Benign Breast Disease and the Risk of Breast Cancer
Lynn C. Hartmann, M.D., Thomas A. Sellers, Ph.D., Marlene H. Frost, Ph.D., Wilma L. Lingle, Ph.D., Amy C. Degnim, M.D., Karthik Ghosh, M.D., Robert A. Vierkant, M.A.S., Shaun D. Maloney, B.A., V. Shane Pankratz, Ph.D., David W. Hillman, M.S., Vera J. Suman, Ph.D., Jo Johnson, R.N., Cassann Blake, M.D., Thea Tlsty, Ph.D., Celine M. Vachon, Ph.D., L. Joseph Melton, III, M.D., and Daniel W. Visscher, M.D.

Abstract
BACKGROUND : Benign breast disease is an important risk factor for breast cancer. We studied a large group of women with benign breast disease to obtain reliable estimates of this risk.

METHODS : We identified all women who received a diagnosis of benign breast disease at the Mayo Clinic between 1967 and 1991. Breast-cancer events were obtained from medical records and questionnaires. To estimate relative risks, we compared the number of observed breast cancers with the number expected on the basis of the rates of breast cancer in the Iowa Surveillance, Epidemiology, and End Results registry.

RESULTS : We followed 9087 women for a median of 15 years. The histologic findings were nonproliferative lesions in 67 percent of women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4 percent. To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort was 1.56 (95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at least 25 years after biopsy. The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of 1.27 (95 percent confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history of breast cancer, available for 4808 women, was a risk factor that was independent of histologic findings. No increased risk was found among women with no family history and nonproliferative findings. In the first 10 years after the initial biopsy, an excess of cancers occurred in the same breast, especially in women with atypia.

CONCLUSIONS : Conclusions Risk factors for breast cancer after the diagnosis of benign breast disease include the histologic classification of a benign breast lesion and a family history of breast cancer. [N Engl J Med 2005; 353:229-237.]

Cytologic features of nipple aspirate fluid using an automated non-invasive collection device: a prospective observational study
Kerry AS Proctor¹, Leslie R Rowe² and Joel S Bentz<sup>1

1</sup>Department of Pathology, University of Utah, Salt Lake City, Utah, USA and ²Institute for Clinical and Experimental Pathology, Associated Regional and University Pathologists (ARUP) Laboratories Inc., Salt Lake City, Utah, USA

Email: Kerry AS Proctor - kerry.proctor@hsc.utah.edu; Leslie R Rowe - rowelr@aruplab.com; Joel S Bentz* - joel.bentz@hsc.utah.edu

Abstract
BACKGROUND : Detection of cytologic atypia in nipple aspirate fluid (NAF) has been shown to be a predictor of risk for development of breast carcinoma. Manual collection of NAF for cytologic evaluation varies widely in terms of efficacy, ease of use, and patient acceptance. We investigated a new automated device for the non-invasive collection of NAF in the office setting.

METHODS : A multi-center prospective observational clinical trial involving asymptomatic women designed to assess fluid production, adequacy, safety and patient acceptance of the HALO NAF Collection System (NeoMatrix, Irvine, CA). Cytologic evaluation of all NAF samples was performed using previously described classification categories.

RESULTS : 500 healthy women were successfully enrolled. Thirty-eight percent (190/500) produced fluid and 187 were available for cytologic analysis. Cytologic classification of fluid producers showed 50% (93/187) Category 0 (insufficient cellular material), 38% (71/187) Category I (benign nonhyperplastic ductal epithelial cells), 10% (18/187) Category II (benign hyperplastic ductal epithelial cells), 3% (5/187) Category III (atypical ductal epithelial cells) and none were Category IV (unequivocal malignancy). Overall, 19% of the subjects produced NAF with adequate cellularity and1% were found to have cytologic atypia.

