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Ann Thorac Surg 2006;82:1016-1020
© 2006 The Society of Thoracic Surgeons

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Original article: General thoracic

The Maximum Standardized Uptake Values on Integrated FDG-PET/CT Is Useful in Differentiating Benign From Malignant Pulmonary Nodules

^a Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama
^b Section of Thoracic Surgery at University of Alabama at Birmingham, Birmingham, Alabama
^c Division of Cardiothoracic Surgery, Department of Surgery at the Birmingham Veterans Administration Hospital, Birmingham, Alabama

Accepted for publication March 29, 2006.

^_* Address correspondence to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd., THT 712, Birmingham, AL 35294 (Email: rcerfolio{at}uab.edu).

Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.

	Abstract

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BACKGROUND: Positron emission tomography (PET) is often used for an indeterminate pulmonary nodule.

METHODS: This is a prospective study on a consecutive series of patients who had an indeterminate pulmonary nodule that was 2.5 cm or less, underwent integrated positron emission tomography using fluorodeoxyglucose-PET/computed tomographic [FDG-PET/CT] scan with the maximum standardized uptake values (maxSUVs) reported, and who underwent complete resection.

RESULTS: There were 585 patients (401 men). A total of 496 patients had a malignant nodule and the median maxSUV was 8.5 (range, 0 to 36). Eighty-nine patients had a benign nodule and the median maxSUV was 4.9 (range, 0 to 28, p < 0.001). If the maxSUV was between 0 and 2.5 there was a 24% chance the nodule was malignant, if between 2.6 and 4.0 it was 80%, and if 4.1 or greater it was 96%. False negative FDG-PET/CT was from bronchoalveolar carcinoma in 11 patients, carcinoid in 4, and renal cell in 2. False positives included fungal infections in 16 patients. Nodal involvement, whether malignant or infectious, was more likely with a pulmonary mass that had a higher maxSUV (8.4 vs 3.8 for nonmalignant lesions, 9.8 vs 4.5 for malignant lesions).

CONCLUSIONS: Although integrated FDG-PET/CT is a valuable study for an indeterminate pulmonary nodule, one must be aware of causes of false positives and negatives. There is a 24% chance a suspicious nodule that has a maxSUV of 0 to 2.5 is cancer. The higher the maxSUV of the primary mass the more likely the nodes are to be involved with either malignancy or infection, and this may help direct nodal biopsy instead of pulmonary resection.

	Introduction

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The number of patients who present with indeterminate pulmonary nodules continues to increase. More patients are undergoing routine chest roentgenogram and even computed tomography (CT) as part of a well-visit yearly exam. In addition, many patients involved in motor vehicle collisions often are scanned, asymptomatic patients with a history of smoking are getting chest CT scans, and more patients are undergoing positron emission tomography using fluorodeoxyglucose (FDG-PET) or integrated FDG-PET/CT as part of a work-up for another problem. All these circumstances may lead to the discovery of an indeterminate pulmonary nodule. These patients often seek thoracic surgical consultation. This problem will probably continue to grow. We decided to review our experience in patients with a small ( 2.5 cm) indeterminate pulmonary nodule who underwent resection. The purpose of the study was to determine if the maximum standardized uptake value (maxSUV), which quantifies a tumor's avidity for glucose, could predict the pathology of a pulmonary nodule that is 2.5 cm or less in size. Other goals were to identify causes of false positives and negatives.

	Patients and Methods

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Patients
Between December 2001 and April 2005, all patients who had an integrated FDG-PET/CT scan within 40 days of resection, a pulmonary nodule 2.5 cm or less, and pathologic confirmation of the nodule's histology (by complete resection) were eligible to participate in this study. All preoperative evaluations and pulmonary resections were performed by one general thoracic surgeon. Complete resection of the pulmonary nodule was required for entry into this study. If patients had a transthoracic or transbronchial biopsy performed that was nondiagnostic they were still eligible for this study. Patients who were less than 19 years of age or who had diabetes were excluded.

Patients underwent thoracotomy with complete excision of the pulmonary nodule with frozen section analysis. Selected patients underwent video-assisted thoracoscopic surgery, the nodule was completely removed, and it was sent for frozen section pathologic analysis. If the nodule was malignant a thoracotomy was performed and lobectomy with complete thoracic lymphadenectomy was performed as previously described [1]. Patients who had metastatic disease to mediastinal lymph nodes (N2) or to M1 metastatic sites that was determined by biopsy prior to thoracotomy were also excluded from this study. The University of Alabama at Birmingham Institutional Review Board approved this prospective study and the electronic prospective database used. Patient consent was obtained for entry into the prospective database.

