1. Columnar Cell Lesions Timothy W. Jacobs, M.D. Department of Pathology Virginia Mason Medical Center Seattle, WA

2. Case 5

5. Case 6

7. Columnar Cell Lesions Lesions characterized by the presence of columnar epithelial cells lining TDLUs (WHO 2012) Columnar cell change Columnar cell hyperplasia Flat epithelial atypia (FEA)

8. “I’ve been signing out for years, but have never diagnosed this before!” “Too many confusing terms but no good criteria!” “No one in our group can agree on what FEA is!” “Isn’t this just a form of apocrine metaplasia?” “What does it mean - is it even clinically important?” “What do I do when this is in a core biopsy, excision, at margins, etc.?”

9. Flat/Clinging Intraductal Pattern Columnar cell lesions 1945: Foote and Stewart (Annals of Surgery) “Blunt duct adenosis” 1975: Wellings, Jensen, Marcum (JNCI) “Atypical Lobules Type A” 1979: Azzopardi (Problems in Breast Pathology) “Clinging carcinoma, monomorphic type”

10. Clinging Carcinoma Azzopardi 1979 1.“Variant of comedo cancer” (i.e. high grade DCIS) 2.“No evidence of having originated as a comedo cancer”. “Involved structures are lined by a single or few layers of neoplastic epithelial cells” (i.e. FEA)

11. FEA Timeline 2003 WHO FEA Hypersecretory hyperplasia with atypia Small ectatic ducts lined by atyp cells w/ ap snouts 1980 2000 1990 1979 Azzopardi Clinging CA, Monomorphic 1985 1995 Pretubular hyperplasia Ductal intraepithelial neoplasia flat monomorphic type Columnar cell change w/ atypia, columnar cell hyperplasia w/ atypia Atypical cystic duct Atypical cystic lobule CAPSS with atypia

12. FEA Not “Identified” in Past? Possible Explanations Initial categorization as “DCIS” (Azzopardi 1979): reluctance due to treatment implications, skepticism Pre-mammographic era: patients presented with cancer (inv ± DCIS) - “lesser” lesions not diagnosed? Mammographic screening: increased detection of “earlier lesions”

13. CCL Detection Increased Mammographically Targeted Calcs Needle Loc Exc Fraser 1998 AJSP 22:1521 CNB 11g DVA Senetta 2009 Mod Pathol 22:762 1995-6 (n=100) 2004-6 (n=392) CCL42%40% Ca 2+ in CCL74%88% Cancer with CCL 16% (DCIS) 10% (13 DCIS, 1 inv)

14. Digital mammography: more microcalcifications, more columnar cell lesion without atypia Verschuur-Maes, et al. Mod Pathol 2011;24:1191 Mammography:Film (n=28,646) Digital (n=26,513) CNBn=1424n=2013 CCL: overall4.9%10.8% No atypia (CCC/CCH) 2.8%8.2% Atypia (FEA) 1.8% CCL: Calcs targeted14%28%

15. Columnar Cell Lesions Histologic Features

16. Columnar Cell Change TDLU @ LPVariably dilated (often with irregular contours) Lining1-2 cell layers CytologyNuclei: uniform, ovoid/elongated Perpendicular to BM Nucleoli absent/inconspicuous SnoutsYes (often less prominent) SecretionsYes (often not prominent) CalcsMay be present

17. Columnar Cell Change

20. Columnar Cell Change

21. TDLU @ LPVariably dilated (often with irregular contours) Lining1-2 cell layers CytologyNuclei: uniform, ovoid/elongated Perpendicular to BM Nucleoli absent/inconspicuous SnoutsYes (often less prominent) SecretionsYes (often not prominent) CalcsMay be present

22. Columnar Cell Hyperplasia TDLU @ LPVariably dilated (often with irregular contours) Lining>2 cell layers, stratified ±overlapping/ crowding may be small tufts (not complex) CytologyNuclei: uniform, ovoid/elongated Perpendicular to BM Nucleoli absent/inconspicuous SnoutsYes (often prominent) SecretionsYes (often prominent) CalcsOften (may be psammomatous)

23. Columnar Cell Hyperplasia

26. Columnar Cell Hyperplasia

31. TDLU @ LPVariably dilated (often with irregular contours) Lining>2 cell layers, stratified ±overlapping/ crowding may be small tufts (not complex) CytologyNuclei: uniform, ovoid/elongated Perpendicular to BM Nucleoli absent/inconspicuous SnoutsYes (often prominent) SecretionsYes (often prominent) CalcsOften (may be psammomatous)

