Amorphous breast calcifications: is BI-RADS 4a appropriate?

Objective: To evaluate the positive predictive value (PPV) of amorphous calcifications and to analyze the imaging variables that could alter the risk of malignancy associated with this finding. Materials and Methods: This was a retrospective study of 138 stereotactically guided percutaneous vacuum-assisted biopsies of amorphous calcifications, performed between January 2012 and December 2017. All of the patients included were referred for radiological follow-up for a minimum of one year (if the histopathology showed a benign lesion) or for surgical treatment (if the histopathology showed malignancy or a lesion of uncertain malignant potential). Results: We found that the PPV of amorphous calcifications was 9.42%. However, most of the malignant amorphous calcifications were in cases of invasive carcinoma or high-grade ductal carcinoma in situ, indicating clinically relevant disease. The relative risk of malignancy associated with amorphous calcifications was 6.15 times higher in patients with a family or personal history of breast or ovarian cancer. Neither being postmenopausal nor having dense breasts was found to be predictive of malignancy in patients with amorphous calcifications. Conclusion: Amorphous calcifications in the breast had a PPV for malignancy of 9.42%, indicating the possibility of placing the finding in subcategory 4a, which requires histopathological analysis. Our finding that the risk of malignancy associated with this subtype of calcifications is up to 6.15 times higher in patients with a family or personal history of breast cancer warrants greater concern regarding the clinical, radiologic, and histopathologic correlations after biopsy.

Objetivo: Avaliar o valor preditivo positivo (VPP) das calcificações amorfas e possíveis variáveis clínicas e de imagem que possam influenciar no risco de malignidade deste achado de imagem. Materiais e Métodos: Foram revisados, retrospectivamente, 138 resultados de biópsias percutâneas estereotáxicas a vácuo de calcificações amorfas, entre janeiro de 2012 e dezembro de 2017. Todas as pacientes incluídas apresentavam seguimento radiológico mínimo de um ano (histopatológico benigno) ou tratamento cirúrgico (histopatológico maligno). Resultados: O VPP das calcificações amorfas foi de 9,42%. As lesões malignas corresponderam predominantemente a carcinomas invasivos, indicando doença clinicamente relevante. O risco relativo de malignidade das calcificações amorfas foi 6,15 vezes maior em pacientes com história familiar ou pessoal de neoplasia de mama ou ovário. Status pós-menopausa e mamas densas não foram preditores de malignidade nessas pacientes. Conclusão: As calcificações amorfas na mama apresentaram VPP de malignidade de 9,42%, sugerindo possibilidade de classificação do achado na subcategoria 4a, com necessidade de investigação histopatológica. Em pacientes com história familiar ou pessoal de câncer de mama, o risco de malignidade deste subtipo de calcificações pode ser até 6,15 vezes maior, justificando maior preocupação na correlação clínica, radiológica e histopatológica após biópsia.

Amorphous breast calcifications: is BI-RADS 4a appropriate? / Calcificações amorfas mamárias: BI-RADS 4a é adequado?

Abstract Objective: To evaluate the positive predictive value (PPV) of amorphous calcifications and to analyze the imaging variables that could alter the risk of malignancy associated with this finding. Materials and Methods: This was a retrospective study of 138 stereotactically guided percutaneous vacuum-assisted biopsies of amorphous calcifications, performed between January 2012 and December 2017. All of the patients included were referred for radiological follow-up for a minimum of one year (if the histopathology showed a benign lesion) or for surgical treatment (if the histopathology showed malignancy or a lesion of uncertain malignant potential). Results: We found that the PPV of amorphous calcifications was 9.42%. However, most of the malignant amorphous calcifications were in cases of invasive carcinoma or high-grade ductal carcinoma in situ, indicating clinically relevant disease. The relative risk of malignancy associated with amorphous calcifications was 6.15 times higher in patients with a family or personal history of breast or ovarian cancer. Neither being postmenopausal nor having dense breasts was found to be predictive of malignancy in patients with amorphous calcifications. Conclusion: Amorphous calcifications in the breast had a PPV for malignancy of 9.42%, indicating the possibility of placing the finding in subcategory 4a, which requires histopathological analysis. Our finding that the risk of malignancy associated with this subtype of calcifications is up to 6.15 times higher in patients with a family or personal history of breast cancer warrants greater concern regarding the clinical, radiologic, and histopathologic correlations after biopsy.

