Myxoid/RC Liposarcoma: Prognostic Factors And Survival CTOS 12th Annual Meeting Venice, 2-4 November 2006 Myxoid/RC Liposarcoma: Prognostic Factors And Survival Dear chairman, collegues, thank you for the opportunity to present here the series of myxoid liposarcoma from National Cancer Institute of Milan, Italy Marco Fiore marco.fiore@istitutotumori.mi.it

Soft Tissue Sarcoma INT 1980-2005 23% N° pz. operated 3026 Liposarcoma 685 MFH/Pleomorphic sarcoma 389 Leiomiosarcoma 372 DFSP 260 Aggressive Fibromatosis 240 Synovial Sarcoma 224 MPNST 222 Sarcoma NOS 143 Others 491 In a 25-year time spam more than 3 thousands soft tissue sarcoma have been treated in Milan, liposarcoma accounting for more than 20%

48% 685 Liposarcoma INT 1980-2005 WD Liposarcoma 233 Dediff Liposarcoma 123 Myxoid Liposarcoma 202 Round cell Liposarcoma 66 Pleomorphic Liposarcoma 61 48% Today we are going to review the 3 hundred twenty-nine patient with myxoid and round cell liposarcoma, together with pleomorphic liposarcoma, that is nearly half of the liposarcoma patients.

myxoid round cell pleomorphic FUS/TLS-CHOP t(12;16)(q13;p11) (95%) CHOP/DDIT3 round cell EWS EWS-CHOP t(12;22)(q13;q12) (5%) While myxoid and round cell lipo are recognized as the same histological entity along a spectrum of biological aggressiveness, which tipically harbor the FUS/CHOP translocation, pleomorphic liposarcoma have been considered as an high grade subgroup to compare clinical outcome, because they are somewhat considered more similar to myxoid lipo than, for example , dedifferentiated liposarcoma, from a cytogenetic point of view pleomorphic

329 Myxoid/RC Liposarcoma INT 1980-2005 1% 15 5% 39 12% 273 83% Head & Neck Trunk Retr./Intrapelvic Extremities Liposarcoma from all anatomic sites were considered, with more 80% of extremity tumors and 12% from retoperitoneal/intrabdominal site. Overall 75% of the patients had a lower limb location. 75%

329 Myxoid/RC Liposarcoma INT 1980-2005 Median Age 49 yrs Male : Female 1 : 1 Median Size 8.5 cm Deep Site 84% Grade (FNCLCC) I 54% II 23% III 22% Median tumor size were around 8 cm, with prevalently deep tumors. All pure myxoid liposarcoma were graded as grade I, while round cell and pleomorphic were distributed within the high grade II and III, according to French system.

Primary Recurrent Total 214 65% 115 35% MLPS 132 62% 70 61% RCLPS 44 21% 22 19% PLPS 38 18% 23 20% RT Not Done 130 71 Done 84 39% 38% CT 175 82% 93 81% 39 Two hundred and fourteen patient were primary tumors, while one hundred and fifteen patients presented as locally recurrent. The two groups were homogeneous as far as histological subgroup and adjuvant treatments were concerned.

Primary Recurrent Total 214 65% 115 35% Site** Extremities 190 89% 83 72% Intrabd/RP 16 7% 23 20% Surgical Procedure Limb Sparing 177 83% 75 Amputation 5 2% 6 5% NA (trunk, H&N, RP) 32 15% 34 30% Surgical Margins** Negative 186 87% Positive 28 13% 40 As expected, more retro-intrabdominal tumors were found in the recurrent group, and accordingly an higher proportion of positive surgical margins.

All patients underwent surgery with curative intent at our Institution.

Here you are soma examples of different anatomic presentation in the extremities.

Prognosis depends on… We analized prognostic factors affecting clinical outcome with a multivariate analysis, in order to describe natural history of this disease

the tumor First of all, some prognostic factors are inherent to the tumor

Multivariate Analysis - DSS Hazard Ratio 95% C. I. Presentation: Recurrence ( Primary ) 2.781** 1.659 4.661 Depth: Deep ( Superficial ) 1.632** 0.556 4.794 Size : >5 cm (  5 cm ) 2.161** 0.911 5.124 Site: Extremity ( Other ) 0.580** 0.317 1.062 Grade: II ( I ) 2.356** 1.107 5.013 Grade: III ( I ) 1.853** 0.701 4.899 Histology: PLPS (MLPS ) 0.908** 0.369 2.232 At multivariate analysis, local recurrence presentation,, tumor size bigger than 5 cm, anatomic site other than extremity, and high histological grade resulted as independent prognostic factors for disease-specific survival.

