2522

Myxoid/Round Cell and Pleomorphic Liposarcomas

Prognostic Factors and Survival in a Series of Patients Treated at a Single Institution

Marco Fiore, MD1 BACKGROUND. The objective of this study was to investigate prognostic factors
Federica Grosso, MD2 and clinical outcome of myxoid/round cell and pleomorphic liposarcoma.
Salvatore Lo Vullo, Bsc3 METHODS. Three hundred twenty-nine patients with localized myxoid/round cell
Elisabetta Pennacchioli, MD1 or pleomorphic liposarcoma who underwent surgery at the Istituto Nazionale per
Silvia Stacchiotti, MD2 lo Studio e la Cura dei Tumori (Milan, Italy) over 25 years were reviewed. The
Andrea Ferrari, MD2 reates of local recurrence, distant metastases, and survival were studied.
Paola Collini, MD4 RESULTS. Two hundred fourteen patients presented with primary disease, and
Laura Lozza, MD5 115 patients had locally recurrent tumors. The disease-specific survival rate was
Luigi Mariani, MD3 75% at 10 years, and the local recurrence and distant metastases incidence were
Paolo G. Casali, MD2 25% and 15%, respectively. Presentation with recurrent disease, tumor size (>10
Alessandro Gronchi, MD1 cm), tumor grade (French Federation of Cancer Centers grade II or III vs grade I),
and positive surgical margins were independent predictors of death. Tumor site
1
Department of Surgery, National Cancer Insti- and radiation therapy also played a role, mostly related to their effect on local
tute, Milan, Italy. outcome. Pathologic grade and histologic subtype influenced distant metastases.
2
Department of Cancer Medicine, National Can- Extrapulmonary metastases were associated with poorer postmetastatic disease-
cer Institute, Milan, Italy. specific survival.
3 CONCLUSIONS. Myxoid/round cell liposarcomas shared similar prognostic factors
Department of Biostatistics, National Cancer
Institute, Milan, Italy. with other soft tissue sarcomas and had a relatively good clinical outcome. The
presence of >5% of round cell component singled out a group of patients at
4
Department of Pathology, National Cancer Insti-
greater risk of metastases and death but with a broad spectrum of disease aggres-
tute, Milan, Italy.
siveness. Extrapulmonary metastases were a peculiar pattern of myxoid/round
5
Department of Diagnostic Imaging and Radio- cell liposarcoma that require special consideration for treatment and prognosis.
therapy, National Cancer Institute, Milan, Italy.
Cancer 2007;109:2522–31.
2007 American Cancer Society.

KEYWORDS: sarcoma, myxoid liposarcoma, round cell liposarcoma, surgery, prog-

nosis, survival.

L iposarcoma (LPS) is one of the most common histologic sub-

Address for reprints: Alessandro Gronchi, MD,
Department of Surgery, Istituto Nazionale per lo
Studio e la Cura dei Tumori, via Venezian,1-
20133, Milan, Italy: Fax: (011) 39-02-23902404;
E-mail: alessandro.gronchi@istitutotumori.mi.it
Received January 23, 2007; revision received
February 26, 2007; accepted March 7, 2007.
types of adult soft tissue sarcoma. It can be subdivided in 3 var-
iants: well differentiated/dedifferentiated, myxoid/myxoid round
cell, and pleomorphic. Pure myxoid LPS (MLPS) accounts for 30%
of all LPS.1 Round cell LPS (RCLPS) is defined as a form of MLPS
that has an associated round cell component in >5% of the tumor2
and accounts for 15% of all LPS. The same chromosomal transloca-
tion t(12;16)(q13;p11) has been demonstrated in both in MLPS and
RCLPS,3 resulting in a fusion derived from the t(12;16) malignant
LPS (FUS-CHOP) transcript.
Pleomorphic LPS (PLPS) does not belong directly to the MLPS/
RCLPS group. PLPS tumors appear to be a distinct category, closer
to other pleomorphic sarcomas than to MLPS/RCLPS or well-differ-
entiated LPS.4 Nevertheless, a small round cell variant that contains
pleomorphic lipoblasts and small round cells that is virtually indis-

ª 2007 American Cancer Society

DOI 10.1002/cncr.22720
Published online 17 May 2007 in Wiley InterScience (www.interscience.wiley.com).

