Ductal Carcinoma in Situ. Laura C. Collins, M.D. Department of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA

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1 Ductal Carcinoma in Situ Laura C. Collins, M.D. Department of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA

2 Definition of DCIS WHO 2012 A neoplastic proliferation of epithelial cells confined to mammary ducts and lobules characterized by subtle to marked cytologic atypia and an inherent, but no necessarily obligate, tendency for progression to invasive breast cancer

3 Incidence of DCIS Ernster, JNCI, 2002 DCIS now accounts for 20% of mammographically-detected breast cancers DCIS detected in ~1 per 1300 screening mammograms

4 Heterogeneity of DCIS Presentation Specimen sampling Measurement of extent Pathologic features Differential diagnosis Genetic alterations Ancillary testing Clinical behavior Treatment options

5 Heterogeneity of DCIS Presentation Pathologic features Genetic alterations Clinical behavior

6 Heterogeneity of Presentation Mammographic Calcifications alone Soft tissue abnormality with calcifications Soft tissue abnormality/architectural distortion alone Palpable mass Nipple discharge

7 Specimen Sampling In most cases, there will be a prior CNB diagnosis of DCIS (or ADH) It is prudent to submit the specimen in its entirety if feasible, if not submit all fibrous parenchyma Serial, sequential sampling is recommended Margin evaluation is important Goal is to exclude invasion and determine if the lesion is completely excised Assessment of extent of DCIS is helpful

8 Extent of DCIS Gross lesion size DCIS in one block Margin to margin Serial sequential sampling Block size = 0.4cm Non-sequential sampling CAP DCIS Protocol, 2012

9 Heterogeneity of DCIS Presentation Pathologic features Genetic alterations Clinical behavior

10 Pathologic Heterogeneity of DCIS: Architecture

11 Pathologic Heterogeneity of DCIS: Nuclear Grade Low Intermediate High

12 In most cases the diagnosis of DCIS is straightforward

13 But, because of the pathologic heterogeneity

14 Invasive Cribriform Carcinoma Pleomorphic Lobular Carcinoma in situ Collagenous Spherulosis Lymphovascular Invasion

15 The diagnosis of DCIS is not always straightforward

16 The diagnosis of DCIS is not always straightforward 7/19/10

17 How Often is the Diagnosis of DCIS a Problem?

18 Pathologist Agreement: Local vs. Central Dx Summary Study # % Not DCIS NSABP B % RDOG % CRN DCIS % ECOG % Problems with both under-diagnosis and over-diagnosis

19 Differential Diagnosis

20 Problems in the Diagnosis of DCIS LVI ADH DCIS Microinvasive carcinoma Other intraductal lesions Invasive carcinoma LCIS

21 Problems in the Diagnosis of DCIS LVI ADH DCIS Microinvasive carcinoma Other intraductal lesions Invasive carcinoma LCIS

22 Distinction between ADH and DCIS ADH is composed of the same population of atypical epithelial cells as LG DCIS Incompletely filling the space Some features of UDH Comprises 2 spaces or less or 2mm or less

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26 Size/Extent Criteria for ADH vs. LG DCIS WHO 2012 The WHO working group did not consider it possible to recommend one approach rather than another, and experts use combinations of both in their clinical practice. It should be noted that quantitative thresholds are meant to be pragmatic guidelines that are useful in prevent the categorization of very small, low grade lesions as DCIS and in turn, in avoiding overtreatment of patients with these minimal or equivocal lesions.

27 Problems in the Diagnosis of DCIS LVI ADH DCIS Microinvasive carcinoma Other intraductal lesions Invasive carcinoma LCIS

28 Other Intraductal Proliferative Lesions that May Mimic DCIS Usual ductal hyperplasia Necrosis UDH vs. intermediate nuclear grade DCIS Gynecomastoid hyperplasia Collagenous spherulosis

29 Other Intraductal Proliferative Lesions that May Mimic DCIS Usual ductal hyperplasia Necrosis UDH vs. intermediate nuclear grade DCIS Gynecomastoid hyperplasia Collagenous spherulosis

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33 Other Intraductal Proliferative Lesions that May Mimic DCIS Usual ductal hyperplasia Necrosis UDH vs. intermediate nuclear grade DCIS Gynecomastoid hyperplasia Collagenous spherulosis

34 UDH IG-DCIS

35 UDH IG-DCIS

36 The combination of HMW-CK and ER immunostains may be particularly helpful in distinguishing UDH from intermediate nuclear grade DCIS in problematic cases

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40 CK5/6 ER

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43 CK 5/6

44 HMW-CK in Intraductal Proliferative Lesions Caveats Not helpful in distinguishing ADH from LG-DCIS or IG-DCIS (all generally negative for HMW-CK) Some HG-DCIS are HMW-CK-positive

