Fine-Needle Aspiration Biopsy versus Core-Needle Biopsy in the Primary Diagnosis of Chest Neoplasm

Transcription

1 Evidence Summary A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO) Fine-Needle Aspiration Biopsy versus Core-Needle Biopsy in the Primary Diagnosis of Chest Neoplasm X. Yao, M.S. Tsao, M.M. Gomes, D. Mozeg, C. Allen, W. Geddie, and H. Sekhon Report Date: July 30, 2010 The full Evidence Summary is available on the CCO website ( For information about the PEBC and the most current version of all reports, please visit the CCO website at or contact the PEBC office at: Phone: , ext Fax: ccopgi@mcmaster.ca Journal Citation: Yao X, Gomes MM, Tsao MS, Allen CJ, Geddie W, Sekhon H. Fine-needle aspiration biopsy versus core-needle biopsy in diagnosing lung cancer: a systematic review. Curr Oncol Feb;19(1):e16 e27. doi: /co Evidence Summary Citation (Vancouver Style): Yao X, Tsao MS, Gomes MM, Mozeg D, Allen C, Geddie W, et al. Fine-needle aspiration biopsy versus core-needle biopsy in the primary diagnosis of chest neoplasm. Toronto (ON): Cancer Care Ontario; 2010 Jul 30. Program in Evidence-based Care Evidence Summary No.:

2 Evidence Summary A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO) Fine-Needle Aspiration Biopsy versus Core-Needle Biopsy in the Primary Diagnosis of Chest Neoplasm: An Evidence Summary X. Yao, M.S. Tsao, M.M. Gomes, D. Mozeg, C. Allen, W. Geddie, and H. Sekhon Report Date: July 30, 2010 QUESTIONS What are the diagnostic values (sensitivity, specificity, likelihood ratio, and accuracy) for fine-needle aspiration biopsy (FNAB) versus core-needle biopsy (CNB) to diagnose lung cancer in patients with an undiagnosed chest nodule or mass demonstrated on imaging? Compared with CNB, do FNAB samples have sufficient diagnostic yield for molecular predictive marker studies by mutation analysis and fluorescent in situ hybridization (FISH) in patients with an undiagnosed chest nodule or mass demonstrated on imaging? Target Population for CNB and FNAB Patients with an undiagnosed chest nodule or mass demonstrated on imaging. Target Users of CNB and FNAB Techniques Surgeons, pathologists, radiologists, and respirologists involved in the diagnostic workup of individuals with a chest nodule or mass demonstrated on imaging, and primary care providers responsible for referring patients to these specialists. INTRODUCTION As part of an ongoing quality-improvement initiative at Cancer Care Ontario (CCO), a project to map the diagnostic pathway for lung cancer was conducted by CCO s program for Disease Pathway Management (DPM). The development process is outlined below: An initial draft pathway was mapped on the basis of existing publicly available clinical and research information, as well as the expertise of clinicians and other stakeholders involved in the care of patients with lung cancer. Clinical co-chairs of the DPM lung cancer team edited the draft pathway. A multidisciplinary DPM lung cancer diagnosis team reviewed the draft and provided feedback that was incorporated into subsequent drafts. The DPM lung cancer diagnosis team identified several points in the pathway where an evidence search could be useful in developing guidance for clinicians. In collaboration Evidence Summary Page 1

3 with the Program in Evidence-Based Care (PEBC), four questions were developed to produce evidence summaries that will inform the diagnostic pathway. The pathways were reviewed by the provincial Lung Cancer Disease Site Group, and this feedback was incorporated into subsequent drafts of the pathway by the DPM lung cancer team. This evidence summary addresses the first set of priority questions regarding the diagnostic value of FNAB versus CNB posed above. In collaboration with clinical experts from the DPM lung cancer diagnosis team, the PEBC conducted a systematic review to answer these questions. This systematic review does not form part of a clinical or organizational guideline, as would be typical for the PEBC. Instead, it is intended only to advise the DPM lung cancer diagnosis team in their work on these core issues. METHODS This evidence-based report was developed by CCO s DPM team in collaboration with the PEBC. For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by two members of DPM lung cancer diagnosis team (Drs. Tsao and Gomes) and one methodologist (Dr. Yao). The final document was independently reviewed further by a radiologist (Dr. Mozeg), a respirologist (Dr. Allen), and two cytopathologists (Drs. Geddie and Sekhon). Search Strategy A literature search was performed using MEDLINE and EMBASE through Ovid from January 1, 1990, to September 14, The search strategies are reported in Appendices 1 and 2. The following resources were checked for existing systematic reviews and practical guidelines: the Cochrane Library (to Issue 4, 2009); National Guideline Clearing House, National Institute for Health and Clinical Excellence, and Scottish Intercollegiate Guidelines Network (to August 28, 2009); the American Society of Clinical Oncology guidelines, National Health and Medical Research Council (Australia), New Zealand Guidelines Group, and Canadian Medical Association Infobase (to August 31, 2009); and The Physicians Data Query (to September 8, 2009). Study Selection Criteria Inclusion Criteria Articles were eligible for inclusion in this systematic review if they met all the following criteria: 1. Were published in full text from January 1, 1990, to September 14, Were systematic reviews, meta-analyses, clinical practice guidelines, randomized trials, or comparative cohort studies. 3. Reported or provided sufficient data to calculate at least one diagnostic characteristic (i.e., sensitivity, specificity, positive or negative likelihood ratio, or accuracy) for both FNAB and CNB, or diagnostic yield from FNAB and CNB for molecular predictivemarker studies by mutation analysis or FISH for diagnosing lung cancer. 4. Included patients with an undiagnosed chest nodule or mass demonstrated on imaging. 5. Stated the reference standard for final diagnosis was the histological confirmation from wedge biopsy, surgical resection, metastases, or autopsy; or the clinical followup. Evidence Summary Page 2

