Factors predictive of myoinvasion in cases of Complex Atypical Hyperplasia diagnosed on endometrial biopsy or curettage Jessica Johns, MD Jeffrey Killeen, MD Robert Kim, MD Hyeong Jun Ahn, PhD
None Disclosures
Background Complex Atypical Hyperplasia is a precursor lesion for endometrial cancer Type I: Endometrioid Incidental endometrial carcinoma at the time of hysterectomy 28.1-43.5% Recommendation for Gynecologic Oncologist referral for potential lymphadenectomy/staging Trimble CL, Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Onocology Group study. Cancer 2006 Feb 15; 106 (4). Costales AB Clinically significant endometrial cancer risk following a diagnosis of complex atypical hyperplasia. Gynecol Oncol (2014).
Previous Studies In one retrospective study, estimated risk of lymph node spread was 1.6-2.1% for all women with a preoperative diagnosis of CAH Risk of nodal invasion without myoinvasion in endometrioid cancers <1% Additional pathology comments indicating suspicion of cancer resulted with higher cancer rate at hysterectomy, 69% vs 40% Lee KB1, Ki KD, Lee JM, Lee JK, Kim JW, Cho CH, Kim SM, Park SY, Jeong DH, Kim KT. The risk of lymph node metastasis based on myometrial invasion and tumor grade in endometrioid uterine cancers: a multicenter, retrospective Korean study. Ann Surg Oncol (2009). Elizabeth Suh-Burgmann, M.D., Yun-Yi Hung, Ph.D., and Mary Anne Armstrong, M.A. The value of additional pathology comments indicating suspicion of adenocarcinoma among women diagnosed preoperatively with complex atypical endometrial hyperplasia. Int J Gynecol Pathol (2012)
To stage or not to stage Selective lymph node biopsy vs. complete lymphadenectomy vs. no sampling Risk base vs. universal Little consensus regarding the appropriate indications and extent of lymphadenectomy In Mayo clinic study of >300 patients with low risk (G1 or G2) endometrioid cancer, no cases of nodal metastasis, recurrence or death Dowdy SC, Borah BJ, Bakkum-Gamex JN, Weaver AL, McGree ME, Hass LR. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol 2012; 127:5-10
Lymphadenectomy Lymphedema 5-38% Addition of nodal surgery carries at least some increased risk over cases in which nodal surgery is not added GOG study, 20% complications including 3 deaths Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55 65
Objective To evaluate endometrial biopsy samples with the diagnosis of Complex Atypical Hyperplasia to determine if findings on these samples could help predict uterine cancer with myometrial invasion Primary outcome: myometrial invasion
Methods and Materials Retrospective case control study IRB waiver of authorization Women with CAH diagnosis on previous EMB or D&C who later underwent hysterectomy January 2007-December 2015 Charts reviewed consecutively Analysis of biopsy and final pathology samples Chart review for age, gravity/parity, height, weight, BMI, ethnicity, race, insurance type, date of biopsy, date of hysterectomy
Inclusion Criteria Biopsy or dilation and curettage with diagnosis Complex Atypical Hyperplasia Subsequent hysterectomy within 3 months of CAH diagnosis
Sample Size Utilizing two-sided Fisher s Exact Test Significance level of the test targeted to 0.05 Calculated to detect 25% difference with each independent variable Sample size to be 85 in each group (myoinvasion present or absent) Achieves 90% power to detect difference
Variables Dependent variable: Myoinvasion
Variables Independent variables Necrosis Marked atypia Co-existing non-atypia Immunostain Pax-2 Architectural findings Progesterone Receptors-Glandular Progesterone Receptors-Stromal
Statistical Analysis Chi-square or Fisher s exact tests for categorical variables Two sample t test or Wilcoxon rank sum test for continuous variables Multivariable logistic regressions were performed to control for confounders
Results Biopsy + Hysterectomy Excluded: Hysterectomy >3 months & repeat sampling Inclusion criteria No myoinvasion Myoinvasion present
Patient characteristics Myoinvasion=No n=110 (%) Mean (SD) Myoinvasion=Yes n=27 (%) Mean (SD) P value Age Height (m) Weight (Kg) BMI Gravida Parity 52.02 (10.65) 59.15 (11.50) 0.003 1.61 (0.08) 1.60 (0.06) 0.61 92.72 (29.22) 85.29 (26.04) 0.23 35.61 (10.00) 33.07 (9.27) 0.24 2.28 (2.23) 2.56 (2.55) 0.58 1.75 (1.86) 1.96 (1.79) 0.59
