Prognostic Value of Parapharyngeal Involvement Subclassifications Divided by Parapharyngeal Muscles in Nasopharyngeal Carcinoma: A Study of 1752 Patients from Two Centers
- 1. Department of Laboratory Medicine, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
- 2. Radiotherapy Department of Nasopharyngeal Carcinoma, Cancer Center, The First People’s Hospital of Foshan Affiliated to Sun Yat-sen University, Foshan 528000, China
- 3. Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, China
- 4. Department of Radiology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
- 5. Department of Radiation Oncology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
- #. These authors contributed equally to this work
Abstract
Background: Parapharyngeal Involvement (PI) is common in local invasion but with different degrees in Nasopharyngeal Carcinoma (NPC). This study firstly assessed the prognostic value of PI subclassifications divided by parapharyngeal muscles in NPC.
Methods: 1,752 newly diagnosed NPC patients from two centers were enrolled. The involvement of parapharyngeal muscles including Levator Veli Palatine Muscle (LVPMI), Tensor Veli Palatine Muscle (TVPMI), medial pterygoid muscle (MPMI) and Lateral Pterygoid Muscle (LPMI) was diagnosed by Magnetic Resonance Imaging (MRI). Univariate and multivariate models were constructed to assess the association between PI and survival.
Results: The Progression-Free Survival (PFS), Overall Survival (OS), Distant Metastasis-Free Survival (DMFS), and Locoregional Relapse-Free Survival (LRRFS) between No-PI and LVPMI were similar, p values were 0.446, 0.337, 0.372 and 0.446, respectively, similar to PFS, OS, DMFS and LRRFS between MPMI and LPMI. So PI subclassifications were divided into four degrees: No-PI/LVPMI, TVPMI, MPMI/LPMI, and (infratemporal fossa involvement, IFI). The survival curves among four degrees were statistically different (p < 0.05), except for PFS, OS, and LRRFS between grade 3 and grade 4. Multivariate analyses indicated PI degree (grade 1/2 vs. grade 3/4) was an independent prognostic factor of PFS, OS, DMFS and LRRFS (p < 0.05). If MPMI/LPMI was classified into the T3 stage, there were only 0.6% (10/1,752) incidence rates changing in T2 or T3 stages, and the predictive value was without statistical difference (p > 0.05).
Conclusion: In NPC patients, it was feasible to divide PI by parapharyngeal muscles. The advanced PI predicted poorer survival outcomes than those with mild PI.
Keywords
• Nasopharyngeal carcinoma
• Parapharyngeal involvement subclassifications
• T stage; Prognosis
CITATION
Fu YC, Chen LS, Cui CY, Xie SD, Xu XY, et al. (2024) Prognostic Value of Parapharyngeal Involvement Subclassifications Divided by Parapharyngeal Muscles in Nasopharyngeal Carcinoma: A Study of 1752 Patients from Two Centers. JSM Clin Oncol Res 12(1): 1074.
ABBREVIATIONS
PI: Parapharyngeal Involvement; NPC: Nasopharyngeal Carcinoma; LVPMI: Levator Veli Palatine Muscle; TVPMI: Tensor Veli Palatine Muscle; MPMI: Medial Pterygoid Muscle; LPMI: Lateral Pterygoid Muscle; IFI: Infratemporal Fossa; MRI: Magnetic Resonance Imaging; PFS: Progression Free Survival; OS: Overall Survival; DMFS: Distant Metastasis-Free Survival; LRRFS: Locoregional Relapse-Free Survival; CT: Computed Tomography; 2D-RT: 2-Dimensional Radiotherapy; IMRT: Intensity-Modulated Radiation Therapy; AJCC: The American Joint Commission on Cancer staging system; PTV: Planning Target Volume; CTV: Clinical Target Volume; RT: Radiation Therapy
BACKGROUND
Nasopharyngeal Carcinoma (NPC) has a high incidence rate in South China, compared to a very low incidence rate in most part of the world [1-3]. Radiotherapy is the first and primary treatment strategy for non-metastatic NPC. Thus without pathology, tumor invasion of the anatomical structures around the nasopharynx is diagnosed by imaging. Magnetic Resonance Imaging (MRI), which has good soft tissue contrast resolution, is the best imaging technique for evaluating the extent of primary tumor in NPC [4-6].
