Surg Oncol Clin N Am

14 (2005) 45–68

Ductal lavage for breast cancer risk

assessment
Aeisha Rivers, MDa,
Lisa A. Newman, MD, MPH, FACSb,*
a
Department of Surgery, St. Joseph’s Hospital and Medical Center, Ann Arbor, MI, USA
b
Breast Care Center, University of Michigan Comprehensive Cancer Center, 1500 East
Medical Center Drive, 3308 CGC, Ann Arbor, MI 48109, USA

Ductal lavage is a technology that is available as a means of refining breast

cancer risk assessment in selected women who are candidates for breast
cancer risk prevention strategies. The ductal lavage procedure provides
a noninvasive opportunity to identify abnormal proliferative activity—in the
form of cellular atypia—within the ductal system of a woman who has
clinical evidence of increased breast cancer risk. This article reviews: (1) the
evolution and rationale for breast ductal fluid analysis as a risk assessment
strategy; (2) contemporary applications of ductal lavage as a risk assessment
adjunct, including result-appropriate follow-up strategies; and (3) evidence
that supports the potential for using ductal lavage in translational research
endeavors.

Why study breast ductal fluid in women who face increased breast cancer
risk?
Approximately 212,000 women are diagnosed with breast cancer in the
United States annually [1]. Following breast cancer diagnosis, most women
face treatment decisions that involve some degree of disfiguring surgery,
chemotherapy, or radiation therapy. Although these treatments will be
effective in controlling disease in most cases, risks of relapse and breast
cancer mortality persist over the lifetime. Despite the earlier stage
distribution that has resulted from screening mammography, more than
40,000 American women die of breast cancer each year. The magnitude of
this breast cancer burden has been the driving force behind investigations of

* Corresponding author.
E-mail address: lanewman@umich.edu (L.A. Newman).

1055-3207/05/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.soc.2004.07.004
46 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

risk reduction strategies. Availability of these strategies and characterization

of their potential for adverse events has strengthened the need for accurate
stratification of breast cancer risk. Although statistical models for estimation
of this risk are valuable, there continues to be a need for the development of
maneuvers that will ‘‘fingerprint’’ proliferative activity in the breast, either
through tissue or ductal fluid analyses.
Current options for breast cancer prevention include prophylactic
mastectomy, prophylactic oophorectomy, and endocrine manipulation with
selective estrogen receptor modulators, such as tamoxifen. The degree of
risk reduction is estimated at approximately 90% and 50% for prophylactic
mastectomy [2] and oophorectomy [3], respectively. Chemoprevention with
tamoxifen can decrease breast cancer risk by nearly 50% [4]. Comparison of
the relative risk reduction benefits that are conferred by raloxifene versus
tamoxifen is underway through the National Surgical Adjuvant Breast
Project P-2 phase 3 prospective randomized trial, the Study of Tamoxifen
and Raloxifene. Recent findings from the Arimadex versus Tamoxifen
versus the Combination trial revealed that aromatase inhibitors that are
used as adjuvant therapy also result in diminution of risk for new primary
breast cancer; this may lead to their evaluation in the chemoprevention
setting for postmenopausal women [5].
None of these risk reduction strategies is completely effective and all are
associated with well-recognized risks for potentially life-threatening or
disabling adverse sequelae. Selective estrogen receptor modulator (SERM)
therapy can increase the risk of uterine cancer and thromboembolic phenom-
ena; aromatase inhibitors can increase the risk of osteoporosis; prophylactic
oophorectomy places women at risk for premature menopause; and prophy-
lactic mastectomy is disfiguring, even with the best of reconstruction
techniques. Clearly, these interventions should be reserved for appropriately-
selected women who face the greatest risk of breast cancer development.
Although many clinicopathologic risk factors for breast cancer have been
identified (Table 1), there are few options for estimating an individual
woman’s absolute risk for developing breast cancer. Currently-available
individualized risk assessment tools include the Claus Model [6] and the Gail
Model. The Claus Model was developed by subset analysis of several
thousand participants of the Contraceptives and Steroid Hormone Study,
using a breast cancer case-control statistical design. This model is most
appropriate for women who have a significant risk for genetic breast cancer
susceptibility because it uses history of breast or ovarian cancer in the
extended family, as well as age at diagnosis, to calculate the cumulative pro-
bability for breast cancer development in the individual.
The Gail Model is a mathematical tool that is based on analysis of a case-
control subset of women who participated in the American Cancer Society’s
screening mammography program—the Breast Cancer Detection and
Demonstration project [14]. This model uses four breast cancer risk factors
(age at menarche, parity, first degree family history of breast cancer, and
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 47

Table 1
Risk factors for breast cancer
Risk factor Relative risk
Early menarche (\11 years) [7] 1.1–1.9
Late age at first live birth ([35 years) [8] 1.16
Late menopause [8] 1.44
Prolonged HRT ([4 years) [9] 1.26
Postmenopausal obesity [10] 1.45
Increased mammographic density (25–50% of breast) [11,12] 2.4
Family history [13] One first-degree relative 1.80
Two first-degree relatives 2.93
Abbreviation: HRT, hormone replacement therapy.

biopsy history) to generate an overall relative risk for the individual. This
factor is multiplied by the subject’s age-related baseline risk for developing
breast cancer to yield an individualized estimate of absolute likelihood for
being diagnosed with the disease. The Gail Model has been modified to
account for ethnicity (white American versus African American) in the
baseline risk; to account for increased risk associated with atypia in a past
biopsy; and to calculate the risk of invasive disease only. A 5-year risk of at
least 1.7% (the risk of an average 60-year-old white American woman) is
considered high-risk for the purpose of eligibility to participate in
chemoprevention trials and for identifying women who might benefit from
risk reduction counseling.
Studies that compared the Gail and Claus models showed comparable
risk estimates, although the Gail model estimates tend to be slightly lower
[15]. In general, the Gail model is used more widely and its accuracy was
validated in several populations of white American women [16–19]. The
Gail model is limited by the fact that it does not account for the paternal or
extended family history of breast cancer and little is known about its
accuracy in nonwhite American women. Furthermore, the statistical
discriminatory accuracy of the model is modest, at best’ this indicates that
although the model will identify groups of high-risk women reliably, its
performance is weaker for individualized risk assessment. Rockhill et al [19]
and Newman et al [20] studied the model among participants of the Nurses
Health Study and the Women’s Contraceptives and Reproductive Experi-
ences Study, respectively, and reported concordance statistics of 0.54 to
0.58. This measure suggests that given any breast cancer case and control
pair, the Gail model has only slightly better than a 50% chance of yielding a
higher estimate for the diseased patient.
Other models that are used for breast cancer risk assessment are tailored
more for the prediction of whether a woman is at risk for breast cancer that
is associated with an inherited mutation in one of the breast cancer
susceptibility genes [21]. Typically, these models rely on more detailed
family history information, age at disease onset, and ethnicity (because of
Table 2

48
Risk of breast cancer following diagnosis of atypia
Breast cancer relative
Median Method of risk, (95% confidence
Investigators N Selection criteria follow-up % Atypia detection intervals)

