BREAST CARCINOMA

IN SITU

Dr. Vivek Agrawal

University College of Medical Sciences & Guru

Tegh Bahadur Hospital, Delhi.
 Proliferative abnormalities
• Hyperplasia
• Atypical hyperplasia
• In situ carcinoma ---- Purely non-invasive
cancer. LCIS less studied and less virulent.
• Invasive carcinoma with favourable natural
history (colloid, mucinous, adenoid-cystic,
tubular)

Getting diagnosed due to screening

mammography – 1983.
 BREAST CARCINOMA IN - SITU
• It is a non-invasive cancer of the breast – 10%
• Types # Ductal carcinoma in-situ ---- Duct
# Lobular carcinoma in-situ ---- Lobule -
Terminal Duct Complex
• It is Stage 0
• Tis No Mo
• Routinely treated by mastectomy prior to
establishment of screening mammography
 Evidence Based Medicine “Breast
Cancer Disease Site Group” - Ontario
• Medline and Medical Excerpta databases from
1983 up to March 2006.
• http:\\caonline.amcancersoc.org
• Randomized trial or meta-analysis
• Terms searched – Carcinoma, intraductal,
noninfiltrationg, radiotherapy, mastectomy,
tamoxifen, intraductal carcinoma.
• Textbooks – Devita, Oxford’s, Anderson’s Path.
 In Situ Carcinoma

• GOAL OF TREATMENT IS TO PREVENT

THE OCCURRENCE OF INVASIVE
CANCER
OR

• TO DIAGNOSE THE ASSOCIATION /

DEVELOPMENT OF INVASIVE
COMPONENT
 Lobular Carcinoma in situ
• 0.5 to 3.6% of all breast Ca. and 10 to 30% of
solid noninvasive carcinomas.
• It is Stage 0. Proliferative lesion of mammary
lobule & cells have malignancy features but do
not invade the basement membrane(Muir 1941)
• Tis No Mo. Bilateral mammogram is essential
• Multicentric/bilateral disease, pagetoid extn.
• Clinically occult. Found with histology for other
diseases.
• Histologically aggressive variant (Pleomorphic
LCIS) behaves as DCIS but data is sparse
• Treatment is primarily OBSERVATION.
 LCIS
• Risk of developing invasive cancer is low –
21% in 15 years. (almost like1% per year risk)
• Histology of such invasive cancers is
favourable. Oestrogen positive and rarely
express HER2/neu oncogene.
• Deaths from 2nd invasive cancers is unusual
• B/L mastectomy in patients with BRCA I or 2
mutations, strong family history, high level of
anxiety or concern of developing/harbouring a
malignancy later in life.
• Tamoxifen for 5 years can decrease the risk of
occurrence of invasive cancer by 56%
 LCIS
Controversy regarding whether LCIS is a
PRECURSOR or a HIGH RISK MARKER
for invasive carcinoma development.

Considered “High Risk Marker” for Ca.

• Increased risk of developing a invasive
cancer and that too in the other Breast
• Increased risk of developing ductal
cancer despite it being lobular carcinoma.
 Management of LCIS
• Observation and chemoprevention for cancer
(as it is a marker for Invasive Carcinoma).

