The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.

Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90%. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1% (C.I. 0.6-1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5-22.5) for 6174delT, compared to 31 (C.I. 11-77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative life-time penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations.

Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.

The lifetime risk of breast cancer may approach 80-90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2. A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population. We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, wer heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age (P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation BRCA2 together may account for over a quarter of all early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women.

Male DCIS diagnosed after use of over-the-counter hormonal supplement.

INTRODUCTION: Male breast cancer is a rare disease. Although epidemiologic and genetic factors are associated with male breast cancer, hormonal factors may also play a role. CASE PRESENTATION: We report the case of a 39-year-old BRCA negative male patient taking a sexual performance enhancement supplement who presented with worsening asymmetric gynecomastia and unilateral spontaneous bloody nipple discharge and was found to have ductal carcinoma in-situ. DISCUSSION: The altered cellular environment related to the hormone contents of the supplement coincided with the rapid worsening of his gynecomastia and may have played a role in the development of the ductal carcinoma in-situ, or growth of an existing focus. CONCLUSION: The use of hormonal male enhancement supplements can lead to higher levels of androgens in users. It is possible for this altered hormonal environment to cause the growth of tumor or promote the progression of an existing focus.

Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with an increased risk of breast cancer. Whether women with breast cancer who have inherited mutations in these genes have a different outcome after breast conservation therapy than women with "sporadic" cancer is unresolved. Consequently, we compared the outcomes after breast conservation therapy in Ashkenazi women with or without germline mutations in BRCA1 and/or BRCA2 (hereafter called BRCA). METHODS: We studied 305 women of Ashkenazi Jewish descent undergoing breast-conserving treatment for 329 invasive breast cancers. We reviewed their clinical records, retrieved their archival tissue samples, and tested those samples for the founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. Genetic results were linked to clinical data and outcomes by univariate and multivariate analyses. All Pvalues are two-sided. RESULTS: We detected mutations in BRCA genes in 28 of 305 women. Women with BRCA mutations were more likely to be diagnosed with cancer before the age of 50 years (P<.001) and to have lymph node involvement (P =.04). Ipsilateral breast tumor recurrence was more common in women with BRCA mutations, although this did not reach statistical significance (relative risk [RR] = 1.79; 95% confidence interval [CI] = 0.64-5.03). Women with mutations were more likely to develop contralateral breast cancer (RR = 3.50; 95% CI = 1.78-8.74; P =.001). Distant disease-free survival was shorter in women with mutations (66.2% versus 84.3% at 10 years; P =.05), as was breast cancer-specific survival (71.9% versus 87.2% at 10 years; P =.02). Tumor stage and nodal status, but not mutation status, were predictive of distant disease-free and breast cancer-specific survival in multivariate analysis. CONCLUSIONS: Women with BRCA founder mutations are at increased risk for breast cancer-related events after breast conservation. However, mutation status is not an independent predictor of survival and should not influence decisions regarding adjuvant therapy. The increased contralateral breast cancer risk in women heterozygous for BRCA mutations mandates careful surveillance.

Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas.

A novel gene was identified recently at chromosome 10q23, named PTEN or MMAC1, and based on several criteria it was designated as a potential human tumor suppressor gene. Loss of heterozygosity affecting this region of 10q is observed in several cancer types, especially glioblastoma, and inactivating mutations of the PTEN/MMAC1 gene are found in some of these cancers as well as cell lines and xenografts. Breast cancer is among the tumor types in which mutations are documented, and germline mutations of the gene appear to be responsible for the rare autosomal dominant familial cancer syndrome known as Cowden disease, which includes breast cancer among its clinical features. To further determine the role that PTEN/MMAC1 mutations may play in breast tumorigenesis, the entire coding region was screened for mutations in 54 unselected primary breast cancers. Two mutations were identified, a somatic 2-bp deletion in an apparently sporadic breast cancer, and a germ-line 4-bp deletion in a breast cancer patient with a clinical history consistent with Cowden disease. These data indicate that somatic mutations of PTEN/ MMAC1 occur in only a small fraction of primary breast cancers and confirm the role of this gene in the etiology of Cowden disease. Evidence is also presented suggesting that numerous polymorphisms and missense variants exist in the PTEN/MMAC1 transcript.

