Fever of unknown origin (FUO) is a diagnostic dilemma that needs integration of various clinical and diagnostic procedures to reach the accurate diagnosis. With the evolution of PET/CT using its combined metabolic and anatomical images, it was possible to diagnose the lesions early compared to other modalities of imaging and diagnosis.
In this study, 18-F-FDG-PET/CT was found to provide useful data, that helped to reach a final clinical diagnosis or ruled out a focal lesion as a cause in patients with FUO. Even a negative PET/CT study was helpful in guiding us for further investigations.
Malignant causes
The main etiology of FUO in our study was malignant one (50%) and this was different from most of the reported studies in literature where infectious and inflammatory causes predominate. This difference may be caused by the referral bias as this study was done in a tertiary center and inflammatory causes tend to be diagnosed early in the disease process.
In our study, sensitivity of PET/CT to malignant disorders was 100% which matched that reported by most of the previous authors as Singh et al. [9] and Mahajna et al. [10]. Among the malignant causes, lymphoproliferative disorders/hematological malignancies predominated and this was in concordance with the results published by Gafter-Gvili et al. [11] and Zhu et al. [12].
One of the cases in this category was diagnosed with primary bone marrow lymphoma. Primary bone lymphoma (PBL) represents non‐Hodgkin lymphoma (NHL) that primarily arises in the bone marrow without lymphadenopathy. Our patient had multifocal type in the right acetabulum and femur. She had faint easily missed subtle lytic/sclerotic appearance in the CT alone, yet it showed increased FDG uptake in the PET scan which caught the eye and guided the subsequent guided biopsy. As reported by Lim and Ong [13], radiological appearance of PBL can be normal or very subtle, hence, combined anatomical and metabolic imaging plays a major role in the diagnosis.
Another case was diagnosed with solitary plasmacytoma (SP) by pathological examination of left ischial and acetabular hypermetabolic predominantly lytic lesion. Early diagnosis of solitary bone marrow plasmacytoma is particularly important because most of the cases will eventually evolve into multiple myeloma [14].
We also reported a case of Behcet disease that presented with FUO with his PET/CT showing enlarged metabolically active supra and infradiphragmatic lymph nodes which were proven pathologically to be caused by lymphoma. Behcet disease has been reported in the literature to be linked to many types of malignancies Huang et al. [15] and Meydan et al. [16] have reported cases of similar entity for malignant lymphoma complicating cases of Behcet disease.
Other malignant causes of FUO in our study included metastatic colonic cancer to the liver which is a rare established cause in the literature. Liver metastases cause neoplastic fever with many of the patients displaying significant systemic inflammation [17].
Renal cell carcinoma was found in one of our patients which is a reported cause of FUO in the literature [18]. Another particularly rare cause of FUO reported in the current study is lung cancer. Non-small cell lung cancer was found by Zee and Soo [19] to present with FUO in diagnosis and relapse, thus being a cause of neoplastic fever.
PET/CT was capable to identify focal sites of early malignancy. In the patient with lung cancer, only small spiculated pulmonary nodule with high PET activity was detected together with metabolically active hilar lymph node in absence of any respiratory symptoms which was then confirmed to be malignant by biopsy.
Infectious causes
Infectious causes had the lowest detection rate in our study (57.14%) which run in concordance with the studies done before [9, 20]. The two false negative cases in our study belong to this group. It is likely attributed to low sensitivity of PET/CT in lower urinary tract infection (UTI) and the physiological excretion of FDG in urine. This is consistent with the findings reported by Zhu et al. [12] where four of their false negative cases were secondary to UTI.
In addition, we had one false positive case where FDG uptake was located in the nasopharynx, cervical lymph nodes with metabolically active enlarged spleen and diffuse increased bone marrow activity. This was misinterpreted as suspicious for lymphomatous infiltration. The patient refused tissue diagnosis, further investigations revealed positive serology for Infectious Mononucleosis (IMN) and he markedly improved within two months with no recurrence of fever for the following six months. Uptake of FDG in acute Epstein Barre infection has mimicked malignancy in most of the published studies in this subject. For example, Lustberg et al. [21] have reported FDG uptake in cervical and abdominal lymph nodes together with the liver and spleen in their published case report of a patient with acute infectious mononucleosis. Given the ongoing conflict in diagnosis of such cases, we suggest putting Epstein Barre infection as a differential diagnosis in patients presenting with FUO, especially if accompanied with pharyngitis or sore throat having FDG uptake mainly in the cervical lymph nodes and the enlarged spleen. Patients will still need confirmatory serological and/or pathological tests to confirm/rule out the diagnosis.
