Importance of ultrasonography in predicting malignancy and its correlation with the phenotypes Luminal, Her 2 overexpression and Triple Negative in breast masses classified as category BI-RADS® US 4

Orientador: Sophie Françoise Mauricette DerchainTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Objetivo: Avaliar a importância da ultrassonografia na predição de malignidade e sua correlação com os fenótipos Luminal, Her 2 overexpression e Triplo Negativo nos nódulos de mama classificados na categoria BI-RADS 'MARCA REGISTRADA' US 4. Objetivo Artigo 1: avaliar se a medida ultrassonográfica do diâmetro dos cistos pode contribuir com a predição de malignidade em um tipo específico de nódulos complexos classificados na categoria BI-RADS 'MARCA REGISTRADA' -US 4. Objetivo Artigo 2: avaliar as características ultrassonográficas de nódulos mamários classificados na categoria BI-RADS 'MARCA REGISTRADA' -US 4 associadas aos fenótipos Luminal, HER2 overexpression e Triplo Negativo. Sujeitos e métodos: No primeiro artigo foram incluídos em um estudo de corte transversal 48 casos de nódulos com características ultrassonográficas sugestivas de benignidade, entretanto apresentando no seu interior pelo menos um componente cístico. Todos os nódulos foram biopsiados (25 biópsias de fragmento; 23 biópsias de fragmento seguidas de biópsia excisional). O exame anatomopatológico classificou 12/48 (25%) casos como malignos. O maior diâmetro do nódulo, o maior diâmetro do cisto e o padrão de vascularização ao Doppler foram avaliados na predição de malignidade. No segundo artigo, foram selecionados em um estudo de corte transversal 327 nódulos classificados nas categorias BI-RADS 'MARCA REGISTRADA' -US 4a, 4b e 4c. Todos os nódulos foram biopsiados. Os resultados anatomopatológicos foram classificados em benigno 195 (60%) ou maligno 132 (40%). Os nódulos malignos foram então agrupados em três subtipos fenotípicos: Luminal, Her 2 overexpression e Triplo Negativo. As características ultrassonográficas dos nódulos foram comparadas com a categorização fenotípica. Resultados: no primeiro artigo, o padrão da vascularização[presente na lesão (p=1) ou presente imediatamente adjacente à lesão (p=0,46)] não esteve relacionado com a malignidade, enquanto os maiores diâmetros do nódulo e do cisto apresentaram uma relação significativa com a malignidade (p=0,02 e p<0,001, respectivamente). No segundo artigo, as subcategorias BI-RADS 'MARCA REGISTRADA'-US 4a, 4b e 4c não se relacionaram claramente aos fenótipos Luminal, Her2 overexpression ou Triplo Negativo. Entretanto, margens espiculadas, margens indistintas, halo ecogênico e reforço acústico posterior relacionaram-se significativamente com o fenótipo Luminal. Além disso, margens circunscritas e atenuação das ondas de ultrassom relacionaram-se positivamente com o fenótipo Triplo Negativo. Nenhuma característica ecográfica associou-se ao fenótipo Her2 overexpression. Conclusões: O primeiro artigo traz o conceito inédito de que o diâmetro máximo do cisto é um bom preditor de malignidade em nódulos complexos que, exceto pela presença de um ou mais cistos, seriam classificados como provavelmente benignos (BI-RADS 'MARCA REGISTRADA' -US 3). O segundo artigo está em concordância com o conhecimento atual de que existe associação entre variáveis ultrassonográficas como margens, halo ecogênico e características acústicas posteriores e os subtipos fenotípicos Luminal e Triplo Negativo. Entretanto, na amostra avaliada, essa associação não se manifestou claramente na subcategorização BI-RADS 'MARCA REGISTRADA' -US 4a, 4b e 4cAbstract: Objective: To evaluate the importance of ultrasound in predicting malignancy and its correlation with the phenotypes Luminal, Her 2 overexpression and Triple Negative in breast masses classified as BI-RADS 'TRADE MARK' -US 4. Article 1: To assess whether cyst diameter might contribute to the prediction of malignancy in complex breast masses. Article 2: To assess the sonographic characteristics of BI-RADS 'TRADEMARK'-US 4 breast masses in the Luminal, Triple Negative and HER2 phenotypes. Methods: In the first article, in a cross-sectional study, we identified 48 breast masses that had sonographic features suggestive of benignity, but presenting at least one cystic component. All breast masses were biopsied (25 core-needle; 23 core-needle and excision). Subsequent histologic analysis was performed and 12/48 (25%) malignancies were identified. Different sonographic measurements (largest diameter of the mass and cyst, vascular pattern) were assessed for the detection of malignancy. In the second article, in a cross-sectional study, we selected 327 masses classified in subcategories BI-RADS 'TRADEMARK' -US 4a, 4b and 4c. All masses were biopsied. The pathologic results were classified as benign 195 (60%) or malignant 132 (40%). The malignant masses were further grouped into three phenotypic subtypes: Luminal, Her 2 overexpression and Triple Negative. We then compared the sonographic features of the malignant lesions according to the phenotypic status of the masses. Results: In the first article, among sonographic features, vascular pattern [(present in the lesion (p=1.0) or present immediately adjacent to the lesion (p=0.46)] was not associated with malignancy, whereas the largest mass and cyst dimension had a significantly positive correlation (p=0.02 and p<0.001, respectively) with tumor malignancy. In the second article, the subcategories BI-RADS 'TRADEMARK' -US 4a, 4b and 4c were not clearly related to the phenotypes Luminal, Her2 overexpression or Triple Negative. However, spiculated margins, indistinct margins, echogenic halo, and posterior acoustic shadowing were significantly correlated with the Luminal phenotype. Moreover, circumscribed margins and attenuation were positively related to the Triple Negative phenotype. No sonographic variable was associated with Her2 overexpression phenotype. Conclusions: The first article presents the new concept that cyst diameter is a good predictor of malignancy in complex breast tumors which, except for the presence of the anechoic formation, would otherwise be rendered as probably benign (BI-RADS 'TRADEMARK' 3). The second article is in agreement with current knowledge that there is an association between ultrasound features as margins, posterior acoustic features and lesion boundary and phenotypic subtypes Luminal and Triple Negative. In our sample, this association was not clearly expressed in the subcategorization BI-RADS 'TRADEMARK' -US 4a, 4b and 4cDoutoradoOncologia Ginecológica e MamáriaDoutor em Ciências da Saúd