A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

Fabian 480 University of Kansas 45 months 12%a Periareolar 5.02 (2.01–12.56)
et al, 2000 [29] patients who had high FNAs for
risk by way of cytology
FH/PH breast cancer
or history of
atypical hyperplasia/
DCIS
Wrensch 3633 (Group 1) Group 1: UCSF 21 years (group 1) 2.4% NAF 2.4 (1.6–3.7)
et al, 2001 [30] BCDDP
participants
3271 (Group 2) Group 2: UCSF 9 years (group 2) 0.7% NAF 2.8 (1.5–5.5)
volunteers
Wrensch 2343 General screening 12.7 years 2% NAF 4.9 (1.7–13.9)
et al, 1992 [27] population
Dupont 9494 Vanderbilt 20 years 3.0% Surgical 3.58 (2.6–5.0)
et al, 1999 [31] University biopsy
patients who specimens
had biopsy-proven
benign breast
disease
Bodian 1799 Haagensen patient 20.6 years 19% Surgical 3.0 (1.5–6.0) (moderate/
et al, 1993 [32,33] population from biopsy severe atypia)
Columbia-Presbyterian specimens 2.3 (1.6–3.4)
Medical Center (mild atypia)
who had biopsy-proven
benign breast disease
Hutchinson 1053 Private practice patient 12.9 years 3.1% Surgical 2.85 (0.34–10.28)
et al, 1980 [25] population who had biopsy
biopsy-proven benign specimens
breast disease
Carter 16692 BCDDP participants 8.3 years 7.8% Surgical 3.0 (2.1–4.1)

A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

et al, 1988 [34] who had history of biopsy
biopsy-proven benign specimens
breast disease
Dupont and Page, 3303 History of biopsy-proven 17 years 3.6% Surgical All: 5.3 (3.1–8.8)
1985 [26] benign breast disease biopsy With FH of breast
specimens CA: 8.9 (4.8–17)
Without FH of breast
CA: 3.5 (2.3–5.5)
London 121 breast cancer Nurses Health Study 9 years 22.3% Surgical All: 3.7 (2.1–6.8)
et al, 1992 [35] cases participants who had (cases) biopsy With FH of breast CA:
488 controls cancer or biopsy-proven 9.6% specimens 7.3 (1.1–50.1)
benign breast disease (controls) Without FH of breast
CA: 3.7 (1.9–7.0)
McDivitt 433 breast cancer Cancer and Steroid N/A 15.9% Surgical Odds ratio 2.6 (1.6–4.1)
et al, 1992 [36] cases Hormone Study (cases) biopsy
261 controls participants who had 10.0% specimens
cancer or biopsy-proven (controls)
benign breast disease
Palli et al, 62 breast cancer Women from Florence, N/A 17.7% Surgical Odds ratio 13.0 (4.1–41.7)
1991 [37] cases Italy breast cancer (cases) biopsy
315 controls screening program 2.2% specimens
(controls)
Krieger and Hiatt, 2731 San Francisco Bay, 16 years 12% Surgical Rate ratio 7.2 (Black-
1992 [38] California women biopsy Chabon Score 5/severe
who had biopsy-proven specimens atypia)
benign breast disease
(continued on next page)

49
Table 2 (continued)

50
Breast cancer relative
Median Method of risk, (95% confidence
Investigators N Selection criteria follow-up % Atypia detection intervals)

A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

Dupont 95 breast cancer Breast Cancer Detection N/A 14.7% Surgical Odds ratio 4.3 (1.7–11)
et al, 1993 [39] cases and Demonstration (cases) biopsy
227 controls Project mammography 4.4% specimens
screening program (controls)
participants
Byrne 133 breast cancer Nurses Health Study N/A 25.6% Surgical Odds ratio 3.6 (2.0–6.4)
et al, 2000 [40] cases participants who had (cases) biopsy
610 controls cancer or biopsy-proven 11.8% specimens
benign breast disease (controls)
Carpenter and Initial cohort: Patients undergoing 19.7 years NR Cytology on 2.32 (1.01–4.41)
Love, 2002 414 patients ductography ductogram-
[41] Respondents re: associated
outcome 56 ductal
lavage
Abbreviations: BCDDP, Breast Cancer Demonstration and Detection Project; CA, cancer; DCIS, ductal carcinoma in situ; FH, family history; FNA, fine
needle aspirate; NAF, nipple aspirate fluid; PH, personal history; UCSF, University of California-San Francisco.
a
Atypia found in 12% of FNAs from single aspirates; sequential FNAs over 6 and 12 months resulted in 21% atypia prevalence for pooled samples.
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 51

the influence of founder effects in genetically-transmitted risk). Because only

5% to 10% of breast cancer is related to hereditary disease, these types of
models are not likely to be helpful in evaluating risk among large, unselected
patient populations.
Alternative measures of individualized risk assessment are needed as we
expand chemoprevention programs and as novel risk reduction agents are
developed, and require evaluation in future clinical trials. A pure, individu-
alized predictor would be some feature that can be measured reliably and is
associated consistently with increased risk. Potential candidates include
mammographic density, serologic markers, or tissue characteristics. Data on
magnitude of risk that is conferred by most surrogate markers have been
inconsistent and interlaboratory variability in their measurement has
hindered clinical application. Reproducible and individualized, measurable
features of breast cancer risk are lacking; this deficiency has motivated
interest in the detection of histopathologic risk factors, such as lobular carci-
noma in situ, radial scar, papillomatosis, and atypical hyperplasia. The first
three lesions are uncommon and only can be detected by way of open biopsy
that yields a wedge of tissue for microscopic evaluation. This leaves atypical
hyperplasia as the most promising feature, because atypia can be identified
cytologically and on histopathologic tissue analysis. Breast carcinogenesis
often is viewed as a continuum of morphologic changes at the microscopic
tissue level; atypical hyperplasia appears early in the transformation process.
This model for breast tumorigenesis features the evolution of breast ductal
cells from normal to hyperplastic, followed by the development of atypical
hyperplasia. Accumulation of genetic abnormalities as ductal cells proceed
through the cell cycle leads to the development of carcinoma in situ, and
ultimately, invasive cancer [22]. Autopsy findings suggest that the prevalence
of atypical hyperplasia can be estimated between 12.5% and 26%, de-
pending on the sampling technique [23,24].
Hutchinson et al [25] and Dupont and Page [26] provided some of the
initial data that documented the association between atypical hyperplasia
and breast cancer risk. These retrospective analyses of outcome in several
thousand women who had benign breast biopsies demonstrated relative
risks of 2.85 and 5.3, respectively, in cases that were associated with atypical
hyperplasia. Similarly, Wrensch et al [27] reported that women who had
atypia that was detected cytologically in nipple aspirate fluid had a relative
risk of 4.9 for breast cancer. As shown in Table 2, several other studies have
confirmed this correlation, with relative risk estimates that average between
3 and 5, regardless of whether the atypia is detected in a nipple aspirate,
needle biopsy, or in an open surgical biopsy specimen. The risk that is
associated with atypia may be magnified in the presence of a family history
that is positive for breast cancer. One of the unique aspects of atypia as
a risk indicator is that the subsequent breast cancer risk seems to be
expressed predominantly in the 5 years following detection [28]; therefore,
atypia may provide some temporal measure of breast cancer risk.
52 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

