Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the evaluation of solitary pulmonary nodule: a scoping review

Introduction

If the role of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) is indisputable in the follow-up of lung cancer, whether or not subjected to surgical resection, many perplexities arise in the evaluation of a solitary pulmonary nodule (SPN), especially in lesions with minimal solid component. In fact, the doubts concern the reliability of the maximum standardized uptake value (SUVmax) in relation to the histological type and size of the tumor (1-4). Many authors agree that ¹⁸F-FDG-PET/CT shows high sensitivity but the data are still heterogeneous regarding specificity (5,6). The availability of increasingly sophisticated equipment and the need to formulate a preoperative diagnosis as quickly as possible, put us in front of the following questions: does ¹⁸F-FDG PET/CT represents an essential step in the diagnostic path of SPN? What has changed in the last 5 years? These issues are essential when considering the budgets reduction in healthcare and the cost of the functional imaging in relation to the expected diagnostic benefit. These arguments and the attempt to provide an answer to the questions, prompted us to conduct an analytical evaluation of the most recent data in the literature. We present the following article in accordance with the PRISMA-ScR reporting checklist (available at https://asj.amegroups.com/article/view/10.21037/asj-22-2/rc).

Methods

The search carried out using a combination of words, relevant Medical Subject Headings (MeSH) terms and appropriate filters; the strategy was developed in MEDLINE (via PubMed) between 2016 and 2020. We used as search terms: “¹⁸F-FDG PET/CT AND evaluation AND solitary pulmonary nodule”. Based on the eligibility criteria (articles in English that report data relating to sensitivity, specificity and diagnostic accuracy of the ¹⁸F-FDG PET/CT in the evaluation of pulmonary nodules), the studies were evaluated by two independent authors who also analyzed the literature and assessed the dissimilarities; any biases were discussed and resolved. A flow chart was created with the included and excluded items. The experiences that contained overlapping data were discussed. Any discrepancies were resolved by consensus after extensive discussion. The following elements were extracted from each study, if available: first author surname, year of publication, sensitivity (%), specificity (%) and diagnostic accuracy (%). In the analysis the characteristics of the patients were not considered but only those of the nodules. Furthermore, we only entered the data relating to solid pulmonary nodules not considering subsolid nodules or pure ground glass since they have different problems compared to the solid nodule as regards the role of PET/CT. Data extrapolated from the selected articles were inserted in a calculation software that allowed us to more easily evaluate the individual parameters both independently and as a function of the variations of the others. We focused on the impact of the number of procedures and on sensitivity and specificity values.

Results

One hundred and eight results were found and, after removing the duplicates and non-English articles, 100 articles were identified. After reading the abstract, 68 studies out of 108 were excluded because of irrelevance. Of the remaining 40 articles, only 10 (7-16) were considered relevant after evaluating the content of the full text and included in the data analysis (Figure 1). Information on 3,324 patients undergoing to ¹⁸F-FDG-PET/CT leaded the choice of the following parameters (Table 1): (I) sensitivity, ranged from 77.05% and 98.00%; (II) specificity, ranged from 23.40% and 98.35%; (III) diagnostic accuracy, ranged from 79.20% and 84.00%. Extreme values (maximum and minimum) were not considered statistically relevant. Instead, we considered the system of curves of the respective values; ¹⁸F-FDG-PET/CT shows limits in terms of specificity on larger cohorts, going from 85.00% on a sample of 50 patients to 39.80% on a sample of 1,188 patients. On the other hand, sensitivity remains constantly high and without significant variations. In fact, on 50 patients it stands at values equal to 84.00% while in the largest cohort it is equal to 90.10% (Figure 1). Furthermore, sorting the parameters according to the year of publication of the relative studies no statistically significant data were noticed (Figure 2). In fact, in order to obtain a statistical evaluation on homogeneous data we focused on the values of specificity and sensitivity in relation to the number of non-small cell lung cancer (NSCLC) patients. Others parameters studied in several articles contributed to a heterogeneity of the research and therefore were not included to reduce the statistical bias that make the analysis ineffective. In the large study groups, the specificity of ¹⁸F-FDG PET/CT is extremely low (Figure 3); these data were even more evident when we extrapolated the respective linear curves (Figure 4).

Figure 1 Flow chart of the selected articles.

Figure 2 Graph with curves relating to the studies ordered according to the year of publication.

