Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
1
Page 1
Ductal Carcinoma in Situ:Current Issues and Differential Diagnosis
Laura C. Collins, M.D.Department of Pathology
Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, MA
Definition of DCIS
A proliferation of neoplastic epithelial cells confined to mammary ducts and
lobules without light microscopic evidence of invasion through the
basement membrane into the surrounding stroma
Incidence of DCISErnster, JNCI, 2002
DCIS now accounts for 20% of mammographically-detected breast cancers
DCIS detected in ~1 per 1300 screening mammograms
2
Page 2
Ductal Carcinoma in Situ (DCIS)
Natural history poorly defined
Biologic behavior of
screen-detected
DCIS unclear
Optimal treatment
controversial
Ductal Carcinoma in Situ (DCIS)
Factors determining
which DCIS will recur/progress
to IBC
Which patients can avoid additional therapy
beyond local excision
Risk Factors for Local Recurrence
Clinical factorsYoung age
Treatment factorsExtent of excisionUse of RTUse of Tamoxifen
Tumor factorsSize/extent of lesionNuclear gradeComedo necrosisArchitectural patternVolume of DCIS near
marginMargins
3
Page 3
Young Age and Local Recurrence• Young age has been shown to be a risk factor
for LR in several studies
• But questionable as to whether this is due to other pathology and surgery related factors such as higher grade, greater residual burden and smaller surgical excisions
• Others have shown no difference in LR for younger age
Young Age and Local RecurrenceHughes, JCO, 2009
Women treated with WE alone
Wapnir, JNCI, 2011
NSABP B17 and B24
Young Age and Local RecurrenceTuraka, J Surg Oncol, 2009
4
Page 4
Young Age and Pathologic Features of DCISCollins, Am J Surg Pathol, 2009
• ? As to whether differences in LR among young women are attributable to pathologic features
0.2745%55%
38%62%
45%55%
36%64%
Comedo necrosis AbsentPresent
0.489%57%34%
13%49%38%
11%50%39%
7%59%34%
DCIS nuclear grade LowIntermediate
High
77%
18.6
<45 yrs(n=111)
73%
14.2
45-54 yrs(n=191)
66%
10.8
55-64 yrs(n=160)
<0.000150%Cancerization of lobules
<0.000611.3Extent of DCIS (mean number of low power fields)
p-value65+ yrs(n=195)
Pathologic Feature (n=657)
Inv-IBTR Rates in NSABP B17 and B24 Trials
Wapnir, JNCI, 2011
19.4%
10.0%8.5%
BCS and Local Recurrence
Radiation therapy following breast-conserving surgery is now the standard treatment for most women with DCIS
However, the identification of patients who can be spared RT and be adequately treated by BCS alone is an importantclinical goal
5
Page 5
E5194 EXCISION ALONE WITHOUT RADIATION (+/-TAMOXIFEN): ELIGIBILITY
Hughes, JCO, 2009
• DCIS, locally excised• Two arms:
Low or intermediate grade ≤2.5 cmHigh grade ≤1cm (NG 3 + necrosis)
• Minimum margin width ≥3mm• Specimen sequentially sectioned and completely
embedded to determine grade, size, and margins• Post excision mag mammo negative for
microcalcifications
0 2 4 6 8
0.0
0.05
0.15
Low or intermediate grade
6.1% (4.0%, 8.2%)
Year
Even
t rat
e
14.8% (7.2%, 22.3%)
High grade
ECOG E5194: EXCISION WITHOUT RADIATION (+/-TAM)Ipsilateral events
Pinder, 2010, BrJCancer
Very high=High nuclear grade
>50% solid architecture>50% comedo necrosis
6
Page 6
Risk Factors for Local Recurrence
Clinical factorsYoung age
Treatment factorsExtent of excisionUse of RTUse of Tamoxifen
Tumor factorsSize/extent of lesionNuclear gradeComedo necrosisArchitectural patternVolume of DCIS near
marginMargins
BCT and Local RecurrenceCancer Research Network
Ref0.7-2.50.8-2.5
1.01.31.4
11149
234
5134139
Necrosis NonePunctateComedo
Ref0.6-2.50.4-2.5
1.01.21.0
41210143
2012282
Predominant nuclear grade LowIntermediate
