RESUMEN
BACKGROUND: Sentinel lymph node (SLN) biopsy has become a standard of care for axillary lymph node staging in breast cancer and appears suitable for virtually all patients with clinically node-negative (cN0) invasive disease. However, its role in Paget's disease of the breast, a condition in which invasion may or may not be present, remains undefined. METHODS: Among 7,083 consecutive SLN biopsy procedures, we retrospectively identified 39 patients with Paget's disease of the breast. Nineteen patients had no associated clinical/radiographic features ("Paget's only"), and 20 patients had associated clinical/radiographic findings ("Paget's with findings"). RESULTS: The mean ages for the Paget's alone and with findings groups were 63.6 and 49.6 years, respectively. The use of breast conservation therapy was 32% in the Paget's alone group and 10% in the Paget's with findings group. Invasive carcinoma was found in 27% of patients in the Paget's alone group and 55% of patients in the Paget's with findings group. The success rate of SLN biopsy was 98%, and the mean number of SLNs removed was 3 in both groups. In the entire cohort of Paget's disease, 28% (11/39) of the patients had positive SLNs (11%, Paget's alone; 45%, Paget's with findings). CONCLUSION: In our "Paget's only" cohort, invasive cancer was found in 27% of cases and positive SLNs in 11%. SLN biopsy should be considered in all patients with Paget's disease of the breast, whether associated clinical/radiographic findings are present.
Asunto(s)
Neoplasias de la Mama/patología , Enfermedad de Paget Mamaria/secundario , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Estudios RetrospectivosAsunto(s)
Proteína BRCA2/genética , Neoplasias de la Mama/genética , Mutación , Exones , Femenino , Genes BRCA2 , Humanos , Intrones , Judíos/genéticaRESUMEN
BACKGROUND: Predicting the extent of disease in the breasts of patients with invasive lobular cancer (ILC) can be difficult because of the limits of physical examination and standard imaging. We determined the utility of magnetic resonance imaging (MRI) in finding otherwise unsuspected cancer in the ipsilateral or contralateral breast of patients with ILC. METHODS: Through database review of all breast MRIs performed between January 1, 1999, and December 30, 2002, we identified patients with newly diagnosed ILC who underwent an MRI for extent-of-disease evaluation or contralateral screening. MRI findings separate from the primary tumor were biopsied and correlated with pathology by using MRI-guided biopsy. RESULTS: Sixty-two patients were identified. In all, 59 ipsilateral and 57 contralateral studies were performed. Suspicious lesions separate from the primary tumor were found by MRI in 38 (61%) of 62 patients. Eight patients were excluded from further analysis (seven elected mastectomy without biopsy; one had an unguided excision). Nineteen of 51 patients with an ipsilateral finding underwent MRI-guided biopsy, which revealed cancer in 11, or 22% of those imaged. Twenty of 53 patients with a contralateral finding underwent MRI-guided biopsy, which revealed cancer in 5, or 9% of those imaged. CONCLUSIONS: MRI of the breast identifies unsuspected multicentric or contralateral cancer in patients with ILC. These findings support the use of MRI in selected patients with ILC, particularly in the ipsilateral breast.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Lobular/patología , Imagen por Resonancia Magnética , Neoplasias Primarias Secundarias/patología , Biopsia/métodos , Neoplasias de la Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico , Selección de Paciente , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Internal mammary lymph-node (IMN) metastases in breast carcinomas have a major influence on survival, comparable with the influence of axillary lymph-node metastases (ALNM). Prospective, randomized trials have demonstrated that complete IMN dissection as part of extended radical mastectomy does not improve overall or disease-free survival. In the subset of patients with tumours 1cm or less in size and no ALNM, information on IMN status would provide important information. In these cases, the presence of IMN metastases would change the staging from stage I to stage IIIB, according to the current tumour, node and metastasis classification. More importantly, it would influence these patients' adjuvant treatment. Lymphatic mapping for sentinel lymph-node (SLN) biopsy has demonstrated extra-axillary drainage in up to 35% of patients. Recent reports have demonstrated the feasibility of internal mammary sentinel lymph-node (IM-SLN) biopsy. Here we review the general prognostic and clinical significance of tumor location and lymph-node metastases in breast cancer and discuss the specific factors associated with IMN identification, metastases and treatment in the pre-SLN and SLN eras. Based on our review, we propose an algorithm for a selective approach to IM-SLN in breast cancer.
