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Nuclear Medicine |
1 From the Departments of Diagnostic Radiology, Warren Grant Magnuson Clinical Center (N.A.A., E.C.J.) and Nuclear Medicine (C.C.C., R.D.N.), the Pulmonary-Critical Care Medicine Branch (S.C.C., J.M.), and the Office of Biostatistics Research, Division of Epidemiology and Clinical Applications (M.W.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 10, Rm 1C-660, 10 Center Dr, MSC 1182, Bethesda, MD 20892-1182. From the 1998 RSNA scientific assembly. Received December 9, 1998; revision requested December 30; final revision received May 20, 1999; accepted June 7. Address reprint requests to N.A.A. (e-mail: navila@nih.gov).
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Abstract |
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MATERIALS AND METHODS: V-P scintigraphy, chest radiography, conventional and thin-section CT, and pulmonary function tests were performed in 39 patients. The images were graded on a scale of 0 (normal) to 3 (severely abnormal).
RESULTS: Imaging abnormalities were found on 92% of ventilation scintigrams, 92% of perfusion scintigrams, 79% of chest radiographs, 100% of CT scans, and 100% of thin-section CT scans. On ventilation scintigrams, 28 (72%) patients demonstrated a speckling pattern. On CT scans, all patients had pulmonary cysts. Univariate analysis showed that extent of disease on chest radiographs and CT scans, cyst size, V-P abnormalities, and degree of speckling were inversely correlated with forced expiratory volume in one second (FEV1), diffusing capacity of lung for carbon monoxide, and the ratio of FEV1 to forced vital capacity (FVC) (P < .01) but not with FVC and total lung capacity. Larger cyst size correlated with extent of disease at CT, but not significantly (P = .056).
CONCLUSION: Scintigraphic and radiologic abnormalities are seen in a majority of patients with lymphangioleiomyomatosis. On ventilation scintigrams, a frequently seen speckling pattern may be related to accumulation of radionuclide in pulmonary cysts—a hallmark of the disease at CT. Findings with each imaging modality correlate with certain pulmonary functions.
Index terms: Computed tomography (CT), comparative studies, 60.1211, 60.12118 • Computed tomography (CT), thin-section, 60.12118 • Lung, CT, 60.1211, 60.12118 • Lung, cysts, 60.312 • Lung, diseases, 60.3159, 94.829 • Lymphangiomyomatosis, 60.3159, 94.829 • Radiography, comparative studies, 60.11 • Radionuclide imaging, comparative studies, 60.12171, 60.12176
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Introduction |
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The purpose of this study was to determine the findings on ventilation-perfusion (V-P) scintigrams, chest radiographs, and CT scans and to compare them with the results of pulmonary function tests in a large group of patients with lymphangioleiomyomatosis.
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MATERIALS AND METHODS |
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We examined 39 women (age range, 23–54 years; mean age ± SD, 42 years ± 9) with a previously established diagnosis of lymphangioleiomyomatosis and without evidence of tuberous sclerosis. The mean duration between the diagnosis of disease and the time of our evaluation was 4.0 years ± 3.5 (range, 1 month to 15.5 years). The diagnosis of pulmonary lymphangioleiomyomatosis was established by means of open pulmonary biopsy (17 patients), thoracoscopic pulmonary biopsy (10 patients), transbronchial biopsy (four patients), and retroperitoneal lymph node biopsy (three patients).
Five patients did not have a pulmonary tissue diagnosis of lymphangioleiomyomatosis. These five patients had classic clinical and imaging findings at chest CT, which consisted of diffusely scattered thin-walled pulmonary cysts. Of these five patients, three had a history of pneumothorax and renal angiomyolipoma diagnosed after total nephrectomy, one had persistent chylothorax and a history of hemoptysis and recurrent pneumothoraces, and one had a history of recurrent pneumothoraces and transbronchial biopsy results that were consistent with, but not diagnostic of, lymphangioleiomyomatosis.