High
Ref0.8-3.00.8-3.61.4-8.01.0-4.4
1.01.51.73.32.1
71102642677
2352332655
# of LPFs with DCIS 12-56-9
15-19>20
Ref1.6-4.11.7-6.3
1.02.63.3
18110636
608031
Margins NegativeClose (<1mm)
Positive
1.5
Relative Risk
-
Controls(n=394)
78
Cases(n=225)
1.1-1.9Symptomatic presentation
95%CI
JCO, 2010
7
Page 7
Application of MSK NomogramCancer Research Network
• Women with DCIS treated with breast conserving therapy
• 190 cases, 305 controls
5-Year Recurrence Probability: Observed vs. Nomogram Predicted
0
5
10
15
20
25
30
35
40
0 5 10 15 20 25 30 35 40
Nomogram Predicted 5-Year Probability of IBTR (%)
Obs
erve
d 5-
Yea
r Pro
babi
lity
of IB
TR (%
)
Genetic and molecular alterations underlying the various pathologic types of DCIS are emerging
An understanding of these alterations will provide important information regarding the biology of DCIS and will likely have an impact on pathologic classification and clinical management
Differential Diagnosis
8
Page 8
In most cases the diagnosis of DCIS is
straightforward
But, there is a great deal of pathologic heterogeneity
Invasive Cribriform Carcinoma Pleomorphic LobularCarcinoma in situ
Collagenous Spherulosis Lymphovascular Invasion
9
Page 9
The diagnosis of DCIS is not always
straightforward
The diagnosis of DCIS is not always
straightforward
7/19/10
How Often is the Diagnosis of DCIS a
Problem?
10
Page 10
Pathologist Agreement: Local vs. Central Dx
Summary
Problems with both under-diagnosis and over-diagnosis
9.9%708CRN DCIS7.4%662ECOG
7.0%123RDOG 56.2%818NSABP B-17
% Not DCIS#Study
DCISDCISADHADH Microinvasive Microinvasive carcinomacarcinoma
LCISLCIS
Problems in the Diagnosis of DCIS
Other Other intraductal intraductal
lesionslesions
InvasiveInvasivecarcinomacarcinoma
LVILVI
DCISDCISADHADH Microinvasive Microinvasive carcinomacarcinoma
LCISLCIS
Problems in the Diagnosis of DCIS
Other Other intraductal intraductal
lesionslesions
InvasiveInvasivecarcinomacarcinoma
LVILVI
11
Page 11
Distinction between ADH and DCIS
• ADH is composed of the same population of atypical epithelial cells as LG DCIS
• Incompletely filling the space• Some features of UDH• Comprises 2 spaces or less or 2mm or less
DCISDCISADHADH Microinvasive Microinvasive carcinomacarcinoma
LCISLCIS
Problems in the Diagnosis of DCIS
Other Other intraductal intraductal
lesionslesions
InvasiveInvasivecarcinomacarcinoma
LVILVI
Other Intraductal Proliferative Lesions that May Mimic DCIS
• Usual ductal hyperplasia–Necrosis –UDH vs intermediate nuclear grade
DCIS
• Gynecomastoid hyperplasia• Collagenous spherulosis
12
Page 12
Other Intraductal Proliferative Lesions that May Mimic DCIS
• Usual ductal hyperplasia–Necrosis –UDH vs intermediate nuclear grade
DCIS
• Gynecomastoid hyperplasia• Collagenous spherulosis
UDH DCIS
13
Page 13
Other Intraductal Proliferative Lesions that May Mimic DCIS
• Usual ductal hyperplasia–Necrosis–UDH vs. intermediate nuclear grade
DCIS
• Gynecomastoid hyperplasia• Collagenous spherulosis
UDH IG-DCIS
UDH IG-DCIS
14
Page 14
• HMW-CK immunostains may be particularly helpful in distinguishing UDH from intermediate nuclear grade DCIS in problematic cases
CK5/6, UDH CK5/6, IG-DCIS
HMW-CK in Intraductal Proliferative Lesions
Caveats
• Not helpful in distinguishing ADH from LG-DCIS or IG-DCIS (all generally negative for HMW-CK)
• Some HG-DCIS are HMW-CK-positive
15
Page 15
Other Intraductal Proliferative Lesions that May Mimic DCIS
• Usual ductal hyperplasia–Necrosis –UDH vs intermediate nuclear grade
DCIS
• Gynecomastoid hyperplasia• Collagenous spherulosis
Gynecomastoid Hyperplasia
Micropapillary DCISGynecomastoid Hyperplasia
16
Page 16