Size… STS high grade DFS <2,5 2,5-5 5-10 10-15 15-20 >20 cm This is in accordance with the well-established prognostic factors in soft tissue sarcoma, like tumor size, where prognostic impact has not a cut-off <2,5 2,5-5 5-10 10-15 15-20 >20 cm Suit HD. J Clin Oncol 1988; 6: 854

Site… As far as anatomic site, especially retro- intrabdominal tumors are nearly impossible to be treated with wide surgery. Moreover, in this particular site, local recurrence will be able to directly affect survival.

Grading… OS grade 1 grade 2 grade 3 Also tumor grade is a well-established prognostic factor for soft tissue sarcoma

Round cell component… RC >5% In the case of myxoid liposarcoma, tumor grading is directly dependent on the percentage of round cell component. Tumor with more than 5% of round cells are considered as high grade. Antonescu CR, Clin Cancer Res 2001;7:3977

In the nomogram an even higher risk is documented when round cells are higher than 25%

214 Primary Myxoid/RC LPS - DSS INT 1980-2005 5-yrs 10-yrs Overall 90% 87% MLPS 93% RCLPS 81% PLPS 82% So, when primary liposarcoma were analized 10-year disease-specific survival was quite good, with 90% of suvival for myxoid liposarcoma and 81% for round cell liposarcoma.

214 Primary Myxoid/RC LPS - LR INT 1980-2005 5-yrs 10-yrs Overall 13% 18% MLPS 12% RCLPS 10% 15% PLPS 19% The incidence of local recurrence at 10 years for primary tumors was 18% for myxoid liposarcoma and 15% for round cell liposarcoma.

214 Primary Myxoid/RC LPS - DM INT 1980-2005 5-yrs 10-yrs Overall 10% 11% MLPS 4% 5% RCLPS 23% PLPS 20% Crude cumulative incidence of distant metastases was quite low for myxoid liposarcoma, while it was more than 20% at ten years fro round cell liposarcoma, with significant difference between the histological subgroups. p=.0018

Pattern of Distant Mets 41% extra-pulmonary mets 26% lung mets 33% both A peculiar characteristic of myxoid liposarcoma is extrapulmonary metastases that were found in 74% of the metastatic patients. 74% of metastatic patients had at least one extra-pulmonary mets

Extra-pulmonary metastatic pattern according to histological subtype. MLPS RCLPS PLPS Overall Intrabdominal 6 4/2 5 3/2 - 11 7/4 Bone/Spine 2/4 3 2/1 9 4/5 Paraspinal 0/3 2/3 8 2/6 Extremities 4 2/2 1 1/0 5/3 Soft tissues 0/1 3/1 Thoracic wall 2 0/2 Retroperitoneum 1/2 1/3 Liver 2/0 Heart/Pericardium 1/1 Mediastinum Brain Regional nodes Abdominal wall 33 14/19 29 14/15 5/0 67 33/34 Multiple extra-pulmonary sites 4/4 5/1 14 9/5 * Number of localization at single sites (primary/recurrent cases) in 43 patients with extrapulmonary metastases. 49% 43% Main extra pulmonary metastatic sites were intrabdominal, spine and extremities. For myxoid liposarcoma metastases were extra-pulmonary in half of the cases, while in 43% of the round cell liposarcoma. In 33% of the cases more than one extra-pulmonary site was affected. 33%

Time to Event (mos) MLPS 5 – 96 8 – 72 RCLPS 8 – 66 6 – 54 PLPS 4 – 30 Local Relapse Distant Mets MLPS 5 – 96 36 8 – 72 15 RCLPS 8 – 66 12 6 – 54 20 PLPS 4 – 30 6 – 48 18 Time to local relapse for myxoid liposarcoma varied from 5 to 96 with a median time to the event for those who relapsed of 36 mos For round cell liposarcoma time to local relapse varied from 8 to 66 months with a median for those who relapsed of 12 mos Time to distant metastases in myxoid liposarcoma varied from 8 to 72 months, with a median time to distant metastases for those who relapsed of 15 months And for 6 to 54 months for round cell liposarcoma with a median time od 20 months.

