Diffusion weighted MR imaging of mediastinal lymphadenopathy

Transcription

1 Jpn J Radiol (2015) 33: DOI /s ORIGINAL ARTICLE Diffusion weighted MR imaging of mediastinal lymphadenopathy in children Ahmed Abdel Khalek Abdel Razek 1 Ghada Gaballa 1 Rasha Elashry 2 Sahar Elkhamary 1 Received: 18 September 2014 / Accepted: 2 May 2015 / Published online: 12 June 2015 Japan Radiological Society 2015 Abstract Purpose To assess mediastinal lymphadenopathy in children with diffusion-weighted MR imaging. Materials and methods Retrospective analysis of 29 consecutive children (18 boys and 11 girls aged 2 15 years) with mediastinal lymphadenopathy. They underwent single-shot echo planar diffusion-weighted MR imaging of the mediastinum with b factors of 0, 300, and 600 s/mm 2. The ADC value of the mediastinal lymph nodes was calculated and correlated with biopsy results; statistical analysis was also performed. Results The mean ADC value for malignant mediastinal lymphadenopathy (n = 20) (0.99 ± mm 2 /s) was significantly lower (P = 0.001) than that for benign lymphadenopathy (n = 9) (1.35 ± mm 2 /s). There was significant difference between ADC values for non-hodgkin lymphoma and metastatic nodes (P = 0.04). For differentiating malignant from benign mediastinal lymphadenopathy, the best result was obtained when an ADC value of mm 2 /s was used as a threshold value; area under the curve was 0.861, accuracy 93.1 %, sensitivity 100 %, specificity of 77.8 %, positive predictive value 90.9 %, and negative predictive value of 100 %. Conclusion Diffusion-weighted MR imaging is a promising non-invasive imaging modality that can be used for differentiation of malignant from benign mediastinal lymphadenopathy in children. * Ahmed Abdel Khalek Abdel Razek arazek@mans.edu.eg 1 2 Department of Diagnostic Radiology, Mansoura Faculty of Medicine, Mansoura, DK 13351, Egypt Department of Pediatric Oncology, Mansoura University Oncology Center, Mansoura, Egypt Keywords Diffusion Mediastinum Lymph node MR imaging Child Introduction A range of neoplastic, inflammatory, and granulomatous diseases with mediastinal lymphadenopathy can occur in children. Differentiation of malignant from benign mediastinal lymphadenopathy in children is essential for treatment planning and for prediction of prognosis [1, 2]. CT scanning is commonly used for assessment of mediastinal nodes in children, but it cannot accurately differentiate malignant from inflammatory nodes [3 5]. Recently, dual-energy CT [6, 7] and CT perfusion [8] have been used for assessment of lymph nodes in different regions of the body, but they are associated with exposure of children to radiation. Ultrasound can be used for children but cannot be used to assess mediastinal nodes and is operator-dependent [9]. MR imaging of the chest is of limited value for evaluation of mediastinal lymph nodes in children because of motion artifacts [10, 11]. Biopsy is the recommended method for assessment of mediastinal lymphadenopathy, but is an invasive procedure and may be associated with sampling error [12, 13]. Diffusion-weighted MR imaging is a non-invasive technique not associated with radiation exposure or contrast medium injection. Diffusion of water molecules is affected by many of the characteristic features of malignant tumors, including rapid cell proliferation, high cell density, large nuclei, high intracellular macromolecular proteins, high nuclear/cytoplasm ratio, and reduced extracellular space compared with normal tissue. Diffusionweighted MR imaging of the chest [14, 15] is used for assessment of pulmonary [16] and mediastinal masses

2 450 Jpn J Radiol (2015) 33: [17, 18]. Diffusion-weighted MR imaging has also been used for characterization of mediastinal [19, 20], abdominal [21], neck [22], and axillary [23] lymph nodes. Diffusion-weighted MR imaging has been used for evaluation of mediastinal [24], abdominal [25], and neck masses [26] in children. As far as we are aware, diffusion-weighted MR imaging has not previously been to study mediastinal lymph nodes in children. The purpose of this work was to assess mediastinal lymphadenopathy in children by use of diffusion-weighted MR imaging. Materials and methods Retrospective analysis was performed on 32 children aged less than 17 years with mediastinal lymphadenopathy. The inclusion criterion was children with untreated mediastinal lymphadenopathy clinically suggestive