Each patient underwent the following studies: aerosol V-P scintigraphy, anteroposterior and lateral chest radiography, conventional CT, thin-section CT, and pulmonary function tests. These studies were performed within 5 days of each other in all patients. Imaging studies were interpreted by board-certified radiologists and nuclear medicine physicians who were aware of the patients' diagnosis but blinded to their clinical status or the results of other imaging modalities or pulmonary function tests. In the first 31 patients, each study was read independently by two radiologists (N.A.A., E.C.J.) or by two nuclear medicine physicians (C.C.C., R.D.N.) to determine interobserver variability. For the correlative analysis performed in all 39 patients, studies were scored by a single radiologist (N.A.A.) or nuclear medicine physician (C.C.C.) who used the methods outlined in this article.
Chest Radiography
Chest radiographs were evaluated for the presence and severity of underlying disease in each of three equal pulmonary zones from apex to base. Abnormalities were characterized as cysts, reticulation, pleural thickening, and/or pleural effusion. Cysts were defined as areas of decreased opacity with visible walls. Reticulation was defined as a network of straight or curved lines without associated central lucencies. The severity of abnormalities was graded on a four-point scale for each zone as follows: 0, absent; 1, mild; 2, moderate; 3, severe. For each patient, these grades were averaged across all pulmonary zones to provide a global score for the overall severity of involvement of the pulmonary parenchyma.
CT Scanning
CT scanning (HiSpeed Advantage; GE Medical Systems, Milwaukee, Wis) of the chest was performed in all patients. The scans were obtained with 10.0-mm collimation at 1-cm intervals. In addition, thin-section scans with 1.0-mm collimation were obtained at 3-cm intervals. As with the radiographs, the extent of involvement of each of three equal pulmonary zones was assessed independently and graded according to the percentage of the volume judged abnormal as follows: 0, absent; 1, less than 30% abnormal; 2, 30%–60% abnormal; 3, more than 60% abnormal. A mean, global score was also obtained. Pulmonary cysts were evaluated by using thin-section CT to determine the predominant or mean cyst diameter as follows: 1, less than 0.5 cm; 2, 0.5–1.0 cm; 3, more than 1.0 cm. Furthermore, abnormalities were assessed for symmetry and distribution.
V-P Scintigraphy
Aerosol V-P pulmonary scintigraphy was performed in all patients by using a low-energy all-purpose parallel-hole collimator and a gamma camera (Orbitor; Siemens Medical Systems, Hoffman Estates, Ill) peaked to 140 keV with a 20% window. Technetium 99m diethylenetriaminepentaacetic acid (DTPA; Techneplex; Bracco Diagnostics, Princeton, NJ) aerosol ventilation studies were performed by using nebulizers (Aerovent; Medi Nuclear, Baldwin Park, Calif). Patients were placed in a seated position, the DTPA aerosol was administered until a count rate of approximately 2,000 counts per second was achieved, and images of the lungs were obtained in multiple projections. After this, 5–6 mCi (185–222 MBq) of 99mTc macroaggregated albumin (Pulmolite; Dupont Pharmaceuticals, Billerica, Mass) was administered intravenously, and imaging was repeated.
V-P scintigrams were evaluated qualitatively for abnormalities in ventilation and perfusion by using the following scale: 0, absent; 1, mild; 2, moderate; 3, severe. In addition, ventilation studies were scored for the degree of speckling seen, as distinguished from clumping of aerosol in the large airways. This speckling pattern has been reported before in lymphangioleiomyomatosis and appears distinct from the usual appearance of central clumping (10). Mean, global scores were obtained for ventilation, perfusion, and speckling.
