Columnar Cell Lesions and Flat Epithelial Atypia

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1 Columnar Cell Lesions and Flat Epithelial Atypia Laura C. Collins, M.D. Department of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA

2 Terminology for Columnar Cell Lesions Columnar cell change Columnar cell hyperplasia Flat epithelial atypia (Columnar cell change with atypia) (Columnar cell hyperplasia with atypia)

3 Columnar Cell Lesions Increasingly seen in an era of mammographic screening due to the identification of microcalcifications Further increase noted with introduction of digital mammography (Anoek, Mod Pathol, 2011)

4 Columnar Cell Change WHO, 2003 Variably distended acini of TDLUs lined by columnar cells arranged perpendicular to basement membrane Apical snouts Secretions and microcalcifications in lumens

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7 Columnar Cell Hyperplasia WHO, 2003 Variably distended acini of TDLUs lined by columnar cells arranged perpendicular to basement membrane, some multilayer and piling up of nuclei, but no true micropapillations Apical snouts Secretions and microcalcifications in lumens, may be more pronounced

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11 Flat Epithelial Atypia WHO, 2003 Variably distended acini of TDLUs Monotonous proliferation of cuboidal to columnar epithelial cells Apical snouts Secretions and microcalcifications in lumens

12 Flat Epithelial Atypia Low-grade cytologic atypia Nuclei usually round rather than elongated Loss of polarization Flat growth pattern

13 Flat Epithelial Atypia Features do not fulfill combined architectural and cytologic criteria for diagnosis of ADH or DCIS

14 Flat Epithelial Atypia Given a number of different names Clinging carcinoma (monomorphic type) Atypical cystic lobules type A Columnar cell change/hyperplasia with atypia CAPSS with atypia DIN of the flat type

15 Problems in Breast Pathology Azzopardi, 1979 Underdiagnosis of Malignancy There is a more common form of clinging carcinoma..the involved structures are lined by a single or a few layers of neoplastic epithelial cells.the lesion can be missed entirely since the alteration is cytological rather than anatomical (architectural).

16 Flat Epithelial Atypia The missing link in breast cancer progression?* *Simpson, Am J Surg Pathol, 2005

17 No consistent genetic alterations +1q, -16q, -17p ILC UDH LCIS ALH -CDH1 (e-cad) Normal Epithelium FEA ADH LG-DCIS IG-DCIS HG-DCIS +1q, -16q, -17p LG-Invasive Cancer? +1q, -16q, -17p Low Grade Pathway ER+, HER2-, low prolif rate? -16q??? IG-Invasive? Cancer?? Apocrine Metaplasia??? HG-Invasive Cancer

18 Normal Low grade intraepithelial neoplasia Lobular Neoplasia Columnar cell lesions ADH/DCIS ILC TLC Tubular Ca Low grade invasive carcinomas Low grade breast neoplasia family Adapted from Ellis, Mod Pathol 2010

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25 Differential Diagnosis

26 Differential Diagnosis of Flat Epithelial Atypia Apocrine metaplasia Microcysts ADH Cystic Hypersecretory Hyperplasia FEA LG-DCIS Columnar Cell Change/Hyperplasia

27 Microcysts Single layer of low cuboidal/attenuated epithelial cells Small nuclei May have secretions

28 Apocrine cysts Single layer of low cuboidal cells Abundant pink cytoplasm Round nuclei with prominent nucleoli Calcifications often calcium oxalate

29 Flat Epithelial Atypia Apocrine Metaplasia

30 Flat Epithelial Atypia vs. Apocrine Epithelium FEA Apocrine Epithelium Apical snouts yes yes Granular eosinophilic cytoplasm no yes Hobnail cells yes no Psammomatous calcifications yes no ER expression yes no bcl-2 expression yes no

31 ER and bcl2 Expression FEA Apocrine met ER bcl2

32 Columnar cell lesions without atypia Columnar cells Nuclei elongated Polarization maintained May stratify

33 Columnar Cell Change Flat Epithelial Atypia Columnar Cell Hyperplasia

34 Columnar Cell Change Flat Epithelial Atypia Columnar Cell Hyperplasia Irregular contours Smooth contours Irregular contours

35 FEA CCC

36 Cystic Hypersecretory Hyperplasia

37 Cystic Hypersecretory Hyperplasia

38 Atypical Ductal Hyperplasia Cells with low grade cytologic atypia Architectural atypia also present

39 Low Grade DCIS Cells with low grade cytologic atypia Architectural atypia also present, completely filling a ductal unit

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43 Flat Epithelial Atypia vs. ADH or DCIS Low-grade cytologic atypia Complex architectural patterns FEA Yes No ADH/DCIS Yes Yes

44 High Grade DCIS Clinging carcinoma may present as dilated spaces with single layer of atypical epithelial cells

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46 Differential Diagnosis of Flat Epithelial Atypia Apocrine metaplasia Microcysts ADH Cystic CYTOLOGY Hypersecretory Hyperplasia FEA ARCHITECTURE LG-DCIS Columnar Cell Change/Hyperplasia

47 Interobserver Reproducibility

48 Can Pathologists Reproducibly Distinguish Columnar Cell Lesions That Are Not Atypical From FEA? (O Malley, Mod Pathol 2006) 8 pathologists (including 1 reference pathologist) Training tutorial Written criteria Representative images Test set of 30 cases Each scored as either FEA or not atypical by each of the 8 observers

49 Interobserver Agreement (FEA vs. Not Atypical) Overall agreement among 8 pathologists: 91.8% Multi-rater kappa value: 0.83 ( excellent agreement )

50 Immunophenotype

51 Immunophenotype Immunoperoxidase studies not helpful for separating FEA and CCC/CCH Express CK 19 Lack expression of HMW-CK (CK 5/6) Strong expression of ER and PR Overall higher expression of proliferation and anti-apoptotic markers than normal TDLUs

