January 2004, Vol 26, No. 1
Original Articles

A meta-analysis of observational studies: Risk of preserved salted fish in the etiology of nasopharyngeal carcinoma

J Yeung 楊永堅, J L Tang 唐金陵

HK Pract 2004;26:16-23

Summary

Objective: This meta-analysis aimed to investigate the association between preserved salted fish (PSF) consumption and nasopharyngeal carcinoma (NPC) development.

Design: We searched English and Chinese electronic databases and supplemented with hand searching without language restriction. Two independent reviewers abstracted the data with a standard extraction form without blinding.

Subjects: Twelve studies with 4996 participants were included.

Main outcome measure: Odds ratios of PSF consumption frequency in the development of NPC in different populations.

Results: PSF consumption was associated with NPC development in mature Chinese (mean age=40). The pooled unadjusted odds ratio (OR) was 1.08 (95% CI: 0.89-1.3) for "monthly" exposure [1-3 times/month]; 1.12 (95% CI: 0.79-1.58) for "weekly" exposure [1-6 times/week or 4-24 times/month]; and 2.30 (95% CI: 1.16-4.55) for "weekly or more" exposure [25-28 times/month]. Childhood exposures were associated with greater risks (X2 trend: p<0.005). Individual adjusted OR was consistent with the pooled unadjusted OR when the frequency of consumption was weekly or daily.

Conclusion: Heavy (weekly or more) consumption of PSF is associated with NPC development. Childhood exposure may increase the risk as a result of increased cumulative lifetime exposure. Confounders and effect modifiers such as Epstein Barr virus infection, smoking and fresh fruits/vegetables intake may need further investigations.

Keywords: Preserved salted fish (PSF), nasopharyngeal carcinoma (NPC), meta-analysis

摘要

目的：透過meta-analysis研究進食咸魚和鼻咽癌的關係。

設計：我們搜尋中文和英文的電子數據庫，並輔以人工搜尋有關參考文獻，不設語言限制。由兩位獨立評論員用相同標準的數據表抽取數據。

對象：12個研究合共4996人。

測量內容：不同人群中，進食咸魚的次數與發生鼻咽癌的比對比（Odds ratios）。

結果：成年中國人（平均年齡40歲），進食咸魚和鼻咽癌有關係。若每月都有進食咸魚的習慣 (1-3次/月)，患鼻咽癌的合共比對比為1.08 (95% CI: 0.89-1.3)；若每星期都有進食咸魚的習慣(1-6次/星期或4-24次/月)，患鼻咽癌的合共比對比為1.12 (95% CI: 0.79-1.58)；若每星期或更多有進食咸魚的習慣(25-28次/月) ，患鼻咽癌的比對比則增加為2.3 (95% CI: 1.16-4.55)。年幼者，危險較大(p<0.005)。每星期都有(或更多)進食咸魚的習慣的一組，調整前 後的比對比一致。

結論：大量進食咸魚（每星期或每天有進食咸魚的習慣）跟鼻咽癌有密切的關係。年紀越少危機越大，可能是由於長年積累而成。其他的混淆因素，如Epstein Barr病毒感染、吸煙和進食新鮮水果蔬菜等，仍然須要未來的不斷研究。

主要詞彙：鼻咽癌，咸魚，meta-analysis

Background

Nasopharyngeal carcinoma (NPC) is a rare cancer in most parts of the world but the incidence rates are surprisingly high in some regions such as Southeast Asia, China and Hong Kong. Populations such as Eskimos and Hawaiians have a moderately high incidence compared with other western regions. Descendants who have migrated to other geographical areas from these high rate areas were also reported to retain similar rates of the disease. Although Epstein Barr virus infection is believed to be a necessary factor in its development, dietary factors, especially nitrosamine-containing foods such as preserved salted fish, are considered to be an important risk factor in its development.1-3 This hypothesis was suggested as populations in Southeast China share relative high susceptibility to this cancer when salted fish is a common food item.4-6 Some studies reported that consumption of salted fish during weaning or childhood period is associated with even higher risk of developing NPC but some reported insignificant correlation.7 In experiments, it was suggested that volatile nitrosamines, principally N-nitrosodimethy-lamine (NDMA) and N-nitrosodiethylamine (NDEA) are the carcinogenic agents within preserved salted fish responsible for the development of NPC.8-10 Many reviews have addressed the issue but it is still unclear what dosage of preserved salted fish is associated with NPC development.11-13

Objectives

This meta-analysis aimed to find out the risk of nasopharyngeal carcinoma (NPC) attributable to consumption of preserved salted fish (PSF) in 6 different lifetime periods: (I) recent period (7 to one years before diagnosis); (II) about age 10; (III) between age one and 3; (IV) during weaning; (V) during lactation and (VI) pregnancy. The association between NPC and the frequency of salted fish consumption was also investigated.

