FOCUS ON: Neuroradiology/Head and Neck Imaging
Original Research
Nasopharyngeal Carcinoma Patients With Retropharyngeal Lymph Node Metastases: A Minimum Axial Diameter of 6 mm Is a More Accurate Prognostic Predictor Than 5 mm
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OBJECTIVE. The criteria for the diagnosis of metastatic retropharyngeal lymph nodes (RLNs) have not yet been resolved and are not included in the current edition of the American Joint Committee on Cancer (AJCC) staging system (seventh edition) for the staging of nasopharyngeal carcinoma (NPC). The aim of this study was to use MRI to identify an RLN size criterion that can accurately predict prognosis in patients with NPC.
MATERIALS AND METHODS. Eight hundred seventeen patients with newly diagnosed localized NPC were identified. All of the patients underwent MRI before treatment with definitive radiation therapy. All the MRI studies and medical records were reviewed retrospectively. Overall survival (OS), distant metastasis–free survival (DMFS), and local relapse–free survival (LRFS) were assessed using SPSS software (version 17.0).
RESULTS. RLN size cutoffs of ≥ 5 mm and of ≥ 6 mm were used. There was no significant difference in OS (p = 0.216), DMFS (p = 0.081), or LRFS (p = 0.067) in patients with RLNs ≥ 5 mm and in those with RLNs < 5 mm. When 6 mm was used as a size cutoff, significant differences in OS (p = 0.000) and DMFS (p = 0.001) were identified; there was no significant difference observed for LRFS (p = 0.380).
CONCLUSION. A minimum axial RLN diameter of 6 mm was a more accurate prognostic predictor in NPC patients with RLN metastases than 5 mm.
Keywords: MRI, nasopharyngeal carcinoma, prognostic value, retropharyngeal lymph node, tumor staging
The retropharyngeal lymph nodes (RLNs) in the retropharyngeal space are the primary sites of metastases from tumors of the nasopharynx, oropharynx, hypopharynx, and cervical esophagus [1]. The most common tumor giving rise to RLN metastases is nasopharyngeal carcinoma (NPC). RLNs are regarded as sentinel lymph nodes in patients with NPC [2, 3]. RLN metastases have important prognostic and therapeutic implications and have been classified as N1 lesions in accordance with the seventh edition of the staging system proposed by the American Joint Committee on Cancer (AJCC) [4].
RLN metastases in NPC patients have been correlated with the rate of systemic metastases [3, 5, 6] and were of prognostic value in predicting distant metastasis–free survival (DMFS) [7, 8]. However, the diagnostic criteria for metastatic RLNs have not been clearly defined and are not included in the AJCC staging system [4].
Different RLN size criteria have been suggested. A minimal axial diameter of 5 mm on imaging studies has been proposed as abnormal for RLNs in patients with NPC [3, 7, 8]. Zhang et al. [9] reported the results for 303 NPC patients from a large oncology center. The proposed radiologic criteria for assessing RLNs as being metastases in patients with NPC were a minimal axial diameter of ≥ 6 mm, an RLN with central necrosis, a group of two or more RLNs, and a medial RLN. RLN metastases often are undetectable during routine physical examination and difficult to biopsy because of their deep anatomic location [10]. The diagnosis of metastases is primarily made using imaging studies. MRI offers better soft-tissue differentiation, fewer bone-related artifacts, and better definition of tumor extension and lymph node spread than CT. MRI is widely used for the diagnosis, treatment planning, and monitoring of patients with NPC [11–13].
The goal of this study was to show the prognostic clinical importance of different lateral RLN size criteria (6 and 5 mm) in a large number of patients with NPC.
| Materials and Methods |   |
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From January 1, 2003, to February 28, 2005, a total of 817 patients with newly diagnosed localized NPC were identified. All patients had biopsy-proven disease and had undergone no prior treatment for NPC. Patients with additional known head and neck cancers or acute inflammation were excluded. There were 620 male and 197 female patients. The median patient age was 44 years (age range, 13–76 years). Medical records and imaging findings were reviewed. Tumor restaging according to the 2010 AJCC staging system [4] was performed of all patients after reviewing all medical records. World Health Organization (WHO) histologic classifications of the tumors included type I tumors (nine patients), type II tumors (251 patients), and type III tumors (557 patients). T category classifications included T1 lesions (57 patients), T2 lesions (170 patients), T3 lesions (337 patients), and T4 lesions (253 patients). N category classifications included N0 lesions (180 patients), N1 lesions (335 patients), N2 lesions (255 patients), and N3 lesions (47 patients). Medical staging consisted of 29 stage I patients, 124 stage II patients, 376 stage III patients, and 288 stage IV patients.
The approval of the institutional review board was obtained for this study. All examinations were performed after obtaining written informed consent forms from either patients or their next of kin. All patients underwent a pretreatment evaluation that included MRI of the neck and nasopharynx, radiography of the chest, and sonography of the abdomen. All patients with N2 or N3 disease underwent PET/CT for tumor staging and treatment planning.
