Ann Thorac Surg 2002;73:407-411
© 2002 The Society of Thoracic Surgeons
Original article: general thoracic
Role of fiberscopic transbronchial needle aspiration in the staging of N2 disease due to non–small cell lung cancer
Marco Patelli, MD*a,
Luigi Lazzari Agli, MDa,
Venerino Poletti, MDa,
Rocco Trisolini, MDa,
Alessandra Cancellieri, MDb,
Nicola Lacava, MDa,
Franco Falcone, MDa,
Maurizio Boaron, MDa
a Department of Thoracic Diseases, Maggiore/Bellaria Hospitals, Bologna, Italy
b Department of Pathology, Maggiore/Bellaria Hospitals, Bologna, Italy
Accepted for publication October 24, 2001.
* Address reprint requests to Dr Patelli, Department of Thoracic Diseases, Maggiore Hospital, Largo Nigrisoli 2, 40133 Bologna, Italy
e-mail: marco.patelli{at}ausl.bologna.it
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Abstract
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Background. Transbronchoscopic needle aspiration (TBNA) can offer a unique opportunity to identify surgically unresectable lung cancer and to avoid surgical mediastinal exploration in many patients with mediastinal lymph node extension of the tumor. The aim of this study was to assess the yield of TBNA performed with either histology or cytology needles in mediastinal staging of N2 disease due to non–small cell lung cancer (NSCLC).
Methods. Retrospective chart review was carried out on 194 TBNA procedures performed between January 1997 and September 2000 at a single institution. Inclusion criteria were pathologic evidence of NSCLC; contrast enhancement computed tomography scan of the chest suggesting N2 disease; and negative bronchoscopic examination for possible neoplastic lesions at the site of TBNA.
Results. Overall sensitivity and diagnostic accuracy were 71% and 73%, respectively, with no significant differences between 19-gauge and 22-gauge cytology needles. Procedures performed for right paratracheal and subcarinal lymph node stations had a significantly higher yield than those for the left paratracheal station.
Conclusions. TBNA mediastinal staging, performed during the initial diagnostic evaluation of NSCLC, can spare costs and risks of more invasive procedures in patients with inoperable tumors, in patients who are not candidates for operation because of coexistent significant comorbidities, and in patients with N2 disease.
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Introduction
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Treatment options for patients affected by non–small cell lung cancer (NSCLC) depend mainly on the extent of the disease. In this setting, the evaluation of the mediastinal lymph node (LN) status is crucial because growing data indicate that ipsilateral mediastinal or subcarinal LN malignant disease dramatically reduce the 5-year survival [1–3]. So far, contrast enhancement computed tomography (CT) scan of the chest has been predominantly used in the clinical practice as the first-step technique to assess mediastinal LN involvement. Nevertheless, the specificity of CT scan is unsatisfactory, and more invasive procedures, mainly surgical methods, usually have to be performed to confirm CT data in preparation for a surgical treatment. In the last two decades, the capacity of fiberoptic transbronchial needle aspiration (TBNA) to improve the specificity of CT data by sampling enlarged LN in the 4R (right paratracheal), 4L (left paratracheal), 7 (subcarinal), and 10 (hilar) stations of the ATS classification has been reported more than once [4–12]. In particular, several groups have evaluated the yield of TBNA in the mediastinal staging of NSCLC by using either cytologic [5–9, 12] or histologic [10–12] needles. We report on our experience in the staging of N2 disease due to NSCLC by using 22-gauge cytology and 19-gauge histology needles.
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Material and methods
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Study design
A retrospective chart review of TBNA staging procedures for NSCLC performed at a single institution between January 1997 and September 2000 was carried out. Patients were included in the study when they had pathologic diagnosis of NSCLC, achieved with either bronchoscopic sampling techniques (included TBNA) or percutaneous needle aspiration; contrast enhancement CT scan of the chest suggesting N2 disease (LNs with size greater than 10 mm on their short axis in the 4R, 4L, or 7 station of the ATS classification); and bronchoscopic examination negative for possible neoplastic lesions in the site of TBNA.
