6/3/2010. Outline of Talk. Lobular Breast Cancer: Definition of lobular differentiation. Common Problems in Diagnosing LCIS in Core Biopsies

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1 Outline of Talk Lobular Breast Cancer: Common Problems in Diagnosing LCIS in Core Biopsies Definition of lobular differentiation Variants of LCIS that: carry risk for unsampled invasive cancer mimic DCIS mimic invasive cancer may go undetected Joseph Rabban MD MPH Associate Professor Clinical significance of LCIS in core biopsies Clinical distinction of LCIS vs DCIS Definition of Lobular Differentiation LCIS DCIS Loss of cell-cell cohesion due to defective E-cadherin Biology Marker of risk Precursor of invasion Non-obligate precursor Distribution Multifocal Segmental Treatment Observation Surgical excision? Hormonal Rx Margins Not evaluated Surgical clearance? Radiation TX Dabbs. American Journal of Surgical Pathology. 31(3): , March

2 Definition of Lobular Differentiation Morphologic Features of Classic LCIS Loss of cell-cell cohesion due to defective E-cadherin Possible diagnostic criteria: Molecular: E-cadherin gene mutation Architecture: Low magnification: Lobulocentric (acinar) growth = grape clusters Ductocentric florid growth = solid expanded ducts Ductocentric minimal growth = clover leaf Morphologic: Immunophenotypic: Loss of cell-cell adhesion Loss of E-cadherin expression Cytoplasmic p120 expression Morphologic Features of Classic LCIS Morphologic Features of Classic LCIS Architecture: Low magnification: Lobulocentric (acinar) growth = grape clusters Ductocentric florid growth = solid expanded ducts Ductocentric minimal growth = clover leaf Cytology: Round / polygonal cell shape Round nuclei Intracytoplasmic vacuoles / signet rings (mucicarmine +) Targetoid dot-like material in vacuoles Higher magnification: Loss of cell-cell cohesion Loss of cell polarity Lack of glandular/acinar formation 2

3 Cytology: Morphologic Features of Classic LCIS Lobulocentric Growth of LCIS Grape clusters Round / polygonal cell shape Round nuclei Intracytoplasmic vacuoles / signet rings (mucicarmine +) Targetoid dot-like material in vacuoles Minimal atypia Haagensen Types Type A (classic) Type B (large cell): more cytoplasm larger nuclei variable size/ shape nucleoli Lobulocentric Growth of LCIS Ductocentric Florid Growth of LCIS 3

4 Ductocentric Minimal Growth of LCIS Clover-leaf or Pagetoid pattern Loss of cell to cell adhesion Intracytoplasmic vacuoles Signet Rings Targetoid dots Mucicarmine 4

5 Pleomorphic LCIS Proposed Criteria: Nuclei are 4X size of lymphocyte nuclei Pleomorphic LCIS Type A Classic LCIS Type B Large Cell LCIS Pleomorphic LCIS Type B Large Cell LCIS = 5

6 How specific is lobular architecture alone? How specific is lobular architecture alone? concentric growth single file cords E-cad concentric growth single file cords E-cad How specific is lobular architecture alone? ALH versus LCIS Helpful but not sufficient without cytologic features: Loss of cell-cell adhesion Loss of polarity Absence of micro-acinar formation Intracytoplasmic vacuoles Distinction justified based on behavior difference: Subsequent risk for cancer ALH ~ 4 X LCIS ~ 8-10 X Proposed criteria based on % of expanded acini in TDLU Expanded acinus : >8 cells across acinus at least 50% of acini = LCIS < 50% of acini = ALH Page and Simpson Rosen 6

7 Atypical lobular hyperplasia Pagetoid growth can occur in ALH or LCIS Simpson & Page. The Breast 1998 Definition of Lobular Differentiation E-cadherin loss in LCIS Loss of cell-cell cohesion due to defective E-cadherin myoepithelium Possible diagnostic criteria: Molecular: Morphologic: Immunophenotypic: E-cadherin gene mutation Loss of cell-cell adhesion Loss of E-cadherin expression Cytoplasmic p120 expression 7

