RESUMEN
PURPOSE: Breast fibroglandular tissue (FGT), as visualized on a mammogram (mammographic density, MD), is one of the strongest known risk factors for breast cancer. FGT is also visible on breast MRI, and increased background parenchymal enhancement (BPE) in the FGT has been identified as potentially a major breast cancer risk factor. The aim of this exploratory study was to examine the biologic basis of BPE. METHODS: We examined the unaffected contra-lateral breast of 80 breast cancer patients undergoing a prophylactic mastectomy before any treatment other than surgery of their breast cancer. BPE was classified on the BI-RADS scale (minimal/mild/moderate/marked). Slides were stained for microvessel density (MVD), CD34 (another measure of endothelial density), glandular tissue within the FGT and VEGF. Spearman correlations were used to evaluate the associations between BPE and these pathologic variables. RESULTS: In pre-menopausal patients, BPE was highly correlated with MVD, CD34 and glandular concentration within the FGT, and the pathologic variables were themselves highly correlated. The expression of VEGF was effectively confined to terminal duct lobular unit (TDLU) epithelium. The same relationships of the four pathologic variables with BPE were seen in post-menopausal patients, but the relationships were much weaker and not statistically significant. CONCLUSION: The strong correlation of BPE and MVD together with the high correlation of MVD with glandular concentration seen in pre-menopausal patients indicates that increased breast cancer risk associated with BPE in pre-menopausal women is likely to result from its association with increased concentration of glandular tissue in the FGT. The effective confinement of VEGF expression to the TDLUs shows that the signal for MVD growth arises directly from the glandular tissue. Further studies are needed to understand the basis of BPE in post-menopausal women.
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Neoplasias de la Mama/patología , Mama/patología , Imagen por Resonancia Magnética , Tejido Parenquimatoso/patología , Adulto , Mama/diagnóstico por imagen , Densidad de la Mama/fisiología , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Humanos , Mamografía , Persona de Mediana Edad , Tejido Parenquimatoso/diagnóstico por imagen , Factores de RiesgoRESUMEN
BACKGROUND: The surgical management of mammary intraductal papilloma without atypia (IDP) identified at core-needle biopsy (CNB) is controversial. This study assessed the rate of upgrade to carcinoma at surgical excision (EXC). METHODS: This study identified women with a CNB diagnosis of intraductal papilloma without atypia or carcinoma at a cancer center between 2003 and 2013. Radiologic-pathologic concordance was assessed for all cases, and discordant cases were excluded. The radiologic and clinicopathologic features of patients with a CNB diagnosis of IDP were correlated with an upgrade to carcinoma at EXC. RESULTS: The study population consists of 189 women with 196 IDPs; 166 women (171 IDPs) underwent EXC. The upgrade rate was 2.3% (4 of 171). The upgraded lesions were 2 invasive lobular carcinomas and 2 cases of ductal carcinoma in situ (DCIS). One case of DCIS involved the residual IDP, whereas the other 3 carcinomas were ≥ 8 mm away. Twenty-four women (25 IDPs) did not undergo EXC and had stable imaging on follow-up (median, 23.5 months). CONCLUSIONS: The upgrade rate at EXC for IDPs diagnosed at CNB with radiologic-pathologic concordance was 2.3%. These findings suggest that observation is appropriate for patients with radiologic-pathologic concordant CNB yielding IDP, regardless of its size. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2819-2827. © 2016 American Cancer Society.
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Neoplasias de la Mama/patología , Papiloma Intraductal/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Gruesa/métodos , Neoplasias de la Mama/cirugía , Femenino , Humanos , Persona de Mediana Edad , Papiloma Intraductal/cirugíaRESUMEN
Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER-2 overexpression status for the period 2000-2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000-2003] to 8.7% [2008-2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER-2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER-2-positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12-year period 2000-2011 and no increase in the proportion of young patients presenting with metastatic disease.
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Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Adulto , Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/epidemiología , Carcinoma Intraductal no Infiltrante/patología , Femenino , Pruebas Genéticas/estadística & datos numéricos , Humanos , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Centros de Atención Terciaria/estadística & datos numéricosRESUMEN
PURPOSE: To determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT. METHODS: This retrospective study was performed under IRB waiver. Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET. RESULTS: Following screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET. CONCLUSION: The histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC.