As a highly malignant carcinoma, NPC is easy to infiltrate into the surrounding tissues, including bilateral invasion into the parapharyngeal space. According to our previous study, parapharyngeal muscles were at different risks of tumor invasion. The Levator Veli Palatine Muscle Involvement (LVPMI) And Tensor Veli Palatine Muscle Involvement (TVPMI) were at high risk, with incidence rates of 65.5% and 57.2%. Medial pterygoid muscle involvement (MPMI) and Lateral Pterygoid Muscle Involvement (LPMI) were at medium risk, with incidence rates of 19.9% and 10.6%. Infratemporal Fossa Involvement (IFI) was at low risk of tumor invasion, with incidence rate of 2.9% [7].
Due to the different risks of tumor invasion in the parapharynx, the prognostic value of Parapharyngeal Involvement (PI) subclassifications is a hotspot of researches. There have been some studies evaluating the degrees of PI based on different grading systems, such as Min’s classification, Sham’s classification, Xiao’s classification, and Heng’s classification [8-11]. These hypothetical lines were applicable in Computed Tomography (CT) era, but there were some limitations in dividing PI by hypothetical lines, such as most of them were established on CT and 2-Dimensional Radiotherapy (2D-RT) era, which might be not feasible in MRI and Intensity-Modulated Radiation Therapy (IMRT) era. and, the hypothetical lines were not visual and clear, so it was difficult to remember. Therefore, it might be more advantageous to divid PI to different degrees by parapharyngeal muscles than hypothetical lines.
In the 8th edition of the American Joint Commission on Cancer staging system (AJCC) of NPC, PI including TVPMI, MPMI or LPMI is classsified to T2 stage, and IFI is classsified to T4 stage [12]. However, there are still some controversies in the prognostic value of PI subclassifications in NPC. In Luo et al. study, the OS between patients with IFI was poorer than those with MPMI and/ or LPMI [13]. In Xiao et al. study, the prognosis of patients with LPMI and/or IFI were shown to be significantly worse than those affected only MPMI or the T3-stage disease [14]. It is suggested that PI subclassifications should be considered in future TNM staging revisions.
Thus, in this study, we comprehensively evaluated PI by MRI, and firstly divided PI to different degrees by parapharyngeal muscles in NPC patients on large samples from two centers. We aimed to evaluate the predictive value of this PI subclassification, to evaluate the current TNM staging and to make individualized treatment regimen for NPC patients.
METHODS
Patients
This study was approved by the Ethics Committees of the Third Affiliated Hospital of Sun Yat-Sen University, and the need for informed consent was waived because of the retrospective nature. This study enrolled 1,752 patients with NPC, who were treated from January 2010 to March 2014. Among them, 1,320 patients were treated at Sun Yat-sen University Cancer Center, and 432 patients were treated First People’s Hospital of Foshan Affiliated to Sun Yat-sen University. The inclusion criteria were newly diagnosed, histologically proven, and non-metastatic NPC, prior history of malignant tumors, pretreatment MRI of the nasopharynx and neck, and complete records of clinical data.
All patients included 1,297 men and 455 women (male:female ratio, 2.8:1), with a median age of 46 years (range, 11-80 years). All the patients were restaged according to the 8th edition of the AJCC system [12]. The stage distribution was as follows: 437/1,752 (24.9%) with T1, 227 (13%) with T2, 678 (38.7%) with T3, and 410 (23.4%) with T4; 352 (20.1) with N0, 993 (56.7%) with N1, 289 (16.5%) with N2, and 118 (6.7%) with N3; and 145 (8.3%) with stage I, 394 (22.5%) with stage II, 708 (40.4%) with stage III, and 505 (28.8%) with stage IVa.
