Prognostic Value of Grading Masticator Space Involvement in Nasopharyngeal Carcinoma according to MR Imaging Findings 1

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1 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Original Research n Head and Neck Imaging Guo-Yi Zhang, MD Ying Huang, MD Xiu-Yu Cai, MD Xiang-Ping Chen, MD Tao Xu, MD Jing Wu, MD Wei-Hong Wei, MD Li-Zhi Liu, MD Ze-Li Huang, MD Miao-Miao Zhou, MD Shi-Tong Xia, MD Yue-Jian Wang, MD Prognostic Value of Grading Masticator Space Involvement in Nasopharyngeal Carcinoma according to MR Imaging Findings 1 Purpose: Materials and Methods: To derive a suitable method for grading masticator space invasion in nasopharyngeal carcinoma on the basis of magnetic resonance (MR) images and to determine its prognostic value in patients undergoing intensity-modulated radiation therapy. After institutional review board approval and informed consent were acquired, 808 patients with nasopharyngeal carcinoma who were treated with definitive intensity-modulated radiation therapy were analyzed retrospectively. The anatomic sites of masticator space involvement were identified with MR imaging. Overall survival, local relapsefree survival, and distant metastasis-free survival were calculated by using the Kaplan-Meier method and were compared by using the log-rank test. Potential prognostic factors were identified by means of multivariate analysis. 1 From the Cancer Center, Cancer Research Institute, Foshan Hospital, Sun Yat-sen University, Foshan , Guangdong, People s Republic of China (G.Y.Z., X.P.C., T.X., J.W., W.H.W., Z.L.H., M.M.Z., S.T.X., Y.J.W.); and Department of Radiation Oncology (Y.H.), Department of VIP Region (X.Y.C.), and Imaging Diagnosis and Interventional Center (L.Z.L.), State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, People s Republic of China. Received November 29, 2013; revision requested January 9, 2014; revision received January 25; accepted February 12; final version accepted March 21. Supported by the Science and Technology Planning Program of Guangdong Province (grant ), and Science and Technology Key Project of Foshan City (grant ). Address correspondence to Y.J.W. ( wyjian01@163.com). q RSNA, 2014 Results: Conclusion: Masticator space involvement was diagnosed in 163 of 808 patients (20.2%). Patients with lateral invasion (involvement of the lateral pterygoid muscle of the masticator space and beyond) had significantly poorer overall survival and distant metastasis-free survival than those with medial invasion (involvement of the medial pterygoid muscle of the masticator space) (P =.035 and P =.026, respectively). Furthermore, their overall survival, local relapse-free survival, and distant metastasis-free survival were significantly poorer compared with patients with stage T2 or T3 disease (all P.023) but similar to patients with stage T4 disease. The grade of masticator space involvement was an independent prognostic factor for overall survival, local relapse-free survival, and distant metastasis-free survival (all P.023). Masticator space involvement in nasopharyngeal carcinoma should be graded as medial (stage T2 disease) or lateral (stage T4 disease). This can facilitate staging of nasopharyngeal carcinoma and may be a suitable prognostic indicator of survival. q RSNA, radiology.rsna.org n Radiology: Volume 273: Number 1 October 2014

2 Nasopharyngeal carcinoma (NPC) often extends into the peripheral fascial space and skull base. The masticator space is located laterally to the nasopharynx (1 7) and contains the ramus and posterior body of the mandible and the four muscles of mastication (medial and lateral pterygoid muscles, masseter muscle, and temporalis muscle), which are all enclosed by the superficial layer of the cervical fascias. On the basis of current cancer staging systems, the prognostic significance of masticator space involvement in patients with NPC is ambiguous (3 11). According to the fifth (1997) or sixth (2002) edition of the American Joint Committee on Cancer (AJCC) staging system, extension of the tumor beyond the anterior surface of the lateral pterygoid muscle is classified as stage T4, whereas other regions of masticator space involvement are classified as stage T2 (8 9). The current seventh edition (2010) of the AJCC involves a subtle change to specify tumor invasion into any part of the anatomic masticator space as stage T4 (10). In the Chinese staging system (2008), however, tumor extension into the