Nipple discharge cytology in mass screening for breast cancer

Since 1977 mass screening for breast cancer has been conducted in Miyagi Prefecture, Japan; inspection, palpation and cytologic examination of any nipple discharge are part of the initial screening procedures. Among 149,681 subjects examined, 404 cancer cases and 63 papilloma cases were detected. The nipple discharges from 20,537 women were examined cytologically; of the 61 cancer cases, the smears were positive in 18 cases, suspicious in 7, negative with atypical findings in 12 and negative in 24. Ten of the cancer cases were detected exclusively by the cytologic examination of a nipple discharge. In eight of these ten cancer cases, there was no other initial evidence of the primary tumor. The cytologic diagnosis of discharges without blood from 28 cancer cases was positive or suspicious in 10 cases and negative in 18. Thirty-seven of the papilloma cases were initially detected only by the cytologic examination of a nipple discharge; neither physical examination nor mammography showed any abnormal findings.     

Papillary breast lesions diagnosed on cytology. Profile of 65 cases

OBJECTIVE: To analyze the cytologic features of nipple discharge and fine needle aspiration (FNA) cytologic smears from breast lesions reported as showing papillary features and to correlate them with histopathologic features. STUDY DESIGN: The study group consisted of FNA smears and/or nipple discharge smears from 65 breast lesions diagnosed on cytology as duct papilloma, papillary lesion, fibrocystic condition, fibroadenoma, papillary neoplasm or papillary carcinoma. Cytomorphologic features assessed included cellularity, cell pattern (clusters, papillary, 3-dimensionality, etc.) and cell characteristics (monomorphism, pleomorphism, apocrine change, plasmacytoid features). Histological material was available for review and cytohistologic correlation in all cases. RESULTS: Forty-six specimens were FNA smears, and 16 were nipple discharge smears; in 3 cases FNA and nipple discharge cytologic smears were available for review. Cytologic study could predict the presence of a papillary pattern in all neoplasms with pure or focal papillary differentiation. There was an overlap in cytomorphologic features between papillary and nonpapillary benign lesions as well as between benign and malignant papillary neoplasms. Frank blood in the aspirate, cell dissociation and atypia, however, were more frequent in the last. CONCLUSION: Overlap of cytologic features in nonneoplastic and neoplastic benign papillary lesions and between benign and malignant papillary neoplasms necessitates histologic evaluation in all cases diagnosed as papillary on cytology. Since 49.2% of lesions showing papillary features on cytology prove to be malignant, all cases reported as papillary on cytology should be excised urgently for histologic assessment.     

Repeated Nipple Fluid Aspiration: Compliance and Feasibility Results from a Prospective Multicenter Study

BackgroundDespite intensive surveillance, a high rate of interval malignancies is still seen in women at increased breast cancer risk. Therefore, novel screening modalities aiming at early detection remain needed. The intraductal approach offers the possibility to directly sample fluid containing cells, DNA and proteins from the mammary ductal system where, in the majority of cases, breast cancer originates. Fluid from the breast can non-invasively be obtained by oxytocin-assisted vacuum aspiration, called nipple fluid aspiration (NFA). The goal of this feasibility study was to evaluate the potential of repeated NFA, which is a critical and essential step to evaluate its possible value as a breast cancer screening method.MethodsIn this multicenter, prospective study, we annually collected nipple fluid for up to 5 consecutive years from women at increased breast cancer risk, and performed a questionnaire-based survey regarding discomfort of the aspiration. Endpoints of the current interim analyses were the feasibility and results of 994 NFA procedures in 451 women with total follow-up of 560 person years of observation.ResultsIn this large group of women at increased risk of breast cancer, repetitive NFA appeared to be feasible and safe. In 66.4% of aspirated breasts, nipple fluid was successfully obtained. Independent predictive factors for successful NFA were premenopausal status, spontaneous nipple discharge, smaller breast size, bilateral oophorectomy and previous use of hormone replacement therapy or anti-hormonal treatment. The procedure was well tolerated with low discomfort. Drop-out rate was 20%, which was mainly due to repeated unsuccessful aspiration attempts. Only 1.6% of women prematurely declined further participation because of side effects.ConclusionsRepeated NFA in women at increased breast cancer risk is feasible and safe. Therefore, NFA is a promising method to non-invasively obtain a valuable source of potential breast cancer specific biomarkers.     