Cistos No Interior De Nódulo Mamários Benignos: Risco De Malignidade

The objective of this study is to assess whether the largest cyst diameter is useful for BI-RADS ultrasonography classification of predominantly solid breast masses with an oval shape, circumscribed margins, and largest axis parallel to the skin, which, except for the cystic component, would be likely classified as benign. Methods This study received approval from the local institutional review board. From March 2009 to August 2014, we prospectively biopsied 170 breast masses from 164 women. We grouped the largest cyst and mass diameters according to histopathological diagnoses. We used Student's t-test, linear regression, and the area under the receiver operating characteristic curve (AUC) for statistical assessment. Results Histopathological examination revealed 143 (84%) benign and 27 (16%) malignant masses. The mean largest mass diameter was larger among malignant (mean standard deviation, 34.1 16.6 mm) than benign masses (24.7 16.7 mm) (P &lt; 0.008). The mean largest cyst diameter was also larger among malignant (9.9 7.1 mm) than benign masses (4.6 3.6 mm) (P &lt; 0.001). Agreement between measurements of the largest mass and cyst diameters was low (R2 = 0.26). AUC for the largest cyst diameter (0.78) was similar to the AUC for the largest mass diameter (0.69) ( p = 0.2). A largest cyst diameter &lt; 3, 3 to &lt; 11, and 11 mm had a positive predictive value of 0, 15, and 52%, respectively. Conclusion A largest cystic component &lt; 3 mm identified within breast masses that show favorable characteristics may be considered clinically inconsequential in ultrasonography characterization. Conversely, masses with a largest cystic component 3 mm should be classified as BI-RADS-US category 4.38417017

