Efficiency of Positron Emission Tomography with 18F-Fluorodeoxyglucose, 11С-Methionine and 82Rb-Chloride in Differential Diagnosis of Lung Tumors and Some Inflammatory Pulmonary Diseases

Currently, positron emission tomography (PET) is one of compulsory diagnostic procedures performed in patients with malignant tumors of any localization including pulmonary cancer (PC). It is due to both: high informational content of PET in most oncological diseases, and the introduction of new radioactive preparations (RP). These drugs are biological compounds labeled with positron-emitting radionuclides, which are able to accumulate in some morphological structures and reflect metabolic and dynamic processes. ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG) is currently the most extensively studied and widely used in oncology clinics RP of cyclotron production type. An indubitable advantage of this indicator is relatively large (110 min) half-life period that enables to scan in “the whole body” mode, as well as its capacity to accumulate in an increased amount in malignant tumors. ¹⁸F-FDG accumulation in malignant neoplasms is due to two main reasons: increase in the amount of transport proteins delivering RP in an atypical cell and activity rise of hexokinse catalyzing phosphorylation — the change from administered ¹⁸F-FDG to ¹⁸F-FDG-6-phosphate. The resulting molecule due to its large size and low activity of the following enzyme of glycolytic cascade — phosphohexoisomerase, and falls into a so-called metabolic trap, which promotes imaging of the most malignancies and their metastases as “hot” foci against healthy tissues. However, it is important to note that pathological hyperfixation of RP in pulmonary neoplasm is not always a radiological sign of a malignant process. Sometimes, ¹⁸F-FDG accumulation marks inflammatory changes [1–3]. It occurs, primarily, due to a significant increase of glucose transport proteins, as well as the accumulation of macrophages, neutrophils, eosinophils, granulocytes and other blood corpuscles, which are accumulator-cells, in the area of active inflammation. This property of ¹⁸F-FDG is certainly to restrain PET feasibility in differential diagnosis between PC and inflammatory diseases. In benign tumors, as well as in the area of cicatrical changes, ¹⁸F-FDG metabolic changes do not differ from glycolytic reactions in healthy pulmonary parenchyma. Accordingly, there is no an increased ¹⁸F-FDG scavenging in these diseases being a reliable differential diagnostic sign that makes it possible in PET with ¹⁸F-FDG to differentiate PC, benign tumors and local pulmonary fibrosis.

In literature there are few reports on using another RP in patients with PC — carbon 11 labeled methionine (¹¹С-methionine) [4, 5]. It is important to note that over a number of years this indicator is used for differential diagnosis and treatment efficiency assessment of various brain tumors. However, ¹¹С-methionine is rarely used to detect extracerebral tumors. This is due to the fact that in norm this RP accumulates mainly in internal secretion glands and excretory glands, as well as in bone marrow and spleen. It presents certain problems when estimating tumor extension in cancer patients. Moreover, a short half-life period of ¹¹С (20 min), and, consequently, the problems arising from transporting of the indicator to other laboratories, prevent from its extensive use in isotope facilities with no cyclotron complex.

In its physicochemical properties methionine is a typical aliphatic sulfur-containing amino acid. In norm, after the agent enters blood flow, carrier proteins deliver it inside the cells, where mobile methyl group of amino acid is embedded into purine and pyrimidine bases of DNA molecule. When a normal cell transforms into a malignant one, as a rule, methylation is accompanied by numerous defects resulting in constant methionine deficiency. It is constant demand of atypical cells for methionine that leads to intensive uptake of amino acid exogenous fraction by different malignant tumors [6]. On the other hand, in literature there is information that ¹¹С-methionine, like ¹⁸F-FDG accumulates not only in malignant tumors but also in inflammation area [4]. Despite this fact, in literature one can find reports on higher informativeness of ¹¹С-methionine-PET in differentiation between PC and inflammatory diseases compared to ¹⁸F-FDG. However, it should be said that literature data on applying ¹¹С-methionine-PET in patients with pulmonary masses of uncertain origin date mainly from the middle of the 90-ies and contain the information on the results of studies carried out in small groups of patients, who frequently had received anti-tumor treatment. In this regard, currently, the role of ¹¹С-methionine-PET in the diagnosis of PC and inflammatory diseases needs elaboration.

Single foreign publications represent data on malignant tumor detection by PET with a generator radiotracer — rubidium-82 chloride (⁸²Rb-chloride). It should be said that this radiotracer is used in cardiology to assess myocardial regional blood flow condition. Meanwhile, some authors performed ⁸²Rb-chloride-PET in patients with cardiovascular pathology report about the accidental detection of malignant pulmonary tumors, breast cancer and other tumors fallen within scanning area [7–9]. Moreover, the researchers note adequate imaging of the masses detected. Currently, there are no reports both in foreign and Russian literature on unequivocal use of ⁸²Rb-chloride in cancer patients.

