original article
Annals of Oncology 21: 1915–1921, 2010
doi:10.1093/annonc/mdq039
Published online 18 February 2010
Clinical outcome of leiomyosarcomas of vascular origin:
comparison with leiomyosarcomas of other origin
A. Italiano1*, M. Toulmonde1, E. Stoeckle2, M. Kind3, G. Kantor4, J.-M. Coindre5 & B. Bui1
Departments of 1Medical Oncology; 2Surgery; 3Radiology; 4Radiotherapy and 5Pathology, Institut Bergonié, Bordeaux, France.
Received 5 November 2009; revised 11 January 2010; accepted 12 January 2010
Background: There are no data about the natural history of leiomyosarcoma of vascular origin (vLMS) in comparison
with leiomyosarcoma (LMS) of other origin and about the management of advanced disease.
Methods: Among 1472 patients diagnosed with sarcoma from January 1980 to December 2008 at our institution,
195 patients (13%) had LMS. LMS had a vascular origin in 14 cases (7%).
P = 0.001) and overall survival (OS; 2.1 versus 7 years, P < 0.0001) than patients with LMS of other origin. On
multivariate analysis, grade and vascular origin were the sole independent adverse prognostic factors for OS. Eight
metastatic patients with vLMS received a first-line anthracycline chemotherapy regimen. Two patients had partial
response, four had stable disease and two had progressive disease. OS of patients with metastatic vLMS was not
significantly different from that observed in patients with metastatic LMS of other origin (22.1 versus 16.5 months, P = 0.84).
Conclusions: Vascular origin is an independent adverse prognostic factor for MFS and OS in patients with LMS.
Patients with metastatic vLMS had a similar outcome than patients with metastatic LMS of other origin.
Key words: chemotherapy, leiomyosarcoma of vascular origin
introduction
patients and methods
Leiomyosarcomas of vascular origin (vLMSs) are extremely rare
lesions representing less than one in every 100 000 malignant
tumors [1]. Clinical descriptions are mainly limited to single
case reports and only few instances are recorded in several large
autopsy series [1]. The sites most frequently involved are large
veins such as the vena cava. Pulmonary and systemic arteries’
locations are exceptional. The prognosis for patients with
vLMSs is very poor [2–5]. Surgery is the cornerstone of
treatment and represents frequently a challenge even for the
most experienced surgeons because of disease location. More
than 50% of patients with complete macroscopic resection
experienced disease recurrence and died of disease progression
[2–6]. Moreover, many patients present with locally advanced
or metastatic disease at the time of initial diagnosis and are not
amenable to surgery.
Due to its rarity, no comparison has never been made
between vascular and nonvascular soft tissue leiomyosarcomas
(LMSs). Moreover, there are no data about the medical
management and the role of chemotherapy in patients with
advanced vLMSs. We report here the first series addressing
these specific issues.
patients
*Correspondence to: Dr. A. Italiano, Department of Medical Oncology, Institut Bergonié,
229 cours de l’Argonne, 33076 Bordeaux Cedex, France. Tel: + 33-05-56-33-33-33;
Fax: + 33-05-56-33-33-30; E-mail: [email protected]
From 1980 to 2008, 1472 adult patients (‡16 years old) with a diagnosis of
soft tissue sarcoma were admitted to our institution (Institut Bergonie,
Bordeaux, France). Clinical and pathologic data were collected by reviewing
medical records and were entered in a comprehensive database. Among
these patients, 195 (13%) had a LMS. LMS had a vascular origin in 14 cases
(7%). Histological diagnosis was confirmed for all patients by the same
pathologist (J-MC), according to the World Health Organization (WHO)
Classification of Tumors [7]. Tumor grade was evaluated according to
the Fédération Nationale des Centres de Lutte Contre le Cancer grading
system [8, 9].
