Management of High Risk and
Premalignant Breast Lesions
Jill R. Dietz, MD, FACS
Women’s Health Institute
Development of Breast Cancer
Normal
Duct
Intraductal
Hyperplasia
Predict and
Prevent
Atypical
Ductal
Hyperplasia
Ductal
Carcinoma
In Situ
Invasive
Ductal
Carcinoma
Detect
and Treat
Overview
• Review of high risk lesions
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Histology?
How is the lesion identified?
What is the relative risk?
How is it managed?
Follow up?
Papilloma
• Histology
• If associated with dilated duct
then intracystic papilloma vs
non dilated sometimes called
ductal adenoma
• Proliferation of duct epithelium
on frond-forming fibrovascular
stroma
• Difficult dx by cytology or
frozen so excision
recommended
Papilloma
Identified
• Presents as Pathologic nipple discharge in 86% of
central and 29% of peripheral lesions (where they are
more commonly diagnosed as palpable mass or
mammographic density)
• Associated Risk
• 1% of breast cancer presents as PND and less than
10 % PND is caused by cancer
• Risk goes up with mammographically detected or
palpable (peripheral) papillomas and with Age
• Long-term RR is 2.5 to 3X
Papilloma
Papillomatosis
• Histology
• Also called epitheliosis
• More consistent with micropapillary ductal hyperplasia
than multiple papillomas.
• A ductal hyperplastic lesion in which a fibrovascular
structure supports papillary epithelial hyperplasia
• May occur along side of single or multiple papillomas
Papillomatosis
• Identified
• Pathologic nipple discharge
• Mammographic density or calcifications
• Associated Risk
• 10% risk of cancer on excision
• 3 to 4X subsequent risk
Complex Sclerosing Lesions
• Radial Scar (Sclerosing
Lesion)
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Sclerotic center with central core
of obliterated ducts, elastin
deposits
Corona of contracted ducts and
lobules with associated
proliferative lesions
• Collangenous
Spherulosis
• Hyperplastic epithelium forms
glands and acellular
spherules
• Less association with cancer
Radial Sclerosing Lesion
Identified
• As a mammographically detected spiculated mass
• More commonly identified in specimens of women with breast
cancer
• Multiple lesions in one breast not uncommon
• Age over 30 and under 60
• Associated Risk
• Risk is the chance of it being a cancer on excision vs RSL
• Risk is the associated lesions the most common being LCIS
LCIS (Lobular Carcinoma In situ)
• Histology
Always multiple ducts
Origin from TDLU
Signet-ring cells may be present
Non-palpable/ no mass
50-75% of one duct involved
Neoplastic cells with scant
cytoplasm and small, round,
bland, diploid nuclei in Type A
or classical LCIS
LCIS (Lobular Carcinoma In situ)
Identified
• Coincidentally in biopsy for proliferative lesion causing mass or
mammographic abnormality
• On needle biopsy of calcifications of associated sclerosing
adenosis or benign calcs (LCIS rarely forms calcifications) It is
not mammographically detectable
• Associated Risk
• 50% risk of LCIS in contralateral breast
• RR 8X and absolute 17% at 15 years (ref: Page Human Pathol
1991; 22:1232-1239
Pleomorphic LCIS
• Histology
Type B LCIS The cells are more
varied with hyperdiploid DNA
with more abundant cytoplasm
Difficult to differentiate b/w DCIS
with intralobular spread
Intracytoplasmic Mucin favors
diagnosis of LCIS mucin stain
may be helpful) and Signet
rings are more characteristic of
LCIS thann DCIS
Pleomorphic LCIS
Identified
• Coincidentally in biopsy for proliferative lesion causing mass or
mammographic abnormality
• On needle biopsy of calcifications of associated sclerosing
adenosis or benign calcs (LCIS rarely forms calcifications) It is
not mammographically detectable
• Associated Risk
• Maybe difficult to differentiate from DCIS
• 50% risk of LCIS in contralateral breast
• RR 8X and absolute 17% at 15 years (ref: Page Human Pathol
1991; 22:1232-1239
ALH (Atypical Lobular Hyperplasia)
• Histology
• Same features as LCIS
• Not suffieciently developed
• Qualitative and quantitative
factors distinguish from
LCIS (< 50 to 75% of one
lobule)
ALH (Atypical Lobular Hyperplasia)
Identified
• Coincidentally in biopsy for proliferative lesion
causing mass or mammographic abnormality
• On needle biopsy of calcifications of associated
sclerosing adenosis or benign calcs (rarely forms
calcifications)
• It is not mammographically detectable
• Associated Risk
ALH is considered a pre-malignant lesion
It is associated with an increased risk of BILATERAL
breast cancer 4.5-5 X more than average risk
ADH (Atypical Ductal Hyperplasia)
• Histology
Fills some but not all
criteria of DCIS
About 2 mm
Distinct cell borders,
increased nuc/cyto ratio,
nuclear enlargement,
irregular chromatin or
nucleoli
Changes associated with
proliferation.
