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Clinical Investigations |
1 Department of Diagnostic Radiology, Chang Gung Memorial Hospital and Chang Gung University, Taiwan
2 Department of Nuclear Medicine and Animal Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taiwan
3 Department of Otorhinolaryngology, Chang Gung Memorial Hospital and Chang Gung University, Taiwan
4 Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taiwan
5 Department of Medical Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: 18F-FDG • PET • head and neck neoplasms • cervical lymph nodes
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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18F-FDG PET is a functional imaging technique that provides information about tissue metabolism and has been successfully applied to the evaluation of head and neck cancer. Currently available data from 15 studies (3, 5, 7–19) demonstrate large variations in sensitivity and specificity for 18F-FDG PET in the detection of cervical lymph node metastases in head and neck cancers. These ranged from 67% to 96% for sensitivity and from 82% to 100% for specificity. A review of these studies showed that the majority of the series had small population sizes. Only 4 of 15 series had a patient number of >50, and only 1 series (17) had a patient number of >100 (n = 106). The methodology for calculating sensitivity and specificity also differed among these studies, with some based on patient numbers, some based on neck sides, and the remainder based on individual node numbers. Evaluation based on node numbers usually gives a more favorable specificity, because neck dissection typically reveals a large number of tumor-free lymph nodes. Another problem is that it may be difficult to accurately estimate the true number of foci on images with several contiguous foci using 18F-FDG PET. On the other hand, if 18F-FDG PET has different results in different sites of the same neck or of the same patient, one cannot accurately define the sensitivity and specificity based on neck sides or patient numbers. For instance, some patients may demonstrate true-positive nodes at one neck level but false-negative nodes at the other levels. Since neck dissection with histologic examination is currently the most reliable staging procedure, and recording of the cervical nodal location on morphologic imaging (CT or MRI) and neck dissection generally adopts the system of neck levels according to the imaging-based nodal classification (20), correlation of imaging results with surgical pathology based on neck levels would be more reliable. Therefore, the calculation of the sensitivity and specificity of 18F-FDG PET based on neck levels would be a better method. However, to our knowledge, no previous studies using this criterion have been reported. In addition, it has been shown that the visual correlation of 18F-FDG PET with CT or MRI can have better diagnostic accuracy than 18F-FDG PET alone in the evaluation of lung cancer and nasopharyngeal carcinoma (21, 22), but the actual usefulness of such combined use in oral cavity SCC is unknown. Therefore, we conducted a prospective study to determine the usefulness of 18F-FDG PET, CT/MRI, and their combined use in the detection of primary tumors and neck lymph node involvement of SCC of the oral cavity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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200 ng/mL. Among the 124 patients, 52 (41.9%) had tumors originating from the buccal mucosa, 48 (38.8%) from the tongue, 19 (15.3%) from the gum, 3 (2.4%) from the mouth floor, and 2 (1.6%) from the retromolar trigone. Of the 124 patients, 16 (12.9%) had T1 tumor stage, 56 (45.2%) had T2 tumor stage, 19 (15.3%) had T3 tumor stage, and 33 (26.6%) had T4 tumor stage. In these patients, the preoperative evaluation was accomplished using 18F-FDG PET for all patients (n = 124) as well as MRI (n = 82) and CT (n = 42) within 2 wk before surgery.
18F-FDG PET
The Institute of Nuclear Energy Research of Taiwan produced the 18F-FDG used for the PET studies. All 18F-FDG PET scans were acquired with a dedicated PET system (ECAT EXACT HR+; Siemens/CTI), using a 4.5-mm full width at half maximum and a transaxial field of view of 15 cm. All patients abstained from food and drink for 6 h before undergoing PET. After intravenous injection of 370 MBq (10 mCi) of 18F-FDG, the patients were kept at rest in a quiet, dimly lit room for at least 40 min. Talking, walking, or other physical activities were avoided to reduce muscle uptake.
During imaging, patients kept their arms still over their head, aided by a headrest and a holding bar. We obtained transmission scans with 68Ge rod sources. We obtained the emission and transmission scans in an alternating sequence per bed position. Reconstruction of both transmission and emission scans used accelerated maximum-likelihood reconstruction and ordered-subset expectation maximization, which reduces image noise and avoids reconstruction artifacts resulting from filtered backprojection reconstruction of data with low count densities. We viewed maximum-intensity-projection images on a workstation that allowed simultaneous display of coronal, sagittal, and transverse planes as well as a 3-dimensional rotating projection.
CT/MRI
CT was performed with patients in the supine position with contrast axial scans parallel to the ramus of the mandible from the skull base to the supraclavicular fossa with a 5-mm-thick contiguous section. We also obtained contrast coronal scans with a 3-mm-thick contiguous section. The field of view varied between 16 and 18 cm, depending on the size of the patient. In addition to the soft-tissue window settings, we reconstructed all images with bone algorithms.
