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?

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 Pathology, 3rd edition.

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%

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 , P<  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 Gynecologic Oncology. 2. Cohn et al Gynecologic Oncology.

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

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.

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

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]

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

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

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

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 (16%)73 (30%) 210 (27%)90 (36%) 321 (57%)82 (34%) Lesion size1.00 < 2cm1 (3%)13 (8%) > 2 cm21 (95%)142 (92%) Myom. invasion None1 (3%)52 (22%) < 1/29 (25%)92 (39%) > 1/226 (72%)92 (39%)

ASSOCIATIONS WITH RECURRENCE-FREE SURVIVAL CovariateHR95% CIp-value Age , LVSI , White , Parity > , Stage III , 11.99< Grade , Type II ,

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) (1.00, 1.06)0.050 LVSI1.90 (1.01, 3.58)0.045 White0.38 (0.21, 0.69) (0.21, 0.71) Stage = 2 (vs. 1)1.44 (0.60, 3.44) (0.61, 3.50)0.39 Stage = 3 (vs. 1)5.86 (2.76, 12.47)< (3.40, 14.43)< Type II (vs. I)1.49 (0.79, 2.79) (0.85, 2.97)0.15 Model C-index

ASSOCIATIONS WITH OVERALL SURVIVAL CovariateHR95% CIp-value Age , 1.12< LVSI , White , Parity> , Stage III , Grade , Type II ,

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) (1.03, 1.11) LVSI1.88 (0.85, 4.17) White0.33 (0.16, 0.69) (0.16, 0.70) Stage = 2 (vs. 1)1.71 (0.64, 4.59) (0.64, 4.70)0.28 Stage = 3 (vs. 1)3.50 (1.26, 9.69) (1.75, 11.89) Type II (vs. I)1.67 (0.75, 3.74) (0.76, 3.89)0.20 Model C-index

CovariateHR95% CIp-value Log(lesion size) , LVSI , White , Stage III , 17.67< Grade , Adjuvant therapy , Type II , COMPETING RISKS ANALYSIS

Solid line- LVSI; Dashed line- no LVSI

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

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 RR and UL1 TR