Editorial. CT of Mediastinal Lymph Nodes in Lung Cancer: Is There a "State of the Art"? Selection of Patients

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1 1081 Editorial CT of Mediastinal Lymph Nodes in Lung Cancer: Is There a "State of the Art"? As our technology improves, much of what has been done must be reevaluated. Initial reports of new techniques often are glowing, with nay-sayers in the minority. No one wants to be left behind; we radiologists want to be out in front and our colleagues expect no less of us. Enthusiasm frequently carries the day, but later assessment sometimes calls for reservations. The use of computed tomography (CT) in the evaluation of mediastinal lymph nodes in lung cancer may be a case in point. Reported accuracy rates and utility vary appreciably. On careful inspection of the reports, none are structured the same way. These differences raise significant questions. Do we have satisfactory criteria? How accurate is CT? When should CT be used? Of what use is the information? Writing in 1979, Mintzer et al. [1] concluded CT scans were more sensitive and more specific than conventional tomography for determining mediastinal involvement and thus more accurate in predicting potential resectability. In the same year and using the same equipment (EMI 5005), Underwood et al. [2] concluded that CT scans should not replace conventional surgical staging procedures. Mintzer compares radiographic procedures; Underwood compares CT with surgical findings. Their conclusions sound diametrically opposed. But in fact this is like comparing apples with oranges, and either author could be cited to support a specific point of view. Eight studies published since 1980 were reviewed to see if the questions raised above could be answered. The year 1980 was chosen to ensure that sufficient time had elapsed to reflect a more general experience. Only CT evaluation of mediastinal lymph nodes was considered. Three reports [3-5] are from radiologic journals, two [6, 7] from thoracic journals, and one [8] from a surgical journal. Two reports were excluded, Modini et al. [9] because the chest was examined with only 1 2 slices at 2.5 cm intervals, and Lewis et al. [10] because absolute numbers of cases in various categories could not be extracted. Selection of Patients The studies varied as to which patients were included and the other radiographic methods, if any, that were considered. Osborne et al. [4] and Moak et al. [6] compared CT with plain chest radiographs and conventional tomograms. Faling et al. [7] and Ekholm et al. [5] compared CT with plain chest radiographs. Baron et al. [3] and Rea et al. [8] dealt only with CT findings. Baron et al. [3] excluded patients with clinically evident metastatic disease or with abnormalities so substantial that surgical resection was precluded. Four patients with central submucosal spread documented by bronchoscopic biopsy were also excluded. Included were patients in whom surgical staging, mediastinoscopy, mediastinotomy, or thoracotomy was performed. Small cell carcinomas were included if diagnosed surgically after CT was performed. However, no description of the stage of the tumors was offered. Osborne et al. [4] excluded patients with obvious evidence of mediastinal and/or hilar enlargement on plain radiographs, as well as patients with T,N 0 lesions. He accepted 42 patients with T 2 lesions. An outline of the TNM clinical staging system is shown in table 1 [11]. The series of Moak et al. [6] excluded 41 of 100 consecutive patients with a lung lesion on chest radiographs in whom the mediastinum was not evaluated. Of the 59 other patients, 18 had benign disease; the remaining 41 patients constitute the data base. Staging was not offered. Faling et al. [7] excluded patients with disseminated tumor, patients with known small cell carcinoma, those not surgical candidates because of medical considerations, and patients over 70 years of age with gross mediastinal adenopathy. Forty-nine patients with 51 cancers (28 central, 23 peripheral) are included, but tumor size is not noted. Rea et al. [8] included 22 patients with tumors thought to be resectable on the basis of conventional radiographic studies. TNM staging was not offered. Ekholm et al. [5]