Material and methods

Search strategy

Two independent investigators performed the search and extracted the data with a standard extraction form. There was no blinding and discrepancies were resolved by a third party, an experienced meta-analyst. Electronic databases included MEDLINE (January 1966 to October 2002), EMBASE (1980-2002), ACP Journal Club (1991-2002), Cochrane Collaborative Review Groups (Ear, Nose and Throat Disorders Group), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effectiveness (DARE), CANCERLIT (1975-2002), CSA-Life Sciences Collection (1982-2002), HealthSTAR (1975-2002), Cumulative Index to Nursing and Allied Health Literature (1982-2002), ProQuest Digital Dissertations (1861-2002). We searched the relevant reviews and observational studies with constructed methods14,15 and explored the terms: nasopharyngeal carcinoma; nasopharyngeal cancer; nasopharyngeal neoplasm; NPC; case-control; matched; retrospective; cohort; observational study; salted fish; preserved food; and preserved diet with Ovid software rel 6.1. We hand-searched additional studies in the reference lists of the obtained articles. Efforts were also made to get studies identified through conference abstracts, research theses, and web materials. There was no restriction on language. Multiple publications of the same study were counted once to avoid duplicate publication bias. Studies with only abstracts or unpublished data were also included. Selection of Chinese databases was based on expert opinion, CD ROM availability and relevant hyperlink on internet.

Selection criteria

Populations and study designs

We included all cross-sectional, case-control and cohort studies from which we could obtain original published data for odds ratio or risk ratio. There were no restrictions to populations and geographic locations. Studies with only abstracts or sources from unpublished data, web materials or in press were included only if they included data for meta-analysis. We excluded animal experiment, comment, letter, editorial, review and practice guideline. Studies without pathological confirmation of nasopharyngeal carcinoma were not eligible.

Outcome measures and exposures of interest

Outcome was defined as pathological confirmed malignant neoplasm of nasopharynx (ICD 9th revision no. 147) including three World Health Organization (WHO) subtypes: "WHO type I (keratinizing squamous cell carcinoma)", "WHO type II (non-keratinizing carcinoma)" and "WHO type III (undifferentiated carcinoma)".

The exposure of interest was consumption of vertebrate fish with salty preserved method at least one year before the diagnosis of NPC. We defined those subjects exposed less than once per month (<1/mo) as "non-exposure group" while those exposed equal to or more than once per month (1/mo) as "exposure group". The exposure group was further divided into three subgroups according to the frequency of consumption. "Monthly exposure" was defined as 1 to 3 times per month (1-3/mo); "weekly exposure" 1 to 6 times per week (1-6/week) or 4 to 24 times per month (4-24/mo); and "weekly or more exposure" once or more per day (1/d) or 25 to 28 times per month (25-28/mo). We assumed 28 days a month for the above definition. Subjective unclear measurement such as "always", "often", "sometimes" was excluded.

Data extraction

Extracted data were entered twice and differences were resolved by going back to the original published data. We extracted the exposure levels for cases and controls from the data. The overall odds ratio was examined by comparing the event of "exposure" and "non-exposure" groups. Frequency-response effect was investigated by comparing the "monthly", "weekly", "weekly or more" exposure and non-exposure.

Statistical method

We used fixed effects model to pool the odds ratios in this meta-analysis. Test of heterogeneity was performed and explored with sensitivity analysis. The calculation was done with the statistical software Review Manager 4.2.1.16 We primarily pooled the unadjusted odds ratios with original published data. Individual adjusted odds ratios were also presented without pooling as the confounders adjusted varied greatly. We reported our findings based on the format recommended by the MOOSE group.17

Results

Characteristics of included and excluded studies

Searching with English and Chinese databases generated 74 potentially eligible studies. The flow chart of obtaining eligible studies is shown in Figure 1. Twelve of them (total participants = 4996)18-29 reported the odds ratios with well-specified frequency of exposure and thus were included in this meta-analysis. The characteristics of the included studies were illustrated in Table 1. Ten studies recruited Chinese participants, one23 recruited local residents in Tunisia, Africa and one27 mixed populations from Indian, Malay and Chinese. Mean age of the cases included was about forty years old except Yu28 investigated young cases of age below 35. Subtypes of NPC were reported in four studies.20,21,23,27 All studies included were case-control in design and reported in English language. Exposure was to Chinese PSF in all eleven studies except Jeannel,23 who examined the risk of salted anchovies among residents in Tunisia, Africa.