medial pterygoid muscles is classified as stage T3, while extension into the lateral pterygoid muscle or beyond is classified as stage T4 (11). Several investigators have focused on the prognostic significance of lateral spread in NPC (3 5). The extent of masticator space invasion defined in these studies has mainly been based on anatomic landmarks on computed tomographic (CT) scans in patients undergoing Advance in Knowledge nn We have demonstrated that masticator space involvement in nasopharyngeal carcinoma (NPC) can be graded as medial or lateral invasion according to MR images; patients with lateral invasion had significantly poorer overall survival and distant metastasis-free survival than those with medial invasion (P =.035 and P =.026, respectively), and these grades corresponded to American Joint Committee on Cancer stages T2 and T4, respectively. conventional radiation therapy. These authors suggested that lateral tumor invasion beyond the line joining the free edge of the medial pterygoid plate to the styloid process was an independent prognostic factor in NPC (4,5). Conversely, in a study based on magnetic resonance (MR) imaging, it was suggested that subclassification of masticator space involvement was unnecessary and that any masticator space involvement should be regarded as T4 disease (7). However, this study had been based on different radiation therapy modalities and did not include survival data between cases involving the medial pterygoid muscle and those involving extension into the lateral pterygoid muscle or beyond. These discrepancies indicated that a study involving a large number of patients with NPC was necessary to establish an optimal method for defining different categories of masticator space involvement in NPC. Therefore, we used MR imaging to identify the degree of masticator space involvement in 808 patients with NPC who were undergoing intensity-modulated radiation therapy (IMRT). By comparing our data with established staging systems, we aimed to establish an optimal grading method for masticator space involvement and determine the prognostic value to facilitate treatment strategies in patients with NPC. Materials and Methods Patient Selection and Classification This retrospective study was approved by the institutional review board, and written informed consent was obtained from all participating patients or their next of kin. A total of 824 Chinese patients were initially enrolled in this study. All had received a new diagnosis of untreated and nonmetastatic NPC between Implication for Patient Care nn The grade of masticator space involvement was an independent prognostic factor for survival; therefore, our grading method may facilitate treatment strategies and prognosis in patients with NPC. January 2003 and March 2006, and they were subsequently treated with IMRT. Six patients failed to complete radiation therapy, nine underwent treatments that deviated from institutional guidelines owing to organ dysfunction, and one developed additional esophageal carcinoma; therefore, these patients were excluded. The remaining 808 patients included 615 men (mean age, 46 years; range, years) and 193 women (mean age, 43 years; range, years). All patients underwent a pretreatment evaluation, which included MR imaging of the neck and nasopharynx, chest radiography, abdominal ultrasonography (US), and whole-body bone scanning. Medical records and imaging results were reviewed, and restaging was conducted in all patients according to the AJCC TNM staging system (2010) (10). The pathologic distributions of NPC according to the different classification systems are given in Table 1. Imaging Protocol All patients underwent MR imaging by using a 1.5-T system (Signa CV/i; GE Healthcare, Milwaukee, Wis) with the spin-echo technique. The region from the suprasellar cistern to the inferior margin of the sternal end of the clavicle Published online before print /radiol Content codes: Radiology 2014; 273: Abbreviations: AJCC = American Joint Committee on Cancer DMFS = distant metastasis-free survival IMRT = intensity-modulated radiation therapy LRFS = local relapse-free survival NPC = nasopharyngeal carcinoma OS = overall survival Author contributions: Guarantors of integrity of entire study, G.Y.Z., Z.L.H., Y.J.W.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, all authors; clinical studies, G.Y.Z., Y.H., X.Y.C., T.X., J.W., L.Z.L., Z.L.H., M.M.Z., S.T.X., Y.J.W.; experimental studies, Z.L.H.; statistical analysis, G.Y.Z., Y.H., X.Y.C., X.P.C., T.X., W.H.W., Z.L.H., M.M.Z., S.T.X., Y.J.W.; and manuscript editing, G.Y.Z., Y.H., X.Y.C., T.X., Z.L.H., M.M.Z., S.T.X., Y.J.W. Conflicts of interest are listed at the end of this article. Radiology: Volume 273: Number 1 October 2014 n radiology.rsna.org 137

