Abstract
Background
To investigate the prognostic implications of histology among nasopharyngeal carcinoma (NPC) using the data from a Chinese cohort and the Surveillance, Epidemiology, and End Results (SEER) database.
Methods
We included patients diagnosed with WHO II and III subtypes NPC from two independent cohorts (Xiamen [XM]-NPC cohort and SEER-NPC cohort).
Results
We identified 726 patients in the XM-NPC cohort and 1334 patients in the SEER cohort. In the XM-NPC cohort, 94 (12.9%) and 632 (87.1%) patients had WHO II and III subtypes, respectively. In the SEER-NPC cohort, 839 (62.9%) and 495 (37.1%) patients had WHO II and III subtypes, respectively. WHO II subtype patients had a higher smoking rate than the WHO III subtype (57.4% vs. 43.4%) in the XM-NPC cohort. There were no significant differences in age, gender, tumor stage, or nodal stage between the two subtypes in both cohorts. In the XM-NPC cohort, patients with the WHO II subtype had worse locoregional relapse-free survival (82.2% vs. 89.5%, p = 0.063), distant metastasis-free survival (72.4% vs. 85.9%, p = 0.028), disease-free survival (61.6% vs. 78.8%, p = 0.003), and overall survival (OS) (71.7% vs. 84.0%, p = 0.035) than those with WHO III subtype. In the SEER-NPC cohort, patients with the WHO II subtype had worse NPC-specific survival (81.1% vs. 89.4%, p < 0.001) and OS (71.6% vs. 78.8%, p < 0.001) than those with WHO III subtype. The multivariate analysis showed that histology was an independent prognostic factor associated with outcomes in both cohorts.
Conclusions
Our study demonstrates the significant influence of histological subtypes on outcomes in NPC among various populations, highlighting substantial disparities between the WHO II and WHO III subtypes.
Keywords: Nasopharyngeal carcinoma, histology, Chinese, SEER, outcome
KEY MESSAGES
The impact of histology on the outcomes of NPC remains controversial.
We assessed the prognostic implications of histology among NPC patients using data from endemic areas of China and validated our findings using the data from the SEER database.
WHO II subtype patients had a higher smoking rate than the WHO III subtype in the XM-NPC cohort.
Histology is an independent factor that impacts NPC outcomes in both endemic and non-endemic areas.
Introduction
Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma originating from the mucosa of the nasopharynx, exhibiting significant geographical and ethnic variations worldwide [1]. In southern China, the incidence is about 20 cases per 100,000 people, but the incidence is less than 1 case per 100,000 people in Europe and the United States (US) [2]. With the progress of comprehensive treatment, the survival rate of NPC has been significantly improved, and the 5-year overall survival (OS) rate is about 85%, but approximately 20–30% of patients will develop locoregional recurrence and/or distant metastasis after treatment [3]. Factors contributing to disease recurrence include anatomical features [4], resistance to radiotherapy and chemotherapy [5], biological characteristics of the cancer cells [6], immune system status by Epstein-Barr virus (EBV) viral infection [7], and lifestyle factors [8]. Currently, the main prognostic factors for NPC include the tumor (T) stage, nodal (N) stage, and EBV DNA levels [9].
There are currently three common World Health Organization (WHO) histological subtypes of NPC, including keratinizing squamous cell carcinoma (WHO I subtype), differentiated non-keratinizing squamous cell carcinoma (WHO II subtype), and undifferentiated non-keratinizing squamous cell carcinoma (WHO III subtype) [10]. WHO I subtype represents only 20% of global NPC cases and is generally not associated with EBV infection. However, WHO II and III subtypes are closely linked to EBV infection and account for over 95% of NPC cases in endemic areas [11]. Notably, there exist substantial variations in histology across different countries, ethnic groups, and endemic areas. For instance, approximately 40–50% of patients in the US were diagnosed with the WHO I subtype [12,13]. Conversely, the WHO III subtype was predominant (95%), followed by the WHO II subtype (4%), while the WHO I subtype constituted merely 1% in the endemic areas of southern China [14].
The impact of histology on the outcomes of NPC remains controversial. Several studies have suggested that the prognosis of the WHO III subtype is better than those with WHO I and II subtypes [12,15]. However, there were also studies that showed comparable outcomes among the histological subtypes [16,17]. Ethnicity, regional specificity as well as the sample size of patients were the potential reasons for the conflict results of the above studies. In light of this, this study aimed to investigate the prognostic implications of histology among NPC patients using data from endemic areas of China while validating our findings using the data from the Surveillance, Epidemiology and End-Results (SEER) database from non-endemic areas.
