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The Importance of Histologic Subtype for Outcome Prediction in Primary
Retroperitoneal Sarcoma: A Single-Institution Study of 675 Patients
Marcus Tan, Murray F Brennan, Deborah Kuk, Li-Xuan Qin, Narasimhan Agaram, Nicole Moraco,
Aimée Crago, Samuel Singer
Memorial Sloan-Kettering Cancer CenterSarcoma Disease Management Program
Retroperitoneal sarcomas (RPS)• Complete resection is the only chance for cure• Role of radiation therapy and chemotherapy
remain controversial• AJCC staging system of limited utility• Increasing understanding of differences in
histologic types and subtypes– Need for histology-based models to better predict
patterns of failure for individual patients
Histology & RP sarcoma
Aim and Hypothesis
• Aim: To determine the prognostic significance of histologic type/subtype in a large series of patients with primary retroperitoneal sarcoma
• Hypothesis: Each histologic type/subtype of retroperitoneal sarcoma is associated with distinct patterns of local and distant recurrence
Histology & RP sarcoma
Methods
• Retrospective review of prospectively-maintained sarcoma database from July 1982 to July 2010
• 675 patients with primary, non-metastatic RPS (excluding desmoid & GIST)
• Median follow-up for survivors 4.3 years• Survival calculated from time of initial operation
Histology & RP sarcoma
Tumor CharacteristicsVariable n %Histologic subtype Liposarcoma: well-differentiated & myxoid 186 28% Liposarcoma: dedifferentiated, round cell & pleomorphic 213 32% Leiomyosarcoma: low grade 18 2% Leiomyosarcoma: high grade 132 20% Solitary fibrous tumor 33 5% Malignant peripheral nerve sheath tumor 23 3% Translocation-associated 20 3% Not otherwise specified (NOS) 35 5% Other 14 2%Grade Low 242 36% High 431 64%
Histology & RP sarcoma
Operative DetailsVariable n %
Completeness of resection R0 337 50% R1 237 35% R2 58 9% Exploratory laparotomy only, no resection* 43 6%Number of organs resected 0 284 42% 1 207 31% 2 112 16% ≥3 72 11%Vascular resection performed 67 10%
Histology & RP sarcoma
*Subsequently excluded from analyses
5 years
10 years
DSD (n=632) 31% 45%
Histology & RP sarcoma
0 5 10 15 20
0.0
0.2
0.4
0.6
0.8
1.0
Years from Initial Operation
Pro
ba
bili
ty o
f d
ea
th d
ue
to
dis
ea
se
n=632* p<0.0001
Disease-Specific Death (DSD) by histologic type/subtype
(n=21)
(n=32)
(n=184)
(n=227)(n=119)
*Resected patients only
Multivariate analysis of DSDVariable HR 95% CI p-value
Histologic subtype (compared to well-differentiated LPS)
Dedifferentiated, round cell & pleomorphic LPS, sarcoma NOS 3.4 2.3-5.1 <0.001
Low grade leiomyosarcoma 1.2 0.3-4.9 0.78
High grade leiomyosarcoma 3.9 2.5-6.3 <0.001
Solitary fibrous tumor 2.3 1.1-4.5 0.02
Malignant peripheral nerve sheath tumor 4.3 2.0-9.2 <0.001
Translocation-associated sarcoma 3.8 2.0-7.3 <0.001
Size
10-20cm vs <10cm 1.2 0.8-1.8 0.44
≥20cm vs <10cm 1.5 1.0-2.3 0.07
Number of organs resected (≥3 vs <3) 1.9 1.3-2.8 0.002
Completeness of resection (R2 vs R0/R1) 2.5 1.6-3.8 <0.001
Histology & RP sarcoma
0 5 10 15 20
0.0
0.2
0.4
0.6
0.8
1.0
Years from Initial Operation
Pro
ba
bili
ty o
f lo
cal r
ecu
rre
nce
Local Recurrence (LR) by histologic type/subtype
5 years
10 years
LR(n=574) 39% 45%
n=574*p<0.0001
Histology & RP sarcoma
*R0/R1 resections only
(n=18)
(n=29)
(n=173)
(n=197)(n=113)
Multivariate analysis of LRFactor HR 95% CI PHistologic subtype (compared to well-differentiated LPS) Dedifferentiated, round cell & pleomorphic LPS, sarcoma NOS 2.3 1.7-3.1 <0.001 Low grade leiomyosarcoma 0.5 0.1-2.0 0.31 High grade leiomyosarcoma 0.8 0.5-1.5 0.55 Solitary fibrous tumor 0.1 0.02-0.8 0.03 Malignant peripheral nerve sheath tumor 1.1 0.4-2.6 0.92 Translocation-associated sarcoma 1.1 0.4-2.9 0.91Completeness of resection (R1 vs R0) 1.5 1.1-1.9 0.01Size 10-20cm vs <10cm 1.6 0.9-2.8 0.08 ≥20cm vs <10cm 2.1 1.2-3.8 0.01Age (>60 vs ≤60 years) 0.6 0.5-0.8 p<0.01
Histology & RP sarcoma
Local Recurrence Nomogram
DD LPS
Low grade LMS
High grade LMS WD LPS
MPNST
SFT
Concordance index 0.69
Histology & RP sarcoma
0 5 10 15 20
0.0
0.2
0.4
0.6
0.8
1.0
Years from Initial Operation
Pro
ba
bili
ty o
f d
ista
nt
recu
rre
nce
Distant Recurrence (DR) by histologic type/subtype
5 years
10 years
DR(n=632) 24% 28%
n=632*p<0.0001
Histology & RP sarcoma
(n=21)
(n=32)
(n=184)
(n=227)(n=119)
*Resected patients only
Multivariate Analysis of DRFactor HR 95% CI PHistologic subtype (compared to well-differentiated LPS)