tinguishable from RCLPS has been observed.5
Recently, a rare epithelioid variant of PLPS carrying
the typical MLPS/RCLPS FUS-CHOP transcript also
has been described.6
MLPS/RCLPS tumors are known as particularly
sensitive to radiotherapy and chemotherapy compared
with other histologic subtypes of soft tissue sar-
coma.7,8 Recent data have raised new interest in
medical treatments for MLPS/RCLPS.9 Therefore, we
undertook the current retrospective analysis of our
institutional series of patients with MLPS/myxoid
RCLPS and PLPS to investigate prognostic factors and
long-term outcomes and to gain a better understand-
ing of the possible role of new therapeutic approaches.
MATERIALS AND METHODS
Between January 1980 and December 2005, 3025
consecutive patients with soft tissue sarcomas under-
went surgery with the intent of eradicating disease at
the National Institute for the Study and Cure of
Tumors in Milan, Italy. In this series, 329 patients
had a diagnosis of localized MLPS/RCLPS or PLPS.
Tumors were located mainly at the extremities
and girdles. Retroperitoneal or other abdominal
(intra-abdominal and pelvic) locations were grouped
together. Paraspinal, chest, and abdominal wall were
labeled as trunk locations; whereas the exceptional
head and neck locations were left separate. Tumor
depth was defined in relation to the investing fascia.
All retroperitoneal/other abdominal locations were
considered deep.
With regard to the histotypes, over the years, all
tumors were reviewed by at least 2 experienced
pathologists from our institution. The diagnosis was
confirmed molecularly whenever frozen material was
available. RCLPS was defined by the presence >5%
round cells.
The French Federation of Cancer Centers grading
system10 was used to assign tumor grade in
untreated primary tumors. Grading for recurrent
tumors was performed on the slides from the pri-
mary, untreated tumor seen in consultation.
An attempt to perform a complete resection with
negative margins was performed in all patients. For
tumors of the extremities, the surgical procedure was
similar to what was performed normally for all others
soft tissue sarcomas. Eleven of 273 patients underwent
a major amputation. In retroperitoneal, trunk, head
and neck locations, wide margins were achievable
only rarely. No patients died from surgical complica-
tions. Margins were defined at the time of pathologic
assessment by a dedicated pathologist. The surgical
specimen always was examined in the presence of the
Prognostic Factors of MLPS and RCLPS/Fiore et al. 2523
operating surgeon. The margins were inked and were
sampled separately. The closest margin was categor-
ized microscopically as positive (tumor within 1 mm
from the inked surface) or negative (absence of tumor
within 1 mm from the inked surface).
Clinical data were extracted from a prospective
database of all adult patients with soft tissue sar-
coma who were treated at our institution. The data
retrieved included sex, age at diagnosis, tumor site,
phase at presentation (primary vs recurrent), type of
surgery, tumor size, tumor depth, histotype, patho-
logic grade, margin status, adjuvant treatments, dates
of neoplastic events, site of distant metastasis (DM),
and death or last follow-up.
Radiotherapy was delivered as an adjunct in 128
patients (39%; 84 patients with primary tumors and
44 patients with recurrences). The indication for
radiation therapy was verified both by the operating
surgeon and by the radiation oncologist when, based
on clinical grounds, there was a greater risk of recur-
rence. However, no prospectively selected criteria
were used to this end. External beam radiation was
used in all such patients, and doses ranged from 45
gray (Gy) to 65 Gy (median, 57 Gy).
Chemotherapy was received by 61 patients
(19%), including 39 patients with primary tumors
and 22 patients with recurrent tumors, at the discre-
tion of the multidisciplinary Soft Tissue Sarcoma
Group at our institution or as part of clinical trials.
Antracycline-based regimens were used, in most
patients with ifosfamide.
The median follow-up duration for the entire
group, as of June 2006, was 119 months (interquartile
range, 70–153 months). Ten patients (3%) were lost
to follow-up before 10 years. The current study was
approved by our Institutional Review Board.
Statistical Methods
The endpoints of this study were disease-specific
survival (DSS), local recurrence (LR) incidence, and
DM incidence. According to the clinical literature,
curves relating to these endpoints were estimated
within each subgroup determined by the status of
disease at presentation to our institution (primary or
recurrent tumor). DSS curves were calculated by
using the Kaplan-Meier method and were compared
by using log-rank tests.
Crude cumulative incidence (CCI) curves for LR
and DM were calculated in a competing-risks frame-
work, as described by Marubini and Valsecchi,11 and
comparisons between curves were performed using
of the Gray test.12 The time to occurrence of any
event was computed from the date of surgery at our
institution to the date when the event first was