Imaging
Before treatment, all patients underwent MRI of the nasopharynx and neck with a 1.5-T or 3.0-T MRI system. Detailed protocol of the MRI scan has been previously described in the reported studies [15,16]. After receiving a head-and-neck combined coil, patients first underwent non-contrast-enhanced T1-Weighted Imaging (T1WI) and T2-Weighted Imaging (T2WI) in the axial, coronal, and sagittal planes. Contrast-enhanced images were then acquired after intravenous injection of contrast agent (Gd-DTPA; 0.1 mmol/kg). The T1WI parameters were FSE, TR = 500–600 ms, and TE = 10–20 ms; the T2WI parameters were FSE, TR = 4000–6000 ms, and TE = 95–110 ms. Section thickness was 5 mm for the axial and coronal planes and 3–4 mm for the sagittal plane; slice gap was 1 mm.
Two radiologists with >10 years’ experience in head and neck carcinomas independently evaluated the MRI scans, and any disagreements were resolved by consensus every two weeks. The PI subclassifications were divided by parapharyngeal muscles, including No-PI, LVPMI, TVPMI, MPMI, LPMI and IFI (Figure 1).
Figure 1: Axial T2-weighted magnetic resonance (MR) image at the level of the nasopharynx shows the parapharyngeal subclassifications as defined with anatomic criteria. LVPMI = levator veli palatine muscle, TVPMI = tensor veli palatine muscle, MPMI = medial pterygoid muscle, LPMI = lateral pterygoid muscle, IF = infratemporal fossa.
The parapharyngeal muscle involvement was diagnosed as follows: 1) the muscle was not distinguishable from the tumor mass, 2) asymmetry in signal intensity existed, 3) the integrity of the muscles of mastication had been disrupted by the tumor [13]. IFI was defined as extension beyond the anterior surface of the LPM or lateral extension beyond the posterolateral wall of the maxillary sinus or pterygomaxillary fissure [17].
Treatment
All patients were treated using IMRT, of which the detailed protocol had been described in the previous reports [18,19]. For Planning Target Volume (PTV) of the primary tumor plus metastatic retropharyngeal lymph nodes, metastatic cervical lymph nodes, high-risk Clinical Target Volume (CTV), and low- risk CTV, the prescribed doses were 66-72 Gy/30-33 fractions, 64-70 Gy/30-33 fractions, 60-63 Gy/30-33 fractions and 50-56 Gy/28-33 fractions, respectively. The Radiation Therapy (RT) was given one fraction daily, and 5 days weekly.
In total, 1,450 patients (1,450/1,752, 82.8%) with locoregionally advanced disease received platinum-based chemotherapy. Of these, 892 received induction chemotherapy plus concurrent chemotherapy, and 558 received concurrent chemotherapy. The induction chemotherapy composed 2-3 cycles of PF, TPF, TP, or GP regimens every three weeks, and concurrent chemotherapy included cisplatin weekly or every three weeks.
The prescription doses had been described in the previous reports [20,21]. In the event of tumor relapse or persistent disease, salvage treatment such as surgery, radiotherapy, or chemotherapy was administered when appropriate.
Follow-up and statistical analysis
Patients were followed up every three months during the first two years after RT and every six months thereafter. The main endpoint was Progression-Free Survival (PFS), which was calculated from the date of starting treatment to the date of disease progress, or death due to any reasons, or last follow-up. The secondary endpoints included Overall Survival (OS), Distant Metastasis-Free Survival (DMFS), and Locoregional Relapse-Free Survival (LRRFS), which were also calculated as above.
All analyses were performed using SPSS 22.0 (IBM Corp, Armonk, NY, USA). Chi-square or Fisher exact test was used to compare categorical data. Univariate analyses were conducted using the Kaplan–Meier method. Multivariable analyses were performed using the Cox proportional hazards model, in which the following parameters were included: age (≤45 years vs. >45 years), gender (male vs. female), chemotherapy (yes vs. no), N category (N0-1 vs. N2-3), skull base involvement (yes vs. no), paranasal sinuses involvement (yes vs. no), intracranial involvement (yes vs. no), orbital involvement (yes vs. no). Two- sided p values < 0.05 were considered statistically significant.