3 Table 1 Figure 1 Characteristics of Patients with NPC Characteristic No. of Patients (n = 808) World Health Organization pathologic classification Type 1 11 (1.4) Type 2 85 (10.5) Type (88.1) T classification T1 158 (19.5) T2 115 (14.2) T3 314 (38.9) T4 221 (27.4) N classification N0 183 (22.6) N1 482 (59.6) N2 115 (14.2) N3 28 (3.5) AJCC stage (2010) I 57 (7.0) II 167 (20.7) III 344 (42.6) IVa b 240 (29.7) Note. Numbers in parentheses are percentages. was examined by using a head-and-neck combined coil. T1-weighted images in the axial, coronal, and sagittal planes (repetition time msec/echo time msec, /10 20), and T2-weighted images in the axial plane ( /95 110) were obtained before injection of gadopentetate dimeglumine at a dose of 0.1 mmol/kg body weight. After intravenous injection, T1-weighted axial and sagittal sequences and T1-weighted fat-suppressed coronal sequences were performed sequentially, with parameters similar to those applied before the contrast agent injection. The respective section thicknesses and intersection gaps were 5 mm and 1 mm for the axial plane and 6 mm and 1 mm for the coronal and sagittal planes. Image Assessment The MR images were evaluated by two independent radiologists (G.Y.Z, L.Z.L) with more than 10 years of experience with MR imaging in patients with NPC. Differences were resolved by means of consensus. The diagnostic criteria for Figure 1: Pretreatment axial T2-weighted MR image of NPC with masticator space invasion in a 45-year-old woman. Image shows the AJCC masticator space (green) in comparison to the anatomic masticator space (purple). The criteria for AJCC masticator space excludes the medial and lateral pterygoid muscles but includes the retromaxillary fat pad. LP = lateral pterygoid muscle, M = masseter muscle, MP = medial pterygoid muscle, RT = retromaxillary fat pad, T = temporalis muscle. invasion of masticator space were abnormal soft tissue with low signal intensity on T1-weighted images and intermediate signal intensity on T2-weighted images that replaced normal structural anatomy and moderate enhancement on contrast material enhanced T1- weighted images (12). MR imaging identification of masticator space invasion was assessed at the following sites: medial pterygoid muscle, lateral pterygoid muscle, and AJCC masticator space, which was defined as tumor involvement beyond the anterior surface of the lateral pterygoid muscle (Fig 1). Patient Treatment All patients were treated with definitive IMRT with 6-MV photons by using an integrated IMRT planning and delivery system (Peacock, Corvus 3.0; NOMOS, Sewickley, Pa). The gross tumor volumes, including the primary tumor and involved cervical lymph nodes, were determined from the imaging and endoscopic findings at presentation. The clinical target volume for the high-risk regions included the primary tumor with a 5 10 mm margin (if possible) and the whole nasopharynx. The clinical target volume for the low-risk regions covered the potential sites of local infiltration (including the parapharyngeal space, posterior third of the nasal cavities and maxillary sinuses, pterygoid processes, lower half of the sphenoid sinus, anterior half of the clivus, and petrous tips) and bilateral cervical lymphatics down to the supraclavicular fossa. The planning target volumes were determined from the gross tumor volumes or clinical target volume, with a 3 5-mm margin for setup variations. The radiation doses for each target volume were as follows: 68 Gy in 30 fractions at 2.27 Gy per fraction to the planning target volumes of primary gross tumor volumes, Gy ( Gy per fraction) to the planning target volumes 138 radiology.rsna.org n Radiology: Volume 273: Number 1 October 2014

