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Ann Thorac Surg 2006;82:417-423
© 2006 The Society of Thoracic Surgeons
a Department of Surgery, Emory University, Atlanta, Georgia
b Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, Alabama
c Division of Cardiothoracic Surgery, Department of Surgery, Birmingham Veterans Administration Hospital, Birmingham, Alabama
d Department of Pathology, Birmingham, Alabama
e Division of Nuclear Radiology, University of Alabama at Birmingham Hospital, Birmingham, Alabama
Accepted for publication December 13, 2005.
* Address correspondence to Dr Bryant, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd., THT 712, Birmingham, AL 35294 (Email: abryant{at}uab.edu).
Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.
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Abstract |
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METHODS: This is a prospective study of consecutive patients with NSCLC, all of whom underwent integrated fluorodeoxyglucose-positron emission-computed tomography (FDG-PET-CT) and had biopsy or resection of their mediastinal lymph nodes.
RESULTS: There were 397 patients. One-hundred and forty-three patients had N2 disease and 1,252 N2 nodes were pathologically examined. The median maxSUV of the nodes that had metastatic disease were the following: for the 2R node, 10.4 (range, 0–18.6); for 4R, 8.6 (range, 0–18.3); for 5, 8.9 (range, 0–26.3); for 6, 7.6 (range, 0–19.6); for 7, 7.7 (range, 0–14); for 8 and 9, 5.4 (range, 0–8.9). The median maxSUV for all of the N2 nodes that were benign was 0 (range, 0–18.8) (p < 0.05 for all stations except for nodes 8 and 9). When a maxSUV of 5.3 is used the accuracy of integrated FDG-PET-CT for each N2 nodal station is maximized and is at least 92% for each.
CONCLUSIONS: The maxSUV of individual mediastinal lymph nodes is a predictor of malignancy. There is overlap between false and true positives. Definitive biopsies are required to prove cancer irrespective of the maxSUV value. However, when a maxSUV of 5.3 is used instead of the traditional value of 2.5, the accuracy for FDG-PET-CT for each N2 nodal station increases to at least 92%.
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Introduction |
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Thus we decided to prospectively assess the accuracy of integrated FDG-PET-CT for each N2 mediastinal lymph node station by comparing the maxSUV value with the actual pathology. We also wanted to identify causes of false positives and negatives, determine the median maxSUV for lymph nodes that harbored metastatic cancer, and compare it with lymph nodes that were benign. Finally, we wanted to identify the maxSUV value that maximized sensitivity, specificity, and accuracy and to examine the prevalence of microscopic nodal disease for those lymph nodes falsely negative and missed by FDG-PET-CT scan.
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Patients and Methods |
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Radiologic Imaging
The FDG-PET-CT scans were performed on an integrated FDG-PET-CT scanner (GE Discovery LS PET-CT Scanner, Milwaukee, WI). This type of PET scan performs both a dedicated PET and a CT scan together in one sitting. It allows for the integration of both the molecular findings of the FDG-PET scan and the anatomic information of the CT scan to be merged. Patients were asked to fast for four hours and then subsequently received 555 MBq (15 mCi) of FDG intravenously followed by positron emission tomography after one hour. The scans were performed from the skull base to mid-thigh level. The CT examination was used for attenuation correction of PET images. The scanning time for emission PET was 5 minutes per bed position. Iterative reconstruction with CT attenuation correction was performed. The most recent CT scan of the chest was also available for visual correlation. Maximum SUV of the primary lung lesion and of each suspicious lymph node station was determined by drawing regions of interest (ROI) on the attenuation corrected FDG-PET images around it. It was then calculated by the software contained within the PET or PET-CT scanner by the formula [9]
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Staging
As shown in Figure 1, all suspicious N2, N3, or M1 areas (maxSUV 
2.5) were biopsied prior to pulmonary resection. Mediastinoscopy was used to biopsy suspicious lymph nodes in the paratracheal area (stations 2R, 4R, 2L, and 4L) and the superior portion of the subcarinal lymph node. Either video-assisted thoracoscopic surgery (VATS) or endoscopic transesophageal ultrasound (EUS) was used to biopsy suspicious posterior aortopulmonary window lymph nodes, subcarinal, periesophageal, and inferior pulmonary ligament nodes. Microscopic disease was defined as tumor invasion of 2 mm or less [10] or disease only detected on immunohistochemical staining. The latter was performed in selected cases only as per the pathologist's discretion. In general there were two slices per lymph nodes used. The University of Alabama at Birmingham's institutional review board approved this study and the electronic prospective database used. In addition, individual patient consent was obtained.
