Integrated positron emission tomography and computed tomography (PET-CT) performed with fluorine-18-fluorodeoxyglucose (18F-FDG) is used to visualize glucose metabolism in living human tissues. Given its high sensitivity in detection of malignancy, 18F-FDG PET-CT is increasingly used in the evaluation of patients with suspected or proven lung cancer,1 both for the primary diagnosis and tumor, node, and metastasis (TNM) classification and for restaging of the disease.2
However, 18F-FDG uptake is not specific for malignancy.3 Inflammatory and infectious diseases can also exhibit 18F-FDG uptake, for example, active granulomatous diseases including tuberculosis or sarcoidosis.4 Also, inflammatory lesions related to surgery or radiotherapy5 associated with wound repair and resorption of necrotic debris and hematoma6 can exhibit 18F-FDG uptake.7,8 The inflammatory response of regional lymph nodes to infection or recent instrumentation can result in elevated 18F-FDG uptake in noncancerous lymph nodes.9 Also interventions, for example, surgery, biopsy, mediastinoscopy, or percutaneous endoscopic gastrostomy, have been described to produce a moderate 18F-FDG uptake.10,11
In patients with suspected or proven lung cancer, PET-CT is normally performed before the invasive procedures with biopsies, for example, flexible bronchoscopy, transthoracic needle aspiration biopsy, endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA), or endoscopic ultrasound–guided fine needle aspiration (EUS-FNA). This order is preferred of 2 reasons. First, PET-CT can guide the clinician as regards to where the biopsies should be taken. Second, the order should prevent false-positive results induced by the invasive procedures. However, the theory that these procedures lead to false-positive PET results is to our knowledge not based on certain evidence.
We experienced that patients in a number of cases had to wait for PET-CT till after the invasive procedures, due to logistic and technical reasons, and we took advantage of this unintended order to assess the theory. For simplicity, we have chosen to only look at the biopsies performed with EBUS from mediastinal lymph nodes (MLNs).
This study investigated the following clinical problem: how often is an EBUS biopsy from a nonmalignant MLN followed by a false-positive result on PET-CT.
We retrospectively searched electronic databases of our 2 hospitals for all patients admitted in the time period of January 2009 to December 2014, with suspected or proven lung cancer and with an indication of invasive pulmonary diagnostic procedures with biopsy. We only looked at data from patients who had done an invasive pulmonary procedure 1 to 13 days before PET-CT. Subsequently, we excluded patients who underwent procedures other than EBUS with biopsy from MLNs. Thus, only patients who had at least 1 nonmalignant MLN biopsied by EBUS 1 to 13 days before PET-CT were included. We then reviewed all nonmalignant MLNs in included patients by looking at the EBUS-TBNA cytology result and the following PET-CT scan. The number of false-positive and true-negative results shortly after EBUS-TBNA of nonmalignant MLNs was found (Fig. 1). Our standard procedure is to do a follow-up of PET-positive MLNs with an invasive procedure and/or image-guided follow-up. Therefore, we also conducted a follow-up on the PET-positive MLNs with a review of all the medical records and pathology results to confirm that the false-positive MLNs were true benign.
The interpretation of the PET scan was based on expert visual interpretation (EVI) from the nuclear medicine specialist. “No 18F-FDG uptake” was defined as no increased metabolic activity in the MLN on the PET scan.
On the basis of the indication, the following invasive pulmonary procedure was carried out: EBUS-TBNA was performed with a flexible EBUS scope using a convex probe with frequency of 7.5 MHz (Olympus XBF-UC40P or Pentax EB-1970UK) and the needle aspiration biopsies were performed with a 22-G needle from either Olympus or Medi-Globe, respectively. The EBUS-TBNA included at least 2 needle passes per lymph node station.
Images were obtained with a Phillips Gemini TF PET-CT scanner in the Department of Nuclear Medicine, Gentofte University Hospital and the Department of Nuclear Medicine, Bispebjerg University Hospital, Denmark. After 6 hours of fasting, 3.5 MBq/kg body weight, maximum 525 MBq at Gentofte University Hospital and 200 MBq at Bispebjerg University Hospital of 18F-FDG was given intravenously. Following an hour of rest, the patient was scanned from the head to the upper thigh on an integrated PET-CT system.