of malignancy who underwent diffusion MR imaging of the chest. Exclusion criteria were poor diffusion-weighted MR image quality because of susceptibility artifact and motion artifacts for 3 children. The children eventually included in the study were 18 boys and 11 girls, age 2 15 years. Patients presented with dyspnea (n = 17), cough (n = 14), and chest pain (n = 9). Final diagnosis of mediastinal lymphadenopathy was by histopathological examination with mediastinoscopy and ultrasound guided percutaneous mediastinal lymph node biopsy. Institutional board approval was obtained and informed consent of parents of patients was waived because this is a retrospective study. MR imaging was performed at 1.5 T (Symphony; Siemens Medical Systems, Erlangen, Germany). The machine was equipped with a self-shielded gradient set (30 mt/m maximum gradient strength and 120 T/m/s slew rate) for echo-planner imaging. All patients underwent axial and coronal true FISP (TR/TE = 4.3/2.1 ms) of the chest and axial T1-weighted spin echo (TR/TE = 600/20 ms) with a section thickness of 8 mm, interslice gap of 1 2 mm, field of view of cm, and acquisition matrix of Diffusion-weighted MR imaging was performed with a multislice, spin-echo, echo-planar image sequence. Diffusion-weighted MR imaging was performed during free breathing without cardiac gating. A set of multiple axial scans (20 25 slices) of the whole chest was obtained. The imaging conditions were TR/TE 6000/108 ms, FOV cm, section thickness of 8 mm, interslice gap 1 2 mm, matrix , number of averages 8, and bandwidth 300 khz. The diffusion gradients were applied in three orthogonal directions. We used the automatic multiangle-projection shim and chemical shift selective fat-suppression (CHESS) technique to reduce artifacts in diffusion-weighted MR imaging. Diffusion-weighted MR imaging was performed with b factors of 0, 300, and 600 s/ mm 2. The ADC maps were automatically generated on the operating console. The data acquisition time for the diffusion-weighted MR imaging was 2 min. Diffusion-weighted MR imaging were interpreted by 2 radiologists (GG, ES) with 12 and 15 years MR experience, unaware of the clinical findings and final diagnosis. Disagreement between the reviewers was solved by consensus. The longest diameter of the mediastinal lymph nodes was calculated. First, both radiologists, by consensus, selected for analysis, lymph nodes that were distant from vascular structures and appeared as homogeneous intermediate signal intensity in true FISP images not affected by artifacts due to chemical shift or magnetic susceptibility. Then, a free hand region of interest (ROI) (3 5 cm 2 ) was placed by one radiologist (GG) on the apparent diffusion coefficient (ADC) map around the selected lymph node that approved by the other radiologist (ES). For patients with multiple enlarged discrete nodes, the ROI was placed around the largest node; for patients with an amalgamated mass of an enlarged lymph node, the ROI was placed where signal intensity was not as high as for cysts and appeared at intermediate signal intensity in true FISP images. Measurement of ADC was performed once for each case. Statistical analysis of data was performed by use of Statistical Package for Social Sciences (version 16; SPSS, Chicago, IL, USA). The mean and standard deviation were calculated for malignant and benign mediastinal lymphadenopathy. A one-way ANOVA test was performed to compare more than two groups and Student s t test was used to compare two groups. The P value was significant if 0.05 at a confidence interval of 95 %. The receiver operating curve (ROC) was drawn to detect the cut off point used to differentiate malignant from benign mediastinal lymphadenopathy with calculation of area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results The pathological causes of malignant mediastinal lymphadenopathy (n = 20) were non-hodgkin lymphoma (n = 8), Hodgkin disease (n = 6), leukemia (n = 3), or metastatic lymph nodes from distant sites (n = 3). The primary tumor was testicular carcinoma (n = 2) or Wilms tumor (n = 1). The histopathological diagnosis of benign mediastinal lymphadenopathy (n = 9) was tuberculous nodes (n = 4), sarcoidosis (n = 3), Langerhans cell histiocytosis (n = 1), and histoplasmosis (n = 1). The mean diameter of benign mediastinal lymph nodes was 2.5 ± 0.8 cm; that of malignant lymph nodes was 3.9 ± 1.2 cm.