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Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Fluorodesoxiglucosa F18 , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estudios RetrospectivosRESUMEN
BACKGROUND: Whether extracapsular extension (ECE) of tumor in the sentinel lymph node (SLN) is an indication for axillary lymph node dissection (ALND) in patients managed by American College of Surgeons Oncology Group Z0011 criteria is controversial. Here we examine the correlation between ECE in the SLN and disease burden in the axilla. METHODS: Patients meeting Z0011 clinicopathologic criteria (pT1-2, cN0 with <3 positive SLNs) were selected from a prospectively maintained database (2006-2013). Chart review documented the presence and extent of ECE. Neoadjuvant chemotherapy patients were excluded. Comparisons were made by presence and extent (≤2 vs. >2 mm) of ECE. RESULTS: Of 11,730 patients, 778 were pT1-2, cN0 with <3 positive SLNs without ECE, and 331 (2.8 %) had ECE. Of these, 180 had ≤2 mm and 151 had >2 mm of ECE. Patients with ECE were older (57 vs. 54 years; p = 0.001) and had larger (2.0 vs. 1.7 cm; p < 0.0001), multifocal (p = 0.006), hormone receptor-positive tumors (p = 0.0164) with lymphovascular invasion (p < 0.0001). Presence and extent of ECE were associated with greater axillary disease burden; 20 and 3 % of patients with and without ECE, respectively, had ≥4 additional positive nodes at completion ALND (p < 0.0001), and 33 % of patients with >2 mm ECE had ≥4 additional positive nodes at completion ALND, compared with 9 % in the <2 mm group (p < 0.0001). On multivariate analysis, >2 mm of ECE was the strongest predictor of ≥4 positive nodes at completion ALND (odds ratio 14.2). CONCLUSIONS: Presence and extent of ECE were significantly correlated with nodal tumor burden at completion ALND, thus suggesting that >2 mm of ECE may be an indication for ALND or radiotherapy when applying Z0011 criteria to patients with metastases in <3 SLNs. ECE reporting should be standardized to facilitate future studies.
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Neoplasias de la Mama/patología , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/cirugía , Femenino , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/cirugía , Mastectomía Segmentaria , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Carga Tumoral , Adulto JovenRESUMEN
Signal transducer and activator of transcription 3 (STAT3) plays a central role in the activation of multiple oncogenic pathways. Splicing variant STAT3ß uses an alternative acceptor site within exon 23 that leads to a truncated isoform lacking the C-terminal transactivation domain. Depending on the context, STAT3ß can act as a dominant-negative regulator of transcription and promote apoptosis. We show that modified antisense oligonucleotides targeted to a splicing enhancer that regulates STAT3 exon 23 alternative splicing specifically promote a shift of expression from STAT3α to STAT3ß. Induction of endogenous STAT3ß leads to apoptosis and cell-cycle arrest in cell lines with persistent STAT3 tyrosine phosphorylation compared with total STAT3 knockdown obtained by forced splicing-dependent nonsense-mediated decay (FSD-NMD). Comparison of the molecular effects of splicing redirection to STAT3 knockdown reveals a unique STAT3ß signature, with a down-regulation of specific targets (including lens epithelium-derived growth factor, p300/CBP-associated factor, CyclinC, peroxisomal biogenesis factor 1, and STAT1ß) distinct from canonical STAT3 targets typically associated with total STAT3 knockdown. Furthermore, similar in vivo redirection of STAT3 alternative splicing leads to tumor regression in a xenograft cancer model, demonstrating how pharmacological manipulation of a single key splicing event can manifest powerful antitumorigenic properties and validating endogenous splicing reprogramming as an effective cancer therapeutic approach.
