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 Center Sarcoma 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 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 Characteristics Variablen % Histologic subtype Liposarcoma: well-differentiated & myxoid186 28% Liposarcoma: dedifferentiated, round cell & pleomorphic213 32% Leiomyosarcoma: low grade18 2% Leiomyosarcoma: high grade132 20% Solitary fibrous tumor33 5% Malignant peripheral nerve sheath tumor23 3% Translocation-associated20 3% Not otherwise specified (NOS)35 5% Other14 2% Grade Low242 36% High431 64% Histology & RP sarcoma

Operative Details Variablen % Completeness of resection R % R % R258 9% Exploratory laparotomy only, no resection*43 6% Number of organs resected % % % ≥372 11% Vascular resection performed67 10% Histology & RP sarcoma *Subsequently excluded from analyses

5 years 10 years DSD (n=632) 31%45% Histology & RP sarcoma n=632* p< Disease-Specific Death (DSD) by histologic type/subtype (n=21) (n=32) (n=184) (n=227) (n=119) *Resected patients only

Multivariate analysis of DSD Variable HR95% CIp-value Histologic subtype (compared to well-differentiated LPS) Dedifferentiated, round cell & pleomorphic LPS, sarcoma NOS <0.001 Low grade leiomyosarcoma High grade leiomyosarcoma <0.001 Solitary fibrous tumor Malignant peripheral nerve sheath tumor <0.001 Translocation-associated sarcoma <0.001 Size 10-20cm vs <10cm ≥20cm vs <10cm Number of organs resected (≥3 vs <3) Completeness of resection (R2 vs R0/R1) <0.001 Histology & RP sarcoma

Local Recurrence (LR) by histologic type/subtype 5 years 10 years LR (n=574) 39%45% n=574* p< Histology & RP sarcoma *R0/R1 resections only (n=18) (n=29) (n=173) (n=197) (n=113)

Multivariate analysis of LR Factor HR95% CI P Histologic subtype (compared to well-differentiated LPS) Dedifferentiated, round cell & pleomorphic LPS, sarcoma NOS <0.001 Low grade leiomyosarcoma High grade leiomyosarcoma Solitary fibrous tumor Malignant peripheral nerve sheath tumor Translocation-associated sarcoma Completeness of resection (R1 vs R0) Size 10-20cm vs <10cm ≥20cm vs <10cm Age (>60 vs ≤60 years) 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

Distant Recurrence (DR) by histologic type/subtype 5 years 10 years DR (n=632) 24%28% n=632* p< Histology & RP sarcoma (n=21) (n=32) (n=184) (n=227) (n=119) *Resected patients only

Multivariate Analysis of DR Factor HR95% CI P Histologic subtype (compared to well-differentiated LPS) Dedifferentiated, round cell & pleomorphic LPS, sarcoma NOS <0.001 Low grade leiomyosarcoma High grade leiomyosarcoma <0.001 Solitary fibrous tumor <0.001 Malignant peripheral nerve sheath tumor Translocation-associated sarcoma <0.001 Number of Organs Resected 1 or 2 vs ≥3 vs Size 10-20cm vs <10cm ≥20cm vs <10cm 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 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

Natural History by Histologic Type/Subtype 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

Natural History by Histologic Type/Subtype 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

Natural History by Histologic Type/Subtype 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

Natural History by Histologic Type/Subtype 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

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 21 st, 2013 Funding: NIH SPORE in Soft Tissue Sarcoma P50 CA NIH Soft Tissue Sarcoma program project grant P01 CA The David and Monica Gorin Sarcoma Fund