Hyperplasia & Cancer Risk Hyperplasia & Cancer Risk Jim Lacey, Ph.D. City of Hope Duarte, CA NCI-Designated Comprehensive Cancer Center
When EH is Diagnosed … When EH is Diagnosed … • What is the risk of concurrent cancer? • What is the risk of future cancer?
E d Endometrial Hyperplasia t i l H l i Normal Proliferative Carcinoma Carcinoma Endometrium Lesion Precursor Endometrial Hyperplasia (EH)
WHO Histologic Distinctions for WHO Histologic Distinctions for Endometrial Hyperplasia (EH) Normal Proliferative Carcinoma Carcinoma Endometrium Lesion Precursor Benign / Atypical Well- Simple Complex Anovulatory / Hyperplasia Differentiated Hyperplasia Hyperplasia Proliferative Carcinoma Endometrium Primarily complex atypical hyperplasia hyperplasia (CAH)
Concurrent Cancer at EH Diagnosis Normal Proliferative Carcinoma Carcinoma Endometrium Lesion Precursor Benign / Well- Simple Complex Atypical Anovulatory / Differentiated Hyperplasia Hyperplasia Hyperplasia Proliferative Carcinoma Endometrium Sampling: Bi Biopsy /curettage only samples a / tt l l portion of the endometrium
Concurrent Cancer at EH Diagnosis Normal Proliferative Carcinoma Carcinoma Endometrium Lesion Precursor Benign / Well- Simple Complex Atypical Anovulatory / Differentiated Hyperplasia Hyperplasia Hyperplasia Proliferative Carcinoma Endometrium Diagnosis / Classification: Under-diagnose carcinoma as EH
H How Often? Oft ? Normal Proliferative Carcinoma Carcinoma Endometrium Lesion Precursor Benign / Well- Simple Complex Atypical Anovulatory / Differentiated Hyperplasia Hyperplasia Hyperplasia Proliferative Carcinoma Endometrium SH or CH: 1% - 2% of biopsies p were up-graded to cancer by experts Lacey JV, et al. Br J Cancer 2008;98:45
H How Often? Oft ? Normal Proliferative Carcinoma Carcinoma Endometrium Lesion Precursor Benign / Well- Simple Complex Atypical Anovulatory / Differentiated Hyperplasia Hyperplasia Hyperplasia Proliferative Carcinoma Endometrium AH: 40% - 50% biopsies p were cancer at hysterectomy Trimble CL, et al. Cancer 2006;812-9
Risk of Progression to Carcinoma Benign / Complex Complex Well- Well- Anovulatory / Anovulatory / Si Simple l C Complex l Atypical Differentiated Proliferative Hyperplasia Hyperplasia Hyperplasia Carcinoma Endometrium <10% 10%-30% >25% Percent of EH lesions that progress to carcinoma “after 1 to 20 years” Kurman RJ, et al. Cancer 1985;403-12
Key Questions Benign / Complex Complex Well- Well- Anovulatory / Anovulatory / Si Simple l C Complex l Atypical Differentiated Proliferative Hyperplasia Hyperplasia Hyperplasia Carcinoma Endometrium What factors predict progression from EH to carcinoma? • SH and CH often over-diagnosed • AH often an under-diagnosis of carcinoma • AH often prompts hysterectomy
EH Progression Study EH Progression Study • Objective: • Objective: – Determine risk of progression from EH to carcinoma • Nested case-control study at large health plan – Kaiser Permanente Center for Health Research Kaiser Permanente Center for Health Research – Linked and computerized: • Pathology archive since 1971 • Medical records since ~1990 • Pharmacy data since 1985 • Tumor registry since the 1960s g y Lacey JV, et al. Br J Cancer 2008;98:45
Study Participants Study Participants • Cases Cases – 214 women diagnosed with cancer at least 1 year after a diagnosis of EH, 1970-2003 • Specific KPNW pathology code for “EH” • EH via biopsy or curettage • Index biopsy: 1 st diagnosis of incident EH de b opsy d ag os s o c de t • Controls – 404 women diagnosed with EH who remained at-risk g for an equivalent interval • Individually matched to case on age at EH & date of EH • Risk free progression interval similar to their index case • Risk-free progression interval similar to their index case Lacey JV, et al. Br J Cancer 2008;98:45
Study Data Study Data Index Biopsy Follow-up Biopsies Diagnosis Date 6/23/1987 2/27/2003 CASE: Tissue blocks Index Biopsy p y Censor Date from from biopsies 1/2/1987 9/8/2002 CTRLS: & cancer 2/17/1988 10/24/2003 5/8/1987 1/12/2003 All slides from cases & controls All lid f & t l Risk factor data via medical records Medication data via pharmacy records • Original diagnoses Original diagnoses • Pathology panel diagnoses for WHO • Diagnoses for other classification systems Lacey JV, et al. Br J Cancer 2008;98:45