Cerumen phenotype and epithelial dysplasia in nipple aspirates of breast fluid

The relationship between presence of dysplastic epithelial cells in nipple aspirates of breast fluid and wet or dry cerumen phenotype was studied in 1,150 white and Asian American women. A statistically significant greater proportion of premenopausal white women of wet cerumen phenotype, compared to women of the dry cerumen type, was found to have cytologic dysplasia (relative risk 6.5 [1.8--22.3]). The effect was not observed in postmenopausal women. The finding offers new support for our hypothesis that an apocrine genetic factor affecting breast gland secretion may influence exposure of the breast epithelium to potential carcinogenic substances of exogenous or endogenous origin.     

Fine needle aspiration cytology of solid papillary carcinoma of the breast. A report of four cases

BACKGROUND: Solid papillary carcinoma of the breast (SPCB) is a distinctive form of papillary carcinoma that tends to occur in older women and usually has a favorable prognosis. CASES: We report the cytologic and histologic findings in four cases of SPCB. All but one of the patients were elderly women (mean age, 66 years). Three patients presented with breast masses, and one patient presented with a breast mass and nipple discharge. Cytology demonstrated moderately to highly cellular smears with irregular groups of predominantly monolayered epithelium composed of small, polygonal or cuboidal cells with eosinophilic cytoplasm and rounded, eccentrically placed nuclei. Papillalike clusters with thin, fibrovascular cores were also observed. Immunocytochemical expression of synaptophysin was present in two cases. The diagnosis of SPBC was subsequently confirmed histologically and immunohistochemically. CONCLUSION: The FNA of SPCB displays some features that may be helpful in its correct identification preoperatively.     

Cytologic diagnosis of male breast cancer with nipple discharge. A case report

The cytologic findings in a nipple discharge from a male patient with breast cancer are described. Malignant epithelial cells and cell clusters believed to be derived from ductal carcinoma were observed. The subsequent mastectomy specimen contained a ductal carcinoma with minute foci of stromal invasion.     

The value of routine cytologic examination of breast cyst fluids

The results of the cytologic examination of 6,782 consecutive breast cyst fluids aspirated from 4,105 women during the period 1976 to 1983 were reviewed to assess the value of the routine cytologic study of such specimens. Cases in which cancer had been suspected by physical examination and/or mammography before aspiration of the cyst were excluded from the evaluation. Five clinically and radiologically inapparent intracystic papillomas were detected overall (0.1%). All cases of intracystic papilloma produced a blood-stained fluid and showed an intracystic mass at pneumocystography. Cytology was negative in two of these cases and falsely positive in one case while correctly identifying the papilloma in two cases. One incidental case of occult in situ lobular carcinoma was also detected. Routine cytologic examination of all breast fluids is thus not recommended as a cost-effective practice. Cytology should be used only when a blood-stained fluid is obtained (2% in the present series) since its indiscriminate application to all cyst fluids does not affect the rate of detection of intracystic lesions, most of which are suspected before the aspiration.     

Value of the history in the office diagnosis of breast cancer.

A review of the histories of 1059 patients with breast problems seen consecutively in office consultation revealed an incidence of breast cancer of 13%. Patients over 50 years of age or whose mother or sister had had breast cancer had a substantially greater likelihood of having breast cancer. The finding of the problem on routine examination, a family history of breast cancer in a relative other than the mother or a sister, or prominent breast pain or nipple discharge made the diagnosis of cancer less likely. Menstrual status, a history of previous benign disease, nulliparity, current hormone therapy and duration of symptoms did not help identify the patient likely to have breast cancer. Much time could be saved for both doctor and patient in taking the history from patients with breast disorders. Only the patient''s age and the history of the mother and sisters with regard to breast cancer will help identify the "high-risk" patient. Other historical findings are either valueless or should be used to reassure these usually anxious women.     

