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Pathology Perspectives of High RiskBreast Lesions
Savitri Krishnamurthy MD
Professor of Pathology
The University of Texas MD Anderson
Cancer Center
HIGH RISK BREAST LESIONS
ELEVATED RISK OF BREAST CANCER
Heterogeneous Group of Lesions
Non-palpable
Pre-mammographic era - 3.6%
Current era - 12-17%
RECOGNITION OF THE LESIONS IN CORE NEEDLE BIOPSY IMPORTANT FOR CLINICAL MANAGEMENT
HIGH RISK BREAST LESIONS
HISTORICAL PERSPECTIVES
Study of 3000 benign breast biopsiesRisk of breast cancer development
Nonproliferative Proliferative without atypia
Atypicalhyperplasia
Dupont W.D Page D.L.,N Eng J Med, 1985
None 1.9 fold 5.3 fold
HIGH RISK BREAST LESIONS
Mathematic models to predict risk of development of breast cancer
Determination of the appropriate model to use taken in the context of the patient’s personal and family history
The models most commonly used :• Claus• BRCAPRO• Tyrer-Cuzick• Gail model
HIGH RISK BREAST LESIONS
CalcificationsMass lesionAsymmetry
DETECTION OF HIGH RISK BREAST LESIONS
IMAGE-GUIDED CNBStereotactic, Ultrasound, MRI
VacuumAssisted device8 – 12 gauge
AutomatedSpring loaded device14 – 18 gauge
Post biopsy imaging to
document the extent
of sampling of the imaging abnormality
HIGH RISK BREAST LESIONS
• Type of biopsy device
• Needle gauge
• Extent of sampling
• Number of cores
• Specimen processing
• Accurate interpretation
• Radiologic - Pathologic Correlation
SENSITIVITY OF CNB FOR DIAGNOSIS
HIGH RISK BREAST LESIONS
PROCESSING OF CNB FOR DIAGNOSIS
• Strategies to prevent loss of tissue fragments
• Maintain linear orientation of tissue cores with minimal kinking, twisting and distortion after
processing and before embedding
• Embedded such that the entire length of the core is represented in the tissue sections
• Study at least 2-3 levels of each tissue block generated from CNB
• Atypical ductal hyperplasia
• Flat epithelial atypia
• Atypical lobular hyperplasia
Lobular carcinoma in situ
• Papilloma
• Radial scar
• Mucocele-like lesion
HIGH RISK BREAST LESIONS
• Lesion can show a spectrum of changes ranging from benign to atypical to malignant
• Lesion can be associated with a higher grade abnormality
• Lesion can be a precursor of higher grade abnormality
• Lesion can be predictive of increased risk in the background breast parenchyma
HIGH RISK BREAST LESIONS
UPGRADE RATE FROM CNB DIAGNOSIS TO SURGICAL EXCISION
RISK FOR FUTURE DEVELOPMENT OF BREAST CARCINOMA
IMPLICATIONS FOR CLINICAL MANAGEMENT
VACUUM ASSICTED CNB
SURGICAL EXCISION
CHEMOPREVENTION
FOLLOW UP IMAGING
HIGH RISK BREAST LESIONS
• Group of lesions with a combination of specifically defined architectural and cytological features that predict an increased risk for subsequent development of breast cancer
• Proliferation of monomorphic, evenly placed, low nuclear grade epithelial cells involving TDLUs
Proliferative lesions that fulfill some but not all the criteria to make a diagnosis of Intraductal carcinoma (DCIS)QUANTITATIVE CRITERIA
• Involvement of less than 2 ductal spaces• Involvement of less than or equal to 2 mm area
ATYPICAL DUCTAL HYPERPLASIA
