Disclosures 5/27/2012. Outline of Talk. Outline of Talk. When Is LCIS Clinically Significant? Classic LCIS. Classic LCIS

Transcription

1 When Is LCIS Clinically Significant? Disclosures I have nothing to disclose Yunn-Yi Chen, MD, PhD Professor Outline of Talk Outline of Talk Classic LCIS Classic LCIS Definition of lobular differentiation Definition of lobular differentiation Variants of LCIS Variants of LCIS Clinical significance and management of LCIS Clinical significance and management of LCIS 1

2 James Ewing James Ewing (Neoplastic Diseases 1919) Am J Pathol 1941 Am J Pathol 1941 An incidental microscopic finding that cannot be recognized clinically or by gross path exam It is always a disease of multiple foci. Hence, it is never safe to leave the breast with local excision only.. It is our feeling that simple mastectomy is essential 2

3 Lobular neoplasia Clinical distinction of LCIS vs DCIS Introduced by Dr. Cushman D. Haagensen in 1978 Reflect LCIS as a risk factor, rather than a true precursor Avoid overtreatment Later used as an umbrella term to include both LCIS and ALH LCIS DCIS Biology Risk for future invasive ca* Direct precursor of Non-obligate precursor invasive ca Distribution discontinuous, multifocal Continuous, segmental Treatment Life-long follow-up Surgical excision (XRT,? Hormonal Rx hormonal Rx) Margins Not evaluated Surgical clearance On CNB management controversial Excision # both LCIS and LG DCIS: 8-10 x risk for subsequent invasive cancer ~1% risk per year for subsequent invasive cancer, bilateral breasts Morphologic features of classic LCIS Architecture-- TDLUs: solid proliferation (grape clusters) Loss of cell-cell cohesion Cytology-- Round/polygonal cell shape Round nuclei, homogeneous chromatin Intracytoplasmic clear (mucin-filled) vacuoles/signet ring Targetoid dot-like material in vacuole Minimal atypia, mitosis rare Classic LCIS: lobulocentric growth, solid pattern grape clusters 3

4 Classic LCIS: loss of cell to cell adhesion Classic LCIS: intracytoplasmic vacuoles (lumen) Mucicarmine stain Signet rings Targetoid dots Outline of Talk Classic LCIS Definition of lobular differentiation Variants of LCIS Clinical significance and management of LCIS 4

5 Definition of lobular differentiation E-cadherin-catenin complex for intercellular tight junction Loss of cell-cell cohesion due to defective E-cadherin CDH1 gene on chromosome 16q Chromosomal loss, mutation, epigenetic inactivation Altered E-cadherin-catenin complex 2 Dabbs D et al:.am J Surg Pathol. 2007;31: IHC distinction between LCIS and DCIS E-cadherin stain: distinguish ductal vs lobular lesion DCIS LCIS LCIS DCIS myoepithelium E-cadherin Negative Membrane α, β, γ- catenin Negative Membrane p120 catenin Cytoplasmic Membrane HMWK (34βE12) Cytoplasmic Negative 5

6 Ductal differentiation (DCIS) Membranous p120 Lobular differentiation (LCIS) Cytoplasmic p120 Pitfalls in interpreting E-cadherin Does any positivity excludes lobular ca? Entrapped native epithelium/myoepithelium Pitfalls in interpreting E-cadherin Does any positivity excludes lobular ca? Aberrant E-cadherin pattern in lobular carcinoma LCIS ILC ~15% lobular ca have some E-cad staining Aberrant E-cad pattern-- -Dot-like staining -Granular or cytoplasmic staining -Partial membrane staining -Circumferential yet weak membrane staining Circumferential strong membrane staining -usually with impaired E-cad/catenin complex (abnormal staining pattern with other catenins) *Da Silva et al: Am J Surg Pathol 2008 *Choi et al: Mod Pathol 2008 *Rakha et al: Am J Surg Pathol

