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Journal of Clinical Oncology, Vol 24, No 27 (September 20), 2006: pp. 4371-4376 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.7349 Prospective Study of [18F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography and Magnetic Resonance Imaging in Oral Cavity Squamous Cell Carcinoma With Palpably Negative Neck
From the Departments of Diagnostic Radiology, Nuclear Medicine, Radiation Oncology, Medical Oncology, Pathology, and Otorhinolaryngology and Molecular Imaging Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan, Republic of China Address reprint requests to Chun-Ta Liao, MD, Department of Otorhinolaryngology, Chang Gung Memorial Hospital, Linkou Medical Center, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan; e-mail: liaoct{at}adm.cgmh.org.tw
PURPOSE: To assess the clinical usefulness of [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) as well as computed tomography (CT) or magnetic resonance imaging (MRI) in oral squamous cell carcinoma (SCC) patients with palpably negative neck. PATIENTS AND METHODS: In total, 134 oral SCC patients with palpably negative neck were prospectively evaluated with [18F]FDG PET, CT/MRI, and their visual correlation. Histopathologic analysis was used as the gold standard for assessment of these imaging techniques. RESULTS: Thirty-five (26.1%) of our 134 patients were found to have neck metastases. On a level-by-level basis, the sensitivity of [18F]FDG PET for nodal metastases was two-fold higher than that of CT/MRI (41.2% v 21.6%, respectively; P = .021). Visual correlation of [18F]FDG PET and CT/MRI yielded slightly higher sensitivity and specificity than [18F]FDG PET alone (47.1% v 41.2%, P = .25; 98.0% v 96.8%, P = .125, respectively). On a patient-by-patient basis, the sensitivity of [18F]FDG PET for neck metastases was 51.4% and increased to 57.1% after visual correlation with CT/MRI. The probabilities of occult neck metastasis after using [18F]FDG PET were 6.7% in T1 tumors, 10.8% in T2 tumors, 13.3% in T3 tumors, and 25% in T4 tumors and decreased to 3.3% in T1 tumors and to 9.2% in T2 tumors after visual correlation with CT/MRI. CONCLUSION: [18F]FDG PET was superior to CT/MRI for detecting palpably occult neck metastasis of oral SCC. Because [18F]FDG PET could reduce the probability of occult neck metastasis to less than 15% in T1 to T3 tumors, it should be indicated for evaluation of these subpopulations.
The presence of cervical nodal metastasis is one of the most important prognostic factors in head and neck squamous cell carcinoma (SCC). However, the proper management of oral SCC patients with a clinically negative neck remains controversial. Such patients are known to be at risk for nodal metastases and usually undergo an elective neck treatment, either neck dissection or radiotherapy. The disadvantage of this strategy is that most patients do not harbor metastases, and therefore, they may be subjected to additional costs and the morbidity of unnecessary treatment.1 Treatment polices can be determined by considering the probability of nodal metastases. Elective neck treatment is thought to be indicated if the risk of occult metastasis is judged to be greater than 15% to 20%.1-3 Currently, computed tomography (CT) or magnetic resonance imaging (MRI) is usually used for preoperative assessment of the primary tumor and cervical status. These imaging techniques are comparable to each other in detecting cervical metastasis and may detect some occult nodal metastases missed by physical examination.4-6 However, their reported capability to detect small cancerous nodes is limited.3,7-10 [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) has been reported to be more accurate than CT/MRI in identifying cervical nodal metastasis of head and neck cancer,11-17 with the reported sensitivities ranging from 72% to 96% and specificities ranging from 83% to 100%. Up to now, only seven articles about [18F]FDG PET for the evaluation of clinically negative neck in oral SCC patients have been published,18-24 and the results and clinical implications of these studies were diverse. All seven studies were performed on small populations (eight to 19 individuals) and reported sensitivities ranging from 0% to 100%. Some authors suggested that [18F]FDG PET might be a promising diagnostic aid in the evaluation of clinically negative necks,18-20 whereas others claimed that it might not be useful.22-25 The methodology used to calculate sensitivity and specificity in these studies depended on patient numbers or neck sides. Thus, the actual data may be difficult to interpret if [18F]FDG PET results differ in different sites of the same neck or of the same patients. Indeed, correlation of imaging results with histopathologic findings on the basis of neck levels would be more reliable because the current CT/MRI imaging-based nodal classification system based on neck levels is widely used for evaluating cervical nodes.25,26 The clinical usefulness of [18F]FDG PET in patients with oral SCC with clinically negative necks is still indeterminate. In some institutions, [18F]FDG PET is used to evaluate patients with early oral SCC, and a wait-and-watch policy may be adopted in patients with a negative [18F]FDG PET. However, the probability of [18F]FDG PET occult nodal metastasis in such a scenario has not been documented. In addition, although it has been reported that visual correlation of [18F]FDG PET with CT/MRI can increase diagnostic accuracy over [18F]FDG PET alone,17,27,28 the clinical efficacy of such combined use in oral cavity SCC with palpably negative neck has not been investigated. In this prospective study, we aimed to assess the clinical usefulness of [18F]FDG PET, CT/MRI, and their visual correlation in oral SCC patients with palpably negative neck.