Resumo Objetivo: Avaliar o valor preditivo positivo (VPP) das calcificações amorfas e possíveis variáveis clínicas e de imagem que possam influenciar no risco de malignidade deste achado de imagem. Materiais e Métodos: Foram revisados, retrospectivamente, 138 resultados de biópsias percutâneas estereotáxicas a vácuo de calcificações amorfas, entre janeiro de 2012 e dezembro de 2017. Todas as pacientes incluídas apresentavam seguimento radiológico mínimo de um ano (histopatológico benigno) ou tratamento cirúrgico (histopatológico maligno). Resultados: O VPP das calcificações amorfas foi de 9,42%. As lesões malignas corresponderam predominantemente a carcinomas invasivos, indicando doença clinicamente relevante. O risco relativo de malignidade das calcificações amorfas foi 6,15 vezes maior em pacientes com história familiar ou pessoal de neoplasia de mama ou ovário. Status pós-menopausa e mamas densas não foram preditores de malignidade nessas pacientes. Conclusão: As calcificações amorfas na mama apresentaram VPP de malignidade de 9,42%, sugerindo possibilidade de classificação do achado na subcategoria 4a, com necessidade de investigação histopatológica. Em pacientes com história familiar ou pessoal de câncer de mama, o risco de malignidade deste subtipo de calcificações pode ser até 6,15 vezes maior, justificando maior preocupação na correlação clínica, radiológica e histopatológica após biópsia.

ABCG2 is a potential marker of tumor-initiating cells in breast cancer.

The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2(+) cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R (2) = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2(+) cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2(Up) breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2(+) cells in breast carcinomas is a marker of resistance to chemotherapy, and based on in vitro assays and the genetic profile, we show, for the first time, that ABCG2 protein can be used as an independent marker for TIC identification in breast cancer.

Volume of breast tissue excised during breast-conserving surgery in patients undergoing preoperative systemic therapy.

PURPOSE: We aimed to determine whether clinical examination could adequately ascertain the volume of tissue to be resected during breast-conserving surgery after neoadjuvant therapy. METHODS: We reviewed the clinical reports of 279 patients with histologically diagnosed invasive breast carcinomas treated with neoadjuvant therapy followed by surgery or with primary surgery alone. We estimated volumes of excised tissues, the volume of the tumor mass and the optimal volume required for excision based on 1 cm of clear margins. The actual excess of resected volume was estimated by calculating the resection ratio measured as the volume of the resected specimen divided by the optimal specimen volume. The study endpoints were to analyze the extent of tissue resection and to ascertain the effect of excess resected tissue on surgical margins in both groups of patients. RESULTS: The median tumor diameter was 2.0 and 1.5 cm in the surgery and neoadjuvant therapy groups, respectively. The median volume of resected mammary tissue was 64.3 cm³ in the primary surgery group and 90.7 cm³ in the neoadjuvant therapy group. The median resection ratios in the primary surgery and neoadjuvant therapy groups were 2.0 and 3.3, respectively (p<0.0001). Surgical margin data were similar in both groups. Comparison of the volume of resected mammary tissues with the tumor diameters showed a positive correlation in the primary surgery group and no correlation in the neoadjuvant therapy group. CONCLUSION: Surgeons tend to excise large volumes of tissue during breast-conserving surgery after neoadjuvant therapy, thereby resulting in a loss of the correlation between tumor diameter and volume of the excised specimen.

Expression of aldehyde dehydrogenase after neoadjuvant chemotherapy is associated with expression of hypoxia-inducible factors 1 and 2 alpha and predicts prognosis in locally advanced breast cancer.