RESULTS
The incidence rates of PI subclassifications
Of the total 1,752 NPC patients recruited, the incidence rates of No-PI, LVPMI, TVPMI, MPMI, LPMI and IFI were 25.5%, 73.9%,58.5%, 18.3%, 8.5%, and 2.8%, respectively. When the degrees of PI were divided by parapharyngeal muscles, the incidence rates of PI subclassifications including No-PI, LVPMI, TVPMI, MPMI, LPMI, and IFI were 25.5%, 15.7%, 40.1%, 9.8%, 6.2%, and 2.8%, respectively. The distribution of PI in T stages was shown in Table 1. It was shown that the more severe PI, the more advanced in the T stages. And it was also shown that most patients with MPMI and/or LPMI were accompanied with stage T3/T4 factors.
Table 1: The distribution of different degrees of parapharyngeal invasion in T stages in 1752 patients with nasopharyngeal carcinoma.
Tumorl Invasion |
T1 |
T2 |
T3 |
T4 |
In Total |
No-PI,n (%) |
357 (80%) |
4 (0.9%) |
78 (17.5%) |
7 (1.6%) |
446 (100%) |
LVPMI, n (%) |
80 (29.1%) |
63 (22.9%) |
118 (42.9%) |
14 (5.1%) |
275 (100%) |
TVPMI, n (%) |
0 |
150 (21.4%) |
395 (56.3%) |
157 (22.4%) |
702 (100%) |
MPMI, n (%) |
0 |
10 (5.8%) |
75 (43.9%) |
86 (50.3%) |
171 (100%) |
LPMI, n (%) |
0 |
0 |
12 (11%) |
97 (89%) |
109 (100%) |
IFI, n (%) |
0 |
0 |
0 |
49 (100%) |
49 (100%) |
Abbreviations: No-PI: No Parapharyngeal Involvement; LVPMI: Levator Veli Palatine Muscle Involvement; TVPMI: Tensor Veli Palatine Muscle Involvement; MPMI: Medial Pterygoid Muscle Involvement; LPMI: Lateral Pterygoid Muscle Involvement; IFI: Infratemporal Fossa Involvement
Prognostic value of parapharyngeal muscles
The estimated 5-year PFS rates in patients with No-PI, LVPMI, TVPMI, MPMI, LPMI and IFI were 87.8%, 85.4%, 73.8%, 62.6%,63.2%, and 49.9%; The estimated 5-year OS rates were 94.2%, 92.5%, 83.2%, 73%, 72%, and 60.3%; 5-year DMFS rates were 93%, 90.7%, 85.1%, 77.9%, 77.4%, and 60.8%; and 5-year LRRFS rates were 95.1%, 94.8%, 88.3%, 83%, 82.8%, and 72.8%, respectively (Figure 2).
Figure 2: Prognostic comparison of 1,752 NPC patients among different parapharyngeal involvement subclassifications. (A) Progression-free survival, (B) Overall survival, (C) Distant metastasis-free survival, (D) Locoregional relapse-free survival.
Univariate analyses indicated PFS, OS, DMFS, and LRRFS between No-PI and LVPMI were similar, p values were 0.446, 0.337, 0.372, and 0.446, respectively. Similar to PFS, OS, DMFS, and LRRFS between MPMI and LPMI, p values were 0.859, 0.698, 0.729, and 0.859, respectively.
Prognostic value of PI subclassifications divided by parapharyngeal muscles
According to the above analysis, the degrees of PI were classified into four degrees: grade 1 (No-PI or LVPMI), grade 2 (TVPMI), grade 3 (MPMI or LPMI), and grade 4 (IFI). The incidence rates of these 4 degrees were 41.2%, 40.1%, 16%, and 2.8%, respectively. The estimated 5-year PFS rates in patients with grade 1, grade 2, grade 3, and grade 4 were 86.6%, 73.8%, 62.8%, and 49.9%; The estimated 5-year OS rates were 93.6%, 83.2%, 72.7%, and 60.3%; 5-year DMFS rates were 92.1%,85.1%, 77.7%, and 60.8%; and 5-year LRRFS rates were 95%,88.3%, 82.9%, and 72.8%, respectively (Figure 3).
Figure 3: Prognostic comparison of 1,752 NPC patients among four different grades of parapharyngeal involvement. (A) Progression-free survival, (B) Overall survival, (C) Distant metastasis-free survival, (D) Locoregional relapse-free survival.
