QuestionsWhat are the histological differences

between atypical ductal hyperplasia (ADH), ductal carcinoma in-situ (DCIS), atypical lobular hyperplasia (ALH) and lobular carcinoma in-situ (LCIS)? How do they each behave?

What are the management options for DCIS and what is the evidence?

What surveillance is recommended for DCIS?

Benign Breast DiseaseNonproliferativeProliferative without atypiaProliferative with atypia

ADH ALH LCIS

Considered “high risk” as they are associated with an increase in the patient’s future risk of developing breast cancer

Not “premalignant”

Aytpical Hyperplasia (AH)Atypical Ductal Hyperplasia

(ADH)Characterised by proliferation

of uniform epithelial cells with monomorphic round nuclei filling part, but not all of the involved duct

Shares some of the cytologic and architectural features of low-grade DCIS

Atypical Lobular Hyperplasia (ALH)Characterised by proliferation

of monomorphic, evenly spaced, dyshesive cells filling part, but not all, of the involved lobule

Can also involve ductsShares some cytologic and

architecural features of LCIS

ADHDCIS and invasive breast cancer is identified

in 33-87% of subsequent excision biopsies reported as ADH in the core biopsy

Risk of Cancer After AHAH (especially multifocal lesions)

Increased risk (RR 3.7-5.3) in ipsilateral and contralateral breast (higher in ipsilateral)

Conflicting data to suggest that the risk is higher with ALH than ADH

Relative risk increases when ADH occurs in women with a family history of breast cancer in a 1st degree relative to 10 times that of the general population with no family history

Lobular NeoplasiaSpectrum of proliferative changes within the

breast lobule that includes both atypical lobular hyperplasia (ALH) and LCIS

Both associated with increased risk of invasive breast cancer

LCIS is non-invasive, multicentric proliferation of the epithelial cells in the lobules and terminal ducts of the breast

HistologyLCIS diagnosed when all of the following

occur:Cellular proliferation is characterised by

round, cuboidal or polyganal cells that are regularly arranged and evenly spaced

Cell nuclei are predominantly round, monotonous and hyperchromatic

Proliferation involves, distends and distorts at least half the acini in the terminal duct-lobular unit and fills involved lobular spaces, resulting in the absence of central lumia

ALH is diagnosed with a lesion fails to meet at least one of the diagnostic criteria for LCIS in over 50% of acini within a lobular unit

LCIS

Cancer RiskALH RR 3-4 (compared with general

population)Greater risk in ipsilateral breast

LCIS RR 7-9Appears to be as common in the contralateral

breast as in the ipsilateral breastPleomorphic variant appears to have an

aggressive biologic profile

Management and Follow-UpCore Bx of ADH excision biopsy due to

association with DCIS or invasive breast cancer

No strong evidence about whether to perform excision biopsy on women with LCIS or ALH on core Bx

Surveillance appears to be best the best management option for women who have been diagnosed with ADH, LCIS or ALH as the only abnormality (annual clinical examination, annual bilateral mammography for at least 15 years following diagnosis)

Management and Follow-UpNo role for CLE or mastectomy in the

management of ADH, LCIS or ALHInsufficient evidence to recommend the use

of tamoxifen for prevention of invasive breast cancer following a diagnosis of ADH, LCIS or ALH (Australian Guidelines)

DCISDefinition

Abnormal proliferative condition of epithelial cells in the mammary ducts

Cells display cytological features of malignancy but unlike invasive cancer, DCIS is confined within the ducts

Why is it clinically significant?Historically data suggests that 20-30% of

untreated DCIS progresses to invasive cancer

No reliable predictors for probability to progression to invasive carcinoma

Risk may be greater when DCIS displays features such as comedo necrosis or high nuclear grade

Natural history is largely unknown

Histology5 architectural subtypes: comedocarcinoma, solid, cribiform, papillary and micropapillary

Majority show a mixture of patterns

Malignant polyclonal population of cells limited to ducts and lobules by the basement membrane

Paget’s DiseaseDCIS arising within the

ductal system that extends up the lactiferous ducts and into the skin of the nipple without crossing the basement membrane

DiagnosisMost commonly detected as

mammographic caclificationBI-RADS Classification

0. Incomplete1.Negative2.Benign3.Probably benign4.Suspicious5.Highly suggestive of malignancy6.Known biopsy-proven malignant

