The Efficacy of MRI with Ultrasmall Superparamagnetic Iron Oxide ...

ANTICANCER RESEARCH 25: 3665-3670 (2005)

The Efficacy of MRI with Ultrasmall Superparamagnetic Iron Oxide Particles (USPIO) in Head and Neck Cancers MEHRAN BAGHI1, MARTIN G. MACK2, MARKUS HAMBEK1, JOERG RIEGER2, THOMAS VOGL2, WOLFGANG GSTOETTNER1 and RAINALD KNECHT1 1Department

of ENT Surgery and 2Department of Diagnostic and Interventional Radiology, University of Frankfurt, 60590 Frankfurt/Main, Germany

Abstract. Background: The objective was to evaluate the diagnostic accuracy of ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) compared to plain MRI in patients with a clinical N+ neck using histology as a gold standard. Materials and Methods: Twenty-eight patients underwent unenhanced and USPIOenhanced MRI using T1-weighted spin echo (SE) sequences and high resolution Turbo-Spin-Echo (TSE) T2-weighted sequences, as well as T2-weighted Gradient Echo (GE) sequences in axial and sagittal slice orientation. The signal intensity (SI) decrease was measured by a region of interest evaluation and visual analysis was performed. Results: Histopathological evaluation of 363 lymph nodes revealed 34 as metastatic. USPIO MRI detected 28 metastases (sensitivity 82.3%) and 329 non-metastatic lymph nodes (specificity 100%). Regarding lymph node size, USPIO MRI was correct in all patients who underwent surgery. One lymph node with microinfiltration of tumor cells was detected by USPIO MRI. Conclusion: There were no side-effects during or after application of the contrast agent. This study confirms the efficacy of MRI with USPIO in patients with head and neck cancer. USPIO-enhanced MRI could have an important effect on surgery planning. Because of its high specificity, USPIOenhanced MRI seems to be a diagnostic modality able to differentiate borderline-sized lymph nodes. The N-staging of patients with head and neck cancer presenting border-line-sized lymph nodes remains problematic. The N-staging is based on different imaging techniques

Correspondence to: Rainald Knecht, MD, Ph.D., ENT Department of Johann Wolfgang Goethe Universitiy Clinic, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany. Tel: +49-69-63014471, Fax: +49-69-63017710, e-mail: [email protected] Key Words: MR lymphography, Sinerem MRI, lymph node staging in head and neck cancers.

0250-7005/2005 $2.00+.40

(ultrasonography, CT, unenhanced or gadolinium-enhanced MR) that use node size and presence of central necrosis as diagnostic criteria (32). These cross-sectional imaging techniques allow visualization of lymph nodes that may not be palpable on physical examination (1). The diagnosis of lymph node metastases is based mainly on the measurement of nodal dimensions, such as maximum transverse diameter (2-8) or ratios of maximum longitudinal to maximum transverse diameter (9). To date, it is still difficult to differentiate nonenlarged, borderline-sized metastatic lymph nodes without central necrosis or extracapsular spread from the enlarged reactive or inflammatory lymph nodes seen in cancer patients. The enhancement pattern, shape and grouping of lymph nodes are further criteria with less importance. All of these criteria remain controversial, and recommendations for differentiating between benign and malignant lymph nodes by imaging studies vary widely (2-8, 10). The currently applied morphological criteria allow reliable detection only of large metastatic lymph nodes with central necrosis or extracapsular spread. Lymph node metastases in the head and neck region will, however, often be less than 10 mm, and occasionally even less than 5 mm in diameter (11, 32). Intravenously-injected small iron oxide particles pass through the vascular endothelium into the interstitium and are eventually taken up by normally functioning lymph nodes and inflamed lymph nodes, to be phagocytosed by components of the reticuloendothelial system, such as macrophages or histiocytes (32). These normal lymph nodes show a signal intensity (SI) decrease on T2-weighted magnetic resonance images (MRI) because of the effects of magnetic susceptibility and T2 shortening on the iron deposits. Metastatic lymph nodes, however, have lost their mechanism for phagocytosis and, therefore, do not show the reduced SI, which potentially allows them to be differentiated from benign lymph nodes (32). The purposes of our study were to compare findings on USPIO-enhanced MRI of the head and neck with those of resected lymph node specimens

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Figure 1. Sinerem®-enhanced T2-weighted TSE sequence in a tonsillar carcinoma with a malignant lymph node on the left side (level II), which is 5 mm in maximum diameter. This lymph node was detected by Sinerem® MRI. The result was the change of diagnosis N0→N1 and of the treatment (neck dissection on the left side).

and to determine the effect of such imaging findings on surgical planning in patients with histopathologically-proven squamous cell carcinoma of the head and neck.

Materials and Methods Contrast agent. The iron contrast agent Sinerem® (Guerbet, Paris, France) was provided as a lyophilized powder consisting of ultrasmall superparamagnetic particles covered with low molecular weight dextran, with a total particle diameter in solution between 170 and 210 Å (17-21 nm). The contrast agent (2.6 mg of iron per kilogram of body weight) was administered intravenously in a single dose by drip infusion through an infusion filter (0.22 Ìm pore size) at a rate of 4 mL/min. It was diluted in 100 mL of saline. This study was approved by the ethics committee; informed consent was obtained from the patients. Patients. Twenty-eight consecutive patients (26 men, 2 women; mean age, 55.7/55.1 years ; age range, 40-77 years) were examined. The clinical examination and inclusion of patients was performed