45 Other Intraductal Proliferative Lesions that May Mimic DCIS Usual ductal hyperplasia Necrosis UDH vs. intermediate nuclear grade DCIS Gynecomastoid hyperplasia Collagenous spherulosis

46 Gynecomastoid Hyperplasia

47 Gynecomastoid Hyperplasia Micropapillary DCIS

48 Other Intraductal Proliferative Lesions that May Mimic DCIS Usual ductal hyperplasia Necrosis UDH vs. intermediate nuclear grade DCIS Gynecomastoid hyperplasia Collagenous spherulosis

49 Collagenous Spherulosis Cribriform DCIS

50 LCIS in collagenous spherulosis

51 LCIS in collagenous spherulosis

52 LCIS in collagenous spherulosis E-cadherin

53 Problems in the Diagnosis of DCIS LVI ADH DCIS Microinvasive carcinoma Other intraductal lesions Invasive carcinoma LCIS

54 Problems in the Diagnosis of DCIS LVI ADH DCIS Microinvasive carcinoma Other intraductal lesions Invasive carcinoma LCIS

55 Features of DCIS Associated with Microinvasion High grade/comedo histology but, may also be seen in association with other grades/types of DCIS and with LCIS Extent (size, number of involved ducts) Periductal lymphoid infiltrates

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59 Problems in Distinguishing Pure DCIS from DCIS with Microinvasion Over-diagnosis --DCIS may have areas that mimic invasion» Duct branching» Involvement of lobules» Involvement of benign sclerosing lesions» Distortion of involved spaces» Tangential sectioning» Crush artifact» Cautery effect» Artifactual displacement of DCIS cells --Defensive pathology

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61 Distinction Between Mimics of Invasion and Real Invasion Not always possible on H and E sections, even with multiple levels Immunostains for myoepithelial cells

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63 SMMHC

64 Problems in Distinguishing Pure DCIS from DCIS with Microinvasion Over-diagnosis --DCIS may have areas that mimic invasion» Duct branching» Involvement of lobules» Involvement of benign sclerosing lesions» Distortion of involved spaces» Tangential sectioning» Crush artifact» Cautery effect» Artifactual displacement of DCIS cells --Defensive pathology Under-diagnosis Microinvasive foci may be over-looked Microinvasive foci may not be sampled

65 Practical Implications Patients with large areas of DCIS with and without microinvasion should probably be managed similarly?sln biopsy

66 Problems in the Diagnosis of DCIS LVI ADH DCIS Microinvasive carcinoma Other intraductal lesions Invasive carcinoma LCIS

67 Invasive Cancers May Mimic DCIS Invasive cribriform carcinoma Adenoid cystic carcinoma Invasive carcinomas in rounded nests Papillary carcinomas (esp, solid papillary carcinoma) Invasive ductal

68 Invasive Cribriform Carcinoma

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70 DCIS May Mimic Invasive Carcinoma DCIS in adenosis or a pre-existing benign sclerosing lesion can mimic IDC, especially on CNB Conversely There are invasive carcinomas with a lobulocentric pattern that can mimic adenosis

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73 SMMHC

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76 Problems in the Diagnosis of DCIS LVI ADH DCIS Microinvasive carcinoma Other intraductal lesions Invasive carcinoma LCIS

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79 LVI Mimicking DCIS Helpful clue: Pattern of cell nests conforms to location of normal lymphovascular spaces rather than structure of ductal-lobular system»vascular bundles»periductal»interlobular stroma»try to assess relationship of worrisome nests to identifiable ducts and lobules

80 Heterogeneity of DCIS Presentation Pathologic features Genetic alterations Clinical behavior

81 Pathologic Heterogeneity of DCIS: Biological Markers Low grade High grade Aneuploidy infrequent frequent Proliferative rate low high ER/PR+ frequent infrequent bcl2+ frequent infrequent HER2+ infrequent frequent p53 mutations infrequent frequent Angiogenesis infrequent frequent

82 Molecular Phenotypes of DCIS Molecular Category DCIS-NHS (N=264) DCIS-NC (N=229) DCIS-CRN (N=371) Luminal A ER+ and/or PR+, 64.4% 65.1% 74.7% HER2- Luminal B ER+ and/or PR+, 13.6% 10.0% 10.8% HER2+ HER2 ER- and PR-, HER % 16.6% 10.0% Basal-like ER-, PR-, HER2- CK5/6 or EGFR+ 8.0% 8.3% 4.6%

83 Heterogeneity of DCIS: Genetic Alterations Quantitative and qualitative differences in genetic alterations according to grade More numerous genetic abnormalities with higher grade than with lower grade lesions

