1. Introduction
   It has long been known that breast cancer and its precursors arise from the ductal lining. Access to this lining has been limited but recently technological advances have made it possible to both visualize the ductal lining and sample cells from this lining.

   The advantages for this approach include new ways to think about breast cancer risk assessment, early breast cancer diagnosis and therapeutic modalities including directly treating lesions and following cytologic changes to assess response to therapy. Many of these possibilities are hypothetical so today I will focus on two procedures that are currently being used to approach the ductal lining. In our laboratory we first started collecting cells during ductoscopy for cytologic analysis. I will discuss our findings and experience with ductoscopy first and end with a discussion of the less invasive procedure, ductal lavage as a tool for risk assessment

2. Ductoscopy: Introduction
   • Japanese extensive experience with ductoscopy, many were limited by optics, catheter characteristics
   • Acueity Ductoscope (Larkspur, CA} 0.9mm rigid fiberoptic scope with a 200um working channel, excellent visualization of the duct lining, able to lavage area of interest and collect cells.
   
   
3. Ductoscopy: Patient Group - Spontaneous Nipple Discharge Group
   • Standard approach has been: ductography, nipple discharge cytology, surgery
   • 35-48% of women have intraductal papillomas
   • Ductoscopy – ease of cannulation secondary to dilated ducts, visualization of lesion – guide surgery, limited excision, assist pathologist
   • Lavage performed at the time of surgery to correlate cytologic and Histologic findings
   
   
4. Spontaneous Nipple Discharge
   • 91 ductal lavage specimens from 89 patients
   • 14-80 years, mean 54.5 years
   • Ductograms – filling defects in 34 (38%) of patients
   • Ductoscopy – visualized papillomas in 51/89 patients
   • Twelve specimens were acellular
   • Cellular specimens were evaluated for cytologic characteristics
   
   
5. Spontaneous Nipple Discharge: Cytologic and Histologic Findings
   Cytology:
   • Papillomas – moderate to marked nuclear atypia – 15 specimens
   • Large epithelial clusters with papillary architecture with more abundant opaque cytoplasm – characteristic
   • Single cells weren't predictive of pathology
   Histology
   • Intraductal papilloma – 59 (67%)
   • Fibrocystic changes, duct hyperplasia, duct ectasia 23 (26%)
   • DCIS – 2, Invasive carcinoma –1, atypical papilloma/LCIS – 1
   
   
6. Conclusions:
   • SND – cytology of papillomas could be a pitfall for a diagnosis of marked atypia or malignant in lavage specimen
   • Ductoscopy was useful in visualizing and localizing pathology allowing for a more limited resection at times.
   
   
   1. Ductal Lavage : Role in Risk Assessment
      • Effective options for preventing breast cancer have focused attention on risk assessment
      • NSABP P-1 study showed overall 49% reduction in breast cancer for women on tamoxifen, prophylatic mastectomy – 90% reduction
      • Tamoxifen reduced risk 86% in women with atypical ductal hyperplasis
      • Risks of tamoxifen, pulmonary emboli, endometrial cancer, stoke in older women
      • Port, et al found that high risk women reluctant to take Tamoxifen when counseled regarding risk and benefits
      
      
   2. Atypical ductal cells: Can they be used to select patient group most appropriate for Tamoxifen therapy
      • Nipple Aspirate Fluid (NAF) – 2,343 women followed for average of 12.7 years after NAF analyzed cytologically, 4.9x increased risk in women with atypical cells, 18x risk with family history
      • Random FNA: Fabian et al, random FNA, analyzed cytologically followed for median of 45 months, 5.02x risk
      • ADH/Biopsy: Dupont and Page, follow up 10-17 years, 4.3-5.3 x risk and 11-22x risk with family history
      
      
   3. Ductal Lavage vs NAF
      • Dooley, et al, 507 high risk women (elevated Gail Risk >1.7%), NAF and DL performed if fluid yielding ducts are present
      • DL – increased cellular yields, increased atypical diagnoses, method to allow collect of ductal cells to assess for cytologic atypia and risk
      
      
   4. Ductal Lavage
      • Only indicated for use in high risk patients
      •  

        Cytologic Diagnoses	Dooley Paper
        Insufficient cellular Material for Diagnosis (ICMD) (less than 10 epithelial cells)	22%
        Benign	54%
        Mild Atypia	17%
        Moderate atypia	6%
        Malignant	1%

      
      
   5. Issues to consider include:
      • Patient management – approach to patient with atypical cells
      • Negative Predictive value- undefined
      • Reproducibility of cytologic diagnosis
      • Pitfalls in diagnosis – papillomas
      • Role of molecular cytopathology for further defining risk and early detection-Evron, et al – Lancet 2001 methylation specific PCR in ductal lavage cells

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