ADH (Atypical Ductal Hyperplasia)
Identified
• Incidentally on biopsy for benign lesion
• On stereotactic biopsy of mammographic abnormality (usually
indeterminant calcs)
Associated Risk
ADH is considered a pre-malignant lesion
It is associated with an increased risk of BILATERAL breast
cancer 4.5-5 X more than average risk
EX: Dupont and Page: 3303 patients 2.2% NP dev Ca
4.3% with PDWA and 12.9% with atypia in 17 years
American J Epidemiol 1987; 1225: 769-779
Immediate Relative
Risk
Risk
Any Core Biopsy
2-10%
2X
Subareoalar papilloma
5-10%
2-3X
Distal papilloma
>10%
3X
Papillomatosis
10%
10-25%
13%
17%
26%
3-4X
2-5X
4-5X
8-10X
4-5X
Radial Scar
ALH
LCIS
ADH
Increase in Breast
Cancer Relative Risk
Atypical Results Diagnosed by
Cytology or Histology
Confer Similar Breast Cancer Risks
25
20
FNA Cytology
• Fabian, Kimler, et al
15
NAF Cytology
• Wrensch, Petrakis et al
10
5.0
4.3-5.3
Histology
• Dupont and Page
• Dupont et al
• Page et al
4.9
5
0
Atypical
Hyperplasia
with Atypia Hyperplasia
Atypical
Ductal
Hyperplasia
Increase in Breast
Cancer Relative Risk
Risks Rise in Parallel with Atypical
Cells and a Family History of Breast
Cancer
25
FNA Cytology
• Fabian, Kimler, et al
20
18
15
10
5
5.0
4.9
4.3-5.3
11-22
NAF Cytology
• Wrensch, Petrakis et al
Histology
• Dupont and Page
• Dupont et al
• Page et al
0
Atypia
Atypia w/o Fam Hx
Atypia + FHx
Atypia
with Fam Hx
Cytologic Atypia is Predictive
of Short-Term Outcome
The percentage of women with a 10-year Gail risk > 4
developing breast cancer within 3 years:
Without atypical cells:
With atypical cells:
4%
15%
The increase in breast cancer risk from atypical cells is
independent of the Gail risk.
Fabian CJ, Kimler BF, et al. J Natl Cancer Inst. 2000;92:1217-27
Management after Core Biopsy
Surgical Excision
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Borderline breast lesions: comparison of malignancy underestimation rates with 14-guage core needle biopsy versus 11-guage vacuumassisted device.
Londero V, et al
Eur Radiol. 2011 Jun 21(6): 1200-6. Epub 2011 Jan12
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All atypia diagnosed at stereotactic vacuum-assisted breast biopsy do not need surgical excision
De Mascarel I, et al.
Mod Pathol. 2011 May 20 (epub ahead of print)
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Management of lobular carcinoma in-situ and atypical lobular hyperplasia of the breast – a review
Hussain M, et al.
Eur J Surg Oncol. 2011 Apr; 37(4): 279-89
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Vacuum-assisted biopsy diagnosis of atypical ductal hyperplasia and patient management
Ancona A, et al.
Radiol Med. 2011 Mar; 116(2): 276-91. Epub 2011 Jan 12
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Atypical ductal hyperplasia in directional vacuum-assisted biopsy of breast microcalcifications: considerations for surgical excision
Nguyen CV, et al
Ann Surg Oncol. 2011 Mar;18(3): 752-61. Epub 2010 Oct 23
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Identifying patients with atypical ductal hyperplasia diagnosed at core-needle biopsy who are at low risk of malignancy
Albarracin CT, et al.
Radiology. 2010 Dec; 257(3): 893-4; author reply 984. No abstract available. Erratum in: Radiology. 2011 Mar; 258(3): 962. Weiang, Wei
(corrected to Yang, Wei).
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Outcome of breast lesions diagnosed as lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4) on needle core biopsy,
including detailed review of epithelial atypia
Rakha EA, et al.
