Prevalence of Benign Disease in Patients Undergoing Resection for Suspected Lung Cancer

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1 ORIGINAL ARTICLES: SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. Prevalence of Benign Disease in Patients Undergoing Resection for Suspected Lung Cancer Michael A. Smith, MD, Richard J. Battafarano, MD, PhD, Bryan F. Meyers, MD, MPH, Jennifer Bell Zoole, BSN, Joel D. Cooper, MD, and G. Alexander Patterson, MD Department of Surgery, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, Missouri Background. In this era of expanded lung cancer screening, accurate differentiation of benign from malignant lesions remains an important problem. We sought to characterize our experience with focal pulmonary lesions suggestive of lung cancer and subsequently proven benign on surgical resection. Methods. A retrospective analysis was performed on 1,560 patients who underwent resection for focal pulmonary lesions at our institution from January 1995 to December Computed tomography and pathology reports were reviewed for all patients. Fluorine-18-fluorodeoxyglucose positron emission tomography studies were performed on 43 patients. Results. Benign processes were found on pathologic examination in 140 patients (9%). Resection was accomplished by thoracotomy in 103 patients (74%), videoassisted thoracoscopy in 36 patients (26%), and sternotomy in 1 patient (0.7%). Seventy patients (50%) underwent mediastinoscopy before resection. There was 1 (0.7%) perioperative death. Pathologic diagnoses from the pulmonary resections revealed granulomatous inflammation in 91 patients (65%), hamartoma in 17 patients (12%), pneumonia or pneumonitis in 14 patients (10%), fibrosis in 5 patients (4%), and other in 13 patients (9%). Fluorine-18-fluorodeoxyglucose positron emission tomography imaging suggested malignancy in 22 of 43 patients and benign lesion in 20 of 43 patients (1 study was not interpretable). Thirty-eight patients underwent needle biopsy before surgery. Of these, 29 samples were nondiagnostic, 5 samples were negative, and 4 samples were considered positive for malignancy. Conclusions. Despite thorough clinical assessment, advanced imaging technology, and needle biopsy, many patients continue to undergo surgery for benign disease. Aggressive attempts to diagnose and treat early stage lung cancer must be tempered with this understanding. (Ann Thorac Surg 2006;81:1824 9) 2006 by The Society of Thoracic Surgeons Lung cancer is the leading cause of cancer deaths for men and women in the United States [1]. Early detection and surgical management provides the best chance for cure. However, the majority of lung cancers present at advanced stages and are not amenable surgery. Despite the failure of earlier trials to show a survival advantage after lung cancer screening with chest radiography and sputum cytology [2], there has been renewed interest in lung cancer screening with computed tomographic (CT) scanning [3, 4]. In addition, many indeterminate pulmonary lesions are found on CT scans performed for other reasons. The dilemma of how to manage these lesions discovered incidentally and on screening CT is becoming increasingly common. Accepted for publication Nov 4, Presented at the Fifty-first Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 2 4, Address correspondence to Dr Battafarano, Suite 3108 Queeny Tower, One Barnes-Jewish Hospital Plaza, St. Louis, MO 63110; battafaranor@wustl.edu. When faced with an indeterminate pulmonary lesion, the clinician must assess the likelihood of lung cancer. An initial impression of the likelihood of lung cancer is based on clinical and radiographic factors. If there is any concern for lung cancer, most patients undergo further imaging with fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) or attempts to obtain tissue diagnosis. Percutaneous fine-needle aspiration biopsy can be performed for peripheral lesions. Occasionally, bronchoscopy with transbronchial biopsy or brushings and washings can yield a tissue diagnosis. These are the least invasive methods of obtaining tissue for diagnosis and are very useful when a specific benign or malignant result is obtained. However, these tests will often be nondiagnostic. In these cases the clinician faces the choice of following the lesion radiographically or performing an excisional