8 Dot-like perinuclear E-cadherin:? Diagnosis Pitfalls in Interpreting E-cadherin Does any positivity exclude LCIS? No. Entrapped native epithelium / myoepithelium Aberrant expression in LCIS Is partial loss of E-cadherin sufficient to call LCIS? No. Aberrant expression in DCIS Aberrant E-cadherin positivity in lobular carcinoma Aberrant E-cadherin positivity in lobular carcinoma Choi et al. Mod Pathol 2008; 21: 1224 Da Silva et al. Am J Surg Pathol 2008; 32: 773 8

9 Aberrant E-cadherin partial loss in ductal carcinoma Interpreting E-cadherin Defects in E-cadherin gene can cause: Loss of protein absent immunostaining Loss of function aberrant immunostaining Choi et al. Mod Pathol 2008; 21: 1224 Interpreting E-cadherin p120 localization depends on E-cadherin Defects in E-cadherin gene can cause: Loss of protein absent immunostaining Loss of function aberrant immunostaining Staining results: Complete absence Partial absence partial membranous granular cytoplasmic Complete presence lobular lobular or ductal ductal Defer to morphology Dabbs et al Am J Surg Pathol. 2007; 31:

10 Ductal differentiation = Membranous p120 Normal TDLU DCIS Invasive Ductal Carcinoma Ductal differentiation (DCIS) Membranous p120 Lobular differentiation (LCIS) Cytoplasmic p120 Typical immunoprofile Lobular type Ductal type E-cadherin: Complete loss Membranous p120: Cytoplasmic Membranous Defer to morphology if aberrant results Outline of Talk Definition of lobular differentiation Variants of LCIS that: carry risk for unsampled invasive cancer mimic DCIS mimic invasive cancer may go undetected Clinical significance of LCIS in core biopsies 10

11 LCIS with higher risk of associated invasive cancer Florid / Extensive LCIS has higher risk for invasion LCIS with necrosis Florid LCIS Pleomorphic LCIS When in core biopsy, consider excision to exclude invasive cancer *Fisher: Cancer 1996;1403 *Page: Hum Pathol 1991;1232 Invasion next to LCIS with necrosis Invasion next to LCIS 11

12 Outline of Talk LCIS Variations that Mimic DCIS Definition of lobular differentiation Variants of LCIS that: carry risk for unsampled invasive cancer mimic DCIS mimic invasive cancer may go undetected Clinical significance of LCIS in core biopsies Mimic lower grade DCIS LCIS in collagenous spherulosis Florid LCIS Solid LCIS in lobules LCIS with necrosis Mimic higher grade DCIS Pleomorphic LCIS LCIS within Collagenous Spherulosis Mimics cribriform DCIS LCIS within Collagenous Spherulosis Key clues: Hyaline ring around lumens Nucleus embedded in ring No epithelium forming lumen Loss of cell adhesion 12

13 LCIS within Collagenous Spherulosis E-cadherin Calponin Positive in myoepithelium Negative in epithelium Positive in myoepithelium Solid Pattern In Situ Carcinoma when it s too packed to appreciate cell adhesion status Lobulocentric Solid LCIS DCIS with cancerization of lobules Ductocentric Florid LCIS Solid DCIS Florid LCIS (may mimic solid DCIS) Florid LCIS (may mimic solid DCIS) 13

14 Florid LCIS (may mimic solid DCIS) Solid LCIS DCIS, Cancerization of lobules Solid Pattern In Situ Carcinoma Solid Pattern In Situ Carcinoma when it s too packed to appreciate cell adhesion status Micro-acinar growth Cell polarization Well-developed cell membranes Higher nuclear grade Cytoplasmic vacuoles Favor DCIS Favor LCIS + 14

15 Solid Pattern In Situ Carcinoma Micro-acini in solid DCIS E-cadherin Micro-acini favor DCIS Well-developed cell membranes = need to exclude DCIS Solid Pagetoid in Situ Carcinoma: DCIS or LCIS? 15