Materials and methods
Patients
Our study analyzed data from two distinct cohorts. The first cohort, referred to as the Xiamen [XM]-NPC cohort, was sourced from the First Affiliated Hospital of Xiamen University. The second cohort, known as the SEER-NPC cohort, was derived from the SEER database. Due to the limited number of WHO I subtype cases in our database, our analysis focused exclusively on patients with WHO II and III subtypes. For inclusion in the XM-NPC cohort, patients had to meet the following criteria: 1) Diagnosed of NPC patients between January 2015 and December 2021; 2) Aged ≥18 years; 3) Stage I-IVA according to the 8th edition of the American Joint Committee on Cancer (AJCC) NPC staging system; 4) Histological subtypes classified as WHO II or WHO III subtype; 5) Receipt of comprehensive treatment according to the treatment guidelines for NPC. Exclusion criteria included patients with unknown T stage and N stages. The SEER-NPC cohort was derived from the SEER database, which is maintained by the National Cancer Institute and covers approximately 47.9% of the US population [18]. Inclusion criteria for this cohort were: 1) Diagnosis of NPC between 2010 and 2017; 2) Age ≥18 years; 3) Stage I-IVB according to the 7th edition of AJCC NPC staging system; 4) Histological subtypes classified as WHO II (ICD-O-3 codes 8072 and 8073) or WHO III subtype (ICD-O-3 codes 8020, 8021, 8082 and 8083); 5) Receipt of external radiation therapy. Patients with unknown T stage, N stage, or those receiving non-external irradiation were excluded. This study was approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University (approval number: XMYY-2023KYSB194). Written informed consent was obtained from all patients in the XM-NPC cohort. Written informed consent was not required from the SEER-NPC cohort due to the use of publicly available databases.
Variables
In the XM-NPC cohort, we extracted various patient characteristics, including age, gender, histological subtype, smoking history, drinking history, clinical stage, T stage, N stage, and EBV DNA levels. The cutoff point of EBV DNA was set at 430 IU/mL, based on our previous study [19]. For the SEER-NPC cohort, we primarily focused on age, gender, histological subtype, race, clinical stage, T stage, N stage, and treatment modalities (radiotherapy and/or chemotherapy).
Treatment
At our institution, the prescribed dose for intensity-modulated radiation therapy (IMRT) were as follows: 70 gray (Gy)/32-33 fractions for the primary nasopharyngeal tumor, 66-70Gy/32-33 fractions for cervical metastatic lymph nodes, 62 Gy/32-33 fractions for high-risk clinical target volume, and 56 Gy/32-33 fractions for low-risk clinical target volume. Institutional guidelines recommended IMRT solely for stage I NPC, platinum-based concurrent chemoradiotherapy (CCRT) for stage II NPC, and a combination of induction chemotherapy (IC) followed by platinum-based CCRT for stage III-IVA NPC. Due to the SEER database’s lack of detailed records on radiotherapy techniques, doses, and specific chemotherapy regimens, we were only able to document the types of radiotherapy and chemotherapy administered to patients.
Survival outcomes
In the XM-NPC cohort, the study endpoints were locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and OS. LRFS was defined as the time from the diagnosis of NPC to the occurrence of local or regional recurrence or both. DMFS was defined as the time from NPC diagnosis to the occurrence of distant recurrence. DFS was defined as the time from NPC diagnosis to disease progression or death from any cause. OS was defined as the time from NPC diagnosis to death from any cause or the last follow-up. In the SEER-NPC cohort, the study endpoints included NPC-specific survival (NPC-SS) and OS. NPC-SS was defined as the time from NPC diagnosis to death specifically from NPC, or the last follow-up.
Statistical analysis
Patient characteristics between WHO II and WHO III subtypes were compared using the chi-square test or Fisher’s exact test. Survival rates were estimated with the Kaplan-Meier method, and the survival differences were compared using the log-rank test. Multivariate Cox regression analyses were performed to determine independent prognostic factors associated with survival outcomes. All statistical analyses were conducted using the SPSS statistical software package (version 26.0; IBM Corporation, Armonk, NY, USA), with statistical significance set at a P-value of less than 0.05.