Figure 1: Flow chart of including observational studies for the meta-analysis of preserved salted fish on nasopharyngeal carcinoma


Table 1: Characteristics of the twelve included observational studies

Study Locality * NPC subtype(s) Age of cases Total no. of subjects +Adjustments Control Interviewers
Yuan JM
200018		 Shanghai,
China		 NS 15-74 1967 Smoking, education, smoke from rapeseed oil and coal, chemical fumes, chronic nose/ear condition Same town residents nA
Ward MH
200019 		Taiwan NS <75 702 Ethnicity Same town residents A
Zheng YM
199420 		Guangxi,
China		 Undifferentiated 32-52 264 Sociodemographic score Neighbours nA
Zheng X
199421 		Guangzhou,
China		 Low and undifferentiated 24-56 410 Ig A-VCA, 1st degree relatives with NPC, polluted water and chemical exposure Neighbours or friends NS
Lee HP
199422 		Singapore NS <30 - >40 606 Education, maternal dialect group Hospital cancer patients NS
Jeannel D
199023 		Tunisia,
Africa		 WHO I = 18,
WHO II = 14,
WHO III = 43,
NS = 5 		17-63 240 Living condition score Neighbours nA
Ning JP
199024 		Tianjin,
China		 NS <64 400 Salted shrimp paste, carrot Neighbours A
Yu MC
198925 		Guangdong,
China		 NS <50 612 Salted fish during weaning Neighbours nA
Yu MC
198826		 Guangxi,
China		 NS <45 462 Salted duck egg, mustard green, chung choi, dried fish, fermented soy bean paste Neighbours nA
Armstrong RW
198327		 Malaysia Squamous cell 45 (mean) 300 Ethnicity Neighbours NS
Yu MC
198628 		Hong Kong NS <35 500 NS Close friends A
Geser A
197829 		Hong Kong NS 15-65 300 NS Hospital cancer patients NS
               
* NS = not specified
  WHO I = keratinizing squamous cell carcinoma
  WHO II = non-keratinizing carcinoma
  WHO III =

undifferentiated carcinoma

       
+ All studies had adjusted for age and sex by matching or stratified analysis;
  NS =

not specified

       
nA = non-author
  A = author
  NS = not specified
       
Note:
All studies recruited Chinese subjects, except Jeannel,23 who examined salted anchovies exposure, recruited local residents in Africa and Amstrong27 recruited mixed ethnicities from Indian, Malay and Chinese.

Sixty-two studies were excluded because of narrative review, case report or animal experiment in design, subjective measurement of exposure frequency, unspecified reference group or not at all, inadequate original published data for odds ratio synthesis. Two theses restricted external access and four Chinese articles reported missing. We excluded four more studies that were found to be duplicates.

The pooled unadjusted odds ratios

Consumption of salted fish was found to be significantly associated with the development of NPC during six different lifetime periods (Table 2). The pooled OR increased from 1.35 (for recent exposure) to 3.15 (during weaning period). However, the ORs were heterogeneous except for exposure between age 1 to 3. The ORs were similar for exposure during lactation and fetal periods. To resolve the above heterogeneity, subgroup analysis was done under different populations (Table 3). It was found that the pooled ORs were significant in mature Chinese populations (mean age around 40), especially when the intake period was around age 10 or even earlier. The ORs became homogeneous (except exposure around age 10) and the chi square test for trend was statistically significant among mature Chinese participants (p<0.005). One study28 reported that the OR was 2.55 (95% CI: 1.77-3.66) among young Chinese subjects (age less than 35) and it seemed that the risk for young Chinese was greater than that for mature Chinese participants. Insignificant increase in ORs among local residents in Africa23 and mixed populations27 were reported by a single study.

