The diagnostic accuracy of technetium-99m methoxyisobutylisonitrile (Tc-MIBI) single photon emission computed tomography (SPECT) and computed tomography (CT) of the head and neck for differentiating recurrent or residual nasopharyngeal carcinomas (NPC) from benign lesions after radiotherapy was compared with positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (FDG).
Thirty six NPC patients underwent head and neck CT, Tc-MIBI SPECT, and FDG-PET four months after radiotherapy to differentiate recurrent or residual NPC from benign lesions. Histopathologic examinations of nasopharyngeal biopsies were performed for all 36 patients. No patients had multiple foci of NPC.
Based on biopsy results, the sensitivity, specificity, and accuracy of CT for differentiating recurrent or residual NPC from benign lesions were 73%, 88%, and 83%, respectively. The sensitivity, specificity, and accuracy of Tc-MIBI SPECT were 73%, 96%, and 89%, respectively. The sensitivity, specificity, and accuracy of FDG-PET were 100%, 96%, and 97%, respectively. Combination CT and Tc-MIBI SPECT for 28 NPC patients with congruent results showed the same sensitivity, specificity, and accuracy of 100%, 96%, and 96%, respectively, as FDG-PET for differentiating recurrent or residual NPC from benign lesions. In eight patients with incongruent results between CT and Tc-MIBI SPECT, FDG-PET correctly differentiated two benign lesions and six recurrent or residual NPCs.
After radiotherapy (RT), computed tomography (CT) on the basis of anatomic changes has low sensitivity and specificity for detecting recurrent or residual nasopharyngeal carcinoma (NPC) and distinguishing NPC from changes after RT.1, 2 Computed tomography findings of nasopharyngeal mass or asymmetry are often falsely positive due to some degree of fibrosis after RT.1 Changes after RT may last for a long time.3 Therefore, CT may easily overlook recurrent or residual NPC.
Recently, positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (FDG) has been introduced to image NPC.4, 5 However, FDG is expensive and often not readily available. Technetium-99m in a kit form is more available and practical than PET. Technetium-99m methoxyisobutylisonitrile (Tc-MIBI) has been used to detect NPC as a potential tumor imaging agent. However, its diagnostic accuracy has varied.6–11
The purpose of the current study was to evaluate CT and Tc-MIBI single photon emission computed tomography (SPECT) of the head and neck for differentiating recurrent or residual NPC from benign lesions in comparison with FDG-PET in NPC patients who had undergone RT.
MATERIALS AND METHODS
Patients were not included in the study if they were pregnant, had known diabetes, or were younger than 18 years of age. Thirty six randomly selected NPC patients (12 women and 24 men, ages 18-67 years) fulfilled the inclusion criteria for the current study and received a complete course of RT of at least 7000 rad tumor dose administered to the nasopharynx within 7 weeks of diagnosis. No patients had multiple foci of NPC. Head and neck CT, Tc-MIBI SPECT, and FDG-PET were performed four months after the completion of RT to detect recurrent or residual NPC. After completion of head and neck CT, Tc-MIBI SPECT, and FDG-PET studies, biopsies were taken from the irradiated nasopharyngeal regions of all 36 patients, and the diameter of the largest dimension of each lesion was determined. In the current study, head and neck CT, Tc-MIBI SPECT, FDG-PET, and biopsies were all performed within one week.