Cancer Risk among Women Diagnosed with EH Normal Proliferative Carcinoma Carcinoma Endometrium Lesion Precursor Benign / Anovulatory / Simple Complex Atypical Well- Proliferative Endometrium Hyperplasia Hyperplasia Hyperplasia Differentiated CA 100.0 14.2 10.0 RRs adjusted for age, j g 2 8 2.8 date, progression interval, 2.0 AH RR 1.0 BMI, repeat biopsies, & MPA treatment 1.0 SH CH DPEM Panel Diagnosis of Index Biopsy 0.1 Lacey JV, et al. Br J Cancer 2008;98:45
Absolute Risks of Progression Absolute Risks of Progression Lacey JV, et al. J Clin Oncol 2010;28:788-92
1000 EH Patients 1000 EH Patients Lacey JV, et al. J Clin Oncol 2010;28:788-92
% Undergoing Hysterectomy SH <5% CH 15% AH 80%
% Hysterectomies Showing Cancer SH 15%-20% CH 15%-20% AH 50%
% Patients with Undetected Cancer SH 1% CH 2% AH ~30%
% At Risk for Progressing to CA SH 94% CH 83% AH 14%
Absolute Risks of CA over 20 Years SH 5% CH 5% AH 30%
Total # of Cancers by EH Type SH 21% CH 16% AH 63%
Conclusions (1) Conclusions (1) • AH has a high risk of concurrent & future cancer AH has a high risk of concurrent & future cancer – A bona fide surrogate endpoint • Risks are lower among non-AH, but they account for 1/3 rd of prevalent & incident cancers – Need better risk prediction & stratification
Conclusions (2) Conclusions (2) • High percentage of AH patients who undergo High percentage of AH patients who undergo hysterectomy represents effective censoring – True burden of uterine cancer is higher than current rates of invasive cancer indicate • EH is a model of effective cancer control f ff – “Prevent” cancer by detecting it early and offering curative treatment curative treatment
Conclusions (3) Conclusions (3) • EIN & WHO EIN & WHO – In a direct comparison, RRs for EIN were slightly lower than the RRs for AH – Fewer data on relative and absolute risks of progression among patients with EIN Lacey JV, et al. Cancer 2008;113:2073
Cancer Risks Among Women Di Diagnosed with EIN d ith EIN 100 0 100.0 17.1 Cancer 10.0 10.0 RR RR EIN 7.8 1.0 Benign 1.0 Lacey JV, et al. Cancer 2008;113:2073
13 cases, 10 controls, RR = 17.1 (4.2-70.1) Panel EIN and Panel WHO: Panel EIN = Benign g Panel EIN = EIN Panel Panel 71 cases, 159 ctrls 42 cases, 65 ctrls EIN = Panel WHO= Panel WHO= Cancer RR = 1.0 (Ref.) RR = 7.8 (3.4-17.9) Normal or Carcinoma Negative Not included Panel WHO = DPEM Panel WHO = SH Panel WHO = CH Panel WHO = AH Not included Not included 33 33 cases, 97 ctrls 97 t l 41 cases, 67 ctrls 21 cases, 43 ctrls 41 67 t l 21 43 t l 43 43 cases, 34 ctrls 34 t l RR = 1.0 (Ref.) RR = 2.2 (1.1-4.7) RR = 14.2 (5.3-38.0) Increasing Severity Collapsed EIN and WHO Categories: g Panel EIN = Benign Panel EIN = EIN or Cancer 71 cases, 159 ctrls 55 cases, 75 ctrls Panel WHO= Panel WHO= RR = 1.0 (Ref.) RR = 9.0 (4.1-19.7) Normal or Carcinoma Negative Negative Not included Panel WHO = DPEM, SH, or CH Panel WHO = AH Not included 95 cases, 207 ctrls 43 cases, 34 ctrls RR = 1.0 (Ref.) RR = 9.2 (3.9-21.8) Area of categories is proportional to the total number of cases & controls in each category, relative to 138 eligible cases & 241 eligible controls. Lacey JV, et al. Cancer 2008;113:2073
Collaborators and Study Team Collaborators and Study Team • NCI – DCEG / HREB • Brigham & Women’s Hosp. – Mark Sherman MD Mark Sherman, MD – George Mutter MD George Mutter, MD – Nilanjan Chatterjee, PhD • Kaiser Permanente Center – Victoria Chia, PhD for Health Research – Douglas Richesson, MPH D l Ri h MPH – Andrew Glass, MD • Johns Hopkins – Brenda Rush, RN – Brigitte Ronnett, MD g tte o ett, • University of Southern Cal University of Southern Cal. • University of Maryland – Bryan Langholz, PhD – Olga Ioffe, MD • Cleveland Clinic • University of Calgary – Charis Eng, MD, PhD – Maire Duggan, MD • Stavanger Hospital – Jan P.A. Baak, MD, PhD Jan P A Baak MD PhD
EIN & D-score vs. WHO EIN & D score vs. WHO • D-score analysis nearly complete – RRs markedly less than 45 • AH vs. all non-AH – Sensitivity = 31% and specificity = 86% • EIN vs. benign – Sensitivity = 37% and specificity = 71% • Neither EIN nor D-score outperformed WHO
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