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Original Research |
1 Department of Radiology, Vancouver General Hospital, University of British
Columbia, 899 W 12th Ave., Vancouver, BC, Canada V5Z 1M9.
2 Department of Radiology and Center for Imaging Science, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul 135-710,
Korea.
3 Department of Medical Physics and Radiology, Osaka University Graduate School
of Medicine, Osaka 565-0825, Japan.
Received October 26, 2004;
accepted after revision February 21, 2005.
Address correspondence to N. L. Müller.
Abstract
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MATERIALS AND METHODS. The study included 206 consecutive patients
from three medical centers with pathologically proven idiopathic pulmonary
fibrosis (n = 136), non-specific interstitial pneumonia (NSIP)
(n = 47), cryptogenic organizing pneumonia (COP) (n = 16),
respiratory bronchiolitis–interstitial lung disease (RB-ILD) (n
= 5), and desquamative interstitial pneumonia (DIP) (n = 2). HRCT
scans were retrospectively reviewed for the presence of mediastinal
lymphadenopathy (short-axis diameter, 
10 mm), predominant parenchymal
pattern, and extent of disease.
RESULTS. Mediastinal lymphadenopathy was seen in 139 (67%) of 206 patients, including 90 (66%) of 136 with idiopathic pulmonary fibrosis, 38 (81%) of 47 with NSIP, six (38%) of 16 with COP, and five (71%) of seven with RB-ILD or DIP. The presence of enlarged nodes was less common in COP than in the other idiopathic interstitial pneumonias (p = 0.04). No significant difference was found in the prevalence of lymphadenopathy in patients with predominant ground-glass opacity (53%) or predominant reticulation (40%). The extent of parenchymal abnormalities was 25–50% in 74 patients (53%), 50–75% in 30 (22%), < 25% in 22 (16%), and > 75% in 13 (9%). A positive correlation between the extent of disease and presence of lymphadenopathy was seen in patients with NSIP (p = 0.01).
CONCLUSION. Mediastinal lymphadenopathy is a common feature in idiopathic interstitial pneumonias, being slightly less common in COP than in the other idiopathic interstitial pneumonias. The presence of lymphadenopathy therefore has limited value in the differential diagnosis. In patients with idiopathic pulmonary fibrosis, the presence of lymph node enlargement did not correlate to any specific HRCT pattern or to the extent of disease.
Keywords: chest • CT • interstitial pneumonia • lung diseases • lymph nodes
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Several studies have shown that high-resolution CT (HRCT) is superior to chest radiography and that, in the proper clinical context, HRCT allows confident diagnosis of idiopathic pulmonary fibrosis in approximately 50% of cases [1–3]. There is considerable overlap however between the HRCT findings of idiopathic pulmonary fibrosis and those of NSIP [4–6]. Distinction between these two entities is important because patients with NSIP have a better response to treatment and a better prognosis than those with idiopathic pulmonary fibrosis. Results of a recent prospective study suggest that the presence of mediastinal lymphadenopathy on CT scans can be helpful in the diagnosis of idiopathic pulmonary fibrosis [2].
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Of the 206 patients who satisfied the inclusion criteria, 58 had the diagnosis of idiopathic interstitial pneumonia made at open-lung biopsy, 142 at videotape-assisted thoracoscopic biopsy, and six at autopsy. The final diagnosis was idiopathic pulmonary fibrosis in 136 patients, NSIP in 47, COP in 16, RB-ILD in five, and DIP in two. Because RB-ILD and DIP are considered as part of the spectrum of the same disease process, these seven patients were considered as one group. Acute interstitial pneumonia and lymphoid interstitial pneumonia were not included in the study because they are rare diseases with clinical and radiologic characteristics that allow prompt distinction from other idiopathic interstitial pneumonias. There were 130 men and 76 women, ranging in age from 33 to 82 years (mean age, 59 years).