The efficacy of chemoprevention is an essential element in the discussion

of strategies (eg, ductal lavage) that are designed to detect breast atypia. The
Surgical Adjuvant Breast and Bowel Project’s (NSABP) initial chemo-
prevention trial of tamoxifen versus placebo in more than 13,000 high-risk
women included approximately 600 women in each arm of this study who
had a history of atypical hyperplasia [4]. Participants who had atypia who
were randomized to tamoxifen had a highly significant, 86% lower breast
cancer incidence compared with the placebo subset; this suggested that
atypia is a pattern of abnormal proliferative activity that is suppressed
effectively by selective estrogen receptor modulators.
Thus, atypia seems to be a valuable and reliable marker of future breast
cancer risk. The strength of this association is unaffected by method of tissue
acquisition and it seems to be a marker of risk that is particularly sensitive to
the antiproliferative effects of chemoprevention with tamoxifen. Therefore, it
is reasonable to seek a reliable and low-morbidity procedure that can identify
women who harbor atypia. The patient population that is most appropriate
for such an intervention are high-risk women who are ambivalent about
committing to a risk reduction strategy. In this setting, the detection of atypia
may facilitate this decision, although the failure to detect atypia should not be
misinterpreted as indicating any decrease in the level of pre-existing risk.
Conventional tissue procurement maneuvers that have been incorporated
into risk assessment algorithms include FNA, core needle biopsy, and open
surgical biopsy.
Random FNA was studied by several investigators in an attempt to
determine its feasibility as a screening tool among high-risk women. The first
few reports were provided by collaborators from the University of Utah in
the early 1990s [42–44]. They evaluated more than 100 women with at least
two first-degree relatives who were affected by breast cancer and more than
30 control patients who had no cancer diagnosis. Each subject underwent
physical examination, screening mammography, and four-quadrant fine
needle breast aspirates with a 1-inch, 22-gauge needle approximately 1 cm
from the areola. Evidence of proliferative breast disease was seen in 35% of
the participants who had a positive family history and otherwise no physical
or radiologic evidence of cancer. Only 13% of the controls revealed cytologic
features of proliferative breast disease (P = .02). Using a similar technique,
Fabian et al [29] performed sequential FNA biopsies on 480 high-risk
women. After a median follow-up of nearly 4 years, their data revealed a
strong relationship between the presence of atypia in conjunction with an
elevated 10-year Gail model risk estimate and an increased short-term risk of
developing breast cancer.
Although the information that was obtained from studies of FNA has
proved to be useful, this sampling technique is not without limitations. The
procedure usually is quick and inexpensive to perform, but random
sampling often yields nonreproducible findings. FNA yields specimens that
are sufficient for cellular and molecular marker evaluation in an estimated
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 53

85% of attempts [45]; however, the probability of obtaining adequate

cellularity decreases with increasing age.
Core needle biopsy has been used in the diagnosis of breast cancer for
several years. Random core needle biopsy is not used often as a method
of sampling breast epithelium and reports of its efficacy are scarce. One
promising study by Stoler et al [46] described an alternative method of
obtaining breast epithelial samples as excess tissue for possible molecular
and cytogenetic studies in patients who undergo core needle biopsies. They
obtained specimens from more than 100 women who underwent core needle
biopsy for lesions that were detected by mammogram. Washings of these
core biopsy specimens yielded an abundance of epithelial cells. Therefore,
this method may become a useful tissue procurement adjunct; however, it
does not fulfill the need for a noninvasive maneuver that can be performed
for pure risk assessment because the candidate patients are undergoing
a diagnostic core needle biopsy as the result of an abnormal breast lesion.
Similarly, a random open surgical biopsy would not be feasible or re-
producible for the sole purpose of risk assessment and is reserved for
histopathologic differentiation between benign and malignant breast lesions.
Studies of nipple aspirates for breast cancer screening and risk assessment
were initiated by investigators several decades ago; however the technique
was never popularized because of the low cellular content and because
chemoprevention was not available in that era which limited the clinical
relevance of any high-risk findings. The earliest attempts at nipple fluid
aspiration were designed with the intent of detecting cancer. In the 1950s,
Papanicolaou and colleagues [47,48] first reported the use of breast massage
and a hand-held pump to obtain samples of nipple fluid in women who did
not have signs or symptoms of breast disease. Sartorius et al [49] applied
a modified version of this technique in 1700 asymptomatic women but
obtained adequate fluid for cytologic evaluation in only half of the cases.
In summary, procedures, such as percutaneous needle biopsy or open
surgical biopsy, that are performed in a random fashion to sample breast
tissue are invasive maneuvers that would be unacceptable for pure risk
assessment. Direct nipple aspirates for cytologic analysis are noninvasive,
but the cellular content of these specimens frequently is low and yields a
nondiagnostic specimen. The goal of ductal lavage is to provide a minimally-
invasive means of extracting ductal fluid that is cytologically-enriched [50].
The ductal lavage procedure is performed in the outpatient setting with
a topical anesthetic. It involves the use of a Food and Drug Administration–
approved double-lumen catheter for cannulation of any fluid-yielding nipple
orifice that can be identified after application of a transparent suction cup–
device to the breast. Techniques that can improve the yield of fluid-
producing ducts include vigorous breast massage by the patient before the
procedure; nipple dekeratinization with a mild abrasive; application of
warm towels; and topical nitroglycerin to the nipple [51]. Cannulation of the
duct is followed by lavage with approximately 10 to 20 mL of saline and
54 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

aspiration for cytology evaluation. The process is repeated for all additional
fluid-yielding ducts, using a separate catheter for each. Technical limitations
of the procedure include nipple sphincter spasm that prevents duct can-
nulation and duct perforation secondary to increased ductal pressures
during lavage. When cannulation, lavage and specimen retrieval are success-
ful, the position of the cannulated duct should be recorded. This can be
accomplished by notation on a diagrammatic grid or by photograph, with a
segment of suture material inserted into the lavaged ducts for documenta-
tion and marking. These records are particularly valuable in cases where
repeat lavage is considered.
A multicenter study that was reported by Dooley et al [52] confirmed the
superiority of ductal lavage over direct aspirates in yielding cytologically-
evaluable fluid among high-risk women. This landmark 2001 report
compared the efficacy of the two techniques in a series of more than 500
women who were identified as being at high-risk for breast cancer on the
basis of family history, personal history of breast cancer, or a 5-year Gail
model breast cancer risk estimate of at least 1.7%. Eighty-four percent of
study participants had fluid-yielding ducts that were amenable to lavage;
82% of these fluid-yielding ducts were cannulated successfully. Among the
population who tolerated cannulation for lavage, 78% had samples with
adequate cellular material for diagnosis. Substantially more cells were
collected with ductal lavage compared with nipple fluid aspiration (13,500
cells per duct versus 120 epithelial cells). Ductal lavage was 3.5 times more
successful at producing cytologically-evaluable fluid compared with paired
nipple aspirates (72% versus 21%, respectively; P \ .001) in this study.
Among the women who were evaluated with ductal lavage, 92 (24%)
subjects showed evidence of cellular abnormalities that were mildly (17%)
or markedly (6%) atypical or malignant (\1%). In contrast, abnormal cells
were detected in only 10% of the women who underwent nipple fluid
aspiration; mild atypia was identified in 6%, marked atypia was identified in
3%, and malignancy was identified in less than 1% of the women who were
evaluated. The collaborators concluded that ductal lavage is the more
sensitive technique for detecting atypia.
Generally, the ductal lavage procedure is well-tolerated by patients. In
the multi-center study by Dooley et al [52], the median discomfort level
that was reported by study participants was 24 on a visual analog scale of
1 to 100, comparable in magnitude to the discomfort level described for
mammography. There also was minimal morbidity, with no major compli-
cations of the procedure and only two cases of suspected infections that were
treated uneventfully with oral antibiotics.
A frequently-cited criticism of the procedure is the fact that there are no
data to confirm the magnitude of future breast cancer risk that is conferred
by the detection of atypia from a ductal lavage specimen. The strength of
this association is similar for all conventional diagnostic procedures (eg,
tissue biopsies versus cytologic assays for nipple aspirates); therefore, it
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 55