Monthly Self examination, periodic physical

evaluation, 6 monthly or yearly Mammogram
for life – 10 to 15 years.
MRI has better potential for diagnosis in
high risk women
 Follow up for LCIS
• Tamoxifen is prescribed
(chemoprevention) and patients are
regularly followed up.
• For LCIS with Bilateral Mastectomy only
local evaluation for recurrence is needed
• Some serotinin reuptake inhibitors
decrease the formation of endoxifen, an
active metabolite of tamoxifen – clinical
impact is unknown
 DCIS
• Proliferation of cancer cells within ducts without
invasion of basement membrane
• Mostly picked up by screening methods & the
behaviour of this sub clinical entity may be
somewhat different from the clinically
diagnosed DCIS.
• The risk of metastasis from sub clinical DCIS is
nearly negligible as compared to the invasive
form of Ca. Breast.
• Local or systemic recurrences after primary
treatment of DCIS could be invasive also – this
guides Tt. methods
 DCIS
• Biologically different from LCIS and Invasive
carcinoma
• In 30% it is multifocal – mainly in same breast
• Associated with invasive carcinoma in 48% of
the patients
• Risk of developing invasive cancer is 30% in
10years
• 50% recurrences mostly occur in DCIS
associated with invasive carcinoma that has
been missed out and are more so seen in
comedo type carcinoma in situ.
 Risk Factors for DCIS
• Similar to that of Invasive carcinoma
• Family history of Breast Cancer
• Previous Breast Biopsy
• Fewer pregnancies
• Late 1st pregnancy
• Late menopause
 Pathological types
1) Comedo - tend to recur, 35 to 50% of all DCIS
2) Non comedo - 5 to 8%
• Cribriform
• Micropapillary - more extensive.
• Papillary
• Solid
• Clinging
Must include nuclear grade and necrosis for
pathological reporting with architecture.
No predictors of invasive or non-invasive
recurrences
 Comedo DCIS - more malignant
• Higher proliferative rate as determined by
thymidine – labeling studies.
• Ducts distend, Cancerization of lobules can occur
• Associated with micro-invasion & coarse granular
or linear microcalcifications
• Exhibits biological markers – may distinguish
them from BBD atypical hyperplasia
- Aneuploidy
- C-erb-2(HER2/neu) overexpression
- Cyclin D1
- p53 oncogenes
- absence of bcl-2 expression
- Angiogenesis
 Non Comedo
• Less aggressive & less recurrences(<5%)
• Smaller and detected by mammograms
• Favourable histology
• Rarely extends into lobules
• Multiple architectural patterns but only one
predominates
 Investigations
• Mammography
• USG
• MRI
• Guided FNAC – difficult to differentiate
between atypical hyperplasia and DCIS
and even on Frozen Sections.
• Image guided biopsy - Core Biopsy or
Open Biopsy
• ER / PR status
 Mammographic evaluation
***Microcalcifications in 90%
• Pleomorphic
• Vary in size, form & density
• Grouped in Clusters – triangular (ductal
DCIS) or irregular (segmental DCIS)
(Lanyi et al)
• Frequently they are linear or segmental –
reflecting the presence of DCIS in ducts
***Masses, nodules or prominent ducts,
other soft tissue changes
***With normal mammogram
 Shortcomings of Mammogram
• Cannot tell of breach of Basement
Membrane i.e. invasive carcinoma
• Peritumoural inflammation and/or fibrosis
can be associated with microcalcifications
• Subtypes of DCIS cannot be differentiated
• Extent of the mass cannot be properly
assessed – maximal span of low or
intermediate grade of DCIS can be
underestimated by 2 cm in 50% patients
• Multricentricity and low resolution
calcifications are difficult to interpret.
Breast Mammography and BI-RADS
Criteria Associated with Criteria Associated with
Benign Lesions Malignant Lesions
Spherical/ovoid/lobulated Irregular shape

Linear margin Poorly defined margin

Homogeneous texture Central shadowing
Isoechoic/anechoic Distorted architecture

Edge shadow Calcifications
Parallel to the skin Skin thickening
Distal enhancement  
Dilated duct/mobile  
LOS Diagnosis Number of Criteria

5 Malignant 5 malignant criteria

4 Probably 3-4 malignant criteria

malignant

3 Indeterminate 1-2 malignant criteria

criteria

2 Probably 0 malignant criteria

benign

1 Benign 0 malignant criteria &

all benign criteria
The positive predictive value of a biopsy for
malignancy increases from
• <2% ... for BI-RADS category 3
• 23% - 30% … for category 4
• 95% … for category 5

Specific mammographic features with the

highest positive predictive value of
malignancy include
• masses with spiculated margins and/or
irregular shape
• calcifications with linear morphology
and/or segmental distribution
 Stereotactic Core Needle Biopsy
Not possible in:
• small breasts
• below the skin or very posteriorly placed
lesions
• widely separated calcifications
• not easily recognized microcalcifications
• uncooperative patient

Leave marker when whole lesion is likely to

come out with biopsy
 Guided wire open biopsy
For localization:
• Hookwire used
• Dye injection
• Both of above.

Incision must be carefully planned and

executed. No tunneling effect should occur.
Specimen to come out in 1 piece. Orient the
specimen. Specimen Mammogram.
 Indications of MRI
Contrast enhanced MRI is very sensitive for
invasive cancer

Preoperative – multicentricity, bilaterality,

size/extent assessment, multifocality

Treatment response can be assessed

Metastasis of the unknown primary

Post operative follow up – post lumpectomy,

post implant
 Lymph node assessment
• No axillary dissection in pure DCIS – 2-3%
mentioned but due to missing of Invasive Ca.
• Some recommend – routine Level I axillary
clearance (invasive Ca. associated in 20%)
• Sentinal LN biopsy. 6% metastasis to sentinal
LN (Pendas et al). Especially recommended for
large and high grade DCIS & detected in ax. tail
• Immunohistochemistry of -ve LNs –
prognostic significance is controversial. Long
term survival 97 to 99%
• Selective approach to Axillary Lymph Nodes
DCIS & CALCIFICATIONS
DCIS MAMMOGRAM
DCIS MAMMOGRAM
 Presentation
• On mammographic screening
• Lump (unusual)
• Bloody discharge from the nipple
• Paget’s disease of the nipple
• Associated with BBD

Recurrence incidence is 4 – 18%.

Death in 4%.
 Treatment
• Patients choice
• DCIS doesn't behave differently from invasive
Carcinoma Breast. Most meticulous local
control doesn’t prevent systemic mets. even
without local recurr.
√ Surgery – Total mastectomy or BCS with RT

√ RT - Make aware of the duration and toxic

effects (skin burn, pneumonitis, # ribs).
- shorter duration RT in patients who desire
shorter time period of treatment
√ Tamoxifen for 5 years
 Parameters to gauge treatment
effectiveness
• Overall survival
• Disease free survival
• Local recurrence
• Breast conservation
• Distant recurrence
• Toxicity
• Quality of life
 Total Mastectomy
• Large tumours
• Small breasts
• Multiple tumours
• Extensive microcalcifications

Chest wall recurrence seen in 1% or less

patients after total mastectomy.
 Axillary dissection
• NO ACTION IN PURE DCIS

• 20% DCIS associated with invasive

carcinoma.
• More chances of lymph node metastasis
with extensive DCIS, high grade DCIS and
when DCIS is detected with masses in
mammogram
• Level I clearance
• Sentinal LN biopsy.
 BCS
• Lagios criteria
- DCIS diagnosed by calcifications only
- < 2.5 cm size (mean size in his study was 7.8mm).
- negative (-ve) margins
- negative biopsy mammogram

After 124 months recurrence rate was 19 % for

grade 3 and 6% for grade 1 tumours. Also,
less recurrences in tumors with free margins of
> 1mm.
 BCS
• Van Nuys Prognostic Index (VNPI) Silverstein et al.
Assigns value of 1 to 3 to each
- tumour size
- margin width
- histological classification
Then make 3 groups with
* 3 – 4 points (low risk) – No RT
* 5 – 7 points (intermediate risk)
* 8 – 9 points (high risk)
Recurrence of 9% in low risk group. Retrospective study,
histology not compared – hence not considered definitive
results
 BCS
• Ideal in single breast – unicentric disease
• With negative resected margins
• Small tumours

Contraindications – large tumour/small breast

• Diffuse suspicious microcalcifications
• Multicentric disease
• Prior radiation treatment
• Active collagen vascular disease
• Pregnancy
Predictors of local control failure
• Age
• Tumour size
• Margin Status
• Grade
• Comedo-type Necrosis (cheesy “comedo-
like” necrotic debris oozes from distended
ducts)

Risk Groups – Low, Intermediate, High

• Low Risk ---------------- ? BCS – patients
attitude towards understanding the risks and
benefits does play a major role in decision
making for addition of RT

• Intermediate Risk ----- BCS & RT

• High Risk --------------- Mastectomy with or

without reconstruction
NEEDS FURTHER STUDIES FOR
AUTHENTICATION
TILL THEN PATHOLOGICAL REPORT MUST
CONTINUE TO GUIDE THE RISK GROUPS
 Management of DCIS
• BCS in limited patients & with caution ??????
• Total Mastectomy - with reconstruction. For
maximal local control (with or without RT)
• Breast Conserving Surgery (Lumpectomy)
“BCS” - with Radiation equals above modality

Mastectomy / Post BCS + Radiation for patients

with high risk of recurrence:
High risk - >5cm size, comedo, positive margin,
(<1mm clear margin have ↑ recurrence)
 Radiation in Breast Conservation
for DCIS – 5000 cGy in 25 fraction
in 5 weeks
Ontario Clinical Oncology Group states 4250 cGy in
16 fractions is equally effective
↓
Breast recurrences (invasive and non-invasive
types), ↓ chances of mastectomy

• Group in whom to give it – In all BCS –ve or +ve

margins (further surgery refused). Start in 2 – 4
weeks once residual tumour is ruled out.

