18F-FDG Uptake Characteristics in Differentiating Benign from Malignant Nasopharyngeal Lesions in Children

The characteristics of FDG uptake in the physiologic and malignant nasopharynx were investigated in the paper which was correlated with either pathologic findings or clinical follow-up. Three patients had pathologically established nasopharyngeal malignancy. In the 3 nasopharyngeal malignancies, 2 had diffusely and expansively increased FDG uptake, and one had asymmetric uptake. Our results indicated that the difference between adenoid hypertrophy and malignancy is asymmetric or diffusely expansive 18F-FDG uptake with or without correlating morphologic lesion on diagnostic CT in children under 10 years of age. The typical characteristics of physiologic and inflammatory 18F-FDG uptake in nasopharynx are symmetrically trapezoid. Diffusely increased nasopharyngeal FDG uptake can be considered physiologic if SUVmax is less than 7.6 but should be carefully assessed by pharyngorhinoscopy if SUVmax is greater than 11 and there is no correlating morphologic lesion on diagnostic CT. The diffusely, expansively increased uptake, and asymmetric uptake in particular, should be considered as malignancy. Further biopsy is especially indicated in patients with retropharyngeal space and bilateral cervical lymph node abnormality but no history of malignancy.


Introduction
Pediatric nasopharyngeal carcinoma (NPC) is rare and usually poorly differentiated [1]. 18 F-FDG PET/CT is a valuable imaging modality for evaluating and monitoring NPC in children [2] and adults [3][4][5][6]. Asymmetric 18 F-FDG uptake in the nasopharynx on PET with a correlating morphologic lesion on fully diagnostic CT may well indicate nasopharyngeal malignancy. However, diffusely increased 18 F-FDG uptake in the pediatric nasopharynx is common for both physiologic and inflammatory changes. Therefore, it is difficult to tell whether diffusely increased 18 F-FDG uptake in the nasopharynx on PET without a correlating morphologic lesion on diagnostic CT suggests nasopharyngeal malignancy. No studies of the probability of NPC vis-à-vis 18 F-FDG uptake have, to our knowledge, been performed. In this investigation, we studied the utility of nasopharyngeal 18 F-FDG uptake in children under 10 years of age to determine the characteristics of FDG uptake in the physiologic and malignant nasopharynx.

Study Population.
From May 2011 to May 2013, 154 children under 10 years of age with either established or suspected malignancy were enrolled in the study and underwent 18 F-FDG PET scanning. The study was approved by the research ethics committee of our hospital. Written informed consent was obtained from the parents or guardians of all included patients before 18 F-FDG PET/CT. The distribution of malignancy and suspected malignancy is listed in Table 1.

18 F-FDG PET/CT Imaging
Protocol. 18 F-fluorine was produced at the PET Centre of Xinhua Hospital, Shanghai. Blood glucose level was measured prior to injection of 18 F-FDG and was normal in all. The patients received a 5.18 MBq/kg dose of 18 F-FDG (±10%; maximum, 444 MBq) intravenously after an overnight fast or, for afternoon studies, a minimally 4-hour fast. After injection, the patients stayed in the PET preparation room and rested for 1 hour. Relaxation with no movement or minimal movement during the uptake phase was encouraged. Just before the end of the 1-hour uptake period, the patients voided their bladders. Transmission CT images for attenuation correction and lesion localization, and PET emission images, were acquired approximately 1 hour after injection using a Biograph PET/CT system (Siemens). The CT images were acquired using slice thickness of 0.3 cm, 0.8 s tube rotation, table speed of 1.5 cm/rotation, pitch of 1.5 : 1, 120 kV, 90 mA, and dose modulation. The PET images were obtained from the vertex of the skull to the mid-thigh level for 5 min per bed position in 2-dimensional mode. The PET/CT scans for each patient were reviewed by 2 nuclear medicine physicians without knowledge of any clinical information. SUV max in the nasopharynx was determined from manually placed regions of interest over the area of tumor activity in multiple planes. Follow-up clinical and pathologic information were recorded for correlation with tumor uptake of 18 F-FDG (SUV max ).

Statistical Analysis.
We analyzed the association between SUV max in the nasopharynx and clinical and pathologic results using the 50th, 75th, 90th, and 95th percentiles for differentiation between benign and malignant nasopharyngeal lesions in children (SPSS software, version 13.0; IBM).

Results
The children had a median age of 4 years, and the maleto-female ratio was 91 : 63. One hundred thirty-seven had established malignancy and underwent PET/CT for staging, postoperative restaging, or therapeutic assessment. The other 17 underwent PET/CT because of suspected malignancy or fever of unknown origin.
The benign increased uptake of 18 F-FDG in nasopharynx of children under 10 years of age is symmetric and trapezoid (see Figure 1). Nasopharyngeal carcinomas (NPC) (2/17, 12%) were confirmed in 17 suspected malignancies of unknown origin. In 137 established malignancies, 1 (1/137, 0.73%) case had lymphoma involvement. Three patients had pathologically established nasopharyngeal malignancy, two had diffusely and expansively increased FDG uptake, and one had asymmetric uptake. The clinical and imaging characteristics of these three children are listed in Table 2. The SUV max value in patient numbers 1−3 was 18, 11, and 8.2, respectively. Patient number 1 with incidental NPC (SUV max , 18; Figure 2) and lymphoma involvement (SUV max , 11) had diffusely increased 18 F-FDG uptake in the nasopharynx (which was not shown).
Patient number 3 ( Figure 3) had asymmetric 18 F-FDG uptake in the nasopharynx (SUV max , 8.2) and multiple metastases on PET with correlating morphologic lesions on diagnostic CT.
The association between SUV max in the nasopharynx and the incidence of NPC using the 50th, 75th, 90th, and 95th percentiles is presented in Table 3. The risk of nasopharyngeal malignancy increased with SUV max : 8.6%, 22%, and 40% in patients with SUV max of at least 7.60, 9.58, and 10.88, respectively.