ATYPICAL DUCTAL HYPERPLASIA
ATYPICAL DUCTAL HYPERPLASIA
ATYPICAL DUCTAL HYPERPLASIA
ATYPICAL DUCTAL HYPERPLASIA
ATYPICAL DUCTAL HYPERPLASIA
FLORID DUCTAL EPITHELIAL HYPERPLASIA WITHOUT ATYPIA
FLORID DUCTAL EPITHELIAL HYPERPLASIA
FLORID DUCTAL EPITHELIAL HYPERPLASIA
ER CK5/6
ATYPICAL DUCTAL HYPERPLASIAER CK5/6
DISTINCTION OF ADH FROM DCIS
EXTENT OF ATYPIA : MORE THAN 2 DUCTAL SPACES, > 2MM
Conservative approach with CNB diagnosis
Relative risk3-5 fold increase applicable to both breasts
Genomic changesLOH 16q, 17p, 11q13. 16q loss
CHANGES SAME AS IN SITU AND INVASIVE LOW GRADE DUCTAL CARCINOMA
NON-OBLIGATE PRECURSOR OF INVASIVE CARCINOMA
ATYPICAL DUCTAL HYPERPLASIA
ATYPICAL DUCTAL HYPERPLASIA
UPGRADE RATE : 23% (0 - 62%)MANAGEMENT
SURGICAL EXCISIONFOLLOW UP : IMAGING,CHEMOPREVENTION
Extent of sampling of calcificationsNumber of TDLUs with ADH
Other features: single cell necrosis Nomogram :Age, menopausal status, hormone therapyPersonal H/O cancer, # cores involvedSolid growth patients, size, mass vs calcs
Khoury T et al Histopath 2015Pena A et al Breast Cancer Research Treat 2017
ATYPICAL DUCTAL HYPERPLASIA
MANAGEMENT
Imaging, Chemoprevention
Incomplete sampling >90% calcs sampled>2 TDLU involved ≤2 TDLU involvedSingle-cell necrosis No single cell necrosis
Krishnamurthy S et al Radiology 2015
Surgical Excision Follow-up
COLUMNAR CELL LESIONS
COLUMNAR CELL CHANGE WITHOUT ATYPIA
COLUMNAR CELL LESION WITH ATYPIA
FLAT EPITHELIAL ATYPIA
COLUMNAR CELL CHANGE WITH FLAT EPITHELIAL ATYPIA
FLAT EPITEHLIAL ATYPIA
COLUMNAR CELL LESIONS WITH ATYPIAFLAT EPITHELIAL ATYPIA
FLAT EPITHELIAL ATYPIA
COLUMNAR CELL LESIONS WITH ATYPIA
• Neoplastic alteration of TDLUs including oneor several layers of a single epithelial typeshowing low-grade cytological atypia
• 3.8% to 10% of benign breast biopsies
• Strong association with :
• ALH/LCIS
• ADH
• DCIS – low grade
• Tubular carcinoma
• Invasive carcinoma- low grade
DUCTAL CARCINOMA IN SITU
FLAT EPITHELIAL ATYPIA
ER CK5/6
Early lesion in the low-grade breast neoplasia pathway
Risk of progression to invasive carcinoma is very low
Relative risk: lower than ADH/ALH
FLAT EPITHELIAL ATYPIA
Systematic review to provide
treatment Recommendations
24 Articles included
POOLED UNDERESTIMATION RISKS FOR
(IN SITU) CARCINOMA
95% CI
CCL without atypia – 1.5% 0.6% to 4.0%
CCL with atypia – 9% 5% to 14%
CCL with ADH – 20% 13% to 28%
SURGICAL EXCISION CCL with atypia
CCL with ADH
Columnar Cell Lesions on Breast Needle Biopsies: ? Surgical Excision
Verschuur-Maes et al, Annals of Surgery, 2012
Interobserver Variability for Making a Diagnosis of Columnar Cell Lesions
Kappa coefficient
Columnar Cell Changes 0.38
Columnar Cell Hyperplasia 0.32
FEA 0.47
ADH 0.44
Gomes DS et al, Diagn Pathol 2014
FLAT EPITHELIAL ATYPIA
UPGRADE RATE 8% (0 - 21%)
MANAGEMENT
Incomplete sampling >90% calcs sampled>2 TDLU involved ≤ 2 TDLU involved
Follow-upSurgical Excision
LOBULAR NEOPLASIA
• 0.5 - 4% of benign breast biopsies
• Premenopausal women
Average age 49 years
• Multicentric in 85%
• Bilateral in 30-67%
Proliferation of small, non-cohesive cells with or without pagetoid spread to terminal ducts.
