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Ductal Carcinoma in Situ

Section: Breast Curriculum: Curriculum, page 10

Definition

  • Ductal carcinoma in situ (DCIS) is a neoplastic proliferation of mammary ductal epithelial cells confined to the ductal-lobular system without evidence of invasion through the basement membrane into the surrounding stroma

Heterogenous disease, probably two distinct entities

  1. Slow transition ADH → LG DCIS → LG IDC
    • Associated with ER +ve
  2. Fast transition HG DCIS → HG IDC
    • Associated with C-erbB2
    • Often larger area at time of diagnosis, younger patients

Epidemiology

  • Accounts for 20% of malignant lesions picked up during screening
    • Probably about 10% of all (screening + symptomatic)
  • Post-mortem studies: 10%
  • Can occur at any age, but declines with age
  • 60% detected by breast screen
  • Progression
    • 60% LG DCIS will become invasive by 40 years
    • 50% HG DCIS will become invasive by 7 years

Genetics

  • Abnormalities on chromosome 16q (low grade) and 17q (high grade)

Risk Factors

AJCC pathological staging

  • TMN (AJCC) – T
    • Tis (DCIS) = Ductal Carcinoma in situ

Clinical

  • Most (90%) asymptomatic; microcalcifications on mammogram = Only manifestation in 75-95%
  • Minority (10%) present with symptoms
    • Mass
    • Nipple discharge
    • Paget’s Disease of the Nipple

Histology

Progression

  • Starts as normal duct → Mild ductal hyperplasia = increased number of cells lining duct and remains uniform
  • Progress to Atypical ductal hyperplasia where both layers and cells become heterogeneous - bigger nuclei, more cell layer that arent uniform
  • DCIS defined >2 ducts or >2mm
  • IDC when these cells invade through the myoepithelial basement membrane
  • Note that nodal involvement → rare

Classification

  • Comedo (presence of luminal necrosis filling at least one duct with large pleomorphic nuclei and abnormal mitosis)
  • Non-comedo (all other subtypes)
    • Cribriform – fenestrated/sieve-like appearance
    • Solid - ducts filled with malignant cells, considered high-grade
    • Micro-papillary – tufts of cells project into duct lumen perpendicular to BM
    • Papillary - projecting tufts larger than micropapillary, and have fibrovascular core
    • Clinging (flat) – variable columnar alterations along duct margins
      • ? Is this truly pre-malignant
      • ? Should be categorised as atypical hyperplasia

Grade

  • Low Grade (Non-comedo necrosis)
    • Evenly spaced cells with central small nuclei, few mitosis and nucleoli not easily seen
    • ER +ve, low Ki67, low apoptosis and rarely HER2 +ve
  • Intermediate Grade
    • Between high- and low-grade features
  • High Grade (Comedo necrosis)
    • Pleomorphic cells with large irregular nuclei (3x size of RBC), prominent nucleoli and frequent mitosis
    • Often solid with comedo necrosis and calcification
    • Often HER2 +ve, or ERGF +ve, Rarely ER +ve, High Ki67, high apoptosis
  • Multicentric = Separate foci of tumour found in more than one breast quadrant or more than 5cm away from initial primary
    • Most DCIS is unicentric, only 1% DCIS multicentric
  • Multifocal = Separate foci in same quadrant that are close to each other
    • More commonly reported if high grade, poorly differentiated lesion

Histology - DCIS and Malignancy

Microinvasive Breast Cancer

  • Foci of tumour cells < 0.1cm in diameter invading the stroma
    • If becomes invasive – retains original morphology & grade
  • Staged as T1mi
  • Invariably encountered in the setting of ductal carcinoma in situ (DCIS)
    • Invasion is present in 25% of pts with DCIS
  • Likely should have SLNB although axilar usually negative
    • Nodal mets 1-10%; long term survival between DCIS & Stage 1

Extensive intraductal component (EIC)

  • DCIS surrounding an Infiltrating Ductal Ca (or within)
    • Definition = DCIS involving > 25% of the area of the invasive tumour, and also present at edge of tumour
  • Can be predicted by area of microcalcifications ≥ 30mm (+ mass) on pre-op mammogram
  • More common in tumours in younger women
  • EIC is possibly predictor of local recurrence
    • x 3-4 if EIC in tumour, but studies did not take positive margins into account
    • If clear margins, no increased rate of local recurrence
  • Tumours with EIC more likely to have residual tumour burden after WLE
  • Nodal involvement is rare
    • 1-2% rate of +ve nodes (from a missed microinvasive focus)

DCIS Investigations

Mammogram

  • Often underestimates extent of disease (esp. low grade micropapillary)
  • Calcifications (Seen in 75-95%)
    • NB: Only 25% of biopsies for calcifications yield carcinoma
  • Fine calcifications – more likely low-grade DCIS
  • Coarse granular/ casting calcifications – more likely high-grade DCIS
  • Soft tissue abnormality (seen in 10%)

MRI

  • esp. good for pts with no calcifications
  • DCIS MRI Sensitivity 90%
  • Compared to mammography sensitivity 75%
  • Good for assessing extent and distribution
  • NB: Substantial false +ve rate & cost ↑