Radiologic Imaging
Integrated FDG-PET/CT scans were performed on an integrated GE Discovery LS PET/CT scanner (GE Healthcare, Milwaukee, WI). Patients were asked to fast for four hours and then subsequently received 555 MBq (15 mCi) of FDG intravenously followed by (PET) 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. The most recent CT scan of the chest was also available for visual correlation. Maximum SUV (maxSUV) of the primary and of each suspicious lymph node station was determined by drawing regions of interest (ROI) on the attenuation corrected FDG-PET/CT images around it. It was then calculated by the software contained within the PET/CT scanner by the formula [2]:

where C = activity at a pixel within the tissue defined by an ROI, ID = injected dose, and w = kg of patient body weight. The maximum SUV within the selected ROIs was used (maxSUV) throughout this study exclusively.

Procedures, Staging, and Surgery
Patients were carefully staged as previously described [1]. If nodal or M1 metastatic disease were suspected and biopsy proven (as previously described) [1] patients underwent mediastinoscopy or endoscopic ultrasound fine needle aspiration, and if they had metastatic disease in an N2 lymph node there were eliminated from this study. If there was no evidence of N2 or higher disease, patients underwent thoracotomy, pulmonary resection, and complete thoracic lymphadenectomy. Pathologic review was performed by standard techniques and immunohistochemical staining was employed when appropriate. A pathologic stage was generated using the tumor, node, metastasis international staging system [3].

Statistical Methods
Data were imported from Excel (Microsoft Inc, Seattle WA) into SAS v. 9.0 (SAS Institute, Cary, NC) for data analysis. Continuous data are presented as medians and categoric data are presented as percentages. The Fisher exact test or Pearson ² test was used to assess categoric data and the Wilcoxon test was used to evaluate continuous variables. Sensitivity was defined as a true positive divided by the sum of the true positives and false negative results on PET scan.

	Results

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Patient characteristics are shown in Table 1. Seventy-three percent had an attempted needle biopsy performed that was nondiagnostic. Patients with a benign nodule were younger than those with a malignant nodule (median age 53 compared with 68 years, respectively, p < 0.001) and less likely to have a history of smoking (p = 0.03). The sensitivity of integrated FDG-PET/CT for determining a malignant nodule was 93% and its sensitivity for determining a benign nodule was 75%.

View larger version (11K): [in this window] [in a new window]   Fig 1. The range and the median maximum standardized uptake value (maxSUV) for benign and malignant nodules (shown by vertical arrows). In addition, the median maxSUV of different types of benign and malignant nodules is also shown (horizontal arrows).

View larger version (10K): [in this window] [in a new window]   Fig 2. The relationship between the size of the pulmonary nodule and the maximum SUV and the pathology (dashed line [] = malignant; solid line [] = benign).

	Comment

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Some physicians perform a needle biopsy of an indeterminate pulmonary nodule. However, in small nodules false negatives are not uncommon and if the nodule is suspicious by CT scan, by patient history, and positive on PET a needle biopsy does not change patient management in our practice. Whether the needle biopsy yields positive or negative results, we recommend resection in medically fit patients if the other factors favor the chance of it being malignant. The argument that a needle biopsy is ordered to help rule-out small cell lung cancer instead of non-small cell lung cancer is not applicable in a patient with a small lung nodule with normal sized, pathologically negative mediastinal lymph nodes, because we still recommend resection. Although, a similar argument can be made about ordering the PET scan, it provides staging information and the maxSUV data, which when carefully interpreted yields information that can help therapy.

This study, unlike others that evaluate PET for indeterminate pulmonary nodules [5–8], selected a very specific group of patients with an indeterminate pulmonary nodule. First, it allowed for larger nodules than other series on this topic. Second, it required complete resection, which biases the series toward malignant lesions or at least suspicious benign lesions, because those patients that were followed and were never resected were eliminated. However, it secures the diagnosis and does not assume, as other studies do, that a benign needle biopsy is correct or that nodules that do not grow over a set period of time are benign.

