PET/CT is a widely used imaging modality in oncology owing to its whole-body imaging coverage allowing detection of metastases in a large part of the body. Routinely, a whole-body PET/CT covers from the skull base to upper thigh region that can be described as lips- to-hips or eyes-to-thighs excluding the brain which makes the term whole body imprecise.
FDG-PET’s role in detecting BM has been frequently questioned in literature and limited due to its low sensitivity [5, 18, 19]. However, this sensitivity increased with the introduction of IV contrast and the development of new fast CT scanners [20]. We addressed the role of including the brain in cancer patient’s whole-body scans to increase the probability of BM being detected. Hence, the term “detection” as part of our aim was more toward the clinical application of the examination making more sense of the name “Whole body scan” and to be used as a single stop shop for patient’s full assessment including the brain saving effort, time, and cost especially in low economy regions.
We examined 420 cases of extra-cranial malignancy from which 30 patients presented with 71 BM lesions with an incidence of 7.1%. Current literature reviewing incidence of BM showed high variability with an incidence proportions percentage ranging from 3 to 50% [10]. This could be explained in the context of methodological constraints related to inconsistency of studied data. The published data could be derived from population-, histology-, radiologic-, surgical-, or medical record-based data studies [4, 12, 21]. In addition, other epidemiological variables as age, sex, race, and regional area (North Africa in our case) can be responsible for the reported variations [10].
In the current study, bronchogenic carcinoma was the most common primary tumor both in the previously diagnosed patients and as more commonly presenting metastases of unknown origin [22]. These results are in accordance with most of the published data where autopsy studies have suggested that lung cancer is the most common tumor to cause BM accounting for two-thirds of patients [12, 23]. In our study, the most common histologic subtype associated with the development of BM was adenocarcinoma. This is in line with prior findings which may be related to the fact that adenocarcinoma is the most common histologic subtype of lung cancer overall [24]. In descending order, the common cancers to send BM in our study were breast carcinoma, renal cell carcinoma, melanoma, non-Hodgkin lymphoma, and thyroid carcinoma. Comparably, studies showed that breast cancer has the second most frequent incidence of BM, where autopsy studies reported an incidence rate of 18–30% [1, 25]. Melanoma is the third most common cause of BM and accounts for nearly 6–11% of lesions, with a higher incidence of metastasis in males [26]. It was reported that 50% of advanced melanoma patients developed BM and 10% of metastatic lesions presented as an intraparenchymal hemorrhage [26]. With respect to renal cell carcinoma, it was estimated that BM occurred in 2–16% of patients and that when BM emerged late in illness, renal cell carcinoma was refractory to other therapies [27]. BM is an unusual event for patients with aggressive lymphoma [28, 29]. Thyroid cancer remote metastasis to the brain occurred in about 0.3-4.6% of cases and was associated with aggressive behavior and worse prognosis [30,31,32]. Studies have shown that FDG-PET/CT detected location in nearly 25% of unknown primary disease patients [33, 34].
Neurological symptom presence may indicate BM. In this study, 16/30 patients (53.3%) with BM had neurological symptoms, whereas the remaining 14/30 patients (46.7%) had no neurological symptoms which represented nearly half of the studied patients. Patients with BM tended to be more appropriately diagnosed as positive by PET/CT in the symptomatic rather than in non-symptomatic patients. This is concordant with the published literature where Kitajima et al.’s study showed no statistical significance between these two patient groups [35]. A study proposed by Nia et al. showed that all studied patients with incidental BM were symptom free [36]. It is important to diagnose BM before patients become symptomatic to avoid dangerous complications as seizures.
Regarding the number of brain lesions, multiple lesions were more common than solitary lesions which agree with the published data [11, 25]. According to site, supratentorial metastases were present in 100% of patients with the parietal lesions representing 50.7%, while infratentorial lesions were detected in 26.7% of the studied patients. Similar results were reported by Delattre et al. [37] and Nussbaum et al. [38] where the supratentorial area was the preferential area for metastasis that can be explained in the context of the respective mass of these structures. This anatomical distribution of the BM being supratentorial in 100% of our studied patients justify the importance of including the brain in the scanned field; otherwise, they would not have been discovered with the routine base of the skull–to–thigh protocol.
In the current study, the enhancement patterns detected varied from none to marginal, ring- and intralesional enhancement. Some of the lesions showed patchy areas of no enhancement and no radiotracer uptake due to associated element of necrosis, calcifications, or hemorrhage. Schwartz et al. evaluated 221 ring-enhancing brain lesions and found that the most frequent pathologies associated with ring-enhancing lesions were gliomas (40%) followed by BM 30% [39].
