M. B. I. Lobbes

The role of MRI in axillary lymph node imaging in breast cancer patients: a systematic review

ObjectivesTo assess whether MRI can exclude axillary lymph node metastasis, potentially replacing sentinel lymph node biopsy (SLNB), and consequently eliminating the risk of SLNB-associated morbidity.MethodsPubMed, Cochrane, Medline and Embase databases were searched for relevant publications up to July 2014. Studies were selected based on predefined inclusion and exclusion criteria and independently assessed by two reviewers using a standardised extraction form.ResultsSixteen eligible studies were selected from 1,372 publications identified by the search. A dedicated axillary protocol [sensitivity 84.7xa0%, negative predictive value (NPV) 95.0xa0%] was superior to a standard protocol covering both the breast and axilla simultaneously (sensitivity 82.0xa0%, NPV 82.6xa0%). Dynamic, contrast-enhanced MRI had a lower median sensitivity (60.0xa0%) and NPV (80.0xa0%) compared to non-enhanced T1w/T2w sequences (88.4, 94.7xa0%), diffusion-weighted imaging (84.2, 90.6xa0%) and ultrasmall superparamagnetic iron oxide (USPIO)- enhanced T2*w sequences (83.0, 95.9xa0%). The most promising results seem to be achievable when using non-enhanced T1w/T2w and USPIO-enhanced T2*w sequences in combination with a dedicated axillary protocol (sensitivity 84.7xa0% and NPV 95.0xa0%).ConclusionsThe diagnostic performance of some MRI protocols for excluding axillary lymph node metastases approaches the NPV needed to replace SLNB. However, current observations are based on studies with heterogeneous study designs and limited populations.Main Messages• Some axillary MRI protocols approach the NPV of an SLNB procedure.• Dedicated axillary MRI is more accurate than protocols also covering the breast.• T1w/T2w protocols combined with USPIO-enhanced sequences are the most promising sequences.

Noninvasive nodal staging in patients with breast cancer using gadofosveset-enhanced magnetic resonance imaging: a feasibility study.

ObjectivesThe objectives of this study were to evaluate whether the axillary lymph nodes show enhancement on magnetic resonance imaging (MRI) after gadofosveset administration, to assess the time to peak enhancement, and to determine the diagnostic performance of gadofosveset-enhanced MRI for axillary nodal staging. Materials and MethodsTen women whose conditions had been diagnosed with invasive breast cancer (>2 cm) underwent both nonenhanced and gadofosveset-enhanced 3-dimensional T1-weighted axillary MRI. Signal intensity of the axillary lymph nodes and different adjacent tissues was measured, and relative signal intensity (rSI) was calculated. A Wilcoxon signed rank test was used to compare results of rSI between different time intervals. A radiologist evaluated all lymph nodes with regard to size, morphologic features, and gadofosveset uptake. All MRI-depicted lymph nodes were matched with the lymph nodes that were removed during surgery. Nodal status was investigated by a pathologist. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of gadofosveset-enhanced MRI for axillary lymph node staging were calculated. ResultsAfter contrast administration, a significant signal increase was observed in the lymph nodes (P < 0.05). When compared with muscle or fat, rSI of the lymph nodes demonstrated a significant postcontrast peak enhancement between 11 minutes and 30 seconds and 20 minutes and 50 seconds (P < 0.05). A total of 152 lymph nodes were harvested during sentinel lymph node biopsy or axillary lymph node dissection, of which 116 were matched with the lymph nodes that were depicted on MRI. Histopathological examination resulted in 21 macrometastases and 8 micrometastases. Using contrast-enhanced MRI, 20 lymph nodes were rated as true positive; 83 as true negative; 4 as false positive; and 9 as false negative. This resulted in an overall node-by-node sensitivity, specificity, PPV, and NPV of 69%, 95%, 83%, and 90%, respectively. If the micrometastases were excluded from the analysis, MRI showed a sensitivity of 86% and a specificity of 94%. Calculated PPV and NPV were 75% and 97%, respectively. ConclusionsThe axillary lymph nodes show enhancement on MRI after gadofosveset administration, with a peak enhancement between 11 minutes and 30 seconds and 20 minutes and 50 seconds. Diagnostic performance of gadofosveset-enhanced axillary lymph node imaging in patients with breast cancer is promising, but further studies need to confirm these results.