Variables collected from the medical records included demographic data,
tumor characteristics and staging, treatment, patterns of recurrence and followup. Cause of death was coded according to the WHO classification [10].
statistical analyses
The statistical analyses of baseline demographics and clinical outcomes were
based on all data available up to the cut-off date of 30 April 2009. Tumor
response was assessed according to RECIST [11]. Overall survival (OS)
was defined as the interval between diagnosis and the time of death.
Progression-free survival was defined for patients treated with
chemotherapy as the interval between initiation of chemotherapy and
the time of progression or death from any cause. Univariate and
multivariate analyses were carried out using Cox regression and included
the following variables: age (<50 or ‡50 years), sex, tumor size (<5 or ‡5
cm), tumor site (extremities, internal trunk, head and neck and trunk
wall), tumor depth (superficial or deep), grade according to the FNCLCC
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
original
article
Results: Patients with vLMS had a significantly worse median metastasis-free survival (MFS) (0.25 versus 9.6 years,
original article
Annals of Oncology
system and vascular origin (yes or no). Variables that were associated
with survival with a P value <.05 in the univariate analysis were included
in the multivariate regression. Analyses were carried out using SPSS 12.0
statistical software (SPSS Inc., Chicago, IL). All statistical tests were
two-sided, and P values <.05 indicated statistical significance.
results
patients
The study population included 195 patients. Their characteristics
are summarized in Table 1. Fourteen patients had a vLMS
(Table 2). Tumors arose from veins in 12 cases (86%) and from
systemic arteries in only 2 cases (14%). Inferior vena cava was
the most frequent tumor location (36%). vLMSs tend to be
larger (‡5 cm) than LMSs of other origin (93% versus 74%,
P = 0.09) and are characterized by a higher rate of synchronous
metastases than LMS of other origin (36% versus 15%, P = 0.04).
patterns of treatment of patients with vascular
LMSs
localized setting. At diagnosis, nine vLMS patients presented
with localized disease (Figures 1–3). Patterns of care and
Table 1. Patients’ characteristics
Characteristic
Age, years
<50
‡50
Sex
Male
Female
Size, cm
<5
‡5
Location
Superficial
Deep
Anatomic site
Extremities
Head and neck
Trunk wall
Internal trunk
FNCLCC grade
Grade 1
Grade 2
Grade 3
Unknown
All (N = 195)
No. of patients
%
Nonvascular leiomyosarcoma (N = 181)
No. of patients
%
Vascular leiomyosarcoma (N = 14)
No. of patients
%
51
144
26
74
49
132
27
73
2
12
14
86
95
100
49
51
87
94
48
52
8
6
57
43
51
144
26
74
50
131
28
72
1
13
7
93
37
158
19
81
37
144
20
80
0
14
0
100
117
7
34
37
60
3.5
17.5
19
110
7
34
30
61
4
19
16
7
0
0
7
50
0
0
50
18
56
109
12
9
29
56
6
18
51
100
12
0
5
9
0
0
36
64
0
P value
0.29
0.51
0.09
0.06
0.42
0.21
FNCLCC, Fédération Nationale des Centres de Lutte Contre le Cancer.
Table 2. Characteristics of patients with vascular leiomyosarcomas (N = 14)
Patient
Sex/age
Eastern Cooperative
Oncology Group
Tumor site
Tumor
size
Grade
Metastases
at diagnosis
Metastatic sites
at diagnosis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Female/69
Male/49
Male/68
Female/83
Female/72
Female/65
Female/84
Male/73
Male/49
Male/51
Male/59
Female/69
Male/58
Male/77
1
2
1
1
1
0
3
3
1
1
1
0
0
1
Great saphenous vein
Inferior vena cava
Great saphenous vein
Great saphenous vein
Femoral vein
Popliteal vein
Common iliac artery
Superficial femoral artery
Great saphenous vein
Inferior vena cava
Inferior vena cava
Inferior vena cava
Inferior vena cava
Inferior vena cava
10
10
10
10
7
4
15
15
9
6
10
9
8
8
3
2
2
3
3
3
3
3
2
3
3
2
3
2
No
No
Yes
No
No
No
Yes
No
No
Yes
Yes
No
Yes
No
–
–
Lung
–
–
–
Lung
_
–
Lung
Liver
–
Liver
–
1916 | Italiano et al.
