of 47 patients
with no lymph node metastasis but with vascular invasion developed recurrent
carcinoma. Nine of these ten patients apparently had extrapelvic recurrences.
CONCLUSIONS. The presence of vascular invasion is a reliable prognostic indicator.
Recording of tumor recurrence pattern may lead to a better selection of patients
for adjuvant systemic therapy after surgery. Cancer 1996; 781447-51.
0 1996 American Cancer Society,
KEYWORDS endometrial carcinoma, vascular invasion, tumor recurrence, prognosis.
T
Address for reprints: Yoshiki Inoue, M.D., Department of Obstetrics and Gynecology, Kinki
University School of Medicine, 377-2, OhnoHigashi, Osaka-Sayama, Osaka 589, Japan.
Received February 29, 1996; revision received
May 28, 1996; accepted May 28, 1996.
0 1996 American Cancer Society
he prognostic factors in endometrial carcinoma that have been
most extensively investigated are histologic grade,’ cell
myometrial i n ~ a s i o n ,and
~ , ~lymph node m e t a ~ t a s i s .Recently,
~,~
invasion of vascular spaces by an endometrial carcinoma has received
particular attention as a prognostic fa~tor.9-l~
Tumor cells first develop the capacity for local tissue invasion and then spread through
gaps between endothelial cells into vascular spaces of the stroma.
Once vascular space penetration has occurred, tumor cells have the
potential for metastasizing to other sites. In general terms, invasion
of vascular spaces by a tumor is indicative of an aggressive neoplasm
that has a marked tendency to metastasize to the lymph node and to
recur locally or distantly. The current investigation attempts to reinforce the effect of vascular invasion on tumor recurrence and survival
in patients with endometrial carcinoma.
SUBJECTS AND METHODS
Subjects for this investigation were 238 patients with endometrial
carcinoma who were treated at the Department of Obstetrics and
1448
CANCER October 1,1996 / Volume 78 I Number 7
TABLE 1
Vascular Invasion in Relation to Histopathologic Variables of
Endometrial Carcinoma
Extent of the primary tumor
Confined to corpus
Extension to cervix
Extrauterine spread
Histologic grade
I
2
3
Myornetrial invasion
Endometrium only
Inner half
Outer half
Tumor cell type
Endometrioid
Adenocarcinoma
Adenosquamous
Adenoacanthoma
Serous
Clear cell
Squamous
a
TABLE 2
Relation between Histologic Grade and Myometrial Invasion and
Vascular Invasion
No. of
patients
Vascular
invasion
157
43
38
39 (25%)
21 (48.8%)
22 (58%)
< 0.01
149
70
19
35 (23.5%)
34 (48.6%)
13 (68.4%)
< 0.01
24
143
71
0 (0%)
33 (23.1%)
49 (69%)
< 0.01
216
9
9
1
2
1
69 (31.9%)
6 (66.7%)
4 (44.4%)
1 (100%)
1150%)
1(100%)
P value
Histologic
“grade”
Myornetrial
invasion
Vascular invasion
positiveltotal (%)
1
Endometrium only
Inner half
Outer half
Endometrium only
Inner half
Outer half
Endometrium only
Inner half
Outer half
0/21 (0%)
191102 (18.6%)
16/26 (61.5%)
0/3 (0%)
12/37 (32.4%)
22/30 (73.3%)
010
2/4 (50%)
11/15 (73.3%)
2
3
< 0.05a
Adenocarcinorna versus adenosquamous,
Gynecology,Kinki University School of Medicine, from
1976 to 1993. All patients were initially treated with a
total abdominal hysterectomy and bilateral salpingooophorectomy without prior radiation therapy. Pelvic
lymph node dissection was performed at the time of
hysterectomy on 210 patients. Selective aortic lymph
node dissection was performed on 42 patients. External radiation to the whole pelvis was used when disease extended outside the uterus and in patients who
had pelvic lymph node metastasis. For patients with
histologically positive aortic lymph nodes, extendedfield radiation therapy with an aortic portal was
planned.