seems reasonable to extrapolate that this consistency would extend to atypia

detected by ductal lavage (see Table 2). Nonetheless, documentation of this
risk based on the long-term follow-up of patients who underwent lavage
remains necessary. Interesting data on the outcome of patients who under-
went a variation of the ductal lavage procedure were provided in a study
that was presented by Carpenter and Love [41]. This study involved an
attempt to compile follow-up information on patients from the Sartorius
breast practice [49] who underwent ductography with concomitant lavage
through the ductogram catheter more than 30 years ago. The power of this
study is limited by the poor follow-up success. The original cohort consisted
of 414 patients; however, there were only 56 respondents out of 191 patients
(29%) who were believed to be alive at the nearly 20-year median follow-up.
Nonetheless, the investigators confirmed that atypia that was detected by
this modified lavage procedure conferred a statistically significant greater
than twofold relative risk for breast cancer.
As a risk assessment adjunct, ductal lavage also would be expected
to identify candidates for chemoprevention trial eligibility. The presence
of atypical hyperplasia provides more concrete and persuasive evidence
of breast cancer risk to candidates for chemoprevention compared with
conventional measures of risk, such as the Gail model; this suggests that
ductal lavage can be a powerful tool in this regard. Port et al [53] reported
the experience of 43 high-risk women who were seen at the Memorial Sloan
Kettering Cancer Center. All patients were counseled about the benefits of
chemoprevention, yet only 2 (4.7%) decided definitively to accept tamoxifen
therapy. Similarly, Vogel et al [54] reported that of risk-eligible women
who were evaluated for participation in the NSABP’s current chemopre-
vention trial to compare tamoxifen and raloxifene, only 21% agreed to
randomization.
In contrast, a diagnosis of atypical hyperplasia substantially escalates
a woman’s interest in chemoprevention therapy or clinical trial participation.
Vogel et al [54] found that of risk-eligible women who also had a history of
atypia, approximately one third agree to randomization. Morrow et al [55]
similarly reported that high-risk women are more likely to accept chemo-
prevention and physicians are more likely to recommend this option if
a diagnosis of atypia has been made. Atypia seems to be a more compelling
motivation that empowers high-risk women to make difficult decisions
regarding risk-reduction strategies. The strength of atypia in identifying
participants for chemoprevention trials motivated the NSABP to allow
inclusion of abnormal lavage findings into Gail model risk calculations. For
assessment of chemoprevention trial eligibility, atypia that is detected on
ductal lavage cytology is entered into the Gail model risk estimate as the
equivalent of one biopsy with atypia; normal ductal lavage data are not
entered into the risk estimate calculations.
Hence, past studies have confirmed that atypical hyperplasia that is
detected by FNA biopsy, nipple aspirate, or surgical biopsy is a reliable risk
56 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

factor for breast cancer and a marker of risk that is suppressed readily by
chemoprevention with tamoxifen. Recent studies demonstrated that ductal
lavage is a well-tolerated, minimally-invasive maneuver that can retrieve
cells readily to aide in the detection of atypia. It can be assumed reasonably
that atypia that is diagnosed with this modality has similar predictive value
as when it is detected by the older methods.

What information is available from clinically-active, contemporary ductal

lavage programs and how should patients be followed?
The next issue to be addressed is related to integration of ductal lavage
into contemporary clinical practice, with an appraisal of its availability and
what the technology has revealed. The length of time that is necessary to
assimilate case series, analyze data, and proceed through peer review to
publication easily can exceed several years; a review of abstracts that are
presented at major academic meetings provides an intermediate barometer of
a new technology’s use. Therefore, it is worthwhile to appraise data that are
presented in abstract and manuscript form regarding experiences with the
ductal lavage technology since the Dooley et al [52] 2001 multi-center study
publication. Interest in ductal lavage has been increasing as reflected by the
number of abstracts that were presented at some of the national academic
meetings that have focused on applications of this technology. A review of
the program proceedings for the meetings of the American Society of Clinical
Oncology and the San Antonio Breast Cancer Symposium revealed 5 ductal
lavage–related presentations in 2001, 10 in 2002, and 11 in 2003.

Reported results of programs that use ductal lavage as a clinical risk

assessment adjunct
Generally, investigators who reported on individual institution/practice
experiences with the ductal lavage procedure had technical success in 70%
to 80% of cases, comparable to the multi-center study [52]. This yield may
be improved by technical modifications, such as topical 2% nitroglycerine
applied to the nipple approximately 30 minutes hour before attempting duct
cannulation. Golewale et al [56] found that this increased lavage success
rates by more than 20%.
As shown in Table 3, data on the prevalence of atypia in ductal lavage
specimens are consistent with earlier investigations of atypia prevalence
from other tissue sources that were based on the study populations. Atypia
is uncommon (2%) in unselected, general populations as demonstrated by
studies of nipple aspirates on average-risk, asymptomatic women [27]. Rates
of atypia are higher (15%–26%) when detected as coexisting lesions in
cancer-bearing biopsy specimens and intermediate (2%–10%) when tissue
specimens from noncancerous biopsies are evaluated [35–37,39,40]. As
expected, the prevalence of atypia that is detected on ductal lavage of
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 57

Table 3
Prevalence of atypia
Proportion of study population
Tissue source Study population who had atypia
Nipple aspirates General population 2%
Random FNA High-risk women 12%
Ductal lavage High-risk women, multi-center 6–17%, minimal to
study [52] moderate-severe
High-risk women, various
backgrounds
12 patients undergoing surgical 1/12; 8%
biopsy, risk status unknown [57]
33 high-risk patients [58]
24 high-risk patients [59] 1/24; 4.2%
90 high-risk patients [60] 4/90; 4.5%
77 high-risk patients [61] 19/77; 25%
93 high-risk patients [62] 25/93; 27%
30 known or suspected BRCA 7/30; 23%
mutation carriers [63]
24 known or suspected BRCA 13/24; 54%
mutation carriers [64]
138 ductography cases with 112/138; 81%
pathologic nipple discharge [65]
29 cancerous breasts undergoing 10/29; 34%
mastectomy [66]
Surgical biopsy Surgical biopsy cases, benign 2–11%
Surgical biopsy cases, cancerous 14–26%

high-risk women tends to fall into the intermediate category but varies with
categories of risk and the type of patient who is evaluated. Ductal lavage
that is performed in the accepted clinical fashion, as a risk assessment
adjunct, reveals cytologic atypia in 4% to 27% of ‘‘conventional’’ high-risk
cases; prevalence of atypia increases to 23% to 54% in known or suspected
carriers of BRCA mutation who undergo lavage. Studies of ductal lavage in
the investigational setting revealed even higher rates of atypia among
women who underwent lavage in conjunction with ductography that was
performed for a pathologic nipple discharge (81%) and in the cancerous
breasts of patients who underwent mastectomy (34%) (see Table 3).
Dooley et al [61] reported that ductal lavage findings are influential in
guiding decisions regarding tamoxifen among women who are high-risk on
the basis of a personal history of unilateral breast cancer. They found that
ductal lavage cytology in the contralateral breast led to a 16% increase in
the use of tamoxifen. Ductal lavage also has been incorporated into
comprehensive screening programs for women who have a hereditary risk of
breast cancer, where it may be a useful adjunct to innovative surveillance
modalities, such as magnetic resonance imaging (MRI) in these carefully-
selected patients [63,67,68]. Other categories of risk that would be
interesting to study in ductal lavage programs include women who have
58 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

a history of therapeutic chest wall irradiation (eg, Hodgkin’s disease) or

a history of prolonged postmenopausal hormone replacement therapy.