biopsy under general anesthesia. Radiographic surveillance is associated with the risk of disease progression, and immediate excision may lead to resection of a benign process. This decision-making process is vital to successful identification and manage by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg SMITH ET AL 2006;81: BENIGN RESECTION FOR SUSPECTED CANCER 1825 Table 1. Clinical Characteristics (n 140) ment of early stage lung cancer, but exposes the patient with benign lesions to unnecessary costs and risks. Although the sensitivity of modern imaging for the detection of focal pulmonary lesions is high, the accurate differentiation of benign from malignant lesions remains an important problem. We sought to characterize our experience with focal pulmonary lesions suggestive of lung cancer and subsequently proven benign on surgical resection. Material and Methods From January 1995 to December 2002 a total of 1,560 patients underwent resection of a focal pulmonary lesion at our institution. One hundred forty patients were found to have benign pathologic diagnosis and form the basis of this study. A retrospective review of a prospective database on these 140 patients was performed. The medical record of each patient was examined for age, sex, smoking history, method of resection, pathologic diagnosis, and perioperative mortality. This study was approved by the institutional review board at Washington University School of Medicine. Computed tomography and pathology reports were reviewed for all patients. Data regarding size, calcification, character of the margins, presence of lymphadenopathy, and interval change in size on CT scan were recorded on these patients. Fluorine-18-fluorodeoxyglucose positron emission tomography studies were performed on 43 patients. Fluorine-18-fluorodeoxyglucose positron emission tomography data recorded included whether the lesion was positive or negative for malignancy on the basis of a standard uptake value (SUV). An SUV of greater than 2.5 was considered to be positive for malignancy. The radiologists overall impression of the study was also recorded for the FDG-PET study. Results Variable Value % Age (y) a Positive smoking history % Males 81 58% Females 59 42% a Value reported as mean SD. Surgical resection was performed on 1,560 patients with focal pulmonary lesions suggestive of lung cancer at our institution during the time period. One hundred forty of these patients were found to have benign lesions on pathologic examination. The average age of this group of patients was years, and 71% were smokers (Table 1). All 140 patients underwent CT imaging. Data regarding size, calcification, character of the margins, presence of lymphadenopathy, and interval change in size are Table 2. Computed Tomography Characteristics (n 140) Characteristic n % Median size (cm) a 1.80 ( ) Appearance Noncalcified % Calcified % Not stated % Margins Irregular % Smooth % Not stated % Lymphadenopathy present Yes % No % Change in size Increase % No change % Decrease 1 0.7% a Value reported as median with range given in parentheses. recorded in Table 2. Forty-three of these patients also underwent FDG-PET imaging. Table 3 shows the FDG- PET scan findings in these patients. Data recorded for FDG-PET include whether the lesion was positive or negative for malignancy on the basis of SUV and the radiologists overall impression of the study. The procedures patients underwent for tissue diagnosis are shown in Table 4. Before resection, 38 patients underwent needle biopsy for attempt at preoperative tissue diagnosis. Of the 38 needle biopsies performed, 29 were nondiagnostic, 5 were negative, and 4 were considered positive for malignancy. In addition, 70 of the patients underwent mediastinoscopy before resection for lymph node staging. All 140 patients underwent a general anesthetic and major thoracic procedure. The approach and extent of resections are listed in Table 4. There was 1 perioperative death. The tissue diagnoses of the resected benign lesions are shown in Table 5. Table 3. Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography Characteristics (n 43) Assessment n % According to SUV Positive by SUV % Negative by SUV % Unable to assess 1 2.3% According to radiologists impression Suspicious % Indeterminate % Benign 4 9.3% No opinion stated 3 7.0% SUV standard uptake value.