FNA

  • Remember invasive malignancy cannot be excluded
  • Comedo (reported as malignant)
    • High cellularity, high grade nuclei, cellular dissociation, background necrosis, foamy macrophages
  • Non-comedo (reported as suspicious)
    • High cellularity, architectural features of papillary, low grade nuclei, palisading, monolayer sheets

Core Biopsy

  • Method of choice
  • Large core, preferably vacuum assisted (mammotome) → X-ray of biopsy to check calcifications
    • NB: 10-20% of DCIS on biopsy will have undiagnosed invasive component
    • Agreement with surgical Bx: 70-99%
  • Under-estimation on core: < 14G = 31%; Mammotome = 2%
  • Need to do ER/PR/HER-2 – gives prognostic information and Tamoxifen indicated as treatment

DCIS Management

Hook-wire WLE

  • WLE with hook-wire guidance preferable (Breast Conserving)
    • Aim for 1cm margins intra-op
    • Orientate specimen
    • Cavity should be marked with clips
    • X-ray specimen to determine if calcifications/mass present
  • Need to consider
    • Size of area to be excised vs size of breast and location
  • If patient cannot have radiotherapy, then cannot have conservative surgery
  • 2mm histological margins acceptable
    • Involved margins - Re-excise
    • Close margins – (< 2mm but not involved)
      • Consider – age, size, grade, presence of comedo necrosis, which margin (deep/ superficial), extent approaching margin
  • Recurrence higher with:
    • Close margins = Strongest predictor of recurrence
    • High grade DCIS (22% recurrence) or DCIS with comedo necrosis (18% recurrence)
    • Poorly Differentiated tumours
    • Young age (< 40 yrs)
    • Size – Not really a factor if you exclude > 4cm lesions which should be tx with mastectomy
    • Can use University of Southern California/Van Nuys Prognostic index (USC/VNPI) which looks at size, margins, pathological classification and patient age to give a score between 4-12 on likelihood of recurrence over next 5 years. 4-6 low risk, 7-9 inter, 10-12 high risk

Mastectomy (+/- Reconstruction)

  • Consider if:
    • Large + poor cosmetic outcome anticipated
    • Multifocal
    • Inability to undergo radiotherapy + High grade

Sentinel lymph node biopsy

  • Indications not clear
  • General consensus: SLNBx if mastectomy
    • Mastectomy ± reconstruction make future SNB impossible
  • But may consider in certain patients:
    • Large volume (> 4.5cm)
    • High-grade
    • Suspicion of invasive disease
    • Mass palpable or suggested on imaging

Axillary Dissection

  • Not indicated, < 2% chance of LN involvement

Radiation

  • All women undergoing breast conserving surgery should be considered for radiotherapy and discussed at MDM level - NZGG/NICE
    • NSABP B17
      • RT vs no RT, included occult invasive cancers & +ve margins
        • Increase event free survival
        • Decreased ipsilateral breast cancer
        • Decreased recurrent DCIS and invasive disease by 50%.
        • No improvement of overall survival!

Van Nuys Prognostic Index

Scoring system used to predict outcomes

  • Score ranges from 4 to 12
  • Score 4-6 = Excision only
  • Score 7-9 = Excision + Radiotherapy
  • Score 10-12 = Mastectomy

Adjuvant Therapy

Tamoxifen

  • NZGG says “consider” after WLE if
    • ER +ve & high risk
      • e.g. Age < 45yrs, involved margin, Comedo necrosis
  • NICE says only if no radiation
  • Conflicting reports
  • NSABP-B24
    • RCT - Tamoxifen after WLE + XRT
      • ↑ Disease Free Survival
      • ↓ Local recurrence (5% absolute)
      • 2% absolute ↓ ipsilateral & contralateral breast CA
      • NO overall survival advantage

Chemotherapy

  • No significant benefit from chemotherapy
  • Survival is already very good and risk of metastatic disease very low

Prognosis/Natural Hx

  • Natural Hx unknown for sure
    • 10-yr risk of ipsilateral Ductal Ca in same quadrant is 30-50%
    • Long-term F/U untreated low-grade DCIS
      • 40% develop invasive Ca
      • 2/3 of these within 10yrs
    • Study of Pts with incorrectly diagnosed benign disease
      • By selection bias will tend to be low grade non-comedo
  • Comedo has greater chance of microinvasion
    • Grows faster & has a higher rate of local recurrence compared to non-comedo
  • Poor prognostic features:

    • 5cm, high grade, “casting” (neoductogenesis)

Recurrence rates following surgery

  • If invasive Ca is present, then pts with extensive in-situ component (EIC) more likely to have close/involved margins
  • No reduction in overall survival, as long as clear margins are obtained (& radiotherapy given if WLE)
  • Risk of metachronous Ca ≈ 1% per year

Follow-up

  • Annual bilateral Mamogram for 5yrs
    • But no diff in DFS or OS if f/up mammo biannual
  • Clinical surveillance – role not clearly supported in the literature

Management of Recurrence

In-situ Recurrence

  • If initially had breast conserving therapy alone
    • Could offer repeat WLE + radiotherapy
  • If has previously had radiotherapy
    • Offer completion mastectomy

Invasive Recurrence

  • Also dependent on initial therapy for DCIS
  • If no previous radiotherapy
    • Could offer WLE + radiotherapy, with axillary staging
  • If WLE not an option
    • Offer mastectomy and axillary staging as per usual Ca

NCCN Guidelines

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