Correlation of ductal lavage cytology with surgical histopathology

Ductal lavage catheters are approved by the Food and Drug Adminis-
tration for use in performing galactography; at least two studies that
correlated diagnostic ductogram findings to lavage results were reported
[65,69]. These studies showed that the lavage procedure can be complemen-
tary to the ductogram; however, its sensitivity is not sufficiently high that
a normal lavage cytology can eliminate the need for surgical follow-up if
otherwise indicated by the clinical scenario and ductographic imaging.
Lawler et al [65] conducted ductal lavage in the form of ductogram flush
washings in 138 patients who were symptomatic for a pathologic nipple
discharge and who subsequently underwent surgical biopsy. Atypical cells
were found in 112 (81%) of the lavage specimens; follow-up biopsies revealed
lobular carcinoma in situ, atypical ductal hyperplasia (ADH), and papillo-
mas in nearly 90% of these cases. The lavage cytology was nonmalignant
in 24 of 27 cases that were found to be cancerous at surgical biopsy (benign
cytology in 3 of 27 [11%] and atypical in 21 of 27 [78%]).
Although atypia on ductal lavage cytology reasonably may be assumed
to represent a marker of increased risk, studies that correlated ductal lavage
with pathology from cancerous mastectomy specimens and from surgical
biopsy specimens confirmed that the lavaged ductal system will not reflect
a documented site of disease consistently in the studied breast. These reports
reaffirm that ductal lavage is not a cancer screening or detection procedure.
Brogi et al [66] performed ductal lavage in 26 breasts that underwent
mastectomy for cancer; none of the retrieved cytologies was clearly
malignant. Khan et al [70] reported an innovative project that involved
ductal lavage of cancerous breasts that was accompanied by the creation of
a castlike impression of the lavaged ductal system by injection of a gelatinous
material after the mastectomy had been completed. This topographic study
demonstrated a correlation between the location of the cancer and the
lavaged ductal system in only two thirds of cases.
Gabram et al [57] performed ductal lavage on 12 women before diagnostic
open biopsy; they found discordant results between the lavage cytology and
the surgical histopathology in nearly half of the cases. At best, the procedure
only evaluates cells from a portion of the ductal system that has been
cannulated. Therefore, it is unlikely to provide sufficient information re-
garding the entire breast.
Dooley et al [71] performed ductal lavage in the contralateral breasts of
women who underwent breast cancer surgery and detected atypia in 32%,
22%, and 6.7% of T1a/b, T1c, and T2 lesions, respectively. Early pathology
studies of atypia demonstrated that breast cancer risk tends to return to
baseline after approximately 5 years if no other risk-related events intervene.
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 59

If a cancer arises within a field of high-risk breast tissue, then surrounding

(including contralateral) breast tissue that previously harbored atypical
hyperplasia may continue to undergo regression in accordance with the data
indicating a return to baseline risk 5 years after the atypia was detected. The
cancerous lesion may lose an association progressively with atypia over time
and will not remain necessarily associated with a fluid-yielding ductal
system. Furthermore, breast cancer pathogenesis is likely to be heteroge-
neous; not every area of ductal atypia is committed to progressing to
invasive cancer if left untreated. Conversely, some cancers may arise without
having passed through an atypical hyperplasia precursor phase [22].

Potential limitations to the incorporation of ductal lavage into breast

cancer risk assessment programs
One issue regarding ductal lavage that requires further investigation is
related to the reproducibility of resulting cytologic analyses. Dr. Bonnie
King participated in the cytopathology review for the Dooley et al [52] study
of ductal lavage and the Wrensch et al [27] study of nipple aspirates and
provided inferential evidence that atypical cells that are retrieved by both
interventions can be well-standardized. Nonetheless, there is established
precedent to confirm the subjectivity and variation that can exist in histo-
pathologic assessment of borderline breast lesions [72] and one might infer
reasonably that differences in the cytologic evaluation of ductal lavage
specimens also might exist. Therefore, it is important to evaluate the inter-
laboratory reproducibility of ductal lavage analyses.
There is no uniformity in reimbursement policies that are offered by third
party payers to cover expenses that are generated by the ductal lavage
procedure. This poses a significant limitation to the availability of ductal
lavage as a clinical service, even among appropriately-selected high-risk
patients. Ozanne and Esserman constructed a mathematical cost-effective-
ness model that demonstrated that ductal lavage could lead to health care
cost-savings if the expected rates of atypia detection resulted in a decreased
number of breast cancers that required treatment with tamoxifen [72a].
Patients who are considering the ductal lavage procedure for risk assessment
must understand that significant out-of-pocket expenses may be incurred.
Access to the ductal lavage technology clearly is not universal.

Follow-up management strategies in ductal lavage cases

After a decision has been made to perform ductal lavage as a risk
assessment strategy, the clinician must be prepared to handle the results and
offer appropriate postprocedural counseling. An essential concept for the
patient and health care provider to understand is that normal cytology on
ductal lavage does not alter the magnitude of any pre-existing breast cancer
risk factors; it does not replace the need for routine breast cancer
60 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

surveillance nor does it have any implications regarding the possible

presence or absence of an occult malignancy. The procedure is clinically
significant only if atypia is detected, in which case it is relevant in
strengthening the patient’s risk profile and may influence decisions regarding
risk-reducing strategies. Morrow et al [73] developed a comprehensive
schema that described the integration of ductal lavage into the breast cancer
risk profile; an algorithm for handling abnormal lavage results is presented
in Table 4. Benign cytology should prompt reinforcement of the routine
breast cancer surveillance message by way of self-examination, clinical
examination, and screening mammography.
When atypia is detected, a second cytopathology opinion is reasonable,
but not absolutely necessary. Quantified risk should be recalculated by
accounting for the atypical lavage in a Gail model risk estimate as the
equivalent of one breast biopsy with atypia. Counseling regarding risk-
reduction strategies should follow, including a reassessment of eligibility for
chemoprevention protocols. Follow-up lavage at 6 to 12 months later,
regardless of whether the patient opts to take tamoxifen, is a reasonable
prospect but is of uncertain significance because the yield of sequential
procedures has not been studied completely. One potential concern might be
the possibility of variation in lavage cytology that is related to the menstrual
cycle. Although serial lavage results have not been reported on any large
patient cohorts, extrapolation from the literature on direct nipple aspirates
offers some encouraging insight that ductal fluid findings are independent of
the menstrual cycle. Mitchell et al [74] performed weekly nipple aspirates on
15 premenopausal volunteers and no significant differences in cellular profile
were detected over the course of two menstrual cycles.
A diagnostic dilemma is created in the disturbing circumstance of frankly
cancerous cells that are detected within a ductal lavage specimen. Because
the ductal lavage procedure is only appropriate as a risk assessment adjunct
for a woman who does not have any evidence of a pre-existing cancer, this
scenario is rare (occurring in fewer than 1% of the cases that were reported
in the multi-center study [52]) and presumably would occur in cases that are
associated with a negative mammogram and clinical examination. Nonethe-
less, it is worthwhile to review and repeat the clinical evaluation of the
affected breast in these cases. Confirmation of the lavage findings by second
opinion cytopathology also is useful. Malignant-appearing cytology can be
caused by a variety of benign and cancerous primary breast lesions, in-
cluding atypical hyperplasia and papillomatosis. A target for biopsy and
histopathologic correlation should be sought aggressively with maneuvers,
such as ductography (perhaps performed in conjunction with repeat lavage),
whole-breast ultrasound, breast MRI, and ductoscopy. If all studies are
negative for identifying a source of the cancerous cytology, the patient is
offered options of observation versus chemoprevention, with consideration
of complete re-evaluation (including a repeat lavage) 6 to 12 months later.
The optimal interval between sequential ductal lavage procedures has not
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 61