2524 CANCER June 15, 2007 / Volume 109 / Number 12
recorded or was censored at the date of last follow-
up assessment in event-free patients.
In the analysis of cause-specific survival, deaths
caused by conditions unrelated to sarcoma were cen-
sored. For the analysis of disease recurrence patterns,
LRs, distant recurrences, and deaths in recurrence-
free patients, whichever occurred first, were regarded
as competing events. Concomitant LRs and DMs
were included in the estimation of the CCI curves as
DM.
Multivariable analyses of DSS, LR-free survival,
and DM-free survival were based on cause-specific
hazards and, thus, were performed using Cox multi-
ple-regression models. Putative prognostic factors
that were included in the models were presentation
(primary or recurrent), tumor site (extremities or
other), tumor size (
5 cm or >5 cm), tumor grade
(Grade I, II, or III), tumor depth (deep or superficial),
margin status (negative or positive), chemotherapy
(yes or no), radiotherapy (yes or no), and histologic
subtype (MLPS, RCLPS, or PLPS). Because of their
strong correlation, grade and histologic subtype had
to be entered separately into the Cox models. The
effects for the remaining factors were estimated from
the models that included histology, the effect of which
was slightly stronger than that observed for grade.
The distribution of patient and disease charac-
teristics was compared between patients with pri-
mary tumors and patients with recurrent tumors by
means of the Wilcoxon rank-sum test and the Fisher
exact test for continuous and categorical variables,
respectively.
We used SAS software (SAS Institute Inc., Cary,
NC) and the S-Plus (StatSci, MathSoft, Seattle, WA)
Design Library (available at URL: http://lib.stat.
cmu.edu) and Cmprsk Library (available at URL:
http://biowww.dfci.harvard.edu/gray/) to perform
the modeling and statistical calculations. For each
test, results were considered statistically significant
whenever a 2-sided P value <.05 (5%) was achieved.
RESULTS
Clinical characteristics are summarized in Table 1.
Disease-Specific Survival
Sixty-nine patients died of disease (24 of 214 patients
with primary tumors and 45 of 115 patients with
recurrent tumors), 27 patients died of intercurrent
disease other than sarcoma, and the remaining 233
patients were alive at the last follow-up. The time to
disease-specific death in the entire series varied from
5 months to 219 months (median for those who
died, 48 months). For patients with MLPS, the time
to disease-specific death varied from 5 months to
219 months (median for those who died, 54 months);
for patients with RCLPS, the time to disease-specific
death varied from 5 months to 127 months (median
for those who died, 27 months); and for the patients
with PLPS, the time to disease-specific death varied
from 6 months to 195 months (median for those
who died, 49 months).
The DSS rates were 83% at 5 years and 75% at 10
years. In the patients who had primary tumors, the
DSS rates were 90% and 87% at 5 years and 10 years,
respectively, whereas, in the patients who had recur-
rent tumors, the DSS rates were 72% and 56%,
respectively, with a significant difference observed
between the 2 groups (P < .001).
Among the patients who had primary tumors,
the 5-year and 10-year DSS rates were 93% and 92%,
respectively, for the MLPS group; 87% and 77%,
respectively, for the RCLPS group; and 81% and 81%,
respectively, for the PLPS group. No significant differ-
ences were observed between the 3 groups (Fig. 1A).
Among the patients who had recurrent tumors,
the 5-year and 10-year DSS rates were 80% and 61%,
respectively, for the MLPS group; 59% and 47%,
respectively, for the RCLPS group; and 64% and 53%,
respectively, for the PLPS group. No significant differ-
ences were observed between the 3 groups (Fig. 1B).
At multivariable analysis, phase at presentation,
tumor size >10 cm, and surgical margins were inde-
pendent prognostic factors for DSS (Table 2). With
regard to histology, there was weak evidence only for
RCLPS compared with MLPS (P ¼ .09), although
RCLPS and PLPS had a significantly greater propor-
tion of DM in both subgroups of patients (primary
tumors and recurrent tumors), as detailed below. Tu-
mor grade was an independent prognostic factor if it
was considered instead of histology (P < .05).
Local Recurrence
Eighty-six patients developed LR after they under-
went surgery at our institute, including 75 first events
(33 patients with primary tumors and 42 patients
with LR at presentation). The time to first LR in the
whole series varied from 2 months to 151 months
(median for those who developed a recurrence, 21
months). For patients with MLPS, the time to first LR
varied from 3 months to 151 months (median for
those who developed a recurrence, 25 months); for
patients with RCLPS, the time to first LR varied from
4 months to 86 months (median for those who devel-
oped a recurrence, 15 months); and, for patients with
PLPS, the time to first LR varied from 2 months to 69
months (median for those who developed a recur-
rence, 14 months).
 Prognostic Factors of MLPS and RCLPS/Fiore et al. 2525

