Acknowledgement

Author wishes to express appreciation to The Department of Nuclear Medicine, Radiology Head and Neck Surgery, Ospedale Niguarda, Milan , Italy for kind hospitality and participation in this collaboration activity. This study was supported by unrestricted grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) and Oncologia Ca’ Granda Onlus (OCGO) Fondazione.

Introduction

NPC is common among the Chinese populations especially in the south China and South East Asia region with incidence of 20 to 50 per 100 000 individuals [1,2]. Despite being uncommon among other ethnic groups including the Europeans, incidence has been reported among the south Indian community as well as in the North African community [3].

Ebstein Barr Viral (EBV) infection is thought to play an important role in initiating the development of this tumour. Multiple literature review revealed coexistence between EBV infection and NPC [4,5,6,7,8,9,10]. Kenneth and colleagues suggested that EBV status can be a reliable predictor for overall survival of NPC patients[11].

Most NPC patients commonly manifest themselves with painless enlarged lymph nodes in the neck which are often bilateral. When these are in association with positive EBV’s DNA, they are highly suspicious for nodal disease from NPC primary [12]. Other clinical features include nasal obstruction and epistaxis which may occur as a result of local tumor infiltration. Patients may also present with hearing problems like hearing loss, tinnitus or recurrent otitis media. In advanced cases, there may be cranial nerve dysfunction. A more generalized presentation like sore throat and headache are not uncommon. These clinical presentations are looked for at diagnosis and follow up.

Besides histological typing, early detection and accurate staging at diagnosis and restaging at follow up are important prognostic determinants. Early and accurate staging at diagnosis will ensure proper treatment deliveries as prevalence of head and neck metastases is as high as 40% at the time of initial presentation. Accurate restaging after therapy is also important to determine treatment response and to answer the question whether the patient requires change in pre planned treatment regime.

In current practice, conventional imaging modalities like CT and MR are routinely employed to assist clinicians in staging NPC patients. Fused integrated morphological and functional imaging modality PET/CT is another possible useful new tool to be utilized in the assessment of NPC patients. This study was conducted in view to evaluate the role of fused Positron Emission Tomography/Computed Tomography (PET/CT) in the management of NPC patients.

Materials and methods

Patients

18F-FDG PET/CT imaging

Image interpretation and data analysis

Statistical Analysis

Results

Patients

From selected 24 patients in our study, we include 37 paired examinations of PET / CT and CT or MRI. At diagnosis, the imaging results were compared with histo pathological findings. At follow up, the standard was taken as final clinical conclusion of disease status done by the clinicians following clinical assessment. The summary of the findings of all enrolled patients are summarized in table 1.

Figure 1

Table 1- Clinical, histopathological and imaging results

There are 17 males and 7 female patients (table 2). Age distribution between 21 to 70 years old with highest frequency of patients aged 61 years and above (table 3).

Figure 2

Table 2 - Sex distribution

Figure 3

Table 3 - Age distribution

Comparing results between imaging modalities at diagnosis

All 18 results at diagnosis were found to be concordant between PET / CT and CT or MRI. When these results were compared with standard (tissue biopsy) the calculated sensitivity and accuracy were found to be equally high (table 4).

Since there were no false negative or false positive results, the specificity is statistically void.

Figure 4

Table 4 - Comparative evaluation results between imaging modalities at diagnosis

Comparing results between imaging modalities for assessment of treatment response

In imaging after therapy, both methods are found to be equally accurate with high positive predictive values. The negative predictive value for PET / CT is found to be higher than the conventional imaging modalities (100.0% for PET and 71.0% for conventional imaging) (Table 5). Overall, PET / CT provides a higher sensitivity in detecting local recurrence disease as compared to conventional imaging modality.

Figure 5

Table 5 - Evaluation results for treatment response assessment between imaging modalities

Figure 6

Figure 1. A 61 year old man who presented with epistaxis at diagnosis of nasopharyngeal carcinoma. Multiplanar reconstructed images obtained during 18F-FDG PET/CT examination revealed mild distortion of the normal anatomy of the left nasopharyngeal region (red crossed cursor). 18F-FDG PET CT demonstrating avid activity with intense metabolic activity deeply seated in the left nasopharyngx.

Figure 7

Figure 2. Follow up 18F-FDG PET / CT imaging of the same patient 6 months upon completion of radiotherapy treatment demonstrating complete metabolic response in the left nasopharynx. Clinically the patient was found to be in complete remission.

Discussion

Accuracy in staging NPC is most crucial during post therapy evaluation at follow up study. Centrally necrotic cervical nodes following therapy may resemble disease progression. Situation can be further complicated with the presence of reconstructive surgical procedures using graft and flap in this region.