All patients underwent MRI on a 1.5-T system (Signa CV/I, GE Healthcare) using a fast spin-echo (FSE) technique. The region from the suprasellar subarachnoid cistern to the inferior margin of the sternal end of the clavicle was examined using a combined head-and-neck coil. T1-weighted images in the axial, coronal, and sagittal planes (TR range/TE range, 500–600/10–20; number of signals acquired, 2; FOV, 22 cm) and T2-weighted FSE images in the axial plane (TR range/TE range, 3000–6000/90–110; number of signals acquired, 2; FOV, 22 cm) were obtained before the injection of contrast material. After IV injection of gadopentetate dimeglumine (Magnevist, Bayer Schering Pharma) at a dose of 0.1 mmol/kg of body weight, T1-weighted fat-suppressed axial, coronal, and sagittal sequences were performed sequentially using the same parameters as the un-enhanced T1-weighted sequence [14]. The section thicknesses and intersection gaps were 5 mm and 1 mm, respectively; the matrix size was 256 × 512.
Two radiologists experienced in diagnostic MRI of the head and neck independently evaluated the MR images. Data were measured by these two observers. Data are presented as means ± SDs. Any disagreements were resolved by discussion. RLNs were identified as separate from the primary tumor.
The RLN measurements were performed using the electronic calipers in the PACS (Centricity Radiology RA600, GE Healthcare). The minimum and maximum axial (perpendicular to the course of the internal jugular vein) diameters and the longitudinal diameter of each visible RLN were measured in the largest axial plane. The minimum axial diameter corresponded to the widest diameter of the node in the axial plane that was perpendicular to its maximum axial diameter. The longitudinal diameter paralleled the course of the internal jugular vein [15]. Axial diameter measurements were made using T2-weighted axial images (Fig. 1) and longitudinal diameter measurements were made using unenhanced T1-weighted coronal images [10, 16, 17].
 View larger version (351K) | Fig. 1 —39-year-old man with undifferentiated carcinoma in nasopharynx. Minimum (thick line) and maximum (thin line) axial diameters of each retropharyngeal lymph node (RLN) were measured on T2-weighted axial images of largest axial plane. Minimum axial diameter corresponded to widest diameter of node in axial plane that was perpendicular to its maximum axial diameter. RLNs were identified as separate from primary tumor (arrow). |
The criteria for the diagnosis of nodal central necrosis on MR images were a focal area of high signal intensity on T2-weighted images and a focal area of low signal intensity on T1-weighted images with or without a surrounding rim of enhancement. Nodes with a surrounding rim of enhancement were considered to be extracapsular spread [2, 15, 18]. The criterion for groups of RLNs was two or more lymph nodes in the ipsilateral retropharyngeal space. The diagnostic MRI criteria for a metastatic RLN were a lateral RLN with a minimum axial diameter of ≥ 5 mm or ≥ 6 mm, an RLN with central necrosis or a visible contrast-enhancing rim, a group of two or more RLNs, and a medial RLN.
All patients were treated with radiation therapy (RT) with a curative intent. Details regarding the RT technique were in accordance with some previous articles in the literature [19–22]. A total of 597 of the 817 (73.1%) patients with advanced disease (classified as T3–T4 or N2–N3 disease) received neoadjuvant, concomitant, or adjuvant chemotherapy. All MRI-visible RLNs were included in the gross tumor volume and received the same high dose of RT (68–70 Gy).
All patients were followed regularly with imaging studies and clinical evaluation. The follow-up duration was calculated from the first day of treatment until the date of death or the date of the last MRI study or physical examination [14, 22]. During the first 2 years of follow-up, the patients were examined every 3 months and thereafter, every 5 months. The median follow-up period for the whole group was 69 months (range, 6–110 months).
Tumor and lymph node response to treatment, which include tumor resolution, residual primary tumors, local recurrence, and distant metastases, were assessed using MRI, flexible nasopharyngoscopy, physical examination, biopsy, or a combination of these strategies. The nature of the response to therapy was judged jointly by two experienced radiation oncology radiologists of our research team. Diagnosis was based mainly on the findings of follow-up MRI.
When discrepant findings were reported, the images were reviewed by the two evaluating radiologists together to reach a final conclusion. If RLNs disappeared or were stable in size after RT but enlarged during follow-up, the case was considered positive for malignant involvement (hereafter described as positive). The case was considered to be a benign process if RLNs showed stability in size after RT and the patient remained disease-free during subsequent follow-up (hereafter described as negative) [9, 23, 24].