2 1082 EDITORIAL AJR:141, November 1983 TABLE 1: TNM System for the Clinical Staging of Lung Cancer (adapted from [11]) Primary tumors: T, Tumor =s 30 mm in greatest diameter, surrounded by T 2 lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy Tumor > 30 mm in greatest diameter or a tumor of any size which with its associated atelectasis or obstructive pneumonitis extends to the hilar region. At bronchoscopy the proximal extent of demonstrable tumor must be at least 20 mm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung, and there must be no pleural effusion T 3 Tumor of any size with direct extension into an adjacent structure such as the chest wall, diaphragm, or mediastinum and its contents; or demonstrable bronchoscopically to be < 20 mm distal to the carina; any tumor associated with atelectasis or obstructive pneumonitis of an entire lung or pleural effusion Regional lymph nodes: No No demonstrable metastasis to regional lymph nodes Ni Metastasis to lymph nodes in the ipsilateral hilar region (including direct extension) N 2 Metastasis to lymph nodes in the mediastinum Distant metastases: Mo No distant metastasis Mi Distant metastasis such as in scalene, cervical, or contralateral hilar lymph nodes, brain, bones, lung, liver, etc. excluded patients with small cell carcinoma. TNM staging was not offered. In the series of Osborne et al. [4], the only report in which a tumor size was offered, all T 2 lesions were included. But T 2 includes any tumor larger than 3 cm in diameter as well as tumors of any size with associated atelectasis or obstructive pneumonia (involving less than the entire lung). Variation within T 2 alone can be great and is potentially greater when nodes are not described. The other series offer little information about the extent of the tumors on conventional studies, although the patients described by Rea et al. [8] are assumed to have been operable on the basis of conventional radiographic findings. Any new technique must be evaluated by testing it first against what is known. However, it is imprecise to offer descriptions like "such substantial abnormalities on the plain chest radiograph that surgical resection was precluded" [3] or "obvious evidence of mediastinal and hilar enlargement on the plain radiograph" [4] as exclusionary criteria. If the TNM system does nothing else, it at least provides a method for comparing what was evident on conventional radiographs or tomograms with the CT findings. Equipment and Techniques The CT scanners and scanning techniques varied according to the series. None, however, used first-generation scanners and only one used more than a 10-sec scanning time. The detail visible in the mediastinum has improved with improvements in the scanners; most researchers used intravenous contrast material only in selected cases, when necessary to distinguish between nodes and vascular structures. The equipment and techniques used are presented in table 2. Criteria, Sensitivity, and Specificity The criteria for abnormality of lymph node size varied greatly. These criteria and the sensitivity and specificity reported for each series are presented in table 3. Size is clearly an important factor in the evaluation of lymph node pathology in the mediastinum, although virtually all authors specifically note that "enlarged" nodes need not harbor metastases and that "normal"-sized nodes may be involved with metastatic disease. Schnyder and Gamsu [12] evaluated the pretracheal retrocaval space at the level of the azygous arch, a region accessible to a mediastinoscope. Of 160 lymph nodes viewed in this location in 127 normal subjects, only 11 were larger than 11 mm (11-14 mm) in diameter. From this, they concluded that nodes larger than mm should be viewed with suspicion and nodes larger than 15 mm should be considered abnormal. These guidelines, however, are for a Swiss population in whom there is "an extremely low incidence of granulomatous disease and pneumoconiosis" [12]. It is difficult to apply these data to the United States, especially in areas where the incidence of granulomatous disease may be high. Also, specific subsets of the population (e.g., coal workers) may have to be considered separately. Little information is available regarding size criteria for lymph nodes in other locations in the mediastinum or in other geographic regions. How often are enlarged mediastinal lymph nodes found in a population in which