Asunto(s)
Algoritmos , Neoplasias de la Mama/patología , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela , Femenino , Humanos , Metástasis Linfática , Arterias Mamarias , Estadificación de Neoplasias , Selección de Paciente , Pronóstico , Salud de la MujerRESUMEN
AIMS: The purpose was to identify the independent predictive factors of axillary lymph-node metastases (ALNM) in infiltrating ductal carcinoma (IFDC) and to create a prospective, validated statistical model to predict the likelihood of ALNM in patients in the present era of sentinel lymph-node (SLN) biopsy and enhanced histopathology. METHODS: Univariate and multivariate analyses of 13 clinicopathological variables (including tumour location) were performed to determine predictors of ALNM in 1659 eligible SLN biopsy procedures. A logistic regression model was developed and then prospectively validated on a second population of 187 subsequent consecutive procedures. RESULTS: Age, pathological tumour size, palpability, lymphovascular invasion (LVI), histological grade, nuclear grade, ductal histological subtype, tumour location (quadrant) and multifocality were associated with ALNM in univariate analyses (P < 0.001). Of these, only palpability and histological grade were not statistically associated with ALNM in the multivariate analysis (P> 0.05). The frequency of ALNM in upper-inner-quadrant (UIQ) tumours was 20.6%, compared with 33.2% for all other quadrants (P<0.0005). There was no statistical difference between UIQ and other-quadrant tumours in any clinicopathological variables analysed. The logistic regression model, developed based on the population of 1659, had the same accuracy, sensitivity, specificity, positive predictive value and negative predictive value when applied prospectively to the second population. CONCLUSION: Tumour size, LVI, age, nuclear grade, histological subtype, multifocality and location in the breast were independent predictive factors for ALNM in IFDC. ALNM is less frequent in UIQ tumours than in other-quadrant tumours. Our prospectively validated predictive model could be valuable in pre-operative patient discussions, although staging of the axilla in the individual patient remains necessary.
Asunto(s)
Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Metástasis Linfática/patología , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Axila , Neoplasias de la Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sesgo de Selección , Sensibilidad y Especificidad , Salud de la MujerRESUMEN
BACKGROUND: Among the advocates of blue dye, isotope, or combined dye-isotope mapping of the sentinel lymph node (SLN) for breast cancer, there is no universal consensus as to which technique is optimal and whether the relative value of each method changes with increasing experience. The objective of this study was to examine the relative contributions of blue dye and radioisotope to successful identification of the SLN as the SLN-mapping technique evolved over our first 2,000 consecutive cases. STUDY DESIGN: Using the first 2,000 consecutive SLN biopsy procedures for breast cancer, performed by eight surgeons (none previously experienced in SLN techniques) at one institution, using a combined technique of blue dye and isotope mapping, we report the institutional learning curve and the relative contributions of dye and isotope to identifying both the SLN and the positive SLN, by increments of 500 cases. RESULTS: Comparing the first 500 with the most recent 500 cases, success in identifying the SLN by blue dye did not improve with experience, although success in isotope localization steadily increased, from 86% to 94% (p < 0.00005). With the increasing success of isotope mapping, the marginal benefit of blue dye (the proportion of cases in which the SLN was identified by blue dye alone) steadily declined, from 9% to 3% (p = 0.0001). Parallel to this trend, the proportion of positive SLNs identified by blue dye did not change with experience (89% to 90%), but isotope success steadily increased, from 88% to 98% (p = 0.0015). The proportion of positive SLNs identified by blue dye alone declined from 12% to 2% (p = 0.0015). CONCLUSIONS: Using a combined technique of blue dye and radioisotope mapping, and with refinement of the radioisotope technique, we report 97% success identifying the SLN. Although we continue to recommend the use of both methods in SLN mapping for breast cancer, we observe with experience a declining marginal benefit for blue dye.
