Abstract
The purpose of this study was to evaluate the use of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) to identify extracapsular spread (ECS) with histologic correlations in oral squamous cell carcinoma (OSCC). The medical records of 80 patients who underwent of FDG PET/CT for OSCC before surgery were reviewed. ECS was present in 60% (24/40) dissected necks and in 55% (39/71) of dissected cervical levels. A significant difference was found between the maximum standardized uptake (SUV max ) values of cervical lymph nodes with ECS and without ECS (3.33 ± 1.91 vs. 1.12 ± 1.24, p < 0.001). When receiver operating characteristic (ROC) curve analysis and SUV max values were used to detect ECS, the area under the ROC curve was 0.864 ± 0.045 ( p < 0.001). At an optimal SUV max cut-off value of 2.25 the sensitivity and specificity were 85% and 88%, respectively. The presence of ECS and a SUV max > 2.25 had a significant adverse effect on 5-year disease specific survival. A SUV max > 2.25 was found to be associated with a greater risk of cervical lymph node metastasis in OSCC.
Many variables have been implicated in the prognosis of oral squamous cell carcinoma (OSCC), but the presence of cervical lymph node metastasis remains the most significant prognostic indicator of survival and recurrence. The presence of lymph node metastasis reduces the 5-year survival rate by about 50%. A finding of extracapsular spread (ECS; defined histopathologically as penetration of tumour through the capsule of an involved lymph node) further decreases survival rates and increases the rates of regional recurrence and distant metastases, and the likelihoods of loco-regional recurrence and distant metastasis.
Computed tomography (CT) and magnetic resonance imaging (MRI) are used to diagnose ECS, which may be suspected when nodal margins are poorly defined or when soft tissue infiltration or stranding of muscles or fat in the neck is observed. The sensitivity of CT for the diagnosis of ECS is about 81% and its specificity about 72%, whereas the sensitivity and specificity of MRI range from 57% to 77% and 57% to 72%, respectively. At present, neck dissection with a histological examination is the most reliable means of diagnosing ECS, and it provides important prognostic information. There is a need for a noninvasive procedure that provides prognostic information of the same standard as histopathology.
Positron emission tomography (PET)/CT using 18 F-fluorodeoxyglucose (FDG) is being increasingly carried out for the staging and localization of metastatic disease in patients with a variety of malignancies. PET/CT provides the advantages of the two modalities; the anatomic information provided by spiral CT and the functional information provided by PET. It has been reported to be superior to conventional imaging for the evaluation of patients with a head and neck malignancy, and to have a sensitivity for the detection of cervical lymph node metastases from head and neck cancers of 67–96% and a specificity of 82–100%. In addition, FDG PET/CT has been reported to be more accurate than CT/MRI in patients with oral cavity cancer.
This study was undertaken to assess the value of FDG PET/CT for determining the presence of ECS from cervical lymph nodes in OSCC and to identify its histologic correlates.
Materials and methods
A retrospective chart review was conducted on OSCC patients who were treated at the authors’ hospital between January 2004 and July 2011. Eighty patients, who underwent FDG PET/CT for OSCC before surgery with histologically proven OSCC, no radiological evidence of distant metastases at time of presentation, and who had been treated with curative intent were enrolled in this study. Patients with non-squamous cell carcinoma, an unresectable tumour, distant metastasis, a history of prior head and neck cancer, and those who had previously undergone neck surgery or chemoradiotherapy were excluded. The diagnostic evaluations at presentation included a complete physical examination, panendoscopy, CT and/or an MRI scan of the head and neck, FDG PET/CT, chest radiography, and laboratory tests. CT and/or MRI were always assessed to determine the regional lymph node status and FDG PET/CT used to identify distant metastasis. All patients underwent neck dissection at the time of primary surgery; comprehensive dissection in 35 (44%) and selective dissection in the remaining 45 (56%). Forty-seven (59%) patients with clinical or radiological evidence of disease involving cervical lymph nodes bilaterally underwent bilateral neck dissection. Pathologic margin involvement was observed in 24 (30%) patients and postoperative radiotherapy was performed in 30 (38%).
Histopathologic specimens were reviewed by a head and neck pathologist. Whole, fresh specimens were placed in formalin and processed for paraffin embedding. Up to three longitudinal slices were taken per lymph node. If a node was suspected to contain a tumour or was large or necrotic, further slices were obtained. Particular attention was paid to nodal metastasis in and ECS from neck nodes.
The authors re-assessed the FDG PET/CT images to determine regional lymph node and ECS status. Pathologic lymph node metastases were recorded using the neck level system of the imaging-based nodal classification. In each patient, the largest lymph node (based on maximum axial diameter) at the cervical level was used to determine lymph node diameter. Maximum axial diameter was defined as the greatest dimension observed for all lymph nodes on axial CT images, and was measured using a mouse controlled cursor. Patients were staged according to the 2002 American Joint Committee on Cancer (AJCC) staging system.
All patients were fasted for at least 6 h before the PET/CT study. 18 F-FDG was injected intravenously (370–555 MBq) and scanning began 60 min later. No patient had a blood glucose level exceeding 130 mg/dl before 18 F-FDG injection, and no intravenous contrast agent was administered. Studies were acquired on combined PET/CT in-line systems, that is, either a Biograph Duo or a Biograph Truepoint (Siemens Medical Solutions Knoxville, TN, USA).
