A new prognostic histopathologic classification of nasopharyngeal carcinoma
- Hai-Yun Wang†1, 2,
- Yih-Leong Chang†3,
- Ka-Fai To†4,
- Jacqueline S. G. Hwang†5,
- Hai-Qiang Mai†1, 6,
- Yan-Fen Feng1, 7,
- Ellen T. Chang8, 9,
- Chen-Ping Wang10,
- Michael Koon Ming Kam11,
- Shie-Lee Cheah12,
- Ming Lee5,
- Li Gao13,
- Hui-Zhong Zhang1, 7,
- Jie-Hua He1, 7,
- Hao Jiang14,
- Pei-Qing Ma15,
- Xiao-Dong Zhu16,
- Liang Zeng17,
- Chun-Yan Chen1, 18,
- Gang Chen19,
- Ma-Yan Huang1, 7,
- Sha Fu1, 2,
- Qiong Shao1, 2,
- An-Jia Han20,
- Hai-Gang Li21,
- Chun-Kui Shao22,
- Pei-Yu Huang1, 6,
- Chao-Nan Qian1, 6,
- Tai-Xiang Lu17,
- Jin-Tian Li1, 23,
- Weimin Ye24,
- Ingemar Ernberg25,
- Ho Keung Ng4,
- Joseph T. S. Wee11,
- Yi-Xin Zeng1, 23,
- Hans-Olov Adami24, 26,
- Anthony T. C. Chan11Email author and
- Jian-Yong Shao1, 2Email author
© Wang et al. 2016
Received: 18 December 2015
Accepted: 6 April 2016
Published: 5 May 2016
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.
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).
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).
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.
KeywordsNasopharyngeal carcinoma Pathologic classification Prognosis
Nasopharyngeal carcinoma (NPC) is endemic in North Africa and Southeast Asia and most notably in South China, where the incidence can be as high as 20–40 per 100,000 persons [1–3]. NPC differs from other head and neck cancers with regard to epidemiologic features, histopathologic features, treatment strategies, and response to therapy [4, 5]. Based on the current World Health Organization (WHO) pathologic classification, NPCs are grouped into keratinizing squamous cell carcinoma (KSCC) and non-keratinizing carcinoma. The latter group is further subdivided into non-keratinizing differentiated carcinoma (NKDC) and non-keratinizing undifferentiated carcinoma (NKUC). However, this system is insufficiently informative, as clinical outcomes vary substantially among patients with the same clinical stage and histopathologic subtype [6–8]. Prognosis does not differ significantly between the NKUC and NKDC subtypes [8–10]. Pathologists have observed that NPC tumor cells have obvious morphologic variations, with cells that are small and round, large and round, spindle-shaped, with or without vesicular nuclei, or mixed round and spindle-shaped. Despite this morphologic heterogeneity, proposed NPC histopathologic classifications to date have not demonstrated clinically relevant improvement in prognostic prediction beyond the WHO classification . Therefore, clinicians have continued to appeal to pathologists to propose an NPC histopathologic classification system that better predicts prognosis and that enables personalized treatment of NPC patients.
In advanced NPC, radiochemotherapy (RCT) has been extensively investigated and demonstrated to improve tumor control and patient survival [12–17]. Two recent trials reported no survival benefit of concurrent RCT plus adjuvant chemotherapy versus concurrent RCT for advanced NPC; in addition, no survival benefit was reported with induction chemotherapy plus concurrent RCT versus induction chemotherapy plus radiotherapy (RT) alone for advanced NPC [16, 18]. Therefore, more accurate prognostication is needed to avoid over-treatment and to tailor treatment strategies that are compatible with individual risk patterns in a manner that improves patients’ survival outcomes.
The primary objective of this large, multi-center study was to propose a histopathologic classification system for NPC that offers more information on prognosis than the WHO classification. A secondary, more exploratory objective was to determine whether patients with each histopathologic subtype benefit equally in terms of overall survival (OS) after RCT versus RT alone.