The survival curves among four degrees were statistically different (p < 0.05), except that the PFS, OS, and LRRFS between grade 3 and grade 4 were close to statistical difference, p values were 0.071, 0.078, and 0.101. The negative results might lie in the small patients’number in grade 4 (N=49). The sociodemographic and clinical characteristics of 1,752 NPC patients were shown in table 2. Multivariate analyses indicated that the degree of PI (grade 1/ grade 2 vs. grade 3/grade 4) was an independent predictor of PFS, OS, DMFS, and LRRFS (all p < 0.001, Table 3).
Table 2: Sociodemographic and clinical characteristics of the participants
Variables |
Numbers |
PFS |
|
OS |
|
DMFS |
|
LRRFS |
|
|
N=1752 (100%) |
surv. |
P value |
surv. |
P value |
surv. |
P value |
surv. |
P value |
Sex (%) |
|
|
0.381 |
|
0.006 |
|
0.338 |
|
0.571 |
Male |
1297 (74%) |
76.2% |
|
84% |
|
85.7% |
|
90.6% |
|
Female |
455 (26%) |
78.3% |
|
89% |
|
87.7% |
|
89.2% |
|
Age (years) |
|
|
0.085 |
|
< 0.001 |
|
0.429 |
|
0.444 |
≤ 45 |
858 (49%) |
78.7% |
|
89.3% |
|
87% |
|
90.3% |
|
> 45 |
894 (51%) |
74.8% |
|
81.4% |
|
85.5% |
|
88.9% |
|
N category (%) |
|
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
0.001 |
N0-1 |
1345 (76.8%) |
80.8% |
|
88.9% |
|
89.8% |
|
91.3% |
|
N2-3 |
407 (23.2%) |
63% |
|
72.9% |
|
74.2% |
|
84.8% |
|
Chemotherapy |
|
|
0.157 |
|
0.551 |
|
0.024 |
|
0.065 |
Yes |
1449 (82.7%) |
76% |
|
85.1% |
|
85.4% |
|
89.2% |
|
No |
303 (17.3%) |
80% |
|
86.3% |
|
90.6% |
|
93.5% |
|
Skull base involvement |
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
Yes |
1079 (61.6%) |
71.4% |
|
81% |
|
83.2% |
|
87.2% |
|
No |
673 (38.4%) |
84.9% |
|
91.8% |
|
91% |
|
93.9% |
|
Paranasal sinuses involvement |
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
Yes |
442 (25.2%) |
64.3% |
|
74.7% |
|
75.2% |
|
83.4% |
|
No |
1310 (74.8%) |
80.7% |
|
88.6% |
|
88.7% |
|
91.9% |
|
Intracranial involvement |
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
0.007 |
|
Yes |
341 (19.5%) |
62.7% |
|
71.5% |
|
77.1% |
|
85.1% |
|
No |
1411 (80.5%) |
80% |
|
88.4% |
|
88.3% |
|
91% |
|
Orbital involvement |
|
|
0.009 |
|
< 0.001 |
|
0.015 |
|
0.741 |
Yes |
95 (5.4%) |
65.2% |
|
70.4% |
|
77% |
|
88.7% |
|
No |
1657 (94.6%) |
77.3% |
|
86.1% |
|
86.8% |
|
90% |
|
Parapharyngeal involvement |
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
< 0.001 |
|
G1-2 |
1423 (81.2%) |
80.4% |
|
88.5% |
|
88.7% |
|
91.8% |
|
G3-4 |
329 (18.8%) |
60.9% |
|
70.8% |
|
75.2% |
|
81.5% |
|
Abbreviations: OS: Overall Survival; PFS: Progress-Free Survival; DMFS: Distant Metastasis-Free Survival; LRRFS: Locoregional Relapse-Free Survival; G1-2: No Parapharyngeal Involvement or Levator Veli Palatine Muscle Involvement or Tensor Veli Palatine Muscle Involvement; G3-4, Medial Pterygoid Muscle Involvement or Lateral Pterygoid Muscle Involvement or Infratemporal Fossa Involvement
Table 3: Significant factors included in the multivariate analyses for 1,752 patients with nasopharyngeal carcinoma
Endpoint |
Variable |
HR |
95% CI |
P Value a |
PFS |
N category b |
2.032 |
1.649 - 2.503 |
< 0.001 |
|
Parapharyngeal involvement |