3 Jpn J Radiol (2015) 33: Table 1 ADC values of malignant and benign mediastinal lymphadenopathy in children ADC (mean and SD) ( 10 3 mm/s) ADC (min) ADC (max) Malignant (n = 20) 0.99 ± Non-Hodgkin lymphoma (n = 8) 0.85 ± Hodgkin lymphoma (n = 6) 1.00 ± Leukemia (n = 3) 1.09 ± Metastatic (n = 3) 1.19 ± Benign (n = 9) 1.35 ± Tuberculous (n = 4) 1.50 ± Sarcoidosis (n = 3) 1.44 ± Histoplasmosis (n = 1) 0.82 Langerhans cell histiocytosis (n = 1) 1.01 ADC apparent diffusion coefficient, Max maximum, Min minimum, SD standard deviation Fig. 1 Mediastinal non- Hodgkin lymphoma. a Axial T1-weighted image of the chest shows a large amalgamated mass of enlarged anterior mediastinal lymph nodes. b Axial true FISP image of the chest shows a large amalgamated mass of enlarged anterior mediastinal lymph nodes with intermediate signal intensity. c Axial ADC map shows restricted diffusion of the node with low ADC ( mm 2 /s). d Pathological specimen showing diffuse infiltration by large cells of non-hodgkin lymphoma stained with hematoxylin and eosin The mean ADC value of malignant mediastinal lymphadenopathy (n = 20) was 0.99 ± mm 2 /s; that of benign lymphadenopathy (n = 9) was 1.35 ± mm 2 /s. Table 1 shows the ADC values of malignant and benign mediastinal lymphadenopathy. There was a significant difference between ADC values for malignant and benign lymphadenopathy (P = 0.001). Restricted diffusion and low ADC value were observed for mediastinal malignant lymphadenopathy (Fig. 1). Mean ADC value was lower for patients with non-hodgkin lymphoma (0.85 ± mm 2 /s) than for those with Hodgkin disease (1.0 ± mm 2 /s) although the difference was not significant (P = 0.79). The lowest ADC value ( mm 2 /s) was for in patients with non- Hodgkin lymphoma. ADC value was significantly different for patients with non-hodgkin lymphoma and metastatic lymph nodes (P = 0.04). Unrestricted diffusion and higher ADC values were observed for benign nodes. The mean ADC value for benign mediastinal nodes was 1.35 ± mm 2 /s

4 452 Jpn J Radiol (2015) 33: Fig. 2 Mediastinal sarcoidosis. a Axial T1-weighted image of the chest shows a large amalgamated mass of enlarged anterior mediastinal lymph nodes. b Axial true FISP image of the chest shows a large amalgamated mass of enlarged anterior mediastinal lymph nodes with intermediate signal intensity. c Axial ADC map shows restricted diffusion of the nodes with low ADC ( mm 2 /s). d Pathological specimen showing multiple non-caseating naked epithelioid granulomas stained with hematoxylin and eosin and another with Langerhans cell histiocytosis of the mediastinal node; for these patients the nodes were misdiagnosed as malignant nodes. Intermediate signal intensity on T1-weighted images and true FISP images, similar to results for other benign and malignant lymph nodes in this study, were observed for these nodes. The best result was obtained when an ADC value of mm 2 /s was used as a threshold value for differentiating malignant from benign mediastinal lymphadenopathy; the AUC was 0.861, accuracy 93.1 %, sensitivity 100 %, specificity 77.8 %, PPV 90.9 %, and NPV 100 % (Fig. 3). Discussion Fig. 3 Receiver operating characteristic (ROC) curve. The threshold ADC value used for differentiating malignant from benign mediastinal lymphadenopathy was mm 2 /s; the AUC was 0.861, accuracy 93.1 %, sensitivity 100 %, specificity 77.8 %, PPV 90.9 %, and NPV 100 % (Fig. 2). The highest ADC value was reported for a child with sarcoidosis ( mm 2 /s). The ADC values for sarcoid and tuberculous nodes not significantly different (P = 0.07). Restricted diffusion and low ADC values for nodes were observed for one patient with histoplasmosis