Patient characteristics Myoinvasion=No n=110 (%) Mean (SD) Myoinvasion=Yes n=27 (%) Mean (SD) P value Age Height (m) Weight (Kg) BMI Gravida Parity 52.02 (10.65) 59.15 (11.50) 0.003 1.61 (0.08) 1.60 (0.06) 0.61 92.72 (29.22) 85.29 (26.04) 0.23 35.61 (10.00) 33.07 (9.27) 0.24 2.28 (2.23) 2.56 (2.55) 0.58 1.75 (1.86) 1.96 (1.79) 0.59
Patient characteristics Myoinvasion=No n=110 (%) Mean (SD) Myoinvasion=Yes n=27 (%) Mean (SD) P value Age 52.02 (10.65) 59.15 (11.50) 0.003 Height (m) 1.61 (0.08) 1.60 (0.06) 0.61 Weight (Kg) 92.72 (29.22) 85.29 (26.04) 0.23 BMI 35.61 (10.00) 33.07 (9.27) 0.24 Gravida 2.28 (2.23) 2.56 (2.55) 0.58 Parity 1.75 (1.86) 1.96 (1.79) 0.59
Patient characteristics Race Asian Native Hawaiian White Other race Unknown Insurance Medicaid Medicare Private Others Myoinvasion=No n=110 (%) 44 (40.00) 38 (34.55) 18 (16.36) 6 (5.45) 4 (3.64) 15 (13.64) 16 (14.55) 73 (66.36) 6 (5.45) Myoinvasion=Yes n=27 (%) 5 (18.52) 12 (44.44) 5 (18.52) 4 (14.81) 1 (3.70) 4 (14.81) 6 (22.22) 14 (51.85) 3 (11.11) P value 0.19 0.46
Patient characteristics Race Asian Native Hawaiian White Other race Unknown Myoinvasion=No n=110 (%) 44 (40.00) 38 (34.55) 18 (16.36) 6 (5.45) 4 (3.64) Myoinvasion=Yes n=27 (%) 5 (18.52) 12 (44.44) 5 (18.52) 4 (14.81) 1 (3.70) P value 0.19 Insurance Medicaid Medicare Private Others 15 (13.64) 16 (14.55) 73 (66.36) 6 (5.45) 4 (14.81) 6 (22.22) 14 (51.85) 3 (11.11) 0.46
Histologic findings on biopsy Necrosis No Yes Marked atypia No Yes Percentage of non-atypia <25% 25% Pax2 No Yes Myoinvasion=No n=110 (%) 104 (94.55) 6 (5.45) 97 (88.18) 13 (11.82) 40 (36.36) 70 (63.64) 25 (22.73) 85 (77.27) Myoinvasion=Yes n=27 (%) 25 (92.59) 2 (7.41) 26 (96.30) 1 (3.70) 23 (85.20) 4 (14.80) 5 (18.52) 22 (81.48) P value 0.66 0.31 <.0001 0.64
Co-existing Non-atypia
Histologic findings on biopsy Architectural findings High Risk Non High Risk Glandular 0-<10% 10-50% >50% Stromal 0-<10% 10-50% >50% Myoinvasion=No n=110 (%) 31 (28.18) 79 (71.82) 3 (2.75) 7 (6.42) 99 (90.83) 30 (27.52) 39 (35.78) 40 (36.70) Myoinvasion=Yes n=27 (%) 17 (62.96) 10 (37.04) 1 (3.70) 2 (7.41) 24 (88.89) 13 (48.15) 10 (37.04) 4 (14.81) P value 0.0007 0.95 0.047
Architectural Findings Intermediate vs. High Risk Intermediate Risk High Risk
Histologic findings on biopsy Architectural findings None Intermediate High Risk Glandular 0-<10% 10-50% >50% Stromal 0-<10% 10-50% >50% Myoinvasion=No n=110 (%) 34 (30.91) 45 (40.91) 31 (28.18) 3 (2.75) 7 (6.42) 99 (90.83) 30 (27.52) 39 (35.78) 40 (36.70) Myoinvasion=Yes n=27 (%) 2 (7.41) 8 (29.63) 17 (62.96) 1 (3.70) 2 (7.41) 24 (88.89) 13 (48.15) 10 (37.04) 4 (14.81) P value 0.002 0.95 0.047
OR and CI Percentage of non-atypia (<25% vs. 25%+) Unadjusted OR [95% CI]= 13.68 [4.22, 44.32] Age adjusted OR [95% CI]= 10.93 [3.21, 37.23] Architectural findings (High risk vs. non high risk) Unadjusted OR [95% CI]=4.48[1.84, 10.87] Age adjusted OR [95% CI]=3.85 [1.55, 9.59]
Conclusions Evaluating endometrial biopsies with Complex Atypical Hyperplasia for co-existing non-atypia and high risk architectural features could help predict endometrial cancer with myometrial invasion In our study, a simple hysterectomy would be considered optimal treatment for 80.3% (110/137) of our patients Larger studies needed to confirm these findings to provide evidence based recommendations for endometrial biopsy evaluation
Strengths and Limitations Exclusion time frame, conservative limitation to 3 months Small sample size Hawaii population Retrospective & chart review Biopsy evaluation by one gynecologic pathologist Reproducibility
Thank you Jeffrey Killeen Hyeong Jun Ahn Michael Carney Reni Soon Jennifer Elia Robert Kim Andrea Siu University of Hawaii Department of Obstetrics, Gynecology and Women s Health
Future directions Incorporate new ACOG guidelines dividing our cases into EIN Create a scoring system for biopsy samples and test system prospectively Evaluate the costs associated with simple hysterectomy vs patients requiring more invasive surgery Impact of sentinel lymph node biopsy