Detection of Lymph Node Metastases by Gadolinium-Enhanced MRI
Detection of Lymph Node Metastases by Gadolinium-Enhanced MRI
Background Gadolinium-based contrast agents are used with magnetic resonance imaging (MRI) to highlight tumor vascularity in organs. They are also widely used for primary tumor visualization. We conducted a systematic review and meta-analysis of the existing evidence of the accuracy of gadolinium-enhanced MRI for staging lymph node metastases.
Methods We systematically searched the MEDLINE, Cochrane, CANCERLIT, and EMBASE databases for studies published in English or German from January 1, 1988, to January 1, 2008, that assessed the diagnostic accuracy of gadolinium-enhanced MRI in the evaluation of lymphatic metastases compared with histopathologic examination as the reference test. Based on a priori–defined clinical considerations, we studied three subgroups of studies: those that used a single malignancy criterion and those that used multiple malignancy criteria with or without contrast highlighting. Summaries of MRI sensitivity and specificity for detecting lymph node metastases were calculated using a bivariate regression model. All statistical tests were two-sided.
Results The literature search yielded 43 full-text papers that were considered for inclusion in the meta-analysis. We performed quantitative pooled analyses on the 32 studies that provided data on patient-level diagnosis. The weighted estimates of sensitivity and specificity for all studies combined were 0.72 (95% confidence interval [CI] = 0.66 to 0.79) and 0.87 (95% CI = 0.82 to 0.91). Estimates of sensitivity and specificity were essentially unchanged for studies that used a single malignancy criterion (0.71 [95% CI = 0.61 to 0.79] and 0.88 [95% CI = 0.80 to 0.93], respectively; n = 11 studies) or multiple malignancy criteria without contrast enhancement (0.70 [95% CI = 0.58 to 0.79] and 0.86 [95% CI = 0.68 to 0.94], respectively; n = 6 studies). The sensitivity increased to 0.84 (95% CI = 0.70 to 0.92), with a specificity of 0.82 (95% CI = 0.72 to 0.89) for the nine studies that incorporated contrast enhancement in their multiple malignancy criteria. Six studies did not define the malignancy criteria they used.
Conclusions The overall accuracy of gadolinium-enhanced magnetic resonance imaging for the detection of nodal metastases is moderate. Incorporating contrast enhancement in the malignancy criteria substantially improves the accuracy of this diagnostic test.
Lymphatic metastasis is an important prognostic factor in malignancies. Most tumors are classified according to the TNM staging system, and treatment and prognosis are modified when lymph node metastases are present. Lymph node staging by physical examination is not accurate in discriminating metastatic from benign lymph nodes. Even in superficial areas such as the cervical and inguinal regions, a physical evaluation of lymph nodes cannot reliably detect metastases. The best method and current reference standard for staging lymph node metastases is histopathologic examination. However, this is an invasive surgical procedure in which complications and morbidity may occur. Noninvasive imaging tools, such as computed tomography and magnetic resonance imaging (MRI), are available as methods to enhance the diagnostic evaluation of lymph nodes. However, conventional MRI and computed tomography mainly evaluate the size of lymph nodes. Although it had been assumed that the use of lymph node characteristics, such as homogeneity, margins, and shape, as diagnostic criteria would improve the ability of MRI to discriminate between benign and metastatic lymph nodes, several studies showed that the use of these morphological characteristics did not improve the accuracy of conventional MRI.
Contrast-enhanced MRI has been proposed as a tool for improving the diagnostic accuracy of nodal metastases detection. One of the contrast agents used with enhanced MRI is ultrasmall superparamagnetic iron oxide (USPIO) particles. A meta-analysis of the diagnostic precision of USPIO-enhanced MRI for detection of lymph node metastasis showed an overall sensitivity of 0.88 (95% confidence interval [CI] = 0.85 to 0.91) and specificity of 0.96 (95% CI = 0.95 to 0.97). However, this staging method also has a number of disadvantages, including the need for slow infusion of the contrast agent 24 hours before imaging to minimize hypersensitivity-related side effects. Moreover, interpretation of the magnetic resonance images is not a trivial task. Consequently, the USPIO contrast agent has not yet been registered at the European Medicines Agency nor has it been approved by the US Food and Drug Administration.
It is thought that the lymph node prepares for metastatic cell implantation by reorganizing lymphatic and vascular structures and, as a consequence, new blood vessels develop within and around lymph nodes. The administration of an intravenous contrast agent, such as gadolinium, can reveal these surrounding blood vessels and demonstrate additional morphological characteristics of tumor tissue. Although gadolinium should be used with care in patients with nephropathy, it is generally accepted as a safe contrast agent when compared with USPIO. As such, it has been used extensively to visualize a variety of tumors with increased angiogenesis and blood flow [eg, ].
The number of studies that have evaluated the accuracy of gadolinium-enhanced MRI to detect nodal metastases compared with that of histopathologic examination has increased sharply in the last decade to more than 30. However, to our knowledge, a systematic review of all of these studies has not yet been undertaken. The purpose of this study was to quantitatively summarize, by means of a meta-analysis, all existing evidence in the literature on the diagnostic accuracy of MRI with intravenously administered gadolinium to detect metastatic lymph nodes in any cancer.
