1. Pathologic Features of Prognostic Significance in Primary Retroperitoneal Liposarcoma Amanda J. Cannell 1, Sally M. Burtenshaw 1, Martin E. Blackstein 2, Peter Chung 3, Charles N. Catton 3, Rebecca A. Gladdy 1, Carol J. Swallow 1, Brendan C. Dickson 4 Departments of Surgery 1, Medical Oncology 2, Radiation Oncology 3, and Pathology and Laboratory Medicine 4, Mount Sinai Hospital and Princess Margaret Cancer Centre, University of Toronto; Toronto, ON Canada

2. INTRODUCTION Retroperitoneal liposarcoma Conventional histotypes are well-differentiated (WD) and dedifferentiated (DD) liposarcoma – MDM2 amplification and protein over-expression Myxoid / round cell liposarcoma Pleomorphic liposarcoma Spindle cell (fibrosarcoma-like)

3. RATIONALE Predicting behaviour of primary retroperitoneal liposarcoma (RP LPS) is challenging Conventional indicators not applicable (e.g., TNM) Local recurrence is predominant clinical challenge Lack of consensus on prognostic indicators – Clinical and surgical attributes inconsistent – Pathologic FNCLCC grade Low-grade (LG-) versus high-grade (HG-) dedifferentiation

4. RATIONALE Background - FNCLCC grading system MITOTIC COUNT NECROSIS DIFFERENTIATION

5. Well-differentiated – Lipoma-like – Sclerosing – Inflammatory RATIONALE Background - Differentiation Dedifferentiated – Low-grade (LG-DD) Well-differentiated High-grade – High-grade (HG-DD) Dedifferentiated DIFFERENTIATION Low-grade

6. OBJECTIVE Review of institutional experience with RP LPS to assess variables of potential prognostic significance Pathologic – Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system Tumour differentiation, mitotic index, necrosis – Histotype Well-differentiated vs Dedifferentiated – Extent of dedifferentiation Low-grade vs high-grade MITOTIC COUNT NECROSIS DedifferentiatedWell-differentiated DIFFERENTIATION Low-grade High-grade

7. OBJECTIVE Review of institutional experience with RP LPS to assess variables of potential prognostic significance Pathologic – Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system Tumour differentiation, mitotic index, necrosis – Histotype Well-differentiated vs Dedifferentiated – Extent of dedifferentiation Low-grade vs high-grade MITOTIC COUNT NECROSIS DedifferentiatedWell-differentiated DIFFERENTIATION Low-grade High-grade

8. OBJECTIVE Review of institutional experience with RP LPS to assess variables of potential prognostic significance Pathologic – Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system Tumour differentiation, mitotic index, necrosis – Histotype Well-differentiated vs Dedifferentiated – Extent of dedifferentiation Low-grade vs high-grade MITOTIC COUNT NECROSIS DedifferentiatedWell-differentiated DIFFERENTIATION Low-grade High-grade

9. OBJECTIVE Review of institutional experience with RP LPS to assess variables of potential prognostic significance Pathologic – Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system Tumour differentiation, mitotic index, necrosis – Histotype Well-differentiated vs Dedifferentiated – Extent of dedifferentiation Low-grade vs high-grade MITOTIC COUNT NECROSIS Well-differentiatedDedifferentiated DIFFERENTIATION Low-grade High-grade

10. METHODS Cases identified from prospective database Jan 1996 to Dec 2013 Pathology review of all RP sarcomas (pre- treatment biopsy and resections) – College of American Pathologists: synoptic criteria, incl: FNCLCC Grading Extent of dedifferentiation, based on WHO criteria Statistical analysis by SPSS Chi-squared and Kaplan Meier curves (log-rank)

11. STUDY POPULATION Inclusion Criteria – Primary RP LPS treated with curative intent – Unequivocal diagnosis, based on: Histomorphology – IHC for MDM2 – FISH for MDM2 Exclusion – Other diagnosis (e.g., lipoma, leiomyosarcoma)

12. STUDY COHORT 143 Leiomyosarcoma (23) or other diagnosis (11) Pathology slides/clinical info unavailable (3) 104 Planned R2 excision (2)

13. RESULTS Clinical Summary Entire Cohort (n=104) WD LPS (n=30) DD LPS (n=74) p-value Age, Median (Range) 61 (33 - 82) 60 (33 – 81) 62 (35 – 82) 0.78 Gender, N (%) Male Female 61 (58) 43 (42) 15 (50) 46 (62) 28 (38) 0.20 Tumour Size (cm), Median (range)25.8 (6.0 – 61.0) 25.2 (6.0 – 52.0) 26.5 (6.3 – 61.0) 0.61 Neoadjuvant Treatment, N (%) Surgery Alone RT + Surgery C ±RT + Surgery 15 (14) 84 (82) 4 (4) 7 (21) 23 (79) 0 9 (12) 61 (82) 4 (5) 0.45

