Is There a Role for FDG PET in the Management of Lung Cancer Manifesting Predominantly as Ground-Glass Opacity?
Abstract
OBJECTIVE. The purposes of our study were to evaluate 18F-FDG PET findings of ground-glass opacity (GGO) nodules and to determine the value of FDG PET for the preoperative staging of lung cancer manifesting predominantly as GGO.
MATERIALS AND METHODS. Eighty-nine patients (46 men and 43 women; mean [± SD] age, 62.4 ± 7.2 years [range, 33–81 years] and 61.7 ± 6.7 years [range, 34–75 years], respectively) with 134 GGO nodules (56 single and 78 multiple) who underwent CT and FDG PET before surgery were included. CT and PET findings were assessed in terms of lesion size, GGO percentage, multiplicity, and maximum standardized uptake value (SUVmax). SUVmax was correlated with lesion size and GGO percentage using linear regression. The SUVmax and hypermetabolism rates of solitary and multiple GGO nodules were compared using the Student t test or Fisher exact test. Lymph node and distant organ metastasis staging by FDG PET were correlated with histopathologic findings.
RESULTS. SUVmax was positively correlated with lesion size (mean, 14.5 mm; range, 5–37 mm) (r = 0.6705; p < 0.0001) and was negatively correlated with GGO percentage (mean, 77%; range, 50–100%) (r = –0.7465; p < 0.0001). Solitary nodules showed higher hypermetabolism rates (73% [41/56]) than did multiple nodules (27% [21/78]) (p = 0.0001), but SUVmax was not significantly different between solitary and multiple nodules. There was no true-positive interpretation of nodal or distant metastasis from GGO nodules by FDG PET.
CONCLUSION. FDG PET showed no clear advantage for the staging of lung cancer with predominant GGO because of the low incidences of nodal and distant metastasis.
PET with 18F-FDG is a noninvasive diagnostic technique that provides information about glucose metabolism in lesions and is used routinely for the preoperative staging of non-small-cell lung cancer (NSCLC) because of its higher sensitivity and specificity than other diagnostic modalities [1, 2]. In the most widely cited metaanalysis of FDG PET in NSCLC, Gould et al. [1] found that the technique has a sensitivity of 96.8% and a specificity of 77.8% for lung cancer. However, although FDG PET is a valuable imaging modality for lung cancer staging, there are several pitfalls. It has been reported that bronchoalveolar carcinoma (BAC), which typically manifests as ground-glass opacity (GGO) on CT, is falsely negative on PET [3–5]. Although numerous studies have addressed the performance characteristics of FDG PET in patients with known or suspected lung cancer, few studies have examined the accuracy of PET for BAC or adenocarcinoma with BAC components [6–8]. In addition, the clinical utility of FDG PET for the staging of lung cancer manifesting predominantly as GGO has not been thoroughly examined.
The purposes of our study were to retrospectively evaluate FDG PET findings of GGO nodules and to determine the value of FDG PET for the preoperative staging of lung cancer manifesting predominantly as GGO.
Materials and Methods
The institutional review board of Seoul National University Bundang Hospital approved this study and waived the requirement for patient consent (IRB no. B-1101–120–101).
Study Population
Patients were identified by a retrospective data search using the terms “ground-glass” and “GGO” from the radiologic information system among the patients who underwent curative lung surgery in two tertiary hospitals (Seoul National University Bundang Hospital and Seoul National University Hospital) during January 2002 to February 2007. Patients who fulfilled the following criteria were included: pulmonary nodules with a GGO percentage of 50% or more, pulmonary nodules with pathologic confirmation by surgery, preoperative FDG PET and CT performed within 2 weeks of each other, and surgery performed within 2 weeks after PET. The percentage of GGO was calculated as follows: [(DGGO – D) / DGGO] × 100, where DGGO is the greatest diameter of the lesion, including the GGO area, and D is the greatest diameter of the lesion without GGO [9, 10]. The study cohort comprised 89 patients (46 men and 43 women; mean [± SD] age, 62.4 ± 7.2 years [range, 33–81 years] and 61.7 ± 6.7 years [range, 34–75 years], respectively) with 134 pathologically confirmed GGO nodules.
Fig. 1A —58-year-old woman with known colon cancer.
