Annals of Oncology Advance Access originally published online on October 23, 2006
Annals of Oncology 2007 18(1):29-35; doi:10.1093/annonc/mdl320
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© 2006 European Society for Medical Oncology
epidemiology |
Epidemiology of nasopharyngeal carcinoma in the United States: improved survival of Chinese patients within the keratinizing squamous cell carcinoma histology
1 Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology
2 Genetic Epidemiology Research Institute
3 Division of Epidemiology, Department of Medicine, School of Medicine, University of California Irvine, Irvine, USA
* Correspondence to: Dr S.-H. I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, 101 The City Drive South, Building 56, Room 241, RT 81, Orange, CA 92868-3298, USA. Tel: +1-714-456-8104; Fax: +1-714-456-2242; E-mail: ignatius.ou{at}uci.edu
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Abstract |
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Background: This study examined potential survival differences among nasopharyngeal carcinoma (NPC) patients from various ethnicities in the United States.
Patients and methods: A total of 2436 newly diagnosed NPC patients from 1992 to 2002 were analyzed from the population-based Surveillance, Epidemiology, and End Results (SEER) program. Five-year survival rate estimates and Kaplan–Meier survival curves were calculated. Cox proportional hazard ratios (HRs) were used to identify independent prognostic factors for survival.
Results: By multivariate analyses, early age of diagnosis, localized stage at presentation (versus distant, HR = 0.35; P < 0.0001), radiation therapy (versus none; HR = 0.48; P < 0.0001), undifferentiated non-keratinizing carcinoma (versus keratinizing squamous cell carcinoma; HR = 0.67; P < 0.0001), and Chinese ethnicity (versus Caucasian; HR = 0.78; P = 0.0010) were associated with improved survival. Within keratinizing squamous cell carcinoma histology, the survival advantage of Chinese patients remained even after adjustment for other prognostic factors.
Conclusions: The significant survival advantage of Chinese NPC patients within the keratinizing squamous cell carcinoma histology contributed largely to Chinese ethnicity being an independent and favorable prognostic factor for survival in NPC.
Key words: epidemiology, ethnicity, nasopharyngeal carcinoma, prognosis, SEER
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background |
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Nasopharyngeal carcinoma (NPC) is endemic in Southeast Asia but is relatively rare in the United States [1]. The high incidence of NPC in Southeast Asia is likely due to increased susceptibility for Epstein–Barr virus (EBV) infection to establish latency in the nasopharynx [2]. In 1978, the World Health Organization (WHO) classified NPC into three different histologic types: keratinizing squamous cell carcinoma is classified as WHO Type 1, non-keratinizing carcinoma is classified as WHO Type 2 and undifferentiated carcinoma is classified as WHO Type 3. WHO Type 3 is the major histologic type in endemic areas whereas WHO Type 1 usually comprises fewer than 5% of the endemic population [3]. In 1991, WHO classification retained the keratinizing squamous cell carcinoma subtype (original WHO Type 1) and combined WHO Type 2 and 3 histologic subtypes into ‘non-keratinizing carcinoma’. Non-keratinizing carcinoma was further divided as being ‘differentiated’ and ‘undifferentiated’. The differentiated subtype constituted the original WHO Type 2 and the undifferentiated subtype constituted the original WHO Type 3 [2, 4].
Epidemiologic studies in the United States have identified WHO histologic type as an independent prognostic factor for survival in NPC [5, 6]. Additionally, Chinese- or Asian-Americans have been observed to have improved survival when compared with non-Chinese- or non-Asian-American patients [5–8], although one study from a single institution in the United States did not find any survival advantage for Chinese NPC patients [9]. This superior survival of Chinese/Asian-American NPC patients is generally attributed to the much higher prevalence of the favorable non-keratinizing carcinoma histology diagnosed among Chinese/Asian-American NPC patients [7]. Non-keratinizing carcinoma of the nasopharynx are more often controlled by ionizing radiation than keratinizing histologies, and the 5-year survival rate is significantly better for non-keratinizing carcinoma than keratinizing squamous cell carcinoma of the nasopharynx (51% versus 6%) [10]. In addition, non-keratinizing carcinomas are generally associated with EBV positivity and EBV positivity in turn has been shown to be associated with improved survival [11]. Most of the population-based studies in NPC are from endemic countries where the ethnic makeup of the population was fairly homogeneous and the undifferentiated non-keratinizing type histology is the predominant histology. Thus, it remains unknown whether ethnicity is truly an independent prognostic factor for survival in NPC in general and within each WHO histologic type. A recent study from Australia partially addressed this question but was limited by the few numbers of WHO Type 1 NPC patients [12]. In the United States, every WHO histology is diagnosed in each of the major racial groups [5, 6]. In this study, we tested the hypothesis that the observed survival benefit for Chinese/Asian-American race is attributed solely to the higher proportion of these patients presenting with the favorable NPC non-keratinizing carcinoma histology by examining NPC cases in the Surveillance, Epidemiology, and End Results (SEER) database from 1992 to 2002.
