Ductal Carcinoma In Situ (DCIS) - USCAPuscapknowledgehub.org/site~/101st/pdf/companion26h02.pdf · Ductal Carcinoma In Situ (DCIS) ... FEA TUBULAR CARCINOMA tubular carcinoma . COLUMNAR

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


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


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.


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


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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Correlation with

nuclear grade

ER, PR

HER2

p53

Ki67


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


Basal DCIS and ANY recurrence

Basal

Non-basal

Triple neg

Non-triple neg


What is the

morphologic

precursor of

basal DCIS?

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13

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


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


Benefit of tamoxifen 4 randomized trials with excision of DCIS +/- RT


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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18. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA: a cancer journal for clinicians. 2009;59:225-249. 19. Kerlikowske K, Molinaro AM, Gauthier ML, et al. Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. Journal of the National Cancer Institute. 2010;102:627-637. 20. Lari SA, Kuerer HM. Biological Markers in DCIS and Risk of Breast Recurrence: A Systematic Review. Journal of Cancer. 2011;2:232-261. 21. Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with ductal carcinoma in situ of the breast. Archives of pathology & laboratory medicine. 2009;133:15-25. 22. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Modern pathology. 2006;19:264-271. 23. Livasy CA, Perou CM, Karaca G, et al. Identification of a basal-like subtype of breast ductal carcinoma in situ. Human pathology. 2007;38:197-204. 24. Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, et al. Breast cancer precursors revisited: molecular features and progression pathways. Histopathology. 2010;57:171-192. 25. Muggerud AA, Hallett M, Johnsen H, et al. Molecular diversity in ductal carcinoma in situ (DCIS) and early invasive breast cancer. Molecular oncology. 2010;4:357-368. 26. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clinical cancer research. 2004;10:5367-5374. 27. Page DL, Dupont WD, Rogers LW, et al. Continued local recurrence of carcinoma 15-25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer. 1995;76:1197-1200. 28. Page DL, Dupont WD, Rogers LW, et al. Intraductal carcinoma of the breast: follow-up after biopsy only. Cancer. 1982;49:751-758. 29. Page DL, Rogers LW. Combined histologic and cytologic criteria for the diagnosis of mammary atypical ductal hyperplasia. Human pathology. 1992;23:1095-1097. 30. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-752. 31. Provenzano E, Hopper JL, Giles GG, et al. Biological markers that predict clinical recurrence in ductal carcinoma in situ of the breast. Eur J Cancer. 2003;39:622-630. 32. Rosen PP, Braun DW, Jr., Kinne DE. The clinical significance of pre-invasive breast carcinoma. Cancer. 1980;46:919-925. 33. Rudloff U, Brogi E, Reiner AS, et al. The influence of margin width and volume of disease near margin on benefit of radiation therapy for women with DCIS treated with breast-conserving therapy. Annals of surgery. 2010;251:583-591. 34. Rudloff U, Jacks LM, Goldberg JI, et al. Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. Journal of clinical oncology. 2010;28:3762-3769. 35. Sanders ME, Schuyler PA, Dupont WD, et al. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer. 2005;103:2481-2484. 36. Silverstein MJ, Lagios MD. Use of predictors of recurrence to plan therapy for DCIS of the breast. Oncology (Williston Park). 1997;11:393-406, 409-310; discussion 413-395. 37. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. The New England journal of medicine. 1999;340:1455-1461. 38. Simpson PT, Gale T, Reis-Filho JS, et al. Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis. The American journal of surgical pathology. 2005;29:734-746.

39. Solin LJ, Fourquet A, Vicini FA, et al. Long-term outcome after breast-conservation treatment with radiation for mammographically detected ductal carcinoma in situ of the breast. Cancer. 2005;103:1137-1146. 40. Solin LJ, Kurtz J, Fourquet A, et al. Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. Journal of clinical oncology. 1996;14:754-763. 41. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:10869-10874. 42. Tamimi RM, Baer HJ, Marotti J, et al. Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast cancer research : BCR. 2008;10:R67. 43. Tavassoli FA, Devilee P, eds. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003. 44. van der Groep P, van Diest PJ, Menko FH, et al. Molecular profile of ductal carcinoma in situ of the breast in BRCA1 and BRCA2 germline mutation carriers. Journal of clinical pathology. 2009;62:926-930. 45. Vincent-Salomon A, Lucchesi C, Gruel N, et al. Integrated genomic and transcriptomic analysis of ductal carcinoma in situ of the breast. Clinical cancer research. 2008;14:1956-1965. 46. Virnig BA, Tuttle TM, Shamliyan T, et al. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. Journal of the National Cancer Institute. 2010;102:170-178. 47. Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. Journal of clinical oncology. 2006;24:1031-1036. 48. Yi M, Meric-Bernstam F, Kuerer HM, et al. Evaluation of a breast cancer nomogram for predicting risk of ipsilateral breast tumor recurrences in patients with ductal carcinoma in situ after local excision. Journal of clinical oncology. 2012;30:600-607. 49. Zhou W, Jirstrom K, Johansson C, et al. Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study. BMC cancer. 2010;10:653.

Ductal Carcinoma In Situ (DCIS) - USCAPuscapknowledgehub.org/site~/101st/pdf/companion26h02.pdf · Ductal Carcinoma In Situ (DCIS) ... FEA TUBULAR CARCINOMA tubular carcinoma . COLUMNAR

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