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5/27/2012
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
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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”
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Lobular neoplasia
Introduced by Dr. Cushman D. Haagensen in 1978
Reflect LCIS as a risk factor, rather than a true
precursor
Clinical distinction of LCIS vs DCIS
LCIS
Biology
Risk for future invasive ca*
Non-obligate precursor
Direct precursor of
invasive ca
Distribution
discontinuous, multifocal
Continuous, segmental
Treatment
Life-long follow-up◊
? Hormonal Rx
Surgical excision (XRT,
hormonal Rx)
Margins
Not evaluated
Surgical clearance
On CNB
management controversial
Excision
Avoid overtreatment
Later used as an umbrella term to include both LCIS
and ALH
DCIS
# 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
Classic LCIS: lobulocentric growth, solid pattern
grape clusters
•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
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Classic LCIS: loss of cell to cell adhesion
Classic LCIS: intracytoplasmic vacuoles (lumen)
Mucicarmine stain
Signet rings
Outline of Talk
Targetoid dots
Classic LCIS
Definition of lobular differentiation
Variants of LCIS
Clinical significance and management of LCIS
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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
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IHC distinction between LCIS and DCIS
Dabbs D et al:.Am J Surg Pathol. 2007;31:427-437
E-cadherin stain: distinguish ductal vs lobular lesion
DCIS
LCIS
DCIS
E-cadherin
Negative
Membrane
α, β, γ- catenin
Negative
Membrane
p120 catenin
Cytoplasmic
Membrane
HMWK (34βE12)
Cytoplasmic
Negative
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LCIS
myoepithelium
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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
Aberrant E-cadherin pattern in lobular carcinoma
Does any positivity excludes lobular ca?
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 2010
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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!
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
Solid atypical epithelial proliferation
with H&E features s/o lobular diff
Staining results:
Complete absence
lobular
Aberrant E-cad pattern
lobular
(granular/cytoplasmic, partial membrane, complete weak membrane)
Circumferential strong membrane
Defer to morphology
(± p120 catenin)
If lobular phenotype or abnormal p120
If equivocal/ductal or intact p120
60 y F, stereotactic CNB for microcal
Lobular
Ductal
E-cad stain-circumferential strong
membranous staining
ALH involving sclerosing adenosis?
? ALH
Back to H&E morphology
Final Dx: ALH
p120
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Outline of Talk
Classification of non-invasive lobular disease
Classic LCIS
Atypical lobular hyperplasia
Definition of lobular differentiation
Classic LCIS
Classic small cell type (type A)
Large cell type (type B)
Variants of LCIS
Clinical significance and management of LCIS
Classic LCIS (type A)
LCIS variants
Pleomorphic
Florid or macroacinar
Necrotic
Signet ring cell
Large cell LCIS (type B)
Co-existence of Type A and B cells
Type B LCIS
Pleomorphic LCIS
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Pleomorphic LCIS
Architectural and noncohesive growth of LCIS
Nuclear pleomorphism
+/- necrosis and calcifications
E-cadherin negative
E-cadherin
Pleomorphic LCIS-- cytologic criteria?
Moderate to marked
nuclear pleomorphism
At least some nuclei ≥
4x lymphocyte nucleus
Sneige et al, Mod Pathol 2002
Chen et al, AJSP 2009
Nuclear diameter ≥ 2x
lymphocyte nucleus
AND
At least 2x nuclear size
variation
Ho et al: Mod Pathol 2010 (abst)
Type A
Type B
PLCIS
Apocrine PLCIS
Pleomorphic LCIS with apocrine cytology
(apocrine PLCIS)
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Pleomorphic LCIS: aggressive biomarker profile
PLCIS characteristics (I)
Chen et al, AJSP 2009, 31 pure PLCIS
ER
PR
Clinical
Older, postmenopausal women
Mammographic detection
Biomarker expression
Higher Ki-67
Negative or lower ER/PR
Higher incidence of HER2 gene amplification
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
HER2
Ki67
Florid LCIS (Macroacinar LCIS)
Classic LCIS cells with massive expansion of the
involved spaces, mimicking solid DCIS
Suggestive of more aggressive or advanced lesion
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Florid LCIS characteristics
LCIS variant with necrosis
Cytologic and architectural features of classic LCIS,
E-cadherin negative, but with comedo-type necrosis
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
Suggestive of more aggressive or advanced lesion
*Fisher et al: Cancer 1996;1403-1416
*Shin et al: Mod Pathol 2002:52A
*Bagaria S et al: Ann Surg Oncol 2011
Classic LCIS
*Page et al: Hum Pathol 1991;1232-1239
*Shin et al: Mod Pathol 2010:313A
Necrotic LCIS
Genes Chromosomes Cancer 2010;49:463-470
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
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Signet-ring cell LCIS
Signet-ring cell LCIS--aggressive biomarkers
E-cad
Mucicarmine stain
ER
Distinction of LCIS variant vs classic LCIS
HER2
Outline of Talk
(both: solid pattern, discohesive cells, E-cadherin negative)
Classic LCIS
LCIS variant
Classic LCIS
Age
Postmenopausal (~60 y)
Perimenopausal (~50 y)
Presentation
Mammographic detection
Incidental microscopic
finding
Biomarker
Aggressive
Favorable
Adjacent
Invasive ca
Higher incidence
majority ILC
Lower incidence
ILC or IDC
Genetics
1q+/16q-, and more changes
1q+/16q-, no or few
other changes
Definition of lobular differentiation
Variants of LCIS
Clinical significance and management of LCIS
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LCIS in a core needle biopsy: Is excision needed ?
Which LN in CNB will be upgraded to
malignancy (DCIS, invasion)?
Controversial !
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)
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
Arpino 2004;
Subhawong 2010;
Renshaw 2006;
Alfonso 2012;
Brem 2008;
Desoouki 2012;
Menon 2008;
Hussain 2011*;
Luedtke 2011;
Rendi 2012
Outcome of lobular neoplasia in a CNB (II)
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;
Subhawong 2010;
Renshaw 2006;
Alfonso 2012;
Brem 2008;
Desoouki 2012;
Menon 2008;
Hussain 2011*;
Luedtke 2011;
Rendi 2012
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Management of LN in a core needle biopsy
Management of LCIS variants-A topic of ongoing inquiry, overall manage like DCIS
Consider excision if:
Found in core needle biopsy:
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)
Recommend excision
Found in excision:
Report margin status
Recommend re-excision if close or at the margin
? Adjuvant hormone therapy and radiation
Controversial if:
None of the above
ALH or minimal LCIS
Take home message for LCIS
Most classic LCIS as an incidental microscopic finding;
LCIS variants by mammographic detection
Selected references
•
•
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
•
•
Bagaria SP et al: The florid subtype of lobular carcinoma in situ: Marker or precursor
for invasive lobular carcinoma? Ann Surg Oncol 2011;18:1845-1851.
Chen YY et al: Genetic and phenotypic characterization of pleomorphic lobular
carcinoma in situ of the breast. Am J Surg Pathol 2009;33:1683-1694.
Da Silva L et al. Aberrant expression of E-cadherin in lobular carcinomas of the
breast. Am J Surg pathol 2008;32:773-83.
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;37:279-289.
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;34:1472-1479.
Rakha EA and Ellis IO. Lobular breast carcinoma and its variants. Semin Diagn
Pathol 2010;27:49-61.
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 2012:19:914-921.
Schnitt S and Morrow M. Lobular carcinoma in situ: Current concepts and
controversies. Semin Diagn Pathol 1999;16:209-223.
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;15:1044-1050.
LCIS variants: manage as DCIS
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Thank you!
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