A truncated cyclin D1 gene encodes a stable mRNA in a human breast cancer cell line.

The G1 cyclin D1 is amplified in approximately 20% of human breast cancers and is frequently overexpressed as part of an amplicon in these tumors, suggesting a potential role for this gene in the pathogenesis of breast cancer. Although amplification of cyclin D1 occurs in human breast cancer, it is possible that another gene in the amplicon is the relevant oncogene in these cancers. We now report a truncation of the cyclin D1 gene in a human breast cancer cell line, associated with overexpression of a short cyclin D1 mRNA. In a survey of breast cancer cell lines and tumors by Southern blot hybridization, using a 1.2 kb human cyclin D1 cDNA, we observed that genomic DNA derived from the MDA MB-453 cell line contains an extra band in the Bg1II and BamHI digests, suggesting that one allele of gene is altered. Moreover, the altered allele is amplified three-fold relative to the normal allele, and contains a 3' deletion. On Northern analysis, the MDA MB-453 line has a marked increase in 1.1 to 1.3 kb transcripts, which are truncated at the 3' end, in contrast to the normally predominant 4.2 kb transcript. The 1.1-1.3 kb cyclin D1 mRNA has a longer half-life than the 4.2 kb mRNA, indicating that the 3' truncation may contribute an increased stability and therefore an elevated steady-state level of the short mRNA. These alterations in the cyclin D1 gene and mRNA suggest that altered expression of cyclin D1 may be important in the malignant transformation of this cell line, and support the identification of cyclin D1 as a dominant oncogene at 11q13 in human breast cancer.

p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis.

PURPOSE: The present study explores p53 in relation to the following four aspects of node-negative breast carcinoma: epidemiologic risk factors, tumor histopathology, prognosis, and HER2/neu (HER) expression. MATERIALS AND METHODS: Immunohistochemical (IH) staining for p53 was performed on formaldehyde-fixed, paraffin-embedded primary invasive carcinomas from 440 node-negative patients with a median follow-up duration of 119 months. RESULTS: The IH expression, or lack thereof, of p53 separately or in combination with HER did not prove to be prognostically significant and there was no consistent association of p53 with epidemiologic risk factors. p53 was expressed in 68% of medullary carcinomas (MEDs), which is a significantly higher frequency (P < .001) than in lobular (9%) and duct (23%) carcinomas. p53 was not found in some types of low-grade carcinomas (tubular and papillary), and was observed in a minority of mucinous carcinomas. p53 was present significantly more often in carcinomas with high-grade or poorly differentiated nuclear grade than in low- or intermediate-grade tumors. There was an inverse statistically significant relationship between estrogen receptor (ER) positivity and p53 expression. Tumors with the p53(+)/HER(-) immunophenotype tended to be MEDs or duct carcinomas with a marked lymphoplasmacytic reaction. Infiltrating lobular carcinomas (IFLCs) were largely p53(-)/HER(-). p53(+)/HER(+) carcinomas had the best prognosis. The poorest outcome was associated with the p53(-)/HER(+) immunophenotype. This trend was statistically significant for recurrence-free and overall survival in patients with T1NOMO infiltrating duct carcinoma (IFDC). CONCLUSION: The IH demonstration of p53 was not a reliable prognostic indicator in the node-negative breast carcinoma patients studied and it was not associated with major epidemiologic risk factors. The combined immunophenotypic expression of p53 and HER was significantly associated with some histologic types of breast carcinoma and with prognosis in T1NOMO breast carcinoma.

BRCA-associated breast cancer in young women.