A simple intraductal aspiration method for cytodiagnosis in nipple discharge

OBJECTIVE: To increase cytodiagnostic accuracy for women with spontaneous nipple discharge using a simple intraductal aspiration method. STUDY DESIGN: We compared the cytodiagnostic accuracy of the conventional squeezing collection method and intraductal aspiration by intravenous catheter in a total of 146 women with spontaneous nipple discharge in a single duct without a mass; they had been pathologically identified at Kaohsiung Medical University Hospital. RESULTS: Adequate specimens were collected in 96.6% (141/146 cases) of the sample by the intraductal aspiration method as compared to 76.0% collected by the conventional squeezing method (P < .05). An adequate specimen should consist, at a minimum, of six cohesive clusters of well-preserved epithelial cells, with each cluster composed of at least five cells other than foam cells. The cytologic diagnosis was divided into five categories: positive in 9 cases, suspicious in 10, negative with atypical findings in 59, negative in 33 and inadequate specimens in 35 cases that employed the squeezing method. These results were less satisfactory than with the intraductal aspiration method: the smears were positive in 17 cases, suspicious in 14, negative with atypical findings in 78, negative in 32 and inadequate specimens in 5. Our results showed a sensitivity of 92.3% and specificity of 93.9% for the intraductal aspiration method as compared to a sensitivity of 52.9% and specificity of 89.3% for the squeezing method. Among the 27 cancers in this series, correct cytodiagnosis, including suspicious cases, was made in 24 cases by intraductal aspiration, with an accuracy of 88.9%, as compared to the 33.3% (9/27) accuracy of the squeezing method (P < 0.5). CONCLUSION: For patients with spontaneous nipple discharge, the intraductal aspiration method provides much more accurate cytodiagnosis than does the conventional squeezing method.     

Positive predictive value of fine needle aspiration cytology of breast lesions

The predictive value of fine needle aspiration (FNA) was assessed in 1,181 consecutive cases of breast lesions in which cytologic abnormalities were reported. The positive predictive value (PPV) of an FNA cytologic report of atypia, suspicious or positive was 0.49, 0.95 or 0.996, respectively. In the presence of a suspicious/positive report by both physical examination and mammography, the PPV of a cytologic report of suspicious was 0.99. The PPV was directly correlated with age, partly due to the incidence of fibroadenomas among younger patients; fibroadenomas were present in 53 of 146 cases with a false FNA report of atypia, in 10 of 19 cases with a false FNA report of suspicious and in 2 of 2 cases with a false FNA report of positive. Overall, 93 cases reported as benign by physical examination and mammography were biopsied on the basis of the FNA cytologic report; cancers were diagnosed in 33 of these 93 cases (6 cancers among 42 women less than 40 years old and 27 cancers among 51 women greater than 39 years old). The widespread use of FNA cytology to study breast lesions is thus recommended, without regard to patient age and even in the presence of clinically benign findings, since the increase in the rate of cancer detection is worth the excess of unnecessary biopsies. The predictive value of a positive report of FNA cytology, or even of a suspicious report in the presence of clinical suspicion, is so high that an intraoperative frozen section biopsy might be spared in such cases.     

Cytology of nipple discharge in florid gynecomastia

OBJECTIVE: To determine the cytomorphologic spectrum of nipple discharge in florid gynecomastia. STUDY DESIGN: During a 22-year period (July 1979-June 2001), nipple discharge from nine males with breast lesions were examined. Smears from four of these cases with histologically documented gynecomastia were reviewed along with the tissue sections. RESULTS: In the three patients with florid gynecomastia the smears were cellular, with numerous benign ductal cells and papillary fragments along with foam cells and inflammatory cells. Epithelial atypia was mild in two cases and moderate in one. One of the three cases had an associated breast lump that showed features of florid gynecomastia on fine needle aspiration cytology. The biopsy from this case showed cystic hyperplasia of the breast similar to that in women with an intraductal papilloma. One case of simple gynecomastia on histology showed two fragments of benign ductal cells with occasional apocrine and foam cells. CONCLUSION: Nipple discharge in florid gynecomastia may pose problems in identification as the cellularity and atypia may lead to a misdiagnosis of carcinoma.     

Obesity is associated with atypia in breast ductal lavage of women with proliferative breast disease

Background: Benign proliferative breast disease without atypia slightly increases breast cancer risk but there are currently few clinical options for breast cancer prevention in this group of women. Methods: We conducted a pilot study of women with a past diagnosis of proliferative breast disease with a goal to determine if the characteristics of cells obtained by breast ductal lavage were related to nutritional factors. Results: There were 57 women who enrolled. A total of 39 women yielded nipple aspirate fluid (NAF) samples and 36 underwent breast ductal lavage. Five of the lavage samples were acellular and 28 had at least 200 cells. Surprisingly, atypia was present in 11 women. Presence of atypia was associated with slight changes in morphometric features of the epithelial cells such as measures of circularity as obtained by image analysis, but the only variable significantly different in women with atypia (versus no atypia) was a higher mean body mass index. Body mass index was also significantly correlated with C-reactive protein (CRP) levels in the nipple aspirate fluid, indicating that obesity might have a pro-inflammatory effect on the breast that can contribute to increased rates of atypia. Conclusions: Although the clinical significance of atypia in breast ductal lavage is uncertain, these results support further work on prevention of obesity as a strategy for reducing breast cancer risk.     

