Ductal Carcinoma In Situ (DCIS) - USCAPuscapknowledgehub.org/site~/101st/pdf/companion26h02.pdf ·...
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3/13/2012
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Ductal Carcinoma in Situ Morphology-Based Knowledge
and Molecular Advances
Edi Brogi MD, PhD
Attending Pathologist
Director of Breast Pathology
• Morphology
• Molecular studies
• Immunoreactivity
• Prediction studies
Ductal Carcinoma In Situ
(DCIS)
• Historically, DCIS accounted for only 1-2%
of all breast cancer
• At present, DCIS accounts for 20-30% of
all newly diagnosed breast cancer
*Jemal et al., CA Cancer J Clin 2009;59:225
DCIS: A CHANGING ENTITY
Adapted from Silverstein & Lagios, Oncology 11:393 (1997)
Incidence of DCIS
Virnig BA, JNCI 2010
screening
mammography
Ductal Carcinoma In Situ (DCIS)
Neoplastic intraductal lesion
characterized by
– increased epithelial proliferation
–subtle to marked cellular atypia
–an inherent, but not necessarily
obligate tendency for
progression to invasive breast
cancer.
WHO 2003
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DCIS nuclear grade
feature Grade I
(low)
Grade II
(intermediate)
Grade III
(high)
pleomorphism monotonous
(monomorphic) intermediate
markedly
pleomorphic
size
1X to 2X RBC or
normal ductal cell
nucleus
intermediate
>2.5X RBC or
normal ductal cell
nucleus
chromatin diffuse, finely
dispersed intermediate
vesicular with
irregular chromatin
distribution
nucleoli occasional intermediate prominent, often
multiple
mitoses occasional intermediate may be frequent
orientation polarized toward
luminal space intermediate
usually not
polarized toward
luminal space
Lester S, DCIS protocol, Arch Pathol Lab Med, 2009
Nuclear Grade
low
intermediate
high
E-cadherin
ER
DCIS architecture
Many different patterns
• Cribriform
• Solid
• Papillary
• Micropapillary
• Spindle
• Flat (clinging)
– low NG excluded
• “Pagetoid”
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Necrosis absent
extensive
“comedo” type
necrosis
• Common in high or
intermediate nuclear
grade DCIS
• Often associated with
coarse Ca2+
• Linear branching
pleomorphic Ca2+ on
mammogram
small laminated Ca2+
(calcified secretions) coarse Ca2+ in necrosis
Increased incidence of DCIS
due to increase of non-comedo type R
ate
pe
r 1
00
,00
0 p
op
ula
tio
n
with comedonecrosis
without comedonecrosis
Virnig BA, JNCI 2010
(modified)
DCIS size
• Important to estimate
– probability of residual cancer in the breast
– margin status
– risk of local recurrence
DCIS size Only one slide with DCIS report largest microscopic span
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DCIS size
-Entire specimen is sectioned in
sequence and block location
recorded.
-The size of DCIS can be
determined from the location of
the involved blocks.
-The number of blocks
containing DCIS is used to
estimate the extent:
Serial sequential sampling
# blocks X 0.4 cm thickness of tissue = extent
Lester S, DCIS protocol, Arch Pathol Lab Med, 2009
DCIS size
- The specimen is sampled,
but not in sequence.
- The number of blocks
containing DCIS is used to
estimate the extent
# blocks X 0.4 cm thickness of tissue = extent
Nonsequential sampling
Lester S, DCIS protocol, Arch Pathol Lab Med, 2009
DCIS size
Margins
- If DCIS involves two
opposing margins, the
distance between the
margins can be used as
the extent of the DCIS in
the specimen.
Lester S, DCIS protocol, Arch Pathol Lab Med, 2009
DCIS size correlates with residual
disease at re-excision
and margin status
Cheng L, JNCI 1997, 89:1356-1360
January 31, 2012
Breast Cancer Surgery Rules
Are Called Unclear
• Positive margin = tumor at ink
• Close margin?
Usually <2mm, but also <1mm or <3mm
• Negative margin?
NSABP definition = no tumor at ink
>2 mm? >5 mm? >10 mm?