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Empalme Alternativo/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Animales , Western Blotting , Línea Celular , Cartilla de ADN/genética , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones , Ratones Desnudos , Análisis por Micromatrices , Oligonucleótidos Antisentido/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Non-mammary metastases to the breast and axilla are rare occurrences. However, they are important diagnostic considerations as their treatment and prognosis differ significantly from primary breast cancer. Between 1990 and 2010, we identified a total of 85 patients, 72 women and 13 men, with non-mammary malignancies involving the breast, axilla, or both. The tumor types consisted of carcinoma (58%), melanoma (22%) and sarcoma (20%). Ovary was the most common site of origin for carcinoma, and metastatic high-grade ovarian serous carcinoma was most frequently misdiagnosed as a primary breast carcinoma. Melanoma was the single most common non-carcinomatous tumor type to involve the breast and/or axilla, and uterine leiomyosarcoma was the most common type of sarcoma. Most patients (77%) had other metastases at the time of diagnosis of the tumor, but in 11% the breast or axillary lesion was the first presentation. Without a clinical history, non-mammary metastases were difficult to diagnose because the majority of cases presented with a solitary nodule and lacked pathognomonic pathologic features. There were, however, certain recurrent histological findings identified, such as the often relatively well-circumscribed growth pattern of the metastatic lesion surrounded by a fibrous pseudocapsule, and the absence of an in situ carcinoma. Overall, these patients had poor survival; 96% of patients with follow-up available are dead of disease, with a median survival of 15 months after the diagnosis of the breast or axillary lesion. This finding emphasizes the need to accurately identify these tumors as metastases in order to avoid unnecessary procedures and treatments in these patients.
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Axila/patología , Neoplasias de la Mama/secundario , Carcinoma/secundario , Melanoma/secundario , Sarcoma/secundario , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama Masculina/secundario , Carcinoma/mortalidad , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Sarcoma/mortalidad , Análisis de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
Focal extravasated mucin (EM) with benign or atypical epithelium is a rare finding at breast core needle biopsy (CNB) and usually prompts surgical excision to rule out mucin-producing carcinoma. In the largest detailed series to date, we assessed surgical outcomes in lesions yielding EM with atypical or nonatypical epithelium at CNB. With IRB approval, we retrospectively reviewed 28 consecutive atypical and nonatypical CNBs with EM that underwent surgical excision at our center over a 22-year period. CNB imaging and pathologic findings were concordant if pathology sufficiently explained the radiologic features of the lesions. Pathologic findings in CNB and excision specimens were correlated. Statistical analysis was performed. CNBs sampled mammographic calcifications in 25/28 (89%) women and a mass in 3/28 (11%). All cases had concordant pathologic and imaging findings. At CNB, the epithelium associated with EM was atypical in 18/28 (64%) lesions and nonatypical in 10 (36%). Cancer (one mucinous carcinoma; three ductal carcinoma in situ) was present in 4/28 excision specimens (14%; 95% confidence intervals [CI], 4%-33%). All carcinomas were in lesions with epithelial atypia at CNB (4/18; 22%; 95% CI, 6%-48%) versus none (0/10; 0%; 95% CI, 0%-31%) in nonatypical lesions at CNB; this difference was not statistically significant (p = 0.3). Surgery is warranted for lesions yielding EM with atypia at CNB due to the high (22%) prevalence of cancer. Our data suggest that surgical excision of lesions yielding EM without epithelial atypia at CNB may not be necessary provided that imaging and pathologic findings are concordant.
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Biopsia con Aguja Gruesa/métodos , Mama/patología , Mucinas , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Ultrasonografía IntervencionalRESUMEN
Introduction: The presence of positive margins following tumor resection is a frequent cause of re-excision surgery. Nondestructive, real-time intraoperative histopathological imaging methods may improve margin status assessment at the time of surgery; optical coherence tomography (OCT) has been identified as a potential solution but has not been tested with the most common tissue types in surgical oncology using a single, standardized platform. Methods: This was a proof-of-concept evaluation of a novel device that employs wide-field OCT (WF-OCT; OTIS 2.0 System) to image tissue specimens. Various cadaveric tissues were obtained from a single autopsy and were imaged with WF-OCT then processed for permanent histology. The quality and resolution of the WF-OCT images were evaluated and compared to histology and with images in previous literature. Results: A total of 30 specimens were collected and tissue-specific microarchitecture consistent with previous literature were identified on both WF-OCT images and histology slides for all specimens, and corresponding sections were correlated. Application of vacuum pressure during scanning did not affect specimen integrity. On average, specimens were scanned at a speed of 10.3 s/cm2 with approximately three features observed per tissue type. Conclusion: The WF-OCT images captured in this study displayed the key features of the most common human tissue types encountered in surgical oncology with utility comparable to histology, confirming the utility of an FDA-cleared imaging platform. With further study, WF-OCT may have the potential to bridge the gap between the immediate information needs of the operating room and the longer timeline inherent to histology workflow.