32. Flat Epithelial Atypia TDLU @ LPVariably dilated (darker/bluer, smoother contours) Lining≥1-2 cell layers, uniform, low grade monomorphic atypia Flat, no architecture CytologyNuclei: uniform, more round Lack polarity Nucleoli may or not be prominent SnoutsYes (often prominent) SecretionsYes (often prominent) CalcsOften (may be psammomatous)

33. Low grade monomorphic atypia

38. FEA

46. Flat Epithelial Atypia (FEA) Distinctive Features Low-grade monomorphic cytologic atypia (akin to that in LG DCIS) Nuclei more round No polarization Relatively flat growth, no architecture Do not fulfill combined architectural and cytologic criteria for ADH or DCIS

47. Columnar Cell Lesions CCCCCHFEA

48. Columnar Cell Lesions CCCCCHFEA

49. Flat Epithelial Atypia Differential Diagnosis

50. FEA Differential Diagnosis First: Exclude CCL Equivalents FEA Clinging CA, low grade/ monomorphic type Hypersecretory hyperplasia with atypia CAPSS with atypia Atypical cystic duct Pretubular hyperplasia Atypical cystic lobule DIN flat monomorphic CCC or CCH with atypia BDA and variants CCC/CCH Blunt duct adenosis Columnar alteration of lobules Columnar metaplasia CAPSS without atypia Hyperplastic unfolded lobules Hyperplastic enlarged lobular units Enlarged lobular units w/ columnar alteration (ELUCA)

51. CCC, CCH Microcysts Apocrine metaplasia Secretory change UDH ADH, LG DCIS HG “clinging” DCIS Low Power Architecture ?complex Higher Power Cells ?atypical FEA Differential Diagnosis Next: Consider Distinct Entities

52. Microcysts

54. Snouts Apocrine MetCCLSecretory Ch

55. Apocrine MetaplasiaColumnar Cell Change

56. Apocrine MetaplasiaColumnar Cell Change

57. CCH Apocrine Metaplasia

59. Apocrine MetaplasiaColumnar Cell Lesion ER

60. Apocrine MetaplasiaColumnar Cell Lesion bcl-2

61. Secretory Change

64. Columnar Cell Hyperplasia or UDH?

65. More important to distinguish from FEA

66. FEA___Hyperplasia

67. FEA vs. ADH/LG DCIS FEAADH LG DCIS Monomorphic Atypia Yes Architectural Pattern* NoYes * Micropapillae, bridges, arcades, etc.

68. FEA ADH TDLU with Monomorphic Atypia

71. CNB With Monomorphic Atypia

72. ADH

75. LG DCIS

76. Parts are similar to FEA

79. High Grade DCIS

81. Low Power  Architecture Complex? Yes No ADH, LG DCIS CCC, CCH Microcysts Apocrine Metaplasia Secretory Change Clinging HG DCIS FEA Higher Power  Cells: Atypical? NoYes Pleomorphic Monomorphic

82. Low Power  Architecture Complex? Yes No ADH, LG DCIS CCC, CCH Microcysts Apocrine Metaplasia Secretory Change Clinging HG DCIS FEA Higher Power  Cells: Atypical? NoYes Pleomorphic Monomorphic

83. Case 5

86. Columnar cell hyperplasia

87. Case 6

88. Flat epithelial atypia (FEA)

89. Case 6, et al. ALH

91. FEA

92. CCL, FEA Significance

93. FEA Relationship to Cancer Observational –Proximity –Morphologic similarity –Immunohistochemistry –Genetic Clinical follow-up studies

94. FEA Relationship to Cancer Observational –Proximity ADH, LG DCIS ALH/LCIS Tubular carcinoma Eusebi 1994; Weidner 1995; Page 1996; Goldstein & O’Malley 1997; Fraser 1998; Rosen 1999; Moinfar 2000; Oyama 2000; Brogi 2001; Collins 2007; de Mascarel 2007; Abdel-Fatah 2007; Brandt 2008

95. FEA with Adjacent ALH

98. Tubular CA and Co.

101. FEA Relationship to Cancer Observational –Proximity –Morphologic similarity –Immunohistochemistry –Genetic Clinical follow-up studies

102. FEA - Immunophenotype ER, PR strongly, uniformly pos Luminal CK pos CK 5/6, CK14 neg HER2 neg Low prolif (Ki67) Similar to ADH, LG DCIS, Tubular CA Fraser 1998; Oyama 2000; Allred 2001; Tremblay 2005; Simpson 2005; Lee 2006; Dessauvagie 2007; Abdel-Fatah 2008 Nofech-Mozes 2008