granulomatous pulmonary disease is common? In addition to the question of what is normal, the frequency of enlarged nodes in cases of atelectasis and/or collapse must be considered. This point, raised by Hirleman et al. [13], must be addressed so that "large" nodes in these circumstances are not considered abnormal a priori. Another factor to keep in mind is that many mediastinal lymph nodes, particularly the paratracheal and tracheobronchial nodes, often have a vertical orientation, so that CT does not image the greatest diameter. This can make radiologic-pathologic correlation imprecise, as the pathologist may note the size of the node but is rarely aware of its orientation. It is obvious from the work of Schnyder and Gamsu [12] that every recognizable node cannot be considered abnormal. But at what point are nodes to be considered pathologically large? Size criteria for abnormality (table 3) included nodes of any size up to 20 mm in diameter. The sensitivity (ratio of CT examinations reported as having metastases to those in which metastatic disease was found) and the specificity (ratio of examinations reported as normal to those in which metastatic disease was not found) in the six reports vary in

3 AJR: 141, November 1983 EDITORIAL 1083 TABLE 2: Equipment and Techniques Used in CT Evaluation of Mediastinal Lymph Nodes in Lung Cancer Reference Scanner Scanning Time (sec) Technique Contrast Enhancement? [3] EMI cm intervals, thoracic inlet to diaphragm Selected cases [4] Not noted mm intervals, apex to base Selected cases [5] Philips Tomo Scan cm slices, 1.8 cm intervals, just below aortic arch to level below left atrium [6] EMI cm intervals, thoracic inlet to diaphragmatic hiatus [7] Ohio Nuclear 2010 [8] Ohio Nuclear 2020 TABLE 3: Criteria for Abnormality, Sensitivity, and Specificity in CT Evaluation of Mediastinal Lymph Nodes R, Abnormal Nodal Sensitivity: Specificity: rence Size (mm) No. (%) No. (%) [3]* 5*10 37/39(95) 45/55 (80) 3=20 29/39(74) 55/55(100) [4] >5-6 17/18(94) 15/24 (62) [15]f S10 13/18(72) 20/24 (83) [5] >10 2/7 (29) 13/28 (46) [6] >10 13/17(76) 16/24 (67) [7] 5=15 15/17(88) 32/34 (94) [8] Any node seen 4/5 (80) 13/17 (76) * Researchers used an indeterminate category of nodes mm in diameter, which were considered either CT-positive or CT-negative for statistical analysis. t Recalculation of data from preceding series [4) for different nodal size criteria. part because of the different criteria applied. As would be expected, sensitivity was generally better using smaller size criteria for abnormal nodes, while specificity was better using larger size criteria for normal. The sensitivity and specificity for the series reported by Baron et al. [3] were calculated by considering nodes classified as indeterminate (10-19 mm diam) as either all positive or all negative (table 3). Osborne et al. [4], reporting a sensitivity of 94% and a specificity of 62%, considered nodes larger than 5-6 mm in diameter as abnormal. In response to a query by Faling et al. [14], these figures change to a sensitivity of 72% and a specificity of 83% when nodes 10 mm or more in diameter are considered abnormal [15]. Rea et al. [8] considered any node seen abnormal; Moak et al. [6] and Ekholm et al. [5] used larger than 10 mm as their cutoff point, and Faling et al. [7] used 15 mm. The frequency of metastases in "normal"-sized and palpably normal nodes cannot be determined from the information available. Ekholm et al. [5] documented metastases at mediastinoscopy in only two of 17 patients with nodes larger than 10 mm. However, metastases were found in five of 14 patients with no node larger than 10 mm. All cases Selected 2 1 cm intervals, apex to immediate Most without subdiaphragmatic region cm intervals Most without cases In none of the six reports was total nodal sampling of the mediastinum at thoracotomy the method by which the mediastinal nodes were evaluated. Baron et al. [3] note that 73 patients underwent surgery for evaluation of mediastinal invasion, whereas 25 received mediastinoscopy as the sole staging procedure. The authors exclude these 25 from their analysis, but how many they represent of those called CTpositive is not clear. Moreover, only 57 of 85 patients with peripheral lesions had direct surgical evaluation of the hilus. Thus, the extent of nodal sampling of the mediastinum in