Results
Patient characteristics
There were 726 eligible patients in the XM-NPC cohort, with a median age of 50 years. Of these patients, 513 (70.7%) were male and 631 (86.9%) were stage III-IVA disease. Of the 564 patients with known EBV DNA levels before treatment (77.7%), 40.7% (n = 250) had EBV DNA levels ≥ 430 IU/mL. Regarding histology, 94 (12.9%) and 632 (87.1%) were the WHO II subtype and WHO III subtype, respectively. WHO II subtype patients had a higher smoking rate than WHO III subtype (57.4% vs. 43.4%, p = 0.010), but there were no significant differences in age, gender, drinking history, clinical stage, T stage, N stage, and EBV DNA levels (Table 1).
Table 1.
Patient characteristics in the XM-NPC cohort.
| Variables | n (%) | WHO II subtype | WHO III subtype | P |
|---|---|---|---|---|
| Age (years) | ||||
| < 65 | 633 (87.2) | 82 (87.2) | 551 (87.2) | 0.989 |
| ≥ 65 | 93 (12.8) | 12 (12.8) | 81 (12.8) | |
| Gender | ||||
| Male | 513 (70.7) | 73 (77.7) | 440 (69.6) | 0.110 |
| Female | 213 (29.3) | 21 (22.3) | 192 (30.4) | |
| Smoking history | ||||
| No | 398 (54.8) | 40 (42.6) | 358 (56.6) | 0.010 |
| Yes | 328 (45.2) | 54 (57.4) | 274 (43.4) | |
| Alcohol history | ||||
| No | 510 (70.2) | 60 (63.8) | 450 (71.2) | 0.145 |
| Yes | 216 (29.8) | 34 (36.2) | 182 (28.8) | |
| Clinical Stage | ||||
| I | 9 (1.2) | 1 (1.1) | 8 (1.3) | 0.562 |
| II | 86 (11.9) | 7 (7.4) | 79 (12.5) | |
| III | 344 (47.4) | 47 (50.0) | 297 (47.0) | |
| IVA | 287 (39.5) | 39 (41.5) | 248 (39.2) | |
| T stage | ||||
| T1 | 103 (14.2) | 10 (10.6) | 93 (14.7) | 0.298 |
| T2 | 164 (22.6) | 17 (18.1) | 147 (23.3) | |
| T3 | 313 (43.1) | 43 (45.7) | 270 (42.7) | |
| T4 | 146 (20.1) | 24 (25.5) | 122 (19.3) | |
| N stage | ||||
| N0 | 43 (6.0) | 4 (4.3) | 39 (6.2) | 0.665 |
| N1 | 236 (32.5) | 32 (34.0) | 204 (32.3) | |
| N2 | 282 (38.8) | 40 (42.6) | 242 (38.3) | |
| N3 | 165 (22.7) | 18 (19.1) | 147 (23.3) | |
| EBV DNA levels before treatment (IU/mL) | ||||
| < 430 | 314 (43.3) | 41 (43.6) | 273 (43.2) | 0.996 |
| ≥ 430 | 250 (34.4) | 32 (34.0) | 218 (34.5) | |
| Unknown | 162 (22.3) | 21 (22.3) | 141 (22.3) |
WHO, World Health Organization; T, tumor; and N, nodal.
In the SEER-NPC cohort, a total of 1334 patients were enrolled. With a median age of 53 years, 961 (72.0%) were male and 912 (68.4%) were stage III-IVA disease. In addition, 506 (37.9%), 141 (10.6%), and 260 (19.5%) patients were Caucasian, African American, and Chinese American, respectively. There were 839 patients (62.9%) who had the WHO II subtype and 495 (37.1%) had the WHO III subtype. Caucasian patients were more likely to be the WHO II subtype and Chinese American patients were more likely to be the WHO III subtype (p < 0.001). However, there were no significant differences in age, gender, clinical stage, T stage, N stage, and chemotherapy receipt between the two histological subtypes (Table 2).
Table 2.