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Márgenes de Escisión , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodosRESUMEN
Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia are rare lesions, found incidentally in breast biopsies. They have been regarded traditionally as high-risk lesions, but recent genetic evidence and follow-up data indicates that they also constitute nonobligate precursors of invasive carcinoma. In addition to 16q deletion, a genetic alteration common across the spectrum of low-grade mammary epithelial neoplasia, lobular lesions consistently demonstrate deletion or functional inactivation of the CDH1/E-cadherin gene, with consequent loss of membranous immunoreactivity for the same antigen. The use of E-cadherin in the evaluation of solid mammary carcinoma in situ with ambiguous morphology has identified variants of LCIS characterized by massive acinar expansion and necrosis with calcifications, and/or marked nuclear pleomorphism or signet ring cell formation. In contrast to classic LCIS, these rare lesions are detected mammographically and often occur in association with invasive carcinoma. Genetic analysis of these tumors has confirmed lobular lineage and demonstrated more extensive chromosomal alterations than in classic LCIS. A pleomorphic variant of invasive lobular carcinoma has also been described. Here, we summarize our evolving knowledge of in situ and invasive lobular neoplasia and highlight the implications for patient management.
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Neoplasias de la Mama/patología , Carcinoma Lobular/patología , Antígenos CD , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/terapia , Aberraciones Cromosómicas , Femenino , HumanosRESUMEN
The aim of core needle biopsy (CNB) is to diagnose a breast abnormality prior to open surgical excision. The radiology-pathology correlation helps in interpretation of pathologic findings and is greatly assisted by specimen radiology of all cores performed for calcifications, separation of cores containing calcification from those without, and the availability of the specimen radiograph to the pathologist at the time of reporting. The nature of the imaging abnormality should also be clearly conveyed. CNB is processed in a routine manner for paraffin embedding with preservation of sufficient material in the block for further studies as needed. Possible pitfalls include the loss of calcifications at the time of section cutting, calcium remained in the formalin of the specimen container, and failure to recognize calcium oxalate deposition in the CNB. The challenges of CNB interpretation are complicated by the availability of only limited material, but are generally similar to those encountered in open surgical excision specimens. This discussion focuses on high-risk lesions and lesions that raise management issues. The most prudent approach for the pathologist is to provide sufficient information to prompt a surgical excision without overdiagnosing the lesion, thus placing the patient into the appropriate therapeutic algorithm.
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Neoplasias de la Mama/patología , Mama/patología , Biopsia con Aguja Fina , Carcinoma/patología , Cicatriz/patología , Femenino , Fibroadenoma/patología , Humanos , Hiperplasia/patologíaRESUMEN
Acinic cell carcinoma of breast is a rare subtype of triple-negative breast carcinoma and demonstrates extensive morphologic overlap with acinic cell carcinoma of the salivary gland. In this study, we perform a detailed morphologic and immunohistochemical description of 2 cases of this rare entity and undertake a comprehensive review of all reported cases of breast acinic cell carcinoma in the English language literature to date. One-third of reported cases of breast acinic cell carcinoma have been associated with the presence of a ductal carcinoma not otherwise specified component, which is frequently poorly differentiated. Breast acinic cell carcinoma can demonstrate focal morphologic features similar to microglandular adenosis; these areas are frequently negative for collagen IV and laminin on immunohistochemistry. The true relationship between these 2 entities remains unclear, but we advocate that microglandular adenosis-like areas at the periphery of a breast acinic cell carcinoma should be considered part of the carcinomatous process and re-excised if this process extends to the initial surgical margins.
