Nicholas L. Petrakis

Factors associated with obtaining nipple aspirate fluid: Analysis of 1428 women and literature review

SummaryStudies of cytologic and biochemical constituents of nipple aspirates of breast fluid have contributed to understanding the natural history of benign and malignant breast disease. We conducted multivariate analyses using 1428 women from a recent case-control study of breast disease to determine which factors were independently associated with the ability to obtain breast fluid from nonlactating women. We then compared results from these analyses to the results from five previous studies that also used the aspiration technique of Sartorius. Four factors were consistently associated across studies with increased ability to obtain breast fluid: 1) age up to 35 to 50 years; 2) earlier age at menarche; 3) non-Asian compared to Asian ethnicity; and 4) history of lactation. Exogenous estrogen use, endogenous estrogen concentrations, phase of menstrual cycle, family history of breast cancer, type of menopause, and less than full-term pregnancy consistently did not influence ability to obtain fluid.New findings from this study shed light on some apparently contradictory findings from the previous studies. In particular, this study showed that the effects of age on ability to obtain fluid appeared to be independent of the effects of menopause. Furthermore, discrepancies in previous findings on the effects of parity on ability to obtain fluid may be explained by our finding that the increased ability to obtain fluid from parous compared to nulliparous women applied only to parous women who had breastfed.

Cerumen Genetics and Human Breast Cancer

International mortality and frequency rates for breast cancer seem to be associated with the frequency of the allele for wet-type cerumen. A preliminary retrospective case-control study in California indicates that phenotypically wet-type cerumen is found in Japanese women with breast cancer more often than in healthy Japanese women. Findings support the hypothesis that the apocrine systems genetically determined variation may influence susceptibility to breast cancer.

Nipple Aspirate Fluid Cytology and the Gail Model for Breast Cancer Risk Assessment in a Screening Population

Background: Recent guidelines suggest that chemoprevention with tamoxifen may be appropriate for women who have a 5-year risk of breast cancer greater than 1.66% calculated using the Gail model. Objectives: To determine whether nipple aspirate fluid (NAF) cytology combined with the Gail model provides breast cancer risk assessment that is superior to either method alone. Methods: Prospective observational cohort of 6,904 asymptomatic women. Breast cancer cases were identified through follow-up with the women and linkage to cancer registries. We used proportional hazards modeling to recalculate the coefficients for the predictor variables used in the Gail model. NAF cytology was added to create a second model. The two models were compared using the concordance statistic (c-statistic). Results: During 14.6 years of follow-up, 400 women were diagnosed with breast cancer. There were 940 (14%) women with hyperplasia and 109 (1.6%) women with atypical hyperplasia found in NAF. Adding NAF cytology results to the Gail model significantly improved the model fit (P < 0.0001). The c-statistic for the Gail model was 0.62, indicating only modest discriminatory accuracy. Adding NAF cytology to the model increased the c-statistic to 0.64. NAF cytology results had the largest effect on discriminatory accuracy among women in the upper third of Gail model risk. The relative incidence for the highest quintile of risk score compared with the lowest quintile was 7.2 for the Gail model and 8.0 for the model including NAF cytology. Conclusion: NAF cytology has the potential to improve prediction models of breast cancer incidence, particularly for high-risk women.

Image cytometric classification of premalignant breast disease in fine needle aspirates

Image cytometry for the classification of fine needle aspirate (FNA) biopsies was evaluated in samples from 39 women. Eighteen of them had benign lesions, seven had premalignant lesions, nine had carcinoma in situ and five had carcinoma. The term, premalignant, here refers to lesions with an increased risk of developing into breast cancer (atypical hyperplasia and, to a lesser extent, moderate or florid hyperplasia). The classifications by cytometry were compared with the microscopic diagnoses of the same FNA samples and of tissue from a subsequent surgical biopsy of the same area. One slide from each breast FNA sample was restained in Azure‐A Feulgen. Breast epithelial cells were measured using a texture analysis program on the Leitz TAS‐plus. The mean, standard deviation (SD), and interquartile range were calculated for each of 12 nuclear parameters from 200 cells per slide. A discriminant analysis was used to develop a statistical model for classifying individual samples. Six of seven atypical proliferative lesions (atypical hyperplasia and moderate hyperplasia) were identified by image cytometry, but were unrecognized by conventional microscopic examination.

Genetic factors in the etiology of breast cancer.

Human breast cancer appears to be a heterogeneous disease whose causes are at present unknown. A variety of interrelated genetic, environmental, sociobiologic and physiological factors appear to be associated with increased risk of breast cancer, but no single factor or combination of variables presently known are sufficient to explain the etiology of the disease. Evidence for a genetic role in susceptibility to breast cancer is based on findings from several lines of investigation including: 1) family history of breast cancer, especially bilaterality, 2) marked difference in rates between certain racial groups; 3) lack of major change in incidence of breast cancer over many years despite dramatic changes in other cancers; 4) concordance of breast cancer in monozygotic twins, and 5) concordance of laterality of breast cancer in closely related patients. Recognition of familiality and bilaterality has important clinical value in the identification of high‐risk women for special screening and diagnostic studies. It is not known if a single gene or several genetic mutations are responsible for a specific predisposition to breast cancer. Possible genetic traits that control or influence physiological functions of the breast may be inherited by certain women. These genetic factors that increase or decrease the probability of neoplastic transformation may operate through their control over viral, hormonal or other stimuli and through their regulation of the response of the alveolar‐ductal epithelium of the breast to these stimuli and to secreted extrinsic carcinogens. A working hypothesis has been developed that interrelates genetic‐environmental interactions in breast cancer etiology and pathogenesis. In this model, the turnover rate of breast secretions is the primary determinant of the extent and duration of exposure of the breast epithelium to extrinsic and endogenous carcinogens. The model emphasizes interaction of genetic, physiological, endocrine and environmental factors in the epidemiology of breast cancer.