Abstract and Introduction
Abstract
Background Gadolinium-based contrast agents are used with magnetic resonance imaging (MRI) to highlight tumor vascularity in organs. They are also widely used for primary tumor visualization. We conducted a systematic review and meta-analysis of the existing evidence of the accuracy of gadolinium-enhanced MRI for staging lymph node metastases.
Methods We systematically searched the MEDLINE, Cochrane, CANCERLIT, and EMBASE databases for studies published in English or German from January 1, 1988, to January 1, 2008, that assessed the diagnostic accuracy of gadolinium-enhanced MRI in the evaluation of lymphatic metastases compared with histopathologic examination as the reference test. Based on a priori–defined clinical considerations, we studied three subgroups of studies: those that used a single malignancy criterion and those that used multiple malignancy criteria with or without contrast highlighting. Summaries of MRI sensitivity and specificity for detecting lymph node metastases were calculated using a bivariate regression model. All statistical tests were two-sided.
Results The literature search yielded 43 full-text papers that were considered for inclusion in the meta-analysis. We performed quantitative pooled analyses on the 32 studies that provided data on patient-level diagnosis. The weighted estimates of sensitivity and specificity for all studies combined were 0.72 (95% confidence interval [CI] = 0.66 to 0.79) and 0.87 (95% CI = 0.82 to 0.91). Estimates of sensitivity and specificity were essentially unchanged for studies that used a single malignancy criterion (0.71 [95% CI = 0.61 to 0.79] and 0.88 [95% CI = 0.80 to 0.93], respectively; n = 11 studies) or multiple malignancy criteria without contrast enhancement (0.70 [95% CI = 0.58 to 0.79] and 0.86 [95% CI = 0.68 to 0.94], respectively; n = 6 studies). The sensitivity increased to 0.84 (95% CI = 0.70 to 0.92), with a specificity of 0.82 (95% CI = 0.72 to 0.89) for the nine studies that incorporated contrast enhancement in their multiple malignancy criteria. Six studies did not define the malignancy criteria they used.
Conclusions The overall accuracy of gadolinium-enhanced magnetic resonance imaging for the detection of nodal metastases is moderate. Incorporating contrast enhancement in the malignancy criteria substantially improves the accuracy of this diagnostic test.
Introduction
Lymphatic metastasis is an important prognostic factor in malignancies. Most tumors are classified according to the TNM staging system, and treatment and prognosis are modified when lymph node metastases are present. Lymph node staging by physical examination is not accurate in discriminating metastatic from benign lymph nodes. Even in superficial areas such as the cervical and inguinal regions, a physical evaluation of lymph nodes cannot reliably detect metastases. The best method and current reference standard for staging lymph node metastases is histopathologic examination. However, this is an invasive surgical procedure in which complications and morbidity may occur. Noninvasive imaging tools, such as computed tomography and magnetic resonance imaging (MRI), are available as methods to enhance the diagnostic evaluation of lymph nodes. However, conventional MRI and computed tomography mainly evaluate the size of lymph nodes. Although it had been assumed that the use of lymph node characteristics, such as homogeneity, margins, and shape, as diagnostic criteria would improve the ability of MRI to discriminate between benign and metastatic lymph nodes, several studies showed that the use of these morphological characteristics did not improve the accuracy of conventional MRI.
Contrast-enhanced MRI has been proposed as a tool for improving the diagnostic accuracy of nodal metastases detection. One of the contrast agents used with enhanced MRI is ultrasmall superparamagnetic iron oxide (USPIO) particles. A meta-analysis of the diagnostic precision of USPIO-enhanced MRI for detection of lymph node metastasis showed an overall sensitivity of 0.88 (95% confidence interval [CI] = 0.85 to 0.91) and specificity of 0.96 (95% CI = 0.95 to 0.97). However, this staging method also has a number of disadvantages, including the need for slow infusion of the contrast agent 24 hours before imaging to minimize hypersensitivity-related side effects. Moreover, interpretation of the magnetic resonance images is not a trivial task. Consequently, the USPIO contrast agent has not yet been registered at the European Medicines Agency nor has it been approved by the US Food and Drug Administration.
It is thought that the lymph node prepares for metastatic cell implantation by reorganizing lymphatic and vascular structures and, as a consequence, new blood vessels develop within and around lymph nodes. The administration of an intravenous contrast agent, such as gadolinium, can reveal these surrounding blood vessels and demonstrate additional morphological characteristics of tumor tissue. Although gadolinium should be used with care in patients with nephropathy, it is generally accepted as a safe contrast agent when compared with USPIO. As such, it has been used extensively to visualize a variety of tumors with increased angiogenesis and blood flow [eg, ].
The number of studies that have evaluated the accuracy of gadolinium-enhanced MRI to detect nodal metastases compared with that of histopathologic examination has increased sharply in the last decade to more than 30. However, to our knowledge, a systematic review of all of these studies has not yet been undertaken. The purpose of this study was to quantitatively summarize, by means of a meta-analysis, all existing evidence in the literature on the diagnostic accuracy of MRI with intravenously administered gadolinium to detect metastatic lymph nodes in any cancer.
