Precursors of endometrioid Disclosure carcinoma of the uterus S - PDF document

5/ 12/ 2014 Precursors of endometrioid Disclosure carcinoma of the uterus “ S tate of the Art” * Consultant for Becker (NS F International) for cervical cancer screening Richard J. Zaino, MD Dept. of Pathology Hershey Medical Center Penn S tate University Hershey, PA *and clearly, it is art, not science Learning obj ectives Problems in Defining the Natural History the participant should understand the of Hyperplasia following issues relating to precursors of endometrioid adenocarcinoma 1) pathologic criteria - criteria and diagnostic terminology for the various forms of 1) Natural history hyperplasia have changed repeatedly 2) The lexicon 2) initial sampling - the method of initial 3) Diagnostic reproducibility diagnosis is biopsy or curettage, which removes some or all of the lesion to be studied 4) Current practice 5) Recommended terminology WHO 2014 1

5/ 12/ 2014 What do we know? Problems in Defining the Natural History Etiology and Natural History of Hyperplasia of Hyperplasia 1) endometrial hyperplasia usually occurs in 3) coexisting lesions - other lesions such as the setting of unopposed estrogen adenocarcinoma may coexist at the time of stimulation diagnosis without our knowledge, since the D&C or biopsy samples only a portion of the 2) some hyperplasias regress if the endometrium estrogenic stimulation is withdrawn or in 4) subsequent intervention - hormonal or response to progestin therapy surgical intervention usually interrupts 3) some hyperplasias progress to observations of the natural history of adenocarcinoma in time hyperplasia Regression of hyperplasia Etiology and Natural History of Hyperplasia following hormonal therapy 4) The frequency of hyperplasia is about Author lesion response persistence progression duration 20X that of endometrial carcinoma Kistner hyper/ CIS 100% 0 0 4 weeks S teiner hyper/ CIS 100% 0 0 3 days-3 yrs 5) the probability of progression to Kj orstad atypical 41% 23% 35% 3-10 years adenocarcinoma is related to the Wentz hyper/ atyp 100% 0 0 1-5 years Wentz hyper/ atyp 98% 2% 0 1-4 years degree of cytologic atypia in the Kurman non-atypical 77% 31% 0 1-26 years hyperplasia atypical 50% 20% 30% 1-26 years Gal hyper/ atyp 92% 8% 0 .8-9 years 6) the maj ority of adenocarcinomas which Huang hyper/ atyp 52% 38% 10% 1-12 years Ferenczy non-atypical 80% 20% 0 2-12 years arise in a background of hyperplasia are atypical 0% 75% 25% 2-12 years Randall atypical 94% 6% 0 1-7 years well differentiated, rarely lethal, and often may respond to progestin therapy 2

5/ 12/ 2014 Absolute risk of endometrial carcinoma Progression of hyperplasia during 20 year follow-up among women to carcinoma with endometrial hyperplasia Lacey et al, JCO, 2010 7900 women diagnosed with hyperplasia in Non atypical hyperplasia 3-12% a prepaid health plan; 19 years follow-up* Atypical hyperplasia 25-27% Cumulative progression risk Non-atypical hyperplasia 5% Atypical hyperplasia 28% (Retrospective studies, +/ - intervening therapy, incomplete follow-up of 1-20 years) *retrospective review, intervening hormonal therapy, D&C Coexistence of carcinoma with atypical Coexistence of carcinoma with atypical hyperplasia - carcinoma found in hyperplasia - carcinoma found in hysterectomies hysterectomies (within 12 weeks of initial diagnosis*) (within 12 weeks of initial diagnosis) Author Frequency Gusberg and Kaplan* 21% Author Frequency Tavassoli and Kraus* 25% Trimble et al.* 43% Kurman and Norris* 17% Janicek and Rosenshein* 43% *prospective Gynecologic Oncology Group study, using Leitao et al ( 27% 34% p D&C; 46% p Bx) community diagnosis of atypical hyperplasia. Cancer. 2006 Feb 15;106(4):812-9. (potential bias: these studies were retrospective) 3

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5/ 12/ 2014 Diagnostic reproducibility Comparison of the Reproducibility of the WHO Classifications of 1975 and S kov et al (S candanavia) 1994 of Endometrial Hyperplasia Kendall et al (US - Hopkins) B.G. S kov, M.D., H. Broholm, M.D., U. Engel, M.D., Bergeron et al (Europe) M.-B. Franzmann, M.D., A.L. Nielsen, M.D., Zaino et al (US - G.O.G.) A.F. Lauritzen, M.D., and T. S kov, M.D. International Journal of Gynecological Pathology 16(1): 33- 37, 1997 Overall Agreement and  Values for Diagnosis of Reproducibility of the Diagnosis of Endometrial Hyperplasia Using WHO Classifications Endometrial Hyperplasia, Atypical of 1975 and 1994 by the S ix Observers Hyperplasia, and Well-Differentiated Round 1 Round 2 Round 3 Round 4 Carcinoma Overall agreement 0.47 0.45 0.51 0.41  value 0.24 0.25 0.30 0.20 Brian S. Kendall, M.D., Brigitte M. Ronnett, M.D., Christina Isacson, M.D., Kathleen R. Cho, M.D., Round 1 and 3, WHO 1975; Round 2 and 4, WHO 1994 Lora Hedrick, M.D., Marie Diener-West, Ph.D., classification and Robert J. Kurman, M.D. kappa below 0.40 – fair to poor agreement ,  appa values between 0.40 and 0.8 - moderate to good agreement, The American Journal of Surgical Pathology 22(8):1012-  appa values greater than 0.8 - excellent agreement. 1019, 1998 9