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Neoplasias de la Mama/patología , Carcinoma de Células Acinares/patología , Femenino , Enfermedad Fibroquística de la Mama/patología , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patologíaRESUMEN
INTRODUCTION: Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors. PATIENTS AND METHODS: Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and < 1% negative; HSP90 and HSP70: 0, 1 + negative, and 2+, 3 + positive; phosphatase and tensin homolog: 0 negative, 1 reduced, and 2 positive; HER2: 0, 1 + negative, 2 + equivocal, 3 + positive; and epidermal growth factor receptor: 0 negative, and 1+, 2+, 3 + positive. The expression of the biomarker panel was correlated with clinical benefit (CB) (defined by overall response [ORR] or CB by the "8-week" scan) using Fisher exact test. RESULTS: Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status (P = .001). CONCLUSION: Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Adulto , Anciano , Biomarcadores Farmacológicos/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Receptores ErbB/metabolismo , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Fosfohidrolasa PTEN/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Adulto JovenRESUMEN
Optimal management of a lesion yielding radial scar (RS) without epithelial atypia on breast biopsy is controversial. In this single-institution study spanning 17 years, 53 patients with this biopsy diagnosis were evaluated in terms of clinical, radiologic, and pathologic features and outcomes. RSs were categorized as either "incidental" or as the "targeted" lesion according to defined criteria. Of 48 patients who underwent surgical excision after a diagnosis of RS on biopsy, only 1 had an "upgrade" diagnosis of malignancy (2%). No "incidental" RS was associated with the presence of malignancy on surgical excision. Meta-analysis of 20 RS excision studies demonstrated an overall upgrade rate of 10.4%, with a higher rate in patients with a diagnosis of RS with atypia (26%). The upgrade rate for RS without atypia was 7.5% overall. The lower rate of upgrade to malignancy in this study (2%) is likely related to the thorough radiologic-pathologic review undertaken. In the setting of multidisciplinary agreement and careful radiologic-pathologic correlation, it may be appropriate for patients with a biopsy diagnosis of RS without atypia to forego surgical excision in favor of imaging follow-up.
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Enfermedades de la Mama/patología , Adulto , Anciano , Biopsia con Aguja , Enfermedades de la Mama/cirugía , Femenino , Humanos , Biopsia Guiada por Imagen , Persona de Mediana EdadRESUMEN
The limited translational value in clinic of analyses performed on 2-D cell cultures has prompted a shift toward the generation of 3-dimensional (3-D) multicellular systems. Here we present a spontaneously-forming in vitro cancer spheroid model, referred to as spheroids(MARY-X), that precisely reflects the pathophysiological features commonly found in tumor tissues and the lymphovascular embolus. In addition, we have developed a rapid, inexpensive means to evaluate response following drug treatment where spheroid dissolution indices from brightfield image analyses are used to construct dose-response curves resulting in relevant IC50 values. Using the spheroids(MARY-X) model, we demonstrate the unique ability of a new class of molecules, containing the caged Garcinia xanthone (CGX) motif, to induce spheroidal dissolution and apoptosis at IC50 values of 0.42 +/-0.02 µM for gambogic acid and 0.66 +/-0.02 µM for MAD28. On the other hand, treatment of spheroids(MARY-X) with various currently approved chemotherapeutics of solid and blood-borne cancer types failed to induce any response as indicated by high dissolution indices and subsequent poor IC50 values, such as 7.8 +/-3.1 µM for paclitaxel. Our studies highlight the significance of the spheroids(MARY-X) model in drug screening and underscore the potential of the CGX motif as a promising anticancer pharmacophore.
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Antineoplásicos/química , Evaluación Preclínica de Medicamentos/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Neoplasias/tratamiento farmacológico , Esferoides Celulares/metabolismo , Secuencias de Aminoácidos , Animales , Apoptosis , Línea Celular Tumoral , Garcinia/química , Humanos , Inmunohistoquímica , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Microscopía Confocal , Microscopía Fluorescente , Trasplante de Neoplasias , Células Tumorales Cultivadas/efectos de los fármacos , Xantonas/químicaRESUMEN
The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.
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Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Microtomía/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Técnicas de Cultivo de Tejidos/métodos , Humanos , Microambiente TumoralRESUMEN
INTRODUCTION: Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. AREAS COVERED: The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. EXPERT OPINION: The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.
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Antineoplásicos/uso terapéutico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Predicción , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Neoplasias/metabolismo , Resultado del TratamientoRESUMEN
Invasive breast cancers constitute a heterogeneous group of lesions. Although the most common types are ductal and lobular, this distinction is not meant to indicate the site of origin within the mammary ductal system. The main purpose of the identification of specific types of invasive breast carcinoma is to refine the prediction of likely behavior and response to treatment also offered by the other major prognostic factors, including lymph node stage, histologic grade, tumor size, and lymphovascular invasion.
