Affiliations of authors: Departments of Surgery (SAK, CB, RR, MB, KBB, VLS), Pathology (ELW, NR, RN), Radiology (JW), and Preventive Medicine (AR), Feinberg School of Medicine, Northwestern University, Chicago IL; Department of Pathology, University of California at San Francisco, San Francisco (BML); Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA (MM)
Correspondence to: Seema A. Khan, MD, Department of Surgery, Lynn Sage Comprehensive Breast Center, 675 N. Saint Clair St., Galter 13-174, Chicago, IL 60611 (e-mail: skhan{at}nmh.org)
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ABSTRACT |
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INTRODUCTION |
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We initiated a pilot study to examine the association between histopathologic results from breast tissue removed during mastectomy and cytologic results from ductal lavage material in women undergoing mastectomy, to obtain information about the sensitivity and specificity of ductal lavage in the presence of known breast cancer and to estimate the frequency with which cancer is found in ducts that do not yield fluid and therefore cannot be lavaged. Women at high risk for breast cancer undergoing prophylactic mastectomy were included to enlarge the spectrum of nonmalignant histologic findings.
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PATIENTS AND METHODS |
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Women undergoing mastectomy for breast cancer treatment (i.e., women who had invasive breast cancer or associated ductal carcinoma in situ [DCIS] lesions that were too large to allow breast conservation or who had multicentric breast cancer) or for prophylactic reasons were offered participation in an Institutional Review Boardapproved protocol at Northwestern Memorial Hospital from July 2001 through January 2003. Consecutive eligible patients were approached regarding participation. Exclusion criteria included pregnancy or lactation within the past 12 months, prior radiation therapy to the breast, chemotherapy in the past 6 months, a history of peri-areolar surgery, any use of tamoxifen, or active infection in the breast to be studied. All 39 participants provided written informed consent.
Ductal Lavage Procedure
Participants were instructed to drink fluids the night before surgery and to scrub the nipple with a washcloth on the morning of surgery. While in the preoperative holding area, they were given a warm beanbag to hold over the study breast or breasts. In the operating room, during the administration of general anesthesia, the study breast was massaged. After this massage, aspiration of nipple fluid and cannulation of fluid-yielding ducts was performed with the Cytyc aspirator and catheter (Cytyc, Boxborough, MA), and ductal lavage was performed with Ringers lactate solution (3). The location of the lavaged duct or ducts was noted on an eight-by-eight nipple grid, and the duct orifice was marked on the nipple itself with a skin pencil. The 12-oclock axis of the areola was marked with a suture, and the nipple was photographed. The lavage effluent was placed in Cytolyte solution (Cytyc), processed immediately for cytologic examination, and reviewed by the study cytopathologist (R. Nayar). If the cell yield in the lavage effluent was sufficient for diagnosis, the lavaged ducts in the mastectomy specimen were re-cannulated with the same catheter that had been used for lavage, and the breast was floated in a water bath at 37 °C. Identification of the lavaged duct was aided by the blue dot used to mark the duct orifice in the operating room after lavage, by the photograph, and by a good return of lavage effluent when suction was applied to the nipple ex vivo. A mixture of gelatin, dye, and the radiographic contrast compound Isovue 300 (Iopamidol Injection 61%; Bracco Diagnostics, Princeton, NJ) was inserted into the lavaged duct through the same ductal lavage catheter that was used for the in vivo lavage until it refluxed out of the nipple orifice (usually 12 mL). A different color of gelatin was used for each duct if more than one duct had been lavaged. The specimen was radiographed to confirm the propagation of the dye mixture through the ductal tree (Fig. 1, A). If evidence of extravasation was noted on this radiograph (i.e., puddling of contrast medium in the sub-areolar region), only routine histologic processing (rather than sub-gross sectioning, described below) was performed.
