Schillaci, Orazio; Calabria, Ferdinando; Tavolozza, Mario; Cicciò, Carmelo; Carlani, Marco; Caracciolo, Cristiana R.; Danieli, Roberta; Orlacchio, Antonio; Simonetti, Giovanni
Positron emission tomography (PET) associated with computed tomography (CT) (PET/CT) is an efficient, sensitive and accurate new modality for diagnosis and follow-up of cancer patients. PET/CT improves the diagnostic performance of PET alone and its use has increased rapidly in recent years. Furthermore, the combined use of enhanced CT may improve detection efficiency and result in better localization of neoplastic lesions.
The most used radiopharmaceutical in PET/CT for staging, restaging and monitoring of response to treatment in various malignancies is [18F]fluoro-2-deoxy-D-glucose (18F-FDG), a tracer representative of glucose metabolism in cancer cells. Enhanced 18F-FDG uptake in neoplastic tissues is a consequence of increased expression and activity of glucose transporter proteins and the glucose phosphorylating enzyme, hexokinase.
18F-choline (18F-FCH) is a PET tracer recently introduced in the evaluation of prostate cancer (PC) patients and its accuracy in staging and restaging of this disease has been assessed by previous studies [1–3]. Choline is a component of phosphatidylcholine, an important element of cell membranes; as known, biosynthesis of the cell membrane is very fast in tumour tissues and the up-regulation of choline kinase activity, particularly increased in PC cells, induces an higher uptake of choline. Otherwise, evidence of elevated levels of choline in prostate tumours has also been confirmed by magnetic resonance (MR) spectroscopy .
Many authors support the usefulness of PET/CT with choline in restaging of PC, especially in patients with high prostate specific antigen (PSA) serum levels, because PET/CT represents a single step, whole body, noninvasive examination that allows disease detection and localization [3,5]. It has been shown that PET/CT with choline, labeled with 18F or 11C, can detect more metastatic lymph nodes and bony metastatic lesions than FDG in PC patients [6,7].
Many potential pitfalls and artefacts have been previously described with 18F-FDG PET and PET/CT [8,9]. The recent advent in clinical practice of 18F-FCH PET/CT has brought its own specific pitfalls and artefacts. Knowledge of these potentially false-positive uptake areas is crucial for accurate interpretation of images. In this manuscript we report our experience on abnormal sites of 18F-FCH uptake during PET/CT examinations, to expand the knowledge about physiological uptake of this radiopharmaceutical and to describe those regions that occasionally may present increased activity not related to PC tissue or owing to other nononcologic findings.
Materials and methods
Eighty consecutive patients (median age: 68 years; range: 49–82 years) with histopathologically proven primary PC were submitted to 18F-FCH PET/CT for staging or restaging. The patients had received as initial treatment hormone therapy (n = 25), radiotherapy/hormone therapy (n = 28) or prostatectomy (partial or total) associated with hormone therapy (n = 14) or radiotherapy (n = 13).
Patient preparation and scanning
All patients fasted at least 6 h before 18F-FCH intravenous injection to reduce biliary excretion of choline into the bowel and subsequently increased bowel activity. Furthermore they were asked, in the week before the examination, to avoid foods containing high levels of choline, included in a list prepared by the nutritionist of our university.
Patients received 370 MBq of 18F-FCH as an intravenous injection and hydrated (500 ml of intravenous saline, 0.9% NaCl) to reduce pooling of the radiotracer in the kidneys. About 600 cc of contrast-containing solution were administered per os to make opaque intestinal loops.
PET/CT exams were acquired using a Discovery ST scanner (Discovery ST16 GE Medical Systems, Tennessee, USA). This system combines a high-speed ultra 16-detector row (912 detectors per row) CT unit and a PET scanner with 10 080 bismuth germanate crystals in 24 rings. A low amperage CT scan was performed for attenuation correction of PET images (80 mA, 140 kV, field of view about 420–500 mm, CT slice thickness 3.75). Just after nonenhanced CT, whole-body PET images were acquired 40 min after 18F-FCH intravenous administration, 5–7 bed positions, 4 min per bed, from upper thighs to vertex; images were reconstructed using a standard iterative algorithm (ordered subsets expectation maximization).