A, Axial CT image shows 1.2-cm pure ground-glass opacity nodule (arrow) in left upper lobe with negative FDG activity (maximum standardized uptake value [SUVmax] = 0.5).
Fig. 1B —58-year-old woman with known colon cancer.
B, Axial CT image shows 1.5-cm solid nodule (arrow) in left lower lobe (SUVmax = 1.9; data not shown).
Fig. 1C —58-year-old woman with known colon cancer.
C, Coronal whole-body PET image shows hypermetabolism (arrow) (SUVmax = 9.4) at colon cancer at hepatic flexure. Left upper lobe nodule was confirmed to be bronchoalveolar cell carcinoma, and left lower lobe nodule was confirmed to be pulmonary metastasis from colon cancer.
PET and CT: Imaging Protocol and Analysis
PET was performed using one of two dedicated scanners (Allegro or Gemini, Philips Healthcare). All patients fasted for at least 6 hours before PET. FDG was IV injected at 5.18 MBq/kg, and whole-body scanning was performed at 50 minutes after FDG administration. The 3D row-action maximum-likelihood algorithm was used for the reconstruction of transaxial images of resolution 4.8 mm. For qualitative analysis, the degree of FDG activity in the nodules was defined as either negative (i.e., less than mediastinal blood-pool activity) or positive (i.e., same as or greater than mediastinal blood-pool activity). To analyze FDG accumulation, a circular region of interest was drawn by a board-certified nuclear medicine physician over GGO nodules on transaxial images on a slice-by-slice basis, so as to cover whole lesion volumes. In some patients, no nodules could be detected by PET because of very low FDG uptake. In these patients, regions of interest were drawn on chest CT–predicted locations. Maximum standardized uptake value (SUVmax) was considered representative of FDG uptakes. FDG uptake by lymph nodes and by distant metastases and the presences of concurrent malignancies were also evaluated. When a lymph node had an SUVmax of less than 2.5 g/mL or was read as “no uptake,” the node was considered negative.
CT was performed using several CT scanners (Brilliance-64 and MX-8000 IDT, Philips Healthcare; Sensation-16 and Somatom Plus 4, Siemens Healthcare; and LightSpeed Ultra and HiSpeed Advantage, GE Healthcare) with 120 kVp, 100–200 mA, and a pitch of 0.875–1.5. Thin-section CT images were reconstructed into 0.67 to 1.25-mm-thick sections using high-frequency algorithms. Thicksection CT images were reconstructed as 3 to 5-mm-thick sections using lung reconstruction algorithms.
Images were displayed with lung (level, –600 HU; width, 1500 HU) and mediastinal (level, 30 HU; width, 400 HU) window settings. One chest radiologist with 8 years of experience in chest CT interpretation, who was unaware of clinical findings and histologic diagnosis, reviewed all CT images and measured lesion size and GGO percentage.
Fig. 2A —69-year-old woman with adenocarcinoma with bronchoalveolar cell carcinoma components.
A, Axial CT image shows 2.8-cm mixed ground-glass opacity nodule (arrow) in right lower lobe.
Fig. 2B —69-year-old woman with adenocarcinoma with bronchoalveolar cell carcinoma components.
B, Coronal whole-body PET image shows mild hypermetabolism (arrow) (maximum standardized uptake value = 1.4).
Fig. 3A —73-year-old woman with adenocarcinoma with bronchoalveolar cell carcinoma (BAC) components.
A, Axial CT image shows 2.1-cm mixed ground-glass opacity nodule (arrow) in right upper lobe.
Fig. 3B —73-year-old woman with adenocarcinoma with bronchoalveolar cell carcinoma (BAC) components.
B, Coronal whole-body PET image shows hypermetabolism at right upper lobe nodule (small arrow) (maximum standardized uptake value [SUVmax] = 2.4), right paratracheal lymph node (arrowhead) (SUVmax = 4.0), and subcarinal lymph node (large arrow) (SUVmax = 3.9). Right upper lobe nodule was confirmed to be adenocarcinoma with BAC components, and mediastinal lymph nodes turned out to be chronic granulomatous inflammation of tuberculosis.
