The Contribution of Fluorine 18F-FDG PET/CT to Lung Cancer Diagnosis, Staging and Treatment Planning

Objective: Lung cancer is the most common cause of cancer-related death throughout the world, and the correct choice of treatment based on early diagnosis and staging increases the chance of survival. The present study aims to investigate the contribution of fluorine 18-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) to the management of lung cancer. Methods: In this study, 50 patients who underwent 18F-FDG PET/CT for lung cancer diagnosis and staging between February 2012 and February 2014 were included. The maximum standardized uptake value (SUVmax) of the primary lung lesion along with other findings of 18F-FDG PET/CT and the results of histopathologic and conventional examinations were evaluated retrospectively. The mean survival time of patients was determined, and the findings were compared by using statistical methods. Results: Histopathologic examinations revealed 51 lung cancers in 50 patients. The sensitivity, accuracy and positive predictive value of 18F-FDG PET/CT in detecting primary malignancy were 94%, 94%, 100%, respectively. Adenocarcinoma (n=23, 16.8±13.5) and squamous cell carcinoma (n=15, 17.9±5.6) did not differ significantly regarding their mean SUVmax values (p=0.2). A statistically significant positive correlation (r=0.4) was identified between tumor size and SUVmax value for 51 tumors (p=0.002). The 18F-FDG PET/CT result was true negative in nine, false positive in six, true positive in two, and false negative in four patients who underwent histopathologic evaluation of their lymph nodes. The 18F-FDG PET/CT changed treatment planning in 34% of the patients. No significant relationship was identified between SUVmax value of the tumor and patient survival in patients (p=0.118). Conclusion: The present study concluded that PET/CT was an efficient method in the diagnosis and staging of lung cancer since it provided useful information in addition to conventional methods. It was also observed that PET/CT scanning resulted in a change in therapeutic plans in the majority of patients. However, there was no statistically significant relationship between survival and the SUVmax of the primary mass.


Introduction
Lung cancer is the most frequent malignancy throughout the world since 1985 (1) and the leading cause of cancerrelated death in both men and women (2). Curative treatment can be offered to lung cancer patients with early diagnosis, in whom computed tomography (CT) is the first diagnostic tool (3). One of the most important prognostic factors in lung cancer is tumor stage. Hence, proper staging is very important when determining prognosis and choosing appropriate treatment. T-staging is based on CT findings, although this modality may be unable to distinguish a tumor from atelectasis or show disease extent. Fluorine 18-fluorodeoxyglucose positron emission tomography/CT ( 18 F-FDG PET/CT) is an effective method for the diagnosis, staging, evaluation of treatment response, follow-up for recurrence and re-staging of lung cancer. In our retrospective study, we investigated the contribution of 18 F-FDG PET/CT to lung cancer diagnosis, staging and management, as well as the prognostic and survival effects of the maximum standardized uptake value (SUV max ) of the primary lesion in an 18 F-FDG PET/CT.

Materials and Methods
The present study included 50 patients who have been referred to Ege University Faculty of Medicine, Department of Nuclear Medicine between February 2012 and February 2014, and who have undergone 18 F-FDG PET/CT scanning for the diagnosing and staging of lung cancer. Patients were injected intravenously with 250-400 MBq of 18 F-FDG at least four hours after fasting for 18 F-FDG PET/CT imaging. Approximately one hour after the tracer injection, PET and CT scans were obtained using a PET-CT scanner (biograph high-definition 16-slice CT, Siemens Healthcare, Erlangen, Germany), and the PET and CT images were loaded onto three-dimensional workstations. Visual and semi-quantitative evaluation of the lesions observed on 18 F-FDG PET/CT were carried out. In case of non-physiologically enhanced areas of activity associated with soft/bone tissue on CT, the finding was identified as "PET lesion", and these PET lesions were interpreted as malignant if either the SUV max value >2.5 or when the FDG uptake was significantly higher than the background tissue. Adrenal gland lesions with a higher FDG uptake than the liver were considered as malignant. A total of 30 patients or their close relatives were accessed to assess survival. One of those 30 patients had synchronous double primary lung cancers. The correlation between the SUV max value of the primary lesion and patient survival was evaluated. The findings of 18 F-FDG PET/CT were compared with radiologic and histopathologic results as well as the final clinical decisions and the determined stages.

