Amro Masarwah

Axillary Lymph Node Biopsy in Newly Diagnosed Invasive Breast Cancer: Comparative Accuracy of Fine-Needle Aspiration Biopsy versus Core-Needle Biopsy

PURPOSE To compare the diagnostic accuracy of ultrasonographically (US)-guided fine-needle aspiration biopsy (FNAB) and core-needle biopsy (CNB) of the axillary lymph nodes (LNs) of patients with newly diagnosed invasive breast cancer. MATERIALS AND METHODS This prospective single-center study had institutional review board approval, and written informed consent was obtained. Between April 2011 and March 2012, 178 consecutive patients (182 axillae) were evaluated by using axillary US. Sixty-six axillae fulfilled the inclusion criteria (cortical thickness greater than 2 mm or abnormal morphologic characteristics), and patients with these axillae underwent US-guided axillary LN biopsy. Both FNAB and CNB were obtained from the same suspicious LN. Patients with biopsy-proved metastasis underwent axillary clearance, and those with a negative biopsy underwent sentinel LN biopsy with completion axillary clearance if needed. Diagnostic performance was calculated separately for US, FNAB, and CNB. Statistical differences in sensitivities were evaluated by using the McNemar test. RESULTS From the total study population, 45.6% (83 of 182 axillae) had metastases. A total of 66 axillae underwent both FNAB and CNB. The sensitivity for US was 61.4% (51 of 83 axillae), and specificity was 84.8% (84 of 88 axillae). The sensitivities for FNAB and CNB were 72.5% (37 of 51 axillae) and 88.2% (45 of 51 axillae), respectively (P = .008). Specificity for both was 100% (15 of 15 axillae). The negative predictive value for FNAB was 81.7%, and that for CNB was 91.2%. The positive predictive value was 100% for both methods. CONCLUSION When accurate preoperative staging of the axilla is needed in patients with newly diagnosed invasive breast cancer, CNB is more sensitive than FNAB.

Diffusion-Weighted Imaging in 3.0 Tesla Breast MRI: Diagnostic Performance and Tumor Characterization Using Small Subregions vs. Whole Tumor Regions of Interest

Introduction Apparent diffusion coefficient (ADC) values are increasingly reported in breast MRI. As there is no standardized method for ADC measurements, we evaluated the effect of the size of region of interest (ROI) to diagnostic utility and correlation to prognostic markers of breast cancer. Methods This prospective study was approved by the Institutional Ethics Board; the need for written informed consent for the retrospective analyses of the breast MRIs was waived by the Chair of the Hospital District. We compared diagnostic accuracy of ADC measurements from whole-lesion ROIs (WL-ROIs) to small subregions (S-ROIs) showing the most restricted diffusion and evaluated correlations with prognostic factors in 112 consecutive patients (mean age 56.2±11.6 years, 137 lesions) who underwent 3.0-T breast MRI. Results Intra- and interobserver reproducibility were substantial (κ = 0.616–0.784; Intra-Class Correlation 0.589–0.831). In receiver operating characteristics analysis, differentiation between malignant and benign lesions was excellent (area under curve 0.957–0.962, cut-off ADC values for WL-ROIs: 0.87×10−3 mm2s-1; S-ROIs: 0.69×10−3 mm2s-1, P<0.001). WL-ROIs/S-ROIs achieved sensitivities of 95.7%/91.3%, specificities of 89.5%/94.7%, and overall accuracies of 89.8%/94.2%. In S-ROIs, lower ADC values correlated with presence of axillary metastases (P = 0.03), high histological grade (P = 0.006), and worsened Nottingham Prognostic Index Score (P<0.05). In both ROIs, ADC values correlated with progesterone receptors and advanced stage (P<0.01), but not with HER2, estrogen receptors, or Ki-67. Conclusions ADC values assist in breast tumor characterization. Small ROIs were more accurate than whole-lesion ROIs and more frequently associated with prognostic factors. Cut-off values differed significantly depending on measurement procedure, which should be recognized when comparing results from the literature. Instead of using a whole lesion covering ROI, a small ROI could be advocated in diffusion-weighted imaging.

Preoperative axillary staging with 3.0-T breast MRI: clinical value of diffusion imaging and apparent diffusion coefficient.