Even if the PET scan suggested benign disease, these patients were resected either because of growth of the nodule or its suspicious appearance on the CT scan. This critical point must be taken into account when the results of this study are considered. This may explain why 24% of the FDG-PET/CT negative nodules were malignant; they had other characteristics that made us recommend resection. The study was designed this way in order to avoid missing a slow growing malignancy that was falsely called benign because it was never resected or a patient who failed to come back for follow-up. Thus, complete resection and not just biopsy was mandated. Finally, in clinical practice if one decides not to resect an indeterminate pulmonary nodule careful follow-up with repeat CT scans and integrated FDG-PET/CT scans are needed.

We found that the maxSUV is a predictor of pathology. For instance, if the maxSUV was between 0 and 2.5 there was only a 24% chance the nodule was malignant even in this selected group of patients, all of whom were resected. If the maxSUV was between 2.6 and 4.0 there was an 80% chance the pulmonary nodule was malignant. If the maxSUV was 4.1 or greater there was a 96% chance the nodule would be cancer. The size of the nodules obviously also enters into the decision making. As shown in Figure 2, as benign nodules enlarged their maxSUV increased as well. However, the slope of the curve for the benign nodules is less then the slope of the curve for the malignant nodules; ie, the maxSUV increase is less as benign nodules grow. Nomori and colleagues, in 2004 [9], evaluated both benign and malignant nodules and found that when the nodule size was less than 1 cm in diameter all were negative on PET regardless of histology or maxSUV. In nodules 1 to 3 cm, they found a sensitivity of 70% and specificity of 65%. Imdahl and colleagues, in 2001 [10], also found a relationship between sensitivity and nodule size, with the greatest sensitivity for nodules between 1 and 2 cm and lowest for nodules less than 1 cm. We also showed that there exists a relationship between the size of the nodule and the maxSUV. We have found integrated FDG-PET/CT to be useful in our management of nodules less than 1 cm.

One interesting finding from this report is that as the maxSUV increased the likelihood of the regional lymph nodes harboring the same pathology increased. Thus, perhaps minimally invasive techniques such as mediastinoscopy or endoscopic esophageal ultrasound with fine needle aspiration can be performed.

In this study we had 89 patients with benign disease. Those with fungal infection were most common and had the highest maxSUV values. The surgeon needs to be aware of this information, especially when evaluating an immunocompromised host such as a patient who has a solid organ transplantation performed or one who is HIV positive.

There are strengths and limitation to every study. The strengths of this study include the fact that all nodules were completely resected and one surgeon treated all patients. The main weakness of this report is the selection criteria used, which biases the study towards malignant lesions or infectious processes that "looked" malignant. Another weakness is the fact that we used several different pathologists and nuclear radiologists.

In conclusion, although FDG-PET/CT is a valuable noninvasive study for an indeterminate pulmonary nodule tissue is still required. The FDG-PET/CT provides valuable information as to the biological aggressiveness of a tumor in a patient by providing the maxSUV value of the pulmonary nodule. It also can identify other possible metastatic sites that require biopsy. However, there are significant overlaps between benign and malignant lesions and one must be aware of the various pathologic conditions that can cause false positives and negatives. The higher the maxSUV of the primary mass the more likely the regional lymph nodes are to be involved with either malignancy or infection, and this may help direct nodal biopsy instead of accepting the increased cost and morbidity of a pulmonary resection.

	The Thoracic Surgery Foundation for Research and Education

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Grants, Fellowships, and Career Development Awards

The Thoracic Surgery Foundation for Research and Education (TSFRE) was founded in 1991 to bring together the research and education support efforts of the four major societies in cardiothoracic surgery in the United States: The American Association for Thoracic Surgery, The Society of Thoracic Surgeons, The Southern Thoracic Surgical Association, and the Western Thoracic Surgical Association. Because of its close and continuing relationship with organized cardiothoracic surgery, TSFRE attracts the highest quality research award applicants and truly outstanding reviewers.

Any surgeon who meets the eligibility requirements is invited to submit an application. Research grants will be judged separately from research fellowship applications. In general, top-scoring applications in each category will receive priority with respect to funding.

Multiple fellowship applications under the sponsorship of an individual mentor or multiple grant applications from a single institution will be accepted and reviewed, as long as there is no significant scientific overlap. Only under extraordinary circumstances will the TSFRE fund simultaneous awards to a single institution.