4 of cervical lymph node gross tumor volume, 60 Gy (2.0 Gy per fraction) to the planning target volumes of clinical target volume for the high-risk regions, and 54 Gy (1.8 Gy per fraction) to the planning target volumes of clinical target volume for the low-risk regions. According to our institutional treatment protocol, visible retropharyngeal lymph nodes on the MR images were incorporated into the primary tumor when delineating target volume and received the same dose (68 Gy). IMRT treatment was delivered by using a dynamic multileaf collimator (called MIMiC) on a linear accelerator (600CD; Varian, Palo Alto, Calif). The goal was to deliver at least 95% of the prescribed dose to 100% of the target volume. At the time of study, on the basis of the sixth edition of AJCC staging system, our institutional guidelines recommended radiation therapy alone for stage I disease (57 patients), concomitant chemoradiotherapy for stage II disease (170 patients), and induction or adjuvant chemotherapy together with concomitant chemoradiotherapy for stage III IVB disease (213 and 368 patients, respectively). Concomitant chemotherapy consisted of mg/m 2 of cisplatin administered weekly or mg/m 2 of cisplatin on days 1, 22, and 43 of radiation therapy. Induction or adjuvant chemotherapy consisted of cisplatin and fluorouracil or cisplatin, fluorouracil, and docetaxel repeated every 21 days for two or three cycles. Patient Follow-up Complete follow-up data at 3, 5, and 8 years were available for 97.6%, 96.8%, and 76.1% of patients, respectively. Patients were followed up at least once every 3 months during the first 2 years and then once every 6 months thereafter. The follow-up period was calculated from the date of the first treatment to the date of death or final follow-up. The median follow-up period was 106 months (range, months). The survival end points were defined from the start of treatment and were categorized as follows: overall survival (OS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). Local recurrence or distant metastases were assessed by means of physical examination, fiberoptic endoscopy and biopsy, and imaging methods that included chest radiography, bone scanning, CT or MR imaging, and abdominal US. Statistical Analysis SPSS version 16.0 (SPSS, Chicago, Ill) was used for all statistical analyses. Interreader agreement was assessed with the Cohen k coefficient for diagnosing masticator space invasion. A k value of indicated moderate agreement; , good agreement; and above 0.8, very good agreement (13). Actuarial rates were calculated by using the Kaplan- Meier method and were compared by using the log-rank test (14). Multivariate analysis was performed by using the Cox proportional hazards model to determine the significance of potential prognostic factors by means of backward elimination of insignificant variables (15). Two-tailed P values less than.05 were considered to indicate a significant difference. Results Interobserver Agreement Among our 808 patients with NPC, 161 (19.9%), 69 (8.5%), and 14 (1.7%) patients received a diagnosis of involvement of the medial pterygoid muscle, lateral pterygoid muscle, and AJCC masticator space, respectively, according to observer 1. According to observer 2, 164 (20.3%), 67 (8.3%), and 12 (1.5%) patients received a diagnosis of involvement of the medial pterygoid muscle, lateral pterygoid muscle, and AJCC masticator space, respectively. In the per-site analysis, there was excellent agreement for the diagnosis of masticator space invasion between observers 1 and 2, with a k coefficient of for medial pterygoid muscle, for lateral pterygoid muscle, and for AJCC masticator space. Frequency of Masticator Space Involvement according to Anatomic Site Differences were resolved by means of consensus. Masticator space involvement was diagnosed in 163 of 808 patients (20.2%), medial pterygoid muscle involvement in 162 of 808 patients (20.0%), lateral pterygoid Table 2 Relationship between the Extent of Masticator Space Involvement, N Classification, and Grade in Patients with NPC N Classification* No. of Patients with Masticator Space Extension (n = 808) Grade 0 Grade 1 Grade 2 N0 156 (85.2) 14 (7.7) 13 (7.1) N1 377 (78.2) 60 (12.4) 45 (9.3) N2 90 (78.3) 13 (11.3) 12 (10.4) N3 22 (78.6) 5 (17.8) 1 (3.6) Note. Numbers in parentheses are percentages. Grade 0 = patients without masticator space invasion, grade 1 = patients with medial pterygoid muscle invasion, and grade 2 = patients with lateral pterygoid muscle or AJCC masticator space invasion. Retropharyngeal lymph node invasion was regarded as N1. Lymph node metastasis (N1 3 vs N0) was correlated with masticator space invasion (grade 1 2 vs grade 0) (P =.038); N classification (N1 vs N2 vs N3) was associated with grade 2 masticator space invasion (grade 2 vs grade 0 1) (P =.531); and advanced N stage (N2 3 vs N0 1) was associated with the extent of masticator space invasion (grade 0 vs grade 1 vs