Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women.

PURPOSE: To evaluate the frequency and distribution of BRCA1 and BRCA2 mutations in a cohort of young women with breast cancer and to compare the distribution of mutations as a function of race. METHODS: After IRB approved informed consent, 170 white women and 30 African American women with known breast cancer diagnosed at a young age (45 years or less) underwent complete sequencing of the BRCA1 and BRCA2 genes. Each cohort represented approximately 40% of women of the same ethnic background aged 45 years or younger in a breast cancer database. RESULTS: Of the 200 patients tested, 131 (65%) had wild type mutations, 34 (17%) had deleterious mutations, and 35 (18%) had variants of uncertain significance. There were no significant differences between the white and African American cohorts regarding the percentage of deleterious mutations (17% v 17%). However, most African American patients had mutations in BRCA2 (4/5, 80%), while most mutations in the white cohort were in BRCA1 (20/29, 69%). In addition, 46% of the African American women had variants of uncertain significance, compared to only 12% of the white cohort. CONCLUSIONS: Young African American women with breast cancer have a similar frequency of deleterious mutations as white women, but have a significantly higher frequency of variants of uncertain significance. Review of these variants revealed that the majority were unlikely to be associated with disease risk or were likely to be polymorphisms. The implications for genetic testing and counselling in young women with breast cancer are discussed.

Preoperative chemotherapy and sentinel lymphadenectomy for breast cancer.

BACKGROUND: Sentinel lymphadenectomy (SL) for breast cancer is becoming the standard of care for selected patients treated by experienced surgeons. One of the few contraindications for performing SL alone is prior chemotherapy (PC). There are, however, no data to support that PC interferes with the ability of the sentinel node to predict the presence of disease in the remaining axillary lymph nodes. The goal of this study was to determine the effect of PC on patients undergoing SL for breast cancer. METHODS: A multicenter trial was organized in 1997 to evaluate the diagnostic accuracy of SL in patients with breast cancer. Investigators were recruited after attending a course on the technique of SL. Technetium-99 and isosulfan blue were injected into the peritumor region and a gamma probe was used to aid identification of the sentinel nodes. The only exclusion criteria for entrance into the trial were palpable or suspicious axillary lymph nodes. A total of 968 patients were enrolled in the trial. Twenty-nine patients were treated with PC and compared with 939 patients not receiving PC. RESULTS: The overall, sentinel node identification rate for the PC patients was 93% (27 of 29) compared with 88% (822 of 939) for patients not treated with PC. There were no false negatives in those patients receiving PC compared with a 13% (25 of 193) false negative rate in those patients not receiving PC. The mean tumor size was 1.4 cm for the PC group and 0.6 cm for the remaining patients (P <0.005). The mean number of sentinel nodes found was 2.0 for the non-PC group and 2.5 for the PC group (not significant). As expected, a higher proportion of patients had positive axillary nodes in the PC group (52%, 15 of 29) compared with the remaining patients (21%, 200 of 939). CONCLUSION: In this small group of patients, PC did not adversely impact the false negative or identification rate. Most patients receiving chemotherapy have larger tumors and a higher chance of harboring metastatic disease but a significant group of these patients (48%) without metastases can potentially be spared an axillary node dissection.

Comparison of intradermal and subcutaneous injections in lymphatic mapping.