This year, TSFRE is proud to offer the following awards to the most promising cardiothoracic surgeon-scientists:

The Nina Starr Braunwald Career Development Award
Provides a biennial award of $100,000 for 2 years to support the research career development of a woman cardiac surgeon who holds a full-time faculty appointment and who is within 10 years of completion of thoracic surgery residency. Deadline: November 1

TSFRE Research Grants
Provides operational support of original research efforts by cardiothoracic surgeons who have completed their formal training, and who are seeking initial support and recognition for their research program. Awards of up to $30,000 a year for up to 2 years are made each year to support the work of an early-career cardiothoracic surgeon (within 5 years of first faculty appointment). Deadline: November 1

TSFRE Research Fellowships
Provides support of up to $35,000 a year for up to 2 years for surgical residents who have not yet completed cardiothoracic surgical training. Deadline: November 1

TSFRE Career Development Awards
Provide salary support of up to $50,000 a year for up to 2 years for applicants who have completed their residency training and who wish to pursue investigative careers in cardiothoracic surgery. Deadline: November 1

TSFRE/NHLBI Jointly Sponsored Mentored Clinical Scientist Development Award—K08 or K23
Provides support to outstanding clinician research scientists who are committed to a career in cardiothoracic surgery research and have the potential to develop into independent investigators. The award is $150,000 a year ($75,000 from TSFRE and $75,000 from NHLBI) plus $25,000 indirect support from the NHLBI and supports a 3-, 4-, or 5-year period of didactic training and supervised research experience. Deadline: May 31

TSFRE/NCI Jointly Sponsored Mentored Clinical Scientist Development Award—K08 or K23
Provides support to outstanding clinically trained professionals who are committed to a career in laboratory or field-based research and have the potential to develop into independent investigators. The award is $150,000 a year ($75,000 from TSFRE and $75,000 from NCI) plus $30,000 indirect support from the NCI and supports a 5-year period of supervised research that integrates didactic studies with laboratory or clinically based research. Deadline: February 1 and October 1

The American Association for Thoracic Surgery Awards
Provides $75,000 in support for 1 year through the Evarts A. Graham Memorial Traveling Fellowship to a non-North American young cardiothoracic surgeon future international leader for further development in the United States. The AATS also provides $75,000 a year for 2 years of support for young North American cardiothoracic surgeons committed to pursuing an academic career in cardiothoracic surgery through the AATS Research Scholarship. Additionally, AATS provides $5,000 travel grants to broaden the educational experience of North American residents in their final year of residency through the Resident Traveling Fellowship. Deadline: July 1

Applications will be available online only and can be found at www.tsfre.org. For more information, please address inquiries to:

Chair, Research Committee

Thoracic Surgery Foundation for Research and Education

900 Cummings Center, Suite 221-U

Beverly, MA 01915

Telephone: (978) 927-8330

	References

Top Abstract Introduction Patients and Methods Results Comment The Thoracic Surgery Foundation... References

 

1. Cerfolio RJ, Bryant AS, Ojha B, et al. Improving the inaccuracies of clinical staging of patients with NSCLCa prospective trial. Ann Thorac Surg 2005;80:1207-1214.[Abstract/Free Full Text]
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3. Mountain CF. Revisions in the international staging system for lung cancer Chest 1997;111:1710-1717.[Abstract/Free Full Text]
4. Bryant AS, Cerfolio RJ, Klemm KM, Ojha B. Maximum standard uptake value of mediastinal lymph nodes on integrated FDG-PET-CT predicts pathology in patients with non-small cell lung cancer Ann Thorac Surg 2006;82:417-423.[Abstract/Free Full Text]
5. Dewan NA, Shehan CJ, Reeb SD, Gobar LS, Scott WJ, Ryschon K. Likelihood of malignancy in a solitary pulmonary nodulecomparison of Bayesian analysis and results of FGD-PET/CT scan. Chest 1997;112:416-422.[Abstract/Free Full Text]
6. Herder GJ, van Tinteren, Golding PR, et al. Clinical prediction model to characterize pulmonary nodulesvalidation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest 2005;128:2490-2496.[Abstract/Free Full Text]
7. Nomori H, Watanabe K, Ohtsuka T, Naruke T, Suemasu K, Uno K. Visual and semiquantitative analyses for F-18 fluorodeoxyglucose PET scanning in pulmonary nodules 1 cm to 3 cm in size Ann Thorac Surg 2005;79:984-989.[Abstract/Free Full Text]
8. Kernstine KH, Grannis FW, Rotter AJ. Is there a role for PET in the evaluation of subcentimeter pulmonary nodules? Semin Thorac Cardiovasc Surg 2005;17:110-114.[Medline]
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