4 Exclusion Criteria Articles were excluded if they met any of the following criteria: 1. Recruited only patients who had previous or current diagnosis of lung cancer or other chest malignancies at baseline. 2. Regarded the biopsy results from FNAB and/or CNB as a part of the reference standard. 3. Performed FNAB and CNB on patients with completely different-sized lesions (for example, FNAB was performed on patients with <20-millimeter lesions, and CNB was performed on patients with 20-millimeter lesions). 4. Were published in a language other than English. 5. Were non-systematic reviews, case studies, letters, editorials or commentaries. Data Abstraction One reviewer went through the retrieved citation titles and abstracts from the search sources to identify potentially relevant articles, which were then retrieved for full-text review. Three reviewers independently assessed the articles for possible inclusion. Differences in assessment were resolved by discussion. For each eligible study, one reviewer extracted features of the study design; patient population; information of FNAB and CNB procedures; complications; diagnostic values: sensitivity (proportion of patients with disease who have a positive test), specificity (proportion of patients without disease who have a negative test), likelihood ratio (a given test result would be expected in a patient with disease compared with the likelihood that same result would be expected in a patient without disease), and accuracy (proportion of patients who were correctly diagnosed by the procedure) (Table 1); and diagnostic yield (likelihood that a procedure will provide the information needed to establish a diagnosis) (1). The term disease refers to lung cancer or other thoracic malignancies. A standardized data-extraction sheet was used. All data were audited by a second and independent person. Table 1. Formulae for calculating sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and accuracy of needle biopsy procedure in an undiagnosed chest nodule or mass demonstrated on imaging.* Needle biopsy result Reference standard Benign lesion Lung cancer or other thoracic malignancy Positive a b Negative c d Total a + c b + d Sensitivity: % patients with disease who have a positive test Specificity: % patients without disease who have a negative test Likelihood ratio: Expected results in a patient with disease compared to same result expected in a patient without disease Accuracy: % patients correctly diagnosed by the procedure *Sensitivity = a/(a+c); specificity = d/(b+d); positive likelihood ratio = [a/(a+c)] [b/(b+d)]; negative likelihood ratio =[c/(a+c)] [d/(b+d)]; accuracy = (a+d)/(a+b+c+d). a = true positive: patients identified to have lung cancer or thoracic malignant disease by needle biopsy procedure that had the final diagnosis of lung cancer or thoracic malignant disease; b = false positive: patients identified to have lung cancer or thoracic malignant disease by needle biopsy procedure that had the final diagnosis of benign disease; c = false negative: patients not identified to have lung cancer or thoracic malignant disease by needle biopsy procedure that had the final diagnosis of lung cancer or malignant disease by; d = true negative: patients not identified to have lung cancer or thoracic malignant disease by needle biopsy procedure that had the final diagnosis of benign disease. Evidence Summary Page 3

5 Data Analysis A 2 2 contingency table was constructed for FNAB and CNB, respectively, for each study, if the data were reported. Meta-analyses, if at least three studies showed sufficient clinical and statistical homogeneity, would be conducted using MetaDiSc software (Unit of Clinical Biostatistics, Ramón y Cajal Hospital, Madrid, Spain; available at the summary diagnostic odds ratio (ratio of the odds of positivity in disease to the odds of positivity in non-disease), a measure of the overall accuracy of a test, was calculated. We assessed the heterogeneity of these measures by using both a chi-square test for heterogeneity and the I 2 value; we considered a p-value less than 0.1 on the chi-square test or an I 2 value greater than 50% to be evidence of statistical heterogeneity. To allow inclusion of studies with zero patients in a cell of the contingency table, we added 0.5 to those cells. A receiver operating characteristic (ROC) plane plot was plotted for each study if its sensitivity and specificity values were available. In these plots, the diagonal from the lower left to upper right represents the line of 50% accuracy (i.e., no better than random chance overall). Thus, the upper left-hand corner represents a test with perfect accuracy. These plots can be helpful for visually assessing any trends in accuracy across studies even when formal meta-analyses are not possible or appropriate. Minitab 15 was used as the statistical software to compare FNAB with CNB for the diagnostic values, diagnostic yield, and procedure complications; Stata 9.0 was used to confirm. A two-sided significance level of α = 0.05 was assumed. RESULTS No existing systematic reviews or practice guidelines focusing on the topic of comparing FNAB with CNB for diagnosing lung cancer in patients with a previously undiagnosed chest lesion were found. One hundred twenty-two citations were identified from the electronic search (Appendix 3). Sixty-eight articles were excluded after reviewing the titles and abstracts, and 42 papers were disqualified after reviewing the full texts (Appendix 4), leaving 12 eligible articles. Three additional studies were identified from the reference sections (2-4). Among the 15 potential eligible articles, three articles (4-6) did not state what they regarded as the reference standard to make the final diagnoses for all the patients. We contacted the authors to clarify this information but did not receive any feedback. Thus, we listed these three articles at the end of each table and analyzed them separately from other included studies for the diagnostic values and diagnostic yield. Fifteen studies in total were included in this systematic review (2-16). For a diagnostic study, a prospective cohort study or a randomized controlled trial would be the ideal design, as the quality of data collection in a retrospective study is often compromised. However, only five of 15 included studies were prospective (3,7-10), six were retrospective (2,4,6,11-13), and four did not specify their study designs (5,14-16) (Table 2). Eleven of the 15 indicated the study settings were at university hospitals (2-5,8-10,12-14, 16). FNAB and CNB were performed on the same patient in six studies (3,9,10,13,15,16). Three studies recruited children less than 13 years of age (2,4,13), and 12 studies included seniors more than 80 years of age (3-9,11-14,16). The lesion diameters ranged from three to 150 millimeters in seven studies that reported this information (4,8,11-13,15,16). The lesions were located only in the lungs in six studies (6,7,8,11,14,16); only in the mediastinum in four studies (2,4,5,10); and in the lungs, mediastinum, pleura, or chest wall in five studies (3,9,12,13,15) (Table 2). We included the four studies that focused specifically on mediastinal masses, as some lung cancers may present primarily as mediastinal masses. In fact, the results of these studies included a significant number of positive cases being metastatic lung carcinoma. Evidence Summary Page 4