TABLE 1
Main Patient and Disease Characteristics According to the Phase of Disease

Primary Recurrent Overall

Characteristic No. % No. % No. % P

Total 214 65 115 35 329 100

Median age (IQ range), y 46 (34–57) 55 (46–63) 49 (39–59) <.0001
Sex .9078
Women 99 46 52 45 151 46
Men 115 54 63 55 178 54
Site .0086
Head and neck 1 1 1 1 2 1
Trunk 7 3 8 7 15 5
Retroperitoneum/other 16 7 23 20 39 12
Extremities/girdles 190 89 83 72 273 83
Median size (IQ range), cm* 8 (5–13) 10 (6–19) 9 (5–15) .0009
Depth .0262
Superficial 41 19 11 10 52 16
Deep 173 81 104 90 277 84
Histotype .7161
MLPS 134 63 67 58 201 61
RCLPS 43 20 25 22 68 21
PLPS 37 17 23 20 60 18
Surgical margins <.0001
Negative 186 87 75 65 261 79
Positive 28 13 40 35 68 21
FNCLCC grade .4135
I 133 62 67 58 200 61
II 32 15 24 21 56 17
III 48 22 24 21 72 22
Not available 1 1 — 1 1
Surgical procedure <.0001
Limb-sparing 177 83 75 65 252 77
Amputation 5 2 6 5 11 3
Not applicable 32 15 34 30 66 20
RT .9059
Not done 130 61 71 62 201 61
Done 84 39 44 38 128 39
CT .8821
Not done 175 82 93 81 268 81
Done 39 18 22 19 61 19

IQ range indicates interquartile range; MLPS, myxoid liposarcoma; RCLPS, round cell liposarcoma; PLPS, pleomorphic liposarcoma; FNCLCC, French Federation
of Cancer Centers; RT, radiotherapy; CT, chemotherapy.
* There was 1 missing value in the primary group.

The overall CCI rates for LR were 21.7% at 5 years
and 25.2% at 10 years. In the patients who had pri-
mary tumors, the LR CCI rates were 13.2% and 17.5%
at 5 years and at 10 years, respectively; whereas, in
the patients who had recurrent tumors, the respec-
tive rates were 37.1% and 39.2%, and a significant
difference was obselrved between the 2 groups (P <
.001).
Among the patients who had primary tumors,
the 5-year and 10-year LR CCI rate was 11.3% and
15.9%, respectively, for the MLPS group; 13.7% and
21.9%, respectively, for the RCLPS group; and 19.4%
and 19.4%, respectively, for the PLPS group. No sig-
nificant difference was observed between the 3
groups (Fig. 2A).
Among the patients who had recurrent tumors,
the 5-year and 10-year LR CCI rate was 35.3% and
37.1%, respectively, for the MLPS group; 31.3% and
31.3%, respectively, for the RCLPS group; and 47.8%
and 52.2%, respectively, for the PLPS group. No sig-
nificant difference was observed between the 3
groups (Fig. 2B).
In the multivariable analysis, phase at presenta-
tion, tumor site, and radiotherapy were independent
prognostic factors for LR-free survival (a borderline P
value of .05 was achieved for radiotherapy), as shown
2526 CANCER June 15, 2007 / Volume 109 / Number 12