The study is a retrospective observational study that has been performed in accordance with the Regional Scientific Ethical Committees’ standards of the Capital Region (Region H) of Denmark. An approval was not required.
A total of 1025 patients were reviewed for the trial; 809 were excluded because the PET-CT was conducted before the invasive procedure. This leaves 216 patients, who were referred for PET-CT 1 to 13 days after an invasive pulmonary procedure with biopsy. Of these, we excluded another 107 patients as they underwent invasive procedures other than EBUS, for example, flexible bronchoscopy, transthoracic needle aspiration biopsy, or EUS-FNA of the left adrenal gland (Fig. 1). Two others were excluded as they were biopsied from other lymph nodes than MLN. The remaining 107 patients had at least 1 nonmalignant MLN biopsied. This cohort underwent a total of 198 MLN biopsies with the finding of nonmalignant tissue considered representative for the target biopsied. Of these, 76 (38%) were with 18F-FDG uptake (PET positive) and 122 (62%) were without 18F-FDG uptake (PET negative), as shown in Table 1. Out of the 76 PET-positive lymph nodes, 10 were most likely positive as a result of infection, or due to an inflammatory disorder (Table 2). For the remaining 66, the further cytologic follow-up showed that only 28 MLNs (14%) were true benign. This result was found by either further investigation with EUS, repetition of EBUS, mediastinoscopy, or lobectomy. In 29 MLNs (15%) cytologic follow-up was not available. With few exceptions, these patients were referred directly to the oncology department for treatment, and in some cases for lobectomy, because malignancy was found in other biopsies. We found malignancy in 2 MLNs (1%) at the follow-up (EBUS biopsy and lobectomy) and in the remaining 7 MLNs (3%), the data were not available in the electronic databases. Basically, this means that for the 14% PET-positive MLNs, we have no other reasonable explanation than the possibility that it was caused by the biopsy (Table 3).
The mean time (M±SD) from EBUS-TBNA to PET-CT was 4.5±2.9 days. Up to 3 EBUS-TBNA biopsies per lymph node were performed.
The mean size (M±SD) of PET-positive and PET-negative MLNs were 9.1±4.7 and 10.6±5.7 mm, respectively (Table 1).
PET-CT scan with 18F-FDG is an important imaging technique in the diagnosis and staging of suspected and proven lung cancer. However, it is important to be aware of the risk of false-positive findings,5,12 as nonmalignant conditions can mimic malignancy. Inflammatory cells, such as neutrophils and activated macrophages, at the side of inflammation or infection can show increased FDG accumulation.7 This is also the case for active granulomatous and infectious diseases.12,13 It has been suggested that approximately a quarter of the FDG concentration in a tumor mass is derived from nontumor tissue.14
In our study, we found a majority of PET-negative results shortly after EBUS biopsy of MLNs. In several patients, multiple cytologic biopsies (up to 3) were performed without the finding of metabolic activity at the site in question by the subsequent PET. The mean time interval to PET was relatively short (4.5 d),15 which can also be considered as a strength of the study.
The main findings are that only 14% of MLNs were false PET positive and true pathologically benign at our follow-up of the patients up to 4 weeks after the procedure. This observation could be explained by some inflammatory activity in the MLN, triggered by the EBUS biopsy.
These findings have clinical importance, as they indicate that the nuclear medicine physicians cannot be sure that an EBUS biopsy is always followed by a PET-positive result. Misinterpretations can be avoided with careful attention to technical factors and with the knowledge of the complete clinical history of the patient.