Histopathology. 2011 Mar;58(4): 626-32
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Predictors of breast cancer development in women with atypical ductal hyperplasia and atypical lobular hyperplasia
Whiffen A, et al.
Ann Surg Oncol. 2011 Feb; 18(2): 463-7. Epub 2010 Sep 28
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Flat epithelial atypia of the breast: characteristics and behaviors
Sudarshan M, et al.
Am J Surg. 2011 Feb; 201(2): 245-50 Epub 2010 Sep 22
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Incidentally detected enhancing breast lesions on chest computed tomography.
Lin WC, Hsu HH, et al
Korean J Radiol. 2011 Jan-Feb; 12(1): 44-51. Epub 2011 Jan 3
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Immediate surgical resection of residual microcalcifications after a diagnosis of pure flat epithelial atypia on core biopsy: a word of caution.
Noel JC, et al.
Surg Oncol. 2010 Dec; 19(4): 243-6. Epub 2009 Sep 23
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Stereotactic vacuum-assisted breast biopsy is not a therapeutic procedure even when all mammographically found calcifications are
removed: analysis of 4086 procedures.
Penco S, et al
AJR Am J Roentgenol. 2010 Nov; 195(5): 1255-60
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Lobular carcinoma in situ/atypical lobular hyperplasia on breast needle biopsies: does it warrant surgical excisional biopsy? A study of 27
cases
O’Neil M, et al.
Ann Diagn Pathol. 2010 Aug: 14(4): 251-5
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Risk of upgrade of atypical ductal hyperplasia after stereotactic breast biopsy: effects of number of foci and complete removal of
calcifications
Kohr JR, et al.
Radiology. 2010 Jun; 255(3): 723-30. Epub 2010 Feb 19
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Lobular neoplasia: morphology, biological potential and management in core biopsies
O’Malley FP
Mod Pathol. 2010 May; 23 Suppl 2:S14-25
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Clinical importance of histologic grading of lobular carcinoma in situ in breast core needle biopsy specimens: current issues and
controversies
Gao F, et al.
Am J Clin Pathol. 2010 May; 133(5): 767-71
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Histology after lumpectomy in women with epithelial atypia on stereotactic vacuum-assisted breast biopsy.
Graesslin O, et al.
Eur J Surg Oncol. 2010 Feb; 36(2): 170-5. Epub 2009 Oct 6
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Flat epithelial atypia and atypical ductal hyperplasia: carcinoma underestimation rate.
Ingegnoli A, et al.
Breast J. 2010 Jan Feb; 16(1): 55-9. Epub 2009 Oct 13
Management: Prevention
Multiple national trials have looked at chemoprevention for
risk reduction
Tamoxifen was found to be preventative when the
contralateral breast cancer risk was halved in patients
receiving Tamoxifen as treatment
Breast Cancer Prevention Trial
(BCPT or NSABP P-1)
• 13,338 high-risk women randomized to daily
tamoxifen vs. placebo for 5 years
Enrollment criteria:
• 60 years of age or older, or
• 35-59 years old with 5-year predicted risk for breast
cancer of at least 1.66%, or
• a history of atypical hyperplasia or lobular carcinoma
in situ
Fisher B, Constantino JP, Wickerham DL, et al. J Natl Cancer Inst. 1998;90:1371-1388.
Breast Cancer Prevention Trial
(BCPT or NSABP P-1)
Results:
• Tamoxifen reduced the risk of invasive breast cancer by
49% (89 vs. 175).
• Greatest risk reduction (86%) was in women with
atypical ductal hyperplasia (ADH).
• Tamoxifen increased the rate of endometrial cancer
(36 vs. 15), stroke (38 vs. 24), pulmonary embolism
(18 vs. 6), and deep-vein thrombosis (35 vs. 22).
Fisher B, Constantino JP, Wickerham DL, et al. J Natl Cancer Inst. 1998;90:1371-1388.
BCPT Results: Cumulative
Rate of Invasive Breast Cancer
Events
Rate/1000
40
Placebo
Tamoxifen
175
89
Rate per 1000
43.4
22.0
Placebo
30
P < 0.00001
49%
reduction
20
Tamoxifen
0
1
0
0
1
2
3
4
5
Years
Adapted from Fisher B, Constantion JP, Wickerham DL, et al. J Natl Cancer Inst. 1998;90:1371-1388.