OBJECTIVE: To analyze the expression of hypoxia-inducible factors (hypoxia-inducible factor 1A and hypoxia-inducible factor 2A) and aldehyde dehydrogenase proteins in patients with locally advanced breast carcinoma who were subjected to neoadjuvant chemotherapy. METHODS: We included 90 patients with histologically confirmed stage II and III breast carcinoma who were treated with neoadjuvant chemotherapy between 2000 and 2005. Immunohistochemistry for aldehyde dehydrogenase, hypoxia-inducible factor 1A, and hypoxia-inducible factor 2A was performed before and after neoadjuvant chemotherapy. We analyzed the influence of clinical and pathological features on clinical and pathological response, disease-free survival, and overall survival. RESULTS: An objective clinical response to neoadjuvant chemotherapy was observed in 80% of patients, with 12% showing a complete pathological response. Among all clinical and pathological parameters, only the expression of hypoxia-inducible factor 1A was associated with a pathological response. A positive association was found between expression of aldehyde dehydrogenase and that of hypoxia-inducible factor 1A before and after chemotherapy. Aldehyde dehydrogenase expression was associated with expression of hypoxia inducible-factor 2A in tumors after neoadjuvant treatment. In a univariate analysis, prognosis was influenced by age, pathological response, metastasis to axillary lymph nodes after neoadjuvant chemotherapy, overexpression of hypoxia-inducible factor 2, and the presence of aldehyde dehydrogenase-positive cells within the primary tumor after neoadjuvant chemotherapy. In a multivariate analysis, only age and the presence of aldehyde dehydrogenase-positive cells after chemotherapy were associated with reduced overall survival. CONCLUSION: The presence of aldehyde dehydrogenase-positive cells within the residual tumor after neoadjuvant chemotherapy is associated with an increase in the expression of hypoxia-inducible factor 2A and with poor prognosis in patients with locally advanced breast cancer.

Expression of aldehyde dehydrogenase after neoadjuvant chemotherapy is associated with expression of hypoxia-inducible factors 1 and 2 alpha and predicts prognosis in locally advanced breast cancer

OBJECTIVE: To analyze the expression of hypoxia-inducible factors (hypoxia-inducible factor 1A and hypoxia-inducible factor 2A) and aldehyde dehydrogenase proteins in patients with locally advanced breast carcinoma who were subjected to neoadjuvant chemotherapy. METHODS: We included 90 patients with histologically confirmed stage II and III breast carcinoma who were treated with neoadjuvant chemotherapy between 2000 and 2005. Immunohistochemistry for aldehyde dehydrogenase, hypoxia-inducible factor 1A, and hypoxia-inducible factor 2A was performed before and after neoadjuvant chemotherapy. We analyzed the influence of clinical and pathological features on clinical and pathological response, disease-free survival, and overall survival. RESULTS: An objective clinical response to neoadjuvant chemotherapy was observed in 80% of patients, with 12% showing a complete pathological response. Among all clinical and pathological parameters, only the expression of hypoxia-inducible factor 1A was associated with a pathological response. A positive association was found between expression of aldehyde dehydrogenase and that of hypoxia-inducible factor 1A before and after chemotherapy. Aldehyde dehydrogenase expression was associated with expression of hypoxia inducible-factor 2A in tumors after neoadjuvant treatment. In a univariate analysis, prognosis was influenced by age, pathological response, metastasis to axillary lymph nodes after neoadjuvant chemotherapy, overexpression of hypoxia-inducible factor 2, and the presence of aldehyde dehydrogenase-positive cells within the primary tumor after neoadjuvant chemotherapy. In a multivariate analysis, only age and the presence of aldehyde dehydrogenase-positive cells after chemotherapy were associated with reduced overall survival. CONCLUSION: The presence of aldehyde dehydrogenase-positive cells within the residual tumor after neoadjuvant chemotherapy is associated with an increase in the expression ...

Volume of breast tissue excised during breast-conserving surgery in patients undergoing preoperative systemic therapy / Volume de ressecção cirúrgica no tratamento conservador do câncer de mama em pacientes submetidas a tratamento neoadjuvante

PURPOSE: We aimed to determine whether clinical examination could adequately ascertain the volume of tissue to be resected during breast-conserving surgery after neoadjuvant therapy. METHODS: We reviewed the clinical reports of 279 patients with histologically diagnosed invasive breast carcinomas treated with neoadjuvant therapy followed by surgery or with primary surgery alone. We estimated volumes of excised tissues, the volume of the tumor mass and the optimal volume required for excision based on 1 cm of clear margins. The actual excess of resected volume was estimated by calculating the resection ratio measured as the volume of the resected specimen divided by the optimal specimen volume. The study endpoints were to analyze the extent of tissue resection and to ascertain the effect of excess resected tissue on surgical margins in both groups of patients. RESULTS: The median tumor diameter was 2.0 and 1.5 cm in the surgery and neoadjuvant therapy groups, respectively. The median volume of resected mammary tissue was 64.3 cm³ in the primary surgery group and 90.7 cm³ in the neoadjuvant therapy group. The median resection ratios in the primary surgery and neoadjuvant therapy groups were 2.0 and 3.3, respectively (p<0.0001). Surgical margin data were similar in both groups. Comparison of the volume of resected mammary tissues with the tumor diameters showed a positive correlation in the primary surgery group and no correlation in the neoadjuvant therapy group. CONCLUSION: Surgeons tend to excise large volumes of tissue during breast-conserving surgery after neoadjuvant therapy, thereby resulting in a loss of the correlation between tumor diameter and volume of the excised specimen.