3 1826 SMITH ET AL Ann Thorac Surg BENIGN RESECTION FOR SUSPECTED CANCER 2006;81: Comment Table 4. Procedures Procedure n % Percutaneous fine-needle aspiration cytology (n 38) Cancer % Benign % Nondiagnostic % Staging Cervical mediastinoscopy % Cervical and anterior mediastinoscopy 2 2.9% Resection approach (n 140) Thoracotomy % VATS % Sternotomy 1 0.7% Extent of resection Wedge only 118 Segmentectomy 1 Lobectomy 21 VATS video-assisted thoracoscopic surgery. Table 5. Diagnoses (n 140) Diagnosis n % Granuloma Hamartoma Pneumonia/pneumonitis Fibrosis Other Abscess Aspergilloma Amyloid Bronchogenic cyst Carcinoid tumorlet Clear cell tumor Inflammatory pseudotumor Meningioma Mesothelial hyperplasia Necrosis Rheumatoid nodule It is clear that the rate of unnecessary surgical intervention has decreased as a function of time. Before chest CT scanning became available, rates of surgical excision for ultimately benign solitary pulmonary nodules were as high as 64% [5]. In a later series examining a similar experience from 1970 to 1980, 51% of patients underwent surgical resection of benign lesions [6]. In a more modern series reported by Rubins and associates [7], which analyzed all indeterminate solitary lesions resected between 1981 and 1994, 21% of these lesions were benign. In the current study we report a rate of surgical resection for benign lesions of 9%. It should be noted, however, that in the context of lung cancer screening, rates of surgical resection for benign disease are much lower. In a modern era lung cancer screening program, such as the Early Lung Cancer Action Project (ELCAP), which identified 233 of 1,000 patients with noncalcified pulmonary nodules on low dose CT scans [8], the rate of biopsy for benign disease was 1.7% (4 of 233). Furthermore, no patient underwent a thoracotomy for a benign lesion in the ELCAP study. Complete avoidance of benign lesion resection is admirable and made possible largely by strict adherence to protocols, excellent support from radiology and cytopathology for fine-needle aspiration, and the exclusion of nonsmokers and subjects younger than 60 years of age from the screening study. Studies such as the ELCAP have renewed interest in lung cancer screening, but most centers are not likely to reproduce their low rates of benign resection because of different resources and heterogeneity of patient demographics. Both this renewed interest in lung cancer screening and increased use of CT scanning for nonpulmonary thoracic disease have made the evaluation and management of the indeterminate lesion an increasingly common problem. The optimal management of the indeterminate pulmonary lesion is yet to be determined. It is a careful balance between attempting to identify and resect early stage lung cancer and minimizing the rate of resection of benign pulmonary lesions. Under special circumstances such as the presence of benign calcifications or documented radiographic stability, no further evaluation is needed. In other situations periodic radiographic reevaluation may be more appropriate. However, more immediate information requires FDG-PET imaging, percutaneous fine-needle aspiration, or resection. Fluorine-18-fluorodeoxyglucose positron emission tomography imaging offers the most accurate method of noninvasive diagnosis to date. There is a high falsepositive rate in this series, compared with prior reports [9]. The reason for this is unclear, but it may be related to granulomatous disease endemic to our study population. Indeed, this was the most common benign diagnosis in this study. In most cases of granulomatous disease the increased fluorodeoxyglucose uptake is related to the increased metabolic rate of the accumulated inflammatory cells. Conversely, there were 20 of 43 patients who had a negative positron emission tomographic scan according to SUV but still underwent resection of the lesion. It is also interesting to note that although 20 of 43 lesions in this study were considered benign by SUV, only 4 of 43 were considered benign by radiologists overall impression; suggesting an operator-dependent or reader-dependent nature of the data gained from FDG- PET imaging. The failure of FDG-PET to give definitive diagnostic data leads to subjective interpretation of the information. The clinical decision to proceed with surgical resection in the face of a benign FDG-PET scan varies but is largely based on the clinicians concern for a false-negative result, which can occur in 5% to 10% of tests [10 13] depending on the pretest probability of lung cancer. This can be especially true of subcentimeter lesions [11], bronchioloalveolar carcinoma [11, 14], and carcinoid tumors [11, 15].