Hematoxylin and eosin-stained sections from hysterectomy specimens were examined for the presence
of vascular invasion by tumor cells. Vascular invasion
was considered to be present when tumor cells were
noted within or attached to the wall of a blood vessel
or lymphatic space lined by flattened endothelial cells.
Lymphatic vessel invasion was considered positive
only when tumor cells and the lymphocyte were noted
together in a lymphatic space. Blood vessel invasion
was considered positive only when tumor cells and
red blood cells were noted together in a blood vessel
space. The relationship between vascular space invasion and various histopathologic variables was evaluated. Histologic classification was performed according
to the World Health Organization cla~sification.’~
Once
P value
< 0.01
< 0.01
> 0.05
TABLE 3
Vascular Invasion in Relation to Pelvic and Aortic Lymph Nodes in
Endometrial Carcinoma
Pelvic lymph node
Positive
Negative
Aortic lymph node
Positive
Negative
No. of
patients
Vascular
invasion
29
181
22 (75.9%)
48 (27%)
< 0.01
10
32
9 (90%)
10 (31.3%)
< 0.01
P value
an endometrioid carcinoma with squamous differentiation was identified, the squamous cells were classified
as histologically malignant (adenosquamous carcinoma) as opposed to histologically benign (adenoacanthoma). Statistical analysis of the data was performed
using the chi-square test on tables to determine the
significance of the various correlations with P < 0.05
considered significant.Survivalwas calculated from the
date of surgery according to the method of Kaplan and
Meier.
RESULTS
In a histopathologic review of 238 cases of endometrial
carcinoma, 82 neoplasms demonstrated vascular invasion. The relationship between vascular invasion and
various histopathologic variables of endometrial carcinoma is shown in Tables 1, 2, and 3. The incidence of
vascular invasion increased with the extension of the
primary tumor; 25% in tumors confined to the corpus,
48.8% in tumors that invaded to the cervix, and 58%
in tumors that extended beyond the uterus ( P < 0.01).
The incidence of vascular invasion was 23.5%, 46.8%,
and 68.4% in Grade 1, 2, and 3 carcinomas, respectively. The frequency of vascular invasion increased
with progressing tumor grade ( P < 0.01). Vascular in-
Vascular Invasion in Endometrial Carcinoma/lnoue et al.
1449
T,4BLE 4
Relationship of Vascular Invasion to Tumor Recurrence and the Site of Tumor Recurrence
No. of
patients
Tumor
recurrence
Lymphatic vessel invasion
54
12 (22.2%]
Blood vessel invasion
Lymphatic and blood vessel invasion
13
15
4 (30.8%)
4 (26.7%)
vasion was not found among tumors confined to the
endometrium. The frequency of vascular invasion was
found in 23.1% of patients with tumor invasion to less
than one-half of the myometrium, and 69% of patients
with tumor invasion to more than one-half. The incidence of vascular invasion increased with depth of
myometrial invasion ( P < 0.01). The relationship between histologic grade and myometrial invasion and
vascular invasion is shown in Table 2. As the tumor
becomes less differentiated, the possibility of deep
myometrial invasion increases. In Grade 1 and 2 carcinoma, the incidence of vascular invasion increased
with depth of myometrial invasion ( P < 0.01). Compared with pure adenocarcinoma, adenosquamous
carcinoma had a significantlyhigher incidence of vascular invasion ( P < 0.05). The relationship between
lymph node metastasis and vascular invasion is shown
in Table 3. Of 29 patients with positive pelvic lymph
node metastasis, 11 (37.9%)had Grade 2 carcinomas,
5 (17.2%) had Grade 3 carcinomas, 19 (65.5%) had
tumor invasion to more than one-half of the myometrium, 2 (7%)had adenoacanthoma, 1 (3%)had adenosquamous carcinoma, and 1 (3%)had clear cell carcinoma. Of 10 patients with aortic lymph node metastasis, 5 (50%) had Grade 2 carcinomas, 2 (20%) had
Grade 3 carcinomas, 7 (70%) had tumor invasion to
more than one-half of the myometrium, and all patients had pure adenocarcinoma. Of 9 patients with
both pelvic and aortic lymph node metastasis, 4
(44.4%)had Grade 2 carcinomas, 2 (22.2%)had Grade
3 carcinomas, and 7 (77.8%) had tumor invasion to
more than one-half of the myometrium. The incidence
of vascular invasion was found in 75.9% of patients
with pelvic lymph node metastasis and in 27% of patients without pelvic lymph node metastasis ( P <
0.01). Vascular invasion was found in 90% of patients
with aortic lymph node metastasis and in 31.3% of
patients without aortic lymph node metastasis ( P <
0.01).
