Definition of DCISdistribute.cmetoronto.ca.s3.amazonaws.com/LMP1101/11_1230_Collins.pdfA proliferation of neoplastic epithelial cells confined to mammary ducts and lobules without

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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

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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

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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

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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

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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

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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

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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

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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

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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?

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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


LCISLCIS



lesionslesions


LVILVI

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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


LCISLCIS



lesionslesions


LVILVI

Other Intraductal Proliferative Lesions that May Mimic DCIS

• Usual ductal hyperplasia–Necrosis –UDH vs intermediate nuclear grade

DCIS

• Gynecomastoid hyperplasia• Collagenous spherulosis

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DCIS


UDH DCIS

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• Usual ductal hyperplasia–Necrosis–UDH vs. intermediate nuclear grade

DCIS


UDH IG-DCIS

UDH IG-DCIS

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• 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

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DCIS


Gynecomastoid Hyperplasia

Micropapillary DCISGynecomastoid Hyperplasia

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DCIS


Cribriform DCISCollagenous Spherulosis

LCIS in collagenous spherulosis

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LCIS in collagenous spherulosis

LCIS in collagenous spherulosisE-cadherin


LCISLCIS



lesionslesions


LVILVI

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LCISLCIS



lesionslesions


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

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• 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

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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

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• 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

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Practical Implications

Patients with large areas of DCIS with and without microinvasion should probably be managed similarly

?SLN biopsy


LCISLCIS



lesionslesions


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

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Invasive Cribriform Carcinoma

p63


LCISLCIS



lesionslesions


LVILVI

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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

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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

Definition of DCISdistribute.cmetoronto.ca.s3.amazonaws.com/LMP1101/11_1230_Collins.pdfA proliferation of neoplastic epithelial cells confined to mammary ducts and lobules without

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