In this meta-analysis of 10 studies including 1122 patients with PET-CT–determined stage I (T1-2N0) NSCLC, the summary estimated NPV was 0.93 for mediastinal metastasis. The NPVs for mediastinal metastases in T1 and T2 subgroups were 0.94 and 0.89, respectively. In terms of the overall nodal metastases, the summary estimated NPV of PET-CT was 0.87 for stage I NSCLC. To our knowledge, this is the first combined study systemically evaluating the diagnostic performance of combined FDG-PET and CT for nodal staging in specific stage I NSCLC. All studies included in this meta-analysis were reasonably designed and presented with acceptable quality scores.
In the present analysis, the presence of N2 metastasis in stage I (T1-2N0) and exclusive stage IA (T1N0) disease was almost identical, which resulted from the predominance of the T1 component among the whole study population. Except for 2 studies with 237 patients not specifying substage distribution (T1 vs. T2),26,30
only 153 of 885 patients from the other 8 studies had stage IB (T2N0) disease. Therefore the general results of the present analysis were more likely to represent features of stage IA disease. The estimated 6% presence of occult N2 metastasis is pretty similar to a recent retrospective report, 34
which demonstrated a 7% N2 involvement in patients with pathologic T1 and clinical N0 NSCLC. Notably, a substantial number of patients with clinical T1 disease do not truly have pathologic T1 disease. Stiles et al reported that only 72.2% of patients with stage IA disease retained a pathologic T1 classification after surgical resection and 27.8% had postoperative upstaging of their T classification; the majority changed to stage stage IB/T2 primarily because of the visceral pleural invasion.35
Therefore the patients with truly pathologic T1 disease in our pooled study may have an even lower likelihood of occult mediastinal metastasis.
The low presence of mediastinal metastasis in patients with T1N0 disease that was clinically staged with PET-CT arouses much controversy on the routine practice of invasive staging for this group of patients. The average sensitivity of cervical mediastinoscopy for mediastinal staging is around 80% in an unselected population9,36
and it is likely to be even lower in selected patients with previous normal findings on PET-CT. Given the 6% presence of false-negative findings among patients with T1N0 disease in this study, mediastinal disease would be discovered in < 5% of patients undergoing additional mediastinoscopy. This estimation was consistent with a prospective report, which revealed a 6% detection rate and a 60% sensitivity rate for unsuspected N2 disease by performing both mediastinoscopy and EUS-FNA in patients with NSCLC who are clinically staged as N2 negative after integrated PET-CT and CT scanning.37
Therefore at least 16 patients with T1 disease and normal mediastinal findings on PET and CT would undergo futile invasive staging procedures to prevent 1 unnecessary thoracotomy, suggesting a low yield from routine invasive staging for this group of patients. In terms of T2N0 NSCLC in this pooled study, mediastinal involvement seemed more frequent, showing an NPV of 0.89 and a >10% incidence of unforeseen N2 metastases based on the limited number of patients. This finding is partially consistent with the standpoint that nodal metastasis increases with the tumor size,38,39
suggesting the necessity of further invasive staging procedures for patients with T2 disease despite negative nodal findings on PET & CT.
Conventionally, mediastinal status matters significantly for the determination of treatment strategy, such as the use of neoadjuvant therapy or immediate thoracotomy. N1 disease generally has limited influence on this part of decision making. Nevertheless, occult lymph node involvement regardless of nodal station is one of the main considerations for the implementation of stereotactic body radiation therapy. In this pooled study, the summary estimated NPV for overall nodal metastases in stage I NSCLC by PET-CT was 0.87, indicating up to a 13% false-negative rate. Thereby the invasive procedures should still be strongly recommended to achieve more accurate staging for those who are medically unfit for surgery.
In the present analysis, studies using either integrated PET-CT or a visual combination of PET and CT were all included. Regarding the sensitivity, specificity, and accuracy, a large number of studies have shown that integrated PET-CT is superior to the manual combination of PET and CT in detecting nodal disease.7,8
However limited data are available for the comparison of NPV between these two modalities. One study retrospectively assessed the diagnostic accuracies of fused PET-CT, PET and CT viewed side by side, PET alone, and CT alone for nodal staging in 260 patients with various oncologic diseases, corresponding to the NPVs of 96%, 92%, 91%, and 73%, respectively.40
Another preliminary study including 27 NSCLC patients observed an NPV of 94% for both coregistered PET-CT and dedicated PET.41
One study reported a slight advantage of integrated PET-CT over PET alone when assessing the NPV of N2 disease, though the difference was not significant.42
In light of the similar NPVs of integrated PET-CT and visual correlation of PET and CT for nodal staging, as well as the limited number of eligible studies, it was reasonable to pool these two combination patterns together for this analysis.
Multiple factors such as scanning equipment, observer interpretation of tests, and inherent characteristics of tumors may contribute to false-negative findings on PET-CT. Limited spatial resolution may be the primary cause for PET-based false-negative findings. Spatial resolution of current-generation PET scanners is typically 5–7 mm and theoretically it is difficult to detect lesions <7 mm based on PET imaging. Even so, one report showed that PET correctly detected 88% of false-negative nodes <10 mm that were missed on CT.43
The author speculated that the high-contrast resolution may compensate for the limited spatial resolution and thus enhance the detection of micrometastases. Another study demonstrated that 38% of false-negative nodes on CT (<10 mm in the short axis) were successfully detected by integrated PET-CT and the smallest node on CT that showed a true-positive uptake on integrated PET-CT was 3.8 mm.27
This evidence suggested that positive FDG uptake for even very small nodes should not be ignored. Besides the FDG uptake, CT-de-fined nodal size can still be of great value for the identification of nodal malignancy. A meta-analysis revealed that the predicted posttest probability of malignancy was 5% for enlarged nodes measuring 10 to 15 mm with a normal finding on PET and 20% for those larger than 15 mm.44
This result suggested that nodes larger than 15 mm, although without abnormal FDG uptake, should not be neglected either. In our analysis, 9 of 10 studies took both tumor metabolic activity and size into consideration; either showing abnormality would be considered suspicious for malignancy.
Stage I NSCLC disease is seen in a heterogeneous group of patients with varying tumor size, location, histologic type, and metabolic activity. Besides the previously mentioned lymph node features such as size and metabolic activity, characteristics of primary tumor may also be predictive of nodal involvement. In addition to the aforementioned tumor size and location,45,46
histologic type 38,47
and FDG uptake of primary tumor 39,48,49
may be potential predictors of nodal metastases as well. Based on the specific patient pool, we quantitatively validated that adenocarcinoma carried a much greater risk of nodal involvement, whereas no significant effect was found for tumor location on nodal involvement. Abnormal FDG uptake was the most consistently reported risk factor across studies, although there was dramatic discrepancy in SUV threshold for risk hierarchy. Prospective studies enrolling larger numbers of patients to explore the optimal SUV threshold for prediction of nodal metastasis are warranted. A multiinstitutional clinical trial is ongoing to prospectively investigate the presence of occult N2/3 metastases and the sensitivity of routine cervical mediastinoscopy in potentially high-risk patients with stage I NSCLC (PET- and CT-staged T2N0 NSCLC as well as T1N0 with a maximum SUV > 10 of the primary tumor, NCT01146366).50