OBJETIVO: Foi determinar se a avaliação clínica é adequada na determinação do volume a ser ressecado em cirurgias conservadoras de mama após tratamento neoadjuvante. MÉTODOS: Avaliamos 279 pacientes com diagnóstico histológico de carcinoma invasor de mama submetidas à terapia neoadjuvante seguida de tratamento cirúrgico ou tratadas com cirurgia primária. O volume de tecido excisado, o volume da massa tumoral e o volume ótimo para a excissão cirúrgica baseado em uma margem de 1 cm foram calculados. O excesso de volume excisado foi estimado pelo cálculo da taxa de ressecção determinada pelo volume de tecido excisado dividido pelo volume ótimo para a excisão cirúrgica. Analisamos a extensão da ressecção cirúrgica e o efeito do exesso de tecido ressecado na obtenção de margens cirúrgicas. RESULTADOS: A mediana do diâmetro tumoral foi de 2,0 e 1,5 cm nos grupos de cirurgia primária e terapia neoadjuvante, respectivamente. A mediana do volume de tecido mamário ressecado foi de 64,3 cm³ no grupo de cirurgia primária e de 90,7 cm³ no grupo de tratamento neoadjuvante. A taxa mediana de ressecção nos grupos de cirurgia primária e terapia neoadjuvante foram 2,0 e 3,3 respectivamente (p<0,0001). Os dados relacionados à margem cirúrgica foram similares em ambos os grupos. A comparação do volume de tecido ressecado mostrou correlação positiva no grupo de cirurgia primária, porém não no grupo de tratamento neoadjuvante. CONCLUSÃO: Existe uma tendência dos cirurgiões a removerem maior quantidade de tecido mamário durante cirurgias conservadoras de mama de pacientes que foram submetidas à tratamento neoadjuvante, resultando na perda da correlação entre o diâmetro tumoral e o volume do espécime excisado.

Mouse renal 4T1 cell engraftment as a model to study the influence of hypoxia in breast cancer progression.

PURPOSE: To develop a mouse model to study the influence of hypoxia in breast cancer progression and metastasis. METHODS: The 4T1 cell line was used to engraft the kidneys of female BALB/c mice. Placing an aneurysm clip on the kidney hilum, hypoxia can be directed to tumor site. Histological evaluation was used to analyze the morphological changes induced by ischemia in kidney cortex, and to verify the metastatic potential. RESULTS: 4T1 cells can be engrafted into the renal cortex and the renal ischemia caused by using a clip to clamp the renal hilum induces hypoxia at the tumor site. This procedure maintains the ability of 4T1 cells to metastasize. In fact, our preliminary results showed that tumor hypoxia precipitates the metastatic dissemination of tumor cells. After 14 days of engraftment, lung metastases were observed only in mice that were subjected to tumor hypoxia. CONCLUSION: This model can help us to understand how low oxygen tension mediates hypoxia-induced proteomic and genomic changes in breast cancer.

Mouse renal 4T1 cell engraftment as a model to study the influence of hypoxia in breast cancer progression

PURPOSE: To develop a mouse model to study the influence of hypoxia in breast cancer progression and metastasis. METHODS: The 4T1 cell line was used to engraft the kidneys of female BALB/c mice. Placing an aneurysm clip on the kidney hilum, hypoxia can be directed to tumor site. Histological evaluation was used to analyze the morphological changes induced by ischemia in kidney cortex, and to verify the metastatic potential. RESULTS: 4T1 cells can be engrafted into the renal cortex and the renal ischemia caused by using a clip to clamp the renal hilum induces hypoxia at the tumor site. This procedure maintains the ability of 4T1 cells to metastasize. In fact, our preliminary results showed that tumor hypoxia precipitates the metastatic dissemination of tumor cells. After 14 days of engraftment, lung metastases were observed only in mice that were subjected to tumor hypoxia. CONCLUSION: This model can help us to understand how low oxygen tension mediates hypoxia-induced proteomic and genomic changes in breast cancer.