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in the Department of ENT Surgery of the University Clinic in Frankfurt, Germany. The types of tumors were as follows: squamous cell carcinoma (SCC) of larynx (n=11), SCC of oropharynx (n=14) and SCC of hypopharynx (n=3). According to the results of clinical examination and ultrasound (US) evaluation, 17/28 patients had metastatic involvement of the lymph nodes of the neck. Imaging technique. All MR examinations were performed with a 1.5 Tesla scanner (Symphony Quantum, Siemens, Erlangen, Germany) in the Department of Diagnostic and Interventional Radiology of the University Clinic, Frankfurt. The complete work up included a T1-weighted spin echo (SE) sequence in transverse and coronal slice orientation, high resolution T2-weighted TSE sequences in transverse and sagittal slice orientation, as well as a T2-weighted fat saturated multiecho gradient-echo (GE) sequence in transverse slice orientation. The same set of sequences was performed plain and 24 to 36 hours after contrast infusion for comparative evaluation. Evaluation. Metastatic lymph node involvement was evaluated by examining the neck of each patient and by examining individual

Baghi et al: MRI with USPIO in Head and Neck Cancers

Figure 2. Histopathological section of a lymph node with micrometastatic infiltration (level II), which was detected in Sinerem®-enhanced MRI in a patient with a tonsillar carcinoma on the left side.

nodes with ultrasound. The nodes were grouped according to the guidelines of the American Joint Committee on Cancer and a simplified level classification (7, 12). The signal intensity (SI) of the lymph node was measured on unenhanced and USPIO-enhanced MRI (all three sequences) by using a region of interest (ROI) evaluation in relation to the background noise. In each patient, SI measurements were taken of all malignant lymph nodes and of 10-15 benign lymph nodes for comparison. The SI ratio for each node was determined as follows: SI ratio=(SInode/SIbackground on USPIO-enhanced images)/ (SInode/ SIbackground on unenhanced images). Because this contrast agent has predominantly T2*-shortening effects, low SI ratios represent decreased SI of nodes, which is expected with normal or benign nodes, whereas high SI ratios represent metastatic nodes. SI ratios were finally presented as a percentage decrease in SI (e.g., SI ratio=0.3=70% decrease in SI). For statistical analysis, the tested analysis of variance was used for comparing the SI ratios. Sensitivity, specificity and positive and negative predictive values were calculated on a node-by-node basis, assuming the independence of the nodes. The size of the lymph nodes was further evaluated. The short and the long axes were measured, where the longitudinal dimension was measured perpendicular to the short axis. Visual analysis was based on the following criteria: unenhanced and USPIO-enhanced images

were compared. Lymph nodes with a homogeneous SI decrease on USPIO-enhanced images compared with SI on unenhanced images were considered normal lymph nodes. Those with no SI decrease on USPIO-enhanced images compared with SI on unenhanced images were considered metastatic lymph nodes. Those with a partial SI decrease on USPIO-enhanced images compared with SI on unenhanced images were considered lymph nodes with partial metastatic infiltration. The prospective criterion for judging a lymph node to be positive or negative was based on SI characteristics alone, and it was a qualitative and quantitative judgement. The image evaluation was performed by two experienced head and neck radiologists by consensus. Unenhanced and USPIO-enhanced images were available to both radiologists at the same time. The images were discussed with the surgeons. The surgical plan was based on clinical, endoscopic and US evaluation, with use of size and shape information obtained before MRI, and was reviewed and modified, if necessary, on the basis of the MRI results. The primary tumor was removed, and a radical or limited neck dissection was performed within 10-14 days of USPIO-enhanced MRI. On the basis of the MRI findings, two patients were no longer candidates for surgery because of extensive tumor infiltration in combination with unresectable lymph node metastases. The mean duration between the end of injection and surgery was 12 days. The potential influence of the results of

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Figure 3. Patient with a T2 supraglottic carcinoma staged as N2b in plain MRI; after Sinerem® application, the N-stage was changed to N2c according to the reduced SI decrease (level II on the right side). This lymph node showed histopathologically a metastatic involvement.

USPIO-enhanced MRI on surgical strategy was documented. Resected specimens were analyzed histopathologically by the pathologist and the results were compared with those of unenhanced and USPIO-enhanced MRI by a head and neck radiologist and an ENT surgeon. Specific lymph nodes were compared together by the surgeon, the pathologist and the radiologist, by using the patient’s MRI, with needle marking of the specimen. However, comparison for all lymph nodes was not possible, especially in patients who received only a limited neck dissection. With histopathological examination as the reference standard, sensitivity, specificity and positive and negative predictive values for nodes depicted on USPIO-enhanced MRI were calculated.

Results All patients tolerated the injection of contrast. There were no side-effects during or after infusion. The two patients, who did not undergo surgery because of extension and infiltration of the tumor, underwent primary radiation or combined radiochemotherapy. The extensive tumor infiltration in these patients was demonstrated on the unenhanced MRI. In all patients, a total of 363 lymph nodes were resected. Thirty-four of these lymph nodes showed metastatic involvement and 329 were histopathologically non-metastatic. All 363 lymph nodes could be identified at least on USPIO-enhanced T2-weighted TSE images. The specificity of USPIO MRI was 100%. MRI enabled correct diagnosis of 28 of the 34 lymph node metastases (sensitivity 82.3%) after USPIO application. In plain MRI, 18 of the 34 lymph node metastases (sensitivity 52%) and 280 of the 329

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non-metastatic lymph nodes (specificity 85%) were detected. Further, in USPIO MRI, the delineation of the metastatic lymph nodes from the surrounding structures was better. According to USPIO MRI and histopathological examination, 22/28 patients had metastatic involvement. Image analysis. Although visual analysis demonstrated even benign lymph nodes