Breast Cancer Risk-Reduction for
Tamoxifen Trials
Total Breast Cancers
By Group
95% CI
Trial Name
Placebo
Tamoxifen
NSABP P-11
244/6,707
124/6,681
0.51
0.39-0.66
IBIS-11
101/3,566
69/3,578
0.67
0.49-0.91
Italian2
45/2,708
34/2,700
0.75
0.48-1.18
15/702
3/702
0.18
0.05-0.62
High-risk
OR
1. Chlebowski RT, Col N, Winer EP, et al. J Clin Oncol. 2002;20:3328-3343.
2. Veronesi U, Maisonneuve P, Rotmensz N. J Natl Cancer Inst. 2003:95:160-165.
Why Not Just Treat All High-Risk
Women With Tamoxifen?
• Less than 5% of high-risk women elect to take tamoxifen when
offered.1
• Tamoxifen has some serious side effects (particularly for
women ≥ age 50).2
Type of
event
Endometrial
cancer
Stroke
Pulmonary
embolism
Deep vein
thrombosis
1 Port
Risk Ratio
(all ages)
2.53
Risk Ratio
(ages ≥ 50)
4.01
1.59
3.01
1.75
3.19
1.60
1.71
ER, Montgomery LL, Heerdt AS, Borgen PI. Ann Surg Oncol. 2001;8:580-585.
2 Fisher B, Constantino JP, Wickerham DL, et al. J Natl Cancer Inst.1998;90:1371-1388.
Follow up of High Risk Lesions
• Is the lesion in a high risk patient?
ACS definition of very high risk
• Documented deleterious gene mutation in patient
• Gene mutation in family/ patient untested
• Therapeutic radiation to the chest (b/w age10 and 30)
• Lifetime risk of 20 to 25%
• Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba
syndromes
• ADH or LCIS AND positive family history
High Risk
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2 or more 1st degree relatives at young age
Prior personal history of breast cancer
Extremely dense breasts
HRT > 10 years
ADH, LCIS without family history
Follow up: Surveillance
• Factors to consider
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Age
Breast Density
Relative Risk of patient
Presentation of family members
Insurance
Patient is part of the decision making
Follow up: Surveillance
• Mammography
• Digital vs Analog
• MRI
• SBE
MRI
• Benefits
• No ionizing radiation
• Dense breasts do not interfere
• High sensitivity
• Limitations
• Expensive
• ? Lower specificity
MRI
• Internatioanl Breast Consortium in 2004 showed that
12% of cancers detected by mammogram or CBE were
not detected by MRI (lack of neoangiogenesis)
• MRI as an adjunct to mammography and BE and that a
neg MRI does not overrule a palpable or mammographic
finding just as a negative imaging workup does not
negate the need to biopsy a palpable finding.
JClin Oncol 2004; 22(suppl): 14S.
American Cancer Society Guidelines for Breast Screening with MRI as an
Adjunct to Mammography
Debbie Saslow, PhD; Carla Boetes, MD, PhD; Wylie Burke, MD, PhD; Steven Harms, MD;
Martin O. Leach, PhD; Constance D. Lehman, MD, PhD; Elizabeth Morris, MD; Etta Pisano,
MD; Mitchell Schnall, MD, PhD; Stephen Sener, MD; Robert A. Smith, PhD; Ellen Warner,
MD; Martin Yaffe, PhD; Kimberly S. Andrews; Christy A. Russell, MD (for the American Cancer
Society Breast Cancer Advisory Group)
ABSTRACT New evidence on breast Magnetic Resonance Imaging (MRI) screening has
become available since the American Cancer Society (ACS) last issued guidelines for the early
detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed
new recommendations for women at different defined levels of risk. Screening MRI is recommended
for women with an approximately 20–25% or greater lifetime risk of breast cancer,
including women with a strong family history of breast or ovarian cancer and women who were
treated for Hodgkin disease. There are several risk subgroups for which the available data are
insufficient to recommend for or against screening, including women with a personal history of
breast cancer, carcinoma in situ, atypical hyperplasia, and extremely dense breasts onmammography.
Diagnostic uses of MRI were not considered to be within the scope of this review.
CA Cancer J Clin 2007;57:75–89.) © American Cancer Society, Inc., 2007.
American Cancer Society Guidelines for Breast Screening with
MRI as an Adjunct to Mammography
Literature related to breast MRI screening published between
September 2002 and July 2006 was identified using
MEDLINE (National Library of Medicine), bibliographies of
identified articles, and unpublished manuscripts.
Expert panel members reviewed and discussed data during a
series of conference calls and a working meeting in
August, 2006. When evidence was insufficient
or lacking, the final recommendations incorporated
the expert opinions of the panel members.
CA Cancer J Clin 2007;57:75–89
CA Cancer J Clin 2007;57:75–89