Two of our infectious cases were secondary to Tuberculous infection. T.B. has been described as the most common infection causing FUO in the non-western countries [3, 22, 23].
As this study was done in the era of COVID-19 pandemic, one of our patients showed COVID-19 pattern of pneumonia as a novel source of infectious FUO. Arita et al. [24] have published a case report in 2021 discussing a similar case with COVID-19 infection presented with prolonged intermittent fever after COVID infection.
Non-infectious inflammatory diseases
Non-infectious inflammatory diseases were diagnosed in 6 patients in our study with a PET/CT detection rate of 83.3%. One of the six cases was falsely diagnosed by PET/CT as suspicious for lymphoma or leukemia. The patient had increased FDG uptake in the enlarged spleen and diffuse increased uptake in the bone marrow, yet his bone marrow biopsy revealed no evidence of malignancy with only hypercellularity detected. Final diagnosis of the patient by clinical data and laboratory tests was adult-onset Still disease (AOST). Yamashita et al. [25] studied seven AOSD patients who were evaluated by 18F-FDG PET/CT. Their PET/CT studies revealed 18F-FDG accumulation in the multiple lymph nodes, spleen and BM similar to that observed in malignant lymphoma, which made the differential diagnosis difficult.
Dermatomyositis is a rare cause of FUO in the literature that was found in our study. Lee et al. [26] have reported a similar case presenting as FUO. They concluded that certain subtypes of dermatomyositis can present with atypical presentations as FUO. PET/CT in our case showed diffuse increased FDG uptake in the skeletal muscles mainly muscles of the shoulder girdle, proximal arms, pelvis and thigh muscles.
An interesting finding in our study was that PET/CT was able to successfully diagnose a case of vasculitis affecting the celiac and superior mesenteric arteries. PET/CT has an established role in the literature in diagnosis and monitoring response to therapy in cases with large vessel vasculitis [27]. However, its sensitivity decreases significantly in cases of medium vessel and small vessels vasculitis [28]. In our study, we found increased uptake in the mildly thickened wall of the celiac and superior mesenteric arteries with nearby small metabolically active reactive lymph nodes which are reported findings in cases of vasculitis [29].
Added value of PET/CT over CT in our study
Beside the benefits of PET as a sensitive modality for lesions with high metabolic activity, benefits of the combined contrast enhanced CT were obtained. CT can assess different chest and abdominal organs in the portal phase of contrast enhancement. In our study, there was a patient with sarcoidosis showing increased mediastinal lymph nodes PET activity. Her lung parenchyma was assessed by CT to clarify the small pulmonary nodules and interstitial pulmonary changes. She had similar findings to that reported in the literature in cases of Sarcoidosis [30]. The lung window interpretation was helpful to rule out the malignant etiology and raise the possibility of inflammatory process.
Among the 40 cases with FUO in our study, PET/CT was able to accurately confirm/exclude the diagnosis in 35 cases with diagnostic accuracy of 87.5%. This is close to the reported accuracy in the previous similar studies as those done by Tokmak et al. [31] and Abdelrahman et al. [32] (90% and 94.5%, respectively).
In our study, the malignant neoplastic lesions showed higher values of standardized uptake values (SUV) in comparison to infectious and NIID lesions. SUVmax of infectious and non-infectious inflammatory causes ranged from 3 to 8, while that of the malignant cases ranged from 6 to 45 (Table 1).
Limitations of PET/CT
Previous studies suggested the high cost of PET/CT as a possible disadvantage. This is not going to be a problem in the very near future because PET/CT scanners are more and more available nowadays. However, its use can be limited to the difficult cases of FUO that the clinical methods and routine investigations fail to determine the underlying cause.
Another concern is the exposure to radiation, which seems to be within acceptable range being similar to the dose the patient receives during other routine radiological examination like whole body CT.