Patients The institutional review board of our hospital approved this study, and written informed consent was obtained from all enrolled subjects. From January 2003 to December 2005, a total of 134 patients were prospectively recruited onto this study (129 men and five women; average age, 52.1 years; range, 26 to 82 years). The inclusion criteria were a clinical diagnosis of SCC in the oral cavity without a palpable lymph node in the neck, no prior treatment to the head or neck region, and having been scheduled for surgery. Those patients with other severe medical comorbidities, known distant metastasis, or second primary tumors were excluded. Among our 134 patients, tumors originated from the following sites: tongue (n = 51; 38.1%), buccal mucosa (n = 50; 37.3%), gum (n = 24; 17.9%), retromolar trigone (n = 4; 3.0%), lip (n = 2; 1.5%), mouth floor (n = 2; 1.5%), and hard palate (n = 1; 0.7%). Thirty patients had a tumor stage of T1, 65 had a stage of T2, 15 had a stage of T3, and 24 had a stage of T4. Preoperative evaluation was accomplished within 2 weeks before surgery. All patients were imaged using [18F]FDG PET, whereas 109 of our 134 patients received MRI, and the remaining 25 patients received CT.
[18F]FDG PET
CT/MRI
Image Interpretation and Analysis
CT/MRI was interpreted in a blinded fashion by two radiologists, and any disagreement was resolved by consensus. The radiologists compiled the same checklist, using the same 5-point scale. Nodes were considered metastatic if their shortest axial diameter was The nuclear medicine physicians and radiologists met weekly to perform visual correlation of the [18F]FDG PET and CT/MRI images by viewing the corresponding images side by side. They resolved any discordance by consensus. Differences in overall sensitivity and specificity between the imaging modalities were tested for statistical significance by the McNemar test. To compare the diagnostic accuracy of the imaging procedures, a receiver operating characteristic (ROC) analysis using the method of Metz29 was performed, and the area under the ROC curve was calculated.
Histology
All of our patients underwent primary tumor resection and neck dissection. Of 134 patients, 125 underwent level I to III dissection, six underwent level I to IV dissection, and the remaining three underwent level I to V dissection. Of the 457 neck levels (6,233 nodes) resected in all of our 134 patients, 51 neck levels (91 nodes) contained metastatic disease in 35 patients (26.1%). Among the 51 affected neck levels, 27 (52.9%) occurred at the ipsilateral level I, 15 (29.4%) occurred at the ipsilateral level II, six (11.8%) occurred at the ipsilateral level III, and one each (2.0%) occurred at the ipsilateral level IV, contralateral level I, and contralateral level III. Grossly, the mean size of these 91 metastatic nodes was 9.6 ± 3.2 mm. Microscopically, the mean size and the mean percentage of intranodal tumor deposit were 4.4 ± 3.2 mm and 47.1% ± 30.8%, respectively. None of our patients were found to have distant metastases or second primary tumors. The results of CT/MRI, [18F]FDG PET, and their visual correlation in identifying metastatic neck nodes of our patients are listed in Table 1. On a level-by-level basis, the sensitivity of [18F]FDG PET was two-fold higher than that of CT/MRI (41.2% v 21.6%, respectively; P = .021), whereas the specificity of [18F]FDG PET was 0.7% lower than that of CT/MRI (96.8% v 97.5%, respectively; P = .607). The sensitivity of [18F]FDG PET was highest at level II and lowest at level III, whereas the specificity of [18F]FDG PET was highest at level III and lowest at level I. The area under the ROC curve showed that the diagnostic performance of [18F]FDG PET exceeded that of CT/MRI (0.742 v 0.674, respectively; P = .184). Visual correlation of [18F]FDG PET and CT/MRI yielded higher sensitivity and specificity than [18F]FDG PET alone (47.1% v 41.2%, P = .25; 98.0% v 96.8%, P = .125, respectively). The area under the ROC curve showed that the diagnostic performance of their visual correlation was significantly better than CT/MRI alone (0.773 v 0.674, respectively; P = .031) but was only modestly better than [18F]FDG PET alone (0.773 v 0.742, respectively; P = .234; Fig 1).