The Quality of Tumor Size Assessment by Contrast-Enhanced Spectral Mammography and the Benefit of Additional Breast MRI

Background - Contrast-enhanced spectral mammography (CESM) is a promising new breast imaging modality that is superior to conventional mammography for breast cancer detection. We aimed to evaluate correlation and agreement of tumor size measurements using CESM. As additional analysis, we evaluated whether measurements using an additional breast MRI exam would yield more accurate results. Methods - Between January 1st 2013 and April 1st 2014, 87 consecutive breast cancer cases that underwent CESM were collected and data on maximum tumor size measurements were gathered. In 57 cases, tumor size measurements were also available for breast MRI. Histopathological results of the surgical specimen served as gold standard in all cases. Results - The Pearsons correlation coefficients (PCC) of CESM versus histopathology and breast MRI versus histopathology were all >0.9, p<0.0001. For the agreement between measurements, the mean difference between CESM and histopathology was 0.03 mm. The mean difference between breast MRI and histopathology was 2.12 mm. Using a 2x2 contingency table to assess the frequency distribution of a relevant size discrepancy of >1 cm between the two imaging modalities and histopathological results, we did not observe any advantage of performing an additional breast MRI after CESM in any of the cases. Conclusion - Quality of tumor size measurement using CESM is good and matches the quality of these measurement assessed by breast MRI. Additional measurements using breast MRI did not improve the quality of tumor size measurements.

Density is in the eye of the beholder: visual versus semi-automated assessment of breast density on standard mammograms

ObjectivesVisual inspection is generally used to assess breast density. Our study aim was to compare visual assessment of breast density of experienced and inexperienced readers with semi-automated analysis of breast density.MethodsBreast density was assessed by an experienced and an inexperienced reader in 200 mammograms and scored according to the quantitative BI-RADS classification. Breast density was also assessed by dedicated software using a semi-automated thresholding technique. Agreement between breast density classification of both readers as well as agreement between their assessment versus the semi-automated analysis as reference standard was expressed as the weighted kappa value.ResultsUsing the semi-automated analysis, agreement between breast density measurements of both breasts in both projections was excellent (ICC >0.9, Pu2009<u20090.0001). Reproducibility of the semi-automated analysis was excellent (ICC >0.8, Pu2009<u20090.0001). The experienced reader correctly classified the BI-RADS breast density classification in 58.5% of the cases. Classification was overestimated in 35.5% of the cases and underestimated in 6.0% of the cases. Results of the inexperienced reader were less accurate. Agreement between the classification of both readers versus the semi-automated analysis was considered only moderate with weighted kappa values of 0.367 (experienced reader) and 0.232 (inexperienced reader).ConclusionVisual assessment of breast density on mammograms is inaccurate and observer-dependent.

The value of completion axillary treatment in sentinel node positive breast cancer patients undergoing a mastectomy: a Dutch randomized controlled multicentre trial (BOOG 2013-07)

BackgroundTrials failed to demonstrate additional value of completion axillary lymph node dissection in case of limited sentinel lymph node metastases in breast cancer patients undergoing breast conserving therapy. It has been suggested that the low regional recurrence rates in these trials might partially be ascribed to accidental irradiation of part of the axilla by whole breast radiation therapy, which precludes extrapolation of results to mastectomy patients. The aim of the randomized controlled BOOG 2013–07 trial is therefore to investigate whether completion axillary treatment can be safely omitted in sentinel lymph node positive breast cancer patients treated with mastectomy.DesignThis study is designed as a non-inferiority randomized controlled multicentre trial. Women aged 18xa0years or older diagnosed with unilateral invasive clinically T1-2xa0N0 breast cancer who are treated with mastectomy, and who have a maximum of three axillary sentinel lymph nodes containing micro- and/or macrometastases, will be randomized for completion axillary treatment versus no completion axillary treatment. Completion axillary treatment can consist of completion axillary lymph node dissection or axillary radiation therapy. Primary endpoint is regional recurrence rate at 5xa0years. Based on a 5-year regional recurrence free survival rate of 98xa0% among controls and 96xa0% for study subjects, the sample size amounts 439 per arm (including 10xa0% lost to follow-up), to be able to reject the null hypothesis that the rate for study and control subjects is inferior by at least 5xa0% with a probability of 0.8. Results will be reported after 5 and 10xa0years of follow-up.DiscussionWe hypothesize that completion axillary treatment can be safely omitted in sentinel node positive breast cancer patients undergoing mastectomy. If confirmed, this study will significantly decrease the number of breast cancer patients receiving extensive treatment of the axilla, thereby diminishing the risk of morbidity and improving quality of life, while maintaining excellent regional control and without affecting survival.Trial registrationThe BOOG 2013–07 study is registered in the register of ClinicalTrials.gov since April 10, 2014, Identifier: NCT02112682.