There have been a few limited studies on diffusionweighted MR imaging of mediastinal masses [17, 18] and lymph nodes in adults [19, 20]. Mean ADC values for adult malignant mediastinal tumors are significantly lower than for benign tumors. In this study, selection of mm 2 /s as a cutoff for differentiating malignant from benign mediastinal nodes resulted in accuracy of 93.1 %, sensitivity of 100 %, and specificity of 77.8 %. Another study reported that metastatic lymph nodes are usually more hypointense than benign lymph nodes, and benign lymph nodes are usually hyperintense on ADC maps. When a single-shot echo-planar sequence with

5 Jpn J Radiol (2015) 33: b values of 50 and 400 s/mm 2 are used the ADC is significantly lower (P = ) for metastatic lymph nodes (1.012 ± mm 2 /s) than for benign lymph nodes (1.511 ± mm 2 /s) in adult patients with mediastinal lymphadenopathy. Malignant nodes commonly appear hypointense whereas benign nodes appear hyperintense on ADC maps; however, mixed signal intensities may be obtained for malignant and benign nodes [19]. The mean ADC value for malignant mediastinal lymphadenopathy (1.06 ± mm 2 /s) is significantly (P = 0.001) lower than that for benign lymphadenopathy (2.39 ± mm 2 /s) in images obtained from adult patients and use of b values of 0 and 600 s/mm 2 [20]. These ADC values are significant for detection of malignant lymph nodes, both enlarged mediastinal lymph nodes (P < 0.001) and normal lymph nodes (P < 0.001) [27]. This preliminary study indicates that diffusion-weighted MR imaging can distinguish benign from malignant lymph nodes with high degree accuracy. Restricted diffusion with lower ADC values were observed for malignant mediastinal lymphadenopathy compared with benign nodes. The different ADC value is believed to be because of different cellularity. In highly cellular malignant tumors, extracellular water diffusion is restricted by cell membranes; this will lead to a short diffusional path and a reduced ADC value. Conversely, for benign tumors with fewer structural barriers, the longer diffusional path would be associated with a higher ADC value [14 18]. In another study of adult patients with mediastinal lymphadenopathy [20], an ADC value of mm 2 /s was used as a threshold to differentiate malignant from benign lymphadenopathy. The promising result in our study is different from other literature results [20]. This may be attributed to different methods of calculation of the ADC value, different histopathological causes of mediastinal lymphadenopathy, and different ages of the patients, because our study was performed on children rather than adult patients [20]. Diffusion-weighted MR imaging is used for characterization of malignancy in different part of the body. It is also used for differentiating lymphoma from squamous cell carcinoma of the head and neck [11]. In this study, ADC values were significantly different for non-hodgkin lymphoma and metastatic nodes. This was attributed to high cellularity of lymphomatous nodes with subsequent restricted diffusion and lower ADC value. Two patients with histoplasmosis and Langerhans cell histiocytosis had relatively low ADC values, and mediastinal lymphadenopathy was mistaken for malignant nodes. On T1-weighted images and true FISP images these nodes had intermediate signal intensity similar to other benign and malignant mediastinal nodes reported in this study. Pathological analysis of these two nodes revealed that the 453 dominant reaction was dense fibrous reaction with multiple areas of calcification and subsequent restriction of the water diffusion. The contributions of dense fibrous tissue with multiple areas of