⁸²Rb-chloride is a normal saline containing nuclide ion ⁸²Rb. By its physicochemical and biological properties ion ⁸²Rb is an analogue of ion К⁺. A well known thallium-201 (²⁰¹Tl) used for perfusion myocardial scintigraphy has similar characteristics. When injected intravenously, ⁸²Rb-chloride, by analogy with ²⁰¹Tl, is brought by blood flow to organs and tissues, where it is distributed in proportion to flow rate of regional capillary blood flow, as well as to the activity of sodium-potassium ATP-dependent pump. The mechanism of ⁸²Rb-chloride uptake by malignant cells has not been identified yet. There has been only suggested that rubidium, by analogy with ²⁰¹Tl, can come through membrane of atypical cells providing increased RP accumulation in a malignant tumor, and therefore, its imaging against healthy tissues as a “hot” focus [10].

The current study generalizes the experience of PET with the three above mentioned RP over the period 2011–2014 on the basis of Russian Research Center of Radiology and Surgical Technologies, and with direct participation of several pulmonary and oncology clinics in S. Petersburg.

The aim of the investigation was to study the informativeness ofpositron emission tomography using ¹⁸F-FDG, ¹¹С-methionine and ⁸²Rb-chloride in differential diagnosis of tumor and some inflammatory pulmonary diseases.

Materials and Methods. Chest PET with ¹⁸F-FDG, ⁸²Rb-chloride and ¹¹С-methionine was performed in 378 patients with lung tumors and inflammatory pulmonary diseases. In addition to PET, diagnostic examination of patients included bacteriological analysis of sputum or epithelial lining fluid, diaskintest, serological and polymerase chain reaction of blood plasma components to reveal antigens and DNA of Mycobacterium tuberculosis, as well as fibrobronchoscopy, radiography and computed tomography (CT) of chest. In 332 patients (87.8%) a final diagnosis was made relying on cytological and/or morphological analysis. The rest cases were assessed according to dynamic radiological control findings. Table 1 shows the classification of patients depending on a final diagnosis and RP used.

Table 1. Study design (n=378)

The study complies with the declaration of Helsinki (adopted in June, 1964 (Helsinki, Finland) and revised in October, 2000 (Edinburg, Scotland)) and approved by the Ethics Committee of Russian Research Center of Radiology and Surgical Technologies. Written informed consent was obtained from all patients.

In accordance with a standard program, PET with ¹⁸F-FDG and ¹¹С-methionine were performed 120 and 15 min, respectively, after their intravenous administration; ⁸²Rb-chloride-PET was performed 1 min after distant intravenous administration. Quantitative processing of PET findings regardless RP used included visual image analysis and calculation of Standardized Uptake Value (SUV) in healthy pulmonary parenchyma and in lesion.

The findings were statistically processed using MedCalc 11.0.1 for Windows. In addition, we used parametric and nonparametric techniques including estimated mean (M), mean error (m). Critical significance level of a zero statistical hypothesis was taken equal to 0.05. Sensitivity, specificity, diagnostic accuracy, positive and negative prognostic value were determined using characteristic curve analysis (Receiver Operating Characteristic, ROC). In addition, SUV were cut-off values or numeral classifiers.

Results. Image analysis of tomograms obtained by using ¹⁸F-FDG showed pathological RP uptake in all patients with PC and the patients with inflammatory diseases. No increased accumulation of ¹⁸F–FDG was found in pulmonary benign tumors. No RP accumulation was also recorded in 3 out of 7 patients with neuro-endocrine tumors (NET) and in 7 out of 14 patients with post-tuberculosis pneumofibrosis.

⁸²Rb-chloride-PET revealed foci of increased RP accumulation in the lung in 45 out of 80 patients. In 26 cases the changes were due to PC, in 2 cases — due to NET, in 17 — active tuberculosis. There was recorded no pathological ⁸²Rb-chloride hyperfixation in all patients with benign pulmonary tumors and focal pneumofibrosis, in 3 PC patients, as well as in 4 cases of infiltrative tuberculosis.

Visual analysis of tomoscintigrams taken by chest scanning using ¹¹С-methionine showed foci of pathological RP accumulation in all patients with PC and NET, in 31 out of 35 patients with inflammatory diseases, as well as in 2 out of 7 cases of focal pneumofibrosis. The rest patients were recorded to have background (consistent with intact pulmonary parenchyma) RP distribution in the tumor view. No signs of focal uptake were revealed.

Analysis of SUV recorded in patients with pulmonary tumors and inflammatory diseases detected by PET with focal RP uptake (Table 2) showed SUV recorded in PET with ¹⁸F-FDG and ¹¹С-methionine to be significantly higher in patients with PC than in patients with inflammatory diseases and focal pneumofibrosis (p≤0.05). In addition, ⁸²Rb-chloride-PET showed the opposite results: SUV above the inflammatory foci had significantly higher metabolic activity than those recorded in malignant pulmonary tumors (p=0.0012). ¹⁸F-FDG-PET in patients with NET demonstrated significantly lower SUV than in patients with PC (p=0.0026). However, SUV levels in NET patients did not differ from metabolic activity in foci of inflammation (p=0.1941). Similar findings were obtained in the study with ¹¹С-methionine in patients with PC and NET. The comparison of SUV levels in these patients showed no significant differences (p=0.1341).