Pathologic Diagnoses and Postoperative Follow-Up
Pathologic examinations were performed over the entire volumes of GGO nodules. Resected specimens were fixed in formalin and embedded in paraffin, and all lesion sections were stained with H and E. Hilar or mediastinal lymph node metastases were evaluated when lymph node dissection was performed. In cases with multiple primary tumors, each tumor was staged independently as a primary tumor. Lymph node metastasis or postoperative recurrence was regarded to have resulted from tumors with the most advanced stage or the largest size. Postoperative follow-up results were evaluated on the basis of clinical surveillance and CT findings. Follow-up CT was performed at 3- or 6-month intervals (BAC or adenocarcinoma with BAC components) or at 6- or 12-month intervals (atypical adenomatous hyperplasia [AAH] or focal interstitial fibrosis) in accordance with post-surgical pathologic findings.
Statistical Analysis
The SUVmax was correlated with lesion size and GGO percentage, and the GGO percentage was correlated with lesion size with linear regression analysis. The mean SUVmax and hypermetabolism rates on FDG PET were compared between nodules with different histologic profiles and between solitary and multiple GGO nodules using the unpaired Student t test or Fisher exact test, as appropriate. The GGO percentage was also compared between solitary and multiple GGO nodules using an unpaired Student t test. The proportion of AAH or BAC was compared between solitary and multiple GGO nodules using Fisher exact test; p values of less than 0.05 were considered to indicate statistical significance. Statistical analysis was performed with a statistical software package (SPSS version 15.0, SPSS).
Results
Demographic Findings and Histologic Diagnoses
Of the 89 patients with 134 pathologically confirmed GGO nodules (mean, 1.5 nodules/patient; range, 1–5 nodules/patient), 56 had a solitary GGO nodule and 33 had 78 multiple GGO nodules among a total of 188 GGO nodules detected by CT (mean, 2 nodules/patient; range, 2–15 nodules/patient). The interval between PET and surgery ranged from 1 to 14 days (mean, 7 days). Pathologic specimens were obtained by lobectomy for 105 nodules, by segmentectomy for four, and by wedge resection for 25. Histologic diagnoses of the 56 solitary GGO nodules in 19 women and 37 men (mean age, 57; age range, 33–81 years) included AAH (n = 3), BAC (n = 7) (Figs. 1A, 1B, and 1C), adenocarcinoma with BAC components (n = 45) (Figs. 2A, 2B, 3A, and 3B), and focal interstitial fibrosis (n = 1), and the histologic diagnoses of 78 multiple GGO nodules in 24 women and nine men (mean age, 56 years; age range, 36–71 years) included AAH (n = 19), BAC (n = 26), adenocarcinoma with BAC components (n = 30), and focal interstitial fibrosis (n = 3). The proportion of AAH or BAC in multiple GGO nodules (58% [45/78]) was significantly higher than that of solitary GGO nodules (18% [10/56]) (p = 0.0001).
CT and PET Findings
CT and PET results according to histologies and multiplicities of nodules are summarized in Table 1. The mean diameter of GGO nodules was 15 mm (range, 5–37 mm), and GGO nodule diameter was positively correlated with SUVmax (mean, 1.2; range, 0.2–5.2) (r = 0.67; p < 0.0001). The mean diameter of solitary GGO nodules (17 ± 8.1 mm) was significantly larger than that of multiple GGO nodules (12 ± 7.9 mm) (p < 0.001). The mean GGO percentage was 77% (range, 51–100%) and negatively correlated with SUVmax (r = –0.75; p < 0.0001) and lesion size (r = –0.588; p < 0.001). Hypermetabolism rate, mean SUVmax, and mean diameter of adenocarcinoma with BAC components were significantly larger than those of BAC, AAH, or focal fibrosis (p < 0.0001, respectively). The mean GGO percentage of adenocarcinoma with BAC components was significantly smaller than those of BAC, AAH, or focal fibrosis (p < 0.001, respectively). The hypermetabolism rate and the mean SUVmax of BAC were much larger than those of AAH (p < 0.0001). In terms of multiplicity, 41 of the 56 (73%) solitary GGO nodules showed hypermetabolism, and 21 of the 78 (27%) multiple GGO nodules showed hypermetabolism (per lesion base). The mean SUVmax was 1.3 (range, 0.2–5.2) in solitary GGO nodules and 0.5 (range, 0.2–5.0) in multiple GGO nodules. The hypermetabolism rate was higher for solitary than multiple GGO nodules (p = 0.0001), but the mean SUVmax of solitary compared with multiple GGO nodules was not significantly different (p = 0.7837). The GGO percentage of multiple GGO nodules was significantly larger than that of solitary GGO nodules (p = 0.0002).