calcification may alter the diffusivity of the lesions and account for the relatively low ADC values found in these two patients. Lymph node calcifications can also be found in patients with tuberculous and sarcoidosis, however, and are expected to have lower ADC values because of possible restricted water movement in the presence of calcification. No evidence of calcification was observed for these patients, however, possibly because they were in the early stages of the disease. Further studies on a large number of patients with different stages of the disease may improve the results and aid better understanding the pathophysiological changes that occur in these patients. In this study, echoplanar diffusion-weighted MR imaging was used for evaluation of mediastinal lymphadenopathy in children. Echoplanar MR imaging is a very fast technique that enables data acquisition within a short time but is sensitive to magnetic susceptibility effects. Susceptibility artifacts can be reduced by application of parallel imaging [18 28]. The potential problem when using diffusionweighted MR imaging for mediastinal imaging is intrinsic low spatial resolution. Use of fusion software enables overlaying of anatomic and diffusion-weighted MR imaging sequences, partially solving this problem [14, 15]. This study has a few limitations. First, the small number of patients with mediastinal lymphadenopathy limits its statistical power. Further studies with larger patient cohorts are recommended to confirm these preliminary results. Second, the ROI was placed manually, with bias from selection of region of interest, and it might be difficult to evaluate precisely the ADC for relatively small lymphadenopathy in children. Further studies with application of advanced image analysis, for example histogram analysis, are recommended. Third, CT scanning and routine MR imaging was not conducted for the patients, so calcification was not evaluated by CT and cysts was not evaluated by use of routine MR imaging. Further studies with correlations between ADC maps and routine CT and MR findings are recommended in the future. Conclusion We concluded that diffusion-weighted MR imaging is a non-invasive promising imaging modality that can be used for differentiation of malignant from benign mediastinal lymphadenopathy in children and can be added to routine MR imaging of the chest. Conflict of interest The authors declare that they have no conflict of interest.

6 454 Jpn J Radiol (2015) 33: References 1. Ranganath S, Lee E, Restrepo R, Eisenberg R. Mediastinal masses in children. AJR Am J Roentgenol. 2012;198:W Lee E. Evaluation of non-vascular mediastinal masses in infants and children: an evidence-based practical approach. Pediatr Radiol. 2009;39:S de Jong PA, Nievelstein RJ. Normal mediastinal and hilar lymph nodes in children on multi-detector row chest computed tomography. Eur Radiol. 2012;22: Tang S, Yang Z, Deng W, Shao H, Chen J, Wen L. Differentiation between tuberculosis and lymphoma in mediastinal lymph nodes: evaluation with contrast-enhanced MDCT. Clin Radiol. 2012;67: Razek AA. Pathologies of the mediastinum. In: Luca S, Suri JS, editors. Multi-detector CT imaging: principles, head, neck, and vascular systems. 1st ed. Boca Raton: CRC Press, Taylor and Francis/CRC Press; p Yoo SY, Kim Y, Cho HH, Choi MJ, Shim SS, Lee JK, et al. Dual-energy CT in the assessment of mediastinal lymph nodes: comparative study of virtual non-contrast and true non-contrast images. Korean J Radiol. 2013;14: Tawfik AM, Kerl JM, Razek AA, Bauer RW, Nour-Eldin NE, Vogl TJ, et al. Image quality and radiation dose of dual-energy CT of the head and neck compared with a standard 120 kvp acquisition. Am J Neuroradiol. 