Asunto(s)
Neoplasias de la Mama/patología , Colorantes de Rosanilina , Biopsia del Ganglio Linfático Centinela/métodos , Azufre Coloidal Tecnecio Tc 99m , Neoplasias de la Mama/cirugía , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Inyecciones Intralesiones , Escisión del Ganglio Linfático , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Cintigrafía , Estudios RetrospectivosRESUMEN
PURPOSE: Risk-reducing surgery is an important option for women with BRCA1 and BRCA2 mutations. There are reports in the literature that insurance reimbursement for these procedures varies greatly. Because health insurance coverage significantly affects medical decision-making, current information regarding reimbursement practices of third-party payers is needed. METHODS: Retrospective study of hospital billing records of 38 women with documented BRCA1 or BRCA2 mutations who underwent either a risk-reducing mastectomy or a risk-reducing oophorectomy between March 1, 1997, and July 30, 2000. RESULTS: Complete billing and reimbursement information was available for 35 women undergoing a total of 39 risk-reducing surgeries. A total of 38 of 39 (97%) risk-reducing surgeries were covered in full, less applicable coinsurance and deductibles. The rate of insurance reimbursement did not vary with type of insurance, personal history of cancer, or type of procedure. CONCLUSION: Insurance carriers reimbursed the vast majority of BRCA mutation carriers undergoing risk-reducing surgery.
Asunto(s)
Neoplasias de la Mama/prevención & control , Cobertura del Seguro/estadística & datos numéricos , Reembolso de Seguro de Salud/estadística & datos numéricos , Mastectomía/economía , Neoplasias Ováricas/prevención & control , Ovariectomía/economía , Adulto , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/cirugía , Toma de Decisiones , Femenino , Genes BRCA1 , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Heterocigoto , Registros de Hospitales , Humanos , Programas Controlados de Atención en Salud/economía , Persona de Mediana Edad , Mutación , New York , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Estudios Retrospectivos , Factores de RiesgoRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/patología , Mama/patología , Radioisótopos/administración & dosificación , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Anciano de 80 o más Años , Axila/cirugía , Reacciones Falso Negativas , Femenino , Humanos , Inyecciones , Inyecciones Intradérmicas , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios RetrospectivosAsunto(s)
Neoplasias de la Mama/patología , Carcinoma in Situ/patología , Carcinoma Intraductal no Infiltrante/patología , Biopsia con Aguja , Neoplasias de la Mama/diagnóstico , Carcinoma Intraductal no Infiltrante/diagnóstico , Femenino , Humanos , Estadificación de Neoplasias , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Although the technique of sentinel lymph node (SLN) biopsy in breast cancer is not fully standardized, an increasing number of centers map the SLN by using radioisotope supplemented by blue dye, and most have injected isotope on the day of surgery. Here we directly compare the results of same-day and day-before isotope injection in a large series of breast cancer patients having SLN biopsy with our mature technique. METHODS: Starting with our 961st SLN procedure for breast cancer, 1320 consecutive patients had SLN biopsy after the injection of unfiltered 99mTc-labeled sulfur colloid given as a single-site, low-volume (0.05 ml) intradermal injection: 933 on the day of surgery (1-day protocol) and 387 on the day before (2-day protocol). All had intraparenchymal injection of blue dye. RESULTS: The two groups were comparable in age, tumor location, histopathologic characteristics, and number of SLNs identified. LSG taken at 2 hours in the 2-day protocol was positive more often than LSG performed at 30 minutes in the 1-day protocol, and nonaxillary sites of lymphatic drainage were seen in <1% of each group. Absolute isotope counts and the ratio of SLN to axillary background counts were similar. Isotope localization of the SLN succeeded in a comparable fraction of patients, as did SLN identification overall. CONCLUSIONS: The results of SLN mapping with same-day and day-before injection of radioisotope are virtually identical. The logistical advantages of day-before injection do not compromise the success of the procedure.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma/patología , Carcinoma/secundario , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela/métodos , Adulto , Anciano , Biopsia con Aguja , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Carcinoma/diagnóstico por imagen , Carcinoma/cirugía , Femenino , Humanos , Inyecciones Intradérmicas , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Cuidados Preoperatorios , Probabilidad , Estudios Prospectivos , Cintigrafía , Sensibilidad y Especificidad , Tecnecio/administración & dosificación , Factores de TiempoRESUMEN
BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial demonstrated that tamoxifen reduces the incidence of new breast cancers by 49% in women at increased risk for breast cancer development. Tamoxifen does have side effects, however, including marginally increased risks of endometrial cancer and thromboembolic events. In this study, women at increased risk for breast cancer development were offered tamoxifen. Their knowledge of tamoxifen as a chemopreventive agent was assessed, and factors influencing their acceptance of tamoxifen and willingness to take it were determined. METHODS: Forty-three patients were identified who qualified to take tamoxifen for primary prevention. Patients qualified by having at least a 1.7% 5-year risk of developing breast cancer, the criteria for entry into the NSABP P-1 trial. Patients initially completed questionnaires designed to assess their knowledge of tamoxifen and its associated risks and benefits. Patients were then provided neutral educational sessions and literature delineating the actual risks and benefits of tamoxifen. Subsequently, patients' decisions regarding taking tamoxifen were reassessed. RESULTS: Mean patient age was 52.8 years, with a range of 39 to 74 years. Ten patients (23.2%) qualified based on the presence of lobular carcinoma in situ (LCIS), seven patients (16.3%) qualified based on increased risk secondary to age >60 years, and 26 patients (60.5%) age range 35 to 59 qualified based on risk profiles demonstrating significantly increased risk. Of the total 43 patients, two (4.7%) elected to start taking tamoxifen. Fifteen patients (34.8%) declined immediately, and 26 patients (60.5%) were undecided initially but ultimately declined. Educational sessions did not influence patients' decisions. Fear of side effects, including endometrial cancer, thromboembolic events, and menopausal symptoms, was the most commonly cited reason for declining to take tamoxifen. CONCLUSIONS: In this study, the vast majority of patients at increased risk for breast cancer perceived that the risks of taking tamoxifen outweighed the benefits and declined to take it.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/prevención & control , Tamoxifeno/uso terapéutico , Adulto , Anciano , Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/psicología , Carcinoma in Situ/prevención & control , Carcinoma in Situ/psicología , Carcinoma Lobular/prevención & control , Carcinoma Lobular/psicología , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Persona de Mediana Edad , Encuestas y Cuestionarios , Tamoxifeno/efectos adversos , Negativa del Paciente al Tratamiento/psicologíaRESUMEN
BACKGROUND: Radioisotope mapping is an essential technical component of sentinel lymph node (SLN) biopsy, and most authors define isotope success by an arbitrary threshold SLN-to-background ratio. Few studies have examined the degree to which the relative level of SLN counts correlates with the presence of metastasis. Having removed the SLN with the highest counts, how far should the surgeon persist in removing additional SLN which contain much lower levels of isotope? METHODS: We performed SLN biopsy, using both radioisotope and blue dye, in 2285 consecutive patients with stage I-II breast cancer. Successful isotope localization was defined as an ex vivo SLN-to-axillary background count ratio of at least 4:1, and enhanced pathologic analysis (serial sections and immunohistochemistry) was used throughout. RESULTS: Among the 1566 patients with more than one SLN site identified, the SLN contained metastasis in 463 (30%). In 369 (80%) of these SLN-positive cases, the SLN with the highest count contained tumor, but in 94 (20%) it was benign. Among these 94: (1) the counts of the hottest benign SLN exceeded those of the histologically positive SLN by a ratio of at least 10:1 in 31% (29 of 94) of cases, (2) the counts of the positive SLN were < 4:1 those of the axillary background in 16% (15 of 94) of cases, and (3) blue dye failed to identify 27% of positive SLN. No optimum ratio of SLN-to-SLN or SLN-to-background counts identified the positive SLN in all cases. CONCLUSION: Although the SLN with the highest counts is positive in 80% of breast cancer patients with multiple SLN, neither a relatively high isotope count nor the presence of blue dye consistently predict SLN positivity in all breast cancer patients. For maximum accuracy, SLN biopsy requires (1) the removal of all nodes containing isotope regardless of the relative magnitude of counts, (2) the concurrent use of blue dye to salvage those procedures in which isotope fails, and (3) the removal of all clinically suspicious non-SLN.
