A new prognostic histopathologic classification of nasopharyngeal carcinoma

Abstract

Background: The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response.

Methods: We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS).

Results: The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28).

Conclusions: The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.

Keywords: Nasopharyngeal carcinoma; Pathologic classification; Prognosis.

Fig. 1

Flowchart of the study design shows the inclusion and exclusions of nasopharyngeal carcinoma (NPC) patients with different therapeutic modalities stratified by the proposed classification. SYSUCC Sun Yat-sen University Cancer Center, OS overall survival, RT radiotherapy, RCT radiochemotherapy

Fig. 2

Representative morphologic traits of tumors according to the proposed classification of NPC (H&E, ×400). The epithelial carcinoma (EC) subtype shows small, round cells with cellular stratification and a pavement-like appearance, a low nucleus:cytoplasm ratio, chromatin-rich nuclei (a), and non-prominent nucleoli (b); or syncytial-appearing large tumor cells with indistinct cell borders, round-to-oval vesicular nuclei, and large central nucleoli (c); a round shape with vesicular nuclei and prominent nucleoli accounting for more than 75% of tumor cells (d). The sarcomatoid carcinoma (SC) subtype features irregular small cells, large hyperchromatic cells, or both, or uniformly medium-sized spindle cells (e), together with nucleoli that are less prominent than those in the syncytial-appearing cells (f), dark, smudged nuclei and a dense amphophilic (g), or eosinophilic cytoplasm (h). The mixed sarcomatoid-epithelial carcinoma (MSEC) subtype is characterized by large, round cell nests (i) or scattered infiltration of large, round cells in the spindle cell carcinomatous tissue (j); no obvious boundaries were observed between the tumor and interstitial lymphoid tissue (k) or in the stromal portion that contained cells with eosinophilic cytoplasm (l). The squamous cell carcinoma (SCC) subtype shows well differentiated keratinizing SCC with a large number of whorls (m) and keratin (n), or poorly or moderately differentiated SCC with some individual keratinized spine cells (o) and a small number of basal-like cells (p)

Fig. 3

Kaplan-Meier curves of OS according to the proposed classification, the World Health Organization (WHO) classification, and clinical stage in NPC patients from the training (n = 2716), retrospective validation (n = 1702), and prospective validation cohorts (n = 1613), respectively. OS curves of patients classified with the proposed classification in the training (a), retrospective validation (b), and prospective validation cohorts (c). OS curves of patients classified with WHO classification in the training (d), retrospective validation (e), and prospective validation cohorts (f). OS curves of patients classified with clinical stage in the training (g), retrospective validation (h), and prospective validation cohorts (i). The log-rank test was used to estimate P values. *The training cohort was classified by the 1992 China staging system; the retrospective validation cohort was classified by the 1992 China staging system or the 1997 American Joint Committee on Cancer (AJCC) staging system; the prospective validation cohort was classified by the 1997 AJCC staging system

Fig. 4

Kaplan-Meier survival estimates for NPC patients according to two different staging systems. In all, 3814 (63.2%) NPC patients from mainland China were diagnosed before 2006 and were staged according to the 1992 China staging system, whereas 2217 (36.8%) from Hong Kong, Taiwan, Singapore, and SYSUCC (in mainland China) were diagnosed between 2007 and 2011 and were staged according to the 1997 AJCC staging system. The 5-year OS rate was 69.2% (95% CI = 67.7%–70.6%) for patients classified by the 1992 China staging system (a) and 82.2% (95% CI = 80.3%–83.9%) for patients classified by the 1997 AJCC staging system (b). The OS differed significantly by clinical stage according to the 1992 China staging system (P < 0.001, c) and the 1997 AJCC staging system (P < 0.001, d). The log-rank test was used to calculate P values

Fig. 5

Associations between clinical stage and the proposed histopathologic classification in all NPC patients. The proportions of EC cases are 71.8%, 63.3%, 61.1%, and 60.4% in patients with stages I, II, III, and IV NPC (the 1992 China and 1997 AJCC staging systems combined), respectively, whereas those of SC cases are 9.6%, 11.8%, 13.7%, and 14.6%, respectively. The proportion of SC increased with advanced stage, whereas the proportion of EC decreased with more advanced stage (Chi square test, P = 0.001)

Fig. 6

Kaplan-Meier survival estimates for NPC patients at different clinical stages (the 1992 China and 1997 AJCC staging systems combined) stratified by subtypes according to the proposed histopathologic classification. The OS differed significantly by the proposed classification for patients with stage I (P = 0.015, a), II (P < 0.001, b), III (P < 0.001, c), or IV disease (P < 0.001, d). The log-rank test was used to calculate P values

Fig. 7

Kaplan-Meier survival estimates for NPC patients at different clinical stages in three separate cohorts stratified by subtypes according to the proposed classification. OS curves of NPC patients stratified by subtypes according to the proposed classification with stage I (P = 0.005, a; (P = 0.063, b; c), II (P = 0.057, d; P = 0.030, e; and P < 0.001, f), III (P < 0.001, g and h; P = 0.041, i), and IV disease (P < 0.001, j, k, and l) in the training, retrospective validation, and prospective validation cohorts, respectively. The log-rank test was used to calculate P values. *No test possible because there were no failures

Fig. 8

Kaplan-Meier survival estimates for NPC patients at different clinical stages according to two staging systems and stratified by subtypes according to the proposed classification. The OS differed significantly according to subtype of the proposed classification for patients at different clinical stages classified according to the 1992 China staging system (P = 0.031, a; P = 0.002, c; P < 0.001, e and g) and the 1997 AJCC staging system (all P < 0.001, d, f, and h), respectively. The log-rank test was used to calculate P values

Fig. 9

Kaplan-Meier survival estimates for the 3893 advanced NPC patients with different proposed subtypes who underwent radiochemotherapy (RCT) or radiotherapy (RT) alone. RCT significantly improved survival compared to RT alone for patients with EC (P < 0.001, a) and MSEC (P < 0.001, b), but not for patients with SC (P = 0.826, c); this was also likely the case for those with SCC (P = 0.048, d). The log-rank test was used to compute P values. Hazard ratios (HRs) with 95% confidence intervals (CIs) were computed for each type (RCT versus RT alone)