• Group in which it can be foregone – Studies are on

but till then RT is to be offered in all BCS
 Boost RT
• Since ↑ recurrences seen in younger
patients and those with high risk despite
full RT

“Here boost to tumour bed is helpful”

“+ve margin or <1mm free margin”
(+ve margin – re-surgery and boost)

“Cosmetic results poorer”

 Tamoxifen and DCIS
Decrease in invasive and in situ disease if
tamoxifen is added to surgical excision + RT----
particularly in High Risk Group (younger
patients and those with +ve margin or unknown
margins)
• No benefit in older patients (> 50 years) with
clear margin
• Decreases local recurrence, contralateral
incidence, other Cancer related events
• Some benefit in < 50 years patient without RT
• More benefit in Oestrogen Receptor +ve
Indication of Tamoxifen for 5 years
Before starting -- inform of controversies
and toxic effects (endometrial Ca., stroke,
pulmonary embolism, DVT)

• <50 years of age

• BCS with Positive margins and who refuse
further surgery
• Those who refuse or are unable to
withstand RT and want to avoid
mastectomy
 FINAL HISTOPATHOLOGY
• Association with invasive carcinoma.
• Size of tumour - > 4 cm additional treatment
• Margin and width of clear margin (> 1 cm is
safe and requires no adjuvant treatment). +ve
or <1mm need Boost RT and adj. treatment.
• Grade – high grade need adj. treatments
• Pathological type – comedo-necrosis

Guide further treatment procedures and need to

add adjuvant therapies.
 FOLLOW UP
• Aims: 1) Identify treatment sequelae for
interventions, if necessary.
2) Early pick up or recurrence – invasive
or non-invasive
3) Make database for optimizing Tt.
and global comparisons.
• History, Examination and Mammography
• Routine tests (bone scan, LFT, chest x-ray, CT
scan) not required in asymptomatic DCIS
• 6 monthly for 5years and yearly thereafter.
 POST-OP. MAMMOGRAPHY
• Confirms complete removal of the lesion
• Post surgery effects (masses due to fluid
collections and scarring, oedema, skin
thickening, calcifications) slowly resolve in
6 to 12 months and can take up to 2
years.
• 1st mammogram at the end of 1 year and
continue yearly for future follow ups.
• Add magnification mammography for
calcifications for better resolution and
interpretation of operated site.
• No comparison between Total
Mastectomy and BCS found
• NSABP B – 06 trial on patients with
invasive carcinoma. Pathology review
showed DCIS in certain patients. In these
BCS alone showed more recurrences as
compared to BCS + RT or mastectomy
• Same results in 2 meta-analysis
• No survival benefit reported with any
treatment
• RT with BCS reduced ipsilateral invasive
or non-invasive recurrence but no effect
on distant metastasis or overall survival
 Summary of Treatment of DCIS
• Mastectomy with/without reconstruction – aims
at clear margins – large tumour, multicentric
• BCS with RT – in <5mm, unicentric, low grade
• Axillary lymphnode – Routinely not performed.
Sentinal node biopsy or Level I clearance in
high risk cases or in those where association is
with invasive type
• Tamoxifen for 5 years – in < 50 years, high risk
patients, oestrogen receptor positive patients.
Especially used in BCS + RT or BCS alone.
 Summary of Treatment of in situ Ca.
DCIS LCIS
• Intraductal • Terminal duct-lobule
• Unilateral & continues to complex
grow • Frequently bilateral
• Premalignant condition • High Risk Marker for
• Mastectomy, Malignancy
Lumpectomy with RT, & • Observation, Tamoxifen,
Tamoxifen Chemoprevention
• Follow up – for local • Regular follow up to pick
recurrence, metastasis, up development of early
invasive carcinoma invasive cancer