COMPANION MEETING BREAST. Auditorium 11:15 1:00 am. Convenor: A/Professor Gelareh Farshid, SA Pathology, SA

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1 Australasian Division of the International Academy of Pathology Limited ABN TH Annual Scientific Meeting Darling Harbour Convention Centre, Sydney, Australia June 3-5, 2011 COMPANION MEETING BREAST Auditorium 11:15 1:00 am Convenor: A/Professor Gelareh Farshid, SA Pathology, SA 1. Profiling Ductal Carcinoma In Situ of the Breast Dr Rosemary Balleine, Cancer Institute NSW Fellow, Translational Oncology, Westmead Hospital, Sydney West Local Health Network & Clinical Senior Lecturer, Sydney Medical School 2. Core Biopsy Evaluation of Papillary Lesions of the Breast Dr Nirmala Pathmanathan, Research Fellow, Westmead Millenium Institute & Consultant Pathologist, Singapore General Hospital 3. Genomics and the Hunt for New Therapeutic Targets in Breast Cancer Professor Paul Waring, Professor of Pathology, The University of Melbourne 4. Molecular Classification of screen detected breast cancer A/Prof Gelareh Farshid, Clinical Director, BreastScreen SA & Senior Consultant Pathologist, SA Pathology

2 Profiling ductal carcinoma in situ of the breast. Dr Rosemary L. Balleine Cancer Institute NSW Fellow, Translational Oncology, Sydney West Cancer Network, Westmead Hospital, Sydney Medical School, WESTMEAD NSW Ductal carcinoma in situ (DCIS) was once an uncommon diagnosis but it now constitutes a sizable proportion of breast cancer because of the common use of mammographic screening. Biological heterogeneity is a characteristic of breast cancer that is increasingly assessed to guide management and it is clear that the same level of biological diversity exists in DCIS as invasive breast cancer. However, robust and clinically informative indicators of DCIS biology have been difficult to determine. We have reported on a study aimed at determining a clinically applicable and informative classification of DCIS biology based on a molecular profiling approach (1). To do this we microdissected areas of DCIS from sections of invasive breast cancer and compared the gene expression profiles of DCIS associated with Grade 1 and Grade 3 invasive breast cancers using oligonucleotide microarrays. This showed quite distinct profiles with significantly different expression between the two groups at 173 probes. In a more inclusive group of 61 samples including normal breast, atypical ductal hyperplasia (ADH) and in situ carcinoma of varying grades, expression at this set of probes was used to specify two groups. A low molecular grade group included the normal breast, ADH, low nuclear grade DCIS and a proportion of the intermediate grade DCIS cases. A high molecular grade group included some intermediate nuclear grade and all high nuclear grade DCIS. Comparative genomic hybridisation studies showed that this molecular grade classification was related to the both the character and degree of DNA aberration in the microdissected samples. The list of genes used to specify molecular grade was strongly influenced by cellular proliferation. This was reflected in a significant difference between Ki67 scores for the low and high molecular grade DCIS categories, and we further found that a combination of DCIS nuclear grade and Ki67 score could predict molecular grade quite accurately. To examine the relationship between molecular grade and clinical course, we applied this approach to existing nuclear grade and Ki67 data from a historical cohort of 134 DCIS cases treated by surgery alone with long term follow-up. This showed that the rate of ipsilateral recurrence of DCIS or invasive breast cancer was not different between the low and high molecular grade groups. However, the pattern of recurrence over-time was quite different with recurrences for the high molecular grade group occurring within 48 months of initial surgery, compared with a longer timeframe for recurrences in the low molecular grade group. Overall, this study demonstrated the feasibility of a biologically informative classification of DCIS, and its relationship to clinical course. This approach has potential to bring a more detailed understanding of DCIS to both routine reporting and on-going research into preinvasive disease. (1) R.L.Balleine *, L.R.Webster*, S.Davis, E.L.Salisbury, J.P.Palazzo, G.F. Schwartz, D.B.Cornfield, R.L.Walker, K.Byth, C.L.Clarke, P.S.Meltzer. Molecular grading of ductal carcinoma in situ of the breast. Clin Cancer Res 2008;14(24): * joint first authours

3 Core Biopsy Evaluation of Papillary Lesions of the Breast Dr Nirmala Pathmanathan ICPMR, Westmead

4 Papillary lesions basic structure P63

5 Classification of papillary lesions Benign intraduct papilloma (majority) Atypical papilloma Papilloma with ADH Papilloma with DCIS In situ papillary carcinoma Encysted/intracystic papillary carcinoma Solid papillary DCIS/Ca Collins L C and Schnitt S J. Papillary lesions of the breast: selected diagnostic and management issues. Histopathology 2008; 52:20 29.

6 Diagnosis of papillary lesions on core biopsy For lesions diagnosed as benign on core biopsy, the reported rate of underdiagnosis of atypia or malignancy ranges from 0 to more than 25%. Interpretation of fragmented and distorted material, out of context. Marked variations in histological features -sampling error. Complete excision is generally recommended to establish a definitive diagnosis. An accurate core biopsy prediction of the final diagnosis would be a useful guide to further management.