Computed tomography of the head and neck was performed in the axial and coronal planes after the intravenous injection of contrast medium. Computed tomography scans were obtained with a Somaton DRH CT scanner (Siemens, Erlamgen, Germany) with an axial section thickness of 5 mm from skull base to manubrium. Resulting CT images were reviewed by two experienced radiologists without knowledge of the biopsy findings. The diagnostic criterion for a positive CT finding was the presence of a mass or asymmetry in the nasopharynx beyond that regarded as expected a post-RT change (Figs. 1–3).1
A commercial MIBI preparation (maximum 150 mCi [5.56 GBq] in approximately 1-3 mL) was obtained from DuPont Company (Cardiolite; Dupont Pharmaceuticals Co., Bellerica, MA). Labeling and quality control procedures were carried out according to the manufacturer's instructions. Labeling efficiencies were always higher than 95%. Thirty minutes before intravenous injection of Tc-MIBI, patients were pretreated with 500 mg perchlorate to prevent the uptake of free Tc-99m-pertechnetate in the salivary glands. The Tc-MIBI SPECT of head and neck was performed 10 minutes after the intravenous injection of 740 MBq (20 mCi) Tc-MIBI. Each patient was positioned supine on the imaging table with the forehead and chin strapped to prevent motion. The equipment consisted of a rotating, large field of view gamma camera (Apex 609R, Elscint Ltd., Haifa, Israel) fitted with a low-energy, high-resolution collimator (APC 4R, Elscint Ltd.). Sixty images were acquired for 10 seconds each through 360° of camera rotation. Each image was stored in a 64 × 64 pixel matrix. Reconstruction of the image was performed with attenuation correction, using Hanning filters to produce transaxial slices. These were reoriented parallel to the base of the brain, and sagittal and coronal reconstructions were then obtained. Abnormal Tc-MIBI uptake in the nasopharyngeal areas, other than physiologic uptake (pituitary glands, nasal and oral cavity, bilateral pharyngeal recesses, maxillary sinuses, parotid, palatine, submandibular and sublingual salivary glands), was considered positive for recurrent or residual NPC. If there was no abnormal Tc-MIBI uptake in the nasopharyngeal areas, Tc-MIBI SPECT was interpreted as negative (Figs. 1-3). The Tc-MIBI SPECT images were interpreted by two experienced physicians (C.H.K. and Y.C.S.) via a consensus regarding the findings.
Patients fasted overnight before the FDG-PET. No patient in the current study was found to have a glucose level higher than 120 g/dL. We performed FDG-PET imaging using a GE advance PET scanner (GE Medical Systems, Milwaukee, WI). The GE advance PET scanner produces 4.25 mm thick image planes (18 direct planes and 17 cross planes). The axial field of view was 15 cm and the full-width of the half maximum was 5 mm. Each patient was positioned so that the head and neck were inside the scanner with the nasopharyngeal regions in the center of the field of view. The landmarks for positioning were determined from the CT scans. Transmission scans using a rotating Ge-68 pin source were performed on all patients prior to injection of FDG. Transmission images were reconstructed using filtered back-projection and smoothed with a 7 mm wide Hann window. Emission imaging began 30 minutes after intravenous injection of 370 Mbq (10 mCi) FDG. Emission images of the head and neck were acquired for 20 minutes. Approximately 1 million counts per plane were obtained. Emission images were reconstructed by the filtered back-projection method using a 5 mm wide Hann filter. Emission data were corrected for scatter, random events, and deadtime. Image pixel size was 3 mm in a 128 × 128 array. The transversal PET images were individually reoriented into coronal planes to obtain a better view of the nasopharynx. Two experienced nuclear medicine physicians (C.H.K. and Y.Y.S. or C.H.K. and R.F.Y.) without prior knowledge of the CT and Tc-MIBI SPECT findings or final histopathologic confirmation independently evaluated the images. As no definite FDG-PET criteria exist for determining recurrent NPC, lesions with radioactivity greater than radioactivity of contralateral or neighboring normal aerodigestive mucosa were considered positive (Figs. 1-3).4, 5
From histopathologic confirmation, 25 of the 36 patients had benign fibrosis and 11 had malignant lesions of recurrent or residual NPC. The sensitivity, specificity, and accuracy of CT were 73%, 88%, and 83%, respectively. Eight CT findings were true positive, 3 were false positive, 22 were true negative and 3 were false negative (Table 1). The smallest recurrent or residual NPC detected by CT was 6 mm. The sensitivity, specificity, and accuracy of Tc-MIBI SPECT were 73%, 96%, and 89%, respectively. Eight Tc-MIBI SPECT findings were true positive, 24 were true negative, 1 was false positive and 3 were false negative (Table 1). The smallest recurrent or residual NPC detected by Tc-MIBI SPECT was 9 mm. The sensitivity, specificity, and accuracy of FDG-PET were 100%, 96%, and 97%, respectively. Eleven FDG-PET SPECT findings were true positive, 24 were true negative, and 1 was false positive. There were no false negative FDG-PET findings (Table 1). The smallest recurrent or persistent NPC detected was 6 mm.