Morphologic features of each subtype of the proposed classification of NPC
Inter-observer reproducibility of slide review
Inter-observer reproducibility between two pathologists based on the new nasopharyngeal carcinoma (NPC) histopathologic classification, stratified by area of case origin
Sun Yat-sen University Cancer Center (SYSUCC)
Other hospitals in mainland China
Hong Kong, Taiwan, Singapore
Efficacy of radiotherapy and radiochemotherapy
The patients with advanced NPC who were diagnosed between 2001 and 2011 underwent further analysis of the therapeutic efficacy of RCT versus RT alone and were then stratified by the proposed classification; the patients who were diagnosed before January 1, 2001, and those with early-stage disease were excluded to reduce variation in treatment protocols (Fig. 1). All patients with advanced NPC underwent standard curative RT, and some received additional chemotherapy. Patients in both groups received RT according to the policy at each center. The treatment protocol used at the largest contributing center was reported previously . Generally, a regimen that consisted of 2 Gy per fraction, with 5 daily fractions per week, was used. A minimum dose of 60 Gy was given to gross tumor targets, while 50 Gy was given at sites of local infiltration and bilateral cervical lymphatic metastases. Patients who received RCT were administered neoadjuvant, concurrent, or adjuvant cisplatin (30–40 mg/m2 every week or 100 mg/m2 every 3 weeks) plus 5-fluorouracil (750 mg/m2 per day, days 1–5).
Probabilities of OS were estimated using the Kaplan–Meier method, and the log-rank test was used to detect differences among groups. We assessed the associations between clinical characteristics and subtypes of NPC classified according to the proposed classification using Student’s t test and the Chi square test. To test if the proposed classification was an independent prognostic factor of OS, we adjusted for age, sex, clinical stage, therapeutic modality, and the WHO classification and used multivariate Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CI). The heterogeneity according to clinical stage in the association between histopathologic classification and OS was examined by the inclusion of an interaction term between stage and histology and by the stratification of models by stage at diagnosis. The patients were followed every 6 months, and a 5-year follow-up was achieved for 75.9% (4583/6031) of the NPC patients. However, enrollment in the prospective validation cohort continued until as recently as 2011, and follow-up data were recorded until April 2, 2015; therefore, the 5-year follow-up rate was 38.5% in this cohort. We calculated the OS from the date of diagnosis until the date of death of NPC or the last date of follow-up. All statistical tests were two-sided, and a P value of less than 0.05 was considered statistically significant. All statistical analyses were performed with Stata software (version 13, the University of California, Los Angeles, CA, USA).
Distribution of clinical centers where the 6031 enrolled nasopharyngeal carcinoma patients received a biopsy and therapy
Center for biopsy
Center for therapy
Number of cases
Department of Pathology, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, Guangdong, China
Department of Radiation Oncology, SYSUCC
Department of Pathology, multiple local centers in Guangdong, China
Department of Radiation Oncology, SYSUCC
Department of Pathology, Guangxi Medical University Cancer Center, Nanning, Guangxi, China
Department of Radiation Oncology, Guangxi Medical University Cancer Center
Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS), Beijing, China
Department of Radiation Oncology, Cancer Hospital, CAMS
Department of Pathology, The Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
Department of Radiation Oncology, The Affiliated Hospital of Bengbu Medical College
Department of Pathology, Hunan Provincial Cancer Hospital, Changsha, Hunan, China
Department of Radiation Oncology, Hunan Provincial Cancer Hospital
Department of Pathology, Fujian Provincial Tumor Hospital, Fuzhou, Fujian, China
Department of Radiation Oncology, Fujian Provincial Tumor Hospital
Department of Anatomical and Cellular Pathology, Faculty of Medicine, the Chinese University of Hong Kong (CUHK), Hong Kong, China
Department of Clinical Oncology, CUHK
Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
Department of Otolaryngology, National Taiwan University Hospital
Department of Pathology, Singapore General Hospital, Singapore, Singapore
Department of Radiation Oncology, National Cancer Center, Singapore
Clinical characteristics of NPC patients in the training, retrospective validation, and prospective validation cohorts
Retrospective validation cohort
Prospective validation cohort
Follow-up time (months)
Sex [cases (%)]
Clinical stage [cases (%)]
Therapeutic modality [cases (%)]
Proposed classification [cases (%)]
WHO classification [case (%)]
OS rate (%)
5-year (95% CI)
The proposed classification of NPC and patient survival
Cox proportional regression analysis of the associations between patient characteristics and OS in all 6031 NPC patients
Patients [cases (%)]
OS rate (%)
The association between clinical stage and the proposed NPC classification
Multivariate analysis of OS according to the proposed classification
The proportional hazards assumption for each covariate was tested by graphical methods, and no significant violations were found. In the univariate analyses of OS for all NPC patients, the subtypes of MSEC, SC, and SCC, older age, male sex, RT alone, and advanced clinical stage were associated with significantly shorter OS (Table 4). In the multivariate analysis, the proposed classification independently predicted OS even after adjustments for age, sex, therapeutic modality, tumor stage, and WHO classification. Compared with EC, the HR was 1.44 (95% CI = 1.27–162, P < 0.001) for MSEC, 2.00 (95% CI = 1.76–2.28, P < 0.001) for SC, and 4.23 (95% CI = 3.34–5.38, P < 0.001) for SCC (Table 4). After multivariate adjustment, the SC subtype predicted a higher risk of death compared with the MSEC subtype (HR = 1.40, 95% CI = 1.21–1.61, P < 0.001); moreover, SCC was associated with a higher risk of death compared with SC (HR = 2.11, 95% CI = 1.63–2.75, P < 0.001) (data not shown).