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The mastectomy specimen was weighed and measured, and all external landmarks were recorded. The external surface was inked in three colors for orientation, and the specimen was chilled at 80 °C for 45180 minutes (depending on the size and thickness of the tissue) to firmness. Sub-gross sectioning of the mastectomy specimen was then performed; the breast was sliced at 2- to 3-mm intervals, and slices were laid out in order on disposable towels and fixed in alcoholic formalin for at least 4 hours. After fixation, the slices were rinsed, photographed, and scanned on a photocopier (Fig. 1, B). Each slice was inspected for the presence of gross disease and dye. Tissue sections with suspected areas of disease and any tissue containing dye were submitted for microscopic sectioning and routine histologic tests. The location of each tissue block was recorded on a print made of the scanned slices. Tissue sections were processed overnight by use of a Leica tissue processor and an alcohol-based protocol for breast tissue. Microscopic sections 35 µm thick were cut and stained with hematoxylin and eosin. The sections were reviewed by at least one pathologist (who was blinded to the cytologic findings). Histologic findings in the dye-bearing and nondye-bearing areas were recorded. The blocks taken for routine clinical examination were similarly examined.
Cytologic Processing and Evaluation
Entire ductal lavage specimens were processed by the cytospin technique with the Shandon cytospin (Thermo Electron, Pittsburgh, PA) (15 specimens) or by the ThinPrep technique using the ThinPrep 2000 processor (Cytyc) (16 specimens). All slides were fixed in alcohol and stained by the Papanicolaou technique.
The cytologic criteria used to classify ductal lavage specimens are similar to those established at the National Cancer Institute Consensus Conference for Interpretation of Breast Fine Needle Aspiration Samples in 1997 and similar to those used in the multicenter ductal lavage study (6). The category "inadequate cellular material for diagnosis" included specimens that were acellular or contained fewer than 10 epithelial cells, with or without histiocytes. As the study progressed, it became clear that 10 epithelial cells were insufficient to confidently investigate the association between cytologic results and histologic results, and so we revised the definition of the category "inadequate cellular material for diagnosis" to include specimens that were acellular or contained fewer than 100 epithelial cells, and we excluded two samples with fewer than 100 cells. The number of epithelial cells was estimated for all ductal lavage specimens and classified as follows: scant (fewer than 100 epithelial cells), moderate (10010000 epithelial cells), and abundant (more than 10000 epithelial cells). Although the presence of histiocytes was used as a surrogate marker of successful ductal lavage, histiocytes were not included in the estimated number of epithelial cells. Samples that showed no evidence of architectural or nuclear abnormalities were classified as benign. Samples that showed minimal nuclear enlargement and anisonucleosis, with or without architectural abnormalities were classified as mildly atypical. Samples that showed moderate anisonucleosis along with one or more of the features seen in malignancy (nuclear membrane irregularity, prominence of nucleoli, abnormal chromatin distribution, or disorderly architectural arrangement [more than two cell layers or papillary groups or nuclear overlap]) were classified as marked atypical. In samples with marked atypia, some but not all of the features of malignancy were observed or there were few abnormal cells for an unequivocal diagnosis of malignancy. Samples that showed clear-cut cytomorphologic features of malignancy, with or without additional background features (e.g., necrosis or calcifications), were classified as malignant. The presence of histiocytes and background features, including protein, was noted in a semiquantitative fashion on a scale of 1 to 3 (1 = rare histiocytes, minimal protein; 2 = moderate number of histiocytes, moderate amount of protein; 3 = numerous histiocytes, abundant protein). Examples of dye-containing histologic samples and matching cytologic samples are shown in Fig. 2.
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Histologic diagnoses were categorized as normal and/or nonproliferative, proliferation without atypia, atypical proliferation, carcinoma in situ, or invasive cancer. Cytologic diagnoses were categorized as insufficient epithelial cells for diagnosis, benign, mildly atypical, markedly atypical, or malignant. Analyses were performed at two levels. First, cytologic findings and histologic findings in each duct were compared to assess the precise concordance between cytologic and histologic findings when the cytology sample was known to come from a given (dyed) ductal tree. This comparison was possible only when the cytologic sample contained more than 100 epithelial cells (i.e., was sufficient for diagnosis) and when dye was observed in the histologic sections. Second, the worst cytologic findings and the worst histologic findings from each breast were compared to assess whether a cytologic diagnosis suggestive of malignancy was achieved in women with cancer. Two prophylactically removed breasts were found to have occult malignancy and were treated as cancer-containing breasts in this analysis.
