1. SHELBY ADDISON NEAL, MD MENTORS: WILLIAM T. CREASMAN, MD WHITNEY S. GRAYBILL, MD, MS Lymph-Vascular Space Invasion (LVSI) in Uterine Corpus Cancer What is its Prognostic Significance in the Absence of Lymph Node Metastases?

2. BACKGROUND Uterine corpus cancer is the most common gynecologic malignancy Surgery is curative in ~80% of cases Adjuvant therapy is appropriate for some patients Rubin and Farber. 1999. Pathology, 3rd edition.

3. BACKGROUND Type I (65%)Type II (35%) Estrogen stateExogenous estrogen No association HabitusObeseNon-obese Background endometrium HyperplasticAtrophic HistologyEndometrioidClear cell, serous, anaplastic, MMT Tumor grade1-23 Myometrial invasion 69% superficial66% deep Lymph node mets9%28% Progesterone sensitivity 80%42% 5 year survival86%59%

4. BACKGROUND Lymph node mets are associated with decreased survival Lymph-vascular space invasion (LVSI) is an independent risk factor for lymph node metastases 1  OR 6.34, CI 3.45-11.66, P<0.0001  PPV 33.6% The presence of LVSI in patients with unstaged endometrial cancer may indicate the need for lymphadenectomy or adjuvant therapy 2 Little data is available regarding LVSI as a prognostic factor in the absence of lymph node metastases 1. Guntupalli et al. 2012. Gynecologic Oncology. 2. Cohn et al. 2002. Gynecologic Oncology.

5. OBJECTIVE To determine if there is a difference in recurrence- free survival (RFS) or overall survival (OS) between subjects who have LVSI and subjects who do not have LVSI in the setting of negative lymph nodes

6. HYPOTHESIS In the setting of negative lymph nodes, there is no survival difference between subjects who have LVSI and subjects who do not have LVSI.

7. STUDY DESIGN Retrospective chart review of women treated for uterine corpus cancer at MUSC from 1987 to 2012 Data obtained from charts included the following:  Demographic data  Health history  Surgical pathology  Post-operative clinical course

8. SELECTION OF SUBJECTS Total number of subjects in database n=884 Negative nodes n=359 + LVSI n=37 - LVSI n=245 LVSI unknown n=58 [EXCLUDED] Stage IV disease n=19 [EXCLUDED] Positive nodes n=68 [EXCLUDED] Incompletely staged n=457 [EXCLUDED]

9. Simple regression analysis for the following covariates with recurrence-free and overall survival: Multiple regression analysis incorporating significant covariates METHODS Age Race BMI Parity Co-morbidities Histology Stage Grade Lesion size Depth of invasion Number of nodes Adjuvant therapy

10. Model C-index  Measures concordance between predicted and actual survival for each subject  Higher C-index = more accurate model  C-index calculated for 2 different models: Main model Model excluding LVSI Competing risks analysis  Distinguishes between disease-related outcomes and death due to other causes  Outcome of interest = time to recurrence  Competing risk = death due to other causes METHODS

11. DEMOGRAPHIC CHARACTERISTICS Variable LVSI positive (N=37) LVSI negative (N=245) P-value Age65 (51-84)61 (29-93)0.02 BMI32.0 (20.5-44.5)33.0 (16.9-59.4)0.73 Race0.17 White 23 (62%)181 (74%) Non-white14 (38%)66 (27%) Parity 0.66 05 (14%)45 (18%) 1-321 (57%) 142 (58%) >310 (27%)52 (21%) Comorbidities Diabetes10 (27%)52 (21%) 0.40 Hypertension25 (68%)156 (64%)0.72