N Engl Journal Medicine 1999
No need for RT if margin > 10 mm
Journal Clinical Oncology 2006
158 pts with DCIS Nuclear Grade 1 or 2; size <2.5 cm
Wide excision (margin>10 mm or re-excision w/o DCIS)
no radiotherapy, no tamoxifen
local recurrence rate 2.4% per patient-year (12% at 5 y)
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Solin LJ, Cancer 2005
margin status and local recurrence
of DCIS treated with excision + RT
• 1103 pts
• 10 centers
• Pos margin =
tumor at ink (10)
• Neg margin
– >2 or >2 mm (8)
– >2-3 mm (1)
– >3 mm (1)
margin status and local recurrence
of DCIS treated with excision +/- RT
RT overcomes the benefits of wider excision margins
Rudloff U., 2010 Ann Surgery
margin status and volume
of disease near margin
1 duct
<1 mm
3 ducts
<1 mm
2 ducts
<1 mm
• Volume of disease as # of foci
close (<1 mm) to margin 1 duct vs 2 ducts vs 3 ducts
• >2 foci of DCIS at <1 mm from
margin
high risk of LR w/o RT HR=3.37; p=0.002
greater benefit of RT
HR 0.14; p=0.004
Rudloff U, Ann Surgery 2010; 251:583-591
DCIS and IHC
ER, PR, HER2
Etc...
ER
• About 70% of DCIS is ER positive
– mean expression rate in 36 studies
– range 49-96.6%
• Significant positive correlation with PR
• Inverse correlation with nuclear grade
• Inverse correlation with HER2
Lari SA and Kuerer MH, J Cancer, 2011
ER in DCIS
and risk of local recurrence
• 329 pts
• excision alone between 1983-1994
• median F/U time 8.2 years
• Follow-up
– 72 pts with invasive recurrence
– 71 pts with DCIS recurrence
– 186 pts w/o recurrence
• ER neg status associated with DCIS recurrence
• No association in pts with invasive recurrence
Kerlikowske K, J Natl Cancer Institute, 2010
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Benefit of tamoxifen 4 randomized trials with excision of DCIS +/- RT
Correa C, JNCI monograph 41, 2010
HER2
• About 40% of DCIS is HER2 positive – mean expression rate in 36 studies
– range 9-67%
– assessment based on IHC and/or FISH
• HER2 more common in high grade DCIS
with necrosis
• HER2+ DCIS more likely to recur – recurrence 42% HER2+ vs 12% HER2-
Lari SA and Kuerer MH, J Cancer, 2011
Provenzano E, Eur J Cancer, 2003
DCIS and ER, PR
Assessment of ER suggested, but not required
Assessment of PR not required
HER2; no specific mention
Lester S, DCIS protocol, Arch Pathol Lab Med, 2009
Kerlikowske K, J Natl Cancer Inst, 2010;102:627-637
CK 5/6
• Basal CK
• Present in normal epithelium and UDH
• Not present in FEA, ADH, LG-DCIS
• Present in basal DCIS (discussed later)
• Can be useful in DDX of low grade
epithelial proliferation
– CK14 and 34BE12 show similar reactivity
CK5/6 CK5/6
J Pathol 2001
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DCIS one disease? many?
Nuclear Grade
low high
CARCINOID TUMOR
Low grade nuclei have smooth outline
fine and uniform chromatin Morphologic and cytologic criteria for diagnosis of
Low grade DCIS vs ADH vs UDH
Page DL Rogers LW
UDH ADH Low Grade
DCIS
NUCLEAR
ATYPIA absent low low
MORPHOLOGY not
polarized polarized polarized
ARCHITECTURE irregular,
not rigid
some
complex
and rigid
complex
and rigid
EXTENT not relevant <2 ducts or
< 2mm
>2 ducts or
>2 mm
UDH
ADH
LG-DCIS
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UDH
ADH
