savitri krishnamurthy md professor of pathology the university … · 2020. 1. 30. · savitri...

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


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


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


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


• Type of biopsy device

• Needle gauge

• Extent of sampling

• Number of cores

• Specimen processing

• Accurate interpretation

• Radiologic - Pathologic Correlation

SENSITIVITY OF CNB FOR DIAGNOSIS


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


• 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


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


• 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

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



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


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


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


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


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


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

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 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


• Accurate Diagnosis

• Radiology - Pathology Correlation

• Multidisciplinary planning conference

Radiology, Pathology, Surgery, Cancer chemoprevention

Personalized Treatment Options

• Surgical excision

• Chemoprevention:

• Estrogen inhibitors

• Follow-up


• 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

savitri krishnamurthy md professor of pathology the university … · 2020. 1. 30. · savitri...

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