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Challenges in the Diagnosis of
(Micro)Invasive Carcinoma
Adriana Corben, MD
Director Breast Pathology Fellowship
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Overview
• Microinvasion
– Helpful clues
– Immunostains and pitfalls in interpretation
– Clinical significance
• Invasive ca that mimics benign
• Invasive ca that mimics in situ
• Benign that mimics invasive ca
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Microinvasion
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2010 AJCC Staging Manual
• T1mi
• “Extension of cancer cells beyond the basement
membrane…as an invasive ca with no focus
measuring >1 mm”
• Not connected with CIS
• No need to subtype
• ‼ If multiple foci, should not be added together
• An attempt to quantify them should be included
• Prognosis is generally quite favorable
• Clinical impact of multifocality is not well understood
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Always r/o microinvasion if…
• High grade or comedo-type DCIS
– Other DCIS types can also have it
• Comedo-type or pleomorphic LCIS
• Extensive CIS
• Periductal lymphoid infiltrates
• Mucocele-like lesions
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Useful lower-power field tools
• Irregularity of the contour of the nests/glands
• Retraction around the invasive nests
• Tumor nests/glands without a lobulocentric
organization
• Chronic inflammation
• Reactive stroma
• Increased stromal cellularity
• DCIS: blurred edges of the duct wall due to
tangential sectioning
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Useful higher-power field tools
• Irregularity of the contour of the nests/glands
• No basement membrane (BM): tumor cells
directly abut the stroma/adipose tissue
• No myoepithelial cells on H&E
• Retraction around the invasive nests
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•DCIS with
smooth contours
(below)
•Microinvasive
carcinoma with
irregular contours
(above)
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IDC: absent lobular arrangement around benign
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Invasion
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•Stromal (periductal)
chronic inflammation
needs closer
evaluation
•‼ Useful: at final
margins → levels!
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Invasive lobular carcinoma with lymphocytes
HMW-CK
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Reactive stroma and increased stromal cellularity
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Microinvasive lobular simulates lymphocytes
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DCIS: tangential
sectioning of the
duct wall will
create a blurred
edge
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Helpful studies
• Definitive diagnosis is not always possible
on H&E
• ‼ Most useful adjunctive studies:
– IHC: at least 2 myoepithelial markers
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Assessing invasion by IHC
• Invasive carcinoma:
– Lack of both basement membrane and
myoepithelial cells
• Benign and in situ lesions:
– Presence of both basement membrane and
myoepithelial cells
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Myoepithelial cell markers
Marker Sensitivity Specificity
S-100 Good Unacceptable
Actin Good Poor
SMMHC Good Excellent
Calponin Excellent Very good
HMW-CK Very good Poor
Adapted from Yaziji, et al. Adv Anat Pathol 2000, 7:100-109
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Calponin
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Calponin: easily overlooked microinvasive carcinoma
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An H&E section
paired with 2
myoepithelial cell
markers is critical
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MOST COMMONLY
USED
USED RARELY USED
CALPONIN CK5/6 S100
SMMHC CD10
SMA 34B12
p63
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p63
•p53 family
•Nuclei only
•High sensitivity
•High specificity
•No myofibroblast
staining
•Positive in some
DCIS and IDC
(metaplastic)
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Tubular adenosis
Calponin
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SMMHC
Tubular adenosis
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Invasive tubular ca with SMA positive myofibroblasts
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Myofibroblast cross-reactivity of
myoepithelial cell markers
SMA +++
Calponin ++
SMMHC +
p63 -
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A HMW-CK paired with 2 myoepithelial cell markers is critical
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Lobular carcinoma
cells invade the
interlobular
collagenous stroma
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Multinucleated stromal giant cells
Cytokeratin
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Clinical significance of
microinvasion
• Studies in the past:
– small numbers
– varying definitions
– varying degrees of tissue sampling
• No clear differences from pure DCIS
• Clinical significance is unclear
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Single cells in the stroma:
what do they mean? De Mascarel, Cancer 2002; 94:2134
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Axillary LN involvement
and 10 yrs outcome
De Mascarel, Cancer, 2002
#pts %node+
DCIS 722 1.4%
DCIS +
single cells
in stroma
72 0
DDFS OS
DCIS 98% 96.5%
DCIS +
single cells
in stroma
97% 96.3%
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Single cells in the stroma:
what do they mean?