Lung Cancer Staging: PET and Pathologic Correlations
All patients with malignant nodules underwent curative resection by video-assisted thoracoscopic surgery or open thoracotomy. All malignant GGO nodules were either BAC or adenocarcinoma with BAC components; pT1N0 (n = 93) was the most common stage for both multiple and solitary GGO nodules, followed by pT2N0 (n = 15). Nodal metastases detected by both PET and pathology in two patients with a solitary GGO nodule (one pN1 and one pN2) were regarded to have resulted from concurrent solid lung cancer with a more advanced stage (pT2 adenocarcinomas) rather than from GGO nodules (pT1 BAC and pT1 adenocarcinoma, respectively). Three interpretations of mediastinal nodal metastases by PET turned out to be chronic granulomatous inflammation that was suggested by pathologic examination to be due to tuberculosis (Figs. 3A and 3B); two nodes (< 10 mm in short-axis diameter) showed peripheral calcification, and one node (12 mm in short-axis diameter) showed diffuse higher attenuation (110 HU) than that in surrounding great vessels. Therefore, in the current study, there was no true-positive interpretation of nodal or distant metastasis from GGO nodules by PET. PET depicted hypermetabolism due to concurrent malignancies (n = 6) that were known at the time of PET, including concurrent solid lung cancer in three patients, pulmonary metastasis resulting from gastrointestinal malignancy in one patient, colon cancer in one patient (Figs. 1A, 1B, and 1C), and chondrosarcoma in the humerus in one patient. There was no recurrence over an average follow-up period of 30 months (range, 10–65 months), except for one patient with adenocarcinoma (pT2N0). None of our patients died of the disease during the follow-up period.
Discussion
FDG PET has been shown to accurately stage NSCLC, and as a result has been widely adopted as the standard care for the evaluation of patients with NSCLC. However, the role of PET in the diagnosis and staging of BAC or adenocarcinoma with BAC components, which typically manifest as GGO at CT, has not been determined. Most studies have addressed the presence or absence of FDG uptake in terms of differentiating benign and malignant lesions [4, 11] or BAC from adenocarcinoma with BAC components [6]. Furthermore, few data are available on relationships between CT and PET findings of pulmonary GGO lesions. In the current study, SUVmax showed a positive correlation with lesion size and a negative correlation with GGO percentage, both of which are known to be well correlated with histologic invasiveness and prognosis of BAC and adenocarcinoma with BAC components [12]. This concurs with the findings of Goudarzi et al. [6], who found a correlation between CT findings (i.e., size and CT density) and SUVmax in BAC and adenocarcinoma with BAC components. In terms of the multiplicity of GGO nodules, we found that nodule size and hypermetabolism rate were significantly greater for solitary than multiple GGO nodules. This can be explained by the high incidence of AAH and BAC in multiple GGO nodules, because AAH and BAC are smaller and are associated with a larger proportion of GGO than those of adenocarcinoma with BAC components [10].
Compared with CT, PET was found to contribute little to the primary tumor staging (T staging) of lung cancer with predominant GGO; only 24% of BACs and 69% of adenocarcinomas with BAC components were FDG avid, which was similar to the results of other studies. Higashi et al. [4] reported that four of seven BACs showed negative results on PET, whereas only one of 23 non-BAC tumors showed a negative result. Port et al. [13] found that 23% of adenocarcinomas with BAC components and 58% of adenocarcinomas were FDG avid as compared with 88% of FDG-avid tumors with other histologic profiles. Although Goudarzi et al. [6] asserted that the combined findings from PET and CT could be useful for the diagnosis and management of BAC and adenocarcinoma with BAC components, preoperative differentiation of pure BAC and adenocarcinoma with BAC components cannot be accurate given that the current criteria for BAC mandate that the diagnosis be made only on examination of large (i.e., surgical) biopsy specimens [14]. In addition, although most imaging modalities used for lung cancer staging are generally not able to provide specific information on histologic subtype, lung cancer with predominant GGO at CT can strongly suggest a diagnosis of BAC or adenocarcinoma with BAC components. Therefore, the characteristic CT finding of predominant GGO has more important implications than PET results for these lesions.