All patients underwent MRI with a 1.5-T unit (Vision; Siemens) using spin-echo technique before and after injection of gadolinium diethylenetriaminepentaacetic acid (DTPA). We used a head coil to examine the region from the superior margin of the temporal lobe to the level of the hyoid bone. We then used a neck coil to examine the rest of the neck and the supraclavicular fossa. Unenhanced T1-weighted images were acquired in the sagittal and axial planes with a spin-echo 500/20 (repetition time/echo time, in ms) sequence, a 20-cm field of view, and a 192 x 256 matrix. Axial and coronal T2-weighted fat-suppressed fast-spin-echo images (3,000/85 [effective], 16–echo train length) were also obtained. Section thickness was 5 mm without interslice gap in the axial projection and 4 mm without interslice gap in the sagittal and coronal projections. After gadolinium DTPA injection at a dose of 0.1 mmol/kg of body weight, we obtained T1-weighted fat-suppressed axial, sagittal, and coronal sequences sequentially, with parameters similar to those used before the gadolinium DTPA injection.
Image Interpretation and Analysis
For correlative analysis of nodal staging of 18F-FDG PET, CT/MRI, and the histopathologic examination, the neck was divided into levels based on imaging-based nodal classification (20). Level I corresponds to the submental and submandibular nodes. Level II contains the upper jugular nodes from the level of the skull base to the hyoid bone. Level III contains the middle jugular nodes from the level of the hyoid bone to the cricoid cartilage. Level IV contains the lower jugular lymph nodes from the level of the cricoid cartilage to the clavicle. Level V contains the spinal accessory nodes situated posterior to the posterior edge of the sternocleidomastoid muscle. The surgical specimens were referenced to this schema in terms of the position of malignant histologic foci or normal lymph nodes.
Three experienced nuclear medicine physicians interpreted the 18F-FDG PET studies individually by visual inspection of the scans in transverse, sagittal, and coronal sections. They had no knowledge of the CT/MRI or clinical findings. They evaluated foci of increased 18F-FDG uptake with reference to the normal tissue and scored the 18F-FDG uptake on a 5-point scale: 0 = no abnormal uptake, 1 = benign, 2 = probably benign, 3 = probably malignant, and 4 = definitely malignant. Both grade 3 and grade 4 were considered to be positive results for tumor involvement. A checklist of the distributions of the primary tumors and their metastatic nodes was recorded accordingly. We resolved any initial differences of opinion by consensus. We did not use standardized uptake values for this study, because these numbers cannot provide meaningful help in discriminating between metastatic and reactive lymph nodes (10, 13, 15).
CT or MRI was interpreted in a blinded fashion by 2 radiologists with experience in this field. Any disagreements were resolved by consensus. The radiologists compiled the same checklist using the same 5-point scale as applied to the 18F-FDG PET images. Nodes were considered metastatic if their shortest axial diameter was 11 mm in the jugulodigastric region or 10 mm in other cervical regions, if central necrosis or irregular borders were present, or if there was a cluster of 3 or more lymph nodes of borderline size.
To determine the accuracy of visual correlation of 18F-FDG PET and CT/MRI in evaluation of oral cavity SCC, the nuclear medicine physicians and the radiologists met weekly to view the 18F-FDG PET and CT/MR images side-by-side. The same checklist was complied together and solved any discordance by consensus.
The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 18F-FDG PET and CT/MRI were calculated based on neck levels. In subcategorizing the nodes by level, the numbers per level were reduced and the confidence intervals in each level thereby would become wider. To compensate for this problem and to get more statistically significant data, we grouped all levels together for our results. Differences in cumulative sensitivity and specificity between the imaging modalities were tested for statistical significance using the McNemar test. In addition, to compare the diagnostic accuracy of the imaging procedures, a receiver-operating- characteristic (ROC) curve analysis using the method of Metz (23) was performed, and the area under the ROC curve (area under the curve) was calculated for each modality and compared statistically.