12. HISTOPATHOLOGICAL CHARACTERISTICS Variable LVSI positive (N=37) LVSI negative (N=245) p-value Histology 0.03 Type I16 (43%)155 (62%) Type II21 (57%)93 (38%) Stage <0.001 I23 (62%)211 (86%) II7 (19%)23 (9%) III7 (19%)11 (5%) Grade 0.026 16 (16%)73 (30%) 210 (27%)90 (36%) 321 (57%)82 (34%) Lesion size1.00 < 2cm1 (3%)13 (8%) > 2 cm21 (95%)142 (92%) Myom. invasion0.0003 None1 (3%)52 (22%) < 1/29 (25%)92 (39%) > 1/226 (72%)92 (39%)

13. ASSOCIATIONS WITH RECURRENCE-FREE SURVIVAL CovariateHR95% CIp-value Age1.051.02, 1.080.002 LVSI2.781.52, 5.090.0009 White0.340.20, 0.580.0001 Parity >32.511.07, 5.920.035 Stage III6.063.06, 11.99<0.0001 Grade 32.891.19, 7.040.019 Type II2.101.20, 3.660.0089

14. MULTIPLE REGRESSION MODEL: RECURRENCE-FREE SURVIVAL Model 1: All covariatesModel 2: Without LVSI HR (95% CI)p-valueHR (95% CI)p-value Age1.03 (1.00, 1.06)0.0711.03 (1.00, 1.06)0.050 LVSI1.90 (1.01, 3.58)0.045 White0.38 (0.21, 0.69)0.00150.39 (0.21, 0.71)0.0021 Stage = 2 (vs. 1)1.44 (0.60, 3.44)0.421.46 (0.61, 3.50)0.39 Stage = 3 (vs. 1)5.86 (2.76, 12.47)<0.00017.01 (3.40, 14.43)<0.0001 Type II (vs. I)1.49 (0.79, 2.79)0.221.59 (0.85, 2.97)0.15 Model C-index0.7610.753

15. ASSOCIATIONS WITH OVERALL SURVIVAL CovariateHR95% CIp-value Age1.081.04, 1.12<0.0001 LVSI2.761.30, 5.840.008 White0.270.14, 0.540.0002 Parity>35.271.55, 17.90.008 Stage III4.091.65, 10.110.0023 Grade33.950.17, 13.360.027 Type II2.791.35, 5.760.0056

16. MULTIPLE REGRESSION MODEL: OVERALL SURVIVAL Model 1: All covariatesModel 2: Without LVSI HR (95% CI)p-valueHR (95% CI)p-value Age1.07 (1.03, 1.12)0.000611.07 (1.03, 1.11)0.00087 LVSI1.88 (0.85, 4.17)0.12-- White0.33 (0.16, 0.69)0.00310.33 (0.16, 0.70)0.0038 Stage = 2 (vs. 1)1.71 (0.64, 4.59)0.291.74 (0.64, 4.70)0.28 Stage = 3 (vs. 1)3.50 (1.26, 9.69)0.0164.56 (1.75, 11.89)0.0019 Type II (vs. I)1.67 (0.75, 3.74)0.211.72 (0.76, 3.89)0.20 Model C-index0.7880.791

17. CovariateHR95% CIp-value Log(lesion size)2.111.36, 3.280.00089 LVSI2.461.21, 5.020.013 White0.390.21, 0.710.0023 Stage III8.253.86, 17.67<0.0001 Grade32.531.03, 6.220.043 Adjuvant therapy1.911.04, 3.510.037 Type II2.611.39, 4.870.0027 COMPETING RISKS ANALYSIS

18. Solid line- LVSI; Dashed line- no LVSI

19. CONCLUSIONS There is no survival difference between uterine cancer subjects with negative nodes who have LVSI and those who do not Adjuvant therapy for patients with LVSI and negative nodes should not be administered unless otherwise indicated by stage, grade or histology

20. ACKNOWLEDGEMENTS William Creasman, MD Whitney Graybill, MD, MS Elizabeth Garrett-Mayer, PhD Gweneth Lazenby, MD Jennifer Pierce, MD, MPH Misty McDowell, MD Catie Haar Virginia McLean Lee Bullard Anquinette Gadson This project was supported by the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, through NIH Grant Numbers UL1 RR029882 and UL1 TR000062.