Statistical Analysis
The IBM SPSS V 21.0 software was used for statistical analysis. Kolmogorov-Smirnov and Shapiro-Wilk (S-W) tests were utilized for normality analysis of data distribution, and Mann-Whitney U test was applied to determine the differences between the two groups in case of non-normal distribution. A Spearman's rho correlation test was utilized to investigate the correlation between the parameters, and the Kaplan Meier method was used for survival analysis. The differences in survival curves taking different variables into account were tested by using the log-rank test.

Results
This study included 50 patients (46 males, four female, mean age 63.0±8.6) who underwent 18 Table 1. In terms of detecting malignancy, the 18      Through conventional staging, 11 of these 17 patients were classified as "at a potentially operable" stage (stage 1-3A), five were classified as "at a potentially inoperable" stage (stage 3B-4), and one patient had a lesion that was assessed to be benign by conventional methods. Within the group of 11 patients classified as "at a potentially operable" stage, four had N3 lymph node metastases and five had distant metastases as identified by 18 F-FDG PET/CT. As a result, these patients underwent chemotherapy thus avoiding unnecessary surgery in 9/50 (18%) patients. In the other two patients, N1 lymph node metastasis was detected by 18 F-FDG PET/CT, and neoadjuvant chemotherapy was started prior to the operation. Within the group of five patients who were classified as "at a potentially inoperable" stage, three were identified with M1 disease by conventional staging. The areas considered as distant metastases in these three patients were interpreted as benign by 18 F-FDG PET/CT and thus were accepted as candidates for curative treatment. The other two patients were categorized as stage 3B by conventional methods and were thus planned for chemotherapy and localized radiotherapy. However, distant metastases were detected by 18 F-FDG PET/CT in these two patients who underwent chemotherapy and palliative radiotherapy. Another patient had a lesion that was interpreted as benign by conventional methods while the 18 F-FDG PET/ CT evaluated this mass as malignant, and the patient was started on chemotherapy. The impact of 18 F-FDG PET/CT on patient management is listed in Table 1. Finally, the correlation between SUV max value of the primary lesion and patient survival was evaluated in 30 patients, one of whom was the patient who had synchronous double primary lung cancers. Primarily, the median SUV max (median SUV max = 15.6) was calculated and accepted as the "cut-off" value. The mean survival time was 10.3±2.2 months in patients with SUV max <15.6, and 15.9±1.6 months in those with SUV max ≥15.6. There was no significant difference between the two groups in terms of survival (p=0.118) (Figure 3).