6 Eight studies were published in radiological journals (3,7,8,11,12,14-16), three in chest medicine journals (2,5,13), three in clinical medicine journals (4,6,10), and one in a cytopathological journal (9) (Table 2). Computed tomography (CT) alone was used to guide FNAB and CNB in six studies (4,6,8,11-13); in two studies, some biopsies were guided by fluoroscopy, while others were guided by CT (2,3). CT alone, fluoroscopy plus CT, or multiplanar reconstruction images plus CT were used in patients, respectively, in one study (14), and CT plus fluoroscopy was used in one study (16). Ultrasound (US) alone was used to guide FNAB and CNB in four studies (5,9,10,15), and one study used single-plane fluoroscopy to guide biopsies (7) (Table 3). FNAB and CNB were performed by a radiologist in 11 studies and by a respirologist in four studies (Table 3). An on-site cytopathologist was available in four studies (Table 3). Diagnostic Values Except for the study by Yu et al (5) (one of three studies that did not specify the reference standard), no studies provided sufficient data to calculate the diagnostic values for lung cancer only; instead, data were available to calculate the diagnostic values for lung cancer and other chest malignancies together. The patients who had a chest lesion and needed to be diagnosed by FNAB or CNB would have either thoracic malignant disease (such as malignant lymphoma, thymic neoplasm, germ cell tumour, or lung cancer) or benign disease (such as abscess, tuberculosis, pneumoconiosis). The prevalence of thoracic malignant lesions ranged from 67.3% to 94.3%; however, three papers did not report the prevalence (4,7,9). Thirteen reports provided sufficient data to allow the calculation of at least one of the diagnostic characteristics for FNAB and CNB to identify lung cancer or other thoracic malignancy in patients with a chest lesion (2-5,8-16). Diagnosis in the included studies was defined in two possible ways based on the data reported in the original studies, which we refer to as the overall diagnosis (i.e., benign versus malignant categorization) and specific diagnosis (Tables 4 and 5). In overall diagnosis, the purpose of thoracic biopsy was to differentiate malignant from benign lesions without specific cytological or histological subtype diagnoses. In specific diagnosis, the purpose of biopsy was to determine the specific cytological or histological subtype of malignancies or the specific benign diagnoses. Hence, the true-positive and the true-negative results of FNAB or CNB were exactly the same as the final histological diagnoses listed in the full text for the patients. For example, the cytological diagnosis from FNAB for one patient was thymoma, but the pathological result from surgery was lymphoma. This patient would be regarded as true positive by FNAB for overall diagnosis and would be treated as false negative for specific diagnosis. Five papers reported both overall diagnostic and specific diagnostic values, respectively (2,5,12,13,16). In brief, seven studies reported the overall diagnostic values, and the total sample size was 1,166 (2,5,8,12,13,14,16) (Table 4); 11 studies reported the specific diagnostic values, and the total sample size was 1,088 (2-5,9-13,15,16) (Table 5). Evidence Summary Page 5

7 Table 2. Study and patient information for included studies. Study Publication journal Design Country N, age (mean) Cheong Australasian Radiology Pros Singapore 128, (61.4) y Morrissey Thorax Retro UK 75, 8-78 (NR) y Moulton Interventional Radiology Pros USA 114, (64.7) y* Arakawa Clinical Radiology Retro Japan 107, (62.7) y Staroselsky Chest Retro Israel 182, (62) y Laurent Cardiovascular and Pros France 220, Interventional Radiology (61.9 for FNAB; 65.4 for CNB) y Sagar Acta Radiologica NR India 30, (43.5) y Anderson Clinical Radiology Retro UK 182, (67.5) y Yamagami American Journal of NR Japan 134, Roentgenology (67.1) y Ohno European Journal of NR Japan 390, Radiology (63.3) y Schubert Diagnostic Cytopathology Pros South Africa 85, (56) y Tscheikuna Journal of the Medical Pros Thailand 35, Association of Thailand (42.4) y Yu # Chest NR Taiwan, 58, China (NR) y de Farias # Rev Hosp Clin Fac Med Sao Retro Brazil 86, Paulo 1-95 (median 34) y Lourenco # Medline Revista Portuguesa Retro Portugal 92, de Pneumologia (64.4) y Lesion location Lesion diameter, distance from skin to lesion (mean) (mm) Lung Mean 37, NR Mediastinum NR Lung, mediastinum, and pleura NR Lung, mediastinum, and pleura 5-100, NR Lung, chest wall, mediastinum, , and pleura NR Lung (35.4), NR Lung, mediastinum, and pleura , NR Lung (41), 5-70 (24) Lung (22.1), 0 63 (13.8). Lung 71.0% of lesions >10, NR Lung, chest wall, mediastinum, NR and pleura Mediastinum NR Mediastinum 29 pts had lesions >30, NR Mediastinum (median 50), (median 50) Lung NR Abbreviations: Retro = retrospective, Pros = prospective, N = study population, UK = United Kingdom, USA = United States, y = year, mm = millimeter, NR = not reported. *114 was number of procedure for thoracic masses; age was for 267 patients who had thoracic, hepatic, renal, pancreatic, adrenal, splenic, retroperitoneal, and musculoskeletal soft-tissue masses. 122 patients were recruited, but original authors only reported results of 107 who had final definitive diagnoses; age was for 122 patients. 97 patients were recruited, but original authors only reported results of 85 who underwent both procedures; age was for 97 patients. Age was for 80 patients who were recruited at the baseline. #Study did not specify reference standard. Evidence Summary Page 6