Transbronchial needle aspiration technique and handling of samples
Transbronchial needle aspiration was performed by 3 well-trained endoscopists during a standard flexible bronchoscopy under local anesthesia with either a 22-gauge cytology needle or a 19-gauge histology needle (Mill-Rose, Mentor, OH). The choice of the needle was at the discretion of the operator [12], although the cytology needle was used mainly for staging purposes (when NSCLC had been previously diagnosed), whereas a histology needle was usually preferred when the diagnosis of the pulmonary pathologic process (lung cancer; hematologic malignancy; benignant diseases such as sarcoidosis, tuberculosis; etc) also had to be considered. After an accurate analysis of the CT scan slides, the needle was inserted between adjacent cartilage rings, in LN areas in close contact to the tracheal or bronchial wall. Care was taken to perform TBNA before any distal airway inspection and any sampling techniques (washing, brushing, or biopsy), to avoid the contamination by exfoliated malignant cells. After the removal of the needle, the specimen was collected on clean glass slides. In those cases in which a histologic core of tissue was obtained, the sample was removed gently and placed in formalin solution. Cytologic material was smeared on five to six clean glass slides that were stained with either the Diff-Quick or the Papanicolaou methods.
Pathologic assessment and categorization of samples
The samples were classified as adequate (positive or negative for malignant features), unsatisfactory, or inconclusive by one of us (A.C.). In agreement with literature data [13], negative specimens were considered adequate when they contained a moderate number of lymphocytes. However, because no definite quantitative cut-off value had been proposed for adequate specimens, we arbitrarily required that at least 30% of the cellularity be composed of lymphocytes. Transbronchial needle aspiration-negative specimens whose cellularity contained less than 30% of lymphocytes were defined as inadequate, whereas TBNA specimens reported to have "suspicious or rare" malignant cells were considered as inconclusive.
Statistical analysis
Sensitivity of TBNA was calculated as true positive/true positive + false negative; diagnostic accuracy was calculated as true positive + true negative/true positive + false positive + true negative + false negative; and negative predictive value was calculated as true negative/true negative + false negative. For statistical purposes, all specimens positive for malignancy were assumed to be true positive based on the high specificity of the technique. Among TBNA samples negative for malignancy, we considered the true negative only those procedures that were subsequently confirmed as negative by surgical exploration (mediastinoscopy or video-assisted thoracoscopy). Consequently, even the adequate negative TBNA specimens (not including the inconclusive and inadequate specimens) which could not be confirmed as negative by surgical interventions were assumed to be false negative. The 
2 test was used to determine statistical significance between needle results. A p value less than 0.05 was accepted as statistically significant.
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Results
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Between January 1997 and September 2000, 194 mediastinal TBNA samples were obtained from 183 patients (142 men, 41 women) at Bologna Maggiore Hospital. Table 1
shows the results of TBNA in our series. A malignant adenopathy was demonstrated in 127 samples (66%), whereas 28 samples proved negative for malignancy (14%), and the remaining 39 (20%) were considered either inadequate (35 samples) or inconclusive (4 samples). Eighteen of 28 adequate negative TBNA were surgically controlled, of whom 15 (83%) proved to be true negative (Table 2).
The other 10 adequate negative aspirates could not be surgically confirmed because of the presence of a locally extensive disease, poor ventilatory reserve, or coexistent severe medical illness.
Among the 39 inadequate or inconclusive TBNA specimens, which we considered as failure of the technique, 19 underwent subsequent surgical mediastinal exploration; 12 could not be surgically controlled because of locally extensive disease (6 cases), distant metastatic disease (4 cases), or severe cardiopulmonary comorbidities (2 cases); 8 were lost to follow-up after diagnosis.
In this series, TBNA was the only sampling technique allowing a diagnosis (besides staging) in 48 of 127 cases (38%), with no statistically significant differences between histology and cytology needles (data not shown). The overall sensitivity and accuracy using either needle were 71% and 73%, respectively. The sensitivity and accuracy using different LN stations were respectively 84% and 86% for 4R, 79% and 81% for 7, and 52% and 58% for 4L (Table 3).