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Results |
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identify the pathological characteristics of the false positive lymph nodes and the false negative lymph nodes on FDG-PET-CT. Table 2 shows that microscopic disease was present in 35% of the FDG-PET-CT scans that predicted the lymph nodes to be benign. It was more prevalent in the posterior mediastinal nodes (57%) than the anterior mediastinal nodes (17%).
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Accuracy of FDG-PET-CT maxSUV for N2 Nodal Stations
In two of our previous studies, one in 2003 with 400 patients [14] that evaluated dedicated FDG-PET and the other in 2004 with 129 patients that evaluated integrated FDG-PET-CT [3], we reported the accuracy of PET at each lymph node station. In those reports, as in this study, an arbitrary value for the maxSUV of 2.5 was chosen. Mediastinal N2 lymph nodes with a value of 2.5 or greater were considered positive. We chose this relatively conservative value because we did not want to miss any malignant disease in the N2 lymph nodes prior to resection. Thus we set the threshold low so as to avoid false negatives and in so doing accept a higher incidence of false positives. The accuracy for each nodal station reported in those two studies is remarkably similar to the accuracy reported in this study; thus the data and findings are consistent with other literature. Interestingly the accuracy was quite low for the 4R node and 7 lymph node stations. This is clinically important because the 4R and 7 nodal stations are the two most common locations for metastatic N2 disease to occur [15].
In order to maximize the accuracy of integrated FDG-PET-CT we generate ROC curves. These curves identify the maxSUV value that maximizes the sensitivity and specificity and consequently the accuracy. The value found was 5.3. When a maxSUV value of 5.3 or greater is used to label any N2 node as positive on FDG-PET-CT and less than 5.3 as negative, the accuracy of all stations (as shown in Fig 4) is at least 92%.
False Positive and Negatives
Thirty-five percent of the 34 N2 falsely negative nodes from integrated FDG-PET-CT had microscopic or only immunohistochemically positive disease. The true clinical import of missing microscopic N2 disease prior to resection is unknown. Whether neoadjuvant therapy improves survival in this subset of patients over resection followed by adjuvant chemotherapy is not documented. The current standard of care is to use neoadjuvant therapy. If a maxSUV of less than 5.3 had been used, there would have been no increase in the undetected N2 disease. However, our goal as surgeons should be to identify all metastatic mediastinal nodal (N2) disease prior to resection to entertain the concept of neoadjuvant therapy.
The most common cause of false positive lymph nodes in this study was histoplasmosis infection. The degree and the type of false positives for FDG-PET for mediastinal lymph nodes are often determined by regional factors. For instance, silicosis has been found to be a cause of false positives in Germany [16] and histoplasmosis has been a common cause in the Southeastern United States. The surgeon and radiologist must be aware of these regional differences.
Nodal Trends in maxSUV Uptake
The median maxSUV of lymph nodes that are malignant becomes smaller as one goes from the anterior mediastinal nodes to the posterior mediastinal nodes. The reason for this increase is unclear. The median maxSUV for all the anterior or superior lymph nodes (2R, 4R, 2L, 4L, and 6) is 8.5, whereas it is only 7.2 for the posterior or inferior mediastinal lymph nodes (5, 7, 8, and 9). While it is not yet completely understood, there are a few hypotheses regarding increasing FDG uptake in the lower mediastinum (and thus lower maxSUVs). One is that hypermetabolic brown fat, which is more prevalent in the posterior mediastinum, results in a higher background uptake and this leads to a lower maxSUV [17].