Patient characteristics in the SEER-NPC cohort.
| Variables | n (%) | WHO II subtype | WHO III subtype | P |
|---|---|---|---|---|
| Age (years) | ||||
| < 65 | 1046 (78.4) | 659 (78.5) | 387 (78.2) | 0.876 |
| ≥ 65 | 288 (21.6) | 180 (21.5) | 108 (21.8) | |
| Gender | ||||
| Male | 961 (72.0) | 605 (72.1) | 356 (71.9) | 0.940 |
| Female | 373 (28.0) | 234 (27.9) | 139 (28.1) | |
| Race | ||||
| Caucasian | 506 (37.9) | 342 (40.8) | 164 (33.1) | <0.001 |
| African American | 141 (10.6) | 97 (11.6) | 44 (8.9) | |
| Chinese American | 260 (19.5) | 126 (15.0) | 134 (27.1) | |
| Other | 427 (32.0) | 274 (32.7) | 153 (30.9) | |
| Clinical Stage | ||||
| I | 130 (9.7) | 85 (10.1) | 45 (9.1) | 0.325 |
| II | 292 (21.9) | 184 (21.9) | 108 (21.8) | |
| III | 470 (35.2) | 281 (33.5) | 189 (38.2) | |
| IVA-IVB | 442 (33.1) | 289 (34.4) | 153 (30.9) | |
| T stage | ||||
| T1 | 493 (37.0) | 316 (37.7) | 177 (35.8) | 0.236 |
| T2 | 266 (19.9) | 157 (18.7) | 109 (22.0) | |
| T3 | 255 (19.1) | 154 (18.4) | 101 (20.4) | |
| T4 | 320 (24.0) | 212 (25.3) | 108 (21.8) | |
| N stage | ||||
| N0 | 281 (21.1) | 177 (21.1) | 104 (21.0) | 0.993 |
| N1 | 447 (33.5) | 279 (33.3) | 168 (33.9) | |
| N2 | 453 (34.0) | 287 (34.2) | 166 (33.5) | |
| N3 | 153 (11.5) | 96 (11.4) | 57 (11.5) | |
| Chemotherapy | ||||
| No/unknown | 141 (10.6) | 87 (10.4) | 54 (10.9) | 0.757 |
| Yes | 1193 (89.4) | 752 (89.6) | 441 (89.1) |
WHO, World Health Organization; T, tumor; and N, nodal.
Survival analysis
In the XM-NPC cohort, 5-year LRFS, DMFS, DFS, and OS were 88.6%, 84.3%, 76.6%, and 82.6%, respectively. Patients with WHO II subtype had worse LRFS (82.2% vs. 89.5%, p = 0.063) (Figure 1A), DMFS (72.4% vs. 85.9%, p = 0.028) (Figure 1B), DFS (61.6% vs. 78.8%, p = 0.003) (Figure 1C), and OS (71.7% vs. 84.0%, p = 0.035) (Figure 1D) compared to those with WHO III subtype.
Figure 1.
Survival curves between WHO II and WHO III subtypes in the XM-NPC cohort (A, locoregional relapse-free survival; B, distant metastasis-free survival; C, disease-free survival; D, overall survival).
In the SEER-NPC cohort, 5-year NPC-SS and OS were 84.2% and 74.3%, respectively. Patients with the WHO II subtype had worse NPC-SS (81.1% vs. 89.4%, p < 0.001) (Figure 2A) and OS (71.6% vs. 78.8%, p < 0.001) (Figure 2B).
Figure 2.
Survival curves between WHO II and WHO III subtypes in the SEER-NPC cohort (A, nasopharyngeal carcinoma-specific survival; B, overall survival).
Prognostic analysis
In the XM-NPC cohort, we found that histology was an independent prognostic factor for DMFS and DFS. Patients with the WHO II subtype had significantly inferior DMFS (hazard ratio [HR] 0.554, 95% confidence interval [CI] 0.323–0.951, p = 0.032) and DFS (HR 0.503, 95%CI 0.322–0.786, p = 0.003) than those with WHO III subtype. In addition, histological analysis had a borderline effect on LRFS (HR 0.538, 95%CI 0.277–1.046, p = 0.068), but had no significant difference on OS. Age, gender, T stage, and EBV DNA levels were also the independent prognostic factors affecting survival outcomes (Table 3).
Table 3.
Multivariate analysis of prognostic factors related to survival outcomes in the XM-NPC cohort.