The following endpoints (time to the first defining event) were assessed: overall survival (OS), DMFS, and local relapse–free survival (LRFS). All statistical analyses were performed using statistics software (SPSS, version 17.0, SPSS). The actuarial rates were calculated using the Kaplan-Meier method [25], and the differences were compared using the log-rank test. A two-tailed p value < 0.05 was considered statistically significant.
| Results | |
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No patient had a metastatic median RLN. Size criteria (≥ 5 and ≥ 6 mm), central necrosis, and extracapsular invasion in smaller lymph nodes were used to identify lymph node metastases. The incidence of lateral RLN metastases using 5 mm as a cutoff was 71.0% (580/817 patients, 1027 RLNs), and the incidence of lateral RLN metastases using 6 mm as a cutoff was 59.2% (484/817 patients, 859 RLNs). There was a significant difference between the two incidences based on the different size criteria (≥ 5 and ≥ 6 mm) (p = 0.000). Using ≥ 5 mm as a size cutoff, the mean values of the minimal axial dimension and the maximal axial dimension of the positive RLNs were 7.8 mm (range, 4.5–30.3 mm) and 10.9 mm (range, 5.6–38.7 mm), respectively. Using ≥ 6 mm as a size cutoff, the mean values of the minimal axial dimension and maximal axial dimension were 8.8 mm (range, 4.5–30.3 mm) and 12.0 mm (range, 6.6–38.7 mm), respectively.
There were 132 (12.9%, 5-mm criterion; 15.4%, 6-mm criterion) RLNs with necrosis in 110 patients. Two RLNs were < 5 mm and four were 5–6 mm. All the necrotic RLNs disappeared after treatment. Groups of two or more RLNs were seen in 128 of 817 patients (15.7%). All of the grouped RLNs disappeared after treatment. A total of 140 RLNs in 119 patients displayed extracapsular invasion. All of these RLNs were > 6 mm and disappeared after treatment.
The 5-year OS rate, DMFS rate, and LRFS rate were 87.7%, 96.5%, and 95.7%, respectively, in patients with RLNs ≥ 5 mm. There was no significant difference in OS, DMFS, and LRFS (p = 0.216, p = 0.081, and p = 0.067, respectively) in patients with RLNs ≥ 5 mm and those with RLNs < 5 mm. The 5-year OS rate, DMFS rate, and LRFS rate were 80.3%, 91.5%, and 95.6%, respectively, in patients with RLNs ≥ 6 mm. There was a significant difference in OS (p = 0.000; Fig. 2) and DMFS (p = 0.001; Fig. 3) in patients with RLNs ≥ 6 mm and those with RLNs < 6 mm. No significant difference was seen in LRFS (p = 0.380) based on the ≥ 6 mm size criterion.
 View larger version (46K) | Fig. 2 —Kaplan-Meier overall survival (OS) curves for patients with retropharyngeal lymph nodes < 6 mm and ≥ 6 mm. |
 View larger version (44K) | Fig. 3 —Kaplan-Meier distant metastasis–free survival (DMFS) curves for patients with retropharyngeal lymph nodes < 6 mm and ≥ 6 mm. |
| Discussion | |
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Important morphologic prognostic criteria have been reported for assessing metastatic nodal disease, including nodal size and the presence of central necrosis and extracapsular spread [15, 26]. Nodal necrosis was detected as high signal intensity on T2-weighted images and low signal intensity on T1-weighted images but was not detected on unenhanced studies. Both T1- and T2-weighted imaging help detect extracapsular spread [27]. Nodal size is the only controversial criterion of the morphologic characteristics reported. Several studies have defined radiologic nodal size criteria for metastatic RLNs. The diagnostic criteria proposed by Mancuso et al. [28] and Watarai et al. [29] were based on a lower size limit for classifying RLNs as abnormal. King et al. [2] and Lam et al. [10] suggested a minimum axial diameter of 4 mm or larger and of 5 mm, respectively, as the cutoff for normal. A minimum axial diameter of 5 mm has been proposed for a radiologic diagnosis of abnormal RLNs [3, 7, 10]. Zhang et al. [9] concluded that the best way to diagnose NPC RLN metastases on imaging studies was to use a minimum axial diameter of 6 mm.
The best clinical prediction was obtained using a minimum axial diameter of 6 mm for RLNs. Using this nodal size criterion combined with nodal necrosis and extracapsular involvement, the incidence of RLN metastasis was found to be 59.2%, lower than that using ≥ 5 mm size as a cutoff (71.0%). RLN metastases were found to be significantly related to OS and DMFS on univariate analyses. NPC patients with RLNs ≥ 6 mm were assumed to have tumor proliferation within the lymphatics that might be associated with an increased risk of distant metastasis, one of the major causes of treatment failure [30]. NPC patients with ≥ 6 mm RLNs and no distant metastasis should be considered for induction chemotherapy or concurrent chemoradiation even if tumors are stage T1 or T2 [31].
We should stress that this study was not a radiologic-pathologic correlation study. The evaluation of the nature of the RLNs based on MRI alone could include false-negative and false-positive diagnoses. RLNs ≥ 6 mm could be benign reactive nodes and RLNs < 6 mm could be malignant. It was sometimes diffi-cult to differentiate enlarged RLNs from direct extension of the primary tumor because the two were contiguous and shared the same signal intensity. These pitfalls are common to and unavoidable in any imaging study.
| Acknowledgments | |
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We thank our colleagues in the department of medical records who provided the follow-up data for this study and our colleagues in the institutional review board who approved this study.
Supported by the Science Foundation from the Sci-Tech Office of Guangdong Province (grant 2009B030801102).
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