In procedures performed with the 22-gauge needle, TBNA was positive for malignancy in 63 of 101 procedures (62%), whereas inadequate specimens were obtained in 20 cases (20%) and adequate nonmalignant specimens in 16 (16%) (Table 1). Two cases were reported to have suspicious malignant cells and were therefore considered inconclusive. Nine of the 16 TBNA adequate negative specimens underwent surgical diagnostic control. Of those, 7 could be confirmed as true negative (Table 2). The overall sensitivity and accuracy of TBNA procedures performed with cytology needle were 67% and 69% (Table 4).
Sensitivity and accuracy were respectively 88% and 89% in 4R, 71% and 76% in 7, and 33% and 38% in 4L LN stations. In the 93 TBNA procedures performed with a 19-gauge histology needle we obtained cytology material in all cases and histologic specimens in 69 cases (74%) (Table 1). Cytology was positive for malignancy in 64 of 93 cases (69%), and histology was positive in 38 of 69 cases (55%; Fig 1).
The aspirates were classified as inadequate in 15 samples with cytologic material and in 28 samples with histologic specimens. Twelve cytologic (with 2 histologic specimens) were adequate negative, of which 9 underwent surgical procedures and 8 proved to be true negative (Table 2). The 19-gauge histology specimen sensitivity was 57%, whereas the 19-gauge cytology sensitivity was 75% (Table 4). When the 19-gauge histology specimens and cytology material were combined, the overall sensitivity was 78% and the accuracy was 80% (Table 4). Sensitivity and accuracy for different LN stations were, respectively, 77% and 83% for 4R, 89% and 90% for 7, and 73% and 77% for 4L.
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Fig 1. A needle-shaped specimen in which mediastinal lymph node tissue focally infiltrated by squamous carcinoma is present along with normal tissue from the bronchial wall. (Hematoxylin and eosin, x40 before 33% reduction.)
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Despite having better results with 19-gauge histology needle than with the 22-gauge cytology needle in sensitivity (78% versus 67%) and accuracy (80% versus 69%), the differences were not statistically significant (Table 4). Transbronchial needle aspiration procedures performed in the left paratracheal station (sensitivity 52%; accuracy 58%) were significantly less sensitive and accurate than those performed in either the right paratracheal (sensitivity 84%, p = 0.001; accuracy 86%, p = 0.002) or the subcarinal (sensitivity 79%, p = 0.01; accuracy 81%, p = 0.02) LN stations (Table 3).
No significant complications occurred in our series with either size needle. Minor, localized, self-resolving bleeding frequently occurred at the puncture site. Two cases of clinical, self-resolving pneumothorax were also observed.
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Comment
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A correct assessment of the mediastinal lymph node status in potentially surgical NSCLC is mandatory because the result of primary operation in patients with N2 disease is poor, with a 9.1% 5-year survival for cases with subcarinal neoplastic LN involvement [14]. A 5-year survival rate of higher than 20% after operation is expected only in patients with so called "unforeseen" N2 findings or with minimal N2 disease at mediastinoscopy [15, 16]. The available imaging techniques do not provide a satisfactory specificity in detecting malignant mediastinal adenopathy, although positron emission tomography with 18fluorodeoxyglucose has emerged as a promising tool and will probably be in common use for mediastinal staging of NSCLC [17, 18]. Mediastinoscopy, therefore, has been a mainstay in the diagnosis of N2 disease [18, 19]. More recently, fiberoptic TBNA has been considered a safe and effective procedure in the mediastinal staging of NSCLC because it can avoid the costs and morbidity associated with surgical procedures in many N2 and N3 cases.