The sensitivity of MRI was slightly higher than CT (22.2% v 20.0%, respectively; P = .86), whereas their specificities were similar (97.5% v 97.3%, respectively; P = .883). CT/MRI findings were positive in 21 neck levels, of which 11 were truly positive and 10 were falsely positive. Five of the 11 true-positive levels harbored necrotic nodes. In the 10 false-positive levels of CT/MRI, [18F]FDG PET showed true-negative findings in four levels. However, CT/MRI failed to identify metastatic neck disease in 40 levels, in which [18F]FDG PET showed true-positive results in 13 levels (Fig 2) but showed false-negative results in the other 27 levels (Figs 3 and 4).
[18F]FDG PET had positive findings in 34 neck levels, of which 21 were truly positive and 13 were falsely positive. Among the 13 false-positive [18F]FDG PET results, 10 were caused by reactive or inflammatory nodes. The other three were caused by misinterpretation of mouth angle abscess (n = 1) and tumor invasion to the submandibular space (n = 2) as the level I nodal metastases. [18F]FDG PET findings were negative in 423 neck levels, of which 393 were truly negative and 30 were falsely negative. Compared with the [18F]FDG PET true-positive nodes, the mean gross nodal size of the [18F]FDG PET false-negative nodes was 18.3% smaller (8.9 v 10.9 mm, respectively; P = .024), whereas their mean size of microscopic intranodal tumor deposits was 54.5% smaller (3.0 v 6.6 mm, respectively; P < .0001). Of the 30 neck levels where [18F]FDG PET was falsely negative for metastatic neck disease, CT/MRI showed true-positive findings at three levels that harbored metastatic nodes with central necrosis. On a patient-by-patient basis, [18F]FDG PET had negative findings in 108 patients, of whom 91 were truly negative and 17 were falsely negative. Of the 91 patients with true-negative results, 26 had T1 tumors, 47 had T2 tumors, eight had T3 tumors, and 10 had T4 tumors. The sensitivity of [18F]FDG PET for neck metastases was higher than that of CT/MRI (51.4% v 31.4%, respectively; P = .065). Visual correlation of [18F]FDG PET and CT/MRI showed a trend of modestly increased sensitivity compared with [18F]FDG PET alone (57.1% v 51.4%, respectively; P = .5). Among our 35 patients with pathologically positive nodes, the frequency of palpably occult neck metastasis increased with increasing T stage (13.3% in T1 patients, 23.1% in T2, 33.3% in T3, and 45.8% in T4; Table 2). The frequency of occult neck metastases after CT/MRI, PET, and their visual correlation increased with increasing T stage as well. In our 30 patients with T1 tumors, the false-negative rates of [18F]FDG PET, CT/MRI, and their visual correlation were 6.7%, 10.0%, and 3.3%, respectively. In our patients with T2 tumors, the false-negative rate of [18F]FDG PET was 10.8%, but this rate decreased to 9.2% after visual correlation with CT/MRI. In our patients with T3 and T4 tumors, the false-negative rates of [18F]FDG PET were 13.3% and 25%, respectively, and neither of these rates decreased after visual correlation with CT/MRI.