A contrast-enhanced CT scan [120–140 kV, automatic milliamperage (limit: 330–350 mA), thickness 3.750 mm (reconstructed at 1.25 mm), acquisition mode 27.50/1.375 : 1, gantry rotation time 0.6 s, large field of view, matrix 512×512] was carried out with intravenous administration of nonionic iodinated contrast material (100–120 ml, 370 mgI/ml, 420 mgI/kg at 3 ml/s), obtaining one stack of scan, extended from the neck to the pelvis with a 60–80 s delay. Following these acquisitions, a further stack of scans has been performed in the case of equivocal hepatic or uro-genital lesions. Finally, axial scans of the skull were acquired, with the patient's arms along the trunk.
All patients gave their written informed consent for the examination; the study was approved by our local ethics committee.
The 18F-FCH PET/CT data set was evaluated in consensus by two nuclear medicine physicians on a dedicated workstation (Advantage-Windows 4.4, GE; General Electric Medical System, Tennessee, USA). All clinical, histological, radiological, nuclear medical informations, available within the 3–6 months before examination, were consulted to verify suspected 18F-FCH findings.
Normal distribution of 18F-choline and its variation
18F-FCH follows metabolic pathways of choline. The most prominent and intense physiological tracer uptake was in the liver and pancreas; moderate-to-high uptake was usually observed in the spleen and in salivary and lachrymal glands.
Less intense uniform uptake was present in bone marrow, especially in dorsal vertebrae; other sites of mild uptake were the small and large intestines (in these cases a very high inter-subject variability was observed).
18F-FCH has a renal elimination; therefore there is usually activity in kidneys, urinary bladder and ureters, with some variability.
Tables 1 and 2 summarize the standardized uptake value (SUV) in various organs.
18F-FCH uptake in the brain was usually negligible except in the choroid plexus. In only one patient intense tracer uptake was visible in pituitary gland; MR imaging subsequently performed did not show any abnormality so we considered this finding as physiological uptake .
Moreover, the route of administration (i.e. arm vein) was frequently seen (in 12 of 80 patients, 9.6%), and in two cases activity in axillary lymph nodes, because of tracer extravasation, was also observed.
Finally, it is also possible to detect 18F-FCH uptake of tracer near osteoarthritis sites, both in early and advanced phases, especially when osteophytes are present.
Among the 80 examined patients, we report 15 (18.7%) with abnormal PET findings, dubious or unexpected; outcomes in some of these were suspicious for false positives.
Four (5%) patients (mean age: 68 years; mean PSA value of 2.3 ng/ml; range: 1.2–3.6 ng/ml), evaluated for restaging of PC after partial prostatectomy (n = 1) and total prostatectomy (n = 3), showed 18F-FCH uptake in CT enlarged lymph nodes of uncertain nature in axillar (n = 10), abdominal/pelvic (n = 5) and inguinal (n = 7) regions. These findings were not considered suspicious for metastatic localization of PC because of extensive supradiafragmatic and abdominal/pelvic nodes' enlargement.
In particular, a 58-year-old patient, previously submitted to radical prostatectomy for adenocarcinoma (Gleason score 8; T2 N0), underwent 18F-FCH PET/CT during follow-up for the increment of PSA serum levels (2.4 ng/ml) 18 months after the surgery. PET/CT revealed the presence of six enlarged lymph nodes in axillary, obturatory and inguinal sites: these nodes showed increased 18F-FCH uptake (Fig. 1). Pathological sample after the biopsy showed follicular lymphoma.
In the other three cases, nonspecific inflammation was found on histological samples.
In four (5%) patients (mean age: 69 years), with increased PSA serum level (mean value: 4.5 ng/ml; range: 3.8–9.3 ng/ml), 18F-FCH uptake was visible only in six of 12 enlarged mediastinal lymph nodes.
In particular, we describe a 72-year-old patient who underwent PET/CT for the increment of PSA serum level (0.05–1.2 ng/ml). He had undergone total prostatectomy (Gleason score 7; T1 N0) for PC 20 months earlier.
18F-FCH PET/CT revealed only moderate tracer uptake in a 17 mm node on the left ilo-mediastinic side with a maximum SUV (SUVmax) of 2.2.
At clinical examination the patient reported symptoms suggestive of community-acquired pneumonia such as cough and dyspnoea with fever in the previous 20 days.
In the remaining three patients, we observed a negligible SUVmax (<1.1) without clinical or anamnestic data suggestive for respiratory diseases.