The axillary staging in newly diagnosed breast cancer is under major evolution. The aims of this study were to define the diagnostic performance of 3.0-T diffusion-weighted imaging (DWI) in the detection of axillary metastases in newly diagnosed breast cancer, to assess apparent diffusion coefficients (ADCs) for histopathologically confirmed metastatic lymph nodes in a clinical setting. Altogether 52 consecutive breast cancer patients underwent magnetic resonance imaging and DWI in addition to axillary ultrasound. ADCs of axillary lymph nodes were analysed by two breast radiologists and ultrasound-guided core biopsies were taken. In a separate reading by one radiologist two types of region of interests were used for a smaller group of patients. Altogether 56 axillae (121 lymph nodes) were included in the statistical analysis. Metastatic axillae (51.8%) had significantly lower ADCs (p<0.001). Mean ADCs were 0.663–0.676 x 10-3 mm2/s for the histologically confirmed metastatic LNs and 1.100–1.225 x 10-3 mm2/s for the benign. The sensitivity, specificity, and accuracy of DWI were 72.4%, 79.6%, and 75.9%, respectively with threshold ADC 0.812 x 10-3 mm2/s. Region of interest with information on the minimum value increased the diagnostic performance (area under the curve 0.794 vs. 0.619). Even though ADCs are significantly associated with histopathologically confirmed axillary metastases the diagnostic performance of axillary DWI remains moderate and ultrasound-guided core biopsies or sentinel lymph node biopsies cannot be omitted.

UDP-sugar accumulation drives hyaluronan synthesis in breast cancer

Increased uptake of glucose, a general hallmark of malignant tumors, leads to an accumulation of intermediate metabolites of glycolysis. We investigated whether the high supply of these intermediates promotes their flow into UDP-sugars, and consequently into hyaluronan, a tumor-promoting matrix molecule. We quantified UDP-N-Acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcUA) in human breast cancer biopsies, the levels of enzymes contributing to their synthesis, and their association with the hyaluronan accumulation in the tumor. The content of UDP-GlcUA was 4 times, and that of UDP-GlcNAc 12 times higher in the tumors as compared to normal glandular tissue obtained from breast reductions. The surge of UDP-GlcNAc correlated with an elevated mRNA expression of glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), one of the key enzymes in the biosynthesis of UDP-GlcNAc, and the expression of GFAT1 was also elevated. The contents of both UDP-sugars strongly correlated with tumor hyaluronan levels. Interestingly, hyaluronan content did not correlate with the mRNA levels of the hyaluronan synthases (HAS1-3), thus emphasizing the role of the UDP-sugar substrates of these enzymes. The UDP-sugars showed a trend to higher levels in ductal vs. lobular cancer subtypes. The results reveal for the first time a dramatic increase of UDP-sugars in breast cancer, and suggest that their high supply drives the accumulation of hyaluronan, a known promoter of breast cancer and other malignancies. In general, the study shows how the disturbed glucose metabolism typical for malignant tumors can influence cancer microenvironment through UDP-sugars and hyaluronan.

Comprehensive MR Urography Protocol: Equally Good Diagnostic Performance and Enhanced Visibility of the Upper Urinary Tract Compared to Triple-Phase CT Urography

Objectives To prospectively compare the diagnostic performance and the visualization of the upper urinary tract (UUT) using a comprehensive 3.0T- magnetic resonance urography (MRU) protocol versus triple-phase computed tomography urography (CTU). Methods During the study period (January-2014 through December-2015), all consecutive patients in our tertiary university hospital scheduled by a urologist for CTU to exclude UUT malignancy were invited to participate. Diagnostic performance and visualization scores of 3.0T-MRU were compared to CTU using Wilcoxon matched-pairs test. Results Twenty patients (39 UUT excreting units) were evaluated. 3.0T-MRU and CTU achieved equal diagnostic performances. The benign etiology of seven UUT obstructions was clarified equally with both methods. Another two urinary tract malignant tumors and one benign extraurinary tumor were detected and confirmed. Diagnostic visualization was slightly better in the intrarenal cavity areas with CTU but worsened towards distal ureter. MRU showed consistently slightly better visualization of the ureter. In the comparison, full 100% visualizations were detected in all areas in 93.6% (with 3.0T-MRU) and 87.2% (with CTU) and >75% visualization in 100% (3.0T-MRU) and 93.6% (CTU). Mean CTU effective radiation dose was 9.2 mSv. Conclusions Comprehensive 3.0T-MRU is an accurate imaging modality achieving comparable performance with CTU; since it does not entail exposure to radiation, it has the potential to become the primary investigation technique in selected patients. Trial Registration ClinicalTrials.gov NCT02606513