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patients and methods |
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study cohort and diagnostic codes
We identified 2640 incident NPC cases from 1992 to 2002 using the 2003 public data of the SEER-13 Program of the National Cancer Institute [13]. SEER-13 comprises the states of Connecticut, Iowa, Hawaii, New Mexico, and Utah and metropolitan areas of Atlanta, GA; Detroit, MI; Los Angeles County, CA; San Francisco–Oakland, CA; San Jose–Monterey, CA; Seattle–Puget Sound, WA; and two supplemental registries (Alaska native and rural Georgia).
Tumor site and histology were coded according to criteria specified by the WHO in International Classification of Diseases for Oncology (ICD-O-3) [14]. All new NPC cases (SEER site code 20060) diagnosed from 1992 to 2002 were identified. Histologic types of the tumors were grouped according to the WHO classification scheme using the ICD-O-3 codes. Squamous cell carcinoma (ICD-O codes 8070 and 8071) formed the keratinizing squamous cell carcinoma group. Large- and small-cell non-keratinizing carcinomas (ICD-O codes 8072 and 8073) formed the differentiated non-keratinizing carcinoma group. Undifferentiated, anaplastic, lymphoepithelial carcinoma (ICD-O codes 8020, 8021, and 8082) formed the undifferentiated non-keratinizing carcinoma group. Patients with ‘carcinoma not otherwise specified’ (ICD-O code 8010) (N = 525) were classified as carcinoma NOS. Patients with prior diagnosis of malignancies (N = 198) and ‘carcinoma in situ’ (N = 6) were excluded. A total of 2436 patients were analyzed in this study.
Staging was grouped into three broad categories: localized, regional, and distant disease according to the SEER summary staging classification [15]. Patient age was categorized in 20-year age group increments from age 0 to 39 years and in 10-year age group increments from 40 years of age upwards. Race was coded as African-American, Caucasian, Chinese, Hispanic, and Other (Native Americans/non-Chinese Asian).
statistical analysis
Comparisons of demographic, clinical, and pathologic variables between patients with various categories were carried out using Pearson chi-square statistic or Fisher's exact test for nominal variables and Student's t-test for continuous variables. Analysis of variance with Tukey's post hoc test was used for multiple comparisons of continuous variables. Survival curves were constructed using the Kaplan–Meier method and compared with the log-rank test. Multivariate Cox regression analyses were used to determine factors significantly associated with survival. All statistical analyses were conducted using SAS version 9.1 statistical software (SAS Institute, Cary, NC). Statistical significance was assumed for a two-tailed P value <0.05.
ethical considerations
This research study involved analysis of existing data from the aforementioned SEER database with no subject intervention. Information was recorded without identifiers linked to subjects. The University of California, Irvine, Institutional Review Board (IRB) approved this study under the category ‘exempt’ status (IRB #2005-4265).
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results |
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age at diagnosis
The mean age of diagnosis for the entire group was 52.7 years. The mean age of diagnosis for African-Americans was 48.2 years, 57.4 years for Caucasians, 50.8 years for Chinese, 48.3 years for Hispanics, and 55.1 years for Other. The mean age of diagnosis for keratinizing squamous cell carcinoma patients was 55.8 years, 53.8 years for differentiated non-keratinizing carcinoma patients, 47.9 years for undifferentiated non-keratinizing carcinoma patients, and 52.1 years for carcinoma NOS. For the whole cohort, age group 40–49 years was the most common age group (23.8%) closely followed by age group 50–59 years (23.2%).
sex
In all, 29.1% of the patients were female and there was no statistical difference in the male : female ratio among the four different WHO histologic groups in this study (P = 0.37) (Table 1). The proportion of female NPC patients increased with increasing age (P = 0.0001).