All patients had undergone thin-collimation (1–1.5 mm) CT with scans obtained throughout the lungs at 10-mm intervals with the patient in the supine position and photographed with appropriate lung (window width, 1,000–1,500 H; window level, -600 to -700 H) and mediastinal (window width, 350–450 H; window level, 30–50 H) window settings. HRCT images were available on hard copy or at a PACS. The examinations were retrospectively reviewed by two observers in each center who reached a decision by consensus; results were recorded on a standard form. The presence of lymph node enlargement was defined as a diameter of 10 mm or more in the short axis [8]. Measurements were obtained in transverse images photographed on soft-tissue window settings using physical calipers in the cases available on film and electronic calipers in those on the PACS. The distribution of enlarged nodes was recorded according to the ATS mediastinal node classification [9]. Hilar lymph nodes were not evaluated because the CT scans were obtained without IV contrast medium. HRCT scans photographed with lung window settings were assessed for the presence and extent of reticulation (interlobular septal thickening, intralobular thickening, or honeycombing), ground-glass attenuation, and airspace consolidation. The overall extent of abnormalities was classified as involving < 25%, 25–50%, 50–75%, or > 75% of lung parenchyma.
Statistical analysis was performed using stepwise logistic regression. Analysis was performed for each disease separately and combined, and we tested for all potential interactions.
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Lymphadenopathy was more commonly observed in men (95 of 139 patients, 68%) than in women (44 of 139 patients, 32%) (p = 0.02). The prevalence of lymphadenopathy varied significantly according to the medical center involved in the study (p < 0.001), being considerably greater in patients from the hospital in Japan (85%) than in those from South Korea (66%) and Canada (39%). The frequency of lymph node enlargement in each one of the three institutions according to the pathologic diagnosis is summarized in Table 1.
In the majority of patients, lymphadenopathy occurred in one (58 patients, 42%) or two (39 patients, 28%) nodal stations. In only 18 patients (13%) were four or more nodal stations involved, with a maximum involvement of six regions in one patient. The enlarged nodes were most commonly seen at station 7 (Table 2).
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No statistically significant difference was found between the different HRCT patterns and the presence of lymphadenopathy. The overall extent of parenchymal abnormalities in patients with lymphadenopathy was 25–50% in 74 patients (53%), 50–75% in 30 (22%), < 25% in 22 (16%), and > 75% in 13 (9%). Statistical analysis showed a positive correlation between the extent of parenchymal involvement and the presence of lymphadenopathy in patients with NSIP (p = 0.01). The predominant HRCT pattern and the extent of parenchymal involvement associated with lymphadenopathy for each disease are summarized in Table 3.
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The diagnostic approach based on HRCT has been limited to the evaluation of abnormalities in the lung parenchyma. Recently, Hunninghake et al. [2] suggested that the presence of lymph node enlargement in correlation with the parenchymal findings on HRCT could be helpful in the diagnosis of idiopathic pulmonary fibrosis. The authors described a prevalence of mediastinal lymphadenopathy of 55% (28 of 51) in patients with biopsyproven idiopathic pulmonary fibrosis, contrasting with a prevalence of 21% (seven of 34) in patients with other interstitial lung diseases (p = 0.002). Various authors had previously reported an increased frequency of enlarged mediastinal nodes in patients with usual interstitial pneumonia, the prevalence varying from 48% to 90% in different series [7, 12–15]. It should be noted that these studies preceded the ATS/ERS classification and did not compare the prevalence of enlarged nodes in other idiopathic interstitial pneumonias. The study by Hunninghake et al. was based on the current classification but included only a small number of patients with interstitial diseases other than idiopathic pulmonary fibrosis and did not state how many had NSIP or COP.
To our knowledge, the present study is the first to assess the prevalence of mediastinal lymphadenopathy in the different idiopathic interstitial pneumonias according to the current consensus classification and to correlate the presence of enlarged nodes to the pattern and extent of parenchymal abnormalities. The prevalence of mediastinal lymphadenopathy in patients with idiopathic pulmonary fibrosis was 66%, being similar to those described in previous series [12, 14]. Surprisingly, a higher prevalence was observed in patients with proved NSIP (80%). Although the presence of enlarged nodes correlated with the pathologic diagnosis (p = 0.04), there was considerable overlap in the prevalence of lymphadenopathy in idiopathic pulmonary fibrosis, NSIP, and RB-ILD or DIP (Table 1). These results show that although frequent, the presence of mediastinal lymphadenopathy is not helpful in the differential diagnosis of the various idiopathic interstitial pneumonias.
Mediastinal lymphadenopathy associated with usual interstitial pneumonia typically involves only one or two nodal stations and the nodes usually measure less than 15 mm. The most frequently involved stations vary according to the study [13–16]. In our series, enlarged nodes were seen in only one or two nodal stations in 70% of cases, more commonly in station 7 (Table 2).
