1. IMPACT OF TUMOR MORCELLATION ON THE NATURAL HISTORY OF UTERINE LEIOMYOSARCOMA César Serrano, Titilope Oduyebo, Judith Manola, Yang Feng, Michael G. Muto, Suzanne George Dana-Farber Cancer Institute, Brigham and Women’s Hospital; Harvard Medical School, Boston, USA Paper 011 CTOS 18 th Annual Meeting Oct 30 - Nov 2, 2013 New York

2. Uterine leiomyosarcoma (ULMS) accounts for about 1.5% of all uterine malignancies and 30% of uterine sarcomas. Complete surgical excision is the only established curative treatment modality for localized disease. Minimally invasive techniques are increasingly used in the surgical treatment of uterine leiomyoma. No specific symptoms/signs or diagnostic imaging can reliably differentiate ULMS from leiomyoma preoperatively. Because of this, inadvertent morcellation of ULMS is increasingly seen in clinical practice. Background

3. Lungs are the most common site of recurrence. Background (con’t) Pautier P, et al. 2000 Historically, ~50% of localized ULMS recurs following resection. Major FJ, et al. 1993 Kapp DS, et al. 2008

4. Tumor morcellation involves fragmenting of lesions in the abdominal cavity such that they can pass through the laparoscopic ports. Tumor morcellation has been associated with dispersal of microscopic tumor fragments, which entails potential seeding in the peritoneum. One retrospective study observed that tumor morcellation is an adverse prognosis factor associated with shorter disease-free survival and overall survival. Uterine morcellation Seidman MA et al. 2012 Park JY et al. 2011

5. To retrospectively assess the impact of tumor morcellation on the natural history and outcomes of patients with ULMS when compared to patients who underwent total abdominal hysterectomy (TAH) as the primary procedure. Aims of the study

6. Patients with ULMS seen at Dana-Farber Cancer Institute and Brigham and Woman’s Hospital from 2007-2012 were reviewed. Patients with surgically resectable disease confined to the uterus at presentation and adequate follow-up were included. Morcellation cohort included only those cases with intra-peritoneal morcellation  Cases which underwent morcellation in a bag intra- operatively were excluded TAH cohort included cases who underwent complete hysterectomy without tumor disruption. Methods

7. Patients characteristics (n=68) Total (n=68) Total Abdominal Hysterectomy (n=52) Morcellation (n=16) p-value Age (mean)53.555.347.80.0187 Size - image9.910.19.50.9848 Mitosis (10hpf)25.727.221.70.2131 Grade [n(%)] 14 (6.5)4 (8.3)0 (0.0) 211 (17.7)10 (20.8)1 (7.1)0.295 347 (75.8)34 (70.8)13 (92.9) FIGO Stage I37 (77.1) N.A. II3 (6.3) N.A. III8 (16.7) N.A.

8. Patients characteristics (n=68) Total (n=68) Total Abdominal Hysterectomy (n=52) Morcellation (n=16) p-value Age (mean)53.555.347.80.0187 Size - image9.910.19.50.9848 Mitosis (10hpf)25.727.221.70.2131 Grade [n(%)] 14 (6.5)4 (8.3)0 (0.0) 211 (17.7)10 (20.8)1 (7.1)0.295 347 (75.8)34 (70.8)13 (92.9) FIGO Stage I37 (77.1) N.A. II3 (6.3) N.A. III8 (16.7) N.A.

9. Patients characteristics (con’t) Total (n=68) Total Abdominal Hysterectomy (n=52) Morcellation (n=16) p-value Oophorectomy [n(%)] no28 (41.2)13 (25.0)15 (93.8) <0.001 yes40 (58.8)38 (75.0)1 (6.3) Adjuvant therapy [n (%)] none41 (60.3)29 (55.8)12 (75.0) chemotherapy19 (27.9)16 (30.8)3 (18.8)0.703 radiotherapy6 (8.8)5 (9.6)1 (6.3)

10. Morcellation is associated with a significantly increased rate of LMS recurrence Morcellation (n=16) TAH (n=52) Total (n=68) p-value Failure102636 Time (months)216.1151240.5751456.69 Incidence Rate (person months) 0.0460.0210.0250.023 When adjusting for differences in follow-up between the two cohorts, the incidence rate of recurrence among pts who underwent morcellation is more than two times the rate of those who had tumor removed by TAH.

11. Tumor morcellation led to a decrease in Recurrence Free Survival (RFS)

12. Higher incidence of peritoneal recurrence after tumor morcellation Site of first recurrence Total (n=68) Total Abdominal Hysterectomy (n=52) Morcellation (n=16) p-value Abdomen/pelvis 16 (44.4)6 (23.1)10 (100.0) <0.001 Other 16 (44.4)16 (61.5)0 (0.0) Both 4 (11.1)4 (15.4)0 (0.0)

13. UNIVARIATEMULTIVARIATE HRp-valueHRp-value TAH11 Morcellation2.1750.0392.7570.033 Size (image) 1.1270.005 Mitosis 1.0210.011 Tumor morcellation is an independent risk factor for recurrence We investigated the relationship between each covariant and RFS. Only morcellation, size and mitosis were found significant in the statistical model.

14. Conclusions Uterine morcellation of presumed leiomyomas inadvertently result in an increase in morcellated ULMS. Morcellation alters the natural course of ULMS leading to an increased incidence and earlier recurrences. Recurrences following tumor morcellation are significantly more likely to occur in the peritoneum. Additional studies are needed to identify patients at high risk for ULMS prior to presumed leiomyoma resection in order to reduce the risk of inadvertent tumor morcellation.

15. Brigham and Women’s Hospital Pathology Department Christopher P. Crum Marisa R. Nucci Division of Obstetrics and Gynecology Michael M. Muto Titilope Oduyebo Co-authors / Acknowledgments Dana-Farber Cancer Institute Center for Sarcoma and Bone Oncology George D. Demetri James E. Butrynski David R. D’Adamo Suzanne George Jeffrey A. Morgan Andrew J. Wagner Department of Biostatistics and Computational Biology Constance Barysauskas Yang Feng Judith Manola ASCO Young Investigator Award Spanish Society of Medical Oncology Translational Award Driscoll Family Leiomyosarcoma Fund