Other Intraductal Proliferative Lesions that May Mimic DCIS
• Usual ductal hyperplasia–Necrosis –UDH vs intermediate nuclear grade
DCIS
• Gynecomastoid hyperplasia• Collagenous spherulosis
Cribriform DCISCollagenous Spherulosis
LCIS in collagenous spherulosis
17
Page 17
LCIS in collagenous spherulosis
LCIS in collagenous spherulosisE-cadherin
DCISDCISADHADH Microinvasive Microinvasive carcinomacarcinoma
LCISLCIS
Problems in the Diagnosis of DCIS
Other Other intraductal intraductal
lesionslesions
InvasiveInvasivecarcinomacarcinoma
LVILVI
18
Page 18
DCISDCISADHADH Microinvasive Microinvasive carcinomacarcinoma
LCISLCIS
Problems in the Diagnosis of DCIS
Other Other intraductal intraductal
lesionslesions
InvasiveInvasivecarcinomacarcinoma
LVILVI
Features of DCIS Associated with Microinvasion
High grade/comedo histologybut, may also be seen in association with other grades/types of DCIS and with LCIS
Extent (size, number of involved ducts)
Periductal lymphoid infiltrates
19
Page 19
• Over-diagnosis--DCIS may have areas that mimic invasion
» Duct branching» Involvement of lobules» Involvement of benign sclerosing
lesions» Distortion of involved spaces» Tangential sectioning» Crush artifact» Cautery effect» Artifactual displacement of DCIS
cells--Defensive pathology
Problems in Distinguishing “Pure” DCIS from DCIS with Microinvasion
20
Page 20
Distinction Between Mimics of Invasion and Real Invasion
Not always possible on H and E sections, even with multiple levels
Immunostains for myoepithelial cells
SMMHC
21
Page 21
• Over-diagnosis--DCIS may have areas that mimic invasion
» Duct branching» Involvement of lobules» Involvement of benign sclerosing
lesions» Distortion of involved spaces» Tangential sectioning» Crush artifact» Cautery effect» Artifactual displacement of DCIS
cells--Defensive pathology
• Under-diagnosis– Microinvasive foci may
be over-looked– Microinvasive foci may
not be sampled
Problems in Distinguishing “Pure” DCIS from DCIS with Microinvasion
22
Page 22
Practical Implications
Patients with large areas of DCIS with and without microinvasion should probably be managed similarly
?SLN biopsy
DCISDCISADHADH Microinvasive Microinvasive carcinomacarcinoma
LCISLCIS
Problems in the Diagnosis of DCIS
Other Other intraductal intraductal
lesionslesions
InvasiveInvasivecarcinomacarcinoma
LVILVI
Invasive Cancers that May Mimic DCIS
Invasive cribriform carcinoma
Adenoid cystic carcinoma
Invasive carcinomas in rounded nests–Papillary carcinomas (esp, solid papillary
carcinoma)– Invasive ductal
23
Page 23
Invasive Cribriform Carcinoma
p63
DCISDCISADHADH Microinvasive Microinvasive carcinomacarcinoma
LCISLCIS
Problems in the Diagnosis of DCIS
Other Other intraductal intraductal
lesionslesions
InvasiveInvasivecarcinomacarcinoma
LVILVI
24
Page 24
LVI Mimicking DCISHelpful clue: Pattern of cell nests conforms to location of normal lymphovascular spaces rather than structure of ductal-lobular system
»Vascular bundles»Periductal» Interlobular stroma»Try to assess relationship of worrisome
nests to identifiable ducts and lobules
25
Page 25
ConclusionsCurrent issues with management
Diagnosis of DCIS straightforward in most cases
Problems with both under-diagnosis and over-diagnosis
With careful attention to histologic cues and judicious use of appropriate immunostains, correct diagnosis should be possible in virtually all cases
Genetic and molecular alterations underlying the various pathologic types of DCIS beginning to emerge
An understanding of these alterations will provide information regarding the biology of DCIS and have an important impact on classification and management