Twenty-six of the 238 patients in this investigation
developed recurrent endometrial carcinoma. Recurrent cancer was documented in 20 (24.4%) of 82 patients with vascular invasion as opposed to 6 (3.8%)
of 156 patients without this finding ( P < 0.01). Tumor
Site of recurrence
Lung: 4; abdominal cavity: 2; lunglabdominal cavity: 1;vaginal cuff 1;
vestibule: 1; aortic lymph node: 1; hone: 1; Virchow's lymph node: 1
Lunn: 2; abdominal cavitv: 1; vaginal cuff: 1
Lung: 2; abdominal cavity: 1; ab;iorninaJ cavitylaortic lymph node: 1
TABLE 5
Tumor Recurrence in 180 Patients without Lymph Node Metastasis in
Relation to Vascular Invasion
Vascular invasion
Present
Absent
No. of
patients
Tumor
recurrence
47
133
10 (21.3%)
3 (2%1
P value
< 0.01
characteristics of 20 patients with vascular invasion
who had recurrent cancer are shown in Table 4. Lymphatic vessel invasion was found in 54 patients, blood
vessel invasion in 13, and lymphatic and blood vessel
invasion in 15. Recurrence was detected in 12 of 54
patients with lymphatic vessel invasion, in 4 of 13 patients with blood vessel invasion, and in 4 of 15 patients with lymphatic and blood vessel invasion. The
difference in the recurrence rates was not significant.
The most frequent sites of recurrence in the three
groups were the lung and the abdominal cavity.
Tumor recurrence in 180 patients without lymph
node metastasis in relation to vascular invasion is presented in Table 5. Of 133 patients without vascular
invasion, only 3 developed tumor recurrence. In contrast, 10 of 47 patients with vascular invasion developed recurrent cancer. Of these ten patients, six had
Grade 2 carcinomas, one had Grade 3 carcinoma, and
six had tumor invasion to more than one-half of the
myometrium. In these ten patients, recurrence occurred in the lung (four), abdominal cavity (one), abdominal cavity/aortic lymph node (one), Virchow's
lymph node (one), vestibule (one), bone (one), and
vaginal cuff (one). Eight of these patients apparently
had extrapelvic recurrences.
Survival at 5 years for patients with vascular invasion was 73.4%. This was significantly lower than the
survival rate of 91.5% for women without vascular invasion (P< 0.001). Survival from vascular invasion for
patients without lymph node metastasis is shown in
Figure 1. Among patients without lymph node metastasis, the 5-year survival rate was 80.2% for the vascu-
CANCER October 1,1996 I Volume 78 I Number 7
1450
increased with the progressing extent of the primary
tumor, tumor grade, and depth of myometrial invasion. Patients with lymph node metastasis had a significantly higher incidence of vascular invasion. Patients with vascular invasion had a significantly higher
recurrence rate and a significantly poorer survival rate
Vascular invasion
than those without vascular invasion. In this series,
p o s i t i v e n=49
only 1 case (0.4%) was serous. This is a low number
by North American standards. The reason is unknown.
However, in a population-based study from Norway,
p(0. 05
it was only l.l%24
and in Australia 2.8%.'5 This may
be typical of the distribution of cell types in Japan.