Table 1. Distribution of CT, Tc-MIBI SPECT and FDG-PET Findings versus Biopsy Results
In five cases there were congruently positive findings of CT and Tc-MIBI SPECT. In 22 cases there were congruently negative findings of CT and Tc-MIBI SPECT. The sensitivity, specificity, and accuracy of combined CT and Tc-MIBI SPECT were the same as for FDG-PET (100%, 96%, and 96%, respectively) in these 28 NPC patients. Five findings were true positive, 22 were true negative, 1 was false –positive, and none were false-negative (Table 2). For eight NPC patients with incongruent results between CT and Tc-MIBI SPECT, FDG-PET correctly differentiated two benign lesions and six recurrent or residual NPCs (Table 1).
Table 2. Distribution of Congruent CT/Tc-MIBI SPECT and FDG-PET Findings versus Biopsy Results
Congruent CT and Tc-MIBI SPECT
CT: computed tomography; Tc-MIBI: technetium-99m methoxyisobutyliso nitrile; SPECT: single photon emission computed tomography; FDG-PET: 18-fluoro-2-deoxyglucose position emission tomography.
Nasopharyngeal carcinoma is very common in southern China, occurring in 10-30 people per 100,000 per year, and is distinct from other head and neck cancers. Radiotherapy is the mainstay of treatment but has several drawbacks.12, 13 Early diagnosis and accurate identification of recurrent or residual NPC are essential for proper patient management.14 Currently, CT is the first line imaging modality of choice and is used to outline the NPC involved anatomical planes.15, 16 However, following RT, there are a variety of changes, such as edema, loss of tissue planes, fibrosis, and scarring, which may interfere with the detection of recurrent or residual NPC. Computed tomography cannot differentiate between inflammatory tissue, post-RT fibrosis, and recurrent or residual tumors, consequently falling short of providing reliable indices of the presence or absence of recurrent or residual NPC.17, 18 Therefore, in the current study, three cases had false positive CT findings and three cases had false negative CT findings (Table 1).
In the tumor cell, Tc-MIBI binds to the cytosol, as in the myocardium;19, 20 Tc-MIBI is cationic and lipophilic. The mitochondrial/plasma membrane potentials and cellular mitochondrial content of tumor cells can all play significant roles in tumor uptake of this agent. The uptake may also be influenced by an indirect phenomenon, such as increased tumor blood flow or capillary permeability.19, 20 In the current study, false negative results of Tc-MIBI SPECT in three patients with recurrent or residual NPC could be attributed to the small diameters (< 9 mm) of the lesions in relation to the resolution of the camera and partial volume effects. In addition, significant scatter effects from physiologic but intense Tc-MIBI uptake of the salivary glands may also decrease the sensitivity of Tc-MIBI SPECT for detecting recurrent or residual NPC (Figs. 1–3). In the current study, the sole case of a false positive Tc-MIBI SPECT finding was probably due to the accumulation of Tc-MIBI in an inflammatory lesion.21 In addition, we found that determining the precise location and the relationship between the recurrent or residual NPC and the surrounding structures is difficult using Tc-MIBI SPECT alone (Figs. 1–3). Therefore, a combination of anatomic imaging, such as CT with Tc-MIBI SPECT, is necessary to ascertain the location of recurrent or residual NPC.
For distinguishing recurrent or residual NPC (increased radioactivity) from fibrosis or scar tissue (reduced radioactivity) in irradiated fields with distortion of normal architecture, FDG-PET is definitely superior to CT.4, 5 In the current study, very good results were obtained from visual interpretation with sensitivity of 100%, specificity of 96%, and accuracy of 97%. However, some clinical22, 23 and laboratory studies24 have shown increased FDG uptake in inflammatory tissues. In the current study, one case showed accumulated FDG in benign and inflammatory tissues. However, FDG-PET correctly diagnosed all nine cases with incongruent findings between CT and Tc-MIBI SPECT. Because both primary NPC and neighboring metastatic lymph nodes have similar high FDG uptakes, and due to a lack of FDG uptake, no normally anatomic landmarks could be seen on FDG-PET images as references; we do not think that FDG-PET can differentiate primary NPC and neighboring metastatic lymph nodes.4, 25
We conclude that FDG-PET is the best tool to detect recurrent or residual NPC among the three imaging modalities. However, the combined use of CT and Tc-MIBI SPECT could reach the same sensitivity, specificity, and accuracy as FDG-PET. Because of the high cost and lack of availability, FDG-PET should be considered only when incongruent results exist between CT and Tc-MIBI SPECT for differentiating benign lesions and recurrent or residual NPC.