5/ 12/ 2014 Microscopic Criteria Differentiating Endometrial Interobserver Agreement* Hyperplasia and Adenocarcinoma Microscopic Criteria Adenomatous Hyperplasia Atypical Hyperplasia Adenocarcinoma Diagnosis Round 1 Interpretation Round 2 Interpretation Nuclei Profiles S moot h and oval Irregular Irregular Proliferative endometrium 0.86 Almost perfect 0.86 Almost S ize Uniform Large, variable Large, variable perfect Nucleoli S mall, round Large, irregular Large, irregular, spiculat ed Simple hyperplasia 0.66 Substantial 0.56 Moderate Mit oses Numerous in st roma and Numerous Variable Complex hyperplasia 0.49 Moderate 0.41 Moderate glands Simple atypical hyperplasia 0.19 Slight 0.13 Slight Cyt oplasm Abundant , amphophilic S omet imes scant ; may be S cant , pale, very abundant , wit h amphophilic Complex atypical hyperplasia 0.40 Moderate 0.49 Moderate dense eosinophilia Well-differentiated carcinoma 0.79 Substantial 0.83 Almost Glands Lining epithelium Tall columnar, single layered S trat ificat ion, loss of polarity Loss of polarity perfect Profiles Dilat ed, irregular, wit h out - Irregular, wit h int raglandular Irregular, wit h pouching and infoldings t uft ing but no bridging cribriform Combined (for all diagnoses) 0.67 Substantial 0.65 Substantial pattern and int raglandular bridging S ize Variable Variable Variable *  values for six diagnostic categories. S troma Usually abundant, cellular S cant , wit h crowding S cant Adapt ed from Tavassoli F, Kraus FT. Am J Clin Pat hol 70:770-779, 1978. Histologic Features for Hyperplasia vs. Histologic Features for Proliferative Atypical Hyperplasia* Endometrium vs. Hyperplasia* Histologic Feature Univariable Multivariable Histologic Feature Univariable Multivariable Nuclear enlargement 5 1 Gland crowding 5 5 Vesicular change 5 1 Gland branching 5 2 Nuclear pleomorphism 5 – Nuclear rounding 4 2 Chromatin irregularities 4 1 Loss of polarity 2 – Loss of polarity 4 1 Nuclear enlargement 2 1 Nuclear rounding 3 – Fibrosis 1 – Nucleoli 3 3 Glandular confluence 1 – * Number of pathologists (of 5) showing an association by univariable and multivariable logistic regression analysis with the diagnosis of * Number of pathologists (of 5) showing an association by univariable hyperplasia and the listed feature. and multivariable logistic regression analysis with the diagnosis of hyperplasia and the listed feature. 10

5/ 12/ 2014 Mean Intraobserver Agreement on Principal Diagnosis A Multicentric European Study Testing the Based on Seven and Three Diagnostic Categories Reproducibility of the WHO Classification of Endometrial Hyperplasia With a Proposal of a 7 diagnoses 3 diagnoses Simplified Working Classification for Biopsy Diagnostic Category % Agreement Diagnostic Category % Agreement and Curettage Specimens Proliferative 73 Secretory 75 Cyclic endometrium 79 Other 29 Christine Bergeron, M.D., Ph.D., Francisco F. Nogales, M.D., Simple hyperplasia 63 Marco Masseroli, Ph.D., Vera Abeler, M.D., Pierre Duvillard, Hyperplasia 61 M.D., Elisabeth Müller-Holzner, M.D., Heinz Pickartz, M.D., Complex hyperplasia 42 Atypical hyperplasia 45 and Michael Wells, M.D., F.R.C.Path Neoplasia 79 Well-differentiated carcinoma 66 The American Journal of Surgical Pathology 23(9): 1102- Combined † Combined † 74 85 1108, 1999 [kappa 0.68] [kappa 0.76] † For all diagnostic categories. Zaino et al, (2004) GOG #167 atypical endometrial hyperplasia Panel diagnosis* frequency % of total 306 endometrial samples community diagnosis of AEH Nml 20 7% Hyperplasia 54 18% Hysterectomy within 12 weeks AEH 116 39% Carcinoma 87 29% Insufficient 3 1% Independent reviews of endo sample No agreement 21 7% Panel review of hysterectomy * Compared to community diagnosis (2/ 3 or 3/ 3 panelists agreement) 11