Discussion
18 F-FDG PET/CT is helpful for staging and posttreatment assessment of adult NPC [3][4][5][6]. However, in children diffusely increased 18 F-FDG uptake and thickening of the nasopharynx are common for physiologic and inflammatory reasons. Therefore, it is difficult to tell whether increased  nasopharyngeal 18 F-FDG uptake without a correlating morphologic lesion on diagnostic CT suggests nasopharyngeal malignancy. In this investigation, we retrospectively reviewed nasopharyngeal 18 F-FDG uptake in 154 children and correlated the SUV max with clinical and pathologic results. Diffusely increased nasopharyngeal uptake in children may be due to physiologic changes, inflammation, or malignancy. It is not difficult to diagnose asymmetrically increased 18 F-FDG uptake if there is a corresponding CT abnormality, as illustrated by patient number 3. In our study, uptake having SUV max less than 7.6 in the nasopharynx was considered physiologic. Diffusely increased 18 F-FDG uptake (SUV max > 9.58) without a correlating morphologic lesion on diagnostic CT may be due to inflammation or nasopharyngeal malignancy. Differentiation between nasopharyngeal inflammation and malignancy using PET/CT is difficult. Our results indicated that, in children under 10 years of age, the typical characteristics of physiologic and inflammatory 18 F-FDG uptake in nasopharynx are symmetrically trapezoid with the SUV max less than 11. In our study, 7 children had SUV max of more than 9.58 in the nasopharynx due to viral or bacterial infections. However, the higher the nasopharyngeal SUV max (>10.88), the higher the incidence of nasopharyngeal malignancy (2/5, 40%). Nasopharyngeal malignancy in children may be characterized on PET/CT by asymmetric or expansively diffused, increased nasopharyngeal 18 F-FDG uptake with or without a corresponding CT abnormality with SUV max greater than 11. As shown by patient number 1, nasopharyngeal biopsy may well be indicated in patients with SUV max of more than 11 in the nasopharynx with retropharyngeal space and bilateral cervical lymph node abnormality but no history of malignancy. Meanwhile, carefully diagnosis should be made in patients with SUV max less than 11. Patient number 3 had NPC with SUV max of 8.2 and multiple metastases including liver. The asymmetric 18 F-FDG uptake and correlating morphologic lesions on diagnostic CT are of great help to make the diagnosis of NPC.
NPC is rare in the pediatric age group. In the study, NPC (2/17, 12%) were confirmed in 17 suspected malignancies of unknown origin. In 137 established malignancies, 1 (1/137, 0.73%) case had lymphoma involvement. Children tend to have the poorly differentiated histologic variant of the disease, which is associated with increased locoregional spread and distant metastasis. Splenic metastases have been reported in adult cancers but are unusual in pediatric solid tumors [7]. Bone (67%) and liver (30%) are the most common metastatic sites [8]. PET/CT is valuable for staging of NPC in children. Of the two cases of NPC in our study, one had regional lymphadenopathy and splenic metastases and the other had multiple metastases in bone (bone marrow) and liver that were clearly shown by 18 F-FDG PET/CT. The rarity of splenic and cystic liver metastases in pediatric NPC has also been highlighted in a case report on a 14-year-old boy [7].
Chemoradiotherapy is the preferred treatment for local disease, whereas chemotherapy is the first choice for children with systemic disease [7]. 18 F-FDG PET/CT is also helpful in therapeutic monitoring of children with NPC. In patient number 1 the incidental detection of NPC by 18 F-FDG PET/CT (SUV max 18) was showed in Figures 2(a) and 2(b). PET/CT imaging showed decreased 18 F-FDG (SUV max 4.0) and negative lymph nodes, which indicated a good response to chemotherapy and local radiotherapy, thus demonstrating the potential usefulness of the technique in metastatic pediatric NPC.
However, there are some limitations of this paper. We excluded malignancy in the other children according to the follow-up PET/CT or CT except for the three patients who had been diagnosed as malignancy. Only three children with nasopharyngeal malignancy were included. Further study will focus on the details about the children with physiologic or inflammatory nasopharyngeal 18 F-FDG uptake, including the distribution pattern (symmetrical or not) and the correlation of SUVs with the children's age and gender, the softtissue thickness of the nasopharynx, and recent history of rhinitis.

Conclusion
The difference between adenoid hypertrophy and malignancy is asymmetric or diffusely expansive 18 F-FDG uptake with or without correlating morphologic lesion on diagnostic CT. In children under 10 years of age, the typical characteristics of physiologic and inflammatory 18 F-FDG uptake in nasopharynx are symmetrically trapezoid. Diffusely increased nasopharyngeal 18 F-FDG uptake can be considered physiologic if SUV max is less than 7.6 but should be carefully assessed if SUV max is greater than 11 and there is no correlating morphologic lesion on diagnostic CT. The diffusely, expansively increased uptake, and asymmetric uptake in particular, should be considered as malignancy. Further biopsy is especially indicated in patients with retropharyngeal space and bilateral cervical lymph node abnormality but no history of malignancy. 18 F-FDG PET/CT is a valuable imaging modality in staging and therapeutic assessment of NPC in children.