Ductal Lavage for Early Detection--What Doesn't Come Out in the Wash
Authors: C. J. Fabian, B. F. Kimler, M. S. Mayo
Journal: JNCI Journal of the National Cancer Institute (2004)

Early detection via screening mammography has played a major role in the declining breast cancer mortality rates over the past decade (1,2). The impact of screening mammography on mortality rates is less for women younger than 50 years because of a lower test sensitivity and a lower rate of breast cancer (3–5). Sensitivity for detection of breast cancer in general screening populations has been reported as 61%–81% for women aged 40–49 years (5) and 87% for women aged 50–64 years (6). The lower sensitivity is in turn attributed to higher breast density in younger women (7). Unfortunately, women at increased risk of breast cancer by virtue of having a family history of breast cancer, proliferative breast disease with or without atypia, or use of hormone replacement therapy with both estrogen and progestin are those most likely to have dense breasts (8–11). Sensitivity was recently reported to be only 33% in a group of 1909 young women (mean age 40 years) with a family history of breast cancer, of which 358 were known mutation carriers (12). Newer imaging modalities, such as magnetic resonance imaging (MRI) (12) and digital mammography, may result in improved sensitivity in high-risk women with dense breasts. However, even these newer imaging modalities are associated with falsenegative results, and the search continues for the nearly infallible early detection technique. One of the classic physical signs of breast cancer is bloody nipple discharge. Because the majority of breast cancers are thought to evolve over a considerable period of time from an intraductal process, it is logical that we should be able to detect cancer at the preinvasive or minimally invasive phase by regularly examining ductal fluid. This hypothesis was certainly supported by the seminal work of Wrensch et al. (13,14), who found that women with atypical cells were at a higher risk of later developing breast cancer than women who did not produce nipple aspiration fluid (NAF). One problem with using NAF for risk assessment and/or early detection is that between 15% and 50% of women do not produce it (13–16) and, of those who do produce NAF, only 27%–84% have sufficient cells to allow a morphologic characterization (13,15). Ductal lavage is an extension of the nipple aspiration technique developed to improve cell yield. For ductal lavage, NAFproducing ducts are cannulated and flushed with a physiologic solution, and the resulting effluent is examined for epithelial cells and cytomorphology. Cannulation of a fluid-producing duct is possible in 80% or more of women who produce NAF after manual massage and 90%–100% in women with spontaneous nipple discharge (15,17). Ductal lavage of NAF-producing ducts has been reported to produce cellular specimens more frequently than NAF alone, and ductal lavage specimens generally have higher numbers of epithelial cells and cell clusters than NAF specimens (15,18). Furthermore, by carefully mapping the location of lavaged ducts and evaluating the cytomorphologic pattern from each duct separately, it is possible to re-examine any duct that contains markedly abnormal cells by a process known as ductoscopy. It is this potential for early detection that sets ductal lavage apart from other minimally invasive methods of examining the breast epithelium for risk assessment. In this issue of the Journal, Khan et al. (19) report the result of a difficult and meticulously performed study in which women undergoing mastectomy predominately for known cancer were studied for the ability to produce NAF and thus permit lavage. Lavage of NAF-producing ducts was carried out in the operating room after the patient was anesthetized. Gelatin-containing colored dye was injected into ducts that had been successfully lavaged. Mastectomy specimens underwent sub-gross sectioning, and areas of staining with and without obvious tumor were identified. Sections for microscopic evaluation were taken from both dye-stained and unstained areas. Thirty-nine women with a mean age of 50 years had 44 breasts removed, and 38 of these breasts were reported to have histologic evidence of cancer, although one had only lobular carcinoma in situ. Twenty-nine (76%) of the 38 breasts with carcinoma in situ and/or invasive cancer produced NAF. Of the 38 cancerous breasts, only five (13%) had markedly atypical or malignant cells and 16 (42%) had mildly or markedly atypical cells in the ductal lavage effluent. Thus, the sensitivity (13%– 42%) for either definition of a positive result is too low to be acceptable for ductal lavage to be considered as a screening procedure for the majority of women at risk of developing breast cancer. The sensitivity for cancer detection by ductal lavage appears to be lower than reported for mammography in a young general screening population or for breast MRI in a high-risk population (5,7,12). However, a trial comparing ductal lavage, digital mammography, and breast MRI in young, high-risk women with high breast density would be of interest. Cytologic evidence of atypia can be the result of a papilloma, duct ectasia, radial scar, or even secretory changes in addition to atypical hyperplasia and cancer (20–22). The high specificity reported by Khan et al. (19) is difficult to interpret, given that there were only six true-negatives (breasts without cancer). An important concern about ductal lavage for either risk assessment or early detection is that epithelial cell examination has traditionally been limited to NAF-producing ducts. How-