PURPOSE: To delineate the clinical characteristics and outcomes of breast cancer that arises in the setting of a germline BRCA mutation and to compare BRCA-associated breast cancers (BABC) with those that arise in women without mutations. PATIENTS AND METHODS: We reviewed the clinical records of 91 Ashkenazi Jewish women ascertained during studies of the genetics of early-onset breast cancer. All women underwent testing for the BRCA1 mutations 185delAG and 5382insC. After the discovery of BRCA2, 79 women were also tested for the BRCA2 mutation 6174delT. RESULTS: Mutations were identified in 30 women (33%). BABC were less likely to present with stage I disease than cases in women without mutations (27% v 46%), more likely to have axillary nodal involvement (54% v46%), and more likely to have extensive axillary involvement (25% v 17%). These differences were not statistically significant. BABC were significantly more likely to be histologic grade III (100% v 59%, P=.04) and to be estrogen receptor-negative (70% v 34%, P=.04). In the entire cohort, there were no significant differences between BABC and non-BRCA-associated cancers in 5-year relapse-free survival (65% v 69%, P=not significant [NS]), 5-year event-free survival (57% v 68%, P=NS), or 5-year overall survival. However, among cases diagnosed within 2 years of study entry, there was a trend toward shorter event-free survival in BRCA heterozygotes, but not relapse-free survival. Women with germline BRCA mutations were significantly more likely to develop contralateral breast cancer at 5 years (31% v 4%, P=.0007). CONCLUSION: BABC present with adverse clinical and histopathologic features when compared with cases not associated with BRCA mutations. However, the prognosis of BABC appears to be similar to that of nonassociated cancer. Further studies of incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.

Biological behavior of human breast cancer micrometastases.

PURPOSE: Clinically undetectable micrometastases may account for disease recurrence in breast cancer patients after variable disease-free intervals. However, little is known about the cellular mechanisms controlling human breast cancer micrometastases. We compared tumor proliferation rate, apoptotic index, and angiogenesis in human breast cancer micrometastases with those of macroscopic axillary lymph node metastases. EXPERIMENTAL DESIGN: Seven breast cancer micrometastases (<2 mm) obtained from the sentinel nodes of seven patients were compared with 13 macrometastases (lymph node replaced with tumor) obtained from 13 patients. The tissue was fixed in formalin, embedded in paraffin, serially sectioned, and evaluated by H&E and immunohistochemistry for cytokeratin. Tumor proliferation rate was assessed as the number of Ki-67-positive nuclei/total number of tumor nuclei. Tumor vascularity was quantified using antibody to factor VIII to identify microvessels per high-power field (at x400). Apoptosis was quantified using the terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling method. Results were analyzed with the Wilcoxon rank-sum test. RESULTS: Median size of micrometastases was 0.5 mm (range, 0.4-1.0), and the median number of tumor nuclei/section was 143 (range, 90-312). Median proliferation rate for macrometastases was greater than for micrometastases (35% versus 12%; P = 0.003). Median microvessel density/high-power field for macrometastases was greater than for micrometastases (17 versus 1; P < 0.001). There was no difference in apoptotic index between macrometastases and micrometastases (1.1% versus 0.7%; P = not significant). CONCLUSIONS: Human breast cancer micrometastases have lower tumor proliferation rates and angiogenesis than breast cancer macrometastases. These characteristics may explain their differential growth patterns.

The influence of older age on breast cancer treatment decisions and outcome.

PURPOSE: Information concerning the differences between older and younger women with breast cancer, treated with standard therapy, is lacking from many prospective series. The purpose of this study is to identify factors that influence treatment decisions and determine if women age 65 and older are treated differently than younger women. The outcomes of older women would then be compared to younger to determine if treatment differences influence outcome. METHODS AND MATERIALS: The records of 558 women with early invasive breast cancer who were treated with breast conserving surgery and radiation therapy were retrospectively reviewed. Four hundred thirty-two women under the age of 65 (range: 24-64) and 126 women age 65 and older (range: 65-85) were assessed for treatment differences including breast reexcision, extent of axillary dissection, extent of breast and nodal irradiation, and the use of chemotherapy or hormonal therapy. Differences in the treatment of the two groups were determined and the end points of local control, disease-free survival, and overall survival were compared. Median follow-up was 5.5 years. RESULTS: The two treatment groups had identical pathologic TNM staging with the exception that 21% of the older age group and 5% of the younger group did not undergo axillary dissection. Women age 65 and older were less likely to have a reexcision, extensive axillary dissection, chemotherapy, or nodal irradiation. They were more likely to receive hormonal therapy. Reexcision in older women was positively influenced by a family history of breast cancer and negatively influenced by a history of previous malignancy. None of the patients who were treated without and axillary dissection suffered a regional recurrence. Although local control was better in older patients, there were no differences in disease-free or overall survival for the two groups. DISCUSSION: The findings of this study reveal that older patients have significant treatment differences as compared to younger patients; however, despite these differences, similar local control and survival were achieved at 5 to 10 years. With the expected survival of older women increasing, the prospective evaluation of treatment options for older women should be considered.