BACKGROUND: Sentinel node biopsy (SNB) for melanoma, with its intradermal (ID) injection, has a higher success rate than SNB for breast cancer, which is typically performed with a subcutaneous (SC) or peritumor injection. It is hypothesized that this is in part due to a slower transit time of lymphatic mapping agents through the parenchymal lymphatics of the breast. No study has investigated differences in transit time between different tissues to account for this clinical observation. The goal of the study was to compare transit time between ID and SC injections with common agents used in lymphatic mapping. METHODS: Four injection sites on five domestic pigs were used. Sites were bilateral and included cervical, forelimb, hindlimb, and flank areas. Agents included technetium sulfur colloid (Tc99, filtered and unfiltered), isosulfan blue (IB) dye, and fluorescein (FL) dye. At each site both ID and SC injections were made and the transit time to reach the sentinel node was recorded. The transit time differences were calculated per centimeter distance from the draining lymph node basin. RESULTS: Sentinel nodes were identified draining all sites and found to be hot, blue, or fluorescent (using a Wood's lamp for identification). The cervical and forelimb injection sites drained to the same cervical lymph node basin and both SC and ID injection sites drained to the same sentinel node. Similarly, the hindlimb and flank injection sites both drained to inguinal lymph node basins. The slowest transit time occurred with Tc99 injected SC and the fastest occurred with Tc99 injected ID, whereas both FL dye and IB traveled rapidly to the sentinel node whether injected SC or ID. Large differences were found using unfiltered Tc99 depending on its injection ID (2.7 s/cm +/- 0.5) vs SC (249 s/cm +/- 14.7, P = 0.008). CONCLUSIONS: Tc99 ID injections were significantly faster than SC injection. The slowest and fastest SC injection agents were unfiltered Tc99 and IB, respectively. Dermal injections provide faster transit of lymphatic agents and may improve the identification rate when applied to patients with breast cancer.

Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye.

OBJECTIVE: To determine the factors associated with false-negative results on sentinel node biopsy and sentinel node localization (identification rate) in patients with breast cancer enrolled in a multicenter trial using a combination technique of isosulfan blue with technetium sulfur colloid (Tc99). SUMMARY BACKGROUND DATA: Sentinel node biopsy is a diagnostic test used to detect breast cancer metastases. To test the reliability of this method, a complete lymph node dissection must be performed to determine the false-negative rate. Single-institution series have reported excellent results, although one multicenter trial reported a false-negative rate as high as 29% using radioisotope alone. A multicenter trial was initiated to test combined use of Tc99 and isosulfan blue. METHODS: Investigators (both private-practice and academic surgeons) were recruited after attending a course on the technique of sentinel node biopsy. No investigator participated in a learning trial before entering patients. Tc99 and isosulfan blue were injected into the peritumoral region. RESULTS: Five hundred twenty-nine patients underwent 535 sentinel node biopsy procedures for an overall identification rate in finding a sentinel node of 87% and a false-negative rate of 13%. The identification rate increased and the false-negative rate decreased to 90% and 4.3%, respectively, after investigators had performed more than 30 cases. Univariate analysis of tumor showed the poorest success rate with older patients and inexperienced surgeons. Multivariate analysis identified both age and experience as independent predictors of failure. However, with older patients, inexperienced surgeons, and patients with five or more metastatic axillary nodes, the false-negative rate was consistently greater. CONCLUSIONS: This multicenter trial, from both private practice and academic institutions, is an excellent indicator of the general utility of sentinel node biopsy. It establishes the factors that play an important role (patient age, surgical experience, tumor location) and those that are irrelevant (prior surgery, tumor size, Tc99 timing). This widens the applicability of the technique and identifies factors that require further investigation.

Circadian coordination of cancer growth and metastatic spread.

To understand whether mammalian circadian time structure measurably affects the host-cancer balance, we studied tumor-take frequency after s.c. tumor cell inoculation and the number of pulmonary tumor nodules after i.v. tumor cell injections at each of 6 equispaced times of day. We employed 2 genetically distinct mouse strains and 2 different tumor model systems, a methylcholanthrene A-induced fibrosarcoma of C(3)HeJ mice and 2 B(16) melanoma cell lines of vastly different metastatic efficiency in C57 Black/6 mice. Fibrosarcoma cells were injected s.c. in 1 of 8 different doses, at 1 of 8 permutated anatomic sites and at 1 of 6 equispaced circadian times, in 96 female C(3)HeJ mice maintained under a synchronizing schedule of 12 hr light alternating with 12 hr dark. Regardless of tumor cell dose and inoculum location, tumor-take frequency depended strongly upon the circadian stage of tumor cell inoculation. Injections of between 2,000 and 50,000 live tumor cells inoculated near the daily sleep/wake interface resulted in the lowest incidence of tumor take compared with inoculation at other times of day. In the experimental i.v. B(16) melanoma metastatic model (N = 110), the capacity of both high and low metastatic potential clones to successfully metastasize to lung depended, to a large extent, upon when in the day each of these clones was injected. Similar to the fibrosarcoma data, the daily sleep/wake boundary was the time of day associated with the greatest resistance to metastatic spread.