4 Ann Thorac Surg SMITH ET AL 2006;81: BENIGN RESECTION FOR SUSPECTED CANCER 1827 Percutaneous fine-needle aspiration is an important technique for obtaining a definitive tissue diagnosis. This minimally invasive method of obtaining a tissue diagnosis has become a very important diagnostic technique [16]. Besides limitations of lesion location, there are other limitations including size-dependent accuracy [17, 18], nonspecific cytopathology, and false-negative results. Much of the accuracy of this test is also dependent on the skill and experience of the radiologist and cytopathologist. These limitations are illustrated by this study, in which 38 of the 140 patients who underwent resections for benign lesions had prior percutaneous fine-needle aspiration cytology performed. Twenty-nine of 38 (79%) of these needle biopsies were considered nondiagnostic. Four others were actually believed to be consistent with cancer. Only 5 of 38 were specific benign diagnoses on fine-needle aspiration and resection. These data are limited by the lack of information regarding the number of patients who were found to have specific benign diagnoses and did not go on to have a resection. We also do not report the number of patients who had fineneedle aspiration consistent with cancer and went on to definitive treatment. These data therefore should not serve to condemn fine-needle aspiration. Tissue can also be obtained by bronchoscopy. More commonly, however, indeterminate pulmonary lesions found incidentally or on screening studies tend to be peripheral and more amenable to a percutaneous approach. We also document the surgical approach used for resection of these indeterminate pulmonary lesions. The majority of patients in this study underwent thoracotomy for resection. In addition, half of them also underwent mediastinoscopy before resection, suggesting a high level of suspicion for lung cancer in these patients. Only 26% of the patients underwent video-assisted thoracoscopic surgery resection. Although video-assisted thoracoscopic surgery for peripheral pulmonary lesions is a very useful technique for the diagnosis of peripheral indeterminate pulmonary lesions and has been widely reported [19], the tendency to use a thoracotomy approach in these patients was based on surgeon preference and lesion accessibility [20, 21]. Video-assisted thoracoscopic surgery is believed to be preferable to open procedures because it reduces surgical trauma, decreases pain and postoperative narcotic use, and preserves pulmonary function [22]. These factors may allow older or sicker patients who are poor candidates for thoracotomy to undergo diagnostic or therapeutic interventions [23]. Patients and surgeons tend to be less apprehensive about a minimally invasive surgical approach. However, lowering the threshold for surgical resection by using a minimally invasive technique may result in rates of benign nodule excision as high as 75% [20]. Despite the minimally invasive nature of this approach, it still carries a greater risk for complications than serial imaging and percutaneous needle biopsy. Smoking is by far the most significant independent risk factor for the development of lung cancer [24]. Given its strong correlation with the development of lung cancer, this clinical element tends to press the issue of obtaining a tissue diagnosis in the evaluation of the indeterminate pulmonary lesion. Historically, it is expected that more than 90% of patients with lung cancer are current or former smokers [25]. In this series of patients who underwent resection of benign lesions, only 71% were smokers. Although the fact that up to 10% of lung cancer patients have never smoked justifies the performance of biopsy in nonsmokers, these data heighten the awareness that lack of smoking history is likely to be associated with a benign result. Patient age is also an important factor in determining evaluation and management of indeterminate pulmonary lesions. The average age of patients in this series who underwent resection of a benign lesion was 58 years. Lung cancer rates peak between ages 65 and 70, and lung cancer is rare before the age of 40 [26]. A review of our experience with resected T1N0 lung cancers revealed a mean age of 67 years in those patients. In addition, studies of CT screening for lung cancer that included patients older than 40 years of age [27, 28] had much lower incidences of cancer in pulmonary nodules than did studies that included patients older than 60 years of age [29, 30]. A less aggressive approach is warranted in younger nonsmokers, especially those with small lesions. Despite the use of FDG-PET imaging and minimally invasive techniques of obtaining tissue for diagnosis, there continues to be a significant number of patients who undergo resection for benign lesions. The approach to the indeterminate lung lesion varies. However, the goals are constant. They are identification and management of early lung cancers but avoidance of unnecessary resections. Although there are many factors that can influence the management of these lesions, particular attention should be given to the age and smoking history of the patient. More aggressive means of obtaining tissue for diagnosis should be reserved for older current or previous smokers. Younger patients with no smoking history and small lesions should be monitored with interval imaging. Although resections of benign lesions are unlikely to be eliminated completely, it is important to work toward making them as uncommon as possible without compromising early diagnosis and resection of actual lung cancers. References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, CA Cancer J Clin 2004;54: Fontana RS. The Mayo Lung Project: a perspective. Cancer 2000;89: Henschke CI. Early lung cancer action project: overall design and findings from baseline screening. Cancer 2000;89: Gohagan J, Marcus P, Fagerstrom R, Pinsky P, Kramer B, Prorok P. Baseline findings of a randomized feasibility trial of lung cancer screening with spiral CT scan vs chest radiograph: the Lung Screening Study of the National Cancer Institute. Chest 2004;126: Steele JD. The solitary pulmonary nodule. Report of a cooperative study of resected asymptomatic solitary pulmonary nodules in males. J Thorac Cardiovasc Surg 1963;46:21 39.