1.662 |
1.314 - 2.101 |
< 0.001 |
|
Skull base involvement |
1.401 |
1.074 - 1.827 |
0.013 |
|
Paranasal sinuses involvement |
1.433 |
1.132 - 1.812 |
0.003 |
OS |
Age |
1.650 |
1.270 - 2.142 |
< 0.001 |
|
Sex |
1.389 |
1.007 - 1.916 |
0.046 |
|
N category b |
2.404 |
1.860 - 3.108 |
< 0.001 |
|
Parapharyngeal involvement |
1.987 |
1.496 - 2.640 |
< 0.001 |
|
Skull base involvement |
1.512 |
1.061 - 2.155 |
0.022 |
|
Paranasal sinuses involvement |
1.475 |
1.104 - 1.970 |
0.009 |
DMFS |
N category b |
2.598 |
1.991 - 3.390 |
< 0.001 |
|
Parapharyngeal involvement |
1.941 |
1.444 - 2.610 |
< 0.001 |
|
Paranasal sinuses involvement |
1.436 |
1.075 - 1.919 |
0.014 |
LRRFS |
N category b |
1.644 |
1.177 - 2.298 |
0.004 |
|
Parapharyngeal involvement |
1.965 |
1.371 - 2.816 |
< 0.001 |
|
Paranasal sinuses involvement |
1.754 |
1.238 - 2.486 |
0.002 |
Abbreviations: HR: Hazard Ratio; CI: Confidence Interval; OS: Overall Survival; PFS: Progress-Free Survival; DMFS: Distant Metastasis-Free Survival; LRRFS: Locoregional Relapse-Free Survivala P-values were calculated using an adjusted Cox proportional hazards model. b According to the 8th AJCC staging system.
The impact of PI subclassifications in T stages
The estimated 5-year PFS rates in patients with T1, T2, T3, and T4 stages were 88.1%, 79%, 75.4%, and 65.2%; The estimated 5-year OS rates were 95.2%, 85.9%, 85.2%, and 74.1%; 5-year DMFS rates were 93.4%, 86.1%, 86.2%, and 78.4%; and 5-year LRRFS rates were 95.1%, 91.8%, 87.9%, and 86.1%, respectively.
The survival curves of PFS, OS, DMFS and LRRFS between T2 and T3 stages were close, p values were 0.354 (Figure 4A), 0.908, 0.889 and 0.186 (Figure 4B).
Figure 4: Prognostic comparison of 1,752 NPC patients among different T staging systems. (A) Progression-free survival in current-T stages, (B) Lcoregional relapse-free survival in current-T stages, (C) Progression-free survival in new-T stages, (D) Lcoregional relapse-free survival in new-T stages.
If MPMI/LPMI was classified into T3 stage, the incidence rates of new T2 and T3 stages were 12.4% (217/1,752) and 39.3% (688/1,752). There were only 0.6% (10/1,752) incidence rates changing in T2 or T3 stages. And the 5-year PFS, OS, DMFS and LRRFS rates between patients with new T2 and T3 stages were 81% vs. 74.8% (Figure 4C, p = 0.119), 87.2% vs. 84.7% (p = 0.462), 87.9% vs. 85.6% (p = 0.521), 87.9% vs. 85.6% (Figure 4D, p = 0.066).
DISCUSSION
In the present study, PI subclassifications were divided by parapharyngeal muscles, including grade 1 (No-PI or LVPMI), grade 2 (TVPMI), grade 3 (MPMI or LPMI), and grade 4 (IFI). The incidence rates of these 4 degrees were 41.2%, 40.1%, 16%, and 2.8%, respectively. The survival curves among four degrees were statistically different (p < 0.05), except for the PFS, OS, and LRRFS between grade 3 and grade 4. The degree of PI (grade 1/grade 2 vs. grade 3/grade 4) was an independent predictor of PFS, OS, DMFS, and LRRFS (all p < 0.001). If MPMI/LPMI was classified into the T3 stage, there were only 0.6% (10/1,752) incidence rates changing in T2 or T3 stages, and the predictive value was without statistical difference (p > 0.05).