Filtered versus unfiltered technetium sulfur colloid in lymphatic mapping: a significant variable in a pig model.

BACKGROUND: Lymphatic mapping with sentinel node biopsy is becoming a standard diagnostic test for melanoma and is being extensively investigated for use with other soft tissue tumors. Both filtered and unfiltered technetium sulfur colloid (Tc 99) have been used for preoperative lymphoscintigraphy, as well as intraoperative lymphatic mapping, and it is not clear if one is preferable over the other. The purpose of this study was to compare these two preparations to determine whether the form of Tc 99 used affects the results of lymphatic mapping. METHODS: Mock skin sites were placed on each extremity of 12 domestic pigs totaling 48 skin sites. Twenty-four of the lesions were injected with unfiltered Tc 99; the remaining 24 were injected with Tc 99 passed over a 0.2-microm filter. Both preparations of Tc 99 were mixed with 1 mL of isosulfan blue before injection. Sentinel node dissection was performed using a gamma probe, with counts recorded over a 10-second period and timed to begin 5 minutes after injection. RESULTS: Sentinel nodes were identified in all 48 lymph node basins draining the mock sites and characterized as hot (10x background), blue, or both. Significantly more sentinel nodes were found in the filtered (105 total, X = 4.4/basin), than in the unfiltered group (total 53, X = 2.2/basin, P <.0001). The filtered group had both a higher number of nodes that were hot (35 vs. 6) and more nodes that were hot and blue (69 vs. 43). In addition, hot secondary level lymph nodes (iliac and deep cervical) were found in 11 of 24 of the basins (46%) in the filtered group compared to 1 of 24 (4%) in the unfiltered group (P <.003). There was no significant difference in injection site or residual basin counts between the two groups, but in vivo counts over the sentinel node sites were significantly lower in the unfiltered group (X = 2670+/-1829 vs. X = 6027+/-4333; P = .003). CONCLUSION: Use of filtered Tc 99 results in more sentinel nodes (both hot/blue and hot non-blue) and a higher proportion of secondary lymph nodes. These findings indicate that the Tc 99 preparation used is a significant variable in the results of lymphatic mapping. It is critical that future clinical studies document which preparation of Tc 99 was used. Only large clinical trials will be able to determine whether the additional nodes found with filtered Tc 99 increase the sensitivity of the technique or merely increase the number of nodes that must be removed unnecessarily.

Fine-needle aspiration cytology of a subareolar abscess of the male breast.

We report on the fine-needle aspiration (FNA) cytology of a subareolar abscess of the breast in a 45-yr-old man. The patient presented with a 1.5-cm mass in the subareolar region. FNA cytology demonstrated the presence of numerous anucleated squamous cells and a few small nucleated squamous cells as well as numerous neutrophils and some lymphocytes in the background. Histiocytes were also present, including some multinucleated foreign-body-type giant cells. No organisms were identified either with special stains or microbiologic cultures. The differential diagnosis of FNA of the male breast is presented, along with other lesions that can potentially contain either benign or malignant squamous cells in the aspirate. The correct FNA diagnosis of this unusual benign lesion involving the male breast should lead to the appropriate treatment. To the best of our knowledge, this is the first published report of FNA cytology of a subareolar abscess of the male breast.

Influence of socioeconomic and cultural factors on racial differences in late-stage presentation of breast cancer.