• No evidence that:
– Is associated with
axillary LN +
– Has adverse clinical
outcome
• In practice, we
consider them
microinvasion
• By using AJCC
definition pts will likely
have:
– Very low rate of ALNM
– Cure rate approaching
100% with good local
treatment
• Goal: identify this
subset of pts
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Invasive Carcinoma
that Mimics Benign
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Useful clues
• Glandular disarray
• Irregular tubules/glands of variable
size/shape/orientation
• Infiltration around benign
• Open glandular lumina
• Lack of BM and myoepithelium
• Stromal hypercellularity
• Stromal desmoplasia
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IDC mimicking benign adenosis
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SMMHC
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Invasive ductal carcinoma surrounding DCIS
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Invasive carcinoma within sclerosing adenosis
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IDC mimics benign breast, but no BM and myoepithelium
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Suspect ILC: Stromal hypercellularity and desmoplasia
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Invasive carcinoma
that mimics in situ
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Problematic patterns
• Nested invasion
• Blunt invasion
• Occlusive LVI
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Clues for nested invasion
• Too confluent and/or haphazard
distribution
• Large nests adjacent to completely normal
lobules
• Irregularities in the contour of the nests
• Reactive stroma (if present)
• The following two pictures show how IDC
can mimic DCIS
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Clues for blunt invasion
• Common in solid papillary carcinoma and
papillary carcinoma
• Too large nests
• Discontinuity along the periphery of the
nests
• Fat, collagen, large vessels or benign
glands entrapped
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Large size of
the nests
raises
concern of
blunt
invasion
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Case initially misdiagnosed as DCIS
p63 SMA
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IDC vs DCIS
Calponin
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Invasive Papillary Carcinoma
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p63
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Clues for occlusive LVI
• Buckshot distribution
• In arteries and veins
• Carcinoma associated with vascular
bundle
• D2-40 + and p63 –
• ‼ Issue: foci near margins
• The next 2 pictures show occlusive LVI
mimicking DCIS
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D2-40
• Ab to human
podoplanin
• Used to identify
lymphatic vessels
• Less myofibroblast
staining
• ‼ DCIS or LCIS with
retraction could be
misinterpreted as LVI
(and viceversa)
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Benign lesions that mimic
invasive carcinoma
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Sclerosing and pseudoinvasive
lesions
• Radial scar/complex sclerosing lesion
• Sclerosing adenosis
• Involvement of benign lesions by CIS
• Microglandular adenosis (MGA)
• Multinucleated stromal giant cells
• Mucocele-like lesions
• Sclerosing papillary lesions
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Radial Scar Nidus
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Tubular Carcinoma
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Radial Scar Nidus
DCIS UDH
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Sclerosing adenosis
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ALH in sclerosing
adenosis
Invasive lobular
carcinoma
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DCIS involving a sclerosing lesion
Calponin
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MGA vs Tubular ca:
• Fibrotic stroma
• Uniform, round
tubules
• No snouts
• Eosinophilic colloid-
like secretion
• Prominent BM
• ER negative
• S100 positive
• ‼ Myoep negative
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MGA reported associated with
ca in up to 25% of cases
• Rosenblum Am J Surg Pathol
1986;10:237
• James Am J Clin Pathol
1993;100:507
• Acs Am J Surg Pathol
2003;27:1052
• Resetkova Arch Pathol Lab
Med 2003;127:77
• Salarieh, Sneige Arch Pathol
Lab Med 2007;131:1397
AMGA
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MGA and Carcinoma
•Similar immunoprofile
• ER -
• Myoeps -
• S100 +
•Overlapping genetic
alterations
•Suggested transition as a
non-obligate precursor
Shin S, et al. Am J Surg Pathol
2009;33;496
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Recurrent issues with MGA
• Core biopsy
– Difficult to recognize
– Recommend excision
• Surgical specimen
– MGA at margin → complete excision
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Artifactual displacement
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Artifactual displacement
• Epithelium confined to
biopsy site
• Benign cytology with
round and “shrunken”
glands
• Benign primary lesion
• Myoepithelial cells may
or may not be retained
– More useful, if positive
– p63 more specific
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Summary
• Microinvasion
– Helpful clues
– Immunostains and pitfalls in interpretation
– Clinical significance
• Invasive ca that mimics benign
• Invasive ca that mimics in situ
• Benign that mimics invasive ca