Figure 3 Graph with curves relating to the studies ordered according to the number of patients.

Figure 4 Linear value curves. Black lines are linear representation of average values.

Discussion

The ¹⁸F-FDG PET/CT has become prominent as a method of SPN evaluation in recent years although its usefulness is unclear. In fact, what is the use of knowing if a patient has increased metabolic activity of lesion suspected for lung cancer when a pulmonary nodule that persists on CT control at 3–6 months is a priority surgical indication? In this situation, the study of the mediastinum through a preoperative “endobronchial ultrasound” is also indicated and, in case of resection of diagnosed bronchogenic carcinoma, systematic nodal dissection is recommended (17,18). Many authors argue that ¹⁸F-FDG-PET/CT provides reliable information especially in nodules with dimensions >12 mm (19-21) but the studies are often in conflict due to the lack of uniformity of the data (22,23). On the basis of recent studies, we did not consider it appropriate to refer to the role of ¹⁸F-FDG-PET/CT in the evaluation of subsolid nodules as, in this context, it has little use (24). Suh et al. (25) analyzed retrospectively 855 patients with NSCLC which radiologically showed itself as subsolid nodules with a solid component equal to or less than 3 cm. Comparing the preoperatory data with the postoperative ones, the ¹⁸F-FDG-PET/CT displayed several limits in the diagnosis and lymph node staging, obtaining a low positive sensitivity and predictive value, equal to 44% and 9.6% respectively. Ruilong et al. (26) performed a meta-analysis starting from 356 articles and obtaining useful results only on 12 of these. Authors noticed a high sensitivity and specificity, equal to 82% and 81% respectively, but underlining the wide range of specificity with values between 58% and 100%. Consequently, must be reconsidered the role of ¹⁸F-FDG-PET/CT in the diagnostic process of the pulmonary nodule in the light of the most recent scientific evidences and above all on sufficiently numerous study groups. A recent meta-analysis by Li et al. (27), aimed at quantifying sensitivity and specificity out of 21 studies and a total of 1,557 pulmonary nodule patients, showed unsatisfactory sensitivity and specificity values of ¹⁸F-FDG-PET/CT, 0.89 [95% confidence interval (CI): 0.87–0.91] and 0.70 (95% CI: 0.66–0.73) respectively. Furthermore, Authors underlined that tendency to give false negatives does not allow it to be considered a substitute for biopsy. Similarly, our analysis showed that studies with a large number of patients enrolled provide reliable results. In addition, we experienced that extreme values of the parameters considered do not provide precise indications on the usefulness of this imaging technique and therefore have no statistical significance. In order to obtain a correct interpretation of data, it is necessary to enter into the system all available values by determining the creation of the respective curves. The calculation software allowed us to plot the curves of the relative parameters on a graph and the lack of homogeneity of the data emerged if considered findings by publication chronology. On the contrary, by plotting the curves with the data ordered according to the number of patients enrolled, the interesting limits of ¹⁸F-FDG-PET/CT have highlighted. In fact, we noted high values of specificity only in studies with a smaller sample (in the large study groups specificity decreased constantly) while high levels of sensitivity were confirmed regardless the number of patients. We think that patient selection and data heterogeneity represent important biases in statistical analysis of results. Therefore, it is necessary to study large samples, for statistically homogenize data and reduce the interpretation errors. Anyway, evidences suggest that biopsy is still mandatory today in the characterization of lung lesions; ¹⁸F-FDG-PET/CT may have a role in directing biopsy sampling more precisely and improving the diagnostic accuracy than CT alone (28).

Conclusions

¹⁸F-FDG-PET/CT certainly represents a valid tool in the evaluation of pulmonary nodules. However, having considerable specificity limits it is necessary to carefully clean and homologate the data to acquire reliable results. Hence, it is an excellent integrative tool in the diagnostic process but cannot replace biopsy until will be demonstrated a valid correlation between SUVmax and the histological type of the lesion.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Surgical Journal for the series “Solitary Pulmonary Nodule”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://asj.amegroups.com/article/view/10.21037/asj-22-2/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-22-2/coif). The series “Solitary Pulmonary Nodule” was commissioned by the editorial office without any funding or sponsorship. DD served as an unpaid Guest Editor of the series and serves as an unpaid editorial board member of AME Surgical Journal from January 2021 to December 2024. RC served as an unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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