While conducting this study, we found more significant variations in imaging results during post treatment evaluation with good statistical consensus at diagnosis.

There are no significant indifferences in the results at diagnosis since our study comprised of small number of patient. Furthermore, this retrospective selection of cases did not reflect the actual progress of clinical work flow for patients investigated for suspicious NPC. This includes identification of infected neck nodes or other nearby pathology at imaging which may resemble the clinical presentation of NPC. These are major contribution towards variation in statistic analysis.

In post therapy evaluation of both imaging modalities at follow up, we found two false negative results on conventional imaging modalities (patient 12 and 23) and 1 false positive result on both imaging modalities including PET/CT (patient 6).

We re-evaluated the retrospective false negative results of the two patients on conventional imaging modalities and reach to an agreement that there were no significant anatomical disruption noted in the nasopharyngeal areas. Furthermore, no loco regional nodal involvement demonstrated in these patients. Thorough search by direct endoscopic visualization confirmed the imaging findings. However, PET / CT evaluation demonstrated lesion with high metabolic activity indicating recurrent NPC. This particular clinical example has been described previously where 15.4% prevalence of residual or recurrent tumors are found to be beyond the reach of routine nasopharyngeal biopsy[13].Therefore, clinical assessment via endoscopic examination may missed deeply seated tumors whilst early tumor development may not manifest themselves clinically. Since conventional imaging modalities like CT or MRI dependent much on anatomical alterations to be readily identified at imaging, this clinical example may have resulted in understaging or missed tumor lesions.

We also performed re-evaluation study on the imaging results of the other patient. Because of doubtful positive imaging findings in the absence of signs and symptoms of disease recurrence, the patient underwent biopsy of the nasopharynx which result was later found to be negative. The remission state was later confirmed at subsequent follow-up. Thus, our reviewers came to an agreement that altered anatomical landmark with reactivity following radio and/ chemotherapy may have been the cause for the false positive interpretation. Although we follow standard recommendations to perform imaging studies after 6 to 8 weeks post therapy period, variations in the rate of recovery and body response towards injury events caused by radiation or chemotherapy may differ from one patient to another[14,15]. In addition, possibility of a brief episode of local inflammatory reaction at the time of imaging as a result of infection cannot be totally segregate from the fact that there is high metabolic activity in PET image acquisition.

Literature search suggested 18F-FDG PET is more specific than conventional imaging modalities in detecting residual or recurrent nodal metastasis in head and neck malignancies. The sensitivities in these articles cited ranging from 67% to 100% and specificities ranging from 77% to 100% (16, 17, 18, 19, and 20). Our results are comparable with these findings (sensitivity 100% and specificity 83%) supporting the assertion that 18F-FDG PET should be a sensitive tool in detecting residual or recurrent nodes in NPC. In fact, by incorporating CT into functional PET imaging, the percentage is expected to be higher as compared to PET imaging alone. The ability of PET in providing functional metabolic activity of tumor infiltrated structures including small nodes is being utilized to enhance the superior capability of CT in demonstrating the precise anatomical location of these lesions. Thus, they are readily detectable on PET imaging and independent on the morphological changes in CT or MR images. The fusion of both imaging modalities in an integrated PET / CT machine should gives better result [21, 22, 23]. Furthermore, useful informations can be obtained during a single seating and also time saving for patient’s convenience.

Within our small study population, we also demonstrated higher negative predictive value of PET / CT in comparison to conventional imaging methods (table 5). This finding signify a more reliable negative PET / CT imaging result in circumstances when actual disease is absent where conventional imaging modality may have 29% chances of false negative interpretation.

Our study encourages the use of PET / CT in post therapy management of NPC patients. We demonstrated the ability of PET / CT in correcting tumor under staging in two of our patients whose results were found to be falsely negative using conventional imaging modality (patient 12 and 23). Aside from treatment response assessment, PET / CT findings can also lead the clinicians in decision making on the choices of clinical approach to be adopted. In the absence of clinical findings, a positive PET / CT result can be used as a general indicator for a more aggressive approach like biopsy in order to confirm the final diagnosis (patient number 6). This modality should be recommended as a preferable tool at follow up [24, 25].

Even though our findings at post therapy assessment are relatively relevant, we suggest more research being granted for assessment of actual value of PET / CT in therapy response within a larger cohort group of NPC patients.

Conclusion

Our study found 18F-FDG PET / CT a suitable imaging modality to be utilized in managing patients with NPC especially at post therapy follow-up. Further evidence is required to seek the actual value of this imaging modality at initial stage of diagnosis and follow up within larger cohort group.