Table 4
Management of patients who have abnormal lavage
Lavage results
Management Atypical cytology Malignant cytology
Patient counseling Recalculate Gail model risk Possible etiologies:
estimate, with lavage Occult malignancy
counted as one biopsy ADH
with atypia Papillary lesion(s)
Repeat risk reduction
counseling, including
consideration of
chemoprevention trial
participation
Confirmation Optional; not necessary Necessary; options include:
of results by Review of cytopathology
second review Consider repeat lavage

Work-up to identify Not necessary if prelavage Necessary:

target lesion for breast imaging and Repeat breast
biopsy examination were normal examination
Review all prelavage
imaging
Repeat breast imaging,
including diagnostic
mammography
views and breast
ultrasound
Ductography
Breast MRI
Consider ductoscopy, if
available
Management options Chemoprevention trial if Observation and
eligible re-evaluation in
Observation and re-evaluation 3–6 months
in 6–12 mo Tamoxifen and re-evaluation
Tamoxifen and re-evaluation in 3–6 months
in 6–12 mo Prophylactic mastectomy
Prophylactic mastectomy
only to be considered by the
highest-risk women (eg
BRCA mutation carriers)
Abbreviation: ADH, atypical ductal hyperplasia.

been defined. The option of performing a blind terminal duct excision might
be considered; however, the disadvantage of this approach is that a tumor
that is shedding malignant cells into the ductal system could be located
peripheral to the subareolar ductal system, and therefore, could easily be
missed with this surgical procedure. Furthermore, after the terminal duct
apparatus has been divided and resected, the option of repeat cannulation
62 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

and ductal lavage is lost. Patients who undergo prophylactic mastectomy

because of cancerous lavage cytology should be forewarned of the
possibility that identification of a primary tumor mass in the breast may
be difficult, if not impossible.

How can the ductal lavage technology be used in the research setting?
Presentations at national meetings provide evidence of active research
endeavors; the proportion of ductal lavage–related projects that have been
related to basic scientific or translational research also has increased steadily
over the past few years. In 2001 and 2002, nearly all such work was related
to clinical applications of the ductal lavage procedure. During 2003 and
2004, however, more than half of the reported studies featured ductal lavage
as a research tool.
Investigators have published successful results in detecting molecular
markers, such as Her2/neu [75], basic fibroblastic growth factor [76], and
carcinoembryonic factor [77], in nipple aspirate fluid. Ductal lavage may be
an additional means of monitoring expression of these proteins and has been
used to detect evidence of cancer by methylation-specific polymerase chain
reaction (PCR) [78]. The evolution of microarray technology for the analysis
of DNA content and ‘‘genetic profiling’’ has added another layer to the

Table 5
Use of ductal lavage as a research tool
Technology applied to
Study lavage specimen Features evaluated
Evron et al, 2001 [78] Methylation-specific PCR Promoter hypermethylation of
cyclin D2, RAR-b2, Twist,
and ER (a cancer-specific
phenomenon)
Kim et al, 2002 [86] Fluorescence in situ Aneusomy at chromosomes
hybridization 1, 8, 11, and 17
Walling et al, 2003 [87] Karyometric measurements Nuclear chromatin
characteristics
Fournier et al, 2003 [88] Surface enhanced laser Proteomic patterns
desorption/ionization protein
chip mass spectrometry
Misell et al, 2003 [89] Stable isotope mass Breast epithelial cell
spectrometry proliferation
Chatterton et al, 2003 [90] Immunohistochemistry Progesterone, EGF, cathepsin
D, estrone sulfate
Arun et al, 2003 [84] Cytology, immunohistochemistry Changes in cytology; levels
pre- and post celecoxib of Ki-67; COX-2; EGFR;
therapy for chemoprevention and p53
Abbreviations: COX, cyclooxygenase; EGF, epidermal growth factor; EGFR, epidermal
growth factor receptor; ER, estrogen receptor; RAR, retinoic acid receptor; ROBE, routine
operative breast endoscopy.
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 63

Box 1. Issues that are related to the use of ductal lavage

Documented, established issues
The magnitude of the breast cancer burden among American
women is substantial
Breast cancer risk-reduction strategies are available, but are
associated with potential morbidity from adverse effects
Existing risk assessment methods have limitations and
alternative, individualized risk-assessment strategies are
needed
Atypia consistently and reliably identifies one category of high-
risk women and is particularly sensitive to the antiproliferative
effects of chemoprevention agents (eg, tamoxifen)
Atypia can be detected on FNAs, core biopsy specimens, tissue
specimens, nipple aspirates, and ductal lavage cytology
Ductal lavage specimens are more likely to yield cytologically-
evaluable fluid compared with direct nipple aspirates
Ductal lavage is not a breast cancer detection/screening modality
Issues that have not been documented
Does atypia within ductal lavage specimens confer the same
magnitude of future breast cancer risk compared with atypia
detected via other sources?
Does atypia on ductal lavage specimens magnify the likelihood
of breast cancer development in women who already are
deemed high-risk on the basis of contralateral breast cancer
or BRCA mutation?
Is the cytologic interpretation of ductal lavage reproducible
or is there interlaboratory variation?
Can ductal lavage correct the deficiencies of existing risk
assessment methods and improve the individualized risk
assessment of nonwhite American women and women who
were exposed to chest wall irradiation or prolonged
postmenopausal hormone replacement therapy?
Is ductal lavage cost effective?
Is the lavaged ductal system likely to be the highest-risk area
of the breast?
What is the significance of cancer cells that are detected in lavage
fluid?
What is the significance of serial ductal lavage studies?
Will cytology from lavage specimens change over time and in
accordance with risk-reducing interventions?
Are there other applications for ductal lavage (eg, the detection
of risk-associated proteins or in providing cells that may be
studied with microarray technology?
64 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

sophistication and complexity of tissue research [79]. The prospect of

applying these strategies to cells that are retrieved from ductal lavage is
provocative. It is important to consider the influence of nonepithelial
cytology components of lavage fluid on these investigations. In particular,
the substantial contribution of macrophage-derived mammary foam cells to
the cellular content of nipple aspirates, as well as lavage fluid was
documented by Krishnamurthy et al [80] and King et al [81]. These foam
cells may affect the observed microarray and DNA patterns. Petricoin et al
[82] also explored the concept of using proteomic pattern diagnostics on
ductal lavage fluid as a means of identifying biomarkers of breast cancer risk.
The primary purpose of the ductal lavage procedure in the clinical setting
is to provide a source for cytology evaluation. Therefore, it is essential that
adequacy of the lavage cellularity for achieving this goal is preserved. As
additional analytic technologies are applied to the retrieved sample,
strategies for safely dividing and allocating the lavage aspirate must be
tested. Accordingly, Clark et al [83] analyzed and confirmed the yield from
ductal lavage after the specimen was split at the bedside and found
equivalence of the divided specimens in regard to cytologic adequacy.
Table 5 summarizes the research strategies that are being explored for
application in the setting of ductal lavage specimen. Some of these pilot
studies include the use of ductal lavage to monitor response to innovative
chemoprevention agents such as celecoxocib [66]; studying expression of
various hormonally-active active substances by way of immunohistochem-
istry; and application of proteomic assays.
As reported elsewhere [85], the known and unknown issues that are
related to the history and possible future of ductal lavage can be sum-
marized as follows (Box 1).