8 Study Cheong 56, G Table 3. Procedure information, diagnostic yield, and complication in 15 included studies. N of procedures, Needle size FNAB Morrissey 60, G Moulton $ Arakawa Staroselsky $ 114, 22 G 47, 20 G 182, 25 G CNB 75, 18; 19.5; or 21.5 G 34, 14 G 114, 18 G 63, 18 G 182, 18 G Image guidance Single-plane fluoroscopy Fluoroscopy for first 24 Proc; CT for late 70 Proc CT for 105 Proc; fluoroscopy for 9 Proc CT Procedure Needle pass Diagnostic yield Complication Performer Onsite FNAB CNB FNAB vs. CNB Radiologist No Usually 1-2 Usually % vs. 71% for Cyto ; (mean 1.9) (mean 1.9) 10% vs. 39% for Histo* Radiologist No Up to 6 Up to 3 100% of FNAB for Cyto, 100% of CNB for Histo Radiologist No % of FNAB for Cyto, 100% of CNB adequate for Histo* Radiologist or resident under supervision No Mean 1.6 Mean % of CNB for Histo, p- value was less than 0.02 for histological diagnostic prediction in favour of CNB. Pneumothorax Pulmonary hemorrhage (FNAB vs. CNB) (FNAB vs. CNB) 35.8% vs. 35.5% 4.5% vs. 12.7% 1.7% needed drainage after FNA 1.7% had haematoma after FNA; 2.9% had transient haemoptysis after CNB 11.4% 2.6% had self-limiting hemoptysis and/or perilesional hemorrhage 34.6% vs. 24.3% (3.8% vs. 4.1% needed drainage) CT Respirologist Yes Mean 2 Mean % vs. 78% for Histo 24.7% (2.7% needed drainage) 5.8% vs. 4.1% for mild hemoptysis 1.1% had moderate hemoptysis Laurent Sagar $ 125, 20 or 22 G 30, 21 G Anderson 151, or 22 G Yamagami $ 138, 21 G Ohno 242, G Schubert $ Tscheikuna $ 85, 22 G 35, 21 G 98, 19.5 G 30, 18 G 44, 18 or 20 G 138, 18 or 20 G 154, 18 G 85, 14 G 35, 16 G CT Radiologist Yes Repeated samples until satisfactory % vs. 99.0% for Cyto, 96% vs. 96.9% for Histo. US Radiologist Yes % vs. 56.5% for malignant lesions; 57.1% vs. 100% for benign lesions CT CT + fluoroscopy CT for 250; CT + fluoroscopy for 81; CT + MRI for 65 Proc Radiologist or resident under supervision No 1-4 (mean 1.8) 1-4 (mean 1.8) 20.0% vs. 15.3% (2.4% vs. 2.0% needed drainage) No NR 35.1% vs. 15.9%* (2% needed drainage) Radiologist No % of FNAB for Cyto, 91.3% of CNB adequate for Histo 32.6% (3.6% needed drainage) Radiologist No NR NR NR 22.7% vs. 28.6% NR US Pulmonologist Yes Up to 3 Up to % of FNAB for Cyto, 80.0% of CNB for Histo US Respirologist No % of FNAB for Cyto, 80.0% of CNB for Histo No major complications 2.9% without drainage 13.6% vs. 28.6% (2.4% vs. 4.1% for mild hemoptysis) No 6 patients had self-limiting hemoptysis. 25.4%; 6.5% had hemoptysis; 0.7% had subcutaneous hematoma No major complications 5.7% had minor bleeding from the puncture sites Evidence Summary Page 7

9 Yu # 58, 22 G de Farias # Lourenco # 49, 22 G 89, 22 G 29 (lesions > 30 mm), 16 G 48, 18 G 13, 18 G US Respirologist No NR NR NR No No CT Radiologist No 1-5 NR 75.5% of FNAB for Cyto, 89.6% of CNB adequate for Histo CT Radiologist No NR NR 80.9% of FNAB for Cyto, 100% of CNB for Histo No complications needed intervention. No complications needed intervention. 7.9% vs. 0% 4.5% (1.1% had hemothorax needed drainage) vs. 0% Abbreviations: FNAB = fine-needle aspiration biopsy, CNB = core-needle biopsy, On-site = on-site cytopathologist, Proc = procedures, N = number, vs. = versus, G = gauge, CT = computed tomography, US = ultrasound, MRI = multiplanar reconstruction image, Histo = histological analysis, Cyto = cytological analysis, NR = not reported. Assumed no on-site cytopathologist available if article did not state. *Significant in favour of CNB. Not significant between FNAB and CNB. Patient numbers inconsistent at one area in article. Patient numbers inconsistent at five areas in article. The diagnostic yield of FNAB or CNB, the author mentioned in article, was the same as the diagnostic value. Significant in favour of FNAB. #Study did not specify reference standard. $FNAB and CNB were performed in each patient. Evidence Summary Page 8

10 Table 4. Overall diagnostic values of FNAB and CNB for identifying chest malignancies versus non-malignancies in patients with an undiagnosed chest nodule or mass demonstrated on imaging.* Study (Prevalence of malignant lesions) Morrissey (72%) Arakawa (67.3%) Staroselsky (77.5%) Laurent (80.5%) Yamagami (68.1% to 71.0%) Ohno (74.7%) Yu # (75.9%) Procedure and p- value Sensitivity (%) (95% CI) Specificity (%) (95% CI) Positive likelihood ratio (95% CI) Negative likelihood ratio (95% CI) Accuracy (%) (95% CI) FNAB 90.2 ( ) ( ) 0.10 ( ) 93.3 ( ) CNB 96.4 ( ) ( ) 0.04 ( ) 97.1 ( ) p-value NA FNAB 81.3 ( ) 46.7 ( ) 1.52 ( ) 0.40 ( ) 70.2 ( ) CNB 85.7 ( ) NR NR NR NR P-value NA NA NA NA FNAB 90.8 ( ) 95.1 ( ) ( ) 0.10 (0.06, 0.16) 91.8 ( ) CNB 91.5 ( ) ( ) 0.09 (0.05, 0.15) 93.4 ( ) p-value Combined NR NR NR NR NR FNAB 82.7 ( ) ( ) 0.18 ( ) 86.4 ( ) CNB 97.4 ( ) 95.0 ( ) ( ) 0.03 ( ) 96.9 ( ) p-value FNAB NR NR NR NR 79.7 ( ) CNB NR NR NR NR 89.1 ( ) p-value NR NR NA NA Combined NR NR NR NR 94.2 ( ) FNAB 90.4 ( ) 75.4 ( ) 3.67 ( ) 0.13 ( ) 86.4 ( ) CNB 89.1 ( ) 88.6 ( ) 7.79 ( ) 0.12 ( ) 89.0 ( ) p-value FNAB 77.3 ( ) NR NR NR NR CNB NR NR p-value NA NA NA NA Abbreviations: FNAB = Fine-needle aspiration biopsy, CNB = Core-needle biopsy, CT = Computed tomography, NA = Not available, NR = Not reported. *Overall diagnosis meant to differentiate malignant from benign lesions without specific cytological or histological subtype diagnoses. Provided from data in article; other numbers calculated from data in article. Combined FNAB and CNB together (two procedures were performed in each patient). Patient number inconsistent at 5 areas in article; reported definitive diagnosis by per patient in FNAB group, but unclear in CNB group. #Study did not specify reference standard. Reported definitive diagnosis by per patient. Reported definitive diagnosis by per biopsy procedure. Reported definitive diagnosis by per lesion. Evidence Summary Page 9