Cistos no interior de nódulo mamários benignos: risco de malignidade

Objective The objective of this study is to assess whether the largest cyst diameter is useful for BI-RADS ultrasonography classification of predominantly solid breast masses with an oval shape, circumscribed margins, and largest axis parallel to the skin, which, except for the cystic component, would be likely classified as benign. Methods This study received approval from the local institutional review board. From March 2009 to August 2014, we prospectively biopsied 170 breast masses from 164 women. We grouped the largest cyst and mass diameters according to histopathological diagnoses. We used Student's t-test, linear regression, and the area under the receiver operating characteristic curve (AUC) for statistical assessment. Results Histopathological examination revealed 143 (84%) benign and 27 (16%) malignant masses. The mean largest mass diameter was larger among malignant (mean standard deviation, 34.1 16.6 mm) than benign masses (24.7 16.7 mm) (P < 0.008). The mean largest cyst diameter was also larger among malignant (9.9 7.1 mm) than benign masses (4.6 3.6 mm) (P < 0.001). Agreement between measurements of the largest mass and cyst diameters was low (R2 = 0.26). AUC for the largest cyst diameter (0.78) was similar to the AUC for the largest mass diameter (0.69) ( p = 0.2). A largest cyst diameter < 3, 3 to < 11, and 11 mm had a positive predictive value of 0, 15, and 52%, respectively. Conclusion A largest cystic component < 3 mm identified within breast masses that show favorable characteristics may be considered clinically inconsequential in ultrasonography characterization. Conversely, masses with a largest cystic component 3 mm should be classified as BI-RADS-US category 4.Objetivo Avaliar se o maior diâmetro do cisto é útil para a classificação ultrassonográfica BI-RADS de nódulos mamários predominantemente sólidos, com forma oval, margens circunscritas e maior eixo paralelo à pele que, exceto pela presença do componente cístico, seriam classificados como provavelmente benignos. Métodos Este estudo foi aprovado pelo Comitê de Ética local. De março de 2009 a agosto de 2014, 170 nódulos mamários de 164 mulheres foram prospectivamente biópsiados. As medidas do maior diâmetro do maior cisto e do maior diâmetro do nódulo foram agrupados de acordo com os diagnósticos histopatológicos. O teste t de Student, a regressão linear e a área sob a curva ROC (AUC) foram utilizados para a avaliação estatística. Resultados O exame histopatológico revelou 143 (84%) nódulos benignos e 27 (16%) nódulos malignos. A média da medida do maior diâmetro dos nódulos foi maior entre os nódulos malignos (média desvio padrão, 34,1 16,6 mm) do que nos nódulos benignos (24,7 16,7 mm) (p < 0,008). A média do maior diâmetro do maior cisto também foi maior entre os nódulos malignos (9,9 7,1 mm) do que nos nódulos benignos (4,6 3,6 mm) (p < 0,001). A concordância entre as medidas dos maiores diâmetros dos nódulos e do maior diâmetro do maior cisto foi baixa (R2 = 0,26). A AUC do maior diâmetro do maior cisto (0,78) foi semelhante à AUC do maior diâmetro do nódulo (0,69) (p = 0,2). Os maiores diâmetros dos maiores cistos medindo < 3; 3 e < 11; e 11 mm tiveram um valor preditivo positivo de 0, 15 e 52%, respectivamente. Conclusão Componentes císticos < 3 mm identificados dentro de nódulos mamários que apresentam as demais características provavelmente benignas podem ser considerados clinicamente irrelevantes na caracterização ultrassonográfica. Por outro lado, nódulos que apresentam um componente cístico medindo 3 mm devem ser classificadas na categoria BI-RADS-US 4.38417017

Desempenho da ultra-sonografia na detecção das metástases em linfonodos axilares em mulheres com câncer de mama Performance of ultrasound in the detection of axillary lymph node metastases in breast cancer patients