grade 2). muscle involvement in 68 of 808 patients (8.4%), and AJCC masticator space involvement in 13 of 808 patients (1.6%). The relationships between the extent of the primary tumor and masticator space involvement suggested a correlation between lateral pterygoid muscle or AJCC masticator space involvement with tumor extension into the nasal cavity, oropharynx, skull base, or paranasal sinus; intracranial invasion; or cranial nerve palsy (all P.002). According to the T classification of the sixth edition of the AJCC staging system, of the 71 patients with lateral pterygoid muscle or AJCC masticator space involvement, 38 of 71 (54%) had stage T4 disease, 31 of 71 (44%) had stage T3 disease, and two of 71 (3%) had stage T2 disease. However, the distribution of N classifications in NPC showed no significant correlation with lateral pterygoid muscle or AJCC masticator space involvement in NPC, with incidence rates of 9.3%, 10.4%, and 3.6% for N1, N2, and N3, respectively (P =.531; Table 2). In addition, there was no statistical difference between the incidence rate of advanced N stage (N2 N3) Radiology: Volume 273: Number 1 October 2014 n radiology.rsna.org 139

5 Figure 2 Figure 2: Kaplan-Meier curves show (a) OS and (b) DMFS in patients with NPC, stratified by three (left) or two (right) grades of masticator space invasion. Differences are shown according to P value, where P,.05 indicates a significant difference. Ga = patients with medial involvement of the masticator space, Gb = patients with lateral involvement of the masticator space, G0 = patients without MS invasion, G1 = patients with involvement of the medial pterygoid muscle but not the lateral pterygoid muscle, G2 = patients with involvement of the lateral pterygoid muscle but not the AJCC masticator space, G3 = patients with involvement of the AJCC masticator space. and the extent of masticator space involvement in NPC (P =.866). Classification and Grading of Masticator Space Involvement During the follow-up period, 88 of 808 patients (10.9%) developed local recurrence, 120 of 808 patients (14.8%) developed distant metastases, and 240 of 808 patients (29.7%) died. The mean 5-year OS, LRFS, and DMFS rates 6 standard deviations were 80.4% 6 1.4, 90.0% 6 1.1, and 86.1% 6 1.2, respectively. To ascertain the prognostic significance of different extents of lateral tumor spread in NPC, we divided masticator space invasion into the following three grades: grade 1, involvement of the medial pterygoid muscle but not the lateral pterygoid muscle; grade 2, involvement of the lateral pterygoid muscle but not the AJCC masticator space; and grade 3, involvement of the AJCC masticator space. The survival curves for OS, LRFS, and DMFS in patients with grades 2 and 3 masticator space 140 radiology.rsna.org n Radiology: Volume 273: Number 1 October 2014

6 involvement overlapped (P =.921, P =.784, and P =.853, respectively). In contrast, the differences in the OS and DMFS rates between patients with grades 1 and 2 masticator space involvement were significantly different (P =.047 and P =.040, respectively). Therefore, we redefined these subclassifications into the following two grades: medial invasion (involvement of the medial pterygoid muscle but not the lateral pterygoid muscle) and lateral invasion (involvement of the lateral pterygoid muscle or AJCC masticator space). Significant differences were observed in the OS and DMFS rates between patients with medial and lateral invasion (P =.035 and P =.026, respectively; Fig 2), which supported these grading criteria for masticator space involvement in NPC. The following parameters were included for multivariate analyses: age, sex, T classification, N classification, use of chemotherapy, and grade of masticator space invasion (none vs medial involvement vs lateral involvement). The results indicated that the grade of masticator space invasion was an independent prognostic factor for OS, LRFS, and DMFS in NPC (all P.023); T classification and N classification were independent prognostic factors for both OS and DMFS; and T classification was an independent prognostic factor for LRFS. In addition, old age was associated with an increased risk of death and local failure (Table 3). Staging Categories for Lateral Masticator Space Involvement To investigate the significance of lateral masticator space invasion in NPC with respect to the AJCC (2002) staging system, we analyzed the differences between OS, LRFS, and DMFS in patients with and