11 Table 5. Specific diagnostic values of FNAB and CNB for identifying chest malignancies versus benign diseases in patients with an undiagnosed chest nodule or mass demonstrated on imaging.* Study (Prevalence of malignant lesions) Procedure and p-value Sensitivity (%) (95% CI) Specificity (%) (95% CI) Positive likelihood ratio (95% CI) Negative likelihood ratio (95% CI) Accuracy (%) (95% CI) Morrissey FNAB NR NR NR NR 76.7 ( ) (72%) CNB NR NR NR NR 94.1 ( ) Moulton (85.1%) Arakawa (67.3%) Staroselsky (77.5%) Sagar (76.7%) Anderson (85.7%) Yamagami (68.1% to 71.0%) Schubert (NR) Tscheikuna (94.3%) Yu # (75.9%) de Farias # (NR) p-value NR NR NA NA FNAB 83.5 ( ) 41.2 ( ) 1.42 ( ) 0.40 ( ) 77.2 ( ) CNB 88.7 ( ) 94.1 ( ) ( ) 0.12 ( ) 89.5 ( ) p-value Combined 92.8 ( ) 94.1 ( ) ( ) 0.08 ( ) 93.0 ( ) FNAB 56.3 ( ) 6.7 ( ) 0.60 ( ) 6.56 ( ) 40.4 ( ) CNB 73.8 ( ) 52.4 ( ) 1.55 ( ) 0.50 ( ) 66.7 ( ) p-value FNAB 86.5 ( ) 31.7 ( ) 1.27 ( ) 0.43 ( ) 74.2 ( ) CNB 78.0 ( ) 87.8 ( ) 6.40 ( ) 0.25 ( ) 80.2 ( ) p-value <0.001 < Combined NR NR NR NR NR FNAB 82.6 ( ) 57.1 ( ) 1.93 ( ) 0.30 ( ) 76.7 ( ) CNB 56.5 ( ) ( ) 0.47 ( ) 66.7 ( ) p-value Combined 91.3 ( ) ( ) 0.09 ( ) 93.3 ( ) FNAB NR NR NR NR 78.1 ( ) CNB NR NR NR NR 93.2 ( ) p-value < in favour of CNB NR NA NA FNAB NR NR NR NR 58.7 ( ) CNB NR NR NR NR 83.3 ( ) p-value NR NR NA NA <0.001 Combined NR NR NR NR 86.2 ( ) FNAB NR NR NR NR 81.2 ( ) CNB NR NR NR NR 80.0 ( ) p-value NR NR NA NA Combined NR NR NR NR 89.4 ( ) FNAB NR NR NR NR 40.0 ( ) CNB NR NR NR NR 88.6 ( ) p-value NR NR NA NA <0.001 Combined NR NR NR NR 91.4 ( ) FNAB 54.5 ( ) 33.3 NR NR 69.8 ( ) CNB NR NR p-value <0.001 <0.001 NA NA FNAB NR NR NR NR 53.1 ( ) CNB NR NR NR NR 81.3 ( ) p-value NR NR NA NA Evidence Summary Page 10

12 Abbreviations: FNAB = Fine-needle aspiration biopsy, CNB = Core-needle biopsy. *Specific diagnosis meant to determine the specific cytological or histological subtype of malignancies or the specific benign diagnoses. Provided from data in article; other numbers calculated from data in article. Combined FNAB and CNB together (two procedures were performed in each patient). Patient number inconsistent at 5 areas in article. #Study did not specify reference standard. Reported definitive diagnosis by per patient. Reported definitive diagnosis by per biopsy procedure. Reported definitive diagnosis by per lesion. Evidence Summary Page 11