Sensitivity and specificity were calculated by one of two methods: 1) with a positive test result defined as marked atypia or malignancy in the ductal lavage sample (high threshold) or 2) with a positive test result defined as mild atypia, marked atypia, or malignancy in the ductal lavage sample (low threshold). Accuracy was defined as the total proportion of samples that showed concordance between cytologic and histologic results. Exact binomial probabilities were used to calculate the 95% confidence intervals (CIs). The Wilcoxon rank sum test and Fishers exact test were used for univariate analyses, and multiple logistic regression analysis was used for multivariable analysis. All statistical tests were two-sided.
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RESULTS |
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A total of 39 eligible women, including 32 with known cancer and seven without known cancer, consented to this study and contributed a total of 44 breasts to the study. Their mean age was 50 years (range = 3287 years). Eight prophylactically removed breasts came from seven women; six were cancer-free, and two contained occult malignancy (one had an occult invasive cancer with DCIS and the other contained lobular carcinoma in situ). For comparison of cytologic and histologic findings, these two prophylactically removed breasts were classified as cancer-containing breasts. Thirty-four women underwent unilateral therapeutic mastectomy; one woman underwent bilateral therapeutic mastectomy and contributed both breasts to this study. Thus, of the 44 breasts analyzed, 38 contained cancer and six were cancer-free. Twenty-nine of the 39 breasts had invasive cancer (mean diameter = 3.2 cm). DCIS was present in association with invasive cancer in 21 of the 29 breasts. The DCIS component measured 1 cm or more in 17 tumors (mean diameter = 3.4 cm, range = 18 cm). Eight patients had pure DCIS (mean diameter = 4 cm), and one had lobular carcinoma in situ.
Success of Study Procedures
Of the 44 study breasts, 38 (86%) had at least one fluid-yielding duct. Lavage of at least one duct was possible in 36 (82%) of 44 breasts, and lavage was possible in 52 (87%) of 60 ducts that yielded nipple aspiration fluid. The number of cells in the ductal lavage specimen was sufficient for a cytologic diagnosis in at least one duct in 31 (70%) of 44 breasts and in 45 (87%) of the 52 fluid-yielding ducts. For various reasons, we could not obtain both cytologic and histologic specimens from 16 breasts (Fig. 3). Six ducts failed ex vivo despite a lavage showing adequate cellular material (i.e., duct failure ex vivo was noted because the specimen radiographs showed extravasation of dye or because dye was not instilled because of inability to recannulate the previously lavaged orifice). Both cytologic and histologic specimens were obtained from 39 ducts in 28 breasts to allow the direct investigation of cytologic and histologic associations by duct in these samples.
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The cytologic and duct-specific histologic data of the 39 ducts with both cytologic and histologic results are shown in Table 1. Fourteen dye-containing ducts contained histologically confirmed cancer, and 25 dye-containing ducts did not. Sensitivity was calculated first by use of markedly atypical or malignant cells to define a positive result (high threshold) and mildly atypical or benign cells to define a negative result. As shown in Table 2, the high-threshold sensitivity for ductal lavage cytology was 43% (95% CI = 23% to 72%; six cytologically positive ducts of 14 dye-containing ducts with histologically confirmed cancer), the specificity was 96% (95% CI = 86% to 100%; 24 cytologically negative ducts of 25 dye-containing ducts without histologically confirmed cancer), and the accuracy was 77% (95% CI = 63% to 89%; 30 of 39 ducts in which the cytologic and histologic results agreed). If, however, mild atypia was also included in the definition of a positive finding (low threshold), the sensitivity rose to 79% (95% CI = 57% to 96%; 11 cytologically positive ducts of 14 dye-containing ducts with histologically confirmed cancer), specificity fell to 64% (95% CI = 46% to 83%; 16 cytologically negative ducts of 25 dye-containing ducts without histologically confirmed cancer), and accuracy was 69% (95% CI = 55% to 83%; 27 of the 39 ducts in which the cytologic and histologic results agreed).