Conclusion
In conclusion, we and others have shown the clinical importance and relevance of the maxSUV of a primary non-small cell lung tumor [1]. It provides information on a tumor's biologic aggressiveness, key pathologic features, and its potential to spread. This report illustrates the importance of the maxSUV of mediastinal (N2) lymph nodes. The maxSUV of the primary tumor along with each lymph node (as well as any potential metastatic site) that is hypermetabolic should be provided by the nuclear radiologist in the text of every PET report. The causes of false positives and false negatives need to be carefully considered based on each patient's individual clinical scenario. For now we still recommend biopsies of all suspicious lymph nodes and a high maxSUV should not be equated with malignancy until tissue confirmation is obtained. However, the maxSUV of mediastinal N2 lymph nodes does provide significant predictive power. Finally, an important unanswered question remains if the maxSUV data from this report are translatable from one center to another. It is known that there may be a 15% to 20% variable rate of the maxSUV between different PET centers for a primary lung tumor. This important potential problem is being minimized as each PET center adopts standardized techniques. Further prospective studies are needed at other centers to evaluate the translatability of the maxSUV of the primary tumor as well as of the lymph nodes at different PET centers around the world.
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Requirements for Recertification/Maintenance of Certification in 2006 |
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The American Board of Thoracic Surgery will no longer publish the names of individuals who have not recertified in the American Board of Medical Specialties directories. The Diplomate's name will be published upon successful completion of the recertification/maintenance of certification process.
The CME requirements are 70 Category I credits in either cardiothoracic surgery or general surgery earned during the 2 years prior to application. SESATS and SESAPS are the only self-instructional materials allowed for credit. Category II credits are not allowed. The Physicians Recognition Award for recertifying in general surgery is not allowed in fulfillment of the CME requirements. Interested individuals should refer to the Booklet of Information for a complete description of acceptable CME credits.
Diplomates should maintain a documented list of their major cases performed during the year prior to application for recertification. This practice review should consist of 1 year's consecutive major operative experiences. If more than 100 cases occur in 1 year, only 100 should be listed.
Candidates for recertification/maintenance of certification will be required to complete all sections of the SESATS self-assessment examination. It is not necessary for candidates to purchase SESATS individually because it will be sent to candidates after their application has been approved.
Diplomates may recertify the year their certificate expires, or if they wish to do so, they may recertify up to two years before it expires. However, the new certificate will be dated 10 years from the date of expiration of their original certificate or most recent recertification certificate. In other words, recertifying early does not alter the 10-year validation.
Recertification/maintenance of certification is also open to Diplomates with an unlimited certificate and will in no way affect the validity of their original certificate.
The deadline for submission of applications for the recertification/maintenance of certification process is May 10 each year. A brochure outlining the rules and requirements for recertification/maintenance of certification in thoracic surgery is available upon request from the American Board of Thoracic Surgery, 633 N St. Clair St, Suite 2320, Chicago, IL 60611; telephone: (312) 202-5900; fax: (312) 202-5960; e-mail: info{at}abts.org. This booklet is also published on the website: www.abts.org.
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Discussion |
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First, why do you regard max SUV as a more accurate predictor of clinical stage than mean SUV? Second, you have reported 12 patients with 34 false negative N2 nodes. Can you tell us how often unsuspected N2 nodes were identified at thoracotomy? And thirdly, drawing from the authors' prior trials looking at integrated PET-CT for clinical staging and lobar location as a predictor of N2 nodes and your current paper on max SUV for predicting N2 nodes, do you have an algorithm you could share with us on which patients you would perform cervical mediastinoscopy, which patients you would perform EUS FNA, and which patients a left VATS for level 5 and 6 lymph node sampling? Thank you.