Nutrients and nipple aspirate fluid composition: the breast microenvironment regulates protein expression and cancer aetiology

The aetiology of breast cancer is complex and multifactorial, and may include diet and xenobiotic compounds. A change in diet affects nutrient levels in blood, but to what extent diet can affect micronutrient concentrations in the breast is not yet well established. Breast nipple aspirate fluids (NAF) can be non-invasively obtained from the breast in most women; it represents a biological tool to assess metabolic changes in the breast ductal microenvironment. A wide variation in biomolecular and hormonal composition of NAFs collected from healthy and breast cancer patient may be due to genetic and nutritional factors; however, micro- and macro-nutrients may influence the secretory status of these women, thus NAF composition and risk of breast carcinoma. The aim of this overview is to highlight the detrimental/beneficial role that diet-related compounds in nipple aspirate fluid can have in breast cancer risk.     

Risk factors for breast cancer in women biopsied for benign breast disease: A nested case-control study

Aim: Women with a history of benign breast disease are at increased risk of subsequent breast cancer. However, few studies have examined whether established breast cancer risk factors other than histology are associated with an altered risk of breast cancer in women with benign breast disease. We used a nested case-control design within a large, multi-center cohort of women biopsied for benign breast disease (BBD) to estimate odds ratios for breast cancer in association with exposure to a range of personal and lifestyle factors. Methods: Cases were women biopsied for BBD who subsequently developed breast cancer; controls were individually matched to cases on center and age at diagnosis and were women biopsied for BBD who did not develop breast cancer in the same follow-up interval as that for the cases. After excluding women with prevalent breast cancer, 1357 records (661 case records and 696 records) were available for analysis. We used conditional logistic regression to obtain crude and multivariable-adjusted estimates of the association between specific factors and risk of breast cancer. Results: In multivariable analyses age at first live birth, number of pregnancies, and postmenopausal status were inversely associated with risk of breast cancer. The odds ratio for women with age at first birth <25 years and ≥3 pregnancies, relative to nulliparous women, was 0.49, 95% confidence interval 0.13–0.79, and that for postmenopausal women relative to premenopausal women was 0.60, 95% CI 0.37–0.99. Conclusions: Further study of personal factors influencing the risk of breast cancer in women with BBD may help to identify subgroups of the population at increased risk of invasive disease.     

Hormone Rhythms and Breast Cancer Chronoepidemiology: Salivary Progesterone Concentrations in Pre- and Post-Menarchal Girls and in Normal Premenopausal Women

Orcadian and circatrigintan time series of salivary progesterone levels in premenarchal and adolescent girls and healthy mature premenopausal women have been investigated as a possible determinant for breast cancer risk. Circadian variations in progesterone appear to be more random than systematic and estimates of total daily progesterone output are better represented by samples pooled from several 2-hr specimens. Different patterns of circatrigintan progesterone secretion in girls are recognised and relate to those experienced in infertile and fertile women, though their relation to chronological or menarchal age is as yet uncertain. These data suggest that the measurement of salivary progesterone at premenarche, adolescence and maturity is a feasible, though statistically difficult, study for prospective identification of individuals at risk for breast cancer.     

Hormone rhythms and breast cancer chronoepidemiology: salivary progesterone concentrations in pre- and post-menarchal girls and in normal premenopausal women

Orcadian and circatrigintan time series of salivary progesterone levels in premenarchal and adolescent girls and healthy mature premenopausal women have been investigated as a possible determinant for breast cancer risk. Circadian variations in progesterone appear to be more random than systematic and estimates of total daily progesterone output are better represented by samples pooled from several 2-hr specimens. Different patterns of circatrigintan progesterone secretion in girls are recognised and relate to those experienced in infertile and fertile women, though their relation to chronological or menarchal age is as yet uncertain. These data suggest that the measurement of salivary progesterone at premenarche, adolescence and maturity is a feasible, though statistically difficult, study for prospective identification of individuals at risk for breast cancer.     