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Early Lung Cancer Action Project: initial findings on repeat screenings. Cancer 2001;92: DISCUSSION DR DANIEL L. MILLER (Atlanta, GA): I enjoyed the presentation. I only have two short comments. One thing, I was a little surprised at your thoracotomy rate for these benign lesions. You had 70% of lesions less than 2 cm, but 73% of your patients underwent a thoracotomy. I thought that was extremely high for the benign nature of these lesions. Also too, you had a 50% false-positive rate for these benign lesions, and I wish you would comment on that and what was the pathology of those lesions. I thought that was extremely high. But also I would like to congratulate you on a very low percentage of benign disease. As you quoted, the majority of the European studies and so forth have been up to 40%, 50%, or 60%. Congratulations. DR SMITH: Thank you for those comments. To answer the first question, I think that most would agree that there is a fairly high proportion of thoracotomies in this patient population. I think that the current era this data goes all the way back to 1995 would probably have more videoassisted thoracoscopic surgery (VATS) procedures in them. A lot of this was based on surgeon preference. But I should also mention that in many of the series you look at where VATS resections are predominant, the rate of benign lesion resection is somewhat higher because of a lower threshold to pursue resection. Data that I didn t show in this population was that fully 50% of these patients also underwent mediastinoscopy. So there was a very high suspicion for cancer in these patients. To answer the question about positron emission tomographic (PET) scanning, I think that the false-positive rate was very high in this group of patients, and I think that a lot of it has to do with the fact that these patients are in an endemic region for granulomatous disease, and that is associated with a fairly high false-positive rate for PET scanning. DR MARK KRASNA (Baltimore, MD): I also enjoyed your talk, Dr Smith. I am glad Dan brought that comment up. Just to take that a step further, my first question would be if you could elucidate for us the location of the majority of those lesions. Obviously if these were peripheral lesions, we would expect that 73% thoracotomy rate to really go down and thus for the numbers to switch, and hopefully, even if you did have to do these benign resections, over 70% of them should be amenable by VATS, I would think. The other question goes to what you are talking about in the PET scan. I think you highlight a very important point. In Maryland certainly we have an endemic area with aspergillosis and histoplasmosis, but all the more reason to take the results of

6 Ann Thorac Surg SMITH ET AL 2006;81: BENIGN RESECTION FOR SUSPECTED CANCER 1829 our PET scans with some caution. I think that when you are going to use a PET scan, even if the PET is positive in the mediastinum as well, you do need to really exhaust all the other opportunities for making a diagnosis. At Maryland we are very fortunate. Our radiologists are able to achieve approximately an 82% benign needle diagnosis rate for any lesion greater than 1 cm, and I would just encourage that if that is possible, obviously a nondiagnostic is not a good answer, but a benign diagnosis in an area that you know is endemic in a low-risk patient to have these identified, I think it is reasonable to consider following that patient. Thank you. DR SMITH: Thank you for those comments. We don t have the exact location of these lesions within our data set, but that is a very important point that you make about location being both amenable to a VATS approach and/or a needle biopsy as well. DR JOHN R. BENFIELD (Los Angeles, CA): I take the liberty of taking issue with two linguistic comments about your use of well-established surgical jargon, and hope that you will accept them in the constructive spirit in which this is offered: We resect lesions, cancers, and we don t resect patients. Secondly, I would prefer that we neither use the word benign to equate with non-cancerous, nor the word malignant to equate with cancer. We have all encountered many non-cancerous lesions of the lung that are terribly malignant and that kill people. More substantively, I want to ask whether you had any cases of actinomycosis in your series of non-cancerous lesions? In my experience, actinomycosis can occasionally mimic cancer in all clinical ways, and be extremely difficult to differentiate from cancer. Finally, I interpret your presentation as a challenge to the rather well accepted surgical concept that removing an indeterminate pulmonary lesion in order to make a definitive diagnosis is nearly always the appropriate way to exclude cancer. Do your data indicate we should soften our traditional stance and that expectant management has a greater place than we afforded it in the past? DR SMITH: Thank you for those comments. I don t recall in this data set any patients that had actinomycosis. There were 2 patients who had aspergilloma and others with typical granulomatous disease and pneumonitis associated lesions. I appreciate your comments regarding terminology used in the presentation. Thanks.