TABLE 2
Hazards Ratio Estimates With 95% Confidence Intervals and
P Values From the Cox Proportional Hazards Model on
Disease-specific Survival

Category (Reference) HR 95% CI P

Presentation: recurrence (primary) 2.76 1.66–4.61 .0001

Depth: deep (superficial) 1.14 0.36–3.57 .8255
Tumor size, cm
5–10 (
5) 1.27 0.47–3.40 .6388
>10 (
5) 3.56 1.40–9.05 .0075
Site: extremity (other) 0.64 0.35–1.17 .1451
Margin: positive (negative) 2.00 1.13–3.54 .0180
RT: yes (no) 0.96 0.58–1.58 .8598
CT: yes (no) 1.41 0.77–2.58 .2666
Histology
RCLPS (MLPS) 1.65 0.92–2.97 .0940
PLPS (MLPS) 1.40 0.76–2.58 .2774
FNCLCC grade
II (I) 1.89 1.06–3.39 .0321
III (I) 1.25 0.69–2.28 .4638

HR indicates hazards ratio; 95% CI, 95% confidence interval; RT, radiotherapy; CT, chemotherapy;
RCLPS, round cell liposarcoma; MLPS, myxoid liposarcoma; PLPS, pleomorphic liposarcoma;
FNCLCC, French Federation of Cancer Centers.

tumors, the DM CCI rates were 10.0% and 10.7% at 5

FIGURE 1. Disease-specific survival by histologic subtype in patients with
(A) primary and (B) recurrent liposarcoma (LPS). MLPS indicates myxoid LPS;
RCLPS, round cell LPS; PLPS, pleomorphic LPS.
in Table 3. With regard to surgical margins, only a
weak impact was observed (P ¼ .07).
Distant Metastases
Fifty-eight patients had DM, including 46 first events,
after the underwent surgery at our institute (21
patients with primary tumors and 25 patients with
LR at presentation). The time to DM in the whole se-
ries varied from 2 months to 187 months (median
for those who developed a recurrence, 20 months).
For patients with MLPS, the time to DM varied from
3 months to 73 months (median time for those
developed a recurrence, 23 months); for patients
with RCLPS, the time to DM varied from 2 months
to 140 months (median for those who developed a
recurrence, 18 months); and, for patients with PLPS,
the time to DM varied from 5 months to 187 months
(median for those who developed a recurrence, 34
months).
The overall CCI rate for DM was 14.5% at 5 years
and 15.3% at 10 years. In the patients with primary
years and 10 years, respectively; whereas, in the
patients who presented with recurrent tumros, the
DM CCI rates were 22.4% and 23.4%, respectively,
and a significant difference was observed between
the 2 groups (P < .05).
Among the patients who presented with primary
tumors, the 5- and 10-year DM CCI rates were 4.0%
and 5.0%, respectively, for the MLPS group; 21.7%
and 21.7%, respectively, for the RCLPS group; and
20.6% and 20.6%, respectively, for the PLPS group. A
significant difference was observed between the 3
groups (Fig. 3A).
Among the patients who presented with recur-
rent tumors, the 5- and 10-year DM CCI rates were
18.0% and 18.0%, respectively, for the MLPS group;
43.2% and 43.2%, respectively, for the RCLPS group;
and 13.0% and 17.4%, respectively, for the PLPS
group. A significant difference was observed between
the 3 (Fig. 3B).
On multivariate analysis, phase at presentation,
tumor size >10 cm, and radiotherapy were inde-
pendent prognostic factors for DM-free survival, as
shown in Table 4. Histology also was identified as an
independent prognostic factor for DM in addition to
tumor grade if it was considered in the multivariable
analysis.
Metastatic Pattern
Overall, 58 patients developed DM. Fifteen patients
(26%) patients had only lung metastases, 24 patients
 Prognostic Factors of MLPS and RCLPS/Fiore et al. 2527

TABLE 3
Hazards Ratio Estimates With 95% Confidence Intervals and
P Values From the Cox Proportional Hazards Model on Local
Recurrence-free Survival