13 Overall Diagnostic Values Four of seven studies in Table 4 provided sufficient data to calculate sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and accuracy for identifying lung cancer or other thoracic malignancies from benign lesions (2,8,13,14). Only one of the four studies was prospective (8) (Table 1). An on-site cytopathologist was available in two studies to assess whether the specimens from FNAB were adequate for cytological analysis, and needle passes were repeated until the samples were satisfactory (8,13). An on-site cytopathologist was not available in the other two studies (2,14) (Table 3). The presence of a cytopathologist during the FNAB procedure has been reported to improve the diagnostic accuracy (17). However, we could not do a subgroup analysis for with and without an on-site cytopathologist, as there were less than three studies in each subgroup; therefore, a metaanalysis was not conducted. Table 4 reports the diagnostic values of FNAB and CNB for overall diagnosis. The range of sensitivity for FNAB and CNB was % and % ( % and % if one study (5) that did not report whether the reference standard was considered); the range of specificity similarly was % and %; and the range of accuracy was % and % (Figure 1). The range of positive likelihood ratio was 3.67 to for FNAB and 7.79 to for CNB; the range of negative likelihood ratio was 0.10 to 0.18 for FNAB and 0.03 to 0.12 for CNB. To reduce bias, we did not analyze the data in studies that reported for one procedure, such as specificity being available only for FNAB and not for CNB in the Arakawa et al study (12). Figures 2 and 3 show ROC plane plots from each study for FNAB and CNB, respectively. Among 21 comparisons in Table 4, only five p-values were <0.05, and all of them favoured CNB against FNAB: sensitivity, negative likelihood ratio, and accuracy in the Laurent et al study (8), accuracy in the Yamagami et al study (16), and sensitivity in the Yu et al study (the study did not specify the reference standard) (5). It was noted that the report by Laurent et al had five areas in which the patient numbers were inconsistent, questioning the reliability of the results. For example, 25 cases in group A had the final diagnosis of benign disease (page 268), but the true negative number that FNAB could identify was 27 (Table 2, page 269). Figure 1. Ranges of overall diagnostic values for FNAB and CNB, excluding the study that did not report the reference standard. Evidence Summary Page 12

14 Figure 2. Overall diagnosis for FNAB. Figure 3. Overall diagnosis for CNB. Sensitivity 1 ROC Plane Sensitivity 1 ROC Plane specificity specificity Specific Diagnostic Values Table 5 shows the studies that reported specific diagnostic values. Four studies provided sufficient data to calculate diagnostic characteristics (3,12,13,15); one study was prospective (3) (Table 2). An on-site cytopathologist was available in only two studies (13,15) (Table 3), rendering a subgroup analysis by the presence or absence of on-site cytopathologist not possible. In Table 5, the range of sensitivity was % for FNAB and % for CNB, but % for FNAB and % for CNB when including the Yu et al study, the one study that did not specify the reference standard (5). Only the Yu et al study had a p-value less than 0.05 for sensitivity in favour of CNB (5) for specific diagnosis. It is noted that sensitivity was marginally higher for FNAB than for CNB in two studies with an on-site cytopathologist (p-values were and 0.054, respectively) (13,15). However, the Anderson et al study, without an on-site cytopathologist, reported the p-value was less than in favour of CNB for sensitivity (11). The range of specificity was % for FNAB and % for CNB. Specificity was significantly or marginally higher for CNB than FNAB in all five studies in which specificities were available (3,5,12,13,15) (including the Yu et al study) (5). It appears that CNB may be significantly or marginally greater than FNAB for classifying benign diseases in patients with a chest lesion. The range of positive likelihood ratio was for FNAB and for CNB; three of four studies supported CNB against FNAB (3,12,13). The range of negative likelihood ratio was for FNAB and for CNB; two of four studies were in favour of CNB (3,12). The accuracy was available in 11 studies. The range of accuracy was % for FNAB and % for CNB ( % for CNB when including the Yu et al study) (5) (Figure 4). Six papers showed statistically significantly higher accuracy for CNB than for FNAB (2,3,10-12,16) (eight when including two studies that did not report the reference standards) (4,5). Evidence Summary Page 13

15 Figure 4. Ranges of specific diagnostic values for FNAB and CNB, excluding the two studies that did not report the reference standards. Figures 5 and 6 demonstrate ROC planes for FNAB and CNB, respectively. Taken together, the data suggest that CNB might be more accurate than FNAB for specific diagnosis, primarily due to the increased specificity of CNB. However, given the limitations of the studies and data, there was no way to formally quantify or statistically demonstrate this potential difference in accuracy. Figure 5. Specific diagnosis for FNAB. Figure 6. Specific diagnosis for CNB. Sensitivity 1 ROC Plane Sensitivity 1 ROC Plane specificity specificity Image Guidance CT has largely replaced fluoroscopy alone or US alone to guide FNAB or CNB in current practice. Thus, a separate subgroup analysis of studies of FNAB and CNB guided by CT, with or without other forms of guidance, is relevant. Eight studies used CT (or CT plus fluoroscopy or multiplanar reconstruction images) in more than 74% of patients (2,3,8,11-14,16) (10 studies if including two studies that did not specify the reference standard) (4,6). For overall diagnosis, all studies in Table 4 employed CT in most patients (2,8,12-14,16), excluding the Evidence Summary Page 14

16 Yu et al study that did not specify the reference standard (5). Hence, the analyses were the same as above. For specific diagnosis in Table 5, six of nine studies utilized CT in most patients (2,3,11-13,16) (seven of 11 when including studies that did not specify the reference standard) (4). Three studies provided sufficient data to calculate diagnostic characteristics (3,12,13), one study was prospective (3), and an on-site cytopathologist was available in one study (13). The range of sensitivity was % for FNAB and % for CNB. It is noted that sensitivity was marginally higher for FNAB than CNB in one study with an on-site cytopathologist (p=0.062) (13). However, the Anderson et al study, without an on-site cytopathologist, reported the p-value was less than in favour of CNB for sensitivity (11). The range of specificity was % for FNAB and % for CNB. Specificity was significantly higher for CNB than for FNAB in all the three studies. The range of positive likelihood ratio was for FNAB and for CNB; all three studies supported CNB against FNAB (3,12,13). The range of negative likelihood ratio was for FNAB and for CNB; two of three studies were in favour of CNB (3,12). The accuracy was available in six studies (seven when including the de Farias et al study that did not specify the reference standard) (4). The range of accuracy was % for FNAB and % for CNB. Five of six papers showed statistically significant higher accuracy for CNB than FNAB (2,3,10,11,12) (six of seven when including the de Farias et al study) (4). The interesting finding is that for the specific diagnosis in Table 5, the Sagar et al study (15), guided by US, had the highest specificity for FNAB and CNB, and the Schubert et al study (9), guided by US as well, had the highest accuracy for FNAB. However, both studies had an on-site cytopathologist. Lung Biopsy Six papers included patients only with lung lesions (as opposed to studies including patients with lung, pleura, chest wall, or mediastinal lesions, or with mediastinal lesions alone). Four of them reported at least one diagnostic value, and the sample size was 926 (8,11,14,16). FNAB and CNB were guided by CT in all four studies. Among three studies reporting overall diagnostic values (8,14,16) (Table 4), two studies had sufficient data to calculate sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and accuracy (8,14). Ohno et al did not find any statistical difference between FNAB and CNB (14); Laurent et al reported that CNB had a significantly higher sensitivity and negative likelihood ratio than FNAB, but as noted previously, the data reported in this study contained inconsistencies (18). Yamagami et al only reported accuracy value and favoured CNB over FNAB. 16 For specific diagnosis (Table 5), accuracy value was only available in two studies (11,16), and one study of them also reported the p-value of the comparison between FNAB and CNB for sensitivity (11); all the three values were in favour of CNB. On-site Cytopathologist Four studies stated that an on-site cytopathologist was present in their centers; these studies included 517 patients (8,9,13,15). Two of four reported the overall diagnostic values (8,13) (Table 4). The Laurent et al study showed that CNB was statistically significantly better than FNAB for sensitivity, negative likelihood ratio, and accuracy (8). As discussed previously, the reliability of the data was questionable in this study because of the inconsistent patient numbers. No significant difference was seen between FNAB and CNB for any diagnostic characteristics in the Staroselsky study (13). For overall diagnostic values (Table 4), the lowest sensitivity for FNAB was reported by Arakawa et al where no on-site cytopathologist was present (12) and excluding the Yu et al Evidence Summary Page 15