| LRFS |
DMFS |
DFS |
OS |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Variables | HR | 95%CI | P | HR | 95%CI | P | HR | 95%CI | P | HR | 95%CI | P |
| Age (years) | ||||||||||||
| < 65 | 1 | 1 | 1 | 1 | ||||||||
| ≥ 65 | 0.999 | 0.577–1.730 | 0.997 | 1.990 | 1.263–3.136 | 0.003 | 1.373 | 0.954–1.976 | 0.087 | 2.096 | 1.318–3.333 | 0.002 |
| Gender | ||||||||||||
| Male | 1 | 1 | 1 | 1 | ||||||||
| Female | 0.893 | 0.428–1.861 | 0.763 | 0.571 | 0.330–0.988 | 0.045 | 0.705 | 0.424–1.172 | 0.178 | 0.464 | 0.257–0.839 | 0.011 |
| Smoking history | ||||||||||||
| No | 1 | 1 | 1 | 1 | ||||||||
| Yes | 0.844 | 0.420–1.697 | 0.635 | 1.014 | 0.590–1.744 | 0.959 | 0.957 | 0.608–1.507 | 0.851 | 1.247 | 0.732–2.123 | 0.416 |
| Alcohol history | ||||||||||||
| No | 1 | 1 | 1 | 1 | ||||||||
| Yes | 1.098 | 0.555–2.172 | 0.788 | 0.895 | 0.528–1.517 | 0.681 | 0.978 | 0.631–1.518 | 0.922 | 0.655 | 0.387–1.107 | 0.114 |
| Histology | ||||||||||||
| WHO II | 1 | 1 | 1 | 1 | ||||||||
| WHO III | 0.538 | 0.277–1.046 | 0.068 | 0.554 | 0.323–0.951 | 0.032 | 0.503 | 0.322–0.786 | 0.003 | 0.718 | 0.414–1.244 | 0.237 |
| T stage | ||||||||||||
| T1 | 1 | 1 | 1 | 1 | ||||||||
| T2 | 0.699 | 0.240–2.038 | 0.512 | 2.535 | 0.860–7.471 | 0.092 | 1.219 | 0.558–2.663 | 0.620 | 0.593 | 0.225–1.565 | 0.291 |
| T3 | 1.369 | 0.559–3.356 | 0.492 | 3.009 | 1.070–8.460 | 0.037 | 1.937 | 0.954–3.933 | 0.068 | 1.360 | 0.603–3.065 | 0.459 |
| T4 | 1.198 | 0.431–3.329 | 0.729 | 3.321 | 1.114–9.899 | 0.031 | 2.281 | 1.063–4.894 | 0.034 | 2.334 | 1.025–5.314 | 0.043 |
| N stage | ||||||||||||
| N0 | 1 | 1 | 1 | 1 | ||||||||
| N1 | 0.815 | 0.231–2.877 | 0.750 | 1.185 | 0.271–5.180 | 0.822 | 1.159 | 0.405–3.315 | 0.783 | 1.110 | 0.326–3.770 | 0.868 |
| N2 | 0.724 | 0.207–2.529 | 0.613 | 1.454 | 0.343–6.170 | 0.612 | 1.174 | 0.417–3.307 | 0.761 | 0.932 | 0.279–3.116 | 0.909 |
| N3 | 1.213 | 0.334–4.410 | 0.769 | 3.179 | 0.744–13.588 | 0.119 | 2.414 | 0.847–6.880 | 0.099 | 1.597 | 0.468–5.445 | 0.455 |
| EBV DNA levels before treatment (IU/mL) | ||||||||||||
| < 430 | 1 | 1 | 1 | 1 | ||||||||
| ≥ 430 | 1.469 | 0.705–3.059 | 0.304 | 2.928 | 1.566–5.475 | <0.001 | 2.253 | 1.382–3.675 | 0.001 | 4.122 | 2.203–7.711 | <0.001 |
| unknown | 1.420 | 0.674–2.989 | 0.356 | 1.853 | 0.933–3.678 | 0.078 | 1.585 | 0.934–2.691 | 0.088 | 2.798 | 1.447–5.410 | 0.002 |
WHO, World Health Organization; T, tumor; N, nodal; LRFS, locoregional relapse-free survival; DMFS, distant metastasis-free survival; DFS, disease-free survival; OS, overall survival; HR, hazard ratio; and CI, confidence interval.
In the SEER-NPC cohort, we found significant prognostic effects of histology in NPC-SS and OS. WHO III subtype had a significantly better NPC-SS (HR 0.550, 95%CI 0.404–0.749, p < 0.001) and OS (HR 0.683, 95%CI 0.550–0.847, p = 0.001) compared to those with WHO II subtype. In addition, age, gender, and T stage were also the independent prognostic factors affecting survival outcomes (Table 4).
Table 4.