Solitary pulmonary node
A 64-year-old patient, who has smoked 20 cigarettes per day for 30 years, submitted to partial prostatectomy for adenocarcinoma 6 years before (Gleason score 8; T2 N1) with negative bone scan and increased PSA levels (3.8 ng/ml), underwent 18F-FCH imaging. PET/CT detected a 2.5 cm pulmonary node in the apical segment of lower right lobe, with moderate 18F-FCH uptake (SUVmax 2.2) and low contrast enhancement (21–24 HU) (Fig. 2). This node did not show any increase in size when compared with a previous (12 months) CT control.
A 71-year-old patient in restaging PC (PSA 4.2 ng/ml; Gleason score 7; T2 N1) 5 months after radical prostatectomy, showed intense radiopharmaceutical uptake in the right lobe of the thyroid gland (Fig. 3). He was consequently submitted to ultrasound sonography that showed a lobe with nonhomogeneous glandular echostructure without focal lesions. Biochemical tests were suggestive for thyroiditis. Neither bone involvement nor suspected node localizations were detected by PET/CT.
A 69-year-old patient, who has smoked 20 cigarettes per day for 25 years with PC (Gleason score 8; T1 N0) treated with partial prostatectomy 17 months before, was submitted to 18F-FCH PET/CT for high PSA serum levels (12 ng/ml) and uncertain findings at bone scan. PET/CT did not show any abnormal uptake in the bone. Nevertheless, a focus of increased activity was found corresponding to a subpleural wall thickening, with SUVmax of 2.8. No pathological specimen was available but according to anamnestic data of pleuritis 9 months before, the finding was considered as highly suspicious for inflammatory residue tissue.
A 72-year-old patient was referred for PET-CT staging of PC, with PSA serum levels of 11 ng/ml and recent biopsy indicative of Gleason score 8.
Only a focal and intense uptake in the distal tract of oesophagus was detected.
Enhanced CT did not show suspected abnormal tissue in correspondence of the site of uptake. Therefore this finding was highly suggestive for oesophagitis according to clinical symptoms (dyspepsia, dysphagia) reported by the patient and confirmed by gastroscopy.
A 74-year-old patient, with previous (10 months) surgical intervention of radical prostatectomy for PC (Gleason score 8; T2 N2) and recent bone scan suspicious for metastasis in the right clavicle was submitted to 18F-FCH PET/CT, during antiandrogenic therapy (PSA serum level 1.1 ng/ml).
Images did not show lymph node involvement and no bony metastases were observed, also in the right clavicle; nevertheless abnormal tracer uptake was clearly visible in the right middle ear and omolateral mastoid cells (SUVmax 3.2).
The patient was then studied by both CT and MR of temporal bones within 7 days. Axial CT scan of the temporal bone showed abnormal attenuation soft-tissue in both right middle ear and omolateral mastoid air cells without erosion of the external cortex. Axial T2-weighted MR images confirmed hyperintense tissue in right mastoid with middle high intensity signal in axial T1-weighted post-contrast administration. The imaging findings obtained were suggestive for a definitive diagnosis of right oto-mastoiditis.
Focal brain uptake
Two (2.5%) patients showed high focal brain uptake of 18F-FCH. Particularly, a 70-year-old patient, with PC (Gleason score 8; T1 N1) submitted 26 months before to total prostatectomy was studied with 18F-FCH PET/CT for the increment of PSA serum level (from 2 to 7 ng/ml) in the previous 9 months. PET/CT show significant uptake in the left obturatory nodes, indicative for neoplastic relapse.
Furthermore, a focal brain uptake was detected in the left posterior parafalcal region, in a lesion with a diameter of 1.5 cm and intense contrast enhancement after iodine medium contrast administration at CT scan.
Afterwards MR imaging was performed with a 3.0 T scanner, showing low signal lesion on T1-weighted images and high signal lesion on T2 FLAIR-weighted images. After contrast administration, the lesion showed homogeneous contrast enhancement. No area of vasogenic oedema around the lesion was seen. All these findings were suggestive of meningioma (Fig. 4).
Brain MR imaging was also performed in the second patient with focal brain uptake; this patient was 73 years old, came for restaging of PC after radical prostatectomy (Gleason score 9; T1 N0) and increment of PSA serum level (4.5 ng/ml) 1 year after the intervention. In this case, PET showed an area of uptake in the left posterior parietal region that was checked on MR as a peripheral mass lesion located on the left posterior parietal lobe, without surrounding oedema or additional necrosis, diagnosed as a low grade glioma.