Volume 21 | No. 9 | September 2010
original article
Annals of Oncology
Figure 1. Locoregional treatment of nine patients with localized leiomyosarcoma of vascular origin.
Figure 2. Chemotherapy in 3 patients with localized leiomyosarcoma of vascular origin.
outcome for these patients are detailed in Figure 1. Seven of
them underwent resection with a curative intent. Complete
gross resection was achieved in all these cases. Two patients
Volume 21 | No. 9 | September 2010
(patients 2 and 12) with localized disease at presentation
received doxorubicin-based chemotherapy in a neo-adjuvant
setting. One of them (case 2) died of cardiac failure before
doi:10.1093/annonc/mdq039 | 1917
original article
Annals of Oncology
Figure 3. Outcome of patients with metastatic leiomyosarcomas of vascular origin treated with chemotherapy.
completion of the neo-adjuvant treatment and was not assessed
for tumor response. One patient (case 14) was deemed
unresectable because of locoregional extension and received
palliative chemotherapy. Patients 12 and 14 were assessable for
response. The best response according to RECIST criteria was
stable disease in both cases. Five out of seven patients with
complete resection received postoperative radiotherapy (RT),
administered as external beam therapy. The median dose of
external beam RT was 45 Gy (range 45–50.4 Gy). In one case
1918 | Italiano et al.
(case 6), additional brachytherapy by intraoperative seed
implantation was carried out.
metastatic setting. Ten patients presented with metastatic
disease at diagnosis (n = 5) or during the course of their disease
(n = 5). The sites of metastases were lung (n = 8), liver (n = 5),
skin (n = 3), bone (n = 1) and brain (n = 1). Eight patients
received chemotherapy for metastases (Table 3). All of them
received an anthracycline-based regimen as first-line therapy.
Volume 21 | No. 9 | September 2010
original article
Annals of Oncology
Their outcome is summarized in Figure 3. The best response
was partial response in two cases, stable disease in four cases
and progressive disease in two cases. Six patients received
second line chemotherapy and one patient received four lines of
chemotherapy. Surgical resection of metastases was carried out
in only one patient (case 9). Two patients had not been treated
with chemotherapy at the time of analysis because of poor
cardiac function (case 4) or low-burden, asymptomatic disease
(case 5). OS of patients with metastatic vLMS was not
significantly different from that observed in patients with
metastatic LMS of other origin (median OS: 22.1 versus 16.5
months, P = 0.84).
metastasis-free survival
The median metastasis-free survival (MFS) for the entire cohort
of LMS patients was 7.4 years [95% confidence interval (CI)
3.3–11.5] (Tables 4 and 5, Figure 4). On univariate analysis,
tumor site, tumor size, tumor depth, grade and vascular origin
were significantly associated with MFS. On multivariate
analysis, grade and vascular origin were the sole independent
prognostic factors of MFS.