Table 2: Pooled odds ratios of preserved salted fish on nasopharyngeal carcinoma during six different periods of lifetime exposures

Period of exposure No. of study No. of participants OR (95% CI) Heterogeneity p-value
Recent 518,19,22,25,28 3815 1.35 (1.15 - 1.58) * 0.002
Around age 10 919,20,22-28 3223 1.70 (1.45 - 2.00) * <0.00001
Age 1 - 3 521,22,24-26 1169 1.76 (1.26 - 2.44) * 0.86
Weaning 621,22,25,26,28,29 1430 3.15 (2.44 - 4.07) * <0.00001
Lactation 322,25,26 683 1.53 (1.03 - 2.27) * 0.72
Fetal 322,25,26 656 1.67 (1.17 - 2.39) * 0.37
         
*   Statistically significant
OR = odds ratio
  CI = confidence interval
  Non-exposure = less than once per month
  Exposure = equal to or more than once per month

Table 3: Sensitivity analysis of preserved salted fish on nasopharyngeal carcinoma across different populations

Exposure in different populations No. of study No. of participants OR (95% CI) Heterogeneity p-value
Local residents in Africa   123 240 2.41 (0.89 - 6.50) NA
Mixed ethnic groups
(Indian, Malay, Chinese) 		  127 178 2.87 (0.98 - 8.44) NA
Young Chinese (age <35)   128 500 2.55 (1.77 - 3.66) * NA
Mature Chinese (mean age around 40)          
  Recent   418,19,22,25 3315 1.16 (0.97 - 1.38) 0.55
  Around age 10   619,20,22,24-26 2309 1.21 (1.01 - 1.45) * 0.0003
  Age 1 - 3   521,22,24-26 1169 1.76 (1.26 - 2.44) * 0.86
  Weaning   521,22,25,26,29 1176 2.18 (1.62 - 2.93) * 0.62
  Lactation   322,25,26 683 1.53 (1.03 - 2.27) * 0.72
  Fetal   322,25,26 656 1.67 (1.17 - 2.39) * 0.37
          X2 for trend (p<0.005)  
* Statistically significant
OR = odds ratio
  CI = confidence interval
  Non-exposure = less than once per month
  Exposure = equal to or more than once per month
Note: NA = not applicable


In Figure 2, frequency response analysis among mature Chinese subjects revealed that recent heavy "weekly or more" consumption was significantly associated with NPC development.18,22 The pooled OR increased from 1.08 for low (monthly) exposure to 2.3 for heavy (weekly or more) exposure. All the results were homogeneous and the chi square test for trend was significant (p<0.005).

Figure 2: Frequency-response effect of recent intake of preserved salted fish (PSF) on nasopharyngeal carcinoma in mature Chinese (mean age about 40) populations


Note: Monthly exposure = 1 to 3 times per month
  Weekly exposure = 1 to 6 times per week or 4 to 24 times per month
  Weekly or more exposure = once or more per day or 25 to 28 times per month
  We assumed 28 days a month for the above definition.

Individual adjusted odds ratios

As seen from Table 1, all studies included had adjusted for age and sex either by matching or stratified analysis but other confounders adjusted varied extensively. The adjusted odds ratio for heavy exposure was found to be 1.82 (95% CI: 0.86-3.88) by Yuan18 who adjusted for smoking and other potential inhaled carcinogens and 5.6 (p=0.003) by Ning24 who adjusted for carrot consumption, a potential protective effect modifier. Lee22 adjusted for education level and maternal dialect group and found that the odds ratio was even protective, 0.4 (95% CI: 0.1 to 1.6) for exposure between 1 and 3 times per week (1-3/week) but the risk increased, 4.4 (95% CI: 0.7 to 25.9), when the exposure was more than 3 per week (>3/week). One study28 stratified gender in the analysis and found that male had a higher risk compared with female when the exposure was around age 10 but it reversed when the exposure was about 3 years ago. Only Zheng21 had adjusted for serum antibody against viral capsid antigen (IgA-VCA) of Epstein Barr virus and it was found that in high level exposure subjects, the odds ratio was 5.6 (95% CI: 1.1-42.2) if the IgA-VCA status was negative but 18 (95% CI: 3.1-138) if positive. Funnel plots were not shown since the number of studies included was small.