OBJETIVOS: avaliar o desempenho de diversas características ultra-sonográficas morfológicas (12) e doplervelocimétricas (7), para detecção de metástases linfonodais em mulheres com câncer de mama. MÉTODOS: foram incluídas 179 mulheres (181 axilas), entre janeiro e dezembro de 2004. Os exames ultra-sonográficos foram realizados com transdutor linear em tempo real (Toshiba-Power Vision-6000 (modelo SSA-370A)). Para o estudo de parâmetros morfológicos foram utilizadas freqüências entre 7,5 e 12 MHz. Para os parâmetros Doppler foi utilizada freqüência de 5 MHz. Subsequentemente, as pacientes foram submetidas a axilectomia dos níveis I, II e III (158) ou à técnica do linfonodo sentinela (23). Foram calculadas a sensibilidade, a especificidade e os valores preditivos positivo e negativo para cada parâmetro. Para a associação de parâmetros foi utilizada a árvore de decisão. Foram estabelecidos os valores de corte para as variáveis contínuas por meio da curva ROC. RESULTADOS: ao exame ultra-sonográfico foi identificado pelo menos um linfonodo axilar em 173 (96%) exames. O exame histológico detectou metástase linfonodal em 87 mulheres (48%). As melhores sensibilidades dos critérios morfológicos foram encontradas com o volume (62%), diâmetro ântero-posterior (62%) e local do centro ecogênico (56%). Embora a especificidade da invasão da gordura adjacente (100%), regularidade das margens (92%) e da ecotextura do parênquima (99%) tenham sido elevadas, a sensibilidade destes parâmetros foi muito baixa. Nenhum critério dopplervelocimétrico alcançou 50% de sensibilidade. A árvore de decisão selecionou a localização do centro ecogênico, a ecotextura do parênquima e a regularidade das margens como melhor associação de parâmetros. CONCLUSÃO: o estadiamento dos linfonodos axilares por método não invasivo ainda é um objetivo não alcançado no tratamento das pacientes com câncer de mama.<br>PURPOSE: to evaluate the role of morphological (12) and Doppler velocimetry (17) ultrasonographic features, in the detection of lymph node metastases in breast cancer patients. METHODS: 179 women (181 axillary cavities) were included in the study from January to December 2004. The ultrasonographic examinations were performed with a real-time linear probe (Toshiba-Power Vision-6000 (model SSA-370A)). The morphological parameters were studied with a frequency of 7.5-12 MHz. A frequency of 5 MHz was used for the Doppler velocimetry parameters. Subsequently, the women were submitted to level I, II and III axillary dissection (158), or to the sentinel lymph node technique (23). Sensitivity, specificity, and positive and negative predictive values were calculated for each parameter. The decision tree test was used for parameter association. The cutoff points were established by the ROC curve. RESULTS: at least one lymph node was detected in 173 (96%) of the women by the ultrasonographic examinations. Histological examination detected lymph node metastases in 87 women (48%). The best sensitivity among the morphological paramenters was found with the volume (62%), the antero-posterior diameter (62%) and the fatty hilum placement (56%). Though the specificity of the extracapsular invasion (100%), border regularity (92%) and cortex echogenicity (99%) were high, the sensitivity of these features was too low. None of the Doppler velocimetry parameters reached 50% sensitivity. The decision tree test selected the ultrasonographic parametners: fatty hilum placement, border regularity and cortex echogenicity, as the best parameter association. CONCLUSION: the detection of axillary cavity lymph node stage by a noninvasive method still remains an unfulfilled goal in the treatment of patients with breast cancer

Diagnostic accuracy of shear wave elastography - virtual touch (TM) imaging quantification in the evaluation of breast masses: impact on ultrasonography's specificity and its ultimate clinical benefit

Objectives: To evaluate the diagnostic performance and the clinical benefit of Shear-Wave Elastography -Virtual Touch T Imaging Quantification (SWE-VTIQ) as a complement to ultrasonography (US). Methods: From October 2016 through Jun 2017, B-mode US and SWE-VTIQ were prospectively performed in 396 breast masses in 357 women who consented to undergo this study. Quantitative elastography values were recorded: V-max (maximum elasticity), Vmean (median elasticity), V-ratio(max) (ratio of V-max and surrounding parenchyma) and Vratio(mean) (ratio of Vmean and surrounding parenchyma). The histopathology of the lesions was considered the reference standard for benign or malignant definition. The performance of the four elastographic parameters was evaluated trough sensitivity, specificity and AUC. The parameter with the best performance was tested in six different diagnostic approaches defined based on clinical practice. Results: Of the 396 masses, 122 (30.8%) were benign and 274 (69.2%) were malignant. All SWE parameters were significantly higher in malignant masses (all p < 0.01). V-max and V-ratio(max) performed significantly better then Vratio(mean) (p=0.01 and p=0.03, respectively). SWE-VTIQ improved US specificity in all diagnostic approaches, except when applied to BI-RADS 3 lesions. SWE-VTIQ reduced the false positive rate in 25% if applied only to BI-RADS 4A masses, maintaining a high sensitivity (98.9%, 95% confidence interval 97.1-100%) and a negative predictive value of 95.5%. When applied to BI-RADS 4A and 4B masses, SWE-VTIQ reduced the false positive rate in 54.4%. However, 13 malignant cases would be missed in this approach (4.7% of all malignant cases). Conclusions: SWE-VTIQ increases US specificity when applied to BI-RADS 4 A lesions, significantly reducing unnecessary interventions and preserving the diagnosis of malignant lesions. When applied also to BI-RADS (R) 4B lesions, SWE-VTIQ increases the number of false negative cases, which should be evaluated with caution.1137480COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESSem informaçã

Four-dimensional translabial ultrasound concordance with digital palpation and surface electromyography during dynamic pelvic floor muscles assessment: a cross-sectional study