Galactography is not an obsolete investigation in the evaluation of pathological nipple discharge

Purpose To evaluate the malignancy rate and diagnostic performance of galactography in patients with pathological nipple discharge (PND) after negative clinical breast examination, mammography and ultrasound. Materials and methods We retrospectively evaluated all galactograms obtained between January 2006 and December 2014 in women with PND. Galactographic findings were classified into 6 groups according to a modified Galactogram Image Classification system (GICS) to comply with the breast imaging reporting and data system classification. Observers were blinded to the final histology and clinical outcome at the time of analysis. MRI was performed as a problem solving ancillary examination. Imaging findings, pathological diagnosis and follow-up data were evaluated. The diagnostic performance of MRI and technically successful galactography in the detection of neoplastic or risk lesions were separately calculated. Results A total of 146 patients with PND (mean age, 51.5 years; range, 17–93) were examined. Malignant lesions were detected in only 4 patients (2.7%) and risk-lesions in 5 patients (3.4%). Only one low-grade ductal carcinoma in situ was missed by galactography (GICS 1) and MRI. MRI examinations were performed in 21 (14.4%) patients; one of these patients (4.8%) had a malignant finding (GICS 0), two (9.5%) had risk-lesions (GICS 2 and 5). In the detection of neoplastic or risk lesions the sensitivity and specificity of galactography were 77.4% and 75.7% and of MRI 85.7% and 71.4%, consecutively. Conclusion The malignancy rate is negligible if clinical, mammography, ultrasound and galactography examinations are negative. Galactography remains a practical, valuable and cost-effective examination procedure. If galactography is technically unsuccessful, MRI should be considered as an additional ancillary tool to evaluate the possible etiology of symptoms, but the routine use of MRI in all patients cannot be justified.

Feasibility of mapping breast cancer with supine breast MRI in patients scheduled for oncoplastic surgery

ObjectivesTo prospectively determine the feasibility of preoperative supine breast MRI in breast cancer patients scheduled for oncoplastic breast-conserving surgery.MethodsIn addition to a diagnostic prone breast MRI, a supplementary supine MRI was performed with the patient in the surgical position including skin markers. Tumours’ locations were ink-marked on the skin according to findings obtained from supine MRI. Changes in tumours’ largest diameter and locations between prone and supine MRI were measured and compared to histology. Nipple-to-tumour and tumour-to-chest wall distances were also measured. Tumours and suspicious areas were surgically removed according to skin ink-markings. The differences between MRI measurements with reference to histopathology were evaluated with the paired-sample t test.ResultsFourteen consecutive patients, 15 breasts and 27 lesions were analysed. Compared to histology, prone MRI overestimated tumour size by 47.1% (p = 0.01) and supine MRI by 14.5% (p = 0.259). In supine MRI, lesions’ mean diameters and areas were smaller compared to prone MRI (– 20.9%, p = 0.009 and – 38.3%, p = 0.016, respectively). This difference in diameter was more pronounced in non-mass lesions (– 31.2%, p = 0.031) compared to mass lesions (– 9.2%, p = 0.009). Tumours’ mean distance from chest wall diminished by 69.4% (p < 0.001) and from nipple by 18.2% (p < 0.001). Free microscopic margins were achieved in first operation in all patients.ConclusionsSupine MRI in the surgical position is feasible and useful in the precise localisation of prone MRI-detected lesions and provides a helpful tool to implement in surgery. Supine MRI more accurately determines tumours’ size and location and might have an important role to diminish overestimations.Key Points•Breath-hold supine breast MRI is feasible using commercially available coils and sequences.•Size and area of lesions on MRI were consistently smaller when measured from the supine position as compared to the prone position.•Supine breast MRI is useful in the precise preoperative localisation of prone MRI-detected lesions.•

Abstract P4-02-14: Incidentally detected enhancing lesions found on preoperative breast MRI: Analysis of T2 signal intensity and apparent diffusion coefficient significantly improve classification

