Does prior mediastinal lymph node aspiration contribute to false-positive positron emission tomography–computed tomography?

Discussion

This retrospective study examined the FPR of PETCT in patients undergoing EBUS-TBNA prior to or after this test. We found no significant evidence that EBUS-TBNA prior to PETCT is associated with an increased PETCT false-positive rate based on initial PETCT clinical interpretation. This finding was consistent when using three alternative definitions for PETCT positivity. Raw FPRs were higher in the EBUS first group when applying a fourth definition which excluded a bilateral inflammatory pattern as false-positive. Potentially the bronchoscopists were more inclined to sample such nodes after PETCT which otherwise would not have been targetted and as such increased the FPR in the PETCT first group. We also noted a trend to higher FPR in early stage lung cancer patients who underwent EBUS first. On the other hand, the presence of a bilateral inflammatory pattern was not a significant factor affecting FPR in the multivariate GEE model. These findings suggest that overall, EBUS-TBNA performed within 30 days of PETCT is not a significant contributor to false-positive PETCT.

False-positive PETCT findings have been described in association with biopsy and surgical sites, prostheses, areas of drainage, port or catheter insertion, and along injection sites (particularly those associated with insulin or colony-stimulating factor) [5, 6]. Given that false-positive SUV uptake can be seen in association with small insults, such as areas of insulin injection or biopsy sites, it is not unwarranted to consider whether this may be the case following EBUS-TBNA. The consequences of a false-positive PETCT result are not insignificant and include the possibility of incorrect stage determination, need for additional, more invasive, testing, and potentially incorrect treatment decisions due to incorrect upstaging.

Lung cancer staging guidelines do not specify if an ideal sequence exists with regard to PETCT and invasive mediastinal staging nor if there exists a need for any delay between biopsy and PETCT. In the American College of Chest Physicians (ACCP) guidelines, both CT and PETCT results are used to determine which patients should undergo invasive mediastinal staging, such as EBUS [2]. When this is indicated based on CT results, however, it is unlikely PETCT will preclude more invasive testing unless occult metastatic disease is detected. Should PETCT confirm metastatic disease, the bronchoscopic procedure may then have already provided the important cytopathological and molecular information required for treatment decisions. As such, proceeding to minimally invasive mediastinal diagnosis and staging with EBUS seems a reasonable path for some patients, particularly if PETCT availability is delayed by health system factors such as is common in our setting. Confirming that this sequence does not hinder the test performance characteristics of the PETCT would remove one of the concerns and causes for delay with this approach.

Only limited published evidence exists on this topic. A small study of 27 patients who underwent CT-guided lung biopsy failed to show any abnormal PETCT abnormalities in the chest wall/needle track area traversed on scans performed within 14 days [7] suggesting that the small injury from a needle sample may not be enough to impact PETCT results. The only study examining PETCT results following EBUS procedures in a cohort of 107 patients with 198 non-malignant lymph nodes found that subsequent PETCT was positive by visual interpretation in 76 lymph nodes (38%) [8]. The authors felt that no other explanation for the PETCT positivity other than the biopsy was present in 14% of cases. Another study published in abstract form only found a false-positive PETCT prevalence of 31% in 71 patients when imaging was performed after EBUS sampling [9]. But since these studies have no control groups, PETCT is known to have a significant FPR [2] and explanations for this are not always evident, attributing any false-positive results to the EBUS procedure would be tenuous at best.

Our study reports on the largest collection of PETCT cases preceded by EBUS but also allowed us to compare this to a group where EBUS-TBNA was performed after PETCT to more objectively determine any impact of the EBUS procedure on FPRs. Using several approaches to classify PETCT positivity including the initial clinical qualitative reports, qualitative and quantitative research re-interpretation of scans, and using a standardised definition of malignant lymph node involvement, we found no evidence that performing EBUS prior to PETCT influenced the false-positive rate. It should be noted that our estimates of PETCT FPR may not be accurate as stand-alone values, but our intent was to compare FPR according to test sequence when attributed with the same (if imperfect) definitions.

The most important limitation of our study is the retrospective design without randomised allocation of test sequence. While consecutive cases were extracted from a comprehensive database, the reasons for which a given patient may have undergone one test over the other first may have an impact on the prevalence of malignancy in lymph nodes and other test performance characteristics. While patients appeared similar in terms of demographics and disease stage, some slight differences in lymph node size were noted, and other unknown factors may exist even if a regression analysis was used to adjust for potential confounders. For example, lymph node targetting during EBUS would be mostly based on size if PETCT was not available, whereas nodal PET activity distribution may alter which nodes are sampled if those results are already available. Interestingly, both groups had similar numbers of lymph node stations sampled during the procedure, as this may relate to the nature of the procedure (diagnostic only versus staging) rather than the actual PETCT results.

In addition, since all the cases were performed with 21G needles, our findings should not be extrapolated to larger 19G devices more recently available, which could theoretically cause more trauma and inflammation [10, 11]. Our data does not allow us to determine if there is a minimal timeline required as an interval between tests. Since our sample was limited with <10% of lymph nodes sampled within 3 days of the PETCT, we cannot exclude that an effect may be present if EBUS precedes the PETCT examination by only a few days. Not all true positive cases were confirmed on cytopathology so that growing but benign inflammatory lymph nodes or skip metastasis could have affected our FPRs. Our study was also conducted at a single centre, and all clinicians involved in EBUS-TBNA had undergone at least one extra year of advanced training in advanced bronchoscopic techniques, including EBUS-TBNA. Thus, the homogeneity of technique and expertise at our centre may not be reflective of all centres performing EBUS-TBNA.

In summary, these results provide some reassurance to clinicians that performing EBUS prior to PETCT testing for patients undergoing investigation for possible chest malignancy should not affect results of the latter scan. This is probably less an issue in scenarios with high pretest probability of mediastinal disease where EBUS and PETCT are both likely to be positive. Importantly, the corollary is also noted that positive findings on PETCT should not be simply attributed to recent EBUS-TBNA testing and may warrant added scrutiny in light of these results. In scenarios with low pretest probability of disease (e.g. staging procedures), we still would advocate performing PETCT prior to EBUS as this may preclude need for EBUS if extrathoracic disease is identified and may impact the thoroughness of the EBUS guided by PETCT results.

The added flexibility to schedule these tests may help reduce strain on the health system and prevent delays in evaluation. These data also provide us with further evidence of the ongoing need for confirmatory testing in the case of positive PETCT results. Given an FPR of 14.6% in either groups, the possibility of inappropriate upstaging warrant confirmatory testing if important for treatment decisions.

Our results suggest that performing EBUS-TBNA within 30 days prior to PETCT does not increase the false-positive rate of PETCT for lymph node evaluation. Selection of which test to perform first should be based on other considerations.