Dedifferentiated, round cell & pleomorphic LPS, sarcoma NOS 4.7 2.4-9.0 <0.001
Low grade leiomyosarcoma 5.3 1.5-19.3 0.01
High grade leiomyosarcoma 11.6 5.7-23.4 <0.001
Solitary fibrous tumor 6.3 2.6-15.3 <0.001 Malignant peripheral nerve sheath tumor 2.4 0.6-9.2 0.21 Translocation-associated sarcoma 6.5 2.7-16.0 <0.001Number of Organs Resected 1 or 2 vs. 0 1.4 0.9-2.0 0.1 ≥3 vs. 0 2.4 1.4-4.4 0.002Size 10-20cm vs <10cm 1.8 1.1-2.8 0.01 ≥20cm vs <10cm 1.2 0.7-2.0 0.51
Histology & RP sarcoma
Distant Recurrence Nomogram
DD LPS
Low grade LMS
High grade LMSWD LPS
MPNST
SFT
Other
Concordance index 0.72
Histology & RP sarcoma
Natural History by Histologic Type/Subtype
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ista
nt
recu
rre
nce
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f lo
cal r
ecu
rre
nce
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ea
th d
ue
to
dis
ea
se
Histology & RP sarcoma
Well-diff & myxoid liposarcoma
Dedifferentiated, RC & pleomorphic liposarcoma
High grade leiomyosarcoma
Solitary fibrous tumor
MPNST (n=21)
(n=32)
(n=184)
(n=227)(n=119)
Disease-Specific Death
Local Recurrence Distant Recurrence
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ea
th d
ue
to
dis
ea
se
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f lo
cal r
ecu
rre
nce
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ista
nt
recu
rre
nce
Natural History by Histologic Type/SubtypeHistology & RP sarcoma
Well-diff & myxoid liposarcoma
Dedifferentiated, RC & pleomorphic liposarcoma
High grade leiomyosarcoma
Solitary fibrous tumor
MPNST (n=21)
(n=32)
(n=184)
(n=227)(n=119)
Disease-Specific Death
Local Recurrence Distant Recurrence
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ea
th d
ue
to
dis
ea
se
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f lo
cal r
ecu
rre
nce
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ista
nt
recu
rre
nce
Natural History by Histologic Type/SubtypeHistology & RP sarcoma
Well-diff & myxoid liposarcoma
Dedifferentiated, RC & pleomorphic liposarcoma
High grade leiomyosarcoma
Solitary fibrous tumor
MPNST (n=21)
(n=32)
(n=184)
(n=227)(n=119)
Disease-Specific Death
Local Recurrence Distant Recurrence
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ea
th d
ue
to
dis
ea
se
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f lo
cal r
ecu
rre
nce
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ista
nt
recu
rre
nce
Natural History by Histologic Type/SubtypeHistology & RP sarcoma
Well-diff & myxoid liposarcoma
Dedifferentiated, RC & pleomorphic liposarcoma
High grade leiomyosarcoma
Solitary fibrous tumor
MPNST (n=21)
(n=32)
(n=184)
(n=227)(n=119)
Disease-Specific Death
Local Recurrence Distant Recurrence
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ea
th d
ue
to
dis
ea
se
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f lo
cal r
ecu
rre
nce
0 5 10 15 20
0.0
0.4
0.8
Years from Initial Operation
Pro
ba
bili
ty o
f d
ista
nt
recu
rre
nce
Natural History by Histologic Type/SubtypeHistology & RP sarcoma
Well-diff & myxoid liposarcoma
Dedifferentiated, RC & pleomorphic liposarcoma
High grade leiomyosarcoma
Solitary fibrous tumor
MPNST (n=21)
(n=32)
(n=184)
(n=227)(n=119)
Disease-Specific Death
Local Recurrence Distant Recurrence
Summary
• Liposarcoma, leiomyosarcoma and SFT are associated with late recurrence and death from disease (as long as 15 years from initial diagnosis)
• Dedifferentiated liposarcoma and high grade leiomyosarcoma have similar DSS, but distinct patterns of local and distant recurrence.
• SFT is associated with low local recurrence (<10%) but high distant recurrence (40% at 5 years)
Histologic type / subtype
Completeness of resection
Tumor size
Number of organs resected
Age
DSD (R2 vs R0/R1) LR (R1 vs R0) DR
Histology & RP sarcoma
Conclusions• Histologic subtypes of RPS have distinct
differences in the incidence and timing of local and distant recurrence, as well as disease specific death
• Multivariate models and nomograms estimating risk of DSD, LR and DR – Inform patients and physicians of an individual’s risk– May prove useful for selection of patients for clinical
trials of:• Neo-adjuvant radiation • Neo-adjuvant/adjuvant chemotherapy • Molecular targeted therapy
Histology & RP sarcoma
Acknowledgements
MSKCC Sarcoma Database• July 1982-present• n=10,150 patients • 10,000 patients reached on
May 21st, 2013
Funding:• NIH SPORE in Soft Tissue Sarcoma P50 CA 140146-01• NIH Soft Tissue Sarcoma program project grant P01 CA 047179• The David and Monica Gorin Sarcoma Fund