Pulmonary Function Studies
Spirometry and measurement of functional residual capacity and diffusing capacity of lung for carbon monoxide (DLCO) were performed with the patients in a seated position and with use of a computerized system (Gold Standard PLUS; Warren E. Collins, Braintree, Mass). Spirometry and DLCO measurements were obtained by using standard techniques recommended by the American Thoracic Society (11,12). Functional residual capacity was measured by using the closed-circuit helium equilibration technique, with equilibration time of 3–10 minutes. The expiratory reserve volume was subtracted from the functional residual capacity to obtain the residual volume, and the vital volume capacity was added to the residual volume to obtain the total lung capacity (TLC). The predicted values for all pulmonary functions were derived from published standards (13–15).
Statistical Methods
The 
statistic for observer agreement of the imaging studies was calculated according to standard methods for proportions: poor, = 0–0.39; fair to good, = 0.40–0.75; excellent, = 0.76–1.00 (16). Spearman rank correlation coefficients were calculated between the pulmonary function measurements and the global scores on the various imaging studies. The significance probabilities, or P values, for these correlation coefficients were derived from the t distribution (17,18). A P value less than .05 was considered to indicate a statistically significant difference. Statistical analyses were performed by using a statistical package (SAS; SAS Institute, Cary, NC) (18).
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RESULTS |
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statistics between readers were 0.78, 0.85, and 0.72 for overall chest radiograph grade, overall CT grade, and predominant cyst size grade, respectively. The statistics for ventilation, perfusion, and speckling were 0.48, 0.62, and 0.43, respectively.
Radiologic Findings
Chest radiography.—Eight (21%) of 39 patients had normal chest radiographs (grade 0); the remaining 79% had increased reticular markings (Table 1). Overall extent of disease on chest radiographs was graded as follows: grade 1, 15 (38%) of 39 patients; grade 2, eight (21%) patients; and grade 3, eight (21%) patients (Table 1). Less common findings on radiographs included pleural effusions in five (13%) patients and pneumothoraces in two (5%). Only three (8%) patients had clearly defined cysts on chest radiographs.
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Other less common findings at CT included pneumothorax in two (5%) of 39 patients, pericardial effusion in two (5%) patients, dilated thoracic duct in six (15%) patients, pleural effusions in six (15%) patients, precarinal lymph nodes in two (5%) patients, and retrocrural lymph nodes in two (5%) patients.
V-P scintigraphy.—One patient had a study that was uninterpretable with respect to ventilation abnormalities owing to marked central clumping. Of the remaining 38 studies, ventilatory abnormalities were judged to be absent (grade 0) in three (8%) patients, grade 1 in 19 (50%), grade 2 in eight (21%), and grade 3 in eight (21%). Of the 39 perfusion scintigrams, three (8%) were normal (grade 0), 15 (38%) were grade 1, 14 (36%) were grade 2, and seven (18%) were grade 3. In general, the location of ventilation and perfusion abnormalities matched. In some cases, however, the severity of the decrease in ventilation may have been more or less than the severity of the decrease in perfusion in the same area. Speckling was seen in 28 (72%) of 39 patients: mild (grade 1) in 11 (28%), moderate (grade 2) in 12 (31%), and marked (grade 3) in five (13%) (Table 1) (Figs 1–3).
Pulmonary function studies.—The results of the pulmonary function studies were abnormal in the majority of patients. Overall, forced expiratory volume in one second (FEV1), the ratio of FEV1 to forced vital capacity (FVC), and DLCO in the study population were substantially lower than the predicted values. In contrast, the FVC and TLC were similar to the predicted values (Table 2).
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Evaluation of the pulmonary cysts in lymphangioleiomyomatosis is best done with CT; chest radiographs often fail to demonstrate or may lead to underestimation of the extent of disease. As reported by others (3,4,8,9,21), we found substantial discrepancies between the radiographic and CT findings in many of the patients in our study. In our series, 36 (92%) of 39 patients had pulmonary cysts on CT scans that were not apparent on radiographs. In most of these patients, only nonspecific irregular linear opacities suggestive of interstitial disease were seen on chest radiographs. Only when the cysts were greater than 1.0 cm in diameter were they recognized on chest radiographs.