Infiltrating breast carcinoma in patients age 30 years and younger: long term outcome for life, relapse, and second primary tumors.

A retrospective study examining the influence of young age, defined as 30 years or less on the outcome of early-staged (American Joint Committee 1978-I, II) breast cancer was undertaken using patients treated between 1950 and 1970 to ensure a long follow-up period. Because of the era of treatment, radical mastectomy without systemic chemotherapy was the predominant treatment. Ninety-nine patients met study criteria, with a median follow-up of 11.4 years (range 0.5 to 41 years). The patient group was compared to patients of all ages, treated at Memorial Sloan-Kettering Cancer Center in 1960 (5 and 10 years) and to patients treated between 1940 and 1943 (30 year follow-up). At the 5, 10, and 30 year follow-up periods, patients in the young age group consistently had disease-specific survival 10-20% lower than their older counterparts. For young patients who survived their first cancer diagnosis, second primaries both in the contralateral breast and elsewhere, played a significant role in determining their subsequent life span. When compared to risks of second primary cancers in the National Cancer Institute's SEER (Surveillance, Epidemiology and End Results Program) Cancer Registry for all ages, the increased risk for very young breast cancer patients was significant (p = 0.000). With these two findings in mind, treatment for young patients with breast cancer should focus not on local therapy options alone but on the increased risk of both systemic disease and of second primaries.

Microdissection and molecular genetic analysis of HER2/neu in breast carcinoma.

Precise correlation of histomorphology with molecular genetic analysis is difficult in tissues composed of heterogeneous cell populations. We describe here a novel microdissection technique employed to correlate HER2/neu (HER2) immunohistochemical staining with HER2 genetic analysis in formalin-fixed, paraffin-embedded breast tissue. Fourteen invasive ductal carcinomas were selected from the pathology files of Memorial Sloan-Kettering Cancer Center that had been immunostained for HER2. Seven tumors showed typical membrane immunoreactivity and seven were negative. A dissecting microscope was then used to isolate minute (< or = 1 mm x 1 mm) areas of invasive carcinoma and normal breast tissue for molecular study. To document the type of cell sample submitted for polymerase chain reaction (PCR) analysis, each microdissected piece of tissue was photographed prior to removal from the glass slide. A preliminary study of four cases compared the results of PCR and genetic analysis using microdissected hematoxylin and eosin (H & E)-stained tissue, unstained dewaxed tissue, and destained dewaxed tissue in four specimens. Similar results were obtained with all three tissue preparations. Thereafter, H & E stained sections were selected as the tissue preparation of choice because tissue details were seen more clearly. There was complete correlation of immunohistochemical staining and HER2 analysis by PCR in all 14 cases. In the final 10 cases, the PCR product was resolved by gel electrophoresis and quantified by optical densitometry. Fourfold to eightfold amplification of HER2 was found in the five tumor specimens that immunohistochemically stained for HER2. A single copy of HER2 was found in all HER2-negative tumors and in normal breast tissue. We conclude that it is possible to quantify gene amplification of HER2 in minute samples of H & E-stained normal and malignant breast tissue. This microdissection technique can be applied to correlative histologic--molecular genetic analysis in a wide variety of tumor types.

Analysis of MTS1/CDK4 in female breast carcinomas.