without lateral masticator space invasion and T classification. The OS, LRFS, and DMFS rates in patients with stage T2 or T3 disease with lateral masticator space invasion were significantly lower than those without lateral masticator space invasion (all P.023) but were not significantly different from those with stage T4 disease (P =.089, P =.710, and P =.098, respectively; Fig 3). Table 3 Multivariate Analyses of Prognostic Factors in Patients with NPC and Masticator Space Involvement End Point and Variable P Value Odds Ratio Death Age (,50 y vs 50 y), (1.622, 2.693) T classification (T1 vs T2 vs T3 vs T4)*, (1.220, 1.696) N classification (N0 vs N1 vs N2 vs N3)*, (1.305, 1.833) Grade of masticator space involvement (1.061, 1.615) Local failure Age (,50 y vs 50 y) (1.052, 2.463) T classification (T1 vs T2 vs T3 vs T4)* (1.136, 2.016) Grade of masticator space involvement (1.054, 2.068) Distant failure T classification (T1 vs T2 vs T3 vs T4)* (1.203, 2.016) N classification (N0 vs N1 vs N2 vs N3)* (1.183, 1.929) Grade of masticator space involvement (1.206, 2.104) Note. Numbers in parentheses are 95% confidence intervals. * According to the seventh edition of the AJCC staging system. This indicated that lateral masticator space invasion (involvement of the lateral pterygoid muscle or AJCC masticator space) should be classified as T4 disease. Discussion Our study demonstrated that the prognosis of patients with medial invasion (medial pterygoid muscle involvement) was significantly higher than that with lateral invasion (lateral pterygoid muscle or AJCC masticator space involvement). The patients with lateral invasion of masticator space were found to have a poorer prognosis, similar to stage T4 disease, compared with those with medial invasion. This indicated that medial and lateral invasion should be defined as T2 and T4 disease, respectively. Therefore, we suggest that lateral invasion of masticator space should be included as a subclassification in the AJCC staging system for NPC. This could facilitate tailored therapeutic approaches, with improved outcomes, in the treatment of patients with NPC. Several investigators have suggested that lateral tumor spread into the masticator space is associated with poorer outcome in patients with NPC (3 5). In these studies, staging was assessed by using CT scans; therefore, distinguishing between tumor infiltration of the masticator space and its displacement would have been difficult (16). Because of the widespread application of MR imaging technology in NPC, the improved softtissue contrast of MR imaging enables the extent of masticator space invasion to be judged more accurately (17 19). Despite these advances, only a few investigators have focused on defining an effective subclassification system for masticator space invasion in NPC on the basis of MR images. These include studies by Tang et al (7) and Sun et al (20), which both suggested that tumor invasion into any part of the anatomic masticator space involvement in NPC should be classified as stage T4. The discrepancy between these studies may be caused by their different classification methods. In the study by Tang et al, they classified involvement of the medial or lateral pterygoid muscle as grade 1 and involvement of the AJCC masticator space as grade 2. They found that the prognosis of patients with grade-1 invasion was similar to that in patients with grade-2 invasion. Sun et al divided masticator space invasion into grade 1, grade 2, and grade 3, as noted earlier in our study, and showed significant differences in OS only between Radiology: Volume 273: Number 1 October 2014 n radiology.rsna.org 141

7 Figure 3 Figure 3: Kaplan-Meier curves show (a) OS, (b) LRFS, and (c) DMFS in patients with NPC, stratified by lateral masticator space invasion together with T classification. Differences are shown according to P value, where P,.05 indicates a significant difference. TM1 = patients with stage T2 disease without lateral masticator space invasion, TM2 = patients with stage T3 disease without lateral masticator space invasion, TM3 = all patients with stage T4 disease, TM4 = patients with stage T2 or T3 disease with lateral masticator space invasion. grade 1 and grade 3 not between other grades. However, such classification methods may be subjective for the following reasons: The low incidence rate of AJCC masticator space involvement (1.6% and 3.1% in our study and the study by Tang et al, respectively) may result in