7 Caution in interpreting E-cadherin Algorithm for classifying atypical epithelial lesion using combined H&E and IHC approach A positive E-cadherin staining does NOT exclude the diagnosis of lobular carcinoma! Solid atypical epithelial proliferation with H&E features s/o lobular diff Our current understanding of outcome and risk for LCIS is based on morphology and not IHC Dx based on H&E morphology rather than E-cad or Combined morphology and IHC approach Staining results: Complete absence Aberrant E-cad pattern (granular/cytoplasmic, partial membrane, complete weak membrane) Circumferential strong membrane lobular lobular Defer to morphology (± p120 catenin) If lobular phenotype or abnormal p120 If equivocal/ductal or intact p120 Lobular Ductal 60 y F, stereotactic CNB for microcal ALH involving sclerosing adenosis? E-cad stain-- circumferential strong membranous staining? ALH Back to H&E morphology Final Dx: ALH p120 7

8 Outline of Talk Classification of non-invasive lobular disease Classic LCIS Definition of lobular differentiation Variants of LCIS Clinical significance and management of LCIS Atypical lobular hyperplasia Classic LCIS Classic small cell type (type A) Large cell type (type B) LCIS variants Pleomorphic Florid or macroacinar Necrotic Signet ring cell Classic LCIS (type A) Large cell LCIS (type B) Co-existence of Type A and B cells Type B LCIS Pleomorphic LCIS 8

9 Pleomorphic LCIS Pleomorphic LCIS-- cytologic criteria? Architectural and noncohesive growth of LCIS Nuclear pleomorphism +/- necrosis and calcifications E-cadherin negative E-cadherin Moderate to marked nuclear pleomorphism At least some nuclei 4x lymphocyte nucleus Nuclear diameter 2x lymphocyte nucleus AND At least 2x nuclear size variation Sneige et al, Mod Pathol 2002 Chen et al, AJSP 2009 Ho et al: Mod Pathol 2010 (abst) Pleomorphic LCIS with apocrine cytology (apocrine PLCIS) Type A Type B PLCIS Apocrine PLCIS 9

10 PLCIS characteristics (I) Chen et al, AJSP 2009, 31 pure PLCIS Clinical Older, postmenopausal women Mammographic detection ER Pleomorphic LCIS: aggressive biomarker profile PR Biomarker expression Higher Ki-67 Negative or lower ER/PR Higher incidence of HER2 gene amplification HER2 Ki67 PLCIS characteristics (II) Chen et al, AJSP 2009, 31 pure PLCIS Genetics: Most 1q +/16q (genetic signature of classic LCIS) More genetic alterations than classic LCIS Florid LCIS (Macroacinar LCIS) Classic LCIS cells with massive expansion of the involved spaces, mimicking solid DCIS Suggestive of more aggressive or advanced lesion 10

11 Florid LCIS characteristics Older women 1q+/16q-, but more genomic changes than classic LCIS Increased risk of subsequent invasion High incidence of adjacent invasion (~80%), almost all ILC LCIS variant with necrosis Cytologic and architectural features of classic LCIS, E-cadherin negative, but with comedo-type necrosis Suggestive of more aggressive or advanced lesion *Fisher et al: Cancer 1996; *Page et al: Hum Pathol 1991; *Shin et al: Mod Pathol 2002:52A *Shin et al: Mod Pathol 2010:313A *Bagaria S et al: Ann Surg Oncol 2011 Classic LCIS Necrotic LCIS Genes Chromosomes Cancer 2010;49: Associated with calcifications 44% with invasive cancer Florid LCIS Apocrine PLCIS 25% HER2+ 1q+/16q-, but more genomic changes than classic LCIS Genetically advanced lesion with considerable resemblance to carcinomas,? the transition state from in situ to invasive carcinoma 11