References
[1] Ries L, Eisner M, Kosary M. SEER Cancer Statistics Review, 1973–1999. Bethesda (MD):
National Cancer Institute; 2002.
[2] Hartmann LC, et al. Efficacy of bilateral prophylactic mastectomy in women with a family
history of breast cancer. N Engl J Med 1999;340(2):77–84.
[3] Rebbeck TR, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.
N Engl J Med 2002;346(21):1616–22.
[4] Fisher B, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical
Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90(18):1371–88.
[5] Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone
or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of
postmenopausal women with early breast cancer: first results of the ATAC randomised trial.
Lancet 2002;359(9324):2131–9.
[6] Claus EB, Risch N, Thompson WD. The calculation of breast cancer risk for women with
a first degree family history of ovarian cancer. Breast Cancer Res Treat 1993;28(2):115–20.
[7] Kelsey J, Gammon M. The epidemiology of breast cancer. CA Cancer J Clin 1991;41(3):
146–65.
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 65

[8] Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk
factor status: data from the Nurses’ Health Study. Am J Epidemiol 2000;152(10):950–64.
[9] Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal
women: principal results from the Women’s Health Initiative randomized controlled trial.
JAMA 2002;288(3):321–33.
[10] Endogenous Hormones and Breast Cancer Collaborative Group. Body mass index, serum
sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003;95:
1218–26.
[11] Wolfe JN. Risk for breast cancer development determined by mammographic parenchymal
pattern. Cancer 1976;37(5):2486–92.
[12] Cuzick J. Epidemiology of breast cancer: selected highlights. Breast 2003;12:405–11.
[13] Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer:
collaborative reanalysis of individual data from 52 epidemiological studies including 58,209
women with breast cancer and 101,986 women without the disease. Lancet 2001;358:1389–99.
[14] Gail MH, et al. Projecting individualized probabilities of developing breast cancer for white
females who are being examined annually. J Natl Cancer Inst 1989;81(24):1879–86.
[15] McTiernan A, et al. Comparisons of two breast cancer risk estimates in women with a family
history of breast cancer. Cancer Epidemiol Biomarkers Prev 2001;10(4):333–8.
[16] Bondy ML, et al. Validation of a breast cancer risk assessment model in women with
a positive family history. J Natl Cancer Inst 1994;86(8):620–5.
[17] Costantino JP, et al. Validation studies for models projecting the risk of invasive and total
breast cancer incidence. J Natl Cancer Inst 1999;91(18):1541–8.
[18] Spiegelman D, et al. Validation of the Gail et al., model for predicting individual breast
cancer risk. J Natl Cancer Inst 1994;86(8):600–7.
[19] Rockhill B, et al. Validation of the Gail et al., model of breast cancer risk prediction and
implications for chemoprevention. J Natl Cancer Inst 2001;93(5):358–66.
[20] Newman LA, Rockhill B, Bondy ML, Abrams JA, Berlin JA, Colditz GA, et al. Validation
of the Gail breast cancer risk assessment model in African American women based on
a multi-center case-control study of 3,283 African American and 5,974 white American
women. Presented at the American Society of Clinical Oncology, 38th Annual Meeting.
Orlando, Florida, May 18–21, 2002.
[21] Euhus DM. Understanding mathematical models for breast cancer risk assessment and
counseling. Breast J 2001;7(4):224–32.
[22] Singletary SE. A working model for the time sequence of genetic changes in breast
tumorigenesis. J Am Coll Surg 2002;194(2):202–16.
[23] Bhathal PS, et al. Frequency of benign and malignant breast lesions in 207 consecutive
autopsies in Australian women. Br J Cancer 1985;51(2):271–8.
[24] Nielsen M, et al. Breast cancer and atypia among young and middle-aged women: a study of
110 medicolegal autopsies. Br J Cancer 1987;56(6):814–9.
[25] Hutchinson WB, et al. Risk of breast cancer in women with benign breast disease. J Natl
Cancer Inst 1980;65(1):13–20.
[26] Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast
disease. N Engl J Med 1985;312(3):146–51.
[27] Wrensch MR, et al. Breast cancer incidence in women with abnormal cytology in nipple
aspirates of breast fluid. Am J Epidemiol 1992;135(2):130–41.
[28] Page DL, Dupont WD. Anatomic indicators (histologic and cytologic) of increased breast
cancer risk. Breast Cancer Res Treat 1993;28(2):157–66.
[29] Fabian CJ, 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(15):1217–27.
[30] Wrensch MR, et al. Breast cancer risk in women with abnormal cytology in nipple aspirates
of breast fluid. J Natl Cancer Inst 2001;93(23):1791–8.
[31] Dupont WD, et al. Estrogen replacement therapy in women with a history of proliferative
breast disease. Cancer 1999;85(6):1277–83.
66 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

[32] Bodian CA. Benign breast diseases, carcinoma in situ, and breast cancer risk. Epidemiol Rev
1993;15(1):177–87.
[33] Bodian CA, et al. Prognostic significance of benign proliferative breast disease. Cancer 1993;
71(12):3896–907.
[34] Carter CL, et al. A prospective study of the development of breast cancer in 16,692 women
with benign breast disease. Am J Epidemiol 1988;128(3):467–77.
[35] London SJ, et al. A prospective study of benign breast disease and the risk of breast cancer.
JAMA 1992;267(7):941–4.
[36] McDivitt RW, et al. Histologic types of benign breast disease and the risk for breast cancer.
The Cancer and Steroid Hormone Study Group. Cancer 1992;69(6):1408–14.
[37] Palli D, et al. Benign breast disease and breast cancer: a case-control study in a cohort in
Italy. Int J Cancer 1991;47(5):703–6.
[38] Krieger N, Hiatt RA. Risk of breast cancer after benign breast diseases. Variation by
histologic type, degree of atypia, age at biopsy, and length of follow-up. Am J Epidemiol
1992;135(6):619–31.
[39] Dupont WD, et al. Breast cancer risk associated with proliferative breast disease and atypical
hyperplasia. Cancer 1993;71(4):1258–65.
[40] Byrne C, et al. Biopsy confirmed benign breast disease, postmenopausal use of exogenous
female hormones, and breast carcinoma risk. Cancer 2000;89(10):2046–52.
[41] Carpenter C, Love SM. Ductal cells, hyperplasia and breast cancer risk: results from a long-
term follow-up study of lavage patients. Presented at the San Antonio Breast Cancer
Symposium. San Antonio, 2002.
[42] Marshall CJ, et al. Cytologic identification of clinically occult proliferative breast disease in
women with a family history of breast cancer. Am J Clin Pathol 1991;95(2):157–65.
[43] Skolnick MH, et al. Inheritance of proliferative breast disease in breast cancer kindreds.
Science 1990;250(4988):1715–20.
[44] Ward JH, et al. Detection of proliferative breast disease by four-quadrant, fine-needle
aspiration. J Natl Cancer Inst 1990;82(11):964–6.
[45] Morrow M, Jordan V. Managing breast cancer risk. In: Jordan V, editor. London: Decker
Inc.; 2003. p. 153.
[46] Stoler D, Stewart C, Stomper P. Breast epithelium procurement from stereotactic core
biopsy washings: flow cytometry-sorted cell count analysis. Clin Cancer Res 2002;8:428–32.
[47] Papanicolaou GN, et al. Cytologic evaluation of breast secretions. Ann N Y Acad Sci 1956;
63(6):1409–21.
[48] Papanicolaou GN, et al. Exfoliative cytology of the human mammary gland and its value in
the diagnosis of cancer and other diseases of the breast. Cancer 1958;11(2):377–409.
[49] Sartorius OW, et al. Cytologic evaluation of breast fluid in the detection of breast disease.
J Natl Cancer Inst 1977;59(4):1073–80.
[50] Newman LA, Blake C. Ductal lavage for breast cancer risk assessment. Cancer Control
2002;9(6):473–9.
[51] Tchou J, Hou R, Jordan RAV, Morrow M. Patient acceptance of tamoxifen as
chemoprevention, abstract 2216. Lynn Sagar Breast Cancer Symposium, Chicago, IL,
September 21, 2003.
[52] Dooley WC, et al. Ductal lavage for detection of cellular atypia in women at high risk for
breast cancer. J Natl Cancer Inst 2001;93(21):1624–32.
[53] Port ER, et al. Patient reluctance toward tamoxifen use for breast cancer primary pre-
vention. Ann Surg Oncol 2001;8(7):580–5.
[54] Vogel VG, et al. Re: tamoxifen for prevention of breast cancer: report of the National
Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 2002;94(19):
1504.
[55] Morrow M, et al. Acceptance of tamoxifen chemoprevention varies with the cause of breast
cancer risk. Presented at the 2003 American Society of Clinical Oncology Annual
Symposium. Chicago, 2003.
 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68 67