Table 2. SUV levels recorded in patients with pulmonary tumors and inflammatory diseases in PET with 18F-FDG, 82Rb-chloride and 11С-methionine manifested by focal RP uptake (M±m)

Thus, imaging findings, as well as the results of comparing mean SUV calculated in PET with ¹⁸F-FDG, ¹¹С-methionine and ⁸²Rb-chloride indicated similar semiotic manifestations and quantitative characteristics in patients with pulmonary tumors and pulmonary inflammatory diseases. In this regard, we performed ROC analysis to determine numerical differential diagnostic criteria, as well as to calculate PET informativeness. Threshold SUV and informativeness of PET with ¹⁸F-FDG, ⁸²Rb-chloride and ¹¹С-methionine in differential diagnosis of pulmonary tumors and inflammatory diseases (Table 3) indicate that maximum values of diagnostic accuracy of PET in differential diagnosis of pulmonary tumor and inflammatory diseases were found in ¹¹С-methionine-PET. And specificity values in ¹⁸F-FDG and ¹¹С-methionine-PET were comparable. Informativeness indices in differentiation of malignant and inflammatory changes in the lungs using ⁸²Rb-chloride-PET were significantly lower than those obtained in ¹⁸F-FDG and ¹¹С-methionine-PET.

Table 3. Threshold SUV and informativeness of PET with 18F-FDG, 82Rb-chloride and 11С-methionine in differential diagnosis of pulmonary tumor and inflammatory diseases, %

Discussion. Currently, ¹⁸F-FDG-PET is widely used in patients with pulmonary masses of uncertain origin. The main advantage of the technique is the possibility to perform differential diagnosis of malignant and benign pulmonary tumors, as well as determine the stage of a tumor process in patients with verified PC. However, despite a long-term experience of using ¹⁸F-FDG-PET in such patients, it would be incorrect to consider the problem of differentiation of PC and inflammatory disease to be resolved. Unfortunately, ¹⁸F-FDG-PET shows malignant and inflammatory processes in the ling as equally increased RP accumulation. So, the search and introduction of more specific radiotracers are required.

For that purpose we compared informativeness of PET performed with a widely used ¹⁸F-FDG with the efficiency of the method using other tracers: ¹¹С-methionine and ⁸²Rb-chloride. The results of visual analysis of PET with ¹⁸F-FDG, ¹¹С-methionine and ⁸²Rb-chloride indicated similar semiotic manifestations of pulmonary tumor and inflammatory diseases. In patients with benign tumors and the most patients with focal pneumofibrosis there was recorded background RP distribution in the pulmonary tissue consolidation area. It enabled to classify reliably benign tumors and focal pneumofibrosis from PC regardless of RP used. However, in PET with ¹⁸F-FDG, ¹¹С-methionine and ⁸²Rb-chloride the most patients with inflammatory diseases, as well as the patients with malignant pulmonary tumors had RP accumulation of different intensity degree in the tumor area. The comparison of SUV levels in patients with PC and inflammatory diseases revealed significant differences between metabolic activity indices using all the tracers under study. SUV were higher than metabolic activity in the inflammation area in PET with ¹⁸F-FDG and ¹¹С-methionine in PC patients. On ⁸²Rb-chloride-PET, SUV levels in inflammatory foci were significantly higher than in malignant tumors. In addition, despite the stated significant differences between SUV levels in patients with PC and inflammatory diseases, and good imaging of pathological masses on ⁸²Rb-chloride-PET, informativeness indices indicated inadequate differential and diagnostic properties of this radiotracer.

The results of ¹⁸F-FDG-PET and ¹¹С-methionine-PET comparison appeared to be more satisfactory. On ¹⁸F-FDG-PET in 3 out of 7 patients with typical pulmonary carcinoids there were recorded no increased accumulation of RP in tumor, i.e. we received false-negative results. Moreover, on ¹¹С-methionine-PET in all patients with NET, RP accumulation was observed in pathological mass of the lung that helped to diagnose a malignant tumor. In addition, on ¹¹С-methionine-PET compared to ¹⁸F-FDG-PET in 4 tuberculosis patients the process in the lung was correctly estimated as inflammatory changes due to the lack of increased RP accumulation in the tumor area. ROC-analysis of ¹¹С-methionine-PET findings enabled to state that the highest informativeness indices in differentiation between pulmonary tumors and pulmonary inflammatory diseases were recorded when using this radiotracer.

Conclusion. The findings on informativeness of positron emission tomography using ¹¹С-methionine suggest high diagnostic accuracy of the technique in differential diagnosis of pulmonary cancer, neuro-endocrine tumors, benign tumors and inflammatory diseases. ⁸²Rb-chloride-PET in spite of good imaging possibilities is unreasonable to use for differentiating pulmonary tumors from pulmonary inflammatory diseases.

Study Funding and Conflict of Interests. The study was not supported by any funds, and the authors have no conflict of interest to disclose.