In patients with oral SCC without palpable lymph nodes in the neck, there is always a risk of subclinical metastases. In our study, 35 (26.1%) of 134 patients with negative necks on clinical palpation were subsequently found to have cervical nodal metastases. These occult metastases commonly occurred at neck levels I and II, accounting for 84.3% of cases. They were occasionally found at level III (13.8%), rarely at level IV (2%), and never at level V. Of note, the frequency of palpably occult neck metastasis was related to T stage, ranging from 13.3% in T1 patients to 45.8% in T4 patients. Our results showed that [18F]FDG PET was twice as sensitive as CT/MRI for detecting cervical nodal metastasis of oral SCC patients with palpably negative neck. The difference in the mean size between false-negative [18F]FDG PET nodes and true-positive [18F]FDG PET nodes was statistically significant, whereas the difference in the mean size of their intranodal tumor deposits was even greater. These results imply that the detection of subclinically metastatic nodes in [18F]FDG PET not only depends on the nodal size but also, to a greater degree, on the intranodal tumor burden. In contrast to most published studies,7,11-14,30 our study showed that the specificity of [18F]FDG PET was marginally lower than that of CT/MRI. False-positive [18F]FDG PET results were predominantly a result of the inherent inability of [18F]FDG PET to differentiate some inflammatory processes from tumor infiltration and partly a result of spatial inaccuracies. Of the 13 false-positive neck levels, only three (23.1%) were a result of misinterpretation of the lesions in the mouth angle or submandibular gland as the level I metastatic adenopathy stemming from poor spatial resolution of [18F]FDG PET. Visual correlation of [18F]FDG PET with CT/MRI has been reported to be more diagnostically accurate than [18F]FDG PET alone.17,27,28 Our study showed that such visual correlation did yield an increase in accuracy compared with [18F]FDG PET alone in detecting subclinical neck metastases. This increment stemmed from the correction of false-negative [18F]FDG PET results caused by necrotic nodes and false-positive [18F]FDG PET results caused by spatial inaccuracy. However, this improvement was not statistically significant, presumably because of the fact that such correlation could not overcome the main diagnostic dilemmas in [18F]FDG PET, namely, false-negative results caused by small intranodal tumor deposits and false-positive results caused by inflammatory changes. Hybrid PET/CT is an imaging modality that permits anatomic and functional imaging on a single scanner with nearly perfect coregistration. It is more accurate than PET alone, CT alone, and probably their visual correlation. However, its usefulness in oral cavity SCC with palpably negative neck has not been defined. In clinical practice, the decision to adopt elective neck treatment or a wait-and-watch policy depends on the probability of occult neck metastasis of the patient rather than the neck level.1-3 Thus, analysis of the sensitivity of imaging studies on a patient-by-patient basis, although less accurate than on a neck-level basis, should be applicable to this clinical situation. In this study, the overall sensitivity of [18F]FDG PET for detecting palpably occult nodal metastasis per patient was 51.4%, and it increased to 57.1% after visual correlation with CT/MRI. By stratifying the false-negative findings on the basis of tumor stage, the probabilities of occult neck metastasis after using [18F]FDG PET were 6.7% in T1 tumors, 10.8% in T2 tumors, 13.3% in T3 tumors, and 25% in T4 tumors. With visual correlation of [18F]FDG PET and CT/MRI, the probability of occult neck metastasis was reduced to 3.3% for T1 tumors and to 9.2% for T2 tumors, but it remained 13.3% for T3 tumors and 25% for T4 tumors. Because [18F]FDG PET could reduce the probability of occult neck metastasis to less than 15% in T1 to T3 tumors, it should be indicated for evaluation of these subpopulations. A negative [18F]FDG PET could justify a wait-and-watch policy in 92 of our 110 patients with T1 to T3 tumors because the probabilities of occult neck metastasis were acceptable, ranging from 7% to 13%. Visual correlation with CT/MRI is always recommended whenever CT/MRI is available because this technique may detect necrotic metastatic nodes occasionally missed by [18F]FDG PET and may correct some spatial inaccuracies of [18F]FDG PET. However, [18F]FDG PET, even visually correlated with CT/MRI, was unable to reduce the risk of occult neck metastasis to below 20% in T4 tumor patients, and neck treatment should be mandatory regardless of [18F]FDG PET results. Therefore, we do not recommend [18F]FDG PET to evaluate T4 oral SCC patients with palpably negative neck. Overall, we estimated that 92 (68.7%) of our 134 patients might avoid elective neck treatment. Of these 92 patients, 81 had positive impact from true-negative [18F]FDG PET results, whereas 11 had negative impact from false-negative [18F]FDG PET results. Further study is warranted to assess the cost effectiveness of [18F]FDG PET used in T1 to T3 oral SCC patients with palpably negative neck.
The authors indicated no potential conflicts of interest.
Supported in part by Grant No. NSC 94-2314-B-182A-109 from the National Science Council-Taiwan and Grants No. CMRPG-32034 and CMRPG-32039 from the Chang Gung Memorial Hospital. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
11 mm in the jugulodigastric region or 