Table 5. Independent prognostic factors on MFS and OS (multivariate
analysis)
Variable
Table 3. Chemotherapy regimens in patients with leiomyosarcoma of
vascular origin
Protocol
Hazard ratio
95% CI
P value
MFS
Drugs
Doxorubicin 20 mg/m2 (days 1–3)
Ifosfamide 2.5 g/m2 (days 1–3)
Dacarbazine 300 mg/m2 (days 1–3)
21-days cycle
AD
Doxorubicin 20 mg/m2 (days 1–3)
Dacarbazine 300 mg/m2 (days 1–3)
21-days cycle
Metronomic etoposide
Oral daily etoposide 75 mg/day on 21
of 28-days cycle
Metronomic cyclophosphamide Oral daily cyclophosphamide 50 mg/
day on 21 of 28-days cycle
Doxorubicin
Doxorubicin 60–75 mg/m2
21-days cycle
Docetaxel–gemcitabine
Gemcitabine 900 mg/m2 (days 1 and 8)
Docetaxel 100 mg/m2 (day 8)
21-days cycle
MAID
FNCLCC grade
Grade 1
Grade 2
Grade 3
Vascular origin
No
Yes
0.3
0.5
1
0.07–1.29
0.27–0.96
1
0.04
0.5
1
0.24–0.99
0.04
OS
FNCLCC grade
Grade 1
Grade 2
Grade 3
Size, cm
<5
‡5
Vascular origin
Yes
No
0.15
0.52
1
0.01–1.12
0.31–0.87
0.01
0.36
1
0.17–0.75
1
0.007
0.5
1
0.27–0.93
0.03
CI, confidence interval; FNCLCC, Fédération Nationale des Centres
de Lutte Contre le Cancer; MFS, metastasis-free survival; OS, overall
survival.
MAID, mesna, adriamycin, ifosfamide, dacarbazine; AD, adriamycin,
dacarbazine.
Table 4. Significant prognostic factors on MFS and OS (univariate analysis)
Variable
Whole population
Anatomic Site
FNCLCC grade
Location
Size, cm
Vascular origin
Extremities
Head and neck
Internal trunk
Trunk wall
1
2
3
Superficial
Deep
<5
‡5
Yes
No
MFS
Median MFS (years)
95% CI
P value
7.4
6.4
NR
2.3
NR
NR
7.3
4.8
NR
3.7
NR
3.6
0.25
9.6
3.2–11.2
2–10
–
1.2–3.2
–
–
6.7–12.7
0.8–8.8
–
0–8.4
–
0.9–6.4
0–3
5.4–13.4
–
0.0002
0.03
0.003
0.0006
0.001
OS
Median OS (years)
95% CI
5.5
6
NR
2.4
9.7
NR
10
3.4
10
4.2
17.3
3.2
2.1
7
3.5–7.5
4–8
–
0.9–3.9
2.1–17.1
–
3.7–15.7
1.7–4.7
8.4–16.4
2.5–5.5
9.5–25
2–4
1.1–3.1
4.9–8.9
P value
–
0.08 (ns)
0.0008
0.0014
<0.0001
<0.0001
CI, confidence interval; FNCLCC, Fédération Nationale des Centres de Lutte Contre le Cancer; MFS, metastasis-free survival; NR, median not reached; ns,
not significant; OS, overall survival.
Volume 21 | No. 9 | September 2010
doi:10.1093/annonc/mdq039 | 1919
original article
Annals of Oncology
Figure 4. Kaplan–Meier curves of metastasis-free (A, C) and overall (B, D) survival of all patients entered into the study (A, B) and according to the
vascular origin (C, D).
overall survival
The median OS for the entire cohort of LMS patients was 5.5
years (95% CI 3.5–7.5) (Tables 4 and 5, Figure 4). On univariate
analysis, tumor size, tumor depth, grade and vascular origin were
significantly associated with OS. In particular, OS of patients
with vLMS was significantly worse than that of patients with
LMS of other origin (median: 2 versus 7 years, P = 0.0001). On
multivariate analysis, tumor size, grade and vascular origin are
the sole independent prognostic factors of OS.
discussion
LMS is generally recognized as an aggressive disease with
a generally poor prognosis compared with other soft tissue
sarcomas. Only one study has compared the prognosis of vLMS
with LMS of other anatomic sites [12]. The authors reported
1920 | Italiano et al.
similar prognosis in localized LMS of different origin. However,
this study included only patients with LMS of the vena cava.