DR BRYANT: Thank you for your excellent questions, Dr Howington. Your first question was regarding mean SUV versus the max SUV. The mean SUV is calculated by taking an average SUV in a particular region of interest, so therefore the region of interest is variable. The max SUV, however, is represented by the brightest pixel in the entire area and therefore it is more reproducible and more objective. Of the 34 false negatives, all of our patients were found at the time of thoracotomy. And lastly, yes, we do now perform preoperative nodal evaluation in almost any patient who presents with a max SUV greater than 10 or who has had a needle biopsy prior that shows poorly differentiated carcinoma. Also, if the primary is in the right upper lobe, we tend to perform a mediastinoscopy, if it is in the lower lobe, we go with an EUS FNA, and if it is in the left upper lobe, we sample the nodes with a VATS. Additionally, we usually biopsy any lymph node with a max SUV of 2.5 or greater, and we definitely biopsy any lymph node that shows a max SUV of 5.3 or greater.
DR THOMAS A. D'AMICO (Durham, NC): Dr Bryant, I very much enjoyed your presentation. I have two questions. You made a point that the use of an integrated PET-CT was used in all patients. I wonder if you could comment on whether or not the specific use of an integrated scan helped you in diagnosing these patients and was that part of why your sensitivity and specificity is better than recent papers? And secondly, you note that the sensitivity and specificity have improved with PET regardless of the site, so not just the mediastinum. Are any patients at your institution currently treated on the basis of a PET scan for a single focus of disease without a biopsy, with chemotherapy or radiation therapy? Thank you very much.
DR BRYANT: Thank you, Dr D'Amico, for your excellent questions as well. We do find integrated PET-CT superior than dedicated PET-CT. In a recently published prospective randomized study, we evaluated dedicated PET-CT compared to integrated PET-CT and found that integrated PET-CT was indeed superior at staging the mediastinum as well as locating N1 and N2 disease. So therefore if somebody is developing a new center, we do recommend that they get an integrated PET-CT over a dedicated PET-CT, not only because it is more accurate but because the CT portion of the machine can be used by itself, therefore increasing its efficiency. Your second question, at our institution we hardly ever go ahead and treat a patient based on the PET scan results. However, in the real world, if the max SUV of the primary tumor and that of the lymph node is equivalent, and the lymph nodes, such as the five and six, are difficult to get to, for example, if there is a bulky tumor obstructing access to those nodes, then, yes, we would go ahead and treat based on the PET scan results.
DR MARK I. BLOCK (Hollywood, FL): Congratulations on a nice presentation. I continue to be impressed by your institution's ability to gather a huge amount of data and make lots of meaningful conclusions based on that. Two questions. The first has to do with the reproducibility of SUVs. My understanding in talking with nuclear medicine physicians is that they are increasingly moving away from quantitating the SUV value because of the difficulty in reproducing it not only from patient to patient but from institution to institution, time of day, etc. There are a number of factors that affect the SUV. I think the downside of this is that we see patients come in from referrings that, well, the PET scan was hot, the SUV was 4, therefore it is cancer, or it was only 1.5, therefore it is not cancer. So I would like to get your sense of whether your nuclear medicine physicians feel that this is going to be applicable broadly, and I wonder if they are wondering whether we are trying to put them out of business? If all you need is a number, then you don't need a nuclear medicine physician to interpret the scan for you. The second question is about methodology. You take a collection of data, you do an ROC curve analysis on it, and then use the results to re-analyze the same data and conclude that your derived test works. What you really need to do is take the results and look at a different set of data. You probably have the data already to do that and I presume you are already doing it. I just wanted to point that out. Thank you.
DR BRYANT: Thank you for your excellent questions. The reproducibility of an SUV, that is an excellent question that we are currently looking at. At our institution, our nuclear radiologists continue to provide us the max SUV. We feel that it is a predictor of the pathology of the tumor. The SUV is generated by a standardized equation, and the one factor in the equation, the timing of the dose, is what tends to be variable across different PET centers, and the nuclear radiologists are attempting to standardize that. Additionally, I think that looking at just the trends within one institution itself is helpful. Also, regarding the ROC curve, yes, I think we definitely should take the 5.3 value and apply that and look at it with other data.
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