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.

• 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

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

• 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

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

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

Pathological types

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
Spherical/ovoid/lobulated Linear margin Homogeneous texture Isoechoic/anechoic Edge shadow Parallel to the skin Distal enhancement Dilated duct/mobile

Malignant Lesions
Irregular shape Poorly defined margin Central shadowing Distorted architecture Calcifications Skin thickening  
 

LOS Diagnosis 5 4 3 Malignant Probably malignant Indeterminate criteria Probably benign Benign

Number of Criteria 5 malignant criteria 3-4 malignant criteria 1-2 malignant criteria

2 1

0 malignant criteria 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

Not possible in: • small breasts • below the skin or very posteriorly placed lesions • widely separated calcifications • not easily recognized microcalcifications • uncooperative patient

Stereotactic Core Needle Biopsy

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%.

• 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

Treatment

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 “comedolike” 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 • Unilateral & continues to grow • Premalignant condition • Mastectomy, Lumpectomy with RT, & Tamoxifen • Follow up – for local recurrence, metastasis, invasive carcinoma • Terminal duct-lobule complex • Frequently bilateral • High Risk Marker for Malignancy • Observation, Tamoxifen, Chemoprevention • Regular follow up to pick up development of early invasive cancer

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