Category (Reference) HR 95% CI P

Presentation: recurrence (Primary) 2.67 1.72–4.16 <.0001

Depth: deep (superficial) 1.00 0.47–2.14 .9912
Tumor size, cm
5–10 (
5) 0.99 0.52–1.91 .9833
>10
5) 1.43 0.72–2.82 .3035
Site: extremity (other) 0.38 0.23–0.64 .0002
Histology
RCLPS (MLPS) 1.17 0.65–2.10 .6091
PLPS (MLPS) 1.46 0.86–2.47 .1627
Margin: positive (negative) 1.67 0.95–2.92 .0758
RT: yes (no) 0.39 0.23–0.65 .0003
CT: yes (no) 1.64 0.92–2.92 .0913
FNCLCC grade
II (I) 1.32 0.75–2.32 .3346
III (I) 1.32 0.77–2.26 .3178

HR indicates hazards ratio; 95% CI, 95% confidence interval; RCLPS, round cell liposarcoma; MLPS,
myxoid liposarcoma; PLPS, pleomorphic liposarcoma; RT, radiotherapy; CT, chemotherapy, FNCLCC,
French Federation of Cancer Centers.

months for patients with MLPS (range, 4 months to

FIGURE 2. Crude cumulative incidence of local recurrence by histologic
subtype in patients with (A) primary and (B) recurrent liposarcoma (LPS).
MLPS indicates myxoid LPS; RCLPS, round cell LPS; PLPS, pleomorphic LPS.
(41%) had only extrapulmonary metastases, and the
remaining 19 patients (33%) patients had both
lung and extrapulmonary metastases. Metastatic
patterns at single extra-pulmonary sites are detailed
in Table 5.
Extrapulmonary metastases affected 49% of
patients with MLPS, 43% of patients with RCLPS,
and only 8% of patients with PLPS. In 14 patients
(33%), multiple sites of either synchronous or meta-
chronous extrapulmonary metastases were documen-
ted. Therefore, 43 patients (74% of the patients with
metastases) had at least 1 extrapulmonary metastatic
site. The extrapulmonary sites that were affected
most frequently were abdomen, bone, paraspinal soft
tissues, and extremities.
The median survival after pulmonary metastases
developed was approximately 2 years for patients
with MLPS and 1 year for patients with RCLPS and
PLPS. Conversely, the median survival after extrapul-
monary metastases developed as a first event was 14
>52 months). For patients with RCLPS and PLPS, the
limited number of extrapulmonary metastasis as a
first event prevented us from calculating the median
survival.
DISCUSSION
In this series of 329 patients with MLPS, RCLPS, and
PLPS of all anatomic sites who underwent surgery
with intent to eradicate disease at our institution
over 25 years, the cumulative incidence of LR and
DM at 10 years was 25.2% and 15.3%, respectively.
DSS at 10 years after definitive surgery was 77% for
the MLPS/RCLPS group. These results are similar to
those reported from the main published series (Table
6). Nevertheless, when evaluating the results accord-
ing to the different histotypes, some differences
could be observed. The Memorial Sloan-Kettering
Cancer Center (MSKCC) group recently reported a
series that included all primary LPS subtypes. In
their report, the 12-year DSS rate was 86% for MLPS,
55% for RCLPS, and 53% for PLPS.16 In the current
series, the 10-year DSS rate was 90% for primary
MLPS, 81% for RCLPS, and 82% for PLPS. This differ-
ence in outcomes for both RCLPS and PLPS mainly
may reflect differences in the referral pattern to these
2 major national referral centers. The median tumor
size in our series was definitively smaller than that
reported in the MSKCC series (9 cm vs 15 cm).
2528 CANCER June 15, 2007 / Volume 109 / Number 12

TABLE 4
Hazards Ratio Estimates With 95% Confidence Intervals and P Values
From the Cox Proportional Hazards Model on Metastasis-free Survival

Category (Reference) HR 95% CI P

Presentation: Recurrence (primary) 2.78 1.62–4.76 .0002

Depth: Deep (superficial) 0.94 0.34–2.60 .9025
Tumor size, cm
5–10 (
5) 1.79 0.69–4.62 .2316
>10 (
5) 3.28 1.29–8.36 .0128
Site: Extremity (Other) 1.45 0.65–3.22 .3643
Histology
RCLPS (MLPS) 2.98 1.62–5.48 .0005
PLPS (MLPS) 2.30 1.16–4.56 .0175
Margin: Positive (negative) 0.94 0.49–1.82 .8621
RT: Yes (No) 1.69 0.99–2.86 .0529
CT: Yes (No) 1.44 0.80–2.62 .2279
FNCLCC grade
II (I) 2.75 1.45–5.21 .0020
III (I) 2.59 1.37–4.91 .0035