LCIS : More than half of acini of a lobular unit
distended and distorted by neoplastic cells
ALH : Lesser involvement
LOBULAR CARCINOMA IN SITU
ATYPICAL LOBULAR HYPERPLASIA
LOBULAR NEOPLASIA
GENETICS LOH at 11q13, 16q, 17p,
17q, 16p, 22q
Complex high level amplifications of 11q13
CCND1 locusDeletion of 16q22.1 CDH1gene mutation, promoter methylation to inactivate
E-cadherin gene
E-CADHERIN
LOBULAR NEOPLASIA
Risk is more for ipsilateral than contralateral breast carcinoma
RISK FACTOR AND NON-OBLIGATE PRECURSOR FOR SUBSEQUENT DEVELOPMENT OF CANCER
Relative Risk
4 to 12 fold increase
ALH half of LCIS
LOBULAR CARCINOMA IN SITU- VARIANTS
E-cadherinPleomorphic
ComedoMacroacinar
LOBULAR NEOPLASIA
TARGETED FINDING
◼ Mass lesions
◼ Indeterminate
calcifications
◼ Asymmetry / Thickening
Surgical excision
INCIDENTAL
◼ Follow-up
◼ Chemoprevention
UPGRADE RATE
ALH: 9% (0-67%)LCIS: 18% (0-60%Incidental : 2%
RADIAL SCAR/COMPLEX SCLEROSING LESION
Lobular architecture distorted by a sclerosing process with elastosis
RADIAL SCAR/COMPLEX SCLEROSING LESION
RADIAL SCAR
Small lesion with stellate configuration
COMPLEX SCLEROSING LESION
Larger lesion with complex features
Detected in 1.7% of breast biopsies
Can be multiple
Can be in both breasts
RADIAL SCAR
RADIAL SCAR
RADIAL SCAR
SMA
RADIAL SCAR/CSL
• Recognition of central area of fibroelastosis
• Document that the entrapped glands are benign
• Recognize florid hyperplasia without atypia
• Presence or absence of associated atypia: ADH/ALH/LCIS/DCIS/Invasive
• Correlate with imaging
• Relative risk : 1.7
Probability of finding atypia :Lesion >0.5 mmAge > 50 years
Not Premalignant
Risk related to pattern of atypia
RADIAL SCAR WITH ADH
RADIAL SCAR
UPGRADE RATE 7% (0 - 16%)
MANAGEMENT
>5mm IncidentalNot well sampled SmallWith atypia Well sampled
Surgical Excision Follow-up
• Mucin Containing Cysts which may rupture with extravasation of mucin into surrounding stroma
• Imaging target : Mass, Calcifications
• Epithelium lining the cysts
Benign ADH DCIS
MUCOCELE-LIKE LESIONS
MUCOCELE-LIKE LESIONBENIGN
MUCOCELE-LIKE LESIONATYPICAL
MUCOCELE-LIKE LESIONATYPICAL
MUCOCELE-LIKE LEISONATYPICAL
MUCOCELE-LIKE LESIONATYPICAL
Mucocele-like lesions of Breast
• Mucocele-like lesions of the breast
• 102 MLL from a single institution from a cohort of 13412 women
• >55 years old (42%)
• Atypical hyperplasia
27% vs 5%
• In women > 45 years no additional risk of breast cancer
Meares AL et al, Hum Pathol 2016
Concern for Undersampling Mucinous DCIS or Invasive Carcinoma
Mucocele – Like Lesion
without atypia
well sampled
Follow-up
with atypia or
not well sampled
Excision
Wang J, et al, Am J Clin Pathol, Collins LC, Adv Anat Pathol 2009
MUCOCELE-LIKE LESIONS
HIGH RISK BREAST LESIONS
• Accurate Diagnosis
• Radiology - Pathology Correlation
• Multidisciplinary planning conference
Radiology, Pathology, Surgery, Cancer chemoprevention
Personalized Treatment Options
• Surgical excision
• Chemoprevention:
• Estrogen inhibitors
• Follow-up
HIGH RISK BREAST LESIONS
• Current risk management approaches are based on population level risks-potential for over and undertreatment
• ? Clinicopathological and molecular predictors of which high risk lesions will progress to invasive carcinoma
Biomarkers to evaluate individual risk
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