CONTEXT: Breast cancer mortality is higher among African American women than among white women in the United States, but the reasons for the racial difference are not known. OBJECTIVE: To evaluate the influence of socioeconomic and cultural factors on the racial difference in breast cancer stage at diagnosis. DESIGN: Case-control study of patients diagnosed as having breast cancer at the University Medical Center of Eastern Carolina from 1985 through 1992. SETTING: The major health care facility for 2 rural counties in eastern North Carolina. SUBJECTS: Five hundred forty of 743 patients with newly diagnosed breast cancer and 414 control women from the community matched by age, race, and area of residence. MAIN OUTCOME MEASURES: Breast cancer stage at diagnosis. RESULTS: Of the 540 patients, 94 (17.4%) presented with TNM stage III or IV disease. The following demographic and socioeconomic factors were significant predictors of advanced stage: being African American (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.9-4.7); having low income (OR, 3.7; 95% CI, 2.1-6.5); never having been married (OR, 2.9; 95% CI, 1.4-5.9); having no private health insurance (OR, 2.5; 95% CI, 1.6-4.0); delaying seeing a physician because of money (OR, 1.6; 95% CI, 1.1-2.5); or lacking transportation (OR, 2.0; 95% CI, 1.2-3.6). Univariate analysis also revealed a large number of cultural beliefs to be significant predictors. Examples include the following beliefs: air causes a cancer to spread (OR, 2.8; 95% CI, 1.8-4.3); the devil can cause a person to get cancer (OR, 2.1; 95% CI, 1.2-3.5); women who have breast surgery are no longer attractive to men (OR, 1.9; 95% CI, 1.1-3.5); and chiropractic is an effective treatment for breast cancer (OR, 2.4; 95% CI, 1.4-4.4). When the demographic and socioeconomic variables were included in a multivariate logistic regression model, the OR for late stage among African Americans decreased to 1.8 (95% CI, 1.1 -3.2) compared with 3.0 (95% CI, 1.9-4.7) for race alone. However, when the belief measures were included with the demographic and socioeconomic variables, the OR for late stage among African Americans decreased further to 1.2 (95% CI, 0.6-2.5). CONCLUSIONS: Socioeconomic factors alone were not sufficient to explain the dramatic effect of race on breast cancer stage; however, socioeconomic variables in conjunction with cultural beliefs and attitudes could largely account for the observed effect.

Coming to terms with advanced breast cancer: black women's narratives from eastern North Carolina.

This paper analyzes in-depth interviews with 26 black women who entered the medical system in rural North Carolina with advanced breast disease. In these narratives, women draw on multiple sources of knowledge in order to come to terms with the diagnosis of breast cancer--a biomedically-defined disease that they often refuse to acknowledge or accept. The analysis demonstrates how women relate the meaning of their individual episodes of illness to one or more of the following sources of knowledge: an indigenous model of health emphasizing balance in the blood, popular American notions about cancer, and particular biomedical conceptions about breast disease and its treatment. These narratives provide an important window into the processes involved when individuals attempt to adapt personal experience to pre-existing cultural models, modify such models in the light of new information, and confront conflicts in their own interpretations of the meaning of a single episode of illness.

Difficulties in diagnosis of carcinoma of the breast in patients less than fifty years of age.

Delay in diagnosis of carcinoma of the breast is a significant cause of medical malpractice suits in the United States. Although less than one-third of the patients with carcinoma of the breast are less than 50 years of age, more than two-thirds of these suits involve women less than 50 years of age. To see whether or not there are medical factors that make diagnosis in young women more difficult, we reviewed all patient visits to the East Carolina University (ECU) Breast Clinic between 1 January 1988 and 30 June 1991. Women less than 50 years of age had many more patient visits (1,567 versus 838 visits) and many fewer carcinomas detected (38 versus 100 visits) than women who were more than 50 years old. The sensitivity and positive predictive value of mammography were significantly lower in young women than older women (68 versus 91 percent, p < 0.005, and 28 versus 53 percent, p < 0.001, respectively). Physical examination in young women was also less satisfactory. Tumors were more ill-defined and the percent that were easily palpable were significantly lower (45 versus 72 percent, p < 0.01). Furthermore, there was a basic difference in the reason tumors were not palpable in each age group. In older women, tumors were nonpalpable because they were small (mean size 1.0 versus 4.1 centimeters, p < 0.01), whereas in younger women, the non-palpable tumors were large (mean size 4.0 versus 3.4 centimeters), suggesting that they were not palpable because of background mammary density or diffuse growth pattern rather than size. Data from the Breast Cancer Detection Demonstration Project were analyzed and also suggested that carcinomas are more difficult to diagnose in young women. The percent of carcinomas that were not detectable by either mammogram or physical examination were inversely proportional to age and ranged from 36 percent at 40 years of age to 9 percent at 75 years of age. In addition, data from Blue Cross and Blue Shield and the ECU Breast Clinic indicated that it costs at least twice as much to diagnose each carcinoma in women less than 50 years of age. In conclusion, we believe that currently available techniques for diagnosis of carcinoma of the breast are not satisfactory for women less than 50 years of age and that this, rather than physician error, may account for the large number of malpractice suits in this age group.