Results of previous studies (8,9) led to similar conclusions. The reticular interstitial pattern shown on chest radiographs in patients with lymphangioleiomyomatosis results from summation of numerous cyst walls. Overall, CT affords a more reliable depiction of pulmonary interstitial morphology by virtue of superior contrast resolution and, with thin-section techniques, reduced superimposition or volume averaging effects (22,23).
Fanti et al (10) described a pattern of "well-defined hot spots" on a Technegas ventilation scintigram in a single patient with lymphangioleiomyomatosis, and they postulated this pattern represented accumulation of radionuclide in peripheral cysts. Aerosol DTPA droplets, which adhere to the cyst walls, presumably coalesce and result in focal collections of activity superimposed on a background of activity within normal alveoli. In this study, we termed this pattern of uptake "speckling" and found the degree of speckling correlated with the extent of disease on CT scans and chest radiographs and with pulmonary dysfunction.
The speckling pattern is nonspecific in its milder forms but has a very distinctive appearance in its severe form, although its actual specificity for lymphangioleiomyomatosis is unknown. For instance, a similar pattern has been described in cystic fibrosis, and it would not be surprising if a similar pattern were seen in other cystic pulmonary diseases such as Langerhans cell histiocytosis (formerly, histiocytosis X) (24). We believe, however, that when severe speckling is present, as seen in 13% of the patients in our study, the pattern strongly suggests the diagnosis of lymphangioleiomyomatosis.
Despite the suggestive appearance of lymphangioleiomyomatosis at CT, the differential diagnosis also includes tuberous sclerosis and Langerhans cell histiocytosis, in addition to emphysema (8,25,26). Identical clinical, radiologic, and histopathologic pulmonary changes may be seen in 1% of patients with tuberous sclerosis (8). Although tuberous sclerosis affects both sexes equally, the pulmonary changes have been described almost exclusively in women (8). Furthermore, tuberous sclerosis, unlike lymphangioleiomyomatosis, is associated with recognized genetic defects. In Langerhans cell histiocytosis, parenchymal cysts are also a primary morphologic feature, although the cyst walls are often more variable in thickness than those seen in lymphangioleiomyomatosis (3,5). In addition, pulmonary nodules and cavitary nodules are a common feature of Langerhans cell histiocytosis (26). Furthermore, Langerhans cell histiocytosis characteristically involves the upper two-thirds of the lungs and spares the costophrenic angles, whereas lymphangioleiomyomatosis involves the lungs diffusely (25,26).
We conclude that lymphangioleiomyomatosis has a characteristic appearance on CT scans and scintigrams, which consists of cysts surrounded by normal lung on CT scans and an abnormal speckling pattern on V-P scintigrams. All major imaging parameters—overall ventilation, perfusion, speckling, extent of disease on CT scans, mean pulmonary cyst size on CT scans, and extent of disease on chest radiographs—correlate significantly with degree of impairment of FEV1, DLCO, and the ratio of FEV1 to FVC (P < .01) but not with FVC or TLC. The sizes of the pulmonary cysts vary and do not correlate significantly with severity of disease at CT. Larger cyst size, however, correlated significantly with worsening scintigraphic abnormalities, including speckling.
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Footnotes |
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Author contributions: Guarantor of integrity of entire study, N.A.A.; study concepts, N.A.A., C.C.C., J.M.; study design, N.A.A., C.C.C., S.C.C.; definition of intellectual content, N.A.A., C.C.C.; literature research, N.A.A., C.C.C.; clinical studies, N.A.A., C.C.C., S.C.C., J.M.; data acquisition, N.A.A., C.C.C., S.C.C., E.C.J., R.D.N.; data analysis, N.A.A., C.C.C., M.W.; statistical analysis, M.W.; manuscript preparation, N.A.A., C.C.C.; manuscript editing and review, all authors
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