14. RESULTS Pathologic Features Entire Cohort (n=104) WD LPS (n=30) DD LPS (n=74) p-value Tumour Size (cm), N (%) <5 5 to 10 >10 0 5 (5) 99 (95) 0 1(3) 29(97) 0 4 (5) 70 (95) 0.67 Mitotic Rate, N (%) (per 1.734 mm 3 ) 0-9 10-19 >20 99 (98) 2 (2) 3 (3) 30(100) 0 69 (93) 2 (3) 3 (4) 0.36 Necrosis, N (%) <50% ≥50% 86 (83) 18 (17) 27 (90) 3 (10) 59 (79) 15 (21)0.23 Margin Status, N (%) R0 R1 22 (21) 82 (79) 4 (14) 26 (86) 18 (24) 56 (76) 0.24

15. RESULTS Pathologic Features (cont) Entire Cohort (n=104) WD LPS (n=30) DD LPS (n=74) p-value Tumour Grade, N (%) FNCLCC I II III 31 (29) 68 (66) 5 (5) 30 (100) 0 1 (1) 68 (92) 5 (7) P<0.01 Dedifferentiation, N (%) Low-grade High-grade N/A 56 (76) 18 (24) N/A

16. RESULTS Survival analysis Local RecurrenceDisease Specific Survival Median Follow Up Time: 50 Months (5 – 218) 5 yr: 26%5 yr: 84% % Survival % Recurrence Follow Up Time (Months) Follow Up Time (Months) n=104

17. RESULTS Histotype (WD vs DD) p=0.01 Local RecurrenceDisease Specific Survival p<0.01 % Survival % Recurrence Follow Up Time (Months) Follow Up Time (Months) n=74 n=30 n=74

18. RESULTS FNCLCC Grade (1, 2, 3) p=0.03p=0.01 Local RecurrenceDisease Specific Survival % Survival % Recurrence Follow Up Time (Months) Follow Up Time (Months) n=31 n=68 n=31 n=68 n=5

19. RESULTS Extent of Differentiation (LG vs HG) p=0.24p=0.91 Local RecurrenceDisease Specific Survival % Survival % Recurrence Follow Up Time (Months) Follow Up Time (Months) n=18 n=56 n=18 n=56

20. DISCUSSION Weaknesses – Small series – Retrospective review Strengths – Pathology review using modern criteria and diagnostic techniques – Single institution

21. CONCLUSIONS Histotype (WD vs DD) is a dominant prognostic indicator MITOTIC COUNT NECROSIS DedifferentiatedWell-differentiated DIFFERENTIATION Low-grade High-grade

22. CONCLUSIONS Histotype (WD vs DD) is a dominant prognostic indicator FNCLCC grade is prognostic – Grade I vs Grade II/III MITOTIC COUNT NECROSIS DedifferentiatedWell-differentiated DIFFERENTIATION Low-grade High-grade

23. CONCLUSIONS Histotype (WD vs DD) is a dominant prognostic indicator FNCLCC grade is prognostic – Grade I vs Grade II/III DedifferentiatedWell-differentiated Low-grade High-grade LG-DD vs HG-DD no prognostic value – Confusing terminology of limited value for RP LPS MITOTIC COUNT NECROSIS Low-grade High-grade DIFFERENTIATION

24. Thank you CTOS 2014 Berlin

25. Sr. Authour (Year) InstitutionPrimary LPS RPS, N Positive Prognosis Lee (2014)Samsung Medical Ctr101CDK4 Amplification Keung (2014) Harvard U119Margins (R0/R1, no rupture), FNCLCC Grade 1 Hoch (2014)U Washington34FNCLCC Grade 1 or 2 Gronchi (2008) IRCCS Istituto Natzionale dei Tumori 93FNCLCC Grade 1, <10/10 Mitoses, <50% necrosis Pollock (2008) UTMDACC89WD LPS Singer (2006) MSKCC268WD LPS, Margin (R0) Brennan (2003) MSKCC144Young age, FNCLCC Grade 1, Margin (R0/R1), WD LPS Weiss (1997) U Michigan88LG-DD (in RP lesions)

26. Distant Disease Total NoYes Well-Differentiated 300 Dedifferentiated 69574 Total 995104 Local Recurrence Total NoYes Well-Differentiated 28230 Dedifferentiated 482674 Total 7628104 p < 0.01 p = 0.14 PATTERNS OF RECURRENCE