Therapeutic efficacy of RCT versus RT alone
Clinical characteristics of 3893 patients with advanced NPC who were treated with different therapeutic modalities
Follow-up time (months)
Sex [cases (%)]
Clinical stage [cases (%)]
Proposed classification [cases (%)]
WHO classification [cases (%)]
OS rate (%)
5-year (95% CI)
Cox proportional regression analysis of associations between clinical characteristics and OS in 3893 patients with advanced NPC
OS rate (%)
Due to the unbalanced distribution of clinical stages III and IV between the RCT and RT alone groups (Table 5), we repeated this analysis after the included cases were restricted to either stage III or stage IV NPC. Consistent with the results for all advanced NPC patients, significant differences in the 5-year OS rates were observed between patients who were treated with RCT and RT alone within the subtypes of EC and MSEC after the cases were restricted to either stage III or stage IV cancers (data not shown).
Prognostic evaluation is pivotal for making decisions concerning appropriate treatment delivery. In our present study, we developed an NPC histopathologic classification that can distinguish among the different subtypes with clinically and statistically significant differences in the 5-year OS rate, even after multivariate adjustment for or stratification by TNM stage. Compared with the training and retrospective validation cohorts, the estimated 5-year OS rate was most likely higher in the prospective validation cohort due to the more widespread delivery of RCT to NPC patients seen between 2007 and 2011 at SYSUCC. An additional explanation for the higher 5-year OS rate in this cohort (83.5% vs. 68.7% and 73.3% in the other two cohorts) is that it also had the shortest median follow-up time (41 vs. 68 and 68 months in the other cohorts), which was due partly to the more recent diagnosis of these patients.
Considerable controversy surrounds the WHO classification and its prognostic value . The WHO KSCC subtype accounts for one-third to one-half of all NPC cases in western populations, and this subtype is associated with a worse prognosis compared with non-keratinizing carcinoma [23, 24]. However, studies have consistently failed to show that the distinction between the WHO NKDC and NKUC subtypes has any clinical relevance [6–8]. These two subtypes comprise more than 95% of NPCs in endemic areas, including in our study population [4, 25].
RCT has consistently produced a survival benefit compared with RT alone, and 5-year OS rates of approximately 70% have been achieved by RCT in patients with stages III and IV NPC [12–15, 18, 26–30]. Lewis et al.  reported that 10.9% of patients received inadequate adjuvant therapy and 4.4% received inadequate radiotherapy based on the US National Comprehensive Cancer Network head-and-neck guidelines for recurrent or residual head-and-neck cancer. Exploratory analyses in our study indicated that compared with RT alone, RCT may improve outcomes in patients with advanced disease for the EC and MSEC subtypes, and possibly for the SCC subtype, but no evidence of an effect for the SC subtype was found. The worse prognosis of patients with the SC and SCC subtypes suggests that the current therapeutic methods are insufficient for these disease subtypes. Our results indicate that the proposed classification system may enable a more tailored approach for optimal clinical treatment decisions, especially for the SC and SCC subtypes, in which patients may need aggressive therapies such as high-dose irradiation, neoadjuvant and/or adjuvant chemotherapy, surgery, and molecularly targeted therapy to yield additional therapeutic gains. The efficacy of such therapies will require randomized clinical trials that stratify patients by histopathologic subtypes.