The intensity of FDG uptake was variable in the current study, where the max SUV value was measured for every lesion separately, the least was 0.2 and the most was 20. In attempt to appropriately assess the FDG uptake by the metastatic deposits in the presence of hypermetabolic background of normal brain tissue, we compared the FDG uptake to the corresponding contralateral gray matter uptake to set a reference range that is reliable for every patient during their specific status of examination. It was noticed that FDG avidity varied in the studied lesions when compared to the corresponding contralateral brain tissue showing iso-, hypo-, and hyper-avidity. It is worth mentioning that bronchogenic carcinoma metastatic deposits exhibited all three FDG uptake varieties.
Analysis of FDG-PET/CT diagnostic performance in the current study showed a moderately good sensitivity (78.1%) and specificity (92.6%) with an insignificant difference in performance as compared to CECT modality alone. In accordance with our data, Hjorthaug et al. studied lung cancer patients with suspected BM using FDG PET/CT as a triage for selecting patients who need further imaging. This study showed PET/CT sensitivity, specificity, and PPV were 72, 100, and 97%, respectively [40]. Several FDG-PET studies have demonstrated a broad range of sensitivities and specificity for identifying brain tumors, whether as known primary brain tumors or recurrence after treatment, ranging from 25–100% and 22-100%, respectively [41]. Sensitivity is limited by false-negative cases that resulted from absent or reduced FDG uptake by suspected brain tumors compared to surrounding normal brain tissue. Meanwhile, specificity is limited by false-positive cases as in cases of inflammation [42, 43].
FDG has been the tracer of choice for oncologic PET imaging, based on the principle of increased glucose metabolism by most tumors [44], long half-life, easy synthesis [15, 45]. Despite its recognized limitations in brain tumor imaging due to the high uptake in the background of normal gray matter, this imaging modality tracer remains the most used nowadays [15, 45]. FDG provides a comprehensive picture of the tumor, predicting aggressiveness, helping to differentiate recurrent tumors from treatment-related changes, and differentiating pharmaco-sensitive tumors [45]. Recent technical improvement in several PET/CT protocols including the implementation of intravenous contrast resulted in improvement of the overall yield of the hybrid study in detecting BM to exceed the reported low sensitivity of a PET alone. Adding that to the whole body coverage (including head) and the accessibility to faster scanners, the CT component of the PET/CT study can work as an independent CT scan of the brain with the possibility to preclude the requirement for a dedicated diagnostic brain CT.
Limitations of the FDG-PET/CT should be recognized. Previous studies suggested limitation of PET scanning as possible false-negative results that could lead to inaccurate disease staging. In a prior study by Kruger et al., BM detected by PET-CT were evident only on the CECT portion of the examination, with FDG-PET only detecting altered metabolism in 1/8 patients [46]. In some patients, particularly those with neurological complaints, there is still a need for more imaging despite the improved diagnostic performance of PET/CT. False sense of security from negative PET/CT results should be regarded and the treating physicians must be informed about the study limits so as to avoid errors in treatment due to potentially misleading PET/CT results. Additionally, logistic issues like scanning time in an active PET service and the extra brain scanning time will reduce the overall number of patients scanned per day [19]. Radiation exposure could be considered a downside of the discussed modality; however, Osipov et al. showed that diagnostic exposure due to repeated PET-CT examinations in a group of oncological patients was not associated with changes in mortality [47]. Reduced kilovolts (kVs) with automatic exposure control were a suggested attempt to optimize the radiation exposure in head and neck scans [48].
We should recognize limitations in the current study as there was lack of a histological proof as a true reference standard for some of the detected lesions. With a reference standard based on imaging, false negatives may arise in small or slowly growing lesions in the absence of substantial morphological changes. Nevertheless, comparable with numerous studies of similar design, acquiring multiple biopsies for tissue confirmation would have been unfeasible and ethically unacceptable [20, 49]. Another recognized limitation could be the number of the studied cases which could have led to underestimating the incidence of BM. We believe that there are sources of bias as the defect in referral system, systemic brain study is not routinely performed or patients with end-stage diseases that may be considered untreatable may not have been included. Further studies aimed at improving brain PET/CT performance and a systemic diagnostic evaluation of FDG-PET/CT for the differentiation of the brain tumor are therefore essential.