Purpose and Background− Reportedly, magnetic resonance imaging (MRI) detects mammographically and sonographically (US) occult incidental lesions in 10-29% of patients with a malignant primary breast lesion. We evaluated diagnostic performance of the BI-RADS reporting system and utility of T2- and diffusion weighted imaging (DWI) for MRI detected additional lesions. Methods− This prospective study protocol included 3.0T structural breast MRI with T2-weighted imaging and DWI performed according to EUSOMA guidelines in 112 consecutive patients with primary breast lesions (mean age 57.0±12.7 years, range 38-80 years). Breast lesions with one or more suspective feature according to the BI-RADS lexigon were biopsied. T2 signal intensity (SI) and DWI findings were assessed. Results− Altogether 33 (29.5%) patients had 36 primarily MRI detected incidental additional lesions. In addition, 36 sographically or mammographically detected lesions were histopathologically confirmed and a total of 8 lesions were followed up. Of incidental lesions, 16 (44.4%) proved to be malignant. Mean size was 0.82±0.29 cm (range 0.5 cm to 1.5 cm) and 1.5±1.61 cm (range 0.5 cm to 5.0 cm) for 29 mass lesions and 7 NMLE lesions, respectively. In mass lesions, traditional morphological or kinetic features were not correlated to malignancy except for fast initial enhancement (P=0.003). The BI-RADS classification produced 100% sensitivity, 40% specificity, 53.3% PPV, 100% NPV and 51.7% overall accuracy. Both the low T2 SI (P=0.05) and low ADC values (P Conclusion− A single suspective morphologic or kinetic MRI feature is the most sensitive parameter to discover an incidental breast malignancy, as some incidental lesions present with only a few suspicious MRI feature. Specificity of MRI is improved when T2 SI or DWI are addressed. Citation Format: Arponen O, Sudah M, Masarwah A, Sutela A, Vanninen R. Incidentally detected enhancing lesions found on preoperative breast MRI: Analysis of T2 signal intensity and apparent diffusion coefficient significantly improve classification. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-14.

Abstract 39: UDP-N-acetylglucosamine as a regulator of cancer cell signaling and microenvironment

A common feature to most cancers is their disturbed glucose metabolism: increased glucose and glutamine uptake combined with preference to utilize aerobic glycolysis, a phenomenon called Warburg effect. In addition to providing fast, yet inefficient way to produce energy, Warburg effect increases the availability of glycolysis intermediates that function as starting points of metabolic pathways facilitating the fast cell proliferation. One of the pathways involved is the hexosamine biosynthesis producing UDP-N-acetylglycosamine (UDP-GlcNAc). UDP-GlcNAc is a nucleotide sugar with pivotal functions as a key substrate for the synthesis of glycoconjugates like hyaluronan, and as a metabolic sensor that controls cell functions through O-GlcNAcylation of intracellular proteins. UDP-GlcNAc is linked to cancer through its dependence on glycolysis intermediate availability and by the fact that both hyaluronan and O-GlcNAcylation are closely involved in the development and progression of various cancers. Our hypothesis is that the disturbed sugar metabolism increases the levels of UDP-GlcNAc, which implements its tumorigenic effects through hyaluronan and O-GlcNAcylation, and that these changes manifest themselves also in clinical data. In order to test our hypothesis we collected 33 biopsy samples from breast cancer patients, and 13 healthy control samples. Clinical data and immunohistochemical samples are available from the operated patients. From these samples we have analyzed UDP-sugar content with HPLC, hyaluronan levels with ELISA-like method and by immunohistochemistry, and measured mRNA expression of key enzymes with quantitative RT-PCR. Our results show for the first time that UDP-sugars levels are indeed elevated in breast cancer patients. The level of UDP-GlcNAc shows a 12-times increase, while other UDP-sugars were 4 to 6 times higher. To investigate the cause of differential increment of UDP-GlcNAc and other UDP-sugars, we measured the mRNA levels of genes regulating the synthesis of UDP-GlcNAc. Cancer patients had increased expression of GFAT2 while others (GFAT1, GNPDA1 and 2) remained unchanged. In accordance to our hypothesis, the increased levels of UDP-GlcNAc correlated with changes in the mRNA expression of enzymes involved in both hyaluronan synthesis and O-GlcNAcylation of proteins. Our results show that the increased glucose uptake associated to aerobic glycolysis dramatically increases UDP-sugars in breast cancer, promoting malignant growth by increased hyaluronan synthesis and O-GlcNAc signaling. Citation Format: Sanna Oikari, Satu Tiainen, Tiia Kettunen, Amro Masarwah, Ritva Vanninen, Markku Tammi, Paivi Auvinen. UDP-N-acetylglucosamine as a regulator of cancer cell signaling and microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 39.