1. Ductal Carcinoma In-Situ (DCIS)

2. Questions
What 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?

3. Benign Breast Disease Nonproliferative Proliferative without atypia
Proliferative 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”

4. 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 ducts
Shares some cytologic and architecural features of LCIS

5. ADH
DCIS and invasive breast cancer is identified in 33-87% of subsequent excision biopsies reported as ADH in the core biopsy

6. Risk of Cancer After AH AH (especially multifocal lesions)
Increased risk (RR ) 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

7. Lobular Neoplasia
Spectrum 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

8. Histology LCIS 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

9. LCIS

10. Cancer Risk ALH RR 3-4 (compared with general population) LCIS RR 7-9
Greater risk in ipsilateral breast
LCIS RR 7-9
Appears to be as common in the contralateral breast as in the ipsilateral breast
Pleomorphic variant appears to have an aggressive biologic profile

11. Management and Follow-Up
Core 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)

12. Management and Follow-Up
No role for CLE or mastectomy in the management of ADH, LCIS or ALH
Insufficient evidence to recommend the use of tamoxifen for prevention of invasive breast cancer following a diagnosis of ADH, LCIS or ALH (Australian Guidelines)

13. DCIS Definition Why is it clinically significant?
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

14. 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

15. Histology
5 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
Ductal carcinoma in situ (DCIS) comedo type. A, The specimen radiogram reveals linear and branching calcifications within the ductal system. B, Ducts filled with punctate areas of necrosis (“comedone” like) and surrounded by periductal fibrosis are seen. C, DCIS with large central zones of necrosis and calcifications fills several adjacent duct

16. Noncomedo DCIS. A, Cribriform DCIS composed of cells forming round, regular (“cookie cutter”) spaces. The lumens are filled with calcifying secretory material. B, This solid DCIS has almost completely filled and distorted this lobule with only a few remaining normal luminal cells visible. This type of DCIS is not usually associated with calcifications and may be clinically occult.
Noncomedo DCIS. A, Papillary DCIS. Delicate fibrovascular cores extend into a duct and are lined by a monomorphic population of tall columnar cells. Myoepithelial cells are absent. B, Micropapillary DCIS. The papillae are connected to the duct wall by a narrow base and often have bulbous or complex outgrowths. The papillae are solid and lack fibrovascular core

17. Paget’s Disease
DCIS arising within the ductal system that extends up the lactiferous ducts and into the skin of the nipple without crossing the basement membrane

18. Diagnosis Most commonly detected as mammographic caclification
BI-RADS Classification
0. Incomplete
Negative
Benign
Probably benign
Suspicious
Highly suggestive of malignancy
Known biopsy-proven malignant

20. General Principles of Management
Small, mammographically detected lesions should be treated with complete local excision
If disease is extensive, total mastectomy may be a more reliable treatment
RCTs demonstrate a reduction in DCIS recurrence and invasive breast cancer if radiotherapy is performed after CLE
ALND is not indicated
Chemotherapy has never been investigated
Tamoxifen in the adjuvant setting reduces risk of DCIS recurrence and invasive breast cancer
MDT

21. Management Options in DCIS
Surgery (breast and axilla)
Radiotherapy
Chemoprophylaxis

22. Surgery
Aim is to ensure complete excision with best possible cosmetic result
Pre-operative localisation is essential for a mammographically detected impalpable lesion
Optimal margins
No reliable definition
Must be completely excised
“Clear margins” (no DCIS at section edge) provides acceptable local control when combined with radiotherapy
<1mm considered inadequate

23. Surgery Axillary Dissection No place for ALND What 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

24. Surgery Mastectomy Widespread contiguous or multi-focal DCIS
Widespread microcalcification in the presence of proven DCIS
Recurrence of DCIS following initial treatmen when either of the above indiciations is present
Woman’s choice
Other relevant risk factors for breast cancer

25. Radiotherapy
Lower 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 )

26. Risk of Recurrence
Relatively low for DCIS with good prognostic pathological features
Clear margins
Low-grade
No necrosis
Small extent (<10mm)
High grade DCIS with necrosis, close margins and larger size should have radiotherapy
But, radiotherapy offers a statistically significant benefit over conservation alone, absolute benefit may be small. Is the gain in local control worth the inconvenience and morbidity of radiotherapy?

27. Systemic Treatment Chemotherapy
Never investigated or used in treatment with DCIS

28. Systemic Treatment Tamoxifen Must have ER + disease
In 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 ), trend to reduction in risk of invasive carcinoma (HR 0.79, 95%CI ), lower risk for contralateral carcinoma (HR 0.57, 95%CI )
No apparent survival benefit
Risks: endometrial cancer, VTE

29. Systemic Treatment NCCN 2013 Guidelines Australian Guidelines 2003
Consider tamoxifen for 5 years:
Patients treated with breast conservation, especially if ER +
Patients treated with surgery alone and ER +
Australian Guidelines 2003
Further research required, tamoxifen may reduce risk of subsequent local invasive breast cancer in women who have had breast conservation treatment
No data for aromatase inhibitors
Limited data for HER2-directed therapy

30. Local Recurrence Rates (%)
The Evidence
Local 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
<
EORTC 10853
1010
4.25 16 9
<0.005
UK ANZ
1707 5 20 8 6
<0.0001
SweDCIS
1067 7 22
NSABP B-24
1807
0.04

31. Post Treatment Surveillance
Overall survival for women >67 is similar to those without breast cancer
Women >67 are more likely to die of cardiovascular disease than breast cancer
Australian Guidelines
No evidence defining optimum follow-up protocol
Consensus recommendation is for annual review with examination and mammography indefinitely

32. Post Treatment Surveillance
NCCN 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 awareness
If treated with tamoxifen
Annual gynae assessment
Opthalmology exam
Manage symptoms as per guidelines