[56] Golewale N, et al. Technical modifications of ductal lavage to improve cell yield. Presented at
the San Antonio Breast Cancer Symposium. San Antonio, 2003.
[57] Gabram S, et al. Correlation of nipple aspiration and ductal lavage with histopathologic
findings for patients prior to scheduled breast biopsy. Presented at the San Antonio Breast
Cancer Symposium. San Antonio, 2003.
[58] Ganz PA, et al. Identification of premalignant and malignant breast cells in mammogram-
and physical exam-negative women by ductal lavage: results from a multicenter trial.
Presented at the American Society of Clinical Oncology Annual Symposium. 2001.
[59] Masood S, et al. Exfoliative breast cytopathology: an experience with ductal lavage.
Presented at the San Antonio Breast Cancer Symposium. San Antonio, 2002.
[60] Willey S, et al. Ductal lavage: initial 18 month experience at a single institution. Presented at
the San Antonio Breast Cancer Symposium. San Antonio, 2002.
[61] Dooley WC, Clarke A. Impact of ductal lavage on risk management in a breast surgical
oncology practice. Presented at the American Society of Clinical Oncology Annual
Symposium. Orlando, 2003.
[62] Cazzaniga M, et al. Identification of atypical cells by ductal lavage in women at increased
high risk for breast cancer. Presented at the American Society of Clinical Oncology Annual
Symposium. 2001.
[63] Hartman AR, et al. Breast magnetic resonance image screening and ductal lavage in women
at high genetic risk for breast carcinoma. Cancer 2004;100(3):479–89.
[64] Mitchell G, et al. Using nipple aspiration and ductal lavage to assess the ductal epithelium
of BRCA 1/2 mutation-carriers. Presented at the American Society of Clinical Oncology
Annual Symposium. Orlando, 2002.
[65] Lawler M, et al. Cytologic evaluation of duct washings does not reliably detect lactiferous
duct pathology. Presented at the San Antonio Breast Cancer Symposium. San Antonio,
2001.
[66] Brogi E, et al. Ductal lavage in patients undergoing mastectomy for mammary carcinoma:
a correlative study. Cancer 2003;98(10):2170–6.
[67] Hartman AR, et al. Comprehensive screening using breast MRI and ductal lavage in high-
risk women. Presented at the San Antonio Breast Cancer Symposium. San Antonio, 2002.
[68] Hartman AR, et al. Results from a pilot breast cancer screening trial using a combination
of clinical breast exam, mammography, breast MRI, and ductal lavage in a high-risk
population. Presented at the San Antonio Breast Cancer Symposium. San Antonio, 2003.
[69] Rossmann M, et al. Galactography versus ductal lavage. Presented at the San Antonio
Breast Cancer Symposium. San Antonio, 2001.
[70] Khan SA, et al. Ductal lavage findings in women with known breast cancer undergoing
mastectomy. Presented at the San Antonio Breast Cancer Symposium. San Antonio,
2002.
[71] Dooley WC, Clark A, Parker J. The frequency of ductal atypia in high-risk breast tissue.
Presented at the 56th Annual Cancer Symposium for the Society of Surgical Oncology. Los
Angeles, 2003.
[72] Rosai J. Borderline epithelial lesions of the breast. Am J Surg Pathol 1991;15(3):209–21.
[72a] Ozanne EM, Esserman LT. Cost effectiveness of ductal lavage: a breast cancer risk
assessment technique. Abstract 547. 2002 San Antonio Breast Cancer Symposium, San
Antonio, Texas, December 13, 2002.
[73] Morrow M, et al. Evaluation and management of the woman with an abnormal ductal
lavage. J Am Coll Surg 2002;194(5):648–56.
[74] Mitchell G, et al. Cellular characteristics of nipple aspiration fluid during the menstrual cycle
in healthy premenopausal women. Cytopathology 2001;12(3):184–96.
[75] Kuerer HM, et al. High and differential expression of HER-2/neu extracellular domain in
bilateral ductal fluids from women with unilateral invasive breast cancer. Clin Cancer Res
2003;9(2):601–5.
[76] Liu Y, et al. Breast-cancer diagnosis with nipple fluid bFGF. Lancet 2000;356(9229):567.
68 A. Rivers, L.A. Newman / Surg Oncol Clin N Am 14 (2005) 45–68

[77] Zhao Y, et al. Nipple fluid carcinoembryonic antigen and prostate-specific antigen in cancer-
bearing and tumor-free breasts. J Clin Oncol 2001;19(5):1462–7.
[78] Evron E, et al. Detection of breast cancer cells in ductal lavage fluid by methylation-specific
PCR. Lancet 2001;357(9265):1335–6.
[79] Weber BL. Cancer genomics. Cancer Cell 2002;1(1):37–47.
[80] Krishnamurthy S, et al. Characterization of foam cells in nipple aspirate fluid. Diagn
Cytopathol 2002;27(5):261–4 [discussion 265].
[81] King BL, et al. Immunocytochemical analysis of breast cells obtained by ductal lavage.
Cancer 2002;96(4):244–9.
[82] Petricoin EE, Paweletz CP, Liotta LA. Clinical applications of proteomics: proteomic
pattern diagnostics. J Mammary Gland Biol Neoplasia 2002;7(4):433–40.
[83] Clark P, et al. Ductal lavage specimens can be successfully split at the bedside without
compromising cytologic diagnosis. Presented at the San Antonio Breast Cancer Symposium.
San Antonio, 2003.
[84] Arun B, et al. Phase II chemoprevention of celecoxib using ductal lavage. Presented at the
San Antonio Breast Cancer Symposium. San Antonio, 2003.
[85] Newman LA. Ductal lavage: what we know and what we don’t. Oncology 2004;18(2):
179–85.
[86] Kim J, et al. Molecular characterization of mammary ductal epithelial cells using interphase
fluorescence in-situ hybridization (FISH). Presented at the San Antonio Breast Cancer
Symposium. San Antonio, 2002.
[87] Walling E, et al. Nuclear chromatin characteristics of breast epithelial cells obtained by
ductal lavage. Presented at the San Antonio Breast Cancer Symposium. San Antonio, 2003.
[88] Fournier K, et al. Feasibility of proteomic evaluation of ductal lavage fluid for breast
diseases. Presented at the San Antonio Breast Cancer Symposium. San Antonio, 2003.
[89] Misell L, et al. A stable-isotope mass spectrometric method for measuring breast epithelial
cell proliferation in vivo in women: a promising biomarker for prevention studies. Presented
at the San Antonio Breast Cancer Symposium. San Antonio, 2003.
[90] Chatterton R, Geiger A, Khan SA. Influence of ovarian secretions, oral contraceptives, and
hormone replacement therapy on progesterone concentrations in breast fluids. Presented at
the San Antonio Breast Cancer Symposium. San Antonio, 2003.