Increasing mammography utilization: a controlled study.

BACKGROUND: Despite the effectiveness of breast cancer screening for women older than 50 years of age, only about one third of these women in the United States receive annual mammography. PURPOSE: This study was designed to determine if a community-wide intervention could increase use of mammography screening for breast cancer. Secondary end points were determination of changes in women's knowledge and attitudes toward mammography and physicians' self-reported screening practices. METHODS: We conducted a controlled study from January 1987 through January 1990 in two eastern North Carolina communities--New Hanover County (the experimental community) and Pitt County (the control community). Before development and implementation of the intervention program in New Hanover County and after the program had been in operation for 1 year, 500 women of ages 50-74 years and all primary-care physicians in each community were interviewed by telephone. In these interviews, we determined the use of mammography for breast cancer screening and the knowledge and attitudes about it. We also established the number of screening mammograms performed in 1987 and 1989 in each county and reviewed medical records to determine the percentage of women the physicians had referred for mammograms. RESULTS: The percentage of women who reported receiving a mammogram in the previous year increased from 35% to 55% in the experimental community and from 30% to 40% in the control community (difference of differences, 10%; P = .03 after adjustment for race, education, age, and having a regular doctor; 95% confidence interval, 1%-18%). Increases were greater in New Hanover County regardless of age, race, income, and education. However, the increase was less for Black women than for White women, both overall and in most demographic subgroups. The total number of mammograms performed increased 89% in the experimental community and 45% in the control community. Women's knowledge about mammography changed little, but the intention to get a mammogram increased 30% in New Hanover County, compared with a 17% increase in Pitt County--a statistically significant difference (P < .01). Physician reports and medical record reviews in the two communities showed similar increases in the number of mammograms ordered. CONCLUSIONS: A community-wide effort to increase use of breast cancer screening was successful, but more work must be done to reach the National Cancer Institute's goal of annual mammograms for 80% of women of ages 50-74.

Mammography and age: are we targeting the wrong women? A community survey of women and physicians.

To determine mammography use among women with a broad range of ages, the authors surveyed women aged 30 to 74 years and physicians practicing primary care in two eastern North Carolina counties. Twenty-five percent of women in their 30s had ever had a mammogram, and 34% intended to have one in the coming year. From 45% to 52% of women in their 40s, 50s, and 60s had ever had a mammogram, and 55% to 57% intended to have one in the next year. Thirty-seven percent of women aged 70 to 74 years had ever had a mammogram, and 40% intended to have one in the following year. Nineteen percent of physicians reported screening nearly all women aged 30 to 39 years, and 14% screened few women aged 50 to 74 years. Younger women were more worried about breast cancer than older women and assessed their risk as higher, attitudes that were generally associated with higher mammography utilization. These community surveys suggest that mammography use may be excessive among younger women; older women continue to be underscreened.

Fine-needle aspiration cytology of postirradiation sarcomas, including angiosarcoma, with immunocytochemical confirmation.

Postirradiation sarcomas are an unusual but well-recognized late effect of cancer therapy. In this article, a fine-needle aspiration (FNA) series of four cases is presented. There were three female patients and one male patient, with an age range of 28-55 yr (mean, 41). Two of the patients were irradiated for uterine cervical carcinoma while the other two received irradiation for malignant lymphoma. The time interval to the development of the postirradiation sarcoma ranged from 10 to greater than 20 yr. There were a postirradiation synovial sarcoma of the buttock region, malignant fibrous histiocytoma of the bone (femur), and rhabdomyosarcoma and angiosarcoma of the retroperitoneum. A spectrum of cytologic findings was encountered, reflecting the specific types of sarcomas. Immunocytochemical studies performed on the aspirated material from the angiosarcoma demonstrated the utility of immunoperoxidase stains for ULEX europaeus agglutinin-1 (UEA-1) and, to a lesser degree, factor VIII-related antigen antibody, confirming the vascular nature of this malignancy. The FNA findings from all four cases demonstrated cytologic features that allowed recognition of this unusual complication of irradiation treatment. This article confirms the utility of FNA cytology in following patients with previous malignancies and differentiating a postirradiation sarcoma from recurrent carcinoma.