52 UDH ADH CCC FEA

53 ER CCC FEA

54 Molecular Alterations

55 Molecular Alterations FEA is a clonal proliferation 16q loss Genetic changes relatively few in number Recurrent loss of 16q reported Abdel-Fatah et al, AJSP, 2007 Aulmann, AJSP, 2012 Verschuur-Maes, BCRT, 2012 Go, Human Pathol, 2012

56 Molecular Alterations Promoter methylation of tumor suppressor genes seen in CCL (CCND2 and ID4) Similar alterations identified in associated LGDCIS or invasive carcinoma Direct transitions from FEA to LG DCIS seen on studies of mdna Abdel-Fatah et al, AJSP, 2007 Aulmann, AJSP, 2012 Verschuur-Maes, BCRT, 2012 Go, Human Pathol, 2012

57 Lesions often associated with FEA Atypical ductal hyperplasia Low grade ductal carcinoma in situ Tubular carcinoma Lobular neoplasia (ALH/LCIS) Fraser, 1998; Rosen, 1999; Brogi, 2001; Collins, 2007; Abdel-Fatah, 2007

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64 Clinical Significance

65 Clinical Significance of FEA Evidence to support relationship to ADH, LG-DCIS, tubular carcinoma and lobular neoplasia Cytologic similarities Coexistence and geographic proximity Immunophenotypic similarities Molecular similarities Brogi, Int J Surg Pathol, 2001 Collins, Am J Surg Pathol, 2007 Abdel-Fatah, Am J Surg Pathol, 2007 Brandt, Adv Anat Pathol, 2008 Aulmann, Am J Surg Pathol, 2012

66 Clinical Significance of FEA Based on observations of association with other lesions and genetic data, FEA appears to be a precursor to, or the earliest manifestation of LG DCIS

67 Relationship between DCIS and FEA Collins, Mod Pathol, 2007 FEA is preferentially associated with DCIS with particular features Low nuclear grade Micropapillary pattern Absence of comedo necrosis Absence of stromal inflammation/desmoplasia

68 Implications Our observations provide further evidence for a precursor-product relationship between FEA and DCIS that exhibit such features

69 Rosen Triad Brandt et al., Adv Anat Pathol, cases of tubular carcinoma 100% of cases with associated CCLs 53% of cases with associated LCIS

70 Rosen Triad Brandt et al., Adv Anat Pathol, 2008 Tubular carcinoma Columnar cell lesions LCIS (Rosen, Am J Surg Pathol, 1999)

71 Tubular ca LN FEA Tubular ca FEA

72 Proposed Evolutionary Pathway for LG Neoplasia Abdel-Fatah et al, AJSP, 2007

73 Clinical Follow-up Studies

74 Eusebi et al 1994 EORTC de Mascarel, et al 2006 # of patients Type of study Retrospective review, biopsies originally considered benign Prospective, randomized clinical trial Retrospective review, clinging carcinoma of the monomorphic type Treatment Diagnostic biopsy; no attempt at excision Excision alone or Excision and radiation Biopsy alone (n=70) Biopsy and radiation (n=45) Follow-up 19.2 years 5.4 years 13.3 years (mean) (median) (median) # (%) with LR 1 (4%) 0 3 (2.6%) # with subsequent IBC (2.6%)

75 Columnar Cell Lesions and Subsequent Breast Cancer Risk Evaluated overall cancer risk in >1,000 CCLs Mild increase in overall cancer risk RR=1.47 with 17 yrs of follow-up (Nashville) OR=1.44 with 9 yrs median follow-up (NHS) RR=2.75 with 13.5 yrs mean follow-up (Mayo) No difference among 3 categories of CCL with regard to future breast cancer risk 2-3 fold increase in AH in presence of CCLs May indicate the presence of a concomitant worse lesion Boulos, Cancer, 2008 Aroner, Breast Cancer Res Treat, 2010 Said, Mod Pathol, A

76 Management Issues

77 Columnar Cell Change/Hyperplasia Found on excision: No further treatment Found on CNB: No excision necessary No additional levels obtained

78 Flat Epithelial Atypia FEA on core biopsy Upgraded in 0-30% of cases But need for excision remains uncertain Rad-path correlation required Khoumais Ann Surg Oncol, 2013 WHO, 2012 Bianchi, Virchow s Arch, 2012 Peres, BCRT, 2012 Lavoue, BCRT, 2011 Lee, Breast Journal, 2010 Ingegnoli, Breast Journal, 2010 Tomasino, J Cell Physiol, 2009 Chivukula, Am J Clin Pathol, 2009 Senetta, Mod Pathol, 2009 Piubello, Am J Surg Pathol, 2009

79 Important to separate implications of FEA on CNB For current management (upgrade rate) And ongoing management (subsequent breast cancer risk)

80 FEA on excisional biopsy Obtain multiple levels looking for areas diagnostic of ADH or LG DCIS Submit all tissue

81 Management Issues FEA in association with ADH Manage as ADH FEA in association with LG DCIS Manage as DCIS Question as to whether FEA included in extent/size of DCIS Question of how to manage FEA at margins remains unanswered

82 FEA is a red flag for the presence of other worse lesions

83 Conclusions CCL and FEA increasingly prevalent in an era of mammographic screening (especially digital mammography) May represent a precursor to LG DCIS Risk of progression to invasive carcinoma appears to be very low (with limited data)

84 Conclusions Presence of FEA should alert pathologist to possible presence of other lesions with which it is frequently associated (e.g., ADH, DCIS, tubular ca, LN) On CNB look very carefully for subtle examples of tubular carcinoma or microinvasive foci of ILC/TC