12 Signet-ring cell LCIS Signet-ring cell LCIS--aggressive biomarkers E-cad Mucicarmine stain ER HER2 Distinction of LCIS variant vs classic LCIS (both: solid pattern, discohesive cells, E-cadherin negative) Outline of Talk LCIS variant Classic LCIS Age Postmenopausal (~60 y) Perimenopausal (~50 y) Presentation Mammographic detection Incidental microscopic finding Biomarker Aggressive Favorable Adjacent Higher incidence Lower incidence Invasive ca majority ILC ILC or IDC Genetics 1q+/16q-, and more changes 1q+/16q-, no or few other changes Classic LCIS Definition of lobular differentiation Variants of LCIS Clinical significance and management of LCIS 12

13 LCIS in a core needle biopsy: Is excision needed? Controversial! Which LN in CNB will be upgraded to malignancy (DCIS, invasion)? 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/gauge needles used Selection bias in who got excision Small numbers of patients Outcome of lobular neoplasia in a CNB (I) Outcome of lobular neoplasia in a CNB (II) 27% upgrade to DCIS/invasive ca in excision 789 patients, range 0-60%* Upgrade rate correlates with types of LN on CNB 19% ALH 32% LCIS 41% PLCIS 29% unspecified LN Most upgrade occurring in LCIS variant Discordant imaging Imaging for high-risk indications (vs routine screen) Concurrent ADH, FEA Cancer in some excisions even without apparent discordance or risk factors (4-5%) Arpino 2004; Renshaw 2006; Brem 2008; Menon 2008; Luedtke 2011; Subhawong 2010; Alfonso 2012; Desoouki 2012; Hussain 2011*; Rendi 2012 Arpino 2004; Renshaw 2006; Brem 2008; Menon 2008; Luedtke 2011; Subhawong 2010; Alfonso 2012; Desoouki 2012; Hussain 2011*; Rendi

14 Management of LN in a core needle biopsy Consider excision if: Controversial if: Mass lesion Discordant radiology-pathology Imaging for high-risk indication LCIS variants Necrosis Florid Pleomorphic Any worse lesion (ADH, flat epithelial atypia, etc) Extensive LN (?definition) None of the above ALH or minimal LCIS Management of LCIS variants-- A topic of ongoing inquiry, overall manage like DCIS Found in core needle biopsy: Recommend excision Found in excision: Report margin status Recommend re-excision if close or at the margin? Adjuvant hormone therapy and radiation Take home message for LCIS Most classic LCIS as an incidental microscopic finding; LCIS variants by mammographic detection Most as risk factor for subsequent invasive cancer; some likely a direct precursor, especially LCIS variants LCIS variants: aggressive biomarker profile, more genetic changes, risk of adjacent cancer Classic LN in CNB: management controversial; prudent to excise or discuss in multidisciplinary tumor board LCIS variants: manage as DCIS Selected references Bagaria SP et al: The florid subtype of lobular carcinoma in situ: Marker or precursor for invasive lobular carcinoma? Ann Surg Oncol 2011;18: Chen YY et al: Genetic and phenotypic characterization of pleomorphic lobular carcinoma in situ of the breast. Am J Surg Pathol 2009;33: Da Silva L et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg pathol 2008;32: Hussain M and Cunnick GH. Management of lobular carcinoma in situ and atypical lobular hyperplasia of the breast--a review. Eur J Surg Oncol 2011;37: Rakha EA et al: Clinical and biological significance of E-cadherin protein expression in invasive lobular carcinoma of the breast. Am J Surg Pathol 2010;34: Rakha EA and Ellis IO. Lobular breast carcinoma and its variants. Semin Diagn Pathol 2010;27: Rendi MH et al: Lobular in-situ neoplasia on breast core needle biopsy: Imaging indication and pathologic extent can identify which patients require excisional biopsy. Ann Surg Oncol 2012:19: Schnitt S and Morrow M. Lobular carcinoma in situ: Current concepts and controversies. Semin Diagn Pathol 1999;16: Sneige N et al: Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol 2002;15:

15 Thank you! 15