Prevalence of sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency.

Abstract The frequency of G-6-PD deficiency and sickle trait was determined in 4028 Negroes living in the San Francisco Bay Area. The frequency of G-6-PD deficiency was significantly higher among younger than older Negro males. No significant alteration by age was found for sickle-trait frequency. G-6-PD deficiency appears to define a group with higher risk of mortality than the general population. Future studies should be directed toward defining the specific clinical effects of the trait on increased mortality.

Cerumen phenotype and proliferative epithelium in breast fluids of U.S.-born vs. immigrant Asian women: a possible genetic-environmental interaction.

SummaryTo determine whether a genetic-environmental interaction exists between the breast, a modified apocrine gland, its secretions, and the genetic polymorphic phenotypes of wet and dry cerumen, we examined nipple aspirate fluid (NAF) for proliferative disease in 172 U.S.-born and immigrant Chinese and Japanese women.Cytologic evidence of proliferative epithelial cells (benign hyperplasia and/or atypical hyperplasia) was found in the NAF of 36 women (20.9%). A significantly higher incidence of proliferative epithelial cells was present in the NAF of U.S.-born than in immigrant Asian women (28.6% vs. 16.5%) (p = 0.05).A higher proportion of U.S.-born Asian women with wet cerumen than women with dry cerumen had proliferative epithelial cells in NAF: 39.3% vs. 20.0% (p = 0.08). No significant difference in NAF proliferative cells was found between immigrant women with wet and dry cerumen: 15.8% vs. 17.3%; p = 0.50. A strong association of proliferative epithelial cells and cerumen phenotype was found in parous U.S.-born women (wet = 47.6% vs. dry = 16.0%; p = 0.002). No significant association with wet and dry cerumen phenotype was found in parous immigrant women (wet = 12.2% vs. dry = 20%).These findings support the hypothesis that an apocrine genetic polymorphic trait differentially influences susceptibility of the breast to proliferative disease in Asian women born in environments presumed to be of high risk for breast cancer compared to women from low risk environments.

Association of breast fluid coloration with age, ethnicity, and cigarette smoking

SummaryNipple aspirates of breast fluid (NAF) occur with different colorations (colorless, white, pale yellow, dark yellow, brown, green, and black). Increasing concentrations of cholesterol, cholesterol 5,6-epoxides, estrogens, and fluorescent products of lipid peroxidation have been positively associated with the dark colorations (dark yellow, brown, green, and black). Because of the absence of data on these variations in breast fluid coloration, we made an exploratory study of their possible associations with age, ethnicity, clinical breast status, and breast cancer risk factors. Dark NAF colorations increased with age among white women from 22.5% at 20–29 years to 49.2% at 50–59 years. Among Chinese and Japanese women, the overall proportion of dark breast fluids was significantly lower (highest proportion 23.5%).A positive association of dark NAF coloration was found with current cigarette smoking (odds ratio = 1.64 [1.04–2.59]). A dose response between amount smoked and dark coloration was found in women <50 years of age, with women who smoked more than one pack per day having an odds ratio of 2.31 (1.30–4.67). No significant association of dark NAF was found with the major breast cancer risk factors or with actual benign or malignant breast disease.The dark colorations may represent pigmented products of apocrine gland secretion, lipofuscin complexes of peroxidated lipoprotein, breakdown products of hemoglobin, and possibly, diet-related secretory products.

Nipple aspirate fluids in adult nonlactating women--lactose content, cationic Na+, K+, Na+/K+ ratio, and coloration.

SummaryThe presence of lactose in nipple secretions is considered biochemical evidence of breast secretory activity, and has been reported to occur more frequently in white compared to brownish or green colored breast fluid. We studied lactose, Na+, and K+ concentrations, the Na+/K+ ratio, and the coloration of nipple aspirate fluid (NAF) from 49 nonpregnant women.A significant relationship was found between the concentrations of lactose, Na+, and K+, and age and the coloration of NAF. Lactose was present in 22/49 (44.8%) of the NAF samples and declined with age from 100% positivity in women ≤29 years to 29% in those ≤35 years. In NAF of deep yellow, brown and green colorations, only traces of lactose were found. Na+ and K+ increased with age and with darker colorations compared to white, pale yellow, or colorless NAF.Lactose was present in NAF samples from both parous and nulliparous younger women, indicating that the breasts of many nonpregnant women respond to prolactin stimulation; hence, lactose may provide a simple marker indicating active physiologic secretory activity of the breast.As reported previously, NAF of darker coloration, containing elevated levels of cholesterol, cholesterol oxidation products, and other substances, suggests retention and impaired reabsorption of these and other products of secretion. Because of the secretion and temporary retention by the breast glands of chemical substances of exogenous and endogenous origin, including mutagens and carcinogens, lactose concentration and coloration of NAF may be useful as markers of secretion and reabsorption in future physiologically based clinical and epidemiologic studies of the pathogenesis of breast disease.

Identification of high risk groups in breast cancer.

In addition to a brief review of earlier work on the epidemiology of breast cancer, recently observed genetic, socioeconomic, and viral associations with this disease are discussed here.