2011;32: Razek AA, Tawfik A, Elsorogy L, Soliman N. Perfusion CT of head and neck cancer. Eur J Radiol. 2014;83: Bosch-Marcet J, Serres-Creixams X, Zuasnabar-Cotro A, Codina-Puig X, Catala-Puigbo M, et al. Comparison of ultrasound with plain radiography and CT for the detection of mediastinal lymphadenopathy in children with tuberculosis. Pediatr Radiol. 2004;34: Boiselle PM. MR imaging of thoracic lymph nodes. A comparison of computed tomography and positron emission tomography. Magn Reson Imaging Clin N Am. 2000;8: Abdel Razek AA, Gaballa G. Role of perfusion MR imaging in cervical lymphadenopathy. J Comput Assist Tomogr. 2011;35: Goussard P, Gie R, Kling S, Nel E, Louw M, Schubert P, et al. The diagnostic value and safety of transbronchial needle aspiration biopsy in children with mediastinal lymphadenopathy. Pediatr Pulmonol. 2010;45: McCrone L, Alexander S, Karsli C, Taylor G, Amaral J, Parra D, et al. US-guided percutaneous needle biopsy of anterior mediastinal masses in children. Pediatr Radiol. 2012;42: Razek AA. Diffusion magnetic resonance imaging of chest tumors. Cancer Imaging. 2012;12: Chen L, Zhang J, Bao J, Zhang L, Hu X, Xia Y, et al. Meta-analysis of diffusion-weighted MRI in the differential diagnosis of lung lesions. J Magn Reson Imaging. 2013;37: Razek AA, Fathy A, Gawad TA. Correlation of apparent diffusion coefficient value with prognostic parameters of lung cancer. J Comput Assist Tomogr. 2011;35: Gümüştaş S, İnan N, Sarisoy H, Anik Y, Arslan A, Çiftçi E, et al. Malignant versus benign mediastinal lesions: quantitative assessment with diffusion weighted MR imaging. Eur Radiol. 2011;21: Razek AA, Elmorsy A, Elshafey M, Elhadedy T, Hamza O. Assessment of mediastinal tumors with diffusion-weighted single-shot echo-planar MR imaging. J Magn Reson Imaging. 2009;30: Kosucu P, Tekinbas C, Erol M, Sari A, Kavgaci H, Oztuna F, et al. Mediastinal lymph nodes: assessment with diffusionweighted MR imaging. J Magn Reson Imaging. 2009;30: Abdel Razek AA, Elkammary S, Elmorsy AS, Elshafey M, Elhadedy T. Characterization of mediastinal lymphadenopathy with diffusion-weighted imaging. Magn Reson Imaging. 2011;29: Cheng J, Wang Y, Deng J, McCarthy R, Wang G, Wang H, et al. Discrimination of metastatic lymph nodes in patients with gastric carcinoma using diffusion-weighted imaging. J Magn Reson Imaging. 2013;37: Abdel Razek AA, Soliman NY, Elkhamary S, Alsharaway MK, Tawfik A. Role of diffusion-weighted MR imaging in cervical lymphadenopathy. Eur Radiol. 2006;16: Luo N, Su D, Jin G, Liu L, Zhu X, Xie D, et al. Apparent diffusion coefficient ratio between axillary lymph node with primary tumor to detect nodal metastasis in breast cancer patients. J Magn Reson Imaging. 2013;38: Abdel Razek AA, Soliman N, Elashery R. Apparent diffusion coefficient values of mediastinal masses in children. Eur J Radiol. 2012;81: Gawande RS, Gonzalez G, Messing S, Khurana A, Daldrup- Link HE. Role of diffusion-weighted imaging in differentiating benign and malignant pediatric abdominal tumors. Pediatr Radiol. 2013;43: AbdelRazek AA, Gaballa G, Elhawarey G, Megahed A, Hafez M, Nada N. Characterization of pediatric head and neck masses with diffusion-weighted MR imaging. Eur Radiol. 2009;19: Xu L, Tian J, Liu Y, Li C. Accuracy of diffusion-weighted (DW) MRI with background signal suppression (MR-DWIBS) in diagnosis of mediastinal lymph node metastasis of nonsmall-cell lung cancer (NSCLC). J Magn Reson Imaging. 2014;40: Abdel Razek AA, Khairy M, Nada N. Diffusion-weighted MR imaging in thymic epithelial tumors: correlation with World Health Organization classification and clinical staging. Radiology. 2014;273: