Despite attempts at earlier detection and treatment,

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1 ORIGINAL ARTICLES: GENERAL THORACIC Factors Associated With False-Positive Staging of Lung Cancer by Positron Emission Tomography Peter F. Roberts, MD, David M. Follette, MD, Derek von Haag, MD, Jason A. Park, MD, Peter E. Valk, MBBS, Thomas R. Pounds, MD, and Donald M. Hopkins, MD Division of Cardiothoracic Surgery, University of California, Davis and Northern California PET Imaging Center, Sacramento, California Background. Positron emission tomography imaging is gaining popularity as a noninvasive staging tool in non-small cell lung cancer. Nonmalignant processes can also affect radio-tracer uptake. This study seeks to identify factors associated with false-positive staging of mediastinal metastases. Methods. A retrospective review was performed of 100 patients with early stage non-small cell lung cancer referred for positron emission tomography scan evaluation. All had pathologic confirmation of their disease. Positron emission tomography scans, radiology records, operative reports, and pathology results were reviewed. Patients with positron emission tomography scans interpreted as positive for mediastinal involvement and negative pathology at operation were selected. Results. Seven patients were found to have a falsepositive positron emission tomography evaluation for mediastinal metastases. All but 1 patient had a concurrent inflammatory process or an anatomic factor associated with the false positive. The sensitivity and specificity in detecting involved mediastinal nodes was 87.5% and 90.7%, respectively. The negative predictive value was 95.8%. Conclusions. Although positron emission tomography has been established as an accurate modality to stage non-small cell lung cancer, false-positive evaluation of mediastinal metastases can occur in the setting of concurrent inflammatory lung diseases or for centrally located tumors. Pathologic evaluation of mediastinal disease should be pursued whenever suggested by a positive positron emission tomography scan especially in the face of those factors described. (Ann Thorac Surg 2000;70: ) 2000 by The Society of Thoracic Surgeons Despite attempts at earlier detection and treatment, lung cancer continues to be the leading cause of cancer death in the United States [1]. Surgical resection has been the mainstay of curative treatment in this disease. Non-small cell lung cancers comprise a majority of these cases, and the presence or absence of tumor cells in the mediastinal lymph nodes of these patients is a critical factor in determining their prognosis and treatment plans. Surgical cures could be expected in as many as 24% of patients with N2 disease [2] and as many as 70% of patients with N0 disease [3]. Resectable patients with N2 disease (stage IIIA) may have improved survival with induction chemotherapy versus operation alone [4, 5]. Early stage patients may not benefit from this combined modality approach and would unnecessarily suffer the added morbidity. This last idea, however, continues to be investigated by many groups using newer chemotherapeutic agents because of the nearly 30% of stage I patients who are nonsurvivors. The ability to accurately stage a patient in a cost-effective, noninvasive, safe, and readily available way before the institution of treatment continues to be an area of intense research. Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31 Feb 2, Address reprint requests to Dr Roberts, Division of Cardiothoracic Surgery, University of California, Davis, 2221 Stockton Blvd, 2nd floor, Sacramento, CA 95817; peter.roberts@ucdmc.ucdavis.edu. Computed tomography (CT) is well entrenched as a tool in the armamentarium in the preoperative staging of lung cancer. It is a vital study in defining the anatomy of the pathologic growth of the tumor. Unfortunately, the size of mediastinal lymph nodes does not always correlate with their tumor involvement [6]. One centimeter is often used as a size criterion in predicting involvement with tumor. However, 21% of nodes less than 1 cm may contain cancer [7], whereas as many as 40% of those greater than 1 cm may not [8]. Mediastinoscopy, mediastinotomy, and thoracotomy remain as definitive means by which tissue is obtained, but are invasive. Presently, magnetic resonance imaging has little role in evaluating the mediastinum. Currently, there is no widely accepted, single, noninvasive way to assess the entire body in a physiologic sense. Positron emission tomography (PET) with 2-( 18 F)fluoro-2-deoxy-D-glucose as a tracer (FDG-PET) is gaining use as a means of physiologically assessing tumor spread. PET is based on the fact that malignant cells have a higher rate of glycolysis than most surrounding normal structures. FDG competes with glucose for uptake into cells and as it accumulates in areas involved with tumor a higher activity is seen. Glucose is also avidly metabolized by tissues involved in a granulomatous or inflammatory processes, and therefore, there will be some false-positive results. Despite this notion, there have been published studies claiming 100% accuracy [9] 2000 by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)

2 Ann Thorac Surg ROBERTS ET AL 2000;70: FACTORS ASSOCIATED WITH FALSE-POSITIVE PET SCANS 1155 and nearly perfect specificity [10]. Overall, PET is gaining a record better than CT scan in predicting mediastinal involvement. This has been found in multiple studies including a metaanalytic comparison of 14 PET studies and 29 CT studies. This demonstrated the sensitivity and specificity of PET to be 79% and 89%, respectively, versus 60% and 77% for CT scan [11]. This included a range in sensitivity from 62% to 97% and specificity from 79% to 99%. However, there have been few reports of the causes of false-positive PET findings. The use of PET scan and its availability are increasing. Its use, in combination with the other studies noted, in staging lung cancer has tremendous variability from practice to practice and across specialties such as family practice, pulmonary medicine, oncology, and thoracic surgery. False-positive results on PET scans have the potential to result in the unnecessary administration of chemotherapy before a curative resection or worse, in the potential denial for a chance at a surgical cure. We reviewed our PET scan experience with the intent of revealing some factors that may influence these results. Material and Methods A retrospective review was performed on the records of all patients referred for PET scan evaluation between January 1995 and April 1999, from one university-based and one community-based thoracic surgery practice. We then selected the patients who were studied for known or suspected lung cancer who later had pathologic confirmation of their cancer and their mediastinal nodal status. PET scan imaging was obtained with a dedicated ECAT EXACT 921 PET system manufactured by CTI (Knoxville, TN) and distributed by Siemans Medical Systems (Iselin, NJ). Data acquisition, reconstruction, and display were performed using standard software. The system has an axial field of view of 16.2 cm with an intrinsic transverse resolution of 6.0 mm and axial resolution of 5.5 mm. All patients fasted for at least 4 hours before the intravenous administration of mci/kg FDG. After a 30- to 45-minute latent period, a six-bed attenuation corrected whole body scan was acquired. Projection and tomographic images in the axial, coronal, and sagittal planes were reconstructed with and without attenuation correction. The studies were immediately read by one or two nuclear medicine physicians with specialty in interpreting PET scan images. The reading physicians had a targeted clinical history and the pertinent CT scans available for review in virtually all patients. Standardized uptake value (SUV) was determined for all primary lesions, but used less consistently in assessing the mediastinum. Standardized uptake value is a semiquantitative method of measuring the uptake of a given lesion. It is obtained by dividing maximum activity in a lesion (micro-curies per milliliter) by the injected dose corrected for body weight (micro-curies per gram). Standardized uptake values were inconsistently applied to mediastinal lesions because of resolution limitations resulting from the small size of many mediastinal foci [12]. Mediastinal nodes were believed to be positive if their activity was slightly, but definitely above, mediastinal activity. This corresponded to an SUV of 2.0 or greater in most patients. Specific lymph node stations were not identified. Foci were described as being present on the right or left side and contained within the mediastinum or hilar area. Midline foci were considered ipsilateral to the tumor. All lymph node tissue obtained from the mediastinum was obtained by mediastinoscopy, mediastinotomy, or thoracotomy. In no patient was bronchoscopic or fine needle aspiration used as a definitive staging tool. All visible and technically accessible lymph nodes were removed. At thoracotomy only ipsilateral nodes were removed. On the right, this typically included stations 4, 7, 8, 9, and 10. When performing a left thoracotomy, stations 5, 8, 9, and 10 were removed and occasionally 6 and 7 according to the American Thoracic Society classification of nodal systems [13]. Pathologic reports were reviewed to determine whether any of the mediastinal lymph nodes contained cancer. The histories and roentgenograms of those patients with false-positive results were then specifically examined to determine whether there were common elements leading to the false result. The sensitivity, specificity, accuracy, and positive and negative predictive values of PET for mediastinal lymph node involvement were calculated in the usual way. Results During the time period listed there were 100 patients who underwent PET scans for known or suspected lung cancer who later had histologic confirmation of their cancer and their mediastinal status. Two of these patients had small cell carcinoma. These were included in our review because the pathology was not known before thoracotomy, and one of these patients had a falsepositive result and is particularly illustrative. The remaining 98 patients had non-small cell lung cancer. Fifteen patients were found to have foci of extrathoracic uptake. These were previously unsuspected and only one was found to be a false positive, a villous adenoma of the cecum. Considering all 100 patients, there were 72 whose PET scans were read as negative in the mediastinum with only three of these subsequently proved to be positive on final pathologic examination. Of the 28 positive studies, seven were shown to be false positives (PET positive with positive pathology, 21 patients, and with negative pathology, 7 patients; PET negative positive with positive pathology, 3 patients, and with negative pathology, 69 patients). Detailed chart reviews of these patients were performed. The sensitivity (21 of 24 patients) and specificity (69 of 76 patients) for predicting mediastinal involvement with tumor was 87.5% and 90.7%, respectively. There was a 75% positive (21 of 28 patients) and a 95.8% negative (69 of 72 patients) predictive value and a 90% overall accuracy (90 of 100 patients). All 7 patients underwent thoracotomy. Five of 7 patients underwent mediastinoscopy before the thoracotomy. One patient did not undergo mediastinoscopy be-

3 1156 ROBERTS ET AL Ann Thorac Surg FACTORS ASSOCIATED WITH FALSE-POSITIVE PET SCANS 2000;70: Table 1. False-Positive PET Scans Patient No. Age/Sex Cell Type CT Adenopathy Associated Factors 1 62/M Adeno Negative Previous thoracotomy 2 69/M Squamous Negative Proximity 3 67/M Squamous Positive Atelectasis 4 76/M Small cell Negative Rheumatoid 5 51/F NSCLC Negative Atelectasis 6 57/F Adeno Negative URI, hemoptysis 7 57/M Large cell Positive Bronchiectasis CT computed tomography; NSCLC non-small cell lung cancer; PET positron emission tomography; URI upper respiratory tract infection. cause of a previous mediastinoscopy and the other because of inaccessibility. A summary of the 7 patients is given in Table 1. In two of the seven false-positive results, CT scans were also read as positive by size criterion for mediastinal adenopathy. In the other 5 patients, there were no CT findings of mediastinal adenopathy. In 2 patients, the positive PET scan results were associated with significant atelectasis seen on CT and also with mediastinal adenopathy in 1 patient. One patient had a significant history of bronchiectasis and also had mediastinal adenopathy on CT scan. A fourth patient had hemoptysis and chest wall pain secondary to invasion. All 4 of these patients had symptoms of cough and mild to moderate symptoms of bronchitis before their studies. One patient had a right lower lobe lesion with marked tracer uptake (SUV 6.0) and mediastinal activity corresponding to an SUV of 3.2. The lung nodule was diagnosed as small cell cancer and the positive mediastinal lymph nodes were found to be secondary to the patient s longstanding rheumatoid disease. One false-positive result was believed to be the incorrect interpretation of primary tumor activity adjacent to the mediastinum. The last patient had undergone a thoracotomy 11 years previously for a squamous cell cancer but no specific factors could be identified to explain the false-positive result in the patient s new adenocarcinoma. Figure 1 shows representative scans from three patients. Comment There continues