Marcus Tan , Murray F Brennan, Deborah Kuk ,

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


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


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%


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%


*Subsequently excluded from analyses

5 years

10 years

DSD (n=632) 31% 45%


0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

1.0

Years from Initial Operation

Pro

babi

lity

of d

eath

due

to d

isea

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


0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

1.0


Pro

babi

lity

of lo

cal r

ecur

renc

eLocal Recurrence (LR)

by histologic type/subtype

5 years

10 years

LR(n=574) 39% 45%

n=574*p<0.0001


*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


Local Recurrence Nomogram

DD LPS

Low grade LMS

High grade LMS WD LPS

MPNST

SFT

Concordance index 0.69


0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

1.0


Pro

babi

lity

of d

ista

nt re

curre

nce

Distant Recurrence (DR) by histologic type/subtype

5 years

10 years

DR(n=632) 24% 28%

n=632*p<0.0001


(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


Distant Recurrence Nomogram

DD LPS

Low grade LMS

High grade LMSWD LPS

MPNST

SFT

Other

Concordance index 0.72


Natural History by Histologic Type/Subtype

0 5 10 15 20

0.0

0.4

0.8


Pro

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of d

ista

nt re

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nce

0 5 10 15 20

0.0

0.4

0.8


Pro

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e

0 5 10 15 20

0.0

0.4

0.8


Pro

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due

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se


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


Pro

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of d

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0 5 10 15 20

0.0

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0.8


Pro

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0 5 10 15 20

0.0

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Pro

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Natural History by Histologic Type/SubtypeHistology & RP sarcoma





MPNST (n=21)

(n=32)

(n=184)

(n=227)(n=119)



0 5 10 15 20

0.0

0.4

0.8


Pro

babi

lity

of d

eath

due

to d

isea

se

0 5 10 15 20

0.0

0.4

0.8


Pro

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of lo

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ecur

renc

e

0 5 10 15 20

0.0

0.4

0.8


Pro

babi

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of d

ista

nt re

curre

nce






MPNST (n=21)

(n=32)

(n=184)

(n=227)(n=119)



0 5 10 15 20

0.0

0.4

0.8


Pro

babi

lity

of d

eath

due

to d

isea

se

0 5 10 15 20

0.0

0.4

0.8


Pro

babi

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of lo

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ecur

renc

e

0 5 10 15 20

0.0

0.4

0.8


Pro

babi

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of d

ista

nt re

curre

nce






MPNST (n=21)

(n=32)

(n=184)

(n=227)(n=119)



0 5 10 15 20

0.0

0.4

0.8


Pro

babi

lity

of d

eath

due

to d

isea

se

0 5 10 15 20

0.0

0.4

0.8


Pro

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of lo

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0 5 10 15 20

0.0

0.4

0.8


Pro

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of d

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MPNST (n=21)

(n=32)

(n=184)

(n=227)(n=119)



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


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


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

Documents

Marcus Tan , Murray F Brennan, Deborah Kuk ,