statistical bias, and the subclassification methods adopted by Tang et al and Sun et al for masticator space involvement can conceal significant differences in prognosis between the medial invasion and lateral invasion of the masticator space. Although we found no significant difference in prognosis in patients with medial or lateral pterygoid muscle involvement compared with those with AJCC masticator space involvement, we observed significantly higher OS and DMFS rates in patients with medial invasion compared with those with lateral invasion of the masticator space, demonstrating that grading masticator space invasion as medial invasion (involvement of the medial pterygoid muscle) or lateral invasion (involvement of the lateral pterygoid muscle or AJCC masticator space) may be a valuable prognosis indicator in NPC. However, these comparisons had not been reported in the studies of Tang et al and Sun et al. We found a significantly higher risk of distant failure in patients with lateral invasion compared with those with medial invasion of masticator space; in contrast, there was no significant difference in local control between these two groups (P =.994), although a significantly higher LRFS rate was observed in patients without masticator space invasion compared with those with medial or lateral invasion of masticator space (P,.001). This may be attributable to the following reasons: All the patients enrolled in this study underwent IMRT, which can provide a biologically effective dose to the tumor target at a sufficiently high dose for severe masticator space invasion. It has also been shown 142 radiology.rsna.org n Radiology: Volume 273: Number 1 October 2014

8 to provide excellent local control in the treatment of NPC (21,22). Second, a bulky primary tumor with lateral masticator space involvement can lead to tumor invasion into the venous plexus, thereby increasing the risk of hematogenous dissemination; furthermore, this risk is not decreased with IMRT (23,24). In this study, lateral involvement of the masticator space was found to be significantly correlated with other features of advanced local disease, such as intracranial extension and skull base erosion. In contrast, there was no correlation between lateral invasion of the masticator space and advanced N classifications. Taken together, these results suggest that the potential of distant spread may be dependent on the propensity of the tumor to invade the venous plexus and not the lymphovascular channels. It should be stressed that the MR imaging method used in this study involved 5- or 6-mm section thicknesses and 1-mm intersection gaps, which may have led to some loss of information. Furthermore, follow-up was incomplete for some patients, and the patients were enrolled from a single district, which may have reduced the generality of our results. Therefore, we acknowledge that prospective, large-sample, multicenter studies, with the use of thinner section thicknesses for MR imaging, are necessary to confirm our findings and recommendation. In conclusion, we recommend that masticator space involvement should be defined as medial or lateral invasion, which correlate to stage T2 and T4 disease, respectively. Furthermore, these grades were found to have prognostic value in the treatment of patients with NPC. Disclosures of Conflicts of Interest: G.Y.Z. No relevant conflicts of interest to disclose. Y.H. No relevant conflicts of interest to disclose. X.Y.C. No relevant conflicts of interest to disclose. X.P.C. No relevant conflicts of interest to disclose. T.X. No relevant conflicts of interest to disclose. J.W. No relevant conflicts of interest to disclose. W.H.W. No relevant conflicts of interest to disclose. L.Z.L. No relevant conflicts of interest to disclose. Z.L.H. No relevant conflicts of interest to disclose. M.M.Z. No relevant conflicts of interest to disclose. S.T.X. No relevant conflicts of interest to disclose. Y.J.W. No relevant conflicts of interest to disclose. References 1. Curtin HD. Separation of the masticator space from the parapharyngeal space. Radiology 1987;163(1): Gupta A, Chazen JL, Phillips CD. Imaging evaluation of the parapharyngeal space. Otolaryngol Clin North Am 2012;45(6): Sham JS, Choy D. Prognostic value of paranasopharyngeal extension of nasopharyngeal carcinoma on local control and short-term survival. Head Neck 1991;13(4): Chua DT, Sham JS, Kwong DL, Choy DT, Au GK, Wu PM. 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