to be varied application and skepticism regarding PET imaging. We believe applications will range from initial evaluation and staging, through assessing response to therapy to long-term follow-up for recurrence. Some groups have also used PET images to plan radiation fields [14]. Errors in the staging of lung cancer will result in poorer outcomes, decrease cost effectiveness, and weaken clinical trials. All new techniques and imaging studies must be put under careful scrutiny. Although our data were examined in a retrospective fashion, we believe the point that the collective patients illustrate is worth examining to better interpret further PET studies. In our study, results were based on surgical staging yielding a sensitivity and specificity of approximately 90%. Our results correlate with previously reported studies that used CT scanning as a complimentary study [11]. The most impressive result in our series is a negative predictive value of 95.8%. Our false-positive cases echo some of the difficulty PET imaging has had with primary lung tumors. Bakheet and Powe [15] listed 19 causes for falsepositive results in lung parenchyma on PET images. These included processes that induce an inflammatory response such as pneumonia, bronchiectasis, and active tuberculosis. Just as inflammation in the lung can produce false-positive results in the parenchyma, our patients illustrate that these processes may cause increased tracer uptake in the mediastinum. Given this notion, it is reasonable to believe that any of the factors described by Bakheet and Powe may be associated with false-positive mediastinal uptake. Because the incidence of some of these processes may vary geographically, such as aspergillosis and histoplasmosis, the incidence of falsepositive results may also vary. Our patients also illustrate one additional cause of false positivity associated with a primary tumor in close proximity to the mediastinum. In this case there was no mediastinal invasion by the tumor or involvement of the lymph nodes as the PET scan predicted. Whether this effect was secondary to resolution issues and shadowing from an intense emission source or a true physiologically active lymph node is unclear. Nevertheless, centrally located tumors may cause false-positive results as do inflammatory processes (Table 2). In 4 of the patients, the false-positive PET findings could be explained on the basis of a corresponding CT finding. In 2 patients, the false result was secondary to physiologic effects that could not have been predicted by CT. In the final patient, his previous thoracotomy may have been a factor if it had been more recent, but its remoteness makes it extremely unlikely. The ability to use PET scanning to accurately stage the mediastinum is even more resolution dependent than determining the functional status of a known pulmonary nodule. It requires a greater ability to detect small amounts of tracer being emitted from small anatomic objects. There is still no clear consensus on defining a positive node. Some groups have chosen a strict SUV value [16], whereas most use a scale relative to the background intensity of the mediastinum [12]. The implications on sensitivity and specificity by setting a SUV too high or too low are obvious. Furthermore, because of technical limitations, it is not possible to accurately determine the SUV in lesions that are less than 2 cm in diameter [12]. Many factors will cause variability in resolution and

4 Ann Thorac Surg ROBERTS ET AL 2000;70: FACTORS ASSOCIATED WITH FALSE-POSITIVE PET SCANS 1157 Fig 1. Representative images from 3 patients with false-positive positron emission tomographic scans. All positron emission tomographic images are in coronal plane. (A) Computed tomographic scan of patient 2 showing tumor in the aortopulmonary window and some mildly prominent mediastinal lymph node. (B) Attenuation corrected coronal positron emission tomographic image of patient 2 showing tumor and suggestion of mediastinal lymph node at inferomedial aspect. (C) Computed tomographic scan of patient 3 demonstrating tumor and associated atelectasis. (D) Positron emission tomographic image of patient 3 in a coronal view showing large tumor with central necrosis and separate intense focus of mediastinal uptake. (E) Computed tomographic image from patient 4 showing right lower lobe mass. (F) Positron emission tomographic image in a coronal view from patient 4 showing intense but small uptake in the upper mediastinum that contained no cancer.