Multivariate analysis of prognostic factors related to survival outcomes in the SEER-NPC cohort.
| NPC-SS | OS | |||||
|---|---|---|---|---|---|---|
| Variables | HR | 95%CI | P | HR | 95%CI | P |
| Age (years) | ||||||
| <65 | 1 | 1 | ||||
| ≥65 | 1.560 | 1.133–2.148 | 0.006 | 2.523 | 2.037–3.124 | <0.001 |
| Gender | ||||||
| Male | 1 | 1 | ||||
| Female | 0.782 | 0.567–1.079 | 0.135 | 0.672 | 0.528–0.856 | 0.001 |
| Race | ||||||
| Caucasian | 1 | 1 | ||||
| African American | 0.850 | 0.539–1.341 | 0.485 | 1.022 | 0.744–1.403 | 0.893 |
| Chinese American | 0.932 | 0.626–1.388 | 0.730 | 0.777 | 0.575–1.050 | 0.101 |
| Other | 0.896 | 0.645–1.246 | 0.514 | 0.846 | 0.664–1.079 | 0.177 |
| Histology | ||||||
| WHO II | 1 | 1 | ||||
| WHO III | 0.550 | 0.404–0.749 | <0.001 | 0.683 | 0.550–0.847 | 0.001 |
| T stage | ||||||
| T1 | 1 | 1 | ||||
| T2 | 1.259 | 0.818–1.937 | 0.295 | 1.222 | 0.909–1.643 | 0.185 |
| T3 | 1.577 | 1.042–2.388 | 0.031 | 1.245 | 0.919–1.686 | 0.157 |
| T4 | 2.923 | 2.062–4.144 | <0.001 | 2.272 | 1.764–2.926 | <0.001 |
| N stage | ||||||
| N0 | 1 | 1 | ||||
| N1 | 0.915 | 0.610–1.371 | 0.667 | 1.021 | 0.767–1.360 | 0.885 |
| N2 | 1.040 | 0.696–1.554 | 0.847 | 1.132 | 0.848–1.512 | 0.399 |
| N3 | 2.158 | 1.387–3.357 | 0.001 | 1.810 | 1.290–2.540 | <0.001 |
| Chemotherapy | ||||||
| No/unknown | 1 | 1 | ||||
| Yes | 0.885 | 0.520–1.507 | 0.653 | 0.954 | 0.658–1.382 | 0.803 |
WHO, World Health Organization; T, tumor; N, nodal; NPC-SS, nasopharyngeal carcinoma-specific survival; OS, overall survival; HR, hazard ratio; and CI, confidence interval.
Discussion
In this study, we used two independent cohorts to evaluate the impact of histology on survival outcomes in NPC patients. Our findings revealed that patients with the WHO II subtype exhibited significantly worse survival outcomes compared to those with the WHO III subtype, irrespective of whether they resided in endemic or non-endemic areas.
Due to the insidious nature of NPC, a significant proportion of patients (70–80%) are diagnosed with locally advanced stages (stage III-IVA) [20]. Our study also observed that 86.9% of patients in the XM-NPC cohort and 68.4% of patients in the SEER-NPC cohort were diagnosed with stage III-IVA disease. Moreover, there was no significant correlation between histological subtype and clinical stage, which is consistent with previous studies [21,22]. Considering the poor prognosis associated with locally advanced NPC, screening in high-risk populations becomes critically important [23]. Studies conducted in the endemic area of NPC in southern China have identified more sensitive screening protocols, such as plasma EBV DNA analysis and a simple two-step serological screening scheme with the combination of EBNA1/IgA and VCA/IgA in the first step and anti-EA antibodies in the second step [24,25]. However, Chinese Americans residing in low-incidence areas such as the US often experience delays in diagnosis due to cultural and environmental differences. Therefore, early screening may be necessary for this population as well. Further investigation is required to determine whether a Chinese-based screening program can be extended to non-endemic areas, including the US and Europe.
We observed different histological subtypes among patients of different races. In the US, more than 64.2% of White patients were diagnosed with the WHO I subtype, while 19.1% had the WHO II subtype and 16.7% had the WHO III subtype [12]. In endemic areas of southern China, 4% and 95% of patients had WHO II and III subtypes, respectively [14]. Due to the low prevalence of the WHO I subtype among the Chinese mainland population (only 1%), we were unable to analyze patients with this subtype. In this study, 94 (12.9%) and 632 (87.1%) patients in the XM-NPC cohort had WHO II and WHO III subtypes, respectively. However, the SEER-NPC cohort had 839 (62.9%) patients with the WHO II subtype and 495 (37.1%) patients with the WHO III subtype.