84 Heterogeneity of DCIS: Genetic Alterations Associations between specific genetic changes and DCIS grade Loss of 16q and 17p in low grade DCIS Gains of 11q, 13q and 17q in high grade DCIS Genetic changes in intermediate grade DCIS more heterogeneous Paradigm shift in tumor progression models

85 Morphologic Spectrum Normal Hyperplasia Atypical hyperplasia CIS Invasive Cancer

86 No consistent genetic alterations UDH? Normal Epithelium ADH LG-DCIS IG-DCIS HG-DCIS LG-Invasive Cancer? +1q, -16q,-17p +1q, -16q,-17p Low Grade Pathway ER+, HER2-, low prolif rate???? IG-Invasive? Cancer High Grade Pathway?? Apocrine Metaplasia ER-, HER2+, p53+, basal, high prolif rate??? HG-Invasive Cancer -11q,-14q,-8p, -13q,+17q, +8q,+5p

87 Heterogeneity of DCIS: Expression Signatures Low and high grade lesions exhibit reciprocal expression patterns Expression signatures characteristic of lesion grade but not stage of progression e.g., low grade DCIS signature more like that of low grade invasive cancer than like high grade DCIS Ma, et al. PNAS 2003; 100:

88 Wiechmann, Cancer 2008

89 Ancillary Testing

90 JCO, 2012 ER positive patients receiving adjuvant tamoxifen showed significant reductions in subsequent breast cancer ER testing for all DCIS

91 Heterogeneity of DCIS: Estrogen Receptor Expression ER positive ER negative

92 DCIS Score Solin, SABCS, 12/11 $4,175

93 Heterogeneity of DCIS Presentation Pathologic features Genetic alterations Clinical behavior

94 Ductal Carcinoma in Situ (DCIS) Natural history poorly defined Biologic behavior of screendetected DCIS unclear Optimal treatment controversial

95 Ductal Carcinoma in Situ (DCIS) Factors determining which DCIS will recur/progress to IBC Which patients can avoid additional therapy beyond local excision

96 Risk Factors for Local Recurrence Clinical factors Young age Treatment factors Extent of excision Use of RT Use of Tamoxifen Tumor factors Size/extent of lesion Nuclear grade Comedo necrosis Architectural pattern Volume of DCIS near margin Margins

97 E5194 EXCISION ALONE WITHOUT RADIATION (+/-TAMOXIFEN): ELIGIBILITY Hughes, JCO, 2009 DCIS, locally excised Two arms: Low or intermediate grade 2.5 cm High grade 1cm (NG 3 + necrosis) Minimum margin width 3mm Specimen sequentially sectioned and completely embedded to determine grade, size, and margins Post excision mag mammo negative for microcalcifications

98 ECOG E5194: EXCISION WITHOUT RADIATION (+/-TAM) Ipsilateral events High grade Low or intermediate grade Event rate % (7.2%, 22.3%) 6.1% (4.0%, 8.2%) Year

99 Collins, BCRT, 2013

100 JCO, 2010

101 Application of MSK Nomogram Cancer Research Network Women with DCIS treated with breast conserving therapy 190 cases, 305 controls Observed 5-Year Probability of IBTR (%) Year Recurrence Probability: Observed vs. Nomogram Predicted Nomogram Predicted 5-Year Probability of IBTR (%)

102 Observed vs. Nomogram Predicted Probability of 10-yr Recurrence Observed 10-Year Probability of IBTR (%) Tendency to overpredict recurrence in RT treated group Nom ogram Predicted 10-Year Probability of IBTR (%) Tendency to underpredict recurrence in surgery alone group

103 JCO 2012

104 Comparison of Study Populations Characteristic MSKCC Cohort MDACC Cohort CRN Controls Median Age 57 yrs 57 yrs 56 yrs Median F/U 5.6 yrs 7.1 yrs 8.0 yrs Postmenopausal 63.5% 70.8% 63.9% Race-white 76.5% 72.1% Race-black 9.4% 9.2% Radiologic presentation 85.0% 79.8% 82.3% Nuclear grade % 13.1% 9.8% Nuclear grade-2 or % 79.5% 90.2% Necrosis-present 62.8% 59.3% 72.4% % of pts with >1 excision 19.5% 62.6% Final margin-neg 80.3% 87.9% 63.6% % receiving RT 48.5% 72.5% 55.7% % receiving Endocrine therapy 21.3% 32.2% 7.9%

105 Heterogeneity of DCIS Summary Diagnosis of DCIS straightforward in most cases Problems with both under-diagnosis and overdiagnosis With careful attention to histologic cues and judicious use of appropriate immunostains, correct diagnosis should be possible in virtually all cases

106 Conclusions Genetic and molecular alterations underlying the various pathologic types of DCIS are emerging

107 Conclusions An understanding of these alterations will provide important information regarding the biology of DCIS and will likely have an impact on pathologic classification and clinical management