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Marked atypical or frankly malignant cytology was detected in five of 38 cancer-containing breasts. The worst cytologic result observed in 11 cancer-containing breasts was mild atypia, and only benign cytology was observed in 14 cancer-containing breasts. Cytologic diagnosis was not possible in two cancer-containing breasts because of an inadequate number of epithelial cells for diagnosis and in six cancer-containing breasts because no ductal fluid was produced. Sensitivity, specificity, and accuracy were determined for all 44 study breasts (Table 2). First, we defined markedly atypical or malignant cytology as a positive test (high threshold) and all other results as negative (benign, mild atypia, or inadequate cellular material for diagnosis cytology, or breasts in which no lavage could be performed). When we used the high threshold, the sensitivity of ductal lavage cytologic results was 13% (95% CI = 6% to 29%; five of the 38 cancer-containing breasts with markedly atypical or malignant cytology result), the specificity was 100% (95% CI = 54% to 100%; six of the six histologically confirmed cancer-free breasts with a benign cytologic result), and accuracy was 25% (95% CI = 14% to 41%; 11 of the 44 total breasts in which cytologic and histologic results agreed). When mild atypia was also defined as a positive test (low threshold), the sensitivity rose to 42% (95% CI = 28% to 60%; 16 of the 38 cancer-containing breasts with a malignant or markedly or mildly atypical cytologic result), specificity remained at 100% (95% CI = 54% to 100%; six of the six histologically confirmed cancer-free breasts with a benign cytologic result), and accuracy increased to 50% (95% CI = 36% to 66%; 22 of the 44 total breasts in which cytologic and histologic results agreed).
If only the 31 breasts with at least one cytologically evaluable duct were considered (i.e., if breasts without nipple aspirate fluid and breasts with inadequate cellular material for diagnostic cytology were excluded), the sensitivity at the marked atypia or malignant level increased slightly to 17% (95% CI = 7% to 35%; five of the 30 histologically confirmed cancer-containing breasts with a markedly atypical or malignant cytologic result), the specificity remained at 100% (95% CI = 5% to 100%; one cytologically benign result of one histologically confirmed cancer-free breast), and an accuracy of 19% (95% CI = 9% to 38%; six of the 31 total breasts in which cytologic and histologic results agreed). With the lower threshold, including mild atypia as a positive test, the sensitivity increased to 53% (95% CI = 37% to 72%; 16 of the 30 histologically confirmed cancer-containing breasts had mildly or markedly atypical cytologic results), the specificity remained at 100% (95% CI = 5% to 100%; one true cytologically benign result of the one histologically confirmed cancer-free breast), and the accuracy was 55% (95% CI = 39% to 73%; 17 of the 31 total breasts in which cytologic and histologic results agreed).
Determinants of a Positive Cytologic Test
We performed univariate and multivariable analyses to investigate the relationships of the presence and size of DCIS, the presence of DCIS within the central ducts underlying the nippleareolar complex, the presence of invasive cancer, and the size of invasive cancer to a positive cytologic test in the 38 breasts with cancer (Table 3). A high-threshold positive test result (marked atypia or worse) was statistically significantly more frequent when DCIS was present in the central ducts. In a univariate analysis by breast, presence of DCIS within the central ducts underlying the nippleareolar complex occurred in seven (70%) of the 10 breasts with a positive cytologic result compared with eight (29%) of the 28 breasts with a negative cytologic result (P = .03). In a multivariable analysis adjusted for the presence of DCIS and of invasive cancer in the breast, nipple disease was also statistically significantly associated more with a positive cytologic test than with a negative cytologic test (P = .03).
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Reproducibility of Cytologic Interpretation
Our study protocol required a blinded second reading of cytologic material by a cytopathologist (B. M. Ljung) experienced in interpretation of ductal lavage samples. Comparison of the two readings (Table 4) showed that the overall concordance was very good, with agreement in the classification of 39 (75%) of the 52 samples (weighted = 0 .70, 95% CI = 0.54 to 0.86). Of the 15 samples that were called mildly atypical by at least one of the cytopathologists, there was concordance on only six samples (40%), with the remainder being classified as benign by the other reader. For the eight samples classified as markedly atypical or malignant, there was only one disagreement between the two cytopathologists.