Asunto(s)
Neoplasias de la Mama/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico por imagen , Niño , Femenino , Humanos , Metástasis Linfática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Cintigrafía , Radiofármacos , Colorantes de Rosanilina , Biopsia del Ganglio Linfático Centinela/métodos , Azufre Coloidal Tecnecio Tc 99mRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/patología , Metástasis de la Neoplasia/patología , Adulto , Anciano , Apoptosis , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/metabolismo , División Celular , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Persona de Mediana Edad , Neovascularización Patológica/patología , Factor de von Willebrand/análisisRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma in Situ/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Metástasis Linfática/patología , Estadificación de Neoplasias/métodos , Estadificación de Neoplasias/normas , Selección de Paciente , Biopsia del Ganglio Linfático Centinela/métodos , Biopsia del Ganglio Linfático Centinela/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Radiofármacos , Colorantes de Rosanilina , Sensibilidad y Especificidad , Azufre Coloidal Tecnecio Tc 99mAsunto(s)
Neoplasias de la Mama/genética , Genes BRCA1/genética , Proteínas de Neoplasias/genética , Factores de Transcripción/genética , Animales , Proteína BRCA2 , Neoplasias de la Mama/epidemiología , Femenino , Citometría de Flujo , Genes Supresores de Tumor , Genes p53/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Síndrome de Li-Fraumeni , Mastectomía , Mastectomía Segmentaria , Mutación , Neoplasias Ováricas/genética , Ovariectomía , Penetrancia , Síndrome de Peutz-Jeghers/genética , Vigilancia de la Población , Factores de RiesgoRESUMEN
TP53 is the most commonly mutated tumor suppressor gene in human cancers. The amplification and overexpression of HDM2 plays a role in tumorigenesis via inactivation of p53-dependent cell cycle arrest. p14ARF, an alternate transcript of the INK4A tumor suppressor locus, prevents hdm2-induced transcriptional silencing of p53 by binding hdm2. The role of this p14ARF-hdm2-p53 regulatory pathway in breast carcinoma is unknown. We hypothesized that p14ARF mutations and HDM2 gene amplification may be alternative mechanisms of p53 inactivation in breast cancer. Mutational analysis of TP53 (exons 5-9) and exon 1beta of pl4ARF was performed by PCR-SSCP and putative mutations were confirmed by sequencing. p14ARF mRNA expression was evaluated by RT-PCR and the presence of HDM2 gene amplification by differential PCR. Among the cell lines, 7/14 (50%) harbored TP53 mutations and 2/14 (14%) had a deletion ofp14ARF exon 1beta with no detectable p14ARF mRNA. None demonstrated HDM2 gene amplification. TP53 mutations were identified in 7/36 (19%) breast tumors and HDM2 amplification in 2/30 (7%) tumors. All the tumors contained an intact p14ARF exon 1beta with corresponding expression of the mRNA. Alterations in the various components of this regulatory pathway were identified in nine (64%) cell lines and 25% of the 36 breast cancers with TP53 mutation being the predominant aberration. Although p14ARF mutations and HDM2 gene amplification appear to be uncommon events in breast carcinoma, deregulation of this pathway may occur via alternative mechanisms in breast carcinogenesis.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma/genética , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Genes p53/genética , Proteínas Nucleares , Proteínas/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias de la Mama/patología , Carcinoma/patología , Ciclo Celular , Transformación Celular Neoplásica , Análisis Mutacional de ADN , Exones , Femenino , Humanos , Proteínas Proto-Oncogénicas c-mdm2 , ARN Mensajero , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Proteína p14ARF Supresora de TumorRESUMEN
Surgery is the most effective therapeutic intervention available for the treatment of breast cancer. It has been responsible for obtaining local control and long-term disease-free intervals in more patients over the past century than any other treatment modality. Trends toward earlier stage at diagnosis are likely to increase the importance of surgery and to secure its central role in the treatment of this disease. Unfortunately, during the 1990s the value of excellent local control of breast cancer has been minimized as the disease has come to be considered systemic from inception and as the results of adjuvant-therapy trials in patients with early-stage breast cancer have revealed survival advantages in patients receiving systemic therapy. Only rarely is it acknowledged that surgery alone achieves long-term disease-free states in 70% to 80% of all patients. At the core of this paradigmatic controversy is management of the axilla. The status of the axilla remains the most powerful predictor of outcome in patients with invasive carcinoma of the breast, and it is likely that a small but identifiable subset of patients obtains a survival benefit from the removal of disease-containing nodes. It is believed that no benefit is derived from the removal of negative nodes, and indeed there are even patients in whom complete elimination of the exploration of the axilla may be considered-all of which underscores the need to investigate the axilla selectively. Lymphatic mapping and sentinel lymph node (SLN) biopsy represents the most exciting development to date toward this end. The challenge today, as we move closer to a selective approach to the axilla, is to ensure that patients with positive nodes have those nodes identified and removed and patients with negative nodes experience minimal disturbance of their axilla.