In this study, the incidence rates of LVPMI, TVPMI, MPMI, LPMI, and IFI were 73.9%, 58.5%, 18.3%, 8.5%, and 2.8%,respectively. These incidence rates were similar to our previously reported data [5]. In the study by Dong et al., the incidence rates of LVPMI, TVPMI, MPMI, LPMI, and IFI were 74.0%, 55.8%, 19.5%,8.2%, and 2.8%, respectively [17]. In this study, it was also shown that the more severe in PI, the more advanced in the T stages, and most of patients with MPMI and/or LPMI was accompanied with stage T3/T4 factors.
In the present study, PI subclassifications were divided by parapharyngeal muscles, including grade 1 (No-PI or LVPMI), grade 2 (TVPMI), grade 3 (MPMI or LPMI), and grade 4 (IFI). The survival curves among four degrees were statistically different (p< 0.05), except the PFS, OS, and LRRFS between grade 3 and grade 4, which were close to statistical difference. The PI degree was an independent prognostic factor of PFS, OS, DMFS and LRRFS. In Huang et al. study, PI was separated into four invasion patterns: pattern A (only post-styloid space), pattern B (post-styloid space, CS extension), pattern C (poststyloid space, pre-styloid space extension), and pattern D (all spaces), which was recommended to optimize T3 heterogeneity [22]. Compared to the reported reports, this grading system was based on parapharyngeal muscles which might be more inherent and clear, and could be easily diagnosed by MRI. Furthermore, this study also confirmed that advanced PI indicated poorer outcomes than those with mild PI, as the results in the previous classification [23].
In this study, if MPMI/LPMI was classified into T3 stage, there were only 0.6% incidence rates changing in T2 or T3 stages, and the predictive value was without statistical difference. In Tang et al. study, when masticator space involvement included MPMI and LPMI, the disease was suggested to be classified as T4 stage [24]. In Zhang et al. study, MPMI could be graded as T2 stage, and LPMI/IFI as T4 stage [25]. In Sze et al. study, NPC with MPMI and/or LPMI alone should be classified as the T2 disease [26]. Based on the controversial resultss, the impact of MPMI/LPMI in T stages should be reassessed in future TNM stages.
To our knowledge, this study is the first study to divide PI by parapharyngeal muscles based on a large sample from two centers. However, our study has some limitations. First, due to the nature of retrospective studies, chemotherapy regimens were diverse, despite this, the treatment outcomes among these regimens were similar according to previous reports [27-29].
Second, the incidence rates of IFI were so low that it might lead to false negative results of survival comparison, so it needed to enroll larger samples in further studies.
CONCLUSION
In summary, in NPC patients, it was feasible to divide PI by parapharyngeal muscles. The advanced PI predicted poorer survival outcomes than those with mild PI. The prognostic value of PI subclassifications divided by parapharyngeal muscles should be reassessed with larger samples in future TNM staging revisions.
Acknowledgement: Not applicable
AUTHOR CONTRIBUTIONS
SBL and XHW was responsible for the study design. YCF was the major contributor in writing the manuscript. LSC and CYC collected the patient data. SDX was responsible for the statistical data. XYX and XHW performed the follow examination. All authors read and approved the final manuscript.
FUNDING
This work was supported by the Science and Technology Bureau of Guangzhou [No. 202201010847]; and the Third Affiliated Hospital of Sun Yat-sen University [No. 2023GZRPYMS14]. The funding provided the resources for the study design, data collection and data analysis, and manuscript polish.
Availability of Data and Materials: Not applicable.
DECLARATIONS
Ethics approval and consent to participate
This study was approved by the Ethics Committees of the Third Affiliated Hospital of Sun Yat-Sen University, and the need for written informed consent was waived.
Consent for Publication: Not applicable.
COMPETING INTERESTS
The authors declare that they have no competing interest.
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