A full-ring PET scanner integrated with a dual section helical CT scanner (Somatom Emotion; Siemens) was used to acquire and co-register PET and CT images in session. Six to eight bed positions were used and the acquisition time was 2 min per position. All patients were placed supine with arms raised. CT imaging began at the orbitomeatal line and progressed to the upper thigh (30 mA s; 130 kV; 5-mm slice thickness), and PET scanning followed immediately over the same body region. CT data were used for attenuation correction and images were reconstructed using a standard ordered-subset expectation maximization algorithm. The axial spatial resolution was 6.5 mm at the center of the field of view.
All PET/CT images were reviewed at a workstation using fusion software (Syngo, Siemens), which provided multiplanar reformatted images and displayed PET images (before or after attenuation correction), CT images, and PET/CT fusion images. One nuclear medicine physician with 10 years of experience reviewed and interpreted PET/CT images visually. If 18 F-FDG uptake was perceptible in a cervical lymph node, the case was deemed positive for metastasis, and conversely, if no 18 F-FDG uptake was observed in the cervical region, the case was regarded as free of cervical lymph node metastasis. For semi-quantitative analysis, 18 F-FDG maximum standardized uptake (SUV max ) values were measured by visually placing regions of interest (ROIs) around cervical lymph nodes with perceptible 18 F-FDG uptake. If multiple nodes showed perceptible uptake, the node with the highest SUV max value was selected. All PET/CT results were compared with postoperative pathology results.
Statistics
Statistical analysis was performed, using the SPSS version 13 (SPSS, Inc., Chicago, IL, USA). Receiver operating characteristic (ROC) curve analysis was performed to differentiate cervical lymph nodes with ECS from those without ECS. Pearson’s correlation analysis was used to assess the relationship between SUV max values and cervical lymph node sizes. Overall survival was calculated using the Kaplan–Meier method. The Cox proportional hazards model, with likelihood ratio statistics, was used to identify variables significantly and independently related to ECS. p Values of <0.05 were considered statistically significant. Numerical data are expressed as means ± standard deviation (SD).
Statistics
Statistical analysis was performed, using the SPSS version 13 (SPSS, Inc., Chicago, IL, USA). Receiver operating characteristic (ROC) curve analysis was performed to differentiate cervical lymph nodes with ECS from those without ECS. Pearson’s correlation analysis was used to assess the relationship between SUV max values and cervical lymph node sizes. Overall survival was calculated using the Kaplan–Meier method. The Cox proportional hazards model, with likelihood ratio statistics, was used to identify variables significantly and independently related to ECS. p Values of <0.05 were considered statistically significant. Numerical data are expressed as means ± standard deviation (SD).
Results
Patients’ characteristics are given in Table 1 . Mean patient age was 54 years (range 23–83 years), and 55 (69%) of the 80 patients were men. PET/CT showed that the primary site of malignancy was the tongue in 58, the mouth floor in 10, the retromolar trigone in 7, the buccal area in 4, and the alveolar ridge in 1. Pathological stages were stage T1–T4 in 29, 33, 14, and 4 patients, respectively, and the disease stages of the cervical lymph nodes were N0–N2 in 45, 11, and 24 patients, respectively. Histologic invasion depths ranged from 1 to 52 mm (mean 10.22 ± 9.00 mm). A significant positive correlation was found between the presence of lymph node metastasis and histologically determined depth of invasion ( p < 0.001). The mean depths of invasion of pathologically positive lymph nodes with ECS, pathologically positive lymph nodes without ECS, and pathologically negative lymph nodes were 16.33 ± 10.16, 10.92 ± 6.85, and 6.84 ± 7.11 mm, respectively. Maximum axial diameter was found to be significantly related to ECS (mean axial diameter of pathologically positive lymph nodes with and without ECS were 21.09 ± 13.02 and 12.22 ± 6.88, respectively, and mean axial diameter of pathologically negative lymph nodes was 5.05 ± 6.91 mm, p < 0.001). Lymphovascular invasion was observed in 30 (38%) patients.
| Parameter | pN+ with ECS ( n = 23) | pN+ without ECS ( n = 12) | pN− ( n = 45) |
|---|---|---|---|
| Age (years) | |||
| Median | 51 | 59 | 54 |
| Range | 23–71 | 41–83 | 27–76 |
| Gender (%) | |||
| Male | 78 | 75 | 62 |
| Female | 22 | 25 | 38 |
| Site (%) | |||
| Tongue | 74 | 58 | 76 |
| Floor of mouth | 13 | 17 | 11 |
| Retromolar trigone | 13 | 0 | 9 |
| Buccal area | 0 | 25 | 2 |
| Alveolar ridge | 0 | 0 | 2 |
| Pathologic T stage (%) | |||
| T1 | 0 | 8 | 62 |
| T2 | 48 | 75 | 29 |
| T3 | 39 | 17 | 7 |
| T4 | 13 | 0 | 2 |
| Depth of invasion (mm) | |||
| Median | 16 | 11 | 7 |
| Range | 3–52 | 1–26 | 1–30 |
| Tumour differentiation (%) | |||
| Well differentiation | 57 | 42 | 56 |
| Moderate differentiation | 39 | 58 | 42 |
| Poorly differentiation | 4 | 0 | 2 |
| Lymphovascular invasion (%) | |||
| Yes | 74 | 92 | 4 |
| No | 26 | 8 | 96 |
| Maximal axial diameter (mm) | |||
| Mean | 21.1 | 12.2 | 5.1 |
| Range | 9–60 | 5–28 | 0–28 |
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