CONCLUSION : The HALO system is a simple, safe, rapid, automated method for standardized collection of NAF which is acceptable to patients. Cytologic assessment of HALO-collected NAF showed the ability to detect benign and pre-neoplastic ductal epithelial cells from asymptomatic volunteers. [BMC Women’s Health 2005, 5:10.]

Current comprehensive assessment and management of women at increased risk for breast cancer
Alan B. Hollingsworth, M.D.^a, S. Eva Singletary, M.D.^b, Monica Morrow, M.D.^c, Darius S. Francescatti, M.D.^d, Joyce A. O’Shaughnessy, M.D.^e, Anne-Renee Hartman, M.D.^f, Becky Haddad, M.T.^g, Freya R. Schnabel, M.D.^h, Victor G. Vogel, M.D.<sup>i

a</sup>Department of Surgery, Mercy Health Center, Mercy Women’s Center, 4300 McAuley Blvd., Oklahoma City, OK 73120, USA
^bDepartment of Surgery, MD Anderson Cancer Center, Houston, TX, USA
^cDepartment of Surgery, Northwestern University, Chicago, IL, USA
^dDepartment of Surgery, Rush Medical College, Chicago, IL, USA
^eBaylor-Sammons Cancer Center, US Oncology, Dallas, TX, USA
^fDepartment of Medicine, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
^gSusan G. Komen Foundation, Dallas, TX, USA
^hDepartment of Surgery, Columbia Presbyterian Medical Center, New York, NY, USA
ⁱDepartment of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Abstract
The potential for reducing the risk of breast cancer through selective estrogen receptor modulators, aromatase inhibitors, and surgery has generated interest in the use of quantitative models of risk assessment. With the addition of ductal lavage cytology to traditional epidemiologic risk factors, a discovery of cellular atypia can result in refinement of assigned risk values, while simultaneously optimizing patient selection for selective estrogen receptor modulators utilization. In view of increasing complexity in this arena, a Risk Assessment Working Group was formed to outline management strategies for the patient at an elevated risk for the development of breast cancer. No longer a statistical exercise, quantitative risk assessment is part of basic breast care and comprehensive management includes a discussion of the following: ductal lavage for improved risk stratification, multiple options for risk reduction, and high risk surveillance strategies that might incorporate investigational imaging protocols. [The American Journal of Surgery 187 (2004) 349–362]

Breast Cancer Risk in Women With Abnormal Cytology in Nipple Aspirates of Breast Fluid
Margaret R. Wrensch, Nicholas L. Petrakis, Rei Miike, Eileen B. King, Karen Chew, John Neuhaus, Marion M. Lee, Moore Rhys

Abstract
BACKGROUND : We previously showed that women with abnormal cytology in breast fluid obtained by nipple aspiration had an increased relative risk (RR) of breast cancer compared with women from whom fluid was not obtained and with women whose fluid had normal cytology. This study extends the follow up in the original study group (n = 4046)and presents the first follow-up for a second group of women (n = 3627).

METHODS : We collected nipple aspirate fluid from women in the San Francisco Bay Area during the period from 1972 through 1991, classified the women according to the most severe epithelial cytology observed in fluid specimens, and determined breast cancer incidence through March 1999. We estimated RRs for breast cancer using Cox regressions, adjusting for age and year of study entry. All statistical tests were two-sided.

RESULTS : For women in the first and second study groups, the median years of follow-up were 21 years and 9 years, respectively, and breast cancer incidences were 7.8% (285 cases in the 3633 women for whom breast cancer status could be determined) and 3.5% (115 of 3271), respectively. Compared with women from whom no fluid was obtained, whose incidences of breast cancer were 4.7% (39 of 825)and 3.3% (65 of 1950)for those in group 1 and group 2, respectively, incidences and adjusted RRs were 8.1% (34 of 422), with RR = 1.4 (95% confidence interval [CI] = 0.9 to 2.3), and 0% (0 of 31), respectively, for those with unsatisfactory aspirate specimens and 8.2% (148 of 1816), with RR = 1.6 (95% CI = 1.1 to 2.3), and 3.1% (25 of 811), with RR = 1.2 (95% CI = 0.8 to 2.0), respectively, for those with normal cytology in aspirates. Compared with women from whom no fluid was obtained, incidences and adjusted RRs for women in group 1 with epithelial hyperplasia and atypical hyperplasia in aspirates were 10.8% (52 of 483), with RR = 2.4 (95% CI = 1.6 to 3.7), and 13.8% (12 of 87), with RR = 2.8 (95% CI = 1.5 to 5.5), respectively, while those for women in group 2 were 5.5% (25 of 457)and 0% (0 of 22), respectively, with a combined RR = 2.0 (95% CI = 1.3 to 3.3).