Multiple factors, both environmental and genetic, are thought to play roles in breast carcinogenesis. The recently cloned multiple tumor suppressor gene (MTS1), the product of which interacts with CDK4 to regulate cell growth, has been found to be mutated with high frequency in a variety of cell lines as well as primary tumors of different histologic types. Using PCR-SSCP, we analyzed exons one (126 bp) and two (307 bp) of the MTS1 gene to determine the incidence of mutation in a population of 50 primary breast adenocarcinomas and corresponding normal tissue. Analysis of five breast tumor cell lines was also performed. We found no mutations in the MTS1 gene in the primary breast tumor samples. One cell line was found to have a homozygous deletion of the gene. Our results suggest that the MTS1 gene is not mutated with increased frequency in primary breast tumors, and thus may not play a major role in breast carcinogenesis.

Intradermal isotope injection is superior to intramammary in sentinel node biopsy for breast cancer.

BACKGROUND: The optimal sentinel lymph node (SLN) biopsy technique remains undefined in breast cancer. Injecting radiotracer or blue dye by a variety of routes seems to stage the axilla with comparable accuracy, and we have hypothesized that the dermal and the parenchymal lymphatics of the breast drain to the same SLN in most patients. Two previous studies from our institution support this concept: (1) a single-surgeon series of 200 consecutive SLN biopsy procedures demonstrating a high dye-isotope concordance for both intradermal (ID) and intraparenchymal (IP) isotope injection, and (2) a series of 100 procedures validated by a backup axillary dissection (ALND) in which the false-negative rate following ID isotope injection was comparable to that of our previous results with IP injection. Here, we directly compare the results of SLN biopsy using either ID or IP isotope injection for our entire experience of SLN biopsy procedures in which a backup ALND was done. METHODS: This is a retrospective, nonrandomized study of 298 clinical stage I to II breast cancer patients having SLN biopsy with a backup ALND planned in advance, comparing the results of ID (n = 164) and IP (n = 134) isotope injection. All patients had IP injection of blue dye. Endpoints included (1) successful SLN identification, (2) false-negative rate, (3) dye-isotope concordance, and (4) the SLN/axillary background isotope count ratio. RESULTS: ID isotope was more successful than IP, identifying the SLN in 98% versus 89% of cases, respectively. False-negative results (4.8% vs 4.4%) and dye-isotope concordance (92% vs 93%) were comparable between the 2 groups, and SLN/axillary background isotope count ratios were significantly higher with ID than with IP injection (288/1 vs 59/1). CONCLUSIONS: ID isotope injection identifies the SLN more often than IP, stages the axilla with comparable accuracy, and is associated with higher levels of SLN isotope uptake. The dermal and parenchymal lymphatics of the breast drain to the same axillary SLN in most breast cancer patients, and ID isotope injection is the procedure of choice in this setting.

Molecular analysis of the INK4A and INK4B gene loci in human breast cancer cell lines and primary carcinomas.

The INK4A and INK4B loci are located at 9p21 and have been implicated in the tumorigenesis of various human malignancies. The INK4A gene encodes two cell cycle regulators, p16(INK4A) and ARF, while INK4B encodes p15(INK4B). Previously, we have shown that the p16(INK4) tumor suppressor was not mutated or deleted in primary breast carcinomas. However, primary and metastatic breast carcinomas exhibited a relative hypomethylation of p16(INK4A), which is associated with expression, compared to normal breast tissue. The present study was conducted to determine if inactivation of p15(INK4B) and INK4A exon 1beta (ARF) are common events in breast carcinoma. Mutational analysis was performed by PCR-SSCP, and mRNA expression was evaluated by RT-PCR. Methylation-specific PCR was used to determine the methylation status of the p15(INK4B) promoter. Our results demonstrate that the p15(INK4B) gene was altered in 3 (21%) of the 14 breast cell lines; one had a silent mutation and two had homozygous deletion of the gene. None of the cell lines showed methylation of p15(INK4B). Two (14%) cell lines had homozygous deletion of INK4A exon 1beta. All normal and malignant breast tissue samples were wild-type and non-methylated for p15(INK4B) and wild-type for exon 1beta. Our results show that these structurally and functionally related genes are not invariably affected together, and the most frequently observed alteration at the INK4A and INK4B loci in breast carcinoma appears to be p16(INK4A) hypomethylation.

Women 35 years of age or younger have higher locoregional relapse rates after undergoing breast conservation therapy.