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WHO histology and ethnicity
In the United States, NPC patients presented most commonly with keratinizing squamous cell carcinoma (39.4%) followed by undifferentiated non-keratinizing carcinoma (25.0%). In all, 21.6% of the NPC cases were not classified further and were grouped under the carcinoma NOS category for this study purpose. The ethnicities of the patients within each WHO histologic type are shown in Table 1. Chinese comprised the majority of the differentiated non-keratinizing carcinoma (55.9%), undifferentiated non-keratinizing carcinoma (58.0%), and carcinoma NOS (61.3%) histologies. On the other hand, Caucasian (55.4%), African-American (44.4%), and Hispanic (41.3%) NPC patients predominantly presented with keratinizing squamous cell carcinoma.
stage at presentation
Stage at diagnosis was available for 86.7% of the cases. Regional disease was the most common stage at presentation among the WHO histologic group (see Table 1). There were no significant differences in stage at presentation among the four histologic categories (P = 0.62).
radiation treatment
Data on radiation treatment were available for 2400 out of 2436 patients (98.5%). Of these 2400 patients, 89% received radiation: 88.3% of keratinizing squamous cell carcinoma, 93.2% of differentiated non-keratinizing carcinoma, 90.9% of undifferentiated non-keratinizing carcinoma, and 85% of carcinoma NOS (P = 0.0011) (Table 1). In all, 90.2% of localized, 93.6% of regional, and 84.7% of distant NPC received radiation (P < 0.0001). In all, 86.3% of Caucasian, 85.7% of African-American, 91.4% of Chinese, 91.3% of Hispanic, and 83.6% of Other received radiation treatment (P = 0.0014). However, when analyzed within individual WHO histological type, there was no statistical difference among the various racial groups who received radiation treatment except within carcinoma NOS: keratinizing squamous cell carcinoma (P = 0.12), differentiated non-keratinizing carcinoma (P = 0.23), undifferentiated non-keratinizing carcinoma (P = 0.41), and carcinoma NOS (P = 0.0007). There was no difference in the proportion of patients annually who received radiation over the 10-year study period (P = 0.36).
overall survival analyses
WHO histology.
Undifferentiated non-keratinizing carcinoma histology had the highest 5-year survival rate (68.1%) followed by differentiated non-keratinizing carcinoma (57.6%), carcinoma NOS (55.9%), and keratinizing squamous cell carcinoma (45.6%) (P <0.0001) (Figure 1).
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ethnicity.
Overall, Chinese had the best 5-year survival rate (63.8%) followed by Caucasian (48.2%), African-American (45.4%), Hispanic (44.0%), and Other (41%) (P <0.0001) (Figure 2).
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When univariate survival analyses were carried out for individual WHO histologic type using ethnicity as a variable, Chinese patients were observed to have the best 5-year survival compared with other ethnic groups within keratinizing squamous cell carcinoma: Chinese (59.0%), Caucasian (40.1%), African-American (35.7%), Hispanic (30.8%), and Other (20.9%) (P <0.0001) (Figure 3). There were no statistical differences in overall survival (OS) across the ethnic groups within differentiated non-keratinizing carcinoma: Chinese (64.1%), Caucasian (49.0%), African-American (44.3%), Hispanic (68.1%), and Other (43.8%) (P = 0.09); or undifferentiated non-keratinizing carcinoma: Chinese (70.2%), Caucasian (69.4%), African-American (74.4%), Hispanic (50.9%), and Other (52.4%) (P = 0.22). Within carcinoma NOS, Chinese (61.9%) had a significant better survival than Caucasian (51.4%), Hispanic (50.6%), African-American (24.7%), and Other (42.5%) (P = 0.0001). When comparing only among Chinese NPC patients by the four histologic types, OS differences did not achieve statistical significance (P = 0.063). Using Chinese patients with keratinizing squamous cell carcinoma as a standard, pairwise comparison of Chinese NPC patients revealed significant OS difference between undifferentiated non-keratinizing carcinoma (P = 0.0090) or Chinese non-keratinizing carcinoma patients (P = 0.011).