Risk of cancer of the breast after legal abortion during first trimester: a Swedish register study.

An increase in induced abortions in Sweden has been accompanied by an increase in the incidence of breast cancer of about 40% in women aged 20-44. To assess whether the apparent risk is real the risk of breast cancer was investigated in practically all Swedish women with a history of a legal abortion in the first trimester before the age of 30 during 1966-74 (n = 49,000). The cohort was followed up in the Swedish cancer register to identify cases of breast cancer diagnosed more than five years after the abortion until the end of 1984. The number of observed cases of breast cancer was 65 compared with an expected number of 84.5, estimated from the contemporary Swedish population with due consideration to age, giving a relative risk of 0.8 (95% confidence interval 0.58 to 0.99). Contrary to most earlier reports, this study did not indicate any overall increased risk of breast cancer after an induced abortion in the first trimester in young women.     

Stress and relapse of breast cancer.

To elucidate the association between stressful life events and the development of cancer the influence of life stress on relapse in operable breast cancer was examined in matched pairs of women in a case-control study. Adverse life events and difficulties occurring during the postoperative disease free interval were recorded in 50 women who had developed their first recurrence of operable breast cancer and during equivalent follow up times in 50 women with operable breast cancer in remission. The cases and controls were matched for the main physical and pathological factors known to be prognostic in breast cancer and sociodemographic variables that influence the frequency of life events and difficulties. Severely threatening life events and difficulties were significantly associated with the first recurrence of breast cancer. The relative risk of relapse associated with severe life events was 5.67 (95% confidence interval 1.57 to 37.20), and the relative risk associated with severe difficulties was 4.75 (1.58 to 19.20). Life events and difficulties not rated as severe were not related to relapse. Experiencing a non-severe life event was associated with a relative risk of 2.0 (0.62 to 7.47), and experiencing a non-severe difficulty was associated with a relative risk of 1.13 (0.38 to 3.35). These results suggest a prognostic association between severe life stressors and recurrence of breast cancer, but a larger prospective study is needed for confirmation.     

Risk of breast cancer in women with history of benign disease of the breast.

A consecutive series of 791 women who had attended diagnostic breast clinics during 1967-70 and been found to be free of malignant disease were later traced to determine their subsequent incidence of breast cancer. Of the 770 (97%) successfully traced, 22 had developed breast cancer. Based on data from the Welsh Cancer Registry only eight cases of breast cancer had been expected, so that the excess risk for the group was 2.7. The increased risk occurred in all age groups and in women deemed "essentially normal" as well as in those who had had a pathological abnormality. The risk was increased when epithelial hyperplasia was present. No excess mortality from breast cancer was apparent, but follow up was short. More breast symptoms were experienced and more biopsies performed than expected in this group of women. Women with a past history of benign breast disease have a slightly increased risk of breast cancer. Selective screening of these women, however, may be uneconomic and a cause of groundless anxiety.     

Cohort study of association of risk of breast cancer with cyst type in women with gross cystic disease of the breast.

OBJECTIVE: To assess correlation between type of breast cyst and risk of breast cancer in women with gross cystic disease of the breast. DESIGN: Cohort study of women with breast cysts aspirated between 1983 and 1993 who were followed up until December 1994 for occurrence of breast cancer. SETTING: Major cancer prevention centre. SUBJECTS: 802 women with aspirated breast cysts. MAIN OUTCOME MEASURES: Type of breast cyst based on cationic content of cyst fluid: type I (potassium:sodium ratio > 1.5), type II (potassium:sodium ratio < 1.5), or mixed (both types). Subsequent occurrence and type of breast cancer. RESULTS: After median follow up of six years (range 2-12 years) 15 cases of invasive breast cancer and two ductal carcinomas in situ were diagnosed in the cohort: 12 invasive cancers (and two carcinomas in situ) among the 417 women with type I cysts, two cancers among the 325 women with type II cysts, and one among the 60 women with mixed cysts. The incidence of breast cancer in women with type I cysts was significantly higher than that in women with type II cysts (relative risk 4.62 (95% confidence interval 1.26 to 29.7)). These results were confirmed after adjustment for several risk factors for breast cancer (relative risk 4.24 (1.12 to 27.5)). CONCLUSIONS: The increased risk of breast cancer of women with breast cysts seems to be concentrated among women with type I breast cysts.