In the specific setting of the N2 disease due to NSCLC, our study demonstrated the strong value of TBNA as a staging tool with an overall sensitivity and accuracy as high as 71% and 73%, respectively. As already reported by other authors, TBNAs performed in the left paratracheal station (sensitivity 52%; accuracy 58%) have been significantly less sensitive and accurate than those performed either in the right paratracheal (sensitivity 84%, p = 0.001; accuracy 86%, p = 0.002) or the subcarinal (sensitivity 79%, p = 0.01; accuracy 81%, p = 0.02) LN stations [12]. Harrow and colleagues [12] have suggested that the protrusion of the aortic knob into the left paratracheal area may explain the difficulty in accessing this LN station and, consequently, for the lower yields observed. Remarkably, TBNA in our series established the diagnosis of NSCLC in 48 of 127 positive adequate samples (38%), this being the highest value reported in literature so far [9, 12, 20, 21].
Unlike results from previous studies, we found no statistically significant advantages for the 19-gauge needle over the 22-gauge needle in terms of sensitivity and accuracy (sensitivity 78% versus 67%; accuracy 80% versus 69%) [12, 22, 23]. Some factors need to be considered in an attempt to justify this finding. First, the technique consisted of the direct deposition of the needle’s contents onto a slide with rapid fixation and staining, which has been reported to enhance the aspirate yield [23, 24]. Furthermore, a longer training period is required for use of the histology needle as compared with the cytology needle [25]. Despite the additional expertise required to use the histology needle, however, the histology needle should be considered superior for several reasons, such as the possibility to diagnose benign diseases [11, 26], to suspect lymphomas [11], to reduce the rate of false-positive procedures [23], and to obviate the need for a cytopathologic support in many cases. In addition, use of the histology needle is reported to be as safe as that of the cytology needle [11, 23].
The main limitation of this retrospective study was probably the low number of TBNAs that have been surgically confirmed, leading us to accept some approximations in the definition of true-positive and false-negative procedures. In particular, all the positive TBNAs have been assumed to be true positive, although literature data have indicated that the sensitivity of a malignant aspirate may be a little lower, ranging from 96% to 100% [27–29]. However, those adequate negative aspirates that could not be confirmed surgically were assumed to be false negative, although literature data suggest a 78% negative predictive value of negative aspirates containing lymphocytes and a negative predictive value as high as 83% (15 of 18) was found in our surgically controlled adequate negative TBNAs (Fig 2, Table 2) [13]. These considerations lead us to suspect that a higher sensitivity and accuracy would have been observed in our series if all of the adequate negative TBNAs had been confirmed with a mediastinal surgical exploration.
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Fig 2. Computed tomography (CT) scan and transbronchial needle aspiration findings in a surgically controlled "true negative." (A) Contrast enhancement CT scan at the level of the tracheal carina showing enlarged (more than 1 cm) lymph nodes in the right paratracheal (4R) station. (B) Cytologic smear from the enlarged lymph nodes in the 4R station shown in (A) revealing numerous lymphocytes and lymphoblasts. (Papanicolaou stain, x100 before 33% reduction.)
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In conclusion, the results of our study have confirmed the usefulness of TBNA in mediastinal staging of NSCLC. Transbronchial needle aspiration may be performed in course of diagnostic bronchoscopy and has an excellent yield mainly when right paratracheal or subcarinal LNs are involved. In N2 and N3 disease, a positive TBNA specimen may preclude the need for additional surgical staging of the mediastinum [30]. Finally, TBNA can spare the associated costs and risks of more invasive surgical procedures in patients with inoperable tumors and in the mediastinal staging of patients who are not candidates for operation because of significant cardiopulmonary and vascular comorbidity [31]. Attempts are being made to improve the yield by coupling TBNA with new imaging techniques and should be encouraged. Endobronchial ultrasound-directed TBNA seems to have a high diagnostic yield and to decrease the number of aspirates required for paratracheal lymph nodes sampling in the setting of rapid onsite cytopathologic evaluation [32]. More recently, the development of CT fluoroscopy might provide an effective, real-time guidance for TBNA procedures and might be useful mainly in those cases with small or less accessible mediastinal lesions [33, 34].
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Abstract
Introduction