17 study that did not specify a reference standard (5). The highest sensitivity came from the Staroselsky et al study for FNAB where an on-site cytopathologist was available (13). The lowest specificity for FNAB was found in the Ohno et al study without an on-site cytopathologist (14). The highest specificity (100%) for FNAB was found in two studies: one study without an on-site cytopathologist (2) and another study with an on-site cytopathologist (8). Both the highest and lowest accuracy for FNAB were in the studies without an on-site cytopathologist (2,16). It seems that an on-site cytopathologist may lead to improved sensitivity (but not specificity and accuracy) for FNAB, but no meta analysis and no statistical comparison between studies could be conducted because of the clinical heterogeneity and limited evidence. The specific diagnostic values were available in three studies (9,13,15) (Table 5). Sagar et al (15) and Staroselsky et al (13) found that FNAB might have a greater sensitivity with marginal significance than CNB (p-values were and 0.062, respectively), but CNB had better specificity than did FNAB. Schubert et al only reported accuracy and showed no difference between the two procedures (9). For specific diagnostic values in Table 5, the lowest sensitivity and specificity for FNAB were in the study without an on-site cytopathologist (12), while the highest was in the two studies with on-site pathologists (13,15). The lowest accuracy for FNAB was in one study without an on-site cytopathologist (10), and the highest accuracy for FNAB was in one study where an on-site cytopathologist was present (9). It appears that an on-site cytopathologist may improve the specific diagnostic values for FNAB. FNAB and CNB performed on same patient Six studies performed FNAB and CNB at the same biopsy session in each patient (3,9,10,13,15,16). Five of six studies performed FNAB first and then CNB (9,10,13,15,16); FNAB was usually done first but not always in one study (3). For specific diagnosis, accuracy was reported in all six studies and was significantly higher for CNB than for FNAB in three studies (3,10,16) (Table 5). The range of accuracy was % for FNAB, % for CNB, and % for the combination. The combined diagnostic values of FNAB and CNB were apparently higher than the diagnostic characteristics of FNAB or CNB from the number values in five studies whose combinations were available (the statistical comparison was not able to be calculated between the combined diagnostic value and either diagnostic value from FNAB or CNB, since they were not independent in each study) (3,9,10,15,16). Two studies reported the accuracy value for the overall diagnosis (13,16). Staroselsky et al did not find any statistical difference between FNAB and CNB for all the diagnostic characteristics (13); Yamagami et al only reported accuracy value and it was higher for CNB than that for FNAB (16). Diagnostic Yield Diagnostic yield refers to the ability of the procedure to produce sufficient material for making a diagnostic assessment. No eligible articles reported the diagnostic yield for molecular predictive marker studies by mutation analysis or FISH in patients with a chest lesion. However, 13 studies reported the diagnostic yield of FNAB and/or CNB for cytological and histological analyses (Table 3) (2-10,12,13,15,16). Three studies compared the diagnostic yield of FNAB with CNB for cytological and/or histological analysis, respectively (3,7,8). Cheong et al compared the diagnostic yield of two different needles under single-plane fluoroscopic guidance (7). The thinner needle (22 gauge) (22 G) had a significantly lower proportion of procedures giving sufficient histological material than did the thicker ones ( G) (10% versus 39%, p < 0.01), but there was no statistically significant difference between two procedures for the adequacy of the cytological materials Evidence Summary Page 16