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stage at presentation.
Localized stage at presentation had the best 5-year survival estimate when compared with other stages at presentation (local = 75.7%; regional = 58.2%; distant = 34.9%; P < 0.0001).
radiation treatment.
Patients who received radiation had a much better 5-year survival than patients who did not receive radiation (58.5% versus 31.2%, P < 0.0001).
sex.
There was no difference in the 5-year survival rate between female (55.7%) and male (54.9%) patients (P = 0.74).
multivariate survival analyses
After adjustment for sex, age at diagnosis, stage of presentation, ethnicity, WHO histology type, and radiation treatment, the variables in each category with the strongest survival characteristics were as follows: early age of diagnosis, localized stage at presentation [versus distant; hazard ratio (HR = 0.35; P < 0.0001)], radiation treatment (versus none; HR = 0.48; P < 0.0001), undifferentiated non-keratinizing carcinoma (versus keratinizing squamous cell carcinoma; HR = 0.67; P < 0.0001), and Chinese race (versus Caucasian; HR = 0.78; P = 0.0010) (Table 2).
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Multivariate Cox proportional hazards models were then carried out for each WHO histologic type. Early age at diagnosis, localized stage at presentation, and radiation treatment were associated with improved survival for each NPC histologic type. After adjustment for sex, age at diagnosis, stage at presentation, and radiation treatment, the Chinese race was the only other significant prognostic factor identified for the keratinizing squamous cell carcinoma histology when compared with Caucasian race (HR = 0.67; P = 0.0001). The HR ratios of individual ethnic groups stratified by WHO histologies are presented in Table 3. Of note, for the undifferentiated non-keratinizing histology, Hispanic and Other had a slight but statistically significant poorer survival when compared with Caucasian and Chinese NPC patients (Table 3).
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discussion |
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TopAbstractbackgroundpatients and methodsresultsdiscussionReferences |
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The present study confirmed a survival advantage of the undifferentiated non-keratinizing carcinoma over differentiated non-keratinizing carcinoma and keratinizing squamous cell carcinoma and that Chinese NPC patients had better OS when compared with other racial groups in the United States as had been reported in other studies [5–8]. This study confirmed that WHO histology is an independent prognostic factor as reported by others [5, 6] and identified Chinese ethnicity as another independent and favorable prognostic factor for survival by multivariate analyses. Therefore, this observed improved survival of Chinese NPC patients cannot simply be explained by the higher proportion of favorable non-keratinizing carcinoma. This study is also the first to report statistically significant improved survival of Chinese keratinizing squamous cell carcinoma NPC patients compared with keratinizing squamous cell carcinoma NPC patients from other ethnicities even after adjustment for other prognostic factors. This survival advantage of Chinese NPC patients with keratinizing squamous cell carcinoma largely contributed to the Chinese race being an independent and favorable prognostic factor in the multivariate analyses. Our study also largely confirmed a report by Corry et al. [12] which demonstrated no statistically significant survival difference between Asian and non-Asian NPC patients with non-keratinizing carcinoma.
What may be the explanation for the improved survival of Chinese NPC patients within the keratinizing squamous cell carcinoma histology? EBV plays a pivotal role in the pathogenesis of non-keratinizing carcinoma, whereas keratinizing squamous cell carcinoma histological type is the least related to EBV infection among the three different histologies [16]. The association of squamous cell carcinoma of the nasopharynx with EBV showed geographical variation with the highest proportion of squamous cell carcinoma in endemic areas to be EBV positive [17]. In non-endemic areas, keratinizing squamous cell carcinoma of the nasopharynx has been associated with cigarette smoking and heavy alcohol consumption [18]. Keratinizing squamous cell carcinoma of the nasopharynx is similar in histology to the majority of the squamous cell carcinoma of the head and neck (SCCHN) region and may represent distinct genetic alterations between Chinese and non-Chinese patients.