Moreover, the comparison was not made with other soft tissue
LMSs but mainly with a small series of selected cases of
visceral LMS (stomach: n = 13, small intestine: n = 18 and
uterus: n = 10). All these cases were diagnosed between
October 1972 and November 1996, e.g. before the discovery of
KIT mutations in stromal gastrointestinal tumors (GIST) and
were not submitted to a central histological review [13].
Therefore, we believe that the gastric and intestinal LMSs
included in this series were not true LMSs but GIST. Indeed,
most tumors referred to as gastrointestinal leiomyomas and
LMSs in the older medical literature are actually GISTs [14].
This may explain the similar or better outcome of LMS of the
vena cava in comparison with the other cases included in this
series.
Volume 21 | No. 9 | September 2010
original article
Annals of Oncology
Our study identified vascular origin as an independent
adverse prognostic factor for MFS and OS in patients with softtissue LMSs. In our experience, vLMSs account for <2% of soft
tissue sarcomas with the inferior vena cava representing the
predominant location.
In the context of localized disease, complete surgical
resection of the vessel segment is the treatment of choice.
However, surgery remains a challenge due to the location of the
tumor. In our series, only eight patients (57%) had potentially
resectable disease at diagnosis. This proportion is consistent
with that of previous reports [6]. Due to its rarity, the role of
neo-adjuvant chemotherapy and RT in the management of this
rare disease is still unknown. RT has been indicated to improve
outcome of patients with LMS of inferior vena cava [12]. In our
small series, only one patient had local recurrence 27 months
after the initial diagnosis. Of the five patients in our series who
received adjuvant RT after resection of their primary tumor,
one developed a local recurrence and four developed distant
metastases. Of the two patients who did not receive adjuvant
RT, one developed distant metastases without evidence of local
recurrence and one remain disease free at last follow-up. In the
series of Ito et al. [15], the rate of local recurrence was not
significantly different between patients who received
perioperative RT and those who did not. Of the eight patients
who received perioperative RT, one developed a local
recurrence, five developed distant metastases and two remained
disease free at last follow-up. Altogether, such data indicate
only a limited role of RT in the management of vLMS which are
essentially characterized by a metastatic risk. In our series, this
metastatic risk is significantly higher than that observed for
LMS of other origin. This difference remained significant even
after exclusion in the second group of the superficial tumors,
which are mainly cutaneous LMSs (data not shown). Several
hypotheses may explain the higher metastatic potential of
vLMS. Obviously, the location of vLMS favors hematogeneous
spread. Intrinsic biological difference between vLMS and LMS
of other origin is possible but not likely. For instance, the
proportion of patients with intermediate-grade (grade 2) and
high-grade (grade 3) disease was similar between the two
groups. Moreover, the survival of patients with metastatic
disease was very similar, whatever the origin of the primary
tumor. Another explanation of the high metastatic potential of
vLMS is related to a possible delay in diagnosis particularly
for those originating form the inferior vena cava. This may
explain the higher proportion of lesions ‡5 cm (93% versus
74%, P = 0.09) and the higher rate of synchronous metastases
(36% versus 15%, P = 0.04) in the group of vLMS even if theses
difference were only marginally significant.
There are no data in the literature about the outcome of
patients with metastatic vLMS. In our study, the objective
response rate of vLMS patients treated with first-line
anthracycline-based chemotherapy was not different from the
results reported by previous studies including patients with
LMS of other sites [16, 17]. Moreover, our results
demonstrated that the survival of patients with metastatic
vLMS was not different from that observed in patients with
LMS of other sites. In our series, the two patients with
metastatic LMS originating from peripheral arteria had the
Volume 21 | No. 9 | September 2010
worst outcome. These data confirm that arterial LMSs tend to
behave more aggressively than their venous counterparts as
suggested by previous authors [18].
In conclusion, our study demonstrates that vascular origin is
an independent adverse prognostic factor for MFS and OS in
patients with LMS. For patients with advanced disease,
standard medical management including first-line
anthracycline-containing regimen produces survival results
that are similar to those observed with other subtypes of
LMSs.
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