Asunto(s)
Neoplasias de la Mama/patología , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Papilar/patología , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma Neuroendocrino/patología , Femenino , Humanos , Invasividad Neoplásica , Neoplasias Ductales, Lobulillares y Medulares/patología , Pronóstico , Carga TumoralRESUMEN
Mucinous micropapillary carcinoma of the breast, also described as "pure mucinous carcinoma with micropapillary pattern," has recently come to attention as an unusual form of invasive breast cancer exhibiting dual mucinous and micropapillary differentiation. Despite increasing awareness of this morphologic variant, its clinical significance has not yet been elucidated. Here, we present 15 additional examples of these rare tumors to highlight some important differences between mucinous micropapillary carcinoma of the breast and ordinary pure mucinous carcinomas. The key features of mucinous micropapillary carcinoma of the breast included (a) largely or entirely mucinous appearance (>90% mucinous morphology), (b) distinctive micropapillary arrangement of the neoplastic cells, (c) intermediate to high nuclear grade, (d) "hobnail" cells, and (e) frequent psammomatous calcifications. In contrast to ordinary pure mucinous carcinomas, 20% of mucinous micropapillary carcinomas of the breast were characterized by human epidermal growth factor receptor 2 positivity, and 23% were p53 positive. More than half of mucinous micropapillary carcinomas of the breast (60%) demonstrated lymphovascular invasion, sometimes extensive. Synchronous axillary lymph node metastases were detected in 33% of patients and, on 2 occasions, involved more than 10 nodes. With a median follow-up of 4.5 years, we identified 1 patient (7%) with chest wall recurrence of mucinous micropapillary carcinoma of the breast after mastectomy. We conclude that mucinous micropapillary carcinomas of the breast constitute a clinically aggressive subset of mucin-producing breast carcinomas characterized by an increased capacity for lymphatic invasion and regional lymph node metastasis, reflective of their dual phenotype. Recognition of the morphologic and biologic heterogeneity within breast cancer subtypes should allow for a more accurate classification of the individual tumors and better patient stratification for treatment.
Asunto(s)
Adenocarcinoma Mucinoso/patología , Neoplasias de la Mama/patología , Carcinoma Papilar/patología , Adenocarcinoma Mucinoso/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Carcinoma Papilar/metabolismo , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Persona de Mediana EdadRESUMEN
CONTEXT: Breast cancer is increasingly treated with neoadjuvant chemotherapy to improve surgical resectability and evaluate tumor response, which is assessed histopathologically. Several histopathologic classification systems have been previously described for assessment of treatment response. OBJECTIVES: To test performance in a side-by-side comparison of several histopathologic classification systems after neoadjuvant chemotherapy with clinical outcome. DESIGN: Sixty-two patients were enrolled in a randomized trial receiving sequential neoadjuvant chemotherapy with doxorubicin and paclitaxel. Histologic sections from the patients' tumors sampled before (core biopsy) and after treatment (excision or mastectomy) were reviewed. Histologic response was assessed following National Surgical Adjuvant Breast and Bowel Project protocol B18, Miller-Payne grading, Sataloff tumor and nodes, Residual Cancer Burden (RCB), and Residual Disease in Breast and Nodes (RDBN). Pathologic classification results were correlated with survival using Kaplan-Meier and Cox hazards regression with a median follow-up of 93 months. RESULTS: RDBN was associated with distant disease-free survival by univariate and multivariate analysis (P = .01 and .004, respectively), as were lymph node metastases (P = .02 and .01, respectively). Five patients (8%) had complete pathologic response after neoadjuvant chemotherapy, and none of them relapsed during the study period. Survival was shorter among patients with higher Residual Cancer Burden scores, but the associations were not significant. Miller-Payne grading and Sataloff tumor scores were not correlated with survival. CONCLUSIONS: Evaluation of breast specimens after neoadjuvant chemotherapy by the composite index RDBN correlates with long-term outcome. The residual disease in breast and nodes system is suitable for routinely processed pathology cases. This study confirms the importance of lymph node status after neoadjuvant chemotherapy and favorable outcome in patients with pathologic complete response.