It is widely accepted that PET improves the detection of local and distant metastases and can prevent futile thoracotomy in patients with NSCLC [15–18]. However, it is unlikely to detect occult lymph nodes or distant metastasis in lung cancer with predominant GGO because of the low rate of metastases shown by these lesions. In the current study, no nodal or distant metastasis was found for lung cancer with predominant GGO, whereas in three patients, false-positive interpretations of mediastinal nodal metastases were made by PET. According to a study on the prognostic importance of thin-section CT features in peripheral lung adenocarcinoma [12], all adenocarcinomas smaller than 2 cm with a GGO proportion exceeding 50% of tumor volume were free of lymph node metastasis and vessel invasion, and all these patients remained alive without recurrence 10 years later. After numerous initial reports proclaiming the benefits of PET in lung cancer staging, several reports have been published on the limitations of PET for the evaluation of small early lung cancer. Port et al. [13] concluded that PET has no demonstrable benefit in terms of diagnosis, staging, or prognosis in patients with a lung cancer of 2 cm or smaller because of the low prevalence of mediastinal nodal and distant metastases. In a study by Kozower et al. [19], PET prevented nontherapeutic thoracotomy in 7.4% of patients with clinical stage IA NSCLC by identifying metastatic disease, and this is significantly lower than 20% prevention rate suggested by two recent trials that both evaluated patients with potentially resectable cancer (stages IA–IIIA) [16, 17]. The frequent false-positive results of PET for early lung cancer and the subsequent burden of expensive and bothersome confirmatory studies are also worrisome. False-positive results of nodal metastasis by PET occur for reactive hyperplasia or granulomatous inflammation, and thus, false-positive rates are highly dependent on the patient population [20]. In our study, all three false-positive interpretations of mediastinal nodal metastases by PET turned out to be granulomatous inflammation of tuberculosis.
The standard treatment for operable NSCLC, even clinical T1N0 disease, remains lobectomy with hilar and mediastinal lymph node dissection [21]. However, clinical investigations to date have suggested that limited resection could be successfully performed for BAC that typically manifests as GGO at CT [22–24]. In addition, a recent study by Okada et al. [25] found that the nodules with GGO greater than 50% had up to 6% of nodal metastasis and up to 4% of recurrence rate and that both decreased to only 1% when the nodules had SUVmax less than 1.5. In our study, FDG PET showed a higher rate of hypermetabolism in adenocarcinoma with BAC components than in BAC. These findings may suggest that a selection of sublobar resection based on a combination of information from both CT and FDG PET could be a potential clinical implication in terms of limited resection [26].
There are several limitations to this study. First, the retrospective nature of the study unavoidably introduces the issue of inherent bias. Second, SUVmax analyzed in our study was subject to variability among subjects, much more than normalized SUV ratios (e.g., normalization by the liver uptake). Third, it was not feasible to evaluate the diagnostic accuracy of PET in the assessment of nodal or distant metastasis staging because no true-positive metastasis case was included. Fourth, the postoperative follow-up period was inadequate in terms of evaluating survival or disease recurrence, and long-term follow-up over several years is needed to assess prognosis accurately in lung cancer with predominant GGO. Fifth, data clustering is another possible limitation, because we included multiple nodules per patient. However, we did not adopt a statistical method, such as a generalized estimating equation approach, to manage this issue, because recent multiclonal BAC and adenocarcinoma studies have suggested that these lesions behave in an independent manner [27–29].
In summary, when CT shows a pulmonary nodule with predominant GGO, FDG PET frequently produces negative results. Furthermore, FDG PET is unlikely to detect lymph nodes or distant metastasis because of their low prevalence and, thus, does not appear to offer a clear advantage in patients with lung cancer manifesting as predominant GGO.
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History
Submitted: March 15, 2011
Accepted: May 13, 2011
First published: November 23, 2012
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