Post-Event Median Survival (mos) Local Relapse Point Estimate 95% CI MLPS >266 143 - RCLPS 103 46 >158 PLPS >97 90 >277 Median survival after local recurrence was good in all histolgical subtypes

Post-Event Median Survival (mos) Lung Mets Extra-Lung Mets Point Estimate 95% CI MLPS 23 7 - 39 14 4 >52 RCLPS >12 . >19 5 PLPS 13 6 98 >42 Especially for myxoid liposarcoma the event of extra-pulmonary metastases was associated with 14 months of post-metastasis survival respect to 23 months after lung metastasis.

This is clear if one consider some special typical site of soft tissue metastasis, like pericardium that is one of the most typical site- and one of the higher risk for survival

the surgeon A part from the prognostic factors inherent to the tumor, also the surgical treatment can eventually affect outcome

Enzinger and Weiss’s SOFT TISSUE TUMORS - 2001 LR Intralesional 100% Marginal 60-80% Wide 10-30% Radical < 5% This is well-known for the rate of local recurrence in soft tissue sarcoma Enzinger and Weiss’s SOFT TISSUE TUMORS - 2001

Multivariate Analysis - DSS Hazard Ratio 95% C. I. P Margins status: +/- 2.161** 1.233 3.787 0.0071 But at multivariate analysis a significant impact also of wide margins was detected for disease-specific survival

Local recurrence has an independent effect on prognosis Surgical positive margins directly correlate with local recurrence, and we can see how in case of myxoid liposarcoma recurrent disease independently affect prognosis

115 Recurrent Myxoid/RC LPS - DSS INT 1980-2005 5-yrs 10-yrs Overall 72% 56% MLPS 79% 62% RCLPS 58% 43% PLPS 64% 53% In fact in the recurrent group disease-free survival at 10-yrs is significantly lower respect primary presentation in all histological subgroups. Myxoid liposarcoma have 62% of 10 years survival, respect 90% in primary disease and round cell liposarcoma have 43% of survival respect 81% in primary disease. This is true also for pleomorphic sarcoma.

115 Recurrent Myxoid/RC LPS - LR INT 1980-2005 5-yrs 10-yrs Overall 37% 39% MLPS 35% RCLPS 31% PLPS 48% 52% As far as local relapse in recurrent disease is concerned, Myxoid liposarcoma have 37% 10 years incidence respect to 18% in primary disease And round cell liposarcoma have 31% of local relapse respect to 15% in primary disease.

115 Recurrent Myxoid/RC LPS - DM INT 1980-2005 5-yrs 10-yrs Overall 22% 23% MLPS 19% RCLPS 44% PLPS 13% 17% Also distant metastases are significantly higher in recurrent group, especially in myxoid liposarcoma with 19% of distant metastases at 10 years, respect to 5% in primary disease For round cell liposarcoma distant metastases are 44% respect to 23% in primary disease.

… in conclusion In brief

Pattern of metastases can affect survival Prognosis of myxoid/round cell liposarcoma is relatively good, if compared with other STS Cut-off of 5% of RC component single out a group tumor with 81% 10-yrs DSS, which is actually in the range of intermediate grade STS As expected, phase at presentation, tumor size and grade, and surgical margins are independent prognostic factors for survival Pattern of metastases can affect survival Prognosis of myxoid/round cell liposarcoma is relatively good, if compared with other STS Cut-off of 5% of RC component single out a group tumor with 81% 10-yrs DSS, which is actually in the range of intermediate grade STS Better stratification of round cell liposarcoma according to the rate of RC could be more appropriate to define the risk of the single patient. As expected, phase at presentation, size and tumor grading are independent prognostic factors for survival Surgical margins are one more independent prognostic factor Patient who experienced extra-poulmonary metastaisis tend to have a shorter survival

… marco.fiore@istitutotumori.mi.it Thank you for your attention … marco.fiore@istitutotumori.mi.it