The cause of lymph node enlargement in chronic interstitial lung diseases is unknown. Some studies have suggested that it may be related to hyperplastic reaction secondary to a chronic inflammatory process [7, 13–15]. It has been postulated that cytokines released by activated alveolar macrophages evoke the expansion of lymphocytes into nearby lymphoid tissue [16]. Histologic evaluation of enlarged nodes in some patients with usual interstitial pneumonia has shown benign nodal hyperplasia [7, 13]. The need for the inflammation to be chronic may also explain the lower prevalence of lymphadenopathy in COP, patients typically have symptoms for weeks or 1–3 months before diagnosis, than in other idiopathic interstitial pneumonias, in which patients typically have symptoms for 6 or more months before diagnosis. Franquet et al. [7], in a retrospective review of 54 cases of idiopathic pulmonary fibrosis, assessed the effect of steroid administration in the prevalence of mediastinal lymphadenopathy. Patients on steroid therapy had a significantly lower prevalence (14%) than those who had not received steroids (71%) (p < 0.001). The authors concluded that the cause of lymph node enlargement in those patients was probably related to benign hyperplasia.
HRCT findings have a good correlation with pathologic findings obtained in lung biopsies [2, 4–6]. On HRCT, active parenchymal inflammation is seen as areas of ground-glass attenuation, whereas established fibrosis correlates to reticulation [1, 17]. In usual interstitial pneumonia, the presence and extent of ground-glass opacities may reflect disease activity and greater likelihood of response to treatment [17]. It has been suggested that the presence of enlarged nodes in patients with usual interstitial pneumonia may correlate with disease activity and the extent of parenchymal involvement [7, 12–15]. Moreover, because lymph nodes decrease in size after treatment with corticosteroids [7], it has also been suggested that presence of enlarged nodes could be potentially helpful in determining the likelihood of response to treatment.
Wechsler et al. [14], in a study of 73 patients with scleroderma and interstitial lung disease, compared the prevalence of mediastinal lymphadenopathy with specific patterns of pulmonary involvement on HRCT scans. Similar to our study, they observed no significant difference in the prevalence of enlarged nodes between patients with predominant ground-glass opacities and patients with predominant reticulation. In the study by Wechsler et al., the prevalence of enlarged nodes was greater in patients with more extensive disease. In the current study, we observed an increase in the prevalence of lymphadenopathy with the extent of disease in patients with NSIP but not in patients with usual interstitial pneumonia (Table 3). It has been shown that the majority of patients with scleroderma develop NSIP rather than usual interstitial pneumonia [17]. Therefore, our results are consistent with those of Wechsler et al. The reason for the lack of correlation between the extent of disease and lymph node enlargement in usual interstitial pneumonia is not clear.
The prevalence of lymphadenopathy varied significantly among the three different medical centers involved in our study (p < 0.001). Patients originally referred to centers in Japan and Korea showed a higher prevalence of lymph node enlargement when compared with patients in Canada (Table 1). A possible explanation for such difference could be interobserver variability. However, the main investigators in each of the three centers have more than 10 years' experience with CT and have previously worked together on analysis of CT scans at the same center for more than 6 months. The disparity among different regions also raises the possibility that there is a racial or environmental influence (or both) in the development of lymphadenopathy.
Our study has several limitations. The study was retrospective and included only patients referred to major medical centers for further assessment and lung biopsy. It therefore may be biased toward patients with more advanced disease or atypical manifestations. It also was limited to the assessment of lymph node size in patients who had 1- to 1.5-mm collimation scans obtained at 10-mm intervals. Therefore it probably underestimates the prevalence of lymphadenopathy in patients with idiopathic interstitial pneumonia.
In summary, mediastinal lymphadenopathy is frequently seen in patients with idiopathic interstitial pneumonias, more commonly associated with NSIP, idiopathic pulmonary fibrosis, and RB-ILD and less commonly seen in COP. Because the prevalence is similar among these diseases, the presence of enlarged nodes has limited diagnostic value in the differential diagnosis of the various idiopathic interstitial pneumonias. In patients with idiopathic pulmonary fibrosis, the presence of lymph node enlargement did not correlate to any specific HRCT pattern or to the extent of disease.
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