103. ER bcl-2

104. LMW CK HMW CK

105. Immunohistochemistry useless to distinguish amongst columnar cell lesions (CCC vs CCH vs FEA)

106. FEA Relationship to Cancer Observational –Proximity –Morphologic similarity –Immunohistochemistry –Genetic Clinical follow-up studies

107. FEA Genetics in Brief FEA is a clonal proliferation LOH at several chromosomal loci 16q losses common (“LG neoplasia pathway” ADH  LG DCIS  CA) Genetic changes overlap with associated DCIS and invasive CA Similar changes in CCC, CCH Moinfar Cancer 2000;88:2072 ♦ Simpson Am J Surg Pathol 2005;29:734 Dabbs Mod Pathol 2006;19:344 ♦ Aulmann Am J Surg Pathol 2009;33:1646 Go Hum Pathol 2012;43:1924 ♦ Aulmann Am J Surg Pathol 2012;36:1247

108. FEA Relationship to Cancer Observational –Proximity –Morphologic similarity –Immunohistochemistry –Genetic Clinical follow-up studies

109. FEA Outcome Studies Eusebi 1994 (Semin Diagn Pathol 11:223) Bijker (EORTC) 2001 (J Clin Oncol 19:2263) de Mascarel 2006 (Mod Pathol 19(S1):25A) StudyRetrospective review, biopsies originally “benign” Prospective, randomized clinical trial Retrospective review, clinging CA monomorphic RxExcisional biopsy, no margins Excision ± radiation F/U (years)19.2 (mean)5.4 (med)13.3 (med) Loc Rec1 (4%)03 (2.6%) Invasive003 (2.6%)

110. CCL and Breast Cancer Risk 1000’s CCL evaluated FEA prevalence low, even less without AH (e.g. Nashville 52 FEA/4569 total BBD) CCL overall mildly increase risk –Nashville: RR = 1.47 (17 yrs f/u) –NHS: OR = 1.44 (9 yrs median f/u) –Mayo: HR = 1.12 (16.8 yrs median f/u) No difference amongst CCL category AH increased in presence of CCL (2-3x) Nashville: Boulos. Cancer 2008;113(9): 2415 NHS: Aroner. Breast Cancer Res;2010;12(4): R61 Mayo: Said. Cancer;2015;121(10):1548

111. Take Home Message Progression to invasive CA appears to be very low FEA is most likely an indolent, non- obligate precursor of DCIS and invasive carcinoma (“LG neoplastic pathway”) FEA may indicate an associated worse lesion but by itself should not be equated with atypical hyperplasia when assessing risk

112. CCL, FEA Practical Issues

113. FEA on CNB Intuitively – classic sampling issue CA at excision 0-40% Issues with studies –Relatively small patient numbers –Retrospective –Pure FEA vs. FEA and ADH –Terminology Need for excision remains unclear Guerra-Wallace 2004, Lim 2006, Kunju 2007, Purdy 2007, Martel 2007, Kumaroswamy 2008, Senetta 2009, Piubella 2009, Chivukula 2009, Tomasino 2009, Sullivan 2009, Rahka 2010, Lee 2010, Ingegnoli 2010, Noske 2010, De Mascarel 2011, Faustin 2011, Lavoue 2011, Solorzano 2011, Bianchi 2012, Peres, 2012, Yamaguchi 2012, Lu 2013, Dialani 2014, Woo 2015

114. Does Isolated Flat Epithelial Atypia on Vacuum-assisted Breast Core Biopsy Require Surgical Excision? Dialani, et al. Breast J. 2014:20(6):606

115. FEA on CNB WHO 2012 “…the need for routine surgical excision following a diagnosis of FEA on needle core biopsy is uncertain. Radiological-Pathological correlation is recommended for determining further management.”

116. Columnar Cell Lesions Management CNB Excision Margins FEA Levels to r/o ADH, DCIS… Excision prn Levels to r/o ADH, DCIS… Submit more Nil CCC, CCH No Excision (Rad-Path OK) Nil

117. CCL Conclusions Recognized for several years (by other names) but prevalence increasing due to mammography Standardized terminology and diagnostic criteria Biologically fascinating apropos the “LG Neoplasia Pathway” Beware of the company they may keep: ADH, lobular neoplasia, DCIS, and invasive CA