5 1158 ROBERTS ET AL Ann Thorac Surg FACTORS ASSOCIATED WITH FALSE-POSITIVE PET SCANS 2000;70: Table 2. Factors Associated With False-Positive Positron Emission Tomographic Scans of the Mediastinum Common Active tuberculosis Granuloma Pneumonia Abscess Sarcoidosis Acute inflammation with bronchiectasis and atelectasis Inflammation Tumors abutting the mediastinum Less Common Aspergillosis Inflammatory anthracosilicosis Acute blastomycosis Reactive mesothelial cell Histoplasmosis Rheumatoid disease Radiation pneumonitis Tumor necrosis Alveolitis Plasma cell granuloma Airway inflammation with asthma accuracy from scanner to scanner. These should be considered when evaluating this extremely high technology-dependent tool. Particularly, the difference in technique and data acquisition between dedicated PET scanners and dual head gamma cameras placed in the coincidence mode may be significant. There are relatively little data on comparison of dedicated PET to dual head gamma camera scans. At least two recent studies showed decreased sensitivity of dual head gamma camera scans with lesions less than 1.5 to 2 cm [17, 18]. This resolution is critical in assessing the mediastinum. Although most studies performed appear to be at large centers with dedicated PET scanners, the number of dual head gamma camera scanners from all vendors is likely to exceed the number of PET scanners very soon [19]. Dual head gamma camera scanners permit centers to do FDG imaging at a lower cost by allowing them to also use the equipment for general nuclear medicine purposes. Rapidly evolving software also affects resolution, creating clear differences in scan quality from center to center. This is analogous to the difference between a highresolution spiral CT of today and a conventional CT from just a few years ago. We will need to determine whether dual head gamma camera scans can stand on their own, or whether larger comparison trials will be needed. The American College of Surgeons Oncology Group is examining the utility of positron emission scanning in lung cancer (Z0050). They have chosen to include only dedicated PET scanners. When this is complete, the data may not be directly applicable to physicians practicing in areas that have access only to converted gamma counters for their PET scan studies. There are data suggesting that using CT and PET data together improves accuracy of either alone [20]. Combining PET and CT data for mediastinal staging will improve anatomic localization of some PET abnormalities, but is unlikely to change a positive or negative result in the absence of the factors we have described. Positive PET findings should not be disregarded on the basis of a negative CT scan. PET can demonstrate metastatic involvement of normal sized lymph nodes in some patients, and for this reason has a higher sensitivity than CT. With a high negative predictive value, a negative study stands on its own. Negative PET findings in enlarged lymph nodes on CT effectively exclude metastasis as PET can be expected to detect tumor focus that is of sufficient volume to cause nodal enlargement. The physiologic information obtained by PET scanning will likely remain a complimentary study to the anatomic details of CT scans for some time. Improvements in technology may some day allow one stop staging for lung cancer. The transmission portion of routine scans may be modified and improved so dramatically that anatomic pictures could be created while emission information provides physiologic detail. This would all be accomplished in one 1-hour scan. It is clear that PET scanning will have some role in staging lung cancer. At distant sites, false-positive PET findings are less common than in the mediastinum, resulting in a positive predictive value of 93% (14 of 15 patients) in this study. PET is also more sensitive for distant metastasis than conventional staging, demonstrating unsuspected distant disease in 14% of our patients. This may be reason enough to obtain PET on all patients with non-small cell lung cancer. We have shown that false-positive results do occur in the mediastinum and have identified factors that contribute to this. We believe the trend of some practitioners to use PET scanning to bypass surgical staging en route to the oncologist is wrong. With the current technology, no patient should ever be denied treatment with curative intent or should definitive plans be made based on a positive PET and other imaging studies only. Because of a positive predictive value of only 75%, we believe a positive PET should be confirmed by mediastinoscopy and biopsy. PET imaging may have greater usefulness in its negative predictive value. In our series, this was greater than 95% and this amount will likely increase further as scanning resolution improves. PET appears to miss only the most limited microscopic spread. This must also occur with currently applied, widely accepted, invasive staging algorithms contributing to the relatively poor survival rate for the earliest stage lung cancers. In the face of a PET scan without evidence of mediastinal or distant disease, we proceed to a very limited thoracotomy and extensive mediastinal dissection with frozen sections. If there is no tumor identified, we undertake resection in a standard fashion. Multicenter trials, such as the ACOSOG Z0050 trial, should help define this modality and resolve some of the issues regarding the variability in imaging devices. When this work and cost analysis has been completed, integrating PET into a definitive