Asunto(s)
Neoplasias de la Mama/patología , Escisión del Ganglio Linfático/métodos , Axila , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Estadificación de Neoplasias , Pronóstico , Biopsia del Ganglio Linfático CentinelaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma/genética , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Cromosomas Humanos Par 9/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Genes p16 , Proteínas Supresoras de Tumor , Southern Blotting , Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma/patología , Proteínas Portadoras/biosíntesis , Islas de CpG , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Exones/genética , Femenino , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Polimorfismo Conformacional Retorcido-Simple , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Eliminación de Secuencia , Células Tumorales Cultivadas , Proteínas Virales/biosíntesis , Proteínas Virales/genéticaRESUMEN
BACKGROUND: Fifty percent of patients with sentinel lymph node (SLN) metastases have no metastatic disease in non-SLNs on axillary lymph node dissection (ALND). The goal of this study is to determine which patients have metastatic disease limited to the SLN, and, therefore, may not require completion ALND. METHODS: Of the first 1000 patients undergoing SLN biopsy at Memorial Sloan-Kettering Cancer Center, using a combined blue dye and isotope technique, 231 (26%) had positive SLN. Of these, 206 underwent completion ALND. They are the study group for this report. RESULTS: The likelihood of non-SLN metastasis was inversely related to three clinicopathologic variables: tumor size < or = 1.0 cm; absence of lymphovascular invasion (LVI); and SLN micrometastases (< or = 2 mm). None of 24 patients with all three predictive factors had non-SLN metastases, whereas 58% of patients with none of the factors had disease in the non-SLN. CONCLUSION: Patients with small breast cancers, no LVI, and SLN micrometastases have a low risk of non-SLN metastases, and may not require completion ALND.
Asunto(s)
Neoplasias de la Mama/patología , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Axila , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/secundario , Carcinoma Ductal de Mama/cirugía , Femenino , Secciones por Congelación , Humanos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Cintigrafía , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The hypothesis that sentinel lymph node (SLN) mapping in breast cancer patients is optimized by combining blue dye and isotope is reasonable and intuitive. Despite this, few studies examine in detail the factors contributing to the success of these techniques, either individually or in combination. METHODS: During a time period of 21/2 years, 1000 consecutive patients at Memorial Sloan-Kettering Cancer Center had SLN mapping performed by using both blue dye and isotope, with preoperative lymphoscintigraphy (LSG). Among the 966 patients with invasive cancer, 12 variables were examined for their correlation with the success of SLN localization by blue dye, by isotope, and by the combined method, using univariate and multivariate models. RESULTS: By univariate analysis, blue dye success was more frequent in association with: a positive LSG (P = .02), age < or = 60 (P < .0005), a previous surgical biopsy (P = .03), and an outer quadrant tumor (P < .0005). Isotope success was more frequent with a positive LSG (P < .0005), age < or = 60 (P = .004), and intradermal isotope injection (P < .0005). Combined (dye and/or isotope) success was more frequent when there was a positive LSG (P < .0005), age < or = 60 (P = .006) and intradermal isotope injection (P < .0005). In multivariate analysis, blue dye success remained uniquely associated with outer quadrant tumor location (P < .0005), and isotope success was uniquely associated with intradermal isotope injection (P = .012). Combined success was more frequent with a positive LSG (P < .0005), age < or = 60 (P = .033), and intradermal isotope injection (P = .003). CONCLUSIONS: The five variables associated with successful SLN localization by blue dye or by isotope overlap but are not identical. Only three of these, intradermal isotope injection, a positive LSG, and age < 60, predicted success by the dye-isotope combination in the multivariate model. Dye and isotope complement each other, and SLN biopsy for breast cancer should use both.