Surgical Procedure or Histology
Neck dissection was planned by our head and neck surgical team based on the clinical and imaging findings. Supraomohyoid neck dissection (levels I–III) was performed in patients with negative neck or a single positive node in the upper neck. Extended supraomohyoid neck dissection (levels I–IV) or modified radical neck dissection (levels I–V) was performed in those patients with >1 involved node or extracapsular nodal spread, depending on the extent of the cervical adenopathy. Bilateral neck dissection was performed in patients with the primary tumor crossing the midline or with probably metastatic nodes in the contralateral neck. The operative surgeon labeled primary tumor and neck dissection specimens in such a way that one could reference the schema used in the interpretation of the 18F-FDG PET and CT/MRI studies. Lymph nodes and tumors were dissected from the specimens and stained with hematoxylin and eosin for histologic analysis. Serial histologic sections were used. An experienced anatomic pathologist examined the specimens and recorded the size of tumor deposition within the affected nodes. In cases with equivocal findings for tumor deposition, cytokeratin stain was performed. We compared the results of preoperative imaging examinations with the results of corresponding histopathologic examinations.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Primary Tumors
18F-FDG PET correctly identified the primary tumor in 122 of the 124 patients. There were only 2 false-negative study results for the detection of the primary tumors (accuracy for the detection of primary tumors): one was a superficial tumor that occurred in the left lateral tongue with histopathologic dimensions of 1.0 x 1.0 x 0.1 cm; the other tumor was a mouth floor SCC, which was misinterpreted as a tongue SCC on the 18F-FDG PET scan. In contrast, CT/MRI correctly identified 108 of the 124 oral cavity SCCs (accuracy, 87.1%). An artifact caused by a metallic dental prosthesis obscured the site of primary tumors in 7 of the 16 false-negative CT/MRI results. The other 9 lesions were small tumors with a T-stage of T1 (i.e., <2 cm in their greatest dimension). Of the 16 primary tumors not identifiable with CT/MRI, 18F-FDG PET detected 15 (Fig. 1). The visually correlated 18F-FDG PET and CT/MRI correctly identified 123 tumors with an accuracy of 99.2%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The present management of head and neck cancer mainly consists of resection of the primary tumor, which may be coupled with neck surgery or subsequent radiotherapy. It is evident from the literature (12, 15, 18) that 18F-FDG PET is very sensitive for detecting primary tumors in the oral cavity, and our data further support these findings. Our data demonstrate an accuracy of 98.4% for 18F-FDG PET in the detection of known primary tumors and of 85.1% for CT/MRI in this setting. 18F-FDG PET missed only 1 small tongue SCC and misinterpreted a mouth floor SCC as a tongue SCC. However, 18F-FDG PET does not provide the detailed information necessary for surgical planning of primary tumor resection, such as information regarding the depth of penetration and any change in neighboring structures. CT or MRI, by virtue of their better anatomic resolution, remain the methods of choice for evaluation of the primary tumor with reliable T-staging in 80%–90% of cases (25, 27). Nevertheless, 18F-FDG PET appears to be helpful for the identification of primary oral cavity tumors not seen in morphologic imaging modalities, particularly those obscured by dental artifacts.
The critical determinant of the utility of an imaging modality for oral cavity SCC is its ability to detect the presence or absence of metastatic neck disease. This information has the potential to alter the treatment plan and patient morbidity. At present, neck dissection with histologic examination is the most reliable staging procedure that provides important prognostic information, but it does involve the resection of a large amount of nondiseased tissue from the neck. In our study with 493 neck levels dissected, only 95 (19.3%) contained metastatic disease. In accordance with most published results (3, 7, 9, 11–16,19), our study showed that 18F-FDG PET was significantly superior to CT/MRI for identifying metastatic neck lesions (area under the curve, 0.911 vs. 0.794; P = 0.0026), with a significantly higher sensitivity (74.7% vs. 52.6%, P < 0.001). 18F-FDG PET disclosed metastatic lesions in approximately half of the morphologically benign nodes; however, the sensitivity of 18F-FDG PET was just 74.7%, and 24 of 95 pathologically positive neck levels (25%) were false-negative on 18F-FDG PET. Therefore, 18F-FDG PET does not provide sufficient information to limit surgical dissection or radiotherapy porta in the neck.
In affected lymph nodes, the size of the node and the size of the intranodal tumor deposits appear to vary widely. As seen in our series, the mean percentage of tumor deposit within the affected nodes was 69.31% ± 27.7%. Previous studies (17, 28) showed that the extent of the intranodal tumor deposit is a more limiting determinate than the nodal size. Wooglar et al. (29) have reported that micrometastases were found as the only metastases in 28% of clinically N0 side of the neck. Crippa et al. (28) subjected 38 patients to preoperative 18F-FDG PET and correlated the sensitivities for detection of nodal metastases with the nodal deposit diameter; they found a nonsignificant correlation between the size of a lymph node metastasis and the ability to detect it (17). On the contrary, 18F-FDG PET has technical resolution limitations of about 5 mm and, thus, is not likely to be able to detect small-volume disease, contributing to false-negative results. Our study showed that the mean intranodal tumor extent of 18F-FDG PET false-negative nodes was half that of 18F-FDG PET true-positive nodes (5.5 vs. 10.2 mm, P = 0.005), whereas the mean size of false-negative nodes was just slightly smaller than that of true-positive nodes (11.4 vs. 14.1 mm, P = 0.061). These results support the notion that intranodal tumor deposits play a determinate role in the sensitivity of 18F-FDG PET and suggest that 18F-FDG PET would be likely to miss those nodes with a mean tumor deposit of about 5.5 mm or less.