6 Ann Thorac Surg ROBERTS ET AL 2000;70: FACTORS ASSOCIATED WITH FALSE-POSITIVE PET SCANS 1159 algorithm for the diagnosis and staging of non-small cell lung cancer may be possible. References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics. Cancer J Clin 1998;48: Miller DL, McManus KG, Allen MS, et al. Results of surgical resection in patients with N2 non-small cell lung cancer. Ann Thorac Surg 1994;57: Little AG, DeMeester TR, Ferguson MK, et al. Modified stage I (T1N0M0, T2N0M0), non-small cell lung cancer: treatment results, recurrence patterns, and adjuvant immunotherapy. Surgery 1986;100: Rosell R, Gomez-Condima J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 1994;330: Roth JA, Atkinson EN, Fossella F, et al. 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PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma. Ann Thorac Surg 1999;68: Weber WA, Neverve J, Sklarek J, et al. Imaging of lung cancer with (F-18)FDG: comparison of a dual-head gamma camera in coincidence mode with a full-ring positron emission system. Eur J Nucl Med 1999;26: Landoni C, Gianolli L, Lucignani G, et al. Comparison of dual-head PET versus ring PET in tumor patients. J Nucl Med 1999;40: Henkin RE. Gamma counter coincidence imaging: an update. Appl Rad 1998;27: Albes JM, Lietzenmayer R, Schott U, Schulen E, Wehrman M, Ziemer G. Improvement of non-small cell lung cancer staging by means of positron emission tomography. Thorac Cardiovasc Surg 1999;47:42 7. DISCUSSION DR LARRY R. KAISER (Philadelphia, PA): Can you clarify whether the nuclear medicine physicians had access to the computed tomographic (CT) scans when they read these studies. You know, there are a number of studies that show, and you pointed it out as well, that when you use the positron emission tomographic (PET) scan in conjunction with the CT scan, that the sensitivity and specificity can be quite high. I was impressed that your specificity was as good as it was because often the incidence of false positives might even be higher. The other thing is, we have had some problem with our nuclear medicine physicians. When you go down and question them, they will change their opinion: Well, yes, maybe that one is negative. Have you had any problem with bias on the part of the nuclear medicine physicians, because, as you mentioned, the software can vary and the attenuation can vary as well. DR ROBERTS: Those are two excellent points. In our particular study, the nuclear medicine physicians did have access to the CT scans, and I believe that often times their impression was made using a combination of the anatomic data as well as the physiologic data. Our radiologists and nuclear medicine physicians, like yours, do waffle a bit, and oftentimes they will say something is positive or negative, and when you go back and really press them, they do change their minds. That is one of the attractive properties of standardized uptake value in pinning down a specific quantitative number. Unfortunately, the resolution at the present time for the mediastinum does not seem to be adequate enough to describe a standardized uptake value for each lesion. DR LESLIE J. KOHMAN (Syracuse, NY): What about the patient who has had induction therapy? Does the PET scan, if they have had it before and then have their induction therapy and then another PET afterward, does the N2 disease revert? Does the mediastinoscopy that you may do early on interfere with the repeat PET scan? Maybe they did not have a PET scan early on and had, either with or without a mediastinoscopy, induction therapy and then had a PET scan before you decide to operate on them. How does this induction therapy or prior mediastinoscopy influence the PET scan? DR ROBERTS: That seems to be another potential application of it, and, as we know, a CT scan or an anatomic image of a tumor does not always correspond with the response to the chemotherapy. Often, the CT image does not change in size and we find no viable tumor at thoracotomy. The PET scan image does seem to respond to chemotherapy, and we have reimaged patients after induction therapy. The decreased active tumor burden does seem to be reflected by decreased fluorodeoxyglucose uptake.