BACKGROUND: The use of breast conservation therapy (BCT) in young women with invasive breast cancer is controversial. To examine this important issue, rates of locoregional recurrence and overall survival after BCT were compared in two subsets of women--those < or = 35 years of age at time of surgery and their older counterparts. STUDY DESIGN: We examined records of 290 women with invasive breast cancer treated with BCT (local excision and axillary dissection) at Memorial Sloan-Kettering Cancer Center between 1984 and 1993. These included 87 patients < or = 35 years of age at time of surgery and 203 randomly selected patients > 35 years of age. Followup was obtained from physician charts or patient interviews, or both. Complete data on clinicopathologic factors, recurrence, and survival were available on 280 patients. RESULTS: Median followup from time of operation was 8.0 years for the entire group. Mean tumor size was 2.0 cm for women < or = 35 years and 1.8 cm for those > 35 (p = 0.07). Involved nodes were found in 48% of the young patients and 36% of the older patients (p = 0.08). Within our study group (n = 280), 274 patients received radiotherapy. Women < or = 35 years of age had significantly higher rates of locoregional recurrence and lower rates of overall survival than their older counterparts (p < 0.05). On multivariate analysis, these results were independent of tumor size and nodal status. A history of locoregional relapse, however, was not associated with a higher rate of death from disease in the entire cohort or in either age group. CONCLUSIONS: Patients < or = 35 years of age undergoing BCT for invasive breast cancer are at higher risk for locoregional recurrence and death from disease. The higher mortality rate, however, does not appear to be a direct result of locoregional relapse. Additional study is required to verify these findings. Currently, young age does not exclude patients from BCT in our practice. But, we include this data as part of the informed consent process.

The breast cancer patient with multiple sentinel nodes: when to stop?

BACKGROUND: During sentinel lymph node (SLN) biopsy for breast cancer, most authors report identifying a mean of 1 to 3 SLNs, but a range of 1 to 8 (or more) SLNs per patient. A significant minority of patients have 4 or more SLNs. Here we seek to determine the significance for the breast cancer patient of finding multiple SLNs, and whether there is an optimal threshold number of SLNs that should be removed. STUDY DESIGN: 1,561 patients who underwent successful SLN biopsy using blue dye and radioisotope in combination. Each SLN site was categorized prospectively by the operating surgeon as a dye success, an isotope success, or both. All SLNs containing counts at least four times greater than the postexcision axillary background were considered to be isotope successes. RESULTS: Fifteen percent of patients (241) had multiple (>3) SLNs. Ninety-eight percent of node-positive patients (440 of 449) were identified within the first three SLN sites examined. In 2% of all SLN positive patients (9 of 449) or 4% of patients with multiple SLN (9 of 241), a positive SLN was detected at site four or more. In eight patients the first positive SLN was found at sites four or more. Blue dye and isotope were equally effective in identifying metastases in patients with multiple SLNs. CONCLUSIONS: Fifteen percent of patients having SLN biopsy for breast cancer have multiple SLNs. Although 98% of positive SLNs were identified within the first three sites sampled, a small number of patients had their first positive SLN at sites 4 to 8. These data suggest that there is no absolute upper threshold for the number of SLNs that should be removed. Sampling a few additional SLNs probably adds little morbidity to the procedure, yet may significantly alter the treatment of some individuals. SLN biopsy should be continued until all blue and hot nodes are removed.

Immediate reconstruction after complete skin-sparing mastectomy with autologous tissue.