Discussion

Among different age groups, we found that the unadjusted odds ratio for developing nasopharyngeal carcinoma (NPC) was 1.16 in mature (mean age around 40 years old) but 2.55 in young Chinese (less than 35 years old). The association between NPC and preserved salted fish (PSF) consumption seemed to be stronger among young Chinese subjects but the odds ratio among young Chinese was derived from a single study.28 It, therefore, may be a result of interaction between other coexisting risk factors such as EBV infection or genetic predisposition or just an overestimation. The pooled odds ratio in mature Chinese was insignificant and the result was homogeneous. Carcinogenic effect of PSF may be too small and need a larger sample size to detect a significant difference. Among mixed ethnic group of Chinese, Malay and Indian, the odds ratio was positive but insignificant as it came from a single study27 with a small sample size. Local residents of Tunisia in Africa consuming salted anchovies also reported an increased odds ratio for developing NPC but again the result was insignificant due to one study of limited power. The salted anchovy in Tunisia, Africa was also different from Chinese preserved salted fish as the exposure of interest.

Concerning the risk for different lifetime exposures among mature Chinese, the odds ratios were positive for all six lifetime periods from fetus to adult. The significant chi square test for trend suggested that the earlier the exposure, the greater the risk of developing NPC. We suggested that it may be a result of increased cumulative exposure in ones' lifetime, especially when early childhood exposure is associated with later adulthood exposure. Genuine increased risk for earlier exposure may be possible but it may be difficult to validate the frequency of early childhood exposure due to recall bias.

Concerning the frequency response relationship, recent exposure was selected as the x-axis as it was less prone to recall bias compared with early childhood exposure. The OR increased (p<0.005) from 1.08 for "monthly" to 2.3 for "weekly or more" exposure. All the results were statistically homogenous but the number of studies to be pooled was inevitably small. This positive dose response effect may be another evidence in supporting salted fish being a risk factor for NPC development. Individual studies adjusting various confounders such as smoking, EBV infection18,21,22,24 also found a significant association when the frequency of consumption was great (more than weekly or even daily).

Although significant risks were found for early childhood exposures and there was a positive dose-response effect for recent adulthood exposure, the pooled odds ratios shown were only adjusted for sex and age by matching and stratified analysis. Other important confounding factors such as EBV infection and genetic predisposition were not adjusted for. Other potential effect modifiers such as smoking, consumption of yellow/orange vegetables, total fiber, fruit and vegetable fiber (as suggested from a cohort of 34651 lowa postmenopausal women30 ) may be present. Dietary risk factors apart form PSF such as preserved eggs, vegetables and meats and occupational risk factors such as exposure to wood, formaldehyde, chlorophenols and chromium compounds31,32 were also suggested to be another important risks in the etiology of NPC. The above mentioned factors however were not adequately evaluated in the included studies of this meta-analysis.

There were few studies included in this study and funnel plots therefore were not shown. Although extensive searching was done with English and Chinese databases, publication bias was still possible to occur in our findings. No quality score was used in our exclusion criteria. Subjective unclear measurement of exposure frequency was the commonest reason for exclusion. Future studies may need to evaluate the association between preserved salted fish and NPC, particularly with well-specified subtypes such as non-keratinizing and undifferentiated carcinoma (WHO types II and III), which are predominant in areas where preserved salted fish is a common food item. Clear definitions and validation of frequency and amount of exposure together with analysis of important potential confounders such as EBV infection, smoking and fresh fruits/vegetables intakes are important as well. As PSF is not a common food item in non-Chinese populations, further studies investigating nitrosamine containing foods in the etiology of NPC in areas of low incidence is valuable.

Conclusion

Heavy consumption (weekly or daily) of preserved salted fish was associated with the development of nasopharyngeal carcinoma. Childhood exposure may increase the risk as a result of increased cumulative lifetime exposure. Confounding factors and effect modifiers such as Epstein Barr virus infection, smoking and fresh fruits/vegetables intake may need further investigations.

Key messages

  1. Heavy (weekly or daily) consumption of preserved salted fish is significantly associated with the development of nasopharyngeal carcinoma (NPC) in Chinese populations.
  2. Significant and positive dose-response effect was found between the consumption frequency and the odds ratio to develop NPC.
  3. Prolonged exposure (e.g. since childhood) also increases the risk to develop NPC.

J Yeung, MSc(Epidemiology & Biostatistics), PDip(Epidemiology & Biostatistics), MBBS(HK)
Physician,

J L Tang, MD, PhD
Professor,
Department of Community and Family Medicine, The Chinese University of Hong Kong.

Correspondence to : Dr J Yeung, Medical Centre, G/F, KMB Building, 1 Po Lun Street, Lai Chi Kok, Kowloon, Hong Kong.

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