operated patients reported by Baron et al. [3] is unclear. Osborne et al. [4] report that at thoracotomy the hilus and mediastinum were inspected and palpated and any suspicious areas were biopsied, with particular attention to areas thought to be abnormal on the imaging studies. They note that there is an element of uncertainty in using surgical criteria for determining mediastinal involvement because only material suspected of being abnormal and accessible to the surgeon was submitted for pathologic assessment. Moak et al. [6] mention that to the extent allowed by the surgical procedure, the mediastinum was carefully explored, particularly in the radiographically suspect areas. Faling et al. [7] observe that mediastinal lymph node dissections were not routinely done and that mediastinal lymph nodes were removed when palpably abnormal, when CT scans revealed lymph nodes adenopathy, and when hilar nodes were grossly positive. In their study, mediastinal nodes alone were available in 14 patients, whereas both hilar and mediastinal nodes were available in 19. But if 10 patients with positive nodes by mediastinoscopy are excluded, then at least 16 of 39 surgical patients (41%) did not have mediastinal nodes removed for pathologic evaluation. Might this not account for the high specificity and sensitivity? We second the concern of Osborne et al. [4] about the uncertainty of surgical staging when only suspect material is submitted for histologic examination. In the absence of total nodal sampling at thoracotomy, accurate correlation of pathology with CT findings will not be available, particularly for those nodes or areas considered normal. Surgical-Pathologic Correlation Commentary Considering the varied structure of these studies, it was unlikely that there would be general agreement in the conclusions; indeed, there is not. Baron et al. [3], Faling et al.

4 1084 EDITORIAL AJR:141, November 1983 [7], and Rea et al. [8] suggest that, given a normal mediastinum by CT, it is appropriate to proceed directly to a thoracotomy. Here two questions must be raised: The first is the likelihood of occult metastases in normal-sized nodes. The second, altogether different (and logically prior) question is whether CT is indicated at all in T,N 0 lesions by conventional radiography. It may well be that TiN 0 lesions on conventional radiographs yield too little mediastinal nodal enlargement to warrant CT. This has been alluded to by Hirleman et al. [13]. Similarly, it would be desirable to know whether certain lesions (perhaps T 2 N t ) have a sufficiently high yield of metastases in normal-sized nodes to warrant mediastinoscopy regardless of the CT observations. Baron et al. [3], Osborne et al. [4], and Rea et al. [8] suggest that CT may be useful in directing the appropriate procedure short of formal thoracotomy. I agree with this suggestion, but as Mintzer and Vanecko [16] and Faling et al. [7] point out, there is no need for CT in the face of obvious mediastinal disease on conventional chest radiographs or conventional tomography. Osborne et al. [4], Moak et al. [6], and Ekholm et al. [5] agree that CT is not accurate enough for routine staging. Ekholm et al. [5] question the use of CT at all. Moak et al. [6] state that "no radiologic modality should replace surgical exploration in staging mediastinal nodal pathology." Indeed, all authors agree either explicitly or implicitly that large nodal size alone is not an accurate criterion for assuming the presence of metastases. Moak et al. [6] observe that the lack of adequate numbers of cases in any category in their series makes meaningful statistical analysis impossible. Considering the variety of cell types and the permutations of the TNM classification, this statement could probably be applied to each of the six reports. Suggestions It makes little difference how a patient is evaluated as long as it is done accurately and without unnecessary expense. The important thing is to arrive at the appropriate therapeutic decision. In the workup of patients with lung cancer the optimal use of CT evaluation of mediastinal lymph nodes is not yet clear. For the radiologist, use of the TNM classification on the plain chest film offers a point of departure. A longitudinal prospective study would be very desirable. Each new, previously untreated patient would be