18 (65% versus 71%). In contrast, Laurent et al did not find differences between CNB and FNAB (the introducer of a fine needle was moved through the lesion to get a small core specimen after the aspirate) under CT guidance for both cytological and histological analyses (8). Arakawa et al reported 90.5% of CNB under CT guidance giving sufficient material for histological analysis (12). Five studies (2-4,6,16) reported that the FNAB specimens were taken for cytological evaluation and the CNB specimens were taken for histological evaluation. Among the studies, only Moulton et al found that CNB had a higher diagnostic yield for histological analysis than did FNAB for cytological analysis (100% versus 96%), and they usually performed FNAB first and then CNB at the same patient (92% of patients were guided under CT) (3). In the four remaining studies (9,10,13,15), the authors reported the FNAB or CNB diagnostic yield as the diagnostic value, instead of considering the real likelihood of FNAB or CNB to yield sufficient material for cytological or histological analysis. For example, Sagar et al reported that the diagnostic yield of FNAB versus CNB was 82.6% versus 56.5% (15). These were the sensitivities for diagnosing malignant lesions (Table 4). Therefore, these four articles did not provide reliable evidence for the diagnostic yield. Complications All 15 papers reported the rates of complications for the two procedures (Table 3). The main complications of FNAB and CNB were pneumothorax and pulmonary hemorrhage. The needle sizes ranged from 20 to 22 G for FNAB and 14 to 21.5 G for CNB in the five prospective studies (3,7-10). In two prospective studies, a comparison between FNAB and CNB were done, and no difference was found between the two procedures for the pneumothorax rates, which were 20.0% and 35.8% for FNAB and 15.3% and 35.5% for CNB, respectively (7,8). Laurent et al also reported no difference between FNAB and CNB for the patients who needed to be drained (2.4% versus 2.0%) (8). The pulmonary hemorrhage rate was significantly higher in CNB than in FNAB in Laurent et al study (8), but not in Cheong et al study (17). A very low mild hemoptysis rate occurred in Laurent et al study (8) and no statistically significant difference between FNAB and CNB (2.4% versus 4.1%). As noted above, there are inconsistencies in the reporting of data in this study. In the remaining three prospective studies, FNAB and CNB were performed at the same visit in each patient, so each procedure that resulted in complications could not be identified separately (3,9,10). Schubert et al reported that no major complications occurred during or after the two procedures in 85 patients (9). Tscheikuna et al reported that one of 35 patients had a mild pneumothorax requiring no drainage, and two patients had minor bleeding from the puncture sites (10); they also indicated that the risk of pneumothorax was less in their study, because all the patients had mediastinal mass, which was usually not covered by pleura and lung tissue. Moulton et al reported pneumothorax in 13 of 114 (11.4%) patients, and 2.6% of patients reported selflimiting hemoptysis and/or perilesional hemorrhage (3). Based on this information, two procedures performed on an individual did not appear to increase the complication rates compared with a single procedure, but no independently statistical comparison could be done. In 10 non-prospective studies (2,4-6,11-16), the needle sizes ranged from 19 to 25 G for FNAB and 14 to 20 G for CNB. The pneumothorax rate varied % for FNAB and % for CNB. Anderson et al (11) and Lourenco et al (6) reported that CNB had a lower pneumothorax rate than did FNAB. Anderson et al explained that the fact that more pleuralbased lesions were biopsied by CNB might be the reason (11). No significant difference for the pulmonary hemorrhage and hemoptysis rates existed between the two procedures in any study. The highest pulmonary hemorrhage rate was 25.4% (35 of 138 patients), which happened in one study (16) where FNAB and CNB were performed on the same patients. In Evidence Summary Page 17

19 that same study, 6.5% (nine patients) had hemoptysis and 0.7% (one patient) had a subcutaneous hematoma (Table 3). Some retrospective studies stated that the frequency of minor complications might be underestimated because they might not be recorded in the medical records (2,4). Apart from pneumothorax, pulmonary hemorrhage, hemoptysis, and subcutaneous hematoma, two other complications were reported. Staroselsky et al reported five patients (2.7%) with chest pain, who were successfully treated with analgesics (13). Tscheikuna et al reported one patient (2.9%) who developed hypotension immediately after CNB but recovered after intravenous fluid administration (10). Procedure Time Three papers mentioned the time required for performing the two procedures (8,14,16). In the Ohno et al study, the mean time was 28 ± 4 minutes (min) (mean ± standard deviation) for FNAB and 33 ± 5 min for CNB (14). In the Laurent et al study, FNAB took longer time than did CNB (41 ± 12 versus 33 ± 8.4 min, p < 0.001). This might have been because an on-site cytopathologist was present during the FNAB procedure, and repeated samples were taken until a satisfactory specimen was obtained (8). Yamagami et al performed two procedures on each patient, but they reported the mean time required for each biopsy procedure was 25.6 ± 10.1 min (range from 10 to 59 min) (16). DISCUSSION The evidence obtained from this systematic literature review has significant limitations. First, the original objective of this systematic review was to compare the diagnostic characteristics and yields of FNAB versus CNB for diagnosing lung cancer. However, except for the study by Yu et al (5) (one of three studies that did not report the reference standard), no study reported or provided sufficient data to calculate the diagnostic values of FNAB and CNB for identifying lung cancer versus non-lung cancer in patients with a chest nodule or mass demonstrated on imaging. Instead, data were only available to calculate the diagnostic values of FNAB and CNB for differentiating between thoracic malignancies and benign diseases. Second, the research question was to compare the diagnostic characteristics and yields of FNAB with CNB to diagnose lung cancer in patients with a chest nodule or mass demonstrated on imaging. Chest nodules or masses may involve the mediastinum, pleura, or chest wall. Some patients with a mediastinal mass in the absence of an apparent parenchymal pulmonary nodule may prove to have direct extension or metastatic involvement from a lung carcinoma. For instance, 35% of patients with a mediastinal nodule or mass were diagnosed as metastatic lung cancer in the Tscheikuna et al study (10). Even for the six studies that recruited only patients with lung lesions at baseline (6-8,11,14,16), some patients were finally diagnosed as having thoracic malignancies (e.g., lymphoma) other than lung cancer. For example, in the Laurent et al study (8), 100 patients had a malignancy and 25 had benign disease in group A; the specific malignant diagnoses included 28 squamous cell carcinomas, 30 adenocarcinomas, three small cell carcinomas, five lymphomas, 33 undifferentiated carcinomas, and one melanoma. This is the reason that studies with lung, mediastinal, pleura, or chest wall nodules or masses were included in this systematic review. Therefore, based on the limited literature evidence, this review attempted to address the research question about comparing the diagnostic characteristics and yields of FNAB versus CNB for diagnosing lung cancer or thoracic malignancies in patients with a chest nodule or mass demonstrated on imaging. This inclusion of a variety of thoracic pathologies other than carcinoma of the lung could have the effect of widening the quoted range of sensitivity of FNAB (Figure 4), since some thoracic lesions are less amenable to diagnosis by FNAB than is carcinoma of the lung. Evidence Summary Page 18