BACKGROUND: Immediate breast reconstruction with autologous tissue can re-create a breast mound that closely resembles the native breast in shape and consistency. Results are limited by scarring and color differences between flap and native breast skin. This study reviews all patients undergoing complete skin-sparing mastectomy with immediate autologous tissue reconstruction over the past 4 years. STUDY DESIGN: Twenty-eight patients with a mean age of 43 years (range, 32-53 years) were retrospectively reviewed. Requirements for the complete skin-sparing approach included a favorable biopsy scar location, adequate areolar diameter, and suitable donor site for autologous tissue reconstruction. Ninety-two percent of patients were reconstructed with a transverse rectus abdominis musculocutaneous flap. RESULTS: There were no instances of flap loss or local recurrence during the followup period (mean, 27 months; range, 14-48 months). Complications at the reconstruction site were minor and limited to cellulitis, periareolar skin loss, and the need for repeat skin excision because of a very close pathologic margin. Donor site complications were seen in five patients. Aesthetic results were judged as excellent or good in 75% of patients. CONCLUSIONS: Complete skin-sparing mastectomy with immediate autologous tissue reconstruction has enhanced immediate breast reconstruction by reducing scar burden and eliminating color differences without an increased incidence of local recurrence. This procedure is limited by appropriate patient selection and technical expertise in performing the mastectomy.

Sentinel lymphadenectomy accurately predicts nodal status in T2 breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has emerged as a reliable, accurate method of staging the axilla for early breast cancer. Although widely accepted for T1 lesions, its use in larger tumors remains controversial. This study was undertaken to define the role of SLNB for T2 breast cancer. STUDY DESIGN: From a prospective breast sentinel lymph node database of 1,627 patients accrued between September 1996 and November 1999, we identified 223 patients with clinical T1-2N0 breast cancer who underwent 224 lymphatic mapping procedures and SLNB followed by a standard axillary lymph node dissection (ALND). Preoperative lymphatic mapping was performed by injection of unfiltered technetium 99 sulfur colloid and isosulfan blue dye. Data about patient and tumor characteristics and the status of the sentinel lymph nodes and the axillary nodes were analyzed. Statistics were performed using Fisher's exact test. RESULTS: Two hundred four of 224 sentinel lymph node mapping procedures (91%) were successful. Median tumor size was 2.0 cm (range 0.2 to 4.8 cm). One hundred forty-five of the 204 patients had T1 lesions and 59 patients had T2 lesions. There were 92 pathologically positive axillae, 5 (5%) of which were not evident either by SLNB or by intraoperative clinical examination. The false-negative rate and accuracy were not significantly different between the two groups, but axillary node metastases were observed more frequently with T2 than with T1 tumors (p = 0.005); other factors, including patient age, prior surgical biopsy, upper-outer quadrant tumor location, and tumor lymphovascular invasion were not associated with a higher incidence of false-negative SLNB in either T1 or T2 tumors. CONCLUSIONS: SLNB is as accurate for T2 tumors as it is for T1 tumors. Because no tumor or patient characteristics predict a high false-negative rate, all patients with T1-2N0 breast cancer should be considered candidates for the procedure. Complete clinical examination of the axilla should be undertaken to avoid missing palpable axillary nodal metastases.

Sentinel lymph node biopsy in breast cancer: unfiltered radioisotope is superior to filtered.

BACKGROUND: The combination of gamma-probe radiolocalization and blue-dye mapping of sentinel lymph nodes (SLNs) has been advocated as the most accurate method for staging the clinically negative axilla in breast cancer patients, but the technical aspects of these procedures are not fully characterized in the literature. In this study, we compared the success of SLN localization in 134 consecutive breast cancer patients using blue dye plus two different preparations of radiocolloid. STUDY DESIGN: A retrospective analysis of a prospectively maintained data base was performed to assess SLN localization in two cohorts of patients. Unfiltered technetium-99m (Tc-99m) sulfur colloid (in 77 patients; group I) was compared with filtered Tc-99m sulfur colloid (in 57 patients; group II). All patients had a peritumoral injection of blue dye and isotope, followed immediately by lymphoscintigraphy to confirm radioactivity at the injection site and to image the SLN. Statistical analysis was performed using the Pearson chi-square test. RESULTS: Unfiltered Tc-99m sulfur colloid was superior to the filtered radiocolloid in localizing the SLN (88% versus 73%; p = 0.03). SLN imaging by lymphoscintigraphy was also more successful in the unfiltered group. Using the combination of blue dye and radiolocalization, SLNs were identified in 94% of patients. CONCLUSIONS: For optimal localization of the SLN in breast cancer patients, surgeons should use the combined technique of blue-dye mapping and gamma-probe localization using unfiltered Tc-99m sulfur colloid.