Aim To investigate whether pelvic floor muscle (PFM) morphological changes obtained through four-dimensional translabial ultrasound (4D TLUS) correlate with a PFM contraction as evaluated by digital palpation and PFM electromyographic activity evaluated by surface electromyography (sEMG). The secondary objective was to investigate which ultrasound parameter is more strongly associated with digital palpation. MethodsThis cross-sectional study included 210 women and their PFMs were evaluated by digital palpation (graded according to the Modified Oxford Scale), sEMG and 4D TLUS. Offline analysis of ultrasound volume datasets was performed for measuring the change in levator plate angle, bladder neck elevation, hiatal area narrowing, puborectalis strain, and puborectalis muscle thickness at rest and during PFM contraction. Statistical analysis included Kruskal-Wallis, Dunn, and Spearman's tests in addition to univariate and multivariate logistic regression, adopting a significance level of 5%. ResultsA weak but significant correlation between the change in levator plate angle and sEMG (P=.04; r=0.14) was found. All 4D TLUS measurements, except the puborectalis muscle thickness, significantly correlated with digital palpation (P<.0001); with the puborectalis strain and the change in levator plate angle having the strongest combined parameters associated with digital palpation (R-2=21.77%), despite the low coefficient of determination. ConclusionWe found that 4D TLUS significantly correlates with digital palpation and sEMG, being the change in the levator plate angle the parameter that best correlates with both methods. While digital palpation is essential during a PFM functional assessment, 4D TLUS is recommended as a beneficial noninvasive clinical tool for a more in-depth evaluation391403411CAPES - Coordenação de Aperfeiçoamento de Pessoal e Nível SuperiorFAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo0012015/22521‐8; 2017/02565‐

Polycystic Ovary Syndrome And Chronic Autoimmune Thyroiditis.

Polycystic ovary syndrome (PCOS) has been associated with an autoimmune origin, either per se or favoring the onset of autoimmune diseases, from a stimulatory action on the inflammatory response. Thus, autoimmune thyroiditis (AIT) could be more prevalent among women with PCOS. To evaluate the prevalence of AIT in women with PCOS. It was a cross-sectional study, in a tertiary center, including 65 women with PCOS and 65 women without this condition. Clinical and laboratory parameters were evaluated and a thyroid ultrasound scan was performed. Levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), anti-thyroid peroxidase (anti-TPO) antibodies, anti-thyroglobulin (anti-TG) antibodies, and thyroid ultrasound findings were evaluated. The prevalence of subclinical hypothyroidism (SCH) in women with PCOS was 16.9% and 6.2% in the non-PCOS group. AIT was more common in the PCOS group compared with the non-PCOS group (43.1% versus 26.2%). But, when it was adjusted by weight and insulin resistance, the difference in the thyroiditis risk was not observed (OR 0.78, CI 0.28-2.16). AIT risk was similar in the PCOS and the non-PCOS group. SCH are more common in women with PCOS, highlighting a need for periodic monitoring of thyroid function.3148-5

Performance of the risk of malignancy index for discriminating malignant tumors in women with adnexal masses

We examined the performance of 4 risk of malignancy index (RMI) variants in a medium-resource gynecologic cancer center. A total of 158 women referred for adnexal masses were evaluated before surgery by the 4 RMI variants. Physicians with varied experience in ultrasound assessment of adnexal masses performed ultrasound examinations. We compared the performance of the 4 RMI variants using receiver operating characteristic curve analyses followed by calculation of sensitivity, specificity, and positive and negative likelihood ratios using the pathologic diagnosis of the masses as the reference standard. Among the 158 women with adnexal masses included in this study, 51 (32%) had malignant tumors; 26 (51%) of them were stage I. All RMI variants performed similarly (accuracy range, 74%-83%), regardless of menopausal status. Considering all women included, the positive likelihood ratios of the 4 RMI variants ranged from 3.52 to 4.41. In subset analyses, all RMI variants had decreased sensitivity for stage I malignant tumors and for those of nonepithelial histologic types. The 4 RMI variants performed acceptably in a medium-resource setting where ultrasound examiners were physicians with varied experience. This finding indicates a good tradeoff between performance and feasibility, since ultrasound RMI protocols are of low complexity.We examined the performance of 4 risk of malignancy index (RMI) variants in a medium-resource gynecologic cancer center. Methods-A total of 158 women referred for adnexal masses were evaluated before surgery by the 4 RMI variants. Physicians with varied e351143152FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2012/15059-8SEM INFORMAÇÃ