HR indicates hazards ratio; 95% CI, 95% confidence interval; RCLPS, round cell liposarcoma; MLPS,
myxoid liposarcoma; PLPS, pleomorphic liposarcoma; RT, radiotherapy; CT, chemotherapy; FNCLCC,
French Federation of Cancer Centers.

that we investigated. This difference well may reflect

FIGURE 3. Crude cumulative incidence of distant metastasis by histologic
subtype in patients with (A) primary liposarcoma (LPSO and (B) recurrent
LPS liposarcoma. MLPS indicates myxoid LPS; RCLPS, round cell LPS; PLPS,
pleomorphic LPS.
Furthermore, the cut-off level of a 5% of round cell
component to differentiate MLPS from the more
aggressive RCPLS variant probably cannot single out
a group of patients with uniform risk. Therefore, our
patients may have been affected by a disease with a
lesser round cell component on average and, thus,
with a subsequently more favorable outcome. A bet-
ter risk stratification in the RCLPS group should be
investigated prospectively.
We also analyzed a number of factors that had a
possible influence on the clinical outcome of
patients with these tumors. Presentation with either
primary or recurrent disease, tumor size, tumor
grade, and surgical margin status were identified as
the most important prognosticators for cause-speci-
fic survival in the current study. Patients who pre-
sented to our institute with an LR had worse
outcomes compared with patients who presented
with primary disease. This negative impact of pre-
sentation was significant for all 3 of the endpoints
the selected subset of patients, but it also suggests
that patients with LR need to be followed even more
carefully, because they bear a 2.8-fold greater risk of
disease mortality.
The impact of tumor size was more evident for
tumors that measured >10 cm. The cut-off size of
5 cm did not seem to single out 2 different risk cate-
gories. Patient who had tumors that measured
>5 cm and <10 cm had a limited increased risk
compared with patients who had tumors that mea-
sured >10 cm, who bore a 3.5-fold greater risk of
dying from their disease.
Tumor grade was identified as a significant factor
for survival in the multivariable analysis. The differ-
ence was observed mainly between grades I and II,
whereas a much weaker difference was observed
between grades II and III. This may reflect the patho-
logic characteristics of the disease. MLPS tumors
always were graded as grade I, whereas RCLPS and
PLPS tumors were graded II or III. Therefore, the dif-
ference in outcome according to tumor grade prob-
ably reflects the difference in outcome according to
the histologic variant. The presence of a >5% round
cell component resulted in a >1.5-fold greater risk of
dying from disease. Different from what has been
reported by others, this difference did not corre-
spond to the rates for high-grade tumors. In the cur-
rent series, RCLPS behaved similarly to intermediate-
grade tumors, and patients with RCLPS had long-
term survival rates between 70% and 80%.
 Prognostic Factors of MLPS and RCLPS/Fiore et al. 2529

TABLE 5
Extrapulmonary Metastatic Pattern According to Histological Subtype*

MLPS RCLPS PLPS Overall

Site Total Primary/Recurrent Total Primary/Recurrent Total Primary/Recurrent Total Primary/Recurrent

Intra-abdominal 6 4/2 5 3/2 — — 11 7/4

Bone/spine 6 2/4 3 2/1 — — 9 4/5
Paraspinal 3 0/3 5 2/3 — — 8 2/6
Extremities 4 2/2 3 2/1 1 1/0 8 5/3
Soft tissues 1 0/1 4 3/1 — — 5 3/2
Thoracic wall 3 2/1 2 0/2 — — 5 2/3
Retroperitoneum 3 1/2 1 0/1 — — 4 1/3
Liver 1 1/0 1 0/1 2 2/0 4 3/1
Heart/pericardium 2 1/1 1 0/1 1 1/0 4 2/2
Mediastinum 2 1/1 2 2/0 — — 4 3/1
Brain — — 1 0/1 1 1/0 2 1/1
Regional lymph nodes 1 0/1 1 0/1 — — 2 0/2
Abdominal wall 1 0/1 — — — — 1 0/1
Overall 33 14/19 29 14/15 5 5/0 67 33/34
Patients with multiple extrapulmonary sites 8 4/4 6 5/1 — — 14 9/5

MLPS indicates myxoid liposarcoma; RCLPS, round cell liposarcoma; PLPS, pleomorphic liposarcoma.
* The number of localizations at single sites (primary/recurrent cases) in 43 patients with extrapulmonary metastases.