16 Solid Pagetoid in Situ Carcinoma: DCIS or LCIS? Pagetoid DCIS Cell membranes favor DCIS Membranous E-cadherin Membranous p120 Solid In Situ Carcinoma At a Margin Solid In Situ Carcinoma At a Margin Ecadherin 16

17 LCIS and DCIS may colonize the same duct! LCIS and DCIS may colonize the same duct! LCIS with necrosis may mimic DCIS LCIS with necrosis may mimic DCIS 17

18 Pleomorphic LCIS may mimic DCIS Pleomorphic LCIS may mimic DCIS ER negative PR negative HER2 positive Pleomorphic LCIS may mimic DCIS E-cadherin negative Outline of Talk Definition of lobular differentiation Variants of LCIS that: carry risk for unsampled invasive cancer mimic DCIS mimic invasive cancer may go undetected Clinical significance of LCIS in core biopsies 18

19 LCIS in sclerosing adenosis may mimic invasive carcinoma LCIS in extensive sclerosing adenosis mimics invasive cancer LCIS in extensive sclerosing adenosis Florid LCIS in sclerosing adenosis LCIS in extensive sclerosing adenosis mimics invasive cancer Florid LCIS in sclerosing adenosis mimics invasive cancer Calponin Calponin 19

20 Florid LCIS in sclerosing adenosis mimics invasive cancer Recommendation: Calponin Presence of nearby sclerosing adenosis should prompt caution before diagnosing invasive cancer Outline of Talk LCIS Variants That May Go Undetected Definition of lobular differentiation Variants of LCIS that: carry risk for unsampled invasive cancer mimic DCIS mimic invasive cancer may go undetected LCIS in fibroadenoma LCIS in papilloma LCIS in atrophic breast Clinical significance of LCIS in core biopsies 20

21 LCIS in Fibroadenoma May Go Undetected LCIS in Fibroadenoma May Go Undetected LCIS in Papilloma May Go Undetected LCIS in Papilloma May Go Undetected 21

22 LCIS in Papilloma May Go Undetected Sub-epithelial cells in a Papilloma Differential Diagnosis LCIS DCIS Prominent myoepithelium Sub-epithelial cells in a Papilloma ALH/LCIS in Atrophic Breast May Go Undetected Differential Diagnosis LCIS DCIS Prominent myoepithelium 22

23 ALH/LCIS in Atrophic Breast May Go Undetected Outline of Talk Definition of lobular differentiation Variants of LCIS that: carry risk for unsampled invasive cancer mimic DCIS mimic invasive cancer may go undetected Clinical significance of LCIS in core biopsies LCIS in a Core Needle Biopsy: Is Excision Needed? LCIS in a Core Needle Biopsy: Is Excision Needed? Controversial! Controversial! Ideally, management should be evidence based: What is the risk of finding a worse lesion in excision? Do LCIS variants have same risk of up-grading? Problems in literature: Not all studies have pathology verified Some studies lump all LCIS types together Some studies lump all clinical/radiologic settings together Different size/guage needles used Selection bias in who got excision Small numbers of patients 23

24 Outcome of ALH/LCIS in a Core Needle Biopsy Outcome of ALH/LCIS in a Core Needle Biopsy LCIS: 26% ALH: 14% risk of DCIS/invasive cancer in excision Risk of DCIS/invasion in excision partly depends on: Discrepant radiologic pathologic findings Variant types of LCIS Arpino et al. Cancer 2004; 101: 242 Menon et al. Virch Archiv 2008; 452: 473 Management of LCIS in a Core Needle Biopsy Management of LCIS in Surgical Excision Consider excision if: Controversial if: Mass lesion Discordant radiology-pathology LCIS variants Necrosis Florid Pleomorphic Any worse lesion (ADH, flat atypia, etc) None of the above ALH or minimal LCIS Classic LCIS: LCIS Variants: No further surgery No need to comment on margins Life-long clinical follow-up Report margin status Probably consider treating as DCIS A topic of ongoing inquiry. 24

25 Outline of Talk Definition of lobular differentiation Variants of LCIS that: carry risk for unsampled invasive cancer mimic DCIS mimic invasive cancer may go undetected Clinical significance of LCIS in core biopsies 25