The reasons for the differences in the prevalence of the WHO II subtype compared to the WHO III subtype of NPC in non-endemic areas are complex and multifactorial. Several potential reasons may lead to the differences in histology in race. Firstly, genetic factors significantly contribute to the increased risk of NPC, with certain populations, such as Asians, showing higher susceptibility to the WHO III subtype NPC. Genomic alternations, DNA repair genes excision repair cross-complementation group 1 (ERCC1), and human leukocyte antigen (HLA) polymorphisms have been associated with an increased risk of the development of the WHO III subtype NPC, although further validation is required for this supposition [26–28]. Secondly, EBV infection may influence the varied distribution of histological subtypes in NPC. Although the incidence of EBV-associated WHO II subtype NPC is rising in the US, particularly among Whites [29], the probability of EBV positivity in WHO II subtype patients remains significantly lower compared to WHO III subtype patients (70% vs. 92.6%) [30]. Moreover, patterns of NPC incidence can change among immigrant populations over successive generations as they adapt to new environments and lifestyles. Second-generation Chinese immigrants in the US who are more assimilated into Western culture may have lower susceptibility to NPC compared to first-generation immigrants from endemic areas [31–33]. Finally, regional differences in race, cultural practices, living habits, and environmental influences can also impact the prevalence of NPC subtypes. Factors such as smoking, consumption of preserved foods, alcohol intake, and oral hygiene practices have been highlighted as potential contributors to NPC risk [1]. Smoking and alcohol consumption are known to introduce carcinogens and promote cellular damage in the nasopharynx, potentially leading to malignant transformation. Preserved foods, which are often high in nitrosamines and salt, have been implicated in carcinogenesis through mechanisms involving DNA damage and inflammation [8]. Additionally, poor oral hygiene practices may facilitate the persistence of EBV in the oral cavity, increasing the likelihood of viral transmission to the nasopharynx and subsequent NPC development [34]. Therefore, differences in etiologic factors between WHO II and WHO III subtypes may explain the variations in genetic susceptibility, EBV infection, lifestyle factors, and cultural influences that contribute to the observed differences in NPC subtype prevalence across different populations. This highlights the complex nature of the disease and underscores the need for further research to fully understand these relationships. The advancement of single-cell sequencing may offer new insights into the heterogeneity between WHO II and WHO III subtypes [35].
In both cohorts, the prognostic value of NPC was significantly influenced by histological subtypes. Although several studies have found similar survival rates between WHO II and WHO III patients, the statistical power is limited by the smaller number of patients with WHO II subtype NPC [16,17]. However, several studies have shown that the WHO II subtype demonstrated a notably worse prognosis compared to the WHO III subtype. A study by Lee et al. found that NPC patients in the US showed considerable improvement in survival rates over time for various histological subtypes. However, Asians with the WHO III subtype exhibited higher survival improvement. This could be attributed to a larger proportion of this population having a more favorable WHO III subtype and being diagnosed at an earlier age [36]. Our previous study revealed that over a follow-up period of more than 5 years, patients with the WHO II subtype had poorer NPC-SS compared to those with the WHO III subtype. The pattern of risk for NPC-related mortality varied significantly across different histological subtypes [37]. A large-scale study based on National Cancer Database (NCDB) data showed that tumor histology was an independent predictor of overall survival (OS). The WHO III subtype displayed the highest 5-year (76%) and 10-year (63%) survival rates, followed by the WHO II subtype (68% and 54%), and the WHO I subtype (55% and 40%) [9]. A SEER study also indicated superior survival outcomes associated with the WHO III subtype compared to the WHO II subtype. It further identified the Chinese race as another independent favorable prognostic factor through multivariate analysis [15]. These findings align with our results, indicating that histology is an independent prognostic factor in diverse populations. Furthermore, we enhanced the reliability and comprehensiveness of our data by combining statistics from endemic areas in China with the SEER database in the US.