TABLE 6
Main Series of Patients With Myxoid Liposarcoma

No. of Age, Median MLPS, RCLPS, LR, DM, Extrapulmonary DSS,

Series patients y Site size, cm % % % % M, % % (y)

Smith et al, 19962 29 31 Extremities 14 76 24 31 34 NS 47 (10)*

Kilpatrick et al, 199613 86 21 Any 11 57 43% 14 35 NS 67 (10)*
Antonescu et al, 200114 79 17 Any NS 57 43 28 38 67 73 (5)
ten Heuvel et al, 200615 49 27 Any 12 83 17 33 27 77 72 (10)
Moore Dalal et al, 200616 144 23 Any NS 100 — NS NS NS 86 (12)
Moore Dalal et al, 200616 81 23 Any NS — 100 NS NS NS 55 (12)
Current series 269y 25 Any 9 75 25 24 14 74% 77 (10)

MLPS indicates myxoid liposarcoma; RCLPS, round cell liposarcoma; LR, local recurrence; DM, distant metastases; M, metastases; DSS, disease—specific survival; NS, not stated.
* Overall survival.
y
Only MLPS and RCLPS.

Patients who had positive surgical margins bore control rates compared with patients who had
a 2-fold greater risk of dying from their disease and a tumors located at other sites. Tumors located in the
1.7-fold greater risk of developing an LR compared trunk bore a nearly 3-fold greater risk of recurring
with patients who did not have positive surgical mar- locally compared with tumors located in the extremi-
gins. The same difference was not observed for ties. This difference in local outcome may reflect the
patients who had metastases. Therefore, patients impact of tumor location on the ability to perform
who had positive surgical margins had a greater risk resection with adequate surgical margins, as reported
of dying mainly from locoregional disease independ- in many series on patients with retroperitoneal and
ent of tumor location, as reported in other series of trunk soft tissue sarcoma,22,23 who also had a nearly
patients with softtissue sarcoma.17–21 2-fold greater risk of dying of their disease, mainly
Two more factors had an affect on recurrence- from locoregional failure. Patients who received
free survival in our series: tumor location and the radiation therapy had approximately 50% of the risk
administration of radiation therapy. Patients who had of developing an LR compared with patients who did
tumors of the extremities had more favorable local not receive radiation therapy.
2530 CANCER June 15, 2007 / Volume 109 / Number 12
With regard to the histologic subtype, a major
difference was observed for the development of DM.
Patients with primary MLPS had a 10-year incidence
of DM of 5%, whereas the incidence of DM was 22%
and 21% for patients with RCLPS and patients with
PLPS, respectively. Only minor differences in 10-year
survival were observed, reflecting the indolent course
of the disease even in the metastatic setting and the
relative greater sensitivity of this disease to chemo-
therapy.8,9 Furthermore, surgical management of
extrapulmonary metastases often was carried out,
although it sometimes was more challenging in
patients with lung nodules, especially with regard to
particular anatomic sites (eg, abdomen, mediasti-
num, and heart/pericaridium) (Table 5).24,25
In conclusion, we observed that patients with
MLPS, RCLPS, and PLPS who had a confirmed have
an indolent course, as reported previously using
predicting tools and based on large case series
analyses,26–28 Presentation with either primary or re-
current disease, tumor size, and tumor grade are of
major importance. Complete tumor resection with
negative margins should be the objective of surgery
with an evident impact on local control. Adjuvant
radiation therapy should be delivered to improve
local control. High-grade and large RCLPS tumros
have a more aggressive behavior; thus, patients with
these tumors may be considered for possible new ad-
juvant medical treatments. The cutoff level for
tumors of a 5% round cell component singles out a
group of diseases with a broad spectrum of aggres-
siveness. Further studies will be needed to determine
whether more precise tools may be obtained by stra-
tifying the round cell cutoff level further or by exam-
ining the different molecular subtypes, allowing a
better selection of high-risk patients as candidate for
newly available agents.
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