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Solitary pulmonary nodule (SPN) is frequently encountered in the clinical imaging but judgment of benign or malignant nature is still a critical issue even if PET/CT has obvious advantage in tumor diagnosis. The varied CT edge signs and diverse FDG uptake reflected upon the nodule by PET/CT all affect diagnosis to some extent. However, is there relevance between edge signs and FDG uptake and what essence it reflected from relevance have not aroused the wide attention, despite quite important. Based on the PET/CT imaging, we compared positive edge signs of solitary malignant pulmonary nodule with its FDG uptake in corresponding regions by restrospective comparative sudy to analyze if there is different FDG distributed in varying edge sign region.
Materials and Methods
Collected 50 cases of SMPN confirmed by pathology who all performed PET/CT scan since January 2011. All images were retrospectively analyzed by 2 PET/CT diagnostic physicians who didn’t be told the pathological result. The selected cases criteria was made as follows: 1) solitary malignant pulmonary nodule in peripheral lung fields; 2) the diameter of nodule ranging from 1.5cm to 5.0cm; 3) nodule with ≥2 edge signs.
All patients were performed on an 64-slice Siemens Discovery LS PET/CT
scanner (LSO crystal, Siemens, GER) routinely. 18F-FDG was injected
with a radiochemistry purity of >95%. The patients fasted for ≥6 hours before the examination. After the injection of 0.15mCi/kg 18F-FDG, the patients rested for 45 to 60 minutes before PET/CT scan. The following scan parameters were used: body CT voltage 120 kV, current 140 mA, pitch 5.0mm, tube rotation time 0.8 s, and thickness 4.25 mm. Images were collected in 2D mode, 3 minutes for each bed position for a mean of 5 to 7 positions. The PET images were calibrated for attenuation correction. Image reconstruction was done by ordered-subsets expectation maximization, with 2
iterations, 8 iteration subsets, and 4.25 mm thickness. Analysis was focused on cross section. Image fusion was performed on an Xeleris work station. After finishing the whole body PET/CT scan, additional thin-section CT scan targeting the SPN were adopted, slice thickness 0.25mm, to acquire PET and thin-section CT fusion images to display the edge signs and FDG uptake in corresponding area.
1. Establishment of diagnostic criteria of edge signs
Edge signs included spiculated sign, lobulated sign, pleural traction sign and vessel convergence sign. 1) spiculated sign: the tumor surface is not smooth, forming stinging, pick-like or thorn-like structure processing the nodule’s surface; 2) lobulated sign: the tumor’s surface is not flat, forming nipple - shaped or petal-shaped protuberance; 3) pleural traction sign: at the outer side of nodule, peripheral pleural form V–shaped, umbellate or triangular structure as tumor’s traction; 4ï¼‰ vessel convergence sign: at the inner side of nodule, theperipheral bronchovascular bundles aggregate into parenchyma of nodule.
2. Definition of region of interest (ROI) at nodule’s edge signs area
For spiculated sign, selected basal part where protrude stinging or prickly structure as the interest region; For lobulated sign, selected the most obvious round projection as the interest region; For pleural traction sign, selected the most central basal area where pulled peripheral pleural at the nodule’s outer side as the interest region; For vessel convergence sign, selected the most central basal area where concentrated vascular bundle as the interest region.
Diagram 1 illustrated ROI of edge signs of nodule.
S: represent ROI of spiculated sign area; P: represent ROI of pleural traction sign area; L: represent ROI of lobulated sign area; V: represents ROI of vessel convergence sign area.
3. Measurement of FDG uptake at ROI.
FDG uptake at measuring area were taken the diameter of 1 cm as the region of interest (ROI), automatically measuring the value of SUVave and SUVmax of ROI on PET/CT workstation.
50 cases of SPNs’ average and maximum FDG value on edge signs area, overall size and average FDG value were listed in table 1. And used the statistical software (SAS8.0) for analyzing if there was difference of FDG uptake in different ROI at nodule’s edge signs area.
The FDG uptake values of different ROI at nodule’s edge signs area were concluded after variance analysis ï¼ˆGLM procedureï¼‰and mean comparison between each 2 groups (DUNCAN method) . SUVave in lobulated sign , spiculated sign, pleural traction sign and vessel convergence sign area were 6.87 ± 3.29, 5.02 ± 3.93, 4.42 ± 2.04 and 6.37±3.93 respectively (p<0.05); SUVmax in lobulated sign , spiculated sign, pleural traction sign and vessel convergence sign area were 8.33±3.98, 5.86±3.44, 5.40±2.45 and 7.77±5.22 respectively (p<0.05). Except SUVave uptake in area of lobulated sign and vessel convergence sign has no obvious difference, while difference exist in SUVmax value; SUVave and SUVmax value in lobulated sign and vessel convergence sign were significantly higher than that of spiculated sign and pleural traction sign, and SUVave and SUVmax value in pleural traction sign were lowest. SUV uptake decreased in sequence of lobulated sign, vessel convergence sign , spiculated sign and pleural traction sign .