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DISCUSSION |
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When we used the conventional diagnostic criterion of markedly atypical or malignant cells and considered all 44 study breasts, the sensitivity of ductal lavage to detect cancer was low (13%). A similar sensitivity (14%) for cancer detection by ductal lavage was reported by Brogi et al. (7) in a study of premastectomy ductal lavage procedures, in which 26 of the 30 breasts studied were known to contain cancer. In their study, successful dye instillation with lymphazurin was possible in 16 breasts. Only four (14%) of 29 of ducts yielded markedly atypical cells, 10 (34%) yielded cells with mild atypia, and 15 (52%) yielded benign cells. However, only routine processing of the mastectomy specimen was performed in this study, so a detailed study of the association of cytologic results with histologic results was not possible. The lack of sensitivity in a study population with a high prevalence of disease is particularly noteworthy, and it is likely to be an even greater problem in a low-incidence population composed of asymptomatic high-risk women. In comparison, mammography combined with physical examination detects breast cancer with a sensitivity of 88% (8), and newer modalities, including magnetic resonance imaging, have been reported to have sensitivities of 71% (9) to 90% (10).
We found that the association between cytologic test results and histologic test results was better in the 39 ducts that were successfully lavaged and filled with gelatin than when whole breasts were considered: 14 benign and eight mildly atypical samples came from ducts with either normal epithelium or usual hyperplasia as their worst finding (true-negative), whereas three benign and six mildly atypical samples came from ducts with carcinoma in situ or invasive cancer as their worst finding (false- negative). The sensitivity of ductal lavage to detect cancer was 43% (95% CI = 23% to 72%) when mild atypia was defined as a benign finding and was 79% (95% CI = 57% to 96%) when mild atypia was defined as a sign of malignancy. Again, the specificity decreased when mild atypia was classified as a positive test, falling from 96% (95% CI = 86% to 100%) to 64% (95% CI = 46% to 83%), and the accuracy remained essentially the same whether mild atypia was considered benign (77%, 95% CI = 63% to 89%) or malignant (69%, 95% CI = 55% to 83%). These data suggest that the specificity of ductal lavage for cancer detection is better than its sensitivity, although because only a small number of non-diseased breasts were examined, the high specificity of ductal lavage in this study should be interpreted with caution.
The single false-positive finding in our study was probably caused by failure of the dye to reach the cancer, because DCIS and a dye-containing normal duct were present in the same histologic section. We classified this breast as false-positive because our protocol required the presence of dye in cancer-containing ducts to declare agreement between the cytology and histology.
None of the markedly atypical or malignant samples in this study came from ducts with benign papillomas. However, a markedly atypical cytologic result in the presence of an intraductal papilloma is a recognized pitfall in cytologic interpretations (11) and should be ruled out as a source of worrisome cytologic findings when ductal lavage is being performed to aid risk assessment in high-risk women.
Because it was not possible to obtain results from both cytologic and histologic tests for 21 of the 60 fluid-yielding ducts, we also compared the location of fluid-yielding ducts with the quadrant location of the cancer; we assumed that, if the location matched, then the duct cytologic test would have been positive. This analysis did not substantially improve the overall results (data not shown), reflecting the fact that many failures of ductal lavage to detect cancer were related to a lack of fluid yield from the cancer-containing ducts and that failure of the protocol in some breasts was not the main explanation for the poor sensitivity observed.