General Principles of ManagementSmall, mammographically detected lesions should be

treated with complete local excisionIf disease is extensive, total mastectomy may be a

more reliable treatmentRCTs demonstrate a reduction in DCIS recurrence

and invasive breast cancer if radiotherapy is performed after CLE

ALND is not indicatedChemotherapy has never been investigatedTamoxifen in the adjuvant setting reduces risk of

DCIS recurrence and invasive breast cancerMDT

•Surgery (breast and axilla)•Radiotherapy•Chemoprophylaxis

SurgeryAim is to ensure complete excision with best

possible cosmetic resultPre-operative localisation is essential for a

mammographically detected impalpable lesionOptimal margins

No reliable definitionMust be completely excised“Clear margins” (no DCIS at section edge) provides

acceptable local control when combined with radiotherapy

<1mm considered inadequate

SurgeryAxillary Dissection

No place for ALNDWhat about SLNB?

High suspicion for invasive cancer Large size Aggressive histologic features Palpable mass

Surgery that will compromise ability to perform SLNB in the future

SurgeryMastectomy

Widespread contiguous or multi-focal DCISWidespread microcalcification in the presence

of proven DCISRecurrence of DCIS following initial treatmen

when either of the above indiciations is presentWoman’s choiceOther relevant risk factors for breast cancer

RadiotherapyLower recurrence rate demonstrated (4 RCTs)

when DCIS is treated with complete local excision (CLE) and adjuvant radiotherapy compared with CLE alone regardless of grade and pathological subgroup

Insufficient statistical power to detect small differences in survival

2009 Meta Analysis of RTx compared to no further treatment following excision showed RTx resulting in reduction in risk of all ipsilateral breast events (HR 0.49; 95% CI 0.41-0.58)

Risk of RecurrenceRelatively low for DCIS with good prognostic

pathological featuresClear marginsLow-gradeNo necrosisSmall extent (<10mm)

High grade DCIS with necrosis, close margins and larger size should have radiotherapy

Systemic TreatmentChemotherapy

Never investigated or used in treatment with DCIS

Systemic TreatmentTamoxifen

Must have ER + diseaseIn women who have breast conservation treatment,

postoperative tamoxifen is more effective than placebo in reducing the risk of invasive breast cancer (NSABP B-17 and B-24) (8.5 vs 10%

Meta-analysis (2009): Tamoxifen reduces recurrence risk of ipsilateral breast (HR 0.75, 95%CI 0.60-.092), trend to reduction in risk of invasive carcinoma (HR 0.79, 95%CI 0.60-1.01), lower risk for contralateral carcinoma (HR 0.57, 95%CI 0.39-0.83)

No apparent survival benefitRisks: endometrial cancer, VTE

Systemic TreatmentNCCN 2013 Guidelines

Consider tamoxifen for 5 years: Patients treated with breast conservation, especially if

ER + Patients treated with surgery alone and ER +

Australian Guidelines 2003Further research required, tamoxifen may

reduce risk of subsequent local invasive breast cancer in women who have had breast conservation treatment

No data for aromatase inhibitorsLimited data for HER2-directed therapy

The EvidenceLocal Recurrence Rates (%)

Trial No. of Patients

Follow up (yr)

CLE CLE + XRT

CLE + XRT + Tam

p value

NSABP B-17

818 12 30.8 14.9 <0.000005

EORTC 10853

1010 4.25 16 9 <0.005

UK ANZ 1707 5 20 8 6 <0.0001

SweDCIS

1067 5 7 22 <0.0001

NSABP B-24

1807 7 9 6 0.04

Post Treatment SurveillanceOverall survival for women >67 is similar to

those without breast cancerWomen >67 are more likely to die of

cardiovascular disease than breast cancerAustralian Guidelines

No evidence defining optimum follow-up protocol

Consensus recommendation is for annual review with examination and mammography indefinitely

Post Treatment SurveillanceNCCN Guidelines

Interval history and physical examination every 6-12 months for 5 years then anually

Mammogram annually and 6-12 months post radiation therapy if breast conserved

Breast awarenessIf treated with tamoxifen

Annual gynae assessment Opthalmology exam Manage symptoms as per guidelines