The reasons for survival differences between WHO II subtype and WHO III subtype NPC remain unclear. Our study found that patients with the WHO II subtype have inferior outcomes in terms of DMFS and DFS, and potentially impact on LRFS. A previous study identified significantly higher expression of the drug resistance-related protein ERCC1 in the WHO II subtype compared to the WHO III subtype in endemic areas (27.1% vs. 80.0%, p < 0.01) [38]. Moreover, patients with ERCC1 overexpression exhibited a higher risk of both locoregional and distant failure compared to those with low ERCC1 expression [27,38]. Overexpression of ERCC1 induces resistance to radiotherapy and platinum-based chemotherapy. Since cisplatin is crucial in CCRT for locally advanced NPC, this resistance further exacerbates the poor prognosis associated with the WHO II subtype [39]. A subgroup analysis stratified by treatment showed that positive ERCC1 expression predicted poor OS in NPC regardless of treatment modality (chemotherapy, radiotherapy, and chemoradiotherapy) [40]. It is plausible that cancer cells with high ERCC1 expression possess enhanced DNA damage repair capabilities, leading to resistance against platinum radiochemotherapy and subsequent poor response to initial radiotherapy and chemotherapy [41]. In addition, overexpression of ERCC1 may also impact the efficacy of immunotherapy [42]. Moreover, our study did not find differences in EBV DNA levels between WHO II and WHO III NPC patients. However, a recent study found that the EBV positivity rate among WHO II subtype patients was notably lower at 68.2%, in contrast to 95.1% among WHO subtype III patients. Notably, EBV-negative tumors exhibited inferior OS compared to EBV-positive tumors [43]. Finally, targeted therapies may hold promise in managing EBV-associated NPC, given the EBV infection can induce overexpression of EGFR, thereby potentially increasing sensitivity to anti-EGFR therapy [44,45]. These factors collectively contribute to poorer outcomes observed in WHO II subtype NPC compared to WHO III NPC, stemming from resistance to various treatment strategies such as radiotherapy, chemotherapy, immunotherapy, and targeted therapy. Consequently, this resistance heightens the risks associated with local recurrence, distant metastasis, and mortality.
Given the varying sensitivities based on histology, we believe that the relatively higher prevalence of the WHO II subtype is a key factor contributing to the poorer survival outcomes observed in non-endemic regions. Further investigation into immunohistochemical staining of ERCC1 in pre-treatment biopsy samples is warranted, as it could offer valuable insights for tailoring optimal radiotherapy and chemotherapy regimens and mitigating the risk of adverse events. Additional research is essential to assess the prognostic implications of different histological subtypes in both endemic and non-endemic areas, guiding personalized treatment approaches and follow-up strategies for patients with NPC.
Our study had certain limitations that should be acknowledged. Firstly, the retrospective nature of our study restricted us from including comprehensive patient characteristics in our analysis. Secondly, the SEER database lacked information on patient recurrence and metastasis, preventing us from evaluating differences in these outcomes among different histological subtypes. Additionally, specific details regarding chemotherapy regimens, techniques, dosages, treatment completion rates, as well as the sequencing of chemotherapy and radiotherapy were not available in the SEER database. Finally, NPC has now fully embraced the era of immunotherapy, prompting further research to ascertain whether distinct histological subtypes still exhibit varying prognoses under contemporary treatment paradigms [46]. Despite these limitations, a key strength of our study lies in its utilization of data from both endemic and non-endemic areas to validate the impact of histology on survival outcomes in patients with NPC.
Conclusions
In conclusion, our study demonstrates the significant influence of histological subtypes on outcomes in NPC among various populations, highlighting substantial disparities between the WHO II and WHO III subtypes. These findings underscore the importance of incorporating histological subtypes into clinical decision-making and risk stratification for NPC patients. Future investigations are encouraged to delve deeper into the molecular mechanisms and therapeutic ramifications linked to these distinct subtypes, aiming to refine personalized treatment approaches and enhance patient outcomes.
Funding Statement
The author(s) reported there is no funding associated with the work featured in this article.
Authors contributions
Lin-Feng Guo: Conceptualization, Data curation, Writing–original draft, Writing–review & editing. Jia-Geng Hong: Data curation, Methodology, Writing–original draft, Writing–review & editing. Run-Jie Wang: Conceptualization, Investigation, Methodology, Writing–review & editing. Gui-Ping Chen: Conceptualization, Resources, Methodology, Supervision, Writing–review & editing. San-Gang Wu: Methodology, Conceptualization, Resources, Investigation, Writing–review & editing. All authors have read and approved the manuscript.
Consent for publication
Written informed consent was obtained from all patients in the XM-NPC cohort. Written informed consent was not required from the SEER-NPC cohort because the data was from public databases.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University (approval number: XMYY-2023KYSB194).
Human rights
This research was conducted on humans in accordance with the Helsinki Declaration of 1975, as revised in 2013 [http://ethics.iit.edu/ecodes/node/3931].
Data availability statement
The data will be shared upon reasonable request made to the corresponding author of the manuscript.
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Associated Data
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Data Availability Statement
The data will be shared upon reasonable request made to the corresponding author of the manuscript.