One reason for this poor sensitivity may be the presence of invasive cancer in 29 of the 44 breasts studied. Theoretically, DCIS is the breast lesion that is most amenable to intraductal diagnosis, and once invasive cancer has developed, the likelihood of detecting an abnormality with lavage may decrease. However, 17 of the patients with invasive cancer had DCIS with a diameter of more than 1 cm associated with the tumor, and markedly atypical or malignant cytology was found in only four of these women, suggesting that a lack of intraductal pathology was not responsible for the low sensitivity observed. Nevertheless, it is possible that ductal lavage would perform better in women with pure DCIS. To test this hypothesis, we have studied a series of 20 women who presented with mammographically detected microcalcifications that were suspicious for malignancy and required biopsy (Khan SA, Wolfman J, Segal L, Nayar R, Wiley EL, et al.: unpublished data). These women consented to undergo ductal lavage and ductography of the lavaged duct or ducts before a core or surgical biopsy examination. Of the 10 women who proved to have DCIS in this series, four produced no nipple aspirate fluid from the affected breast; four underwent lavage of fluid-yielding ducts, but the ductogram showed that the lavaged duct or ducts did not correspond to the duct with calcifications; in one woman, the ductogram showed extravasation of dye; and in one woman, the ductogram confirmed correspondence of the lavaged duct with the calcifications, but the cytologic findings were benign despite a histologic diagnosis of DCIS. These pilot data raise concerns that the lack of fluid yield by diseased ducts observed in this study may also apply to early DCIS lesions and may pose a potential barrier to the use of ductal lavage in cancer detection.
Many of the false-negative ductal lavage samples came from cancer-containing ducts but showed mild atypia. We had prospectively classified mild atypia as a benign finding because we hypothesized that such cells reflect a proliferative change without atypia (analogous to hyperplasia without atypia in the nipple aspirate fluid and random fine-needle aspiration studies) (12,13). Apart from the lack of improvement in the accuracy of ductal lavage with this reclassification, there are additional problems with designating mild atypia as a positive test. The reproducibility of interpretation between cytopathologists in this category is variable (11,14), and in this study, agreement was obtained in only 40% of samples diagnosed as mildly atypical by either cytopathologist. Of the 11 mildly atypical samples with such disagreement, five came from cancer-containing ducts. The variation in diagnosis of mild atypia is particularly troubling because the majority of ductal lavage procedures with abnormal results yield mildly rather than markedly atypical cells: 17% versus 7%, respectively, in the multicenter trial of ductal lavage (3) and approximately 25% versus 2%3% in our experience to date, which includes ongoing studies of asymptomatic, high-risk women participating in phase II chemoprevention studies and in studies by other investigators (6,1517) performing ductal lavage on asymptomatic, high-risk women. In addition, experience interpreting cytopathology samples varies more from institution to institution than does experience interpreting histopathology samples, and variability among inexperienced readers may be higher than that observed in our study. Such variability would lead to difficulties in the management of mildly atypical lavage cytology because its histologic correlates appear to run the gamut from normal to DCIS. The prevalence of cancer in our study population is much higher than that in the high-risk, asymptomatic women undergoing ductal lavage at most centers today; most of these women will have benign histologic changes underlying mildly atypical ductal lavage findings. High-risk women with ductal lavage findings of mild atypia are generally advised to consider therapy with selective estrogen receptor modulators and undergo follow-up ductal lavage in 6 months (18). We observed mild atypia in six (50%) of the 12 cancer-containing ducts and in eight (35%) of the 23 ducts with normal, nonproliferative or hyperplastic epithelium. These results raise the question of which examinations would provide the best information to exclude the presence of carcinoma after a ductal lavage finding of mild atypia. Information to improve the sensitivity of cancer detection in ductal lavage samples may be obtained by investigating molecular markers, such as aneusomy, as reported recently (19), or DNA methylation profiles (20). If confirmed, these and other molecular diagnostic techniques may distinguish between mildly atypical samples from cancer-containing ducts and samples from ducts with proliferative or nonproliferative benign changes.
In summary, we have found poor agreement between ductal lavage cytologic test results and histologic test results in this pilot study of women with known cancer. Although further studies are warranted in women with early lesions, our results and those of others (7,19) indicate that ductal lavage should not be recommended to high-risk women as a technique to detect cancer earlier than imaging modalities. We also found that fluid-yielding ducts are not necessarily the ducts that are most likely to contain disease, so that a benign ductal lavage cytologic result should not be considered evidence of lower than estimated risk. The utility of ductal lavage as a risk assessment tool, however, is more promising because of the longitudinal data that are available regarding the related technique of nipple aspiration fluid and should continue to be evaluated.
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NOTES |
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We thank Eric Burns for his assistance in preparing the specimen radiographs and Lynn Seely, MD, for her contributions to the study design.
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REFERENCES |
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1 Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology 2002;225:16575.
