DCIS and LCIS
DEFINITION

TDLU - terminal duct lobular unit
- all breast cancer arises in

Ductal carcinoma in situ.
A pre-invasive local cancer (clonal proliferation of malignant epithelial cells confined within basement membrane; precursor lesion for invasive cancer) that is a highly curable disease with appropriate therapy.

Lobular carcinoma in situ
Pre-invasive local cancer that is considered to be a marker of increased risk of breast cancer development.
Recent data now suggests it is a precursor lesion to invasive lobular carcinoma, and a risk indicator for IBC.
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EPIDEMIOLOGY

DCIS
Increasing; 7x increase last 30y
50s-60s
- result of better detection and screening mammography
--> currently = ~20% of screen-detected breast cancers.

LCIS
Similarly increasing due to screening
Usually in 40s-50s
10 y earlier than DCIS
Only 10% seen with LCIS after menopause.
Often related to E-cadherin
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AETIOLOGY

Tumour; malignant

DCIS
Rationale for pre-malignant risk is well established
- invasive cancer in untreated pts arises at or near DCIS foci.
--> must rule out associated invasive breast cancer (IBC) at dx (present in 10-25%).
--> and prevent future IBC.

LCIS
Marker for increased risk for carcinoma.
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BIOLOGICAL BEHAVIOUR

DCIS
Represents a spectrum of pathological lesions with variable malignant potential
- potential is determined by histologic architecture, presence of necrosis, and nuclear grade.
Bilateral in 10%

Sub-types
1. Comedo:
- central necrosis, many mitotic figures, and large pleomorphic nuclei
- high grade, prognosis poorer
2. Non-Comedo (cribriform, papillary, Paget's):
- absence of central necrosis and mitotic figures, presence of specific papillary, micropapillary or cribriform architecture carcinoma.
- cribriform: cells in punched-out pattern; relatively low-grade, better outcome
- papillary: fronds of cancer protruding in fibrovascular cores; low-grade, better outcome
Paget's disease: extension up lactoferrous ducts to surface of nipple/areola and invasion out to epidermal plane.

Nuclear grading
Low, intermediate or high
- determined by nuclear morphology and mitotic index.
- high grade = often associated with necrosis; aggressive, high local recurrence rate.

Prognosis
Excellent, regardless of grade, 10-year survival exceeds 95%
 
LCIS

20-40% bilateral; 60% multicentric

Atypical lobular hyperplasia (ALH)
- morphologically similar but less well developed lesions

Subtypes
Classic and pleiomorphic
Classic
LCIS has monomorphic population of small, round, polygonal or cuboidal cell wit a rim of clear cytoplasm and a high nuclear / cytoplasmic ratio
- cells loosely cohesive and regularly spaced; Indian-file fill and distend acini
- small nucleoli and a few mitotic figures.
- Pagetoid spread (extending along adjacent ducts) is frequent
Pleiomorphic
- cells with distinctly larger nuclei and prominent nucleoli with frequent mitotic figures.
- central necrosis and calcification with lobules are common.

For a diagnosis of LCIS, >50% of acini in an involved lobular unit must be filled and distended by LCIS cells; no central lumina.
- ALH is when characteristic cells fill half the acini with no distension of the lobule; or mild distension with lumina visible.

Risk
Risk of developing IBC is 7-18x higher than the general population.
- 7% 10y risk
- 30-40% lifetime risk
- 3x more likely in the ipsilateral breast.
- And 5x more likely to develop invasive lobular carcinoma
--> LCIS may be a precursor lesion to invasive lobular cancer and a risk indicator for IBC.
--> this is supported by studies showing similar molecular signatures in invasive lobular carcinoma and adjacent LCIS foci


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MANIFESTATIONS

DCIS
Mainly screen detected
A few will show with a mass, Paget's disease of nipple or suspicious nipple discharge

LCIS
Often an incidental finding after a breast biopsy performed.
- rarely visible on imaging
- no specific features.

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INVESTIGATIONS

DCIS

Mammography
90-95% show up on screening mammography
- suspiciously grouped, pleomorphic, or fine, linear microcalcs.
--> do a mag view for indeterminant calcification.
Of all incidental calcification on screening mammo:
- 2/3 chance of pure DCIS
- 1/3 chance of DCIS with a focus of invasion
- little (4%) chance of invasive breast cancer.
Higher risk of IBC if:
- larger areas of calcification (>10mm)
- linear versus granular calcification.

Tissue
All need a tissue diagnosis
Stereotactic core needle biopsy is optimal diagnostic tool.
--> accurate staging without deforming operations.
Sometimes stereotactic core needle biopsy is not possible
- when close to chest wall, too superficial, close to implants, or lacking sufficient tissue for compression views.
--> needle localized biopsy.