CONCLUSION : The results obtained with the newly followed women independently confirmed previous findings that women with abnormal cytology in nipple aspirates of breast fluid have an increased risk of breast cancer. [J Natl Cancer Inst 2001;93:1791–8]

Nipple Aspirate Fluid Cytology and the Gail Model for Breast Cancer Risk Assessment in a Screening Population
Jeffrey A. Tice¹, Rei Miike², Kelly Adduci³, Nicholas L. Petrakis², Eileen King², and Margaret R. Wrensch<sup>2

1</sup>Division of General Internal Medicine, Department of Medicine, ²Department of Epidemiology and Biostatistics, and ³Cancer Center, University of California, San Francisco, San Francisco, California

Abstract
BACKGROUND : Recent guidelines suggest that chemoprevention with tamoxifen may be appropriate for women who have a 5-year risk of breast cancer greater than 1.66% calculated using the Gail model.

OBJECTIVES : To determine whether nipple aspirate fluid (NAF) cytology combined with the Gail model provides breast cancer risk assessment that is superior to either method alone.

METHODS : Prospective observational cohort of 6,904 asymptomatic women. Breast cancer cases were identified through follow-up with the women and linkage to cancer registries. We used proportional hazards modeling to recalculate the coefficients for the predictor variables used in the Gail model. NAF cytology was added to create a second model. The two models were compared using the concordance statistic (c-statistic).

RESULTS : During 14.6 years of follow-up, 400 women were diagnosed with breast cancer. There were 940 (14%) women with hyperplasia and 109 (1.6%) women with atypical hyperplasia found in NAF. Adding NAF cytology results to the Gail model significantly improved the model fit (P < 0.0001). The c-statistic for the Gail model was 0.62, indicating only modest discriminatory accuracy. Adding NAF cytology to the model increased the c-statistic to 0.64. NAF cytology results had the largest effect on discriminatory accuracy among women in the upper third of Gail model risk. The relative incidence for the highest quintile of risk score compared with the lowest quintile was 7.2 for the Gail model and 8.0 for the model including NAF cytology.

CONCLUSION : NAF cytology has the potential to improve prediction models of breast cancer incidence, particularly for high-risk women. (Cancer Epidemiol Biomarkers Prev 2005;14(2):324–8)

Cytopathology of abnormal nipple discharge: a cyto-histological correlation
Wen-Ying Lee Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan

Abstract
Spontaneous or expressible nipple discharge may occur in palpable and nonpalpable breast lesions. The aim of the study was to evaluate the sensitivity and specificity of nipple discharge cytology in palpable and nonpalpable breast lesions. One hundred and seventy-four nipple discharge specimens were reviewed, of which 82 had corresponding surgical pathology, including 34 palpable breast lesions and 48 nonpalpable breast lesions. There was good correlation between nipple discharge cytology and concomitant fine needle aspiration (FNA) cytology. Nipple discharge cytology is as specific as concomitant FNA cytology but is slightly less sensitive in detecting papillomas or malignant lesions. The sensitivity and specificity of the nonpalpable and palpable breast lesions were similar. Nipple discharge cytology is very helpful in detecting an underlying breast lesion even if the case has no palpable mass in the breast.
Cytopathology 2003 (14):19-26