Leukocyte Counts, Myeloperoxidase, and Pregnancy-Associated Plasma Protein A as Biomarkers for Cardiovascular Disease: Towards a Multi-Biomarker Approach

We evaluated leukocyte counts and levels of CRP, fibrinogen, MPO, and PAPP-A in patients with stable and unstable angina pectoris, acute myocardial infarction, and healthy controls. All biomarkers were analyzed again after 6 months. Leukocyte counts and concentrations of fibrinogen, CRP, MPO, and PAPP-A were significantly increased in patients with acute myocardial infarction. Leukocyte counts and concentrations of MPO were significantly increased in patients with unstable angina pectoris compared with controls. After 6 months, leukocyte counts and MPO concentrations were still increased in patients with acute myocardial infarction when compared to controls. Discriminant analysis showed that leukocyte counts, MPO, and PAPP-A concentrations classified study group designation for acute coronary events correctly in 83% of the cases. In conclusion, combined assessment of leukocyte counts, MPO, and PAPP-A was able to correctly classify acute coronary events, suggesting that this could be a promising panel for a multibiomarker approach to assess cardiovascular risk.

Noninvasive nodal restaging in clinically node positive breast cancer patients after neoadjuvant systemic therapy: A systematic review

OBJECTIVEnTo provide a systematic review of studies comparing the diagnostic performance of noninvasive techniques and axillary lymph node dissection in the identification of initially node positive patients with pathological complete response of axillary lymph nodes to neoadjuvant systemic therapy.nnnMETHODSnPubMed and Embase databases were searched until May 21st, 2014. First, duplicate studies were eliminated. Next, study abstracts were read by two readers to assess eligibility. Studies were selected based on predefined inclusion criteria. Of these, data extraction was performed by two readers independently.nnnRESULTSnOf the 987 abstracts that were considered for inclusion, four were eligible for final analysis, which included a total of 572 patients. The diagnostic performance of clinical examination, axillary ultrasound, breast MRI, whole body (18)F-FDG PET-CT, and a prediction model to identify patients with pathological complete response were investigated. Studies were often limited by small sample size. Furthermore, systemic therapy regimens and definitions of clinical and pathological complete response were variable, refraining further pooling of data. The reported positive predictive value of different techniques to identify patients with axillary pathological complete response after neoadjuvant systemic therapy varied between 40% and 100%.nnnCONCLUSIONnAt present, there is no accurate noninvasive restaging technique able to identify patients with complete axillary response after neoadjuvant systemic therapy.

Contrast-enhanced spectral mammography in recalls from the Dutch breast cancer screening program: validation of results in a large multireader, multicase study

AbstractObjectivesContrast-enhanced spectral mammography (CESM) is a promising problem-solving tool in women referred from a breast cancer screening program. We aimed to study the validity of preliminary results of CESM using a larger panel of radiologists with different levels of CESM experience.MethodsAll women referred from the Dutch breast cancer screening program were eligible for CESM. 199 consecutive cases were viewed by ten radiologists. Four had extensive CESM experience, three had no CESM experience but were experienced breast radiologists, and three were residents. All readers provided a BI-RADS score for the low-energy CESM images first, after which the score could be adjusted when viewing the entire CESM exam. BI-RADS 1-3 were considered benign and BI-RADS 4-5 malignant. With this cutoff, we calculated sensitivity, specificity and area under the ROC curve.ResultsCESM increased diagnostic accuracy in all readers. The performance for all readers using CESM was: sensitivity 96.9xa0% (+3.9xa0%), specificity 69.7xa0% (+33.8xa0%) and area under the ROC curve 0.833 (+0.188).ConclusionCESM is superior to conventional mammography, with excellent problem-solving capabilities in women referred from the breast cancer screening program. Previous results were confirmed even in a larger panel of readers with varying CESM experience.Key Points• CESM is consistently superior to conventional mammographyn • CESM increases diagnostic accuracy regardless of a reader’s experiencen • CESM is an excellent problem-solving tool in recalls from screening programs

Contrast-enhanced spectral mammography as work-up tool in patients recalled from breast cancer screening has low risks and might hold clinical benefits