2 Porter PL, El Bastawissi AY, Mandelson MT, Lin MG, Khalid N, Watney EA, et al. Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 1999;91:20208.
3 Dooley WC, Ljung B-M, Veronesi U, Ceccarelli C, Elledge RM, OShaughnessy J, et al. Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. J Natl Cancer Inst 2001;93:162432.
4 Khan SA, Baird C, Staradub VL, Morrow M. Ductal lavage and ductoscopy: the opportunities and the limitations. Clin Breast Cancer 2002;3:18591.[Medline]
5 Sartorius OW, Morris PL, Benedict DL, Smith HS. Contrast ductography for recognition and localization of benign and malignant breast lesions: an improved technique. In: Logan WW, editor. Breast carcinoma. New York (NY): Wiley; 1977. p. 281300.
6 Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J, et al. Double-contrast barium meal and upper gastrointestinal endoscopy. Ann Intern Med 1984;101:53845.[ISI][Medline]
7 Brogi E, Robson M, Panageas KS, Casadio C, Ljung BM, Montgomery L. Ductal lavage in patients undergoing mastectomy for mammary carcinoma: a correlative study. Cancer 2003;98:21706.[CrossRef][ISI][Medline]
8 Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 2000;92:14909.
9 Kriege M, Brekelmans CT, Boetes C, Rutgers EJ, Oosterwijk JC, Tollenaar RA, et al. MRI screening for breast cancer in women with high familial and genetic risk: First results of the Dutch MRI screening study (MRISC). J Clin Oncol 2003;21(23 Suppl):238.[CrossRef]
10 Davis PL, McCarty KS, Jr. Sensitivity of enhanced MRI for the detection of breast cancer: new, multicentric, residual, and recurrent. Eur Radiol 1997;7 Suppl 5:28998.[CrossRef][ISI]
11 Masood S, Khan SA, Nayar R. Atypia in ductal lavage: a follow-up experience with ductography, ductoscopy, and tissue biopsy. Mod Pathol 2002;16:40A.
12 Fabian CJ, Kimler BF, Zalles CM, Klemp JR, Kamel S, Zeiger S, et al. Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail Risk Model. J Natl Cancer Inst 2000;92:121727.
13 Wrensch MR, Petrakis NL, Miike R, King EB, Chew K, Neuhaus J, et al. Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid. J Natl Cancer Inst 2001;93:17918.
14 Nayar R, Ramakrishnan R, Baird C, DeFrias D, Masood S, Khan SA. Breast ductal lavage (DL): cytologic findings in 114 samples. Mod Pathol 2003.
15 Khan SA, Baird C, Ramakrishnan R, Staradub VL, Morrow M, DeFrias D, et al. Proportion of cytologically evaluable samples from duct lavage procedures. American Association of Cancer Research Frontiers in Cancer Research; 2002 Oct 14; Boston, MA.
16 Francescatti D, Woods JH. Ductal lavage: the learning curve. Fourth Annual Lynn Sage Symposium; 2002 Nov 1; Chicago, IL; B6.
17 Woods JH, Ekbom GA. Managing high risk patients with ductal lavage. Fourth Annual Lynn Sage Symposium; 2002 Nov 1; Chicago, IL; B5.
18 OShaughnessy JA, Ljung BM, Dooley WC, Chang J, Kuerer HM, Hung DT, et al. Ductal lavage and the clinical management of women at high risk for breast carcinoma: a commentary. Cancer 2002;94:2928.[CrossRef][ISI][Medline]
19 King BL, Tsai SC, Gryga ME, DAquila TG, Seelig SA, Morrison LE, et al. Detection of chromosomal instability in paired breast surgery and ductal lavage specimens by interphase fluorescence in situ hybridization. Clin Cancer Res 2003;9:150916.
20 Evron E, Dooley WC, Umbricht CB, Rosenthal D, Sacchi N, Gabrielson E, et al. Detection of breast cancer cells in ductal lavage fluid by methylation- specific PCR. Lancet 2001;357:13356.[CrossRef][ISI][Medline]
Manuscript received January 15, 2004; revised August 13, 2004; accepted August 20, 2004.
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