UDH
LG-DCIS
Columnar cell change
• Alteration of terminal duct
lobular units
• Often detected due to
associated Ca2+
• BIRADS 3 indeterminate Ca2+
CARCINOID TUMOR
Columnar cell change
immunoprofile
POSITIVE
ER, PR
Bcl-2, cyclin D1
Mib-1 Low (<3%)
NEGATIVE
HER2
GCDFP-15
Basal CKs (CK 5/6)
p53
Am J Surg Pathol 2005
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FLAT EPITHELIAL ATYPIA
SINGLE LAYER OF
MILDLY ATYPICAL
CELLS
STRATIFICATION OF
UNIFORM, CUBOIDAL
TO COLUMNAR CELLS
UP TO 3-5 CELL LAYERS
OFTEN CONTAINS
MICROCALCIFICATIONS
WHO 2003
MORPHOLOGY OF DCIS
ASSOCIATED WITH FEA
Collins L, Mod Pathol, 20, 1149-1155; 2007
LOW NUCLEAR GRADE P<0.0001
CRIBRIFORM AND/OR
MICROPAPILLARY P<0.0001
NO COMEDO NECROSIS P<0.001
NO STROMAL DESMOPLASIA P=0.02
NO STROMAL INFLAMMATION P=0.03
FEA
tubular carcinoma
TUBULAR CARCINOMA COLUMNAR CELL CHANGE
ALH and LCIS
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low grade mammary epithelial neoplasia
modified from
Abdel-Fatah, Am J Surg Pathol, 2007
del 16q (gain 1q)
CCC/FEA
ADH
LG-DCIS
tubular
Inv cribr
tubulolobular
LG inv ductal
ALH
LCIS ILC
E-cadherin
(CDH1 gene)
+
-
Low grade mammary
epithelial neoplasia • Low grade atypia
• Immunophenotype
– ERa, PR, bcl-2, cyclin D1 positive
– Mib1 low (<10% for inv ca)
– CK5/6, CK14, HER2 and p53 negative
– No HER2 gene amplification
– Distinct from high grade epithelial lesions
– “Intrinsic” Luminal A subtype Abdel-Fatah, Am J Surg Pathol, 2007
Abdel-Fatah, Am J Surg Pathol, 2008
Progression of breast carcinoma
what we believed before…
Lopez-Garcia M, Histopathology, 2010 J Pathol 2001
Clin Cancer Res 2008
Breast Cancer Res 2006
Mol Oncol 2010
Clin Cancer Res 2008
J Pathol 2012
Clin Cancer Res, 2008
Gene array profiles of
46 carcinoma in situ associated with invasion
45 DCIS
1 LCIS
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Clin Cancer Res, 2008
Correlation with
nuclear grade
ER, PR
HER2
p53
Ki67
Clin Cancer Res, 2008
low
high
“Intrinsic” Molecular Subtypes
of Invasive Breast Carcinoma
Perou CM, Nature 2000 Sorlie T, PNAS 2001
intrinsic molecular
subtypes
“molecular”
immunoprofile
ER PR HER2
Luminal A + + -
Luminal B + + +
HER2 - - +
basal
- - -
CK5/6+
and /or
EGFR+
Nielsen TO, Clin Cancer Res, 2004
Livasy CA, Mod pathol, 2006
“basal” DCIS
• 6% to 8% of DCIS
• Intermediate to high
nuclear grade
• ER-, PR-, HER2-
• CK 5/6 pos and/or
EGFR pos
• High Ki67
Bryan BB, Mod Pathol 2006
Livasy C, Hum Pathol 2007
“basal” DCIS
• DCIS found in BRCA1
germline mutation
carriers
– DCIS in BRCA2 germline
mutation carriers is usually
luminal type
Van De Groep P, J Clin Pathol 2009
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CK 5/6 immunoreactivity is not uniform
Livasy CA, Hum Pathol 2007
Bryan BB, Mod Pathol, 2006
Basal DCIS
p53 ki67
Livasy CA, Hum Pathol 2007
Basal DCIS
Follow-up study
• 392 women with DCIS
• ER, PR, HER2, CK 5/6 and EGFR
– 32/392 (8.2%) women had “basal” DCIS
• Median F/U 122 months (3-130)
Zhou W, BMC Cancer, 2010
Basal DCIS and LOCAL recurrence
Basal
Non-basal
Triple neg
Non-triple neg
Zhou W, BMC Cancer, 2010
Basal DCIS and ANY recurrence
Basal
Non-basal
Triple neg
Non-triple neg
Zhou W, BMC Cancer, 2010
What is the
morphologic
precursor of
basal DCIS?