In the present study, the MRI and CT information of some patients are unavailable, particularly for the training cohort. The 1997 AJCC staging system is not applicable for these patients. Therefore, the 1992 China staging system was used. Our data clearly showed that different staging systems consistently predict the prognosis of NPC patients. Differences between these two staging systems mainly involve the classification of the borders of the tumor and lymph nodes in advanced disease . Furthermore, Hong et al.  reported a high degree of similarity (72.1%) between the 1992 China staging system and the 5th edition of the AJCC staging system for NPC; the latter was then developed into the 6th AJCC system with minimal modification. In another study that compared the 5, 6, and 7th editions of the AJCC staging system in a total of 985 NPC patients, a minimal magnitude of improvement in prognostication was found . Therefore, the 1992 China and 1997 AJCC staging systems were both acceptable for the prediction of prognosis.
A limitation to consider is in terms of generalizability because all included patients were from NPC-endemic areas in East Asia. The replication of our results in non-Asian patients needs to be confirmed for the use in clinics worldwide. We had incomplete follow-up data for 24% of the cohort, which raises the possibility of selection bias; however, differential follow-up based on histopathologic subtype was unlikely. The distribution of clinical stages differed between the RCT and RT alone groups, in which the patients were not randomized. Therefore, the efficacy of therapeutic strategies in patients with different histopathologic subtypes should be explored in future randomized clinical trials with complete follow-up. We cannot exclude the possibility that shorter survival in some groups is due to comorbidity, performance status, or some other unmeasured prognostic factors, rather than histopathologic subtype. However, no prior studies have demonstrated an association between histopathologic features and comorbidity or performance status, which indicates that they are unlikely to be strong confounders. Finally, complex gene networks may be the underlying mechanisms for the morphologic traits; thus, genomic analyses are warranted for further investigation and verification to elucidate the molecular basis for the proposed classification.
In conclusion, this multi-center study proposes an NPC histopathologic classification system that can significantly distinguish prognosis beyond clinical stage among non-squamous subtypes of NPC. The finding that RCT improves survival over RT alone in patients with advanced EC and MSEC suggests that more attention should be paid to the improvement of clinical outcomes for the SC and SCC subtypes, which are associated with a worse prognosis.
JYS was the principal investigator and participated in the research design, study management, review of the report, and final approval. YXZ and ATCC were involved in conception of the study, study design, data interpretation, and manuscript writing. HYW was involved in the data collection, analysis, data interpretation, and manuscript writing. CPW, MKMK, LG, CNQ, HJ, XDZ, LZ, CYC, TXL, SLC, HQM, GC, PYH, IE, HKN, and JTSW were involved in the follow-up data collection, data interpretation, and patient recruitment. JYS, JTL, KFT, YLC, ML, HZZ, JHH, PQM, AJH, HGL, CKS, JSGH, and YFF were involved in the pathologic slide review. QS, MYH, and SF were involved in provision of study materials and data collection. WY, ETC, and HOA were involved in data analysis and interpretation. All authors contributed to the drafting of the manuscript. All authors read and approved the final manuscript.
This study was supported by grants from the National High Technology Research and Development Program of China (863 Program) (No. 2012AA02A501), the Chinese State Key Basic Research Project (No. 2011CB504805), and the National Natural Science Foundation of China (No. 81272952 and No. 81472522).
The authors thank all pathologists and technicians for their help in retrieving H&E slides for reclassification of nasopharyngeal carcinoma. These include personnel from the Department of Pathology, Guangdong General Hospital, Guangzhou, Guangdong, P. R. China (Yan-Hui Liu); the Department of Pathology, Guangzhou First Municipal People’s Hospital, Guangzhou, Guangdong, P. R. China (Hong Du); the Department of Pathology, the Second Affiliated Hospital of Guangzhou Medical College, Guangzhou, Guangdong, P. R. China (Zhuo-Fang Hao); the Department of Pathology, Shenzhen People’s Hospital, Shenzhen, Guangdong, P. R. China (Min Zuo and Xiao-Mei Wang.); the Department of Pathology, Dongguan People’s Hospital, Dongguan, Guangdong, P. R. China (Yi-Sheng Lu); and all other local hospitals in Guangdong Province, P. R. China.
The authors declare that they have no competing interests.
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