Discussion
Lung cancer is the most common cause of cancer-related death worldwide, and early diagnosis is important for the application of curative treatments. 18 F-FDG PET/CT is used commonly to differentiate benign and malignant lung lesions. Gupta et al. (4) reported the sensitivity and specificity of 18 F-FDG PET/CT in benign-malignant distinction of indeterminate solitary pulmonary nodules as 93% and 88%, respectively. 18 F-FDG PET/CT might yield a false positive result in inflammatory conditions, tuberculosis or granulomatous lesions. A false negative 18 F-FDG PET/CT result is generally associated with nodules measuring less than 1 cm, carcinoid tumors or bronchoalveolar carcinomas (BAC) (5,6,7,8,9). In our study, 18  In the present study, the sensitivity, accuracy and positive predictive value of 18 F-FDG PET/CT in the detection of primary malignancy were calculated as 94%, 94% and 100%, respectively. These results are consistent with that reported in the literature. Several studies indicated that the mean SUV and SUV max differ according to histologic subtypes of lung cancer. In particular, it has been reported that the SUV max of carcinoid tumors and BAC are low (10,11). Vesselle et al. (12) found that the SUV max of BAC was lower than all other subtypes, and that non-BAC adenocarcinomas had lower SUV max values than SCC. The majority of studies in the literature report that the SUV max of adenocarcinomas is lower than that of SCCs (13,14). However, in our study, no statistically significant difference was identified between adenocarcinoma (16.8±13.5) and SCC (17.9±5.6) in terms of mean SUV max (p=0.2). Several studies showed that tumor size is a prognostic factor for survival in NSCLC (15). The correlation between tumor size and SUV max has been previously assessed (16,17). Zhu et al. (18) reported a moderate positive correlation between SUV max value and tumor size (r=0.642, p<0.001). In our study, a positive correlation (p=0.002) was identified between tumor size and SUV max , in line with findings of the earlier studies. The detection of both lymph node and distant metastases is essential for proper staging in lung cancer. The sensitivity of 18 F-FDG PET/CT in lymph nodes greater than 1 cm is high, although the accuracy and specificity rates are low (19). In a study by Detterbeck et al. (20), the false positive rate of PET in mediastinal lymph nodes was reported to be 13-22%, and the false negative rate as 5-8%. In our study, histopathologic lymph node evaluation was carried out in 21 of the 50 patients, and 52% of the 21 patients were correctly staged by 18 F-FDG PET/CT whereas the rate of patients incorrectly downstaged or up-staged by 18 F-FDG PET/CT were detected as 19% and 28%, respectively. In our study, the false positive and false negative lymph node rates in 18 F-FDG PET/CT were found to be higher than that reported in the literature. This finding may be attributed to the fact that histopathologic evaluation was not performed in all lymph nodes evaluated as either positive or negative by 18 F-FDG PET/CT. Furthermore; sarcoidosis, amyloidosis, anthracosis, tuberculosis and organized pneumonia may cause false positive results in lymph nodes. In one patient with a false positive lymph node on 18 F-FDG PET/ CT, histopathologic sampling revealed anthracosis. In addition, pulmonary infections or granulomatous diseases such as tuberculosis or sarcoidosis that are frequent in our country might have contributed to these outcomes. Further investigation of lymph node and distant organ metastases, particularly in patients being considered for surgical therapy, could prevent unnecessary surgery. Van Tinteren et al. (21) reported that performing an 18 F-FDG PET/CT in addition to conventional methods as part of preoperative staging of NSCLC might avoid unwarranted surgery in one-fifth of patients. In a study on patients with NSCLC, an 18 F-FDG PET/CT led to a change in disease stage as determined by conventional methods in 50.6% (41.1% up-staged, 9.5% down-staged) of patients, and alteration in treatment planning in 42.3% (22). In our study, the 18 F-FDG PET/CT resulted in a change in the treatment plan as decided by conventional methods in 34% of all patients, and unnecessary surgery was prevented in 18% of the patients. In 6% of the patients, the 18 F-FDG PET/CT was interpreted as negative for areas identified as metastasis through conventional methods, leading patients to possible curative therapy. In various studies, SUV max of the primary tumor detected by 18 F-FDG PET/CT was used to predict lung cancer prognosis and assess patient survival (23,24). Ahuja et al. (25) found that patients with primary tumors showing a high FDG uptake had lower survival rates than those with a low uptake, while Hoang et al. (26) found no significant association between FDG uptake of the primary tumor and survival in patients with advanced NSCLC. In a metaanalysis published by IASLC in 2008, the SUV max of the primary tumor was a strong determinant of prognosis in NSCLC. However, the need to support this finding with multivariate analysis was emphasized (27). The present study evaluated the relationship between SUV max of the primary tumor and patient survival and no significant difference was identified between those with SUV max below 15.6 (10.3±2.2 months) and above 15.6 (15.9±1.6 months) in terms of mean survival time (p=0.118). Several previous studies support our findings, although a larger number of authors argue that SUV max could be used to predict prognosis and assess survival in case of lung cancer. Our results might be related to the limited number of patients in the study as well as the differences between the two groups (e.g. age, genetic factors, stage, tumor pathology).

Conclusion
Despite the limitations of our study, such as limited number of patients, most of the results are consistent with previous studies. In our study, it is concluded that 18 F-FDG PET/CT contributes to both the diagnosis and management of lung cancer by providing valuable information in addition to conventional methods.