MRI
Evolving role
Mammogram is standard of care; MRI often misses small foci so cannot replace.

LCIS

Incidence on otherwise benign breast biopsies is 0.5-4%
(generally not on screening as not calcified like DCIS)
Characteristically multifocal and bilateral
- over 50% have multiple foci in same breast
- 30% will have have LCIS in the contralateral breast.
--> multifocality in a clinically undetectable lesion means LCIS is a challenging problem
Usually ER/PR+ve and HER2-ve

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MANAGEMENT

DCIS
Controversies surround status as a 'true cancer', methods of control, 
Need to balance risk of local recurrence with unnecessary morbidity
--> therapy evolving with multimodal therapy and less aggressive surgery. 

Principles
 1. Lumpectomy with radiation is appropriate for most patients
2. Women with minimal disease and adequate margins can receive lumpectomy alone
3. Women with extensive disease or large disease/small breast should receive mastectomy with immediate reconstruction.

image

Surgical Therapy
Optimal treatment remains complete surgical excision to clear margins with a cosmetically acceptable result.
- either breast conserving surgery (BCS) and radiotherapy
- or mastectomy
--> no RCTs to guide this, based on evidence from IBC;
--> non-controlled studies suggest that higher recurrence with breast conservation but no change in survival.
Controversies include
- adequate margin size for excision
- need for radiotherapy after lumpectomy
- need for systemic therapy with hormonal agents
Ultimately decisions should be with patient and in MDT context

Mastectomy
Should be considered for multi-centric DCIS, large lesions, central disease
and inadequate margins after repeat attempts of breast conservation.
Immediate reconstruction should be offered
- improved psychological outcomes and similar oncological outcome.

Margins
Controversial.  No definitive data. 
Best evidence suggests need at least a 2-3mm margin if adjuvant radiation will be administered
- 1 mm is probably as getting rads.
Else perhaps a centimeter.
Further excision or possibly mastectomy indicated if margin <2mm.

Rads
Standard external beam radiation is typical.
- 3 prospective trials showing radiation reduces risk of developing recurrent breast Ca.
--> but no clear survival advantage has yet been shown.
Partial breast radiation is investigational.

Sentinel node biopsy?
Indications include:
- extensive disease with core-biopsy diagnosis
- high-grade disease with or without a comedo component.
- evidence or suggestion of micro-invasion
- disease in subareolar area or upper outer quadrant
- treatment with mastectomy.

Adjuvant therapy?
Hormonal therapy available, specifically tamoxifen.
NSABP-B24 study suggests that for ER-positive DCIS, tamoxifen after lumpectomy and radiation will reduce rates of ipsilateral recurrence
- and also reduces contralateral breast disease

Surveillance
1. Physical exam every 6 months for 5y then annually
2. Diagnostic mammogram annually.
- most recurrences occur close to the previous disease site
- local recurrence should be treated with negative margin resection and radiotherapy
- and if recurrence includes IBC then systemic therapy as usual.

Lobular Carcinoma in-situ

image

Screen Detected
Controversy exists regarding need for excision after LCIS or ALH detected on core biopsy
MDT approach required
1. Is there concordance or discordance?
2. Is there other high-grade lesions that will need excision?
--> If LCIS is a true incidental finding with no suspicious features or discordance then excision is not necessary.
3. This is because the risk of IBC is 0.5-1% per year
--> low enough to not warrant resection
--> biology also tends to be more favourable

Positive Margins
When excised (e.g. in presence of another lesion), re-excision is not necessary
- large studies have shown no increased risk in these patients when followed.

Surveillance

1. Counsel the patient.
- advise them of the risk.
- with close surveillance and early pickup, death from IBC should be unlikely.
- see flow diagram above for surveillance method.

2. Role of prophylactic mastectomy.
- special circumstances, e.g. women with BRCA1 or 2 or strong family history.
--> immediate reconstruction ideal

3. Tamoxifen / Raloxifene
- chemoprevention of invasive and noninvasive breast cancer studied in the STAR trial
- Tamoxifen decreased risk of IBC by 49% in all enrolled high-risk women and 56% in LCIS
--> Raloxifene has a lower rate of thromboembolic complications and uterine cancers cf tamoxifen
--> But tamoxifen better for preventing non-invasive breast cancers.

Bottom line
Observation. Consider tamoxifen (raloxifene in postmenopausal women) and prophylactic bilateral mastectomy in special cases.


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REFERENCES

Cameron 10th