Overexpression of the epidermal growth factor receptor (EGFR) gene has been shown to be a poor prognostic factor in NPC patients [19, 20] and similarly in patients with SCCHN [21]. Allelic polymorphisms in the EGFR gene that control its transcription and thus expression level have been identified with Asian/Chinese having a higher proportion of the polymorphism that tend to result in lower EGFR expression [22, 23]. One such polymorphism is a dinucleotide CA repeat within the intron 1 of the EGFR gene. The number of repeats range from 14 to 21 within the general population and showed remarkable interethnic variability with Asians/Chinese having a significant lower proportion of the shorter repeats when compared with Caucasians and African-Americans. For example, the frequency of the allele containing 16 repeats was 43% for Caucasians, 42% for African-Americans, 25% for non-Chinese Asians, and only 6% for Chinese [22]. The level of transcription of the EGFR gene can differ by five-fold depending on the number of the CA repeats, with the longer the repeats, the lower the EGFR gene transcription [24]. The significance of this variation of the number of CA repeats within intron 1 of EGFR gene has been shown to result in a statistically significant difference in the delay of pelvic recurrence in rectal cancer patients treated with chemoradiation [25] and disease progression in colon cancer patients treated with platinum-based therapy, with the longer repeats having delayed recurrence [26]. This CA repeat polymorphism can also occur among intraethnic SCCHN patient population [27]. Another potentially significant EGFR polymorphism is a single-nucleotide polymorphism at –216 position (–216G/T) of the promoter region of EGFR gene which affects the binding affinity of transcription factor Sp1 to these EGFR promoter. Sp1 binds with significantly higher affinity to the T allele than the G allele. The –216T allele also led to significant higher EGFR expression both in vitro and in vivo. Of note, the –216T haplotype had a significant higher distribution in African-Americans (29.3%) and Caucasians (34.1%) when compared with Asians (8.7%) [23]. Therefore, molecular analysis of these EGFR gene polymorphisms may help explain this observed survival advantage of Chinese patients with keratinizing squamous cell carcinoma of the nasopharynx.
There are several limitations in this study of the SEER database. Firstly the use of chemotherapy was not evaluated because SEER data are generally captured from hospital records, and chemotherapy was given outside the hospital setting. In order to capture the use of chemotherapy, the SEER database has to be linked to the Medicare database. The vast majority of NPC patients, however, were diagnosed at a much earlier age to qualify for Medicare (age >65) and thus will be excluded in the SEER–Medicare database. Other limitations of the current study include the inability of the SEER database to provide tobacco exposure, EBV status, concurrent comorbidities, and socioeconomic status that could affect the survival of NPC patients. About 20% of the patients did not have their WHO histologies further classified (NOS) but were included in the analysis in this study. When the carcinoma NOS patients were excluded from the study, the conclusions of this report remained the same.
Studies that reported survival differences among the three WHO histology types did not analyze the interactions among ethnicity, WHO histology, and survival [5–7] or did not have significant numbers of Chinese patients in each of the histologic groups [8]. Most of the NPC studies from endemic countries are with the undifferentiated non-keratinizing carcinoma histology, and thus, comparing the survival among WHO histologies within a homogeneous population in endemic countries yielded limited results. Chan et al. [28] have investigated the survival difference between Chinese NPC patients with keratinizing squamous cell carcinoma and non-keratinizing carcinoma patients in an endemic area. Due to the small number of patients with keratinizing squamous cell carcinoma histology in the study, no difference in disease-free survival and OS was observed. We reported that there was a statistically significant OS advantage of Chinese patients with undifferentiated non-keratinizing carcinoma (P = 0.0090) or patients with non-keratinizing carcinoma as a whole over Chinese patients with keratinizing squamous cell carcinoma (P = 0.011). This study contributes to the existing literature on NPC by identifying Chinese ethnicity as an independent prognostic factor in NPC and that this survival advantage is largely due to better survival within the keratinizing squamous cell carcinoma histology. The observed survival advantage for Chinese patients with keratinizing squamous cell carcinoma may reflect underlying gene and/or environmental exposures. This difference warrants further investigations at the molecular level since keratinizing squamous cell carcinoma is the predominant histology in SCCHN. Thus future molecular and genetic research may yield additional prognostic information on response to chemotherapy and radiation therapy for NPC and SCCHN.
Received for publication June 2, 2006. Revision received July 19, 2006. Accepted for publication July 31, 2006.
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