18F-FDG PET has been reported to have a higher specificity than CT/MRI in detecting cervical nodal disease in most of the published literature (3, 7, 9, 11–18). Only 2 articles (10, 19) reported that 18F-FDG PET had a lower specificity. Our study showed the specificity of 18F-FDG PET was just marginally lower than that of CT/MRI (93.0% vs. 94.5%, P = 0.345). False-positive 18F-FDG PET findings were mainly due to its inherent inability to discriminate inflammatory processes from tumor infiltration since high-level metabolic changes occur in both instances. Spatial inaccuracy contributed to a portion of the false-positive results. The relatively poor spatial resolution of 18F-FDG PET led to misinterpretation of submandibular gland lesions as level I metastatic adenopathy in 3 of our 28 (10.8%) false-positive neck levels.
Nodal central necrosis demonstrated on CT/MRI carries a very high specificity for nodal metastasis; however, the occurrence of such necrosis is not high. Nodal necrosis associates with the loss of viable tumor cells and may cause false-negative findings on 18F-FDG PET when the node is largely necrotic because few viable cells are available to accumulate the tracer (14). Our series demonstrated gross nodal necrosis in 16 of our 95 positive neck levels (16.8%) on CT/MRI, and these were not always associated with false-negative findings on 18F-FDG PET. Of the 16 necrotic nodal groups, only 3 were responsible for the false-negative results on 18F-FDG PET, whereas the remaining 13 still exhibited positive 18F-FDG uptake with nodular or rim configurations.
Some studies have reported that the visual correlation of 18F-FDG PET with CT/MRI has better diagnostic accuracy than 18F-FDG PET alone (21, 22, 30). In this large series of oral cavity SCC, we also evaluated neck levels for nodal metastasis with meticulous side-by-side visual correlation of 18F-FDG PET and CT/MRI. Combined use increased the sensitivity by 3.2% over 18F-FDG PET alone (77.9% vs. 74.7%, P = 0.25). This increment was due to correction of 3 false-negative 18F-FDG PET results attributed largely to necrotic nodes. The specificity of the combined use also increased by 1.5% over 18F-FDG PET alone (94.5% vs. 93.0%, P = 0.18), attributed to the correction of false-positive 18F-FDG PET results due to spatial inaccuracy. The area under the curve obtained from the ROC curve showed that the combined use had a slightly higher diagnostic accuracy than 18F-FDG PET alone (0.913 vs. 0.896, P = 0.28). However, this improvement is not statistically significant, presumably due to the fact that visual correlation of 18F-FDG PET and CT/MRI could not alleviate the main diagnostic difficulties inherent in 18F-FDG PET and CT/MRI, including some false-negative findings due to small intranodal tumor deposits and some false-positive findings due to inflammatory nodal hyperplasia. In our study, the sensitivity of the visual correlation of 18F-FDG PET and CT/MRI was 77.9%, and 21 of 95 pathologic positive neck levels (22%) were false-negative on this methodology. Therefore, its sensitivity was not high enough to replace pathologic lymph node staging of oral cavity SCC based on neck dissection.
Since imaging was used in the planning of neck dissection, some verification bias could have been introduced because the extent of neck dissection would vary with imaging findings. For instance, contralateral neck dissection was performed because imaging showed positive findings for contralateral nodal metastasis. However, this approach represents realistic daily clinical practice and, hence, such bias was essentially unavoidable.
Coregistration of 18F-FDG PET images with CT or MRI scans of the same patient can be performed by a computer algorithm to combine the images in one display using either anatomic landmarks or an automatic algorithm based on matching the pattern of signals from individual voxels. However, in clinical practice, it is time-consuming and somewhat difficult to accomplish due to variations in neck position (31). Recently, integrated PET/CT with simultaneous, coregistered anatomic and functional imaging has been introduced. It is more accurate than PET alone in the detection and anatomic localization of head and neck cancer (31). Such hybrid machines have also been reported to have significantly better diagnostic accuracy than visual correlation of PET and CT in the evaluation of lung cancer (32). If available, it would be worthwhile to test whether this novel technique provides such significant advantages for oral cavity SCC.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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For correspondence or reprints contact: Shu-Hang Ng, MD, Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Linkou Medical Center, 5 Fu-Shin St., Kueishan, Taoyuan 333, Taiwan.
E-mail: Shng6{at}ms25.hinet.net
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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