OBJECTIVEnContrast-enhanced spectral mammography (CESM) is a reliable problem solving tool in the work-up of women recalled from breast cancer screening. We evaluated additional findings caused by CESM alone and outweighed them against the disadvantages of this technique.nnnMETHODSnFrom December 2012 to December 2015, all women recalled from screening who underwent CESM were considered for this study. Radiation exposure and number of adverse contrast reactions were analysed. An experienced breast radiologist reviewed all exams and identified cases with lesions detected by CESM alone and scored their conspicuity. From these cases, data on breast density and final diagnosis were collected. For malignant cases, tumour grade and receptor characteristics were also collected.nnnRESULTSnDuring this study, 839 women underwent CESM after a screening recall, in which five minor adverse contrast reactions were observed. Median radiation dose per exam was 6.0mGy (0.9-23.4mGy). Seventy CESM-only lesions were detected in 65 patients. Of these 70 lesions, 54.3% proved to be malignant, most commonly invasive ductal carcinomas. The remaining CESM-only lesions were benign, predominantly fibroadenomas. No complications were observed during biopsy of these lesions. Retrospectively, the majority of the lesions were either occult or a minimal sign on low-energy CESM images or the screening mammogram.nnnCONCLUSIONnUsing CESM as a work-up tool for women recalled from screening carries low risk for the patient, while additionally detected tumour foci might hold important clinical implications which need to be further studied in large, randomized controlled trials.

Treatment response evaluation by MRI in breast cancer patients receiving neoadjuvant chemotherapy: there is more than just pathologic complete response prediction

In the April 4, 2012, Epub ahead of print issue of this journal, Wu et al. evaluated the role of magnetic resonance imaging (MRI) in breast cancer patients receiving neoadjuvant chemotherapy (NAC). In this review, both diffusionweighted imaging (DWI) and contrast-enhanced breast MRI (CE-MRI) were studied. In this review, consisting of 34 studies (published until January 2012), they showed that the sensitivity of CE-MRI for assessing pathologic complete response (pCR) was moderate [0.68, 95 % confidence interval (CI) 0.57–0.77], but specificity was excellent (0.91, 95 % CI 0.87–0.94). In contrast, sensitivity of DWI proved to be high (0.93, 95 % CI 0.82–0.97), but specificity was slightly less: 0.82 (95 % CI 0.70–0.90). They concluded that both techniques are promising with respect to the evaluation pCR in NAC, especially if they were to be combined. However, they also concluded that large, prospective studies are needed to assess the value of the combination of the two techniques [1]. Although it provides the reader with an excellent overview of the current literature, the study does not address several important issues that might influence the use of breast MRI in the (clinical) setting of NAC in breast cancer patients. As suggested by Wu et al., pCR after completion of NAC is associated with better survival outcomes. However, rates of pCR may vary, dependent on the treatment regime that is used: 6–15 % in anthracycline-based therapies, up to 30 % when adding taxanes [2]. Thus, the majority of patients receiving NAC do not reach pCR, and the value of MRI in these patients was not addressed in their study. An important indication for NAC in breast cancer patients is also enabling breast-conserving surgery in patients that would otherwise undergo mastectomy. Therefore, it would be interesting to evaluate if breast MRI is not only able to assess pCR (which occurs in a minority of patients), but also residual disease. For example, Partridge et al. [3] showed that the correlation coefficient of residual tumor size assessed by MRI and histopathologic examination of the surgical specimen was 0.89. Cheung et al. [4] even found a correlation coefficient of 0.98, but also less favorable coefficients can be found in the literature, for example by Nakahara et al. [5]: 0.21. In general, correlation coefficients of breast MRI tumor size and histopathologic results are good and in the order of 0.7 (Lobbes, unpublished data). Although the diagnostic accuracy of breast MRI for assessing residual disease and/or pCR in breast cancer patients receiving NAC is good, it can be influenced by several important factors that were not discussed by Wu et al. in their meta-analysis. An important limitation of using MRI in this setting is that both overestimation and underestimation were observed when assessing residual disease or pCR. Factors that could result in tumor size overestimation by MRI might be: reactive inflammation caused by tumor response and healing, sclerosis, necrosis, the presence of multiple scattered lesions, and the presence of surrounding ductal carcinoma in situ [6–8]. Overestimation of tumor size by MRI carries the risk of wider surgical margins with poorer cosmetic results, or performing unnecessary breast M. B. I. Lobbes (&) Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands e-mail: marc.lobbes@mumc.nl