Analyzing edge signs of SPN in CT imaging is important before advent of combined PET/CT, and some edge signs are helpful, even essential to discriminate benign or malignant properties [1-2]. Lobulated sign, spiculated sign, pleural traction sign and vessel convergence sign are often used imaging diagnosis up to now. However such signs do not exist in malignant nodules exclusively and the overlap still exists in inflamatory nodule such as tuberculosis granuloma to a certain degree. Even though integrated PET/CT afford more advantages in differentiating nature of tumor [3-5], the mechanism that varying level of FDG uptake exist in same tumor has not yet been clarified.
According to the statistic results, FDG uptake level of ROI areas at nodule’s edge signs decreased in sequence of lobulated sign, vessel convergence sign, spiculated sign and pleural traction sign. FDG uptake value of ROI areas at lobulated sign and vessel convergence sign were greater higher than the other two edge signs area. FDG uptake varying at different areas suggests heterogeneousgrowth in the same malignant tissue.
Lobulated sign, which formed round process out of the tumor’s contour due to rapid growth locally, reflects proliferative growth of tumor’s behaviour on CT image; spiculated sign, pleural traction sign and vessel convergence sign which reveal tumor invading interlobular septum , tracheal vascular bundle and pleura along interstitials respectively reflect infiltrative growth of tumor on CT image. The phenomenon that FDG uptake in tumor’s proliferative growth area was higher than infiltrative growth area show heterogeneous distribution of tumor’s growth pattern. FDG uptake in lobulated sign and vessel convergence sign were not significant differences by SUVave but existed significant differences by SUVmax , which maybe caused by overlapping of two signs. SUVave is regional measurement, which can not accurate differentiate these two signs in FDG uptake value, while SUVmax is point measurement, which can accurately differentiate these two signs.
Tumor’s biological features such as differentiation, proliferation, infiltration and metastasis express throughout the tumor’s growth course. For a specific primary site of tumor, after the differentiation in earlier stage, proliferation and infiltration dominate in middle stage and metastasis occurs in later stage. Proliferation, refers to tumor’s cell multiplication and hyperplasia without restriction, is the most important biological behavior. Proliferative degree of malignant cell is thousands of times as normal cell, and its cell programmed death (apoptosis) is suppressed.In malignancy , glycolysis pathway was strengthened while aerobic oxidation pathway was inhibited ,the energy resource for multiplication and reproduction was adenosin triphosphate (ATP) and it was acquired mainly through glycolytic pathway. The higher the tumor’s proliferative degree is, the greater the energy demands for tumor’s cell is, and the stronger intracellular glycolysis becomes. Therefore, the nutrient materials like glucose flowed mainly into the tumor’s proliferative area. 18F-FDG, a substance similar to glucose, was concentrated into area of intense proliferation in tumor and appeared “hot spot” in PET/CT imaging.
Another important biological behavior of tumor is infiltration, the performance that tumor invade adjacent tissue including tracheal vascular bundle, lobular septal and subpleural interstitial formed speculation, vascular convergence and pleural traction sign in CT imaging respectively. Comparing to the proliferating area, the tumor cells within infiltrative area are relatively mature with stronger invasive ability and distribute sporadicly maybe due to short of intercellular junction and abundant of interstitial tissue, the cell division degree and cell density in infiltrative area are lower than that in proliferating area, such factors may lead the results that FDG distribute in heterogeneity.
There are three sides of lung cancer in spatial field, the proximal side close to hilar; the middle side close to the interlobular septa and the distal side close to pleura. The nutrient materials through the vessels into nodule distribute are not evenly, the proximal side of tumor tissue can grab a large amount of FDG through blood supply which called “steal blood”, and the distal side of tumor tissue get small rest of blood supply. As a result, FDG uptake at proximal side are obviously higher than distal side. The uneven distribution of blood supply may attribute to explain the phenomenon that FDG uptake at vessel convergence sign area were higher than that at pleural traction sign area.
Vesselle et al. conducted a study of 178 cases with NSCLC performed PET/CT scan, a correlated analysis was performed between the lesion FDG uptake level and postoperative pathological subtype, differentiation degree of tumor cell and Ki - 67, and lesion FDG uptake level was significantly related with Ki - 67. Ki - 67 is an index to reflect the degree of tumor proliferation, the higher tumor proliferation is, the more intense the lesion FDG uptake accumulate .This results also confirms our viewpoint that different degree of proliferation activity demonstrate varied FDG uptake.
The degree of cell division and cell density in different areas is not identical reflecting the heterogeneity in tumor biological behavior, or rather, reflect heterogeneity in distribution of proliferation and infiltration. PET/CT can display varied edge signs with different degree of FDG uptake, therefore, heterogeneity of tumors biological behavior can be revealed by PET/CT. Meanwhile, Heterogeneity in vascular distribution can also be displayed indirectly through the edge signs with varied FDG uptake degree by PET/CT.
In a word, there are close relationship between edge signs and its FDG uptake in corresponding areas, proliferating dominant edge sign manifest FDG uptake intensely while infiltrative dominant edge signs with lower FDG uptake, and different infiltrative edge signs also exist a certain difference in FDG uptake. Studying the relationship between FDG uptake and edge signs will be helpful for understanding tumor’s growth pattern and its biological behavior accurately.