7 Aim To determine whether benign papillary lesions could be identified in core biopsies by assessment of histopathological and immunohistochemical features to provide a guide for further management

8 Approach Detailed histopathology review of 127 excised papillary lesions. Immunohistochemical staining for: Cytokeratin 5/6 P63 Ki67 Assigned to diagnostic categories (benign, atypical and malignant) based on histopathological and immunohistochemical features. Aimed to identify distinctive features of benign lesions that could be used for core biopsy diagnosis.

9 Histopathology of papillary lesions Benign (n=78) Single to florid epithelial hyperplasia Continuous staining myoepithelial layers intralesionally and perilesionally Predominantly broad sclerotic cores, thin fibrovascular cores also seen Mosaic pattern of staining for CK5/6

10 Histopathology of papillary lesions Atypical (n=26) greater degree of epithelial proliferation with florid hyperplastic atypical architectural patterns often occupying only a portion of the lesion thin or broad sclerotic fibrovascular cores could be seen Myoepithelial cells were focally or partially absent in most lesions CK5/6 mostly positive, some lesions with focal or partial loss

11 Histopathology of papillary lesions Malignant (n=23) Complex architectural patterns part or all of the lesions, or solid proliferation Majority of lesions thin arborising fibrovascular cores Myoepithelial cells complete loss in 50%, partial or focal loss in the remainder

12 Cellular proliferation Assessed by Ki67 staining. Marked intra-lesional heterogeneity. Separate counts for low and high staining areas. Mean difference of 12.7% (+/-9.7%) between low and high staining areas across the cohort.

13 Cellular proliferation There was no significant difference in Ki67 high scores between benign, atypical and malignant papillary lesions (p=0.66). The difference between the Ki67 low and high scores was not different between benign, atypical and malignant lesions.

14 Predicting the diagnosis of benign papilloma A number of individual features were significantly different between the benign, atypical and malignant categories. However, there was considerable overlap between categories and no individual feature was sufficiently distinctive for use as a diagnostic indicator on core biopsy. Histopathologic features Benign Atypical Malignant n (%) n (%) n (%) p value Total number of cases Nuclear features (cf normal epithelial cells) 1 Small, regular 13 (16.7) 6 (23.1) 0 (0) p< Larger, chromatin margination, smal nucleoli 63 (80.8) 16 (61.5) 15 (65.2) 3 Larger, clumped/ vesicular chromatin 2 (2.6) 4 (15.4) 8 (34.8) Myoepithelial cell layer 1 Present 78 (100) 4 (15.4) 0 (0) p< Focally absent 0 (0) 16 (61.5) 10 (43.5) 3 Partly absent 0 (0) 5 (19.2) 2 (8.7) 4 Completely absent 0 (0) 1 (3.8) 11 (47.8) Fibro-vascular cores 1 Thin and arborising 43 (55.1) 20 (76.9) 20 (87) p= Broad and sclerotic (or both) 35 (44.9) 6 (23.1) 3 (13) CK5/6 1 Absent 2 (2.6) 7 (30.4) 20 (87) p< Present 74 (97.4) 16 (69.6) 3 (13)

15 Predicting the diagnosis of benign papilloma The combination of broad, sclerotic fibro-vascular cores and CK5/6 staining was significantly different between benign and atypical/malignant lesions (p<0.001). 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Thin cores, CK5/6 negative Thin cores CK5/6 neg Thin cores, CK5/6 positive Thin cores CK5/6 pos Thick cores, CK5/6 negative Thick cores CK5/6 neg Thick cores, CK5/6 positive Thick cores CK5/6 pos Atypical / Malignant Benign We postulated that assessment of these two features on core biopsy may be indicative of a benign lesion.

16 Thick fibro-vascular cores + CK5/6 staining as an indicator of a benign papillary lesion on core biopsy The combination of thick fibro-vascular cores and CK5/6 staining on core biopsy was used to designate a benign category in a non-over-lapping series of 42 cases. 25/27 benign lesions (92.6%) were correctly assigned to the benign category. 2/2 atypical lesions were also included in this category. 13/13 malignant cases were correctly assigned. Overall, the sensitivity of the classifier was 86.7% and specificity 92.6%

17 Predicting the diagnosis of benign papilloma Tested with non-overlapping cohort of 42 cases of core biopsied papillary lesions and compared results with the final diagnosis on excision Final Excision Diagnosis 2 (5%) Predicted Diagnosis 13 (31%) 27 (64%) 15 (36%) 27 (64%) Benign Malignant Atypical Benign Malignant/ Atypical

18 Summary The histopathological and immunohistochemical staining features of benign, atypical and malignant papillary lesions were distinctive overall, but individual features showed considerable overlap between categories. Microscopic features show striking intra-lesional heterogeneity. The combination of broad, sclerotic fibro-vascular cores and CK5/6 staining was characteristic of benign papillomas. In a non-overlapping series of cases, evaluation of these two features in core biopsies accurately distinguished benign and malignant lesions but could separate benign and atypical cases.

19 Conclusions Combined assessment of fibro-vascular core thickness and CK5/6 staining features on core biopsy may form a useful adjunct in the clinicopathologic assessment of papillary lesions of the breast.

20 Acknowledgements Ann-Flore Albertini Elizabeth Salisbury Michael Bilous Rosemary Balleine Pamela Provan Karen Byth Jane Milliken

21 Case 3 Presented by: Professor Paul Waring, Professor of Pathology, the University of Melbourne, VIC Genomics and the Hunt for New Therapeutic Targets in Breast Cancer

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