Intraoperative video panendoscopy for diagnosing sites of chronic intestinal bleeding.

Intraoperative video panendoscopy was performed in 14 patients with chronic, recurrent gastrointestinal bleeding. All of the study patients had undergone extensive and expensive diagnostic testing including multiple radiographic contrast studies of the gastrointestinal tract, upper and lower endoscopy, nuclear bleeding scans, and selective mesenteric angiography without definition of the bleeding source. Intraoperative video panendoscopy, employing a segmental advance and look technique, allowed visualization and transillumination of the entire gut and identified mucosal disease in 13 patients (93 percent). Angiodysplasia of the colon and small intestine was the most common pathologic finding. Intraoperative video panendoscopy significantly influenced the operation performed in 13 patients (93 percent). Postoperative complications were minimal, with none being directly attributable to intraoperative video panendoscopy. Bleeding was totally controlled in 10 patients (71 percent) during a mean follow-up period of 25 months. Intraoperative video panendoscopy is a valuable technique for assisting in the management of the patient with recurrent gastrointestinal bleeding.

Fine-needle aspiration cytology of breast masses in pregnant and lactating women.

Eleven pregnant women with breast masses that arose during pregnancy or in the postpartum period underwent fine-needle aspiration biopsies. Cytologic examination demonstrated a spectrum of morphologic features, including (1) a pattern of dissociated epithelial cells stripped of their cytoplasm along with small clusters of cells having a frayed secretory type of cytoplasm; (2) larger epithelial groups with nuclear pleomorphism, prominent irregular nucleoli, and abundant vacuolated cytoplasm; (3) cellular smears, often with an inflammatory background and proteinaceous debris; and (4) microtissue fragments showing features of lobular hyperplasia. This article illustrates the clinical utility of fine-needle aspiration biopsy in evaluating breast masses in pregnant and lactating women and discusses the potential hazards for a false-positive diagnosis of malignancy in these patients.

The triage role of fine needle aspiration biopsy of palpable breast masses. Diagnostic accuracy and cost-effectiveness.

A total of 219 fine needle aspiration (FNA) biopsies of the breast were performed during the period 1983 to 1985 at a tertiary medical center. The series consisted of 215 women (98.2%) and 4 men (1.8%), with an are range of 14 to 90 years (mean of 46.5 years). Histologic confirmation (93 cases) or clinical follow-up for up to two years was obtained. The sensitivity of the FNA procedure was 82.2%, its specificity was 98.8%, and the overall efficiency of the test was 95.4%. The false-negative rate was 4.4%, with no false-positive diagnoses for the primary diagnosis of breast carcinoma. We have found that one of the major advantages of FNA biopsy is that it lowers costs by allowing the surgeon to triage which patients should have an outpatient excisional biopsy under local anesthesia and which patients should have a one-stage inpatient procedure with frozen section confirmation. For this triage role, suspicious diagnoses (3.2%) were included in the positive group and atypical (1.8%) and insufficient diagnoses (6.8%) in the negative group. Taking into account the FNA biopsy cost of $75, the procedure resulted in a savings per case of $262 over the cost that would have occurred if all cases had had routine inpatient biopsy and $154 per case over the cost that would have occurred with routine outpatient biopsy of all cases. Our results indicate that FNA breast biopsy is a diagnostically accurate and economical triage procedure, even when followed by an excisional or frozen-section biopsy for confirmation. The use of FNA biopsy could be expanded to a greater number of medical centers and decrease the potential for false-positive diagnoses by combining FNA biopsy with frozen-section confirmation.