We used nuclear medicine physicians’ interpretations (EVI) of PET scans rather than SUV values, as a recent study showed that objective 18F-FDG PET-CT criteria based on SUV values does not outperform EVI, which can classify mediastinal lymphadenopathy with high accuracy.16
A limitation of our study may, however, be that the MLNs biopsied by EBUS-TBNA in several cases were quite small [size 9.1±4.7 mm (M±SD)], as shown in Table 1. It is possible that lymph nodes below 10 mm should be hypermetabolic to be visualized on PET-CT.5 Therefore, it could be speculated that the biopsy might have been able to induce metabolic activity in these lymph nodes, if they had been larger. Against this theory speaks that PET can detect metastatic disease in lymph nodes <1 cm in size with a sensitivity and specificity of 80% and 95%, respectively.17 Also, we must bear in mind that several lymph nodes were larger than this (Table 1). It is not proved whether there is a correlation between the size of a MLN and the risk for inducing metabolic activity with a biopsy.
In summary, our study demonstrates that EBUS-TBNA with biopsy do not necessarily result in metabolic activity. In our cohort of MLN biopsies, we found that biopsy lead to a false-positive PET result in only 14% of the cases. Therefore, PET-positive results should always be taken seriously, even when PET is performed shortly after biopsies.
1. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer
with combined PET-CT. N Engl J Med. 2009;361:32–39.
2. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer
: diagnosis and management of lung cancer
, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl):e211S–e2150.
3. Culverwell AD, Scarsbrook AF, Chowdhury FU. False-positive uptake on 2-[18
F]-fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography/computed tomography (PET/CT) in oncological imaging. Clin Radiol. 2011;66:366–382.
4. Gorospe L, Raman S, Echeveste J, et al. Whole-body PET/CT: spectrum of physiological variants, artifacts and interpretative pitfalls in cancer patients. Nucl Med Commun. 2005;26:671–687.
5. Griffeth LK. Use of PET/CT scanning in cancer patients: technical and practical considerations. Proc (Bayl Univ Med Cent). 2005;18:321–330.
6. Schlüter B, Grimm-Riepe C, Beyer W, et al. Histological verification of positive fluorine-18 fluorodeoxyglucose findings in patients with differentiated thyroid cancer. Langenbecks Arch Surg. 1998;383:187–189.
7. Kubota K, Matsuzawa T, Fujiwara T, et al. Differential diagnosis of lung tumor with positron emission tomography: a prospective study. J Nucl Med. 1990;31:1927–1932.
8. Kobayashi K, Bhargava P, Raja S, et al. Image-guided biopsy
: what the interventional radiologist needs to know about PET/CT. Radiographics. 2012;32:1483–1501.
9. Alavi A, Gupta N, Alberini J-L, et al. Positron emission tomography imaging in nonmalignant thoracic disorders. Semin Nucl Med. 2002;32:293–321.
10. Rosenbaum SJ, Lind T, Antoch G, et al. False-positive FDG PET uptake—the role of PET/CT. Eur Radiol. 2006;16:1054–1065.
11. Finger PT, Kurli M, Reddy S, et al. Whole body PET/CT for initial staging of choroidal melanoma. Br J Ophthalmol. 2005;89:1270–1274.
12. Chang JM, Lee HJ, Goo JM, et al. False positive and false negative FDG-PET scans in various thoracic diseases. Korean J Radiol. 2006;7:57–69.
13. Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics. 1999;19:61–77; quiz 150–151.
14. Bunyaviroch T, Coleman RE. PET evaluation of lung cancer
. J Nucl Med. 2006;47:451–469.
15. Hung GU, Shiau YC, Tsai SC, et al. Differentiation of radiographically indeterminate solitary pulmonary nodules with. Jpn J Clin Oncol. 2001;31:51–54.
16. Nguyen P, Bhatt M, Bashirzadeh F, et al. Comparison of objective criteria and expert visual interpretation to classify benign and malignant hilar and mediastinal nodes on 18-F FDG PET/CT. Respirology. 2015;20:129–137.
17. Schmidt-Hansen M, Baldwin DR, Hasler E, et al. PET-CT for assessing mediastinal lymph node
involvement in patients with suspected resectable non-small cell lung cancer
. Cochrane Database Syst Rev. 2014;11:CD009519.