PET/CT with F-FDG is a reliable imaging method largely used in staging and monitoring of cancer patients. In addition, recently, 18F-FCH PET/CT has been shown to be a promising technique in staging and restaging of PC patients [1–3].
Various articles are available in literature concerning the correct interpretation of 18F-FDG variability in its physiological distribution, pitfalls and artefacts [8,9]. In contrast, there are few studies about the physiological distribution of 18F-FCH, and its variation but, to the best of our knowledge, no specific articles about potential pitfalls, false positives or negative cases that may occur .
We observed several sites of physiologic uptake of 18F-FCH, which is especially in the liver and pancreas, followed by spleen, salivary and lachrymal glands.
The urinary system has an important variability in the presentation on PET imaging with 18F-FCH: usually both kidneys some tract of ureters and urinary bladder, are clearly visible especially in delay acquisitions.
Other sites of frequent uptake that we observed are bone marrow (dorsal vertebrae) and intestinal tract. Gynaecomastia, a frequent finding in patients with antiandrogenic therapy, did not present tracer uptake in our population.
In 15 of 80 patients (18.7%) some abnormal findings were detected, not suggestive for PC localizations.
In a study using 11C-choline it has been reported that some benign (sarcoidosis, noncaseating granuloma and tuberculosis) and malignant (lymphomas) thoracic diseases may show increased choline uptake .
As a matter of fact, we observed four cases of tracer uptake in patients with systemic lymphoadenopathies; in one case histopathological sample diagnosed follicular lymphoma, whereas in other three cases nonspecific flogosis was found. Moreover, we also detected low 18F-FCH uptake in patients with enlarged mediastinal lymph nodes.
In our series, other findings not related to malignant processes were a solitary pulmonary node, with no morpho-dimensional modifications in the previous 12 months, suspected for granuloma , and a subpleural wall thickening. In this last case, anamnestic data suggested a previous flogistic episode with residual inflammatory tissue.
It is worth noting that 18F-FCH uptake in infectious tissue has been reported in an experimental study on soft tissue infection, using high-resolution PET and autoradiography .
Furthermore, we observed focal uptake in the distal tract of the oesophagus, because choline-PET is able to visualize oesophageal carcinoma and its metastases , it is important to reach a definitive diagnosis. In our patient, contrast-enhanced CT did not show abnormal tissue in the area showing tracer uptake and a subsequent gastroscopy diagnosed chronic esophagitis.
Therefore, also considering the case of an otomastoiditis and one thyroiditis, the most important feature observable in our study is the relationship between the uptake of 18F-FCH and sites of inflammation. In fact, 12 out of 80 patients (15%) showed 18F-FCH accumulation owing to inflammation.
Our findings suggest that in clinical practice the capability of 18F-FCH PET in detecting sites of phlogosis should be considered in image interpretation.
CT enabled differentiation of physiological bowel activity and 18F-FCH uptake excretion in ureters.
Moreover, the information provided by the diagnostic enhanced-CT component of PET/CT imaging may be valuable in situations in which tumours are not choline-avid. However the role of contrast-enhanced CT in PET/CT with 18F-FCH should be further evaluated. Nevertheless, the CT scan seems able to improve 18F-FCH PET interpretation, as previously reported with 18F-FDG [8,15].
In two patients we observed a single focal area of uptake in the brain: in both these cases MR imaging, subsequently performed, was able to allow a correct diagnosis.
In this field, 11C-choline PET has been found to allow a distinction between low-grade and high-grade gliomas. For these authors, the integration of 11C-choline PET and MR imaging may provide an accurate means to identify high-grade gliomas .
Our findings support the combined use of PET and brain MR imaging for the evaluation of brain lesions suspected for glioma or meningioma, also because MR spectroscopy suggests that meningioma presents increased choline distribution .
Our preliminary findings indicate that accurate knowledge of the biodistribution of 18F-FCH is of the utmost importance for the correct interpretation of PET/CT images in patients with PC. In our series 18F-FCH uptake in benign conditions was mainly related to sites of inflammation; however, accumulation in tumor deposits not due to PC cannot be excluded, especially in the brain, where correlative imaging with MR is very useful.
The main limitation of our study is the lack of a suitable follow-up (histological samples, imaging etc.) in all the patients.
Finally, future studies are needed to assess the possible role of SUV calculation for better differentiating inflammatory form neoplastic uptake of 18F-FCH.
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