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Tamimi RM, Breast Cancer Res 2008
“molecular”
subtype
(based on
IHC)
IHC profile DCIS
(n=272)
All inv
(n=2249)
Inv ductal
NOS
(n=1550)
p
DCIS
vs
all inv
p
DCIS
vs
inv
ductal
ER PR HER2 n (%) n (%) n (%)
Lum A + + - 170
(62.5)
1650
(73.4)
1053
(67.9) 0.0002 0.08
Lum B +/- +/- + 36
(13.2)
116
(5.2)
90
(5.8) <0.0001 <0.0001
HER2 - - + 37
(13.6)
128
(5.7)
107
(6.9) <0.0001 <0.0001
basal
- - -
21
(7.7)
245
(10.9)
223
(14.4) 0.15 0.005 CK5/6+
and /or
EGFR+
unclassified not available 8
(2.9)
110
(4.9)
77
(5.0) 0.15 0.14
Tamimi RM, Breast Cancer Res 2008
If DCIS present with inv ca, only inv ca was scored
“molecular” subtypes of DCIS
• Same subtypes as invasive carcinoma
• Each DCIS subtype likely precursor of
same invasive carcinoma subtype – Lum B DCIS Lum A invasive most common exception
Lopez-Garcia M… Reis-Filho J, Histopathology, 2010
BREAST CANCER PROGRESSION MODEL
HIGH GRADE
LOW GRADE
DCIS
Prediction of future events
DCIS invasive ductal
carcinoma
DCIS no event
NATURAL HISTORY OF DCIS
TREATED WITH BIOPSY ALONE
average
F/U
(yrs)
average
time to
recurrence
(yrs)
recurrences
% of
invasive
recurrences
overall
progression
to invasion
Betsill,1978 21.6 9.7 7/10 (70%) 6/7 (86%) 6/10 (60%)
Rosen, 1980 18 9.7 10/15 (68%) 8/10 (80%) 8/15 (53%)
Eusebi, 1989 16 5 1/7 (14%) 1/1 (100%) 1/7 (14%)
Page, 1982 16 6.1 7/25 (28%) 7/7 (100%) 7/25 (28%)
Page, 1995 29 10.8 10/25 (40%) 9/10 (90%) 9/25 (36%)
Sanders, 2005 31 13.8 12/28 (43%) 11/12 (92%) 11/28 (39%)
Collins, 2005 8.6 10.7 10/13 (77%) 6/10 (60%) 6/13 (46%)
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NATURAL HISTORY OF LOW GRADE
DCIS TREATED WITH BIOPSY ALONE
Invasive
carcinoma
develops
within 15 years
in 30% of pts
with untreated
LG-DCIS
Sanders ME, Cancer 2005
Overview of 4 randomized trials
with excision of DCIS +/- RT
Study Years
Patients
elegible
for analysis
Median F/U
(years)
NSABP B-17 1985-90 798 16.5
EORTC 10853 1986-96 918 10.4
SweDCIS 1987-99 1011 8.4
UK/ANZ 1990-98 1002 4.8
Correa C, JNCI monograph 41, 2010
Benefit of radiotherapy 4 randomized trials with excision of DCIS +/- RT
• Half of all LRs are
invasive
• Radiation reduces
LR by 50%
• RT benefit
independent of
any other factor
Correa C, JNCI monograph 41, 2010
Benefit of tamoxifen 4 randomized trials with excision of DCIS +/- RT
Correa C, JNCI monograph 41, 2010
Solin et al., J Clin Oncol 14:754 (1996)
% OF ACADEMIC PHYSICIANS RECOMMENDING
RADIOTHERAPY AFTER WIDE EXCISION OF DCIS
Ceilley et al., Cancer 2004;101:1958
Nuclear
grade
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MSKCC DCIS NOMOGRAM
Rudloff et al., 2010 J Clin Oncol 28:3762
MSKCC DCIS NOMOGRAM
CALIBRATION CURVES
5-YEAR IBTR 10-YEAR IBTR
Rudloff et al., 2010 J Clin Oncol 28:3762
MSKCC nomogram tested on
MD Anderson DCIS Cohort concordance index of 0.63
Yi M. JCO February 20, 2012 vol. 30 no. 6
NOMOGRAM VALIDATION WITH
HARVARD/KAISER POPULATION (N=495)
Collins et al., abstract 118
2012 USCAP meeting
12 gene RT-PCR assay
to assess DCIS score and
estimate risk of local recurrence
Proliferation
Genes
Hormone
Receptor Group
Reference
Group
Ki67
STK15
Survivin
cyclin B1
MYBL2
PR beta-actin
GADPH
RPLPO
GUS
TFRC GSTM1
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ECOG E5194 Prospective multicenter study DCIS
treated by excision alone
n = 670
Cohort 1: Low/intermediate grade, size < 2.5 cm
Cohort 2: High grade, size < 1 cm
Treatment:
Surgical excision with at least 3 mm margin
No radiotherapy
Some pts received tamoxifen
Hughes LL, JCO 2009
12 gene RT-PCR assay to assess DCIS score and
estimate risk of local recurrence
347 patients with 10 year follow-up
ANALYSIS
• Continuous variable
• 3 risk groups
• Low risk (score < 39)
• Intermediate risk (score 39 – 54)
• High risk (score > 55)
• Data presented at SABCS 2011, not yet published
DCIS
• heterogeneous disease
– “intrinsic” molecular subtypes +/- IHC correlation
– no mention of “molecular” classification in dx
• Breast conservation
– RT reduces local recurrence by half
– Hormonal therapy benefit in ER+ DCIS
• Tools for prediction of local recurrence
– MSKCC DCIS nomogram
– 12 gene assay
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