evaluated and changes in the TNM classification noted after each additional radiographic study. The point at which sufficient information is accumulated to determine the appropriate interventional procedure would be noted. The accuracy of studies performed up to that point could then be assessed. Should CT be required in such a longitudinal approach, its role in the ultimate therapeutic decision could be determined; if the patient comes to thoracotomy, adequate mediastinal sampling should be performed to evaluate radiographic findings fully. In this way guidelines might be established to indicate when CT might be unnecessary or of no value either because of the gross size of the initial lesion or conceivably because of the small size of the original lesion. The potential contribution of CT in the more difficult middle zone would also be known. Given the variety of cell types and categories in the TNM classification, it is unlikely that a single institution could accumulate adequate numbers of each permutation to yield statistically significant data even in a relatively long period of time. A multiinstitutional study with a uniform approach and reporting system will be needed. There must be complete understanding among radiologists, chest physicians, thoracic surgeons, and surgical pathologists in this regard. The current movement toward cost containment in medicine is such that a one-of-each-examination approach is no longer feasible; moreover, none of us wants to practice medicine "by the numbers." Unless we radiologists direct and participate in a logical approach to the evaluation not only of lung cancer but of other diseases as well, we may find ourselves no longer in a position to offer our best judgment as to what is appropriate. Such efforts await our initiative. REFERENCES Herman I. Libshitz Department of Diagnostic Radiology M. D. Anderson Hospital and Tumor Institute University of Texas System Cancer Center Houston, TX Mintzer RA, Malave SR, Neiman HL, Michaelis LL, Vanecko RM, Sanders JH. Computed vs. conventional tomography in evaluation of primary and secondary pulmonary neoplasms. Radiology 1979; 132: Underwood GH, Hooper RG, Axelbaum SP, Goodwin DW. Computed tomographic scanning of the thorax in the staging of bronchogenic carcinoma. N Engl J Med 1979:300: Baron RL, Levitt RG, Sagel SS, White MJ, Roper CL, Marbarger JP. Computed tomography in the preoperative evaluation of bronchogenic carcinoma. Radiology 1982;145: Osborne DR, Korobkin M, Ravin CE, et al. Comparison of plain radiography, conventional tomography, and computed tomography in detecting intrathoracic lymph node metastases from lung carcinoma. Radiology 1982;142: Ekholm S, Albrechtsson U, Kugelberg J, Tylen U. Computed tomography in preoperative staging of bronchogenic carcinoma. J Comput Assist Tomogr 1980;4: Moak GD, Cockerill EM, Farber MO, Yaw PB, Manfredi F. Computed tomography vs. standard radiology in the of mediastinal adenopathy. Chest 1982;82:69-75 evaluation 7. Faling LJ, Pugatch RD, Jung-Legg Y, et al. Computed tomographic scanning of the mediastinum in the staging of bronchogenic carcinoma. Am Rev Respir Dis 1981;124: Rea HH, Shevland JE, House AJS. Accuracy of computed tomographic scanning in assessment of the mediastinum in bronchial carcinoma. J Thorac Cardiovasc Surg 1981; 81 : Modini C, Passariello R, lascone C, et al. TNM staging in lung cancer: role of computed tomography. J Thorac Cardiovasc Surg 1982;84: Lewis JW, Madrazo BL, Gross SC, et al. The value of radiographic and computed tomography in the staging of lung

5 AJR:141, November 1983 EDITORIAL 1085 carcinoma. Ann Thorac Surg 1982;34: Mountain CF, Carr DT, Anderson WAD. A system for the clinical staging of lung cancer. AJR 1974;120: Schnyder PA, Gamsu G. CT of the pretracheal retrocaval space. AJR 1981;136: Hirleman MT, Yiu-Chiu VS, Chiu LC, Schapiro RL. The resectability of primary lung carcinoma: a diagnostic staging review. CT 1980;4: Faling LJ, Pugatch RD, Daly BDT, Jung-Legg Y, Hong WK, Snider GL. Detection of intrathoracic lymph node metastases from lung carcinoma (letter). Radiology 1982; 144: Osborne DR, Korobkin M. Detection of intrathoracic lymph node metastases from lung carcinoma (letter). Radiology 1982;144: Mintzer RA, Vanecko RA. The efficacy of noninvasive chest imaging in staging bronchogenic carcinoma. Chest 1982;82:3-4