2o
Vascular invasion comprises lymphatic vessel invasion and blood vessel invasion. Several reports26-28
h
5
on rectal carcinoma indicated that the presence of
venous invasion had an independent effect on survival
FIGURE 1. Survival from vascular invasion for patients without lymph
after radical resection. In contrast, Jass et aLZ9found
node metastasis.
venous invasion to be a weak variable in their new
prognostic system. In addition, Minsky et al.30reported
that blood vessel invasion was not found in their study
to be an independent prognostic variable. In contrast,
lar invasion group compared with 95.3% for patients
without vascular invasion ( P < 0.05).
lymphatic vessel invasion was an independent prognostic variable from a proportional hazards analy~is.~'
DISCUSSION
Only tumor cells with unquestionable endothelialVascular invasion by tumor cells has been shown to be
lined spaces were regarded as evidence of vessel invaof clinical significance in several malignan~ies.+'~~'~-'~
sion. However, it was occasionally difficult to differenTalbot et al." reported that the follow-up studies on
tiate lymphatics from blood vessels. In our study of
patients with rectal carcinoma showed the corrected
82 patients with vascular invasion, 54 had lymphatic
vessel invasion, 13 had blood vessel invasion, and 15
5-year survival rate was significantly worse when vehad lymphatic and blood vessel invasion. In this series,
nous invasion was present. Patients with Stage IB carcinoma of the uterine cervix with vascular invasion
blood vessels were differentiated from lymphatics by
treated by radical hysterectomy had a 59.4% 5-year
the discovery of red blood cells within the lumen, and
survival rate that increased dramatically to 90% when
more smooth muscle than found in lymphatics. Lymthere was no invasion."
phatic vessel invasion was observed most frequently
in patients with vascular invasion. The difference beThere have been several studies of the significance
tween lymphatic vessel invasion and blood vessel inof vascular invasion by endometrial carcinoma. Hanvasion with regard to tumor recurrence and the recurson et aLI3 reported that 16 of 111 Stage I endometrial
rence site was not significant.
carcinomas (14%) had tumors demonstrating vascular
Previous reports indicated that the risk of pelvic
invasion. The frequency of vascular invasion increased
lymph node metastasis is significant in endometrial
with progressing tumor grade and depth of myome~ a r c i n o m a . ~ In
' - ~this
~ series, tumor recurrence and
trial invasion. Vascular invasion was noted most comsurvival for patients without lymph node metastasis
monly in adenosquamous carcinomas, but was conwas evaluated. Patients with vascular invasion have
spicuously absent in adenoacanthomas. Tumor recura significantly poorer prognosis than those without
rence developed in 44% of patients whose tumors
vascular invasion. It must be emphasized that poor
demonstrated vascular invasion as opposed to only
prognosis with vascular invasion was also a feature of
2% of patients without this finding. They concluded
patients without lymph node metastasis. Ten of 47
that vascular invasion by tumor cells is an important
prognostic variable in Stage I endometrial carcipatients with no lymph node metastasis with vascular
invasion developed recurrent cancer. Nine of these ten
noma.13
patients had apparently extrapelvic recurrences. The
Sivridis et aI.l4 reported that a multivariative remainstay of treatment for endometrial carcinoma is
gression analysis showed that vascular invasion was a
separate indicator of poor prognosis that was indepensurgery. However, this alone is obviously an incomplete therapy for patients with endometrial carcinoma
dent of stage, histologic grade, or depth of myometrial
invasion.
whose tumor has invaded vascular spaces. We conclude that examining for the presence of vascular invaIn this study, the frequency of vascular invasion
Vascular invasion
n e g a t i v e n=132
t
Vascular Invasion in Endometrial Carcinoma/lnoue et al.
sion gives reliable prediction of recurrences after resection of endometrial carcinoma. Recording of tumor
recurrence pattern may lead to a better selection of
patients for adjuvant systemic therapy after surgery.
The usefulness of adjunctive hormonal and nonhornional cytotoxic chemotherapy in patients at high risk
has to be investigated. Only prospective randomized
studies can help achieve this goal.
16.
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