Advances in Infectious Diseases, 2013, 3, 17-34 Published Online March 2013 ( 17
The Relationship between Human Papillomavirus and
Oesophageal Squamous Cell Carcinoma in China—A
Review of the Evidence*
Surabhi S. Liyanage1#, Qian Li2, Yang Zheng3, Holly Seale1, Philip J. Crowe4, Anthony T. Newall1,
Bayzidur Rahman1, Eva Segelov5, Chenxu Qu6, Fanghui Zhao6, Junfeng Liu2, Zhanhai Gao1,
Weixian Shi3, Peng Yang3, Aye Moa1, Chandini Raina MacIntyre1
1School of Public Health and Community Medicine, The University of New South Wales Medicine, The University of New South
Wales, Sydney, Australia; 2Department of Surgery, Fourth Hospital, Shijiazhuang, China; 3Centre for Disease Control and Prevention,
Beijing, China; 4Department of Surgery, Prince of Wales Hospital Clinical School, The University of New South Wales, Sydney,
Australia; 5Department of Medicine, St. Vincent’s Hospital Clinical School, The University of New South Wales, Sydney, Australia;
6Department of Cancer Epidemiology, Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical College,
Beijing, China.
Received December 6th, 2012; revised January 7th, 2013; accepted February 9th, 2013
Background: China has one of the highest incidence rates of oesophageal cancer in the world. The role of human
papillomavirus (HPV) has been extensively researched in oesophageal squamous cell carcinoma (OSCC) with indeter-
minate results. The majority of these studies have been conducted in the Chinese population. Evidence for a definitive
HPV-OSCC association could potentially support prophylactic vaccination in target populations, highlighting the need
for ongoing investigation. The aim of this review is to summarise the findings of HPV DNA in OSCC tissue in Chinese
subjects, with a view to informing further research in this area. Methods: A systematic literature search of the Chinese
National Knowledge Infrastructure (CNKI) database, Medline, Embase and PubMed was conducted for all studies in
English and Chinese language, examining OSCC tissue for HPV DNA in China. Reference lists of retrieved articles
were reviewed and hand searches of relevant, key journals were conducted, to source articles wh ich were not electroni-
cally indexed. Sixty-four studies met our selection criteria. Data from case-control and cross-sectional studies were
analysed separately for any HPV-OSCC association, using the Epi Info 3.5.3 software program. Results: From all
studies conducted in the Chinese population, 2166 /5953 (36%) of all OSCC tissue and 478 /1684 (28%) of healthy con-
trol tissue, tested p ositive for HPV. We found that 11/16 case-contro l and cross-sectional studies had a statistically sig-
nificant crude odds ratio, which supported a potential HPV-OSCC association. The largest study, carried out in the high
incidence County of Anyan g in Henan Province, reported 207/265 (78%) OSCC tissues testing positive for HPV DNA
against 203/357 (57%) controls and had an unadjusted odds ratio of 2.71 (p-value < 0.0001). Conclusion: A rigorous
meta-analysis would improve interpretation of the d ata and a well-d esigned large-scale case-control study is warranted.
If a link is found between HPV and OSCC, prophylactic HPV vaccines could be of significant benefit in China.
Keywords: Human Papillomavirus; Oesophageal Carcinoma; Squamous Cell Carcinoma; HPV Vaccine; China
1. Background
The role of human papillomavirus (HPV) as a potential
aetiological factor in oesophageal squamous cell carci-
noma (OSCC) has been debated for the last three decades
[1]. The pathogenesis of HPV in cervical cancer is well
established and th e International Agency on Research on
Cancer (IARC) has accepted the role of HPV in several
head and neck cancers [2]. However, evidence for a de-
finitive link between HPV and OSCC remains controver-
*HS currently holds a National Health and Medical Research Council
(NHMRC) Training Fellowship (1012631)—Australian Based Public
Health Fellowship). ATN currently holds a National Health and Medi-
cal Research Council (NHMRC) Training Fellowship (630724—Aus-
tralian Based Public Health Fellowship). ATN has previously received
research funding for other projects from a manufacturer of HPV vac-
#Corresponding author.
The development of prophylactic HPV vaccines is
predicted to have a major public health impact in the
field of cervical cancer. If HPV is established as an aeti-
ologic factor in OSCC, the prophylactic HPV vaccines
may play an important part in reducing mortality from
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence
OSCC, particularly in a country such as China where
oesophageal cancer (OC) contributes significantly to the
nation’s cancer burden.
1.1. HPV
Papillomaviruses have non-capsulated icosahedral viri-
ons which are approximately 55nm in diameter and con-
tain a genome of approximately 8000 base pairs [3]. The
genome is surrounded by 72 capsomeres. The outer coat
of the virus is comprised of a major and minor capsid
protein. The HPV genome is comprised of three major
regions and consists of circular double-stranded DNA
which codes for 8 proteins. The Early region (E1-8) co-
des for genes associated with transcription, plasmid rep-
lication and transformation. The Late region consists of
genes which code for the major (L1) and minor (L2) cap-
sid proteins. The control region is responsible for pro-
ducing the vital factors in the regulation of transcription
and replication [4].
HPV infections have been linked to a broad range of
mucocutaneous diseases, from benign skin warts to pre-
malignant lesions and invasive carcinoma. Of the cur-
rently characterized HPV types, infection has been de-
scribed in epithelial layers of the skin, the anogenital
region and the oropharyngeal mucosa [5].
1.2. Human Papillomaviruses in Cancer
Currently, it has been estimated that HPV is responsible
for 5.1 percent of the global cancer burden [6,7]. The
mechanism of oncogenesis of HPV in cervical cancer has
been well documented and may also be applicable to
oesophageal mucosa if HPV is an aetiologic factor in
OSCC. The integration of viral DNA into the host ge-
nome appears to be an important step in establishing the
pathway to carcinogenesis [8]. Integration of HPV dis-
rupts the viral E2 gene, which acts as a negative regulator
of the E6/E7, the main viral genes responsible for im-
mortalization and malignant transformation of the in-
fected host cell. With loss of E2 control, unregulated ex-
pression of the E6 and E7 oncopro teins cause proteolytic
degradation of the p53 and retinoblastoma (pRb) tumor
suppressor genes respectively, effectively establishing
malignancy [8,9].
To date, there has been no definitive description of
how HPV could infect the oesophagus. However, as the
oesophageal mucosa is continuous with that of the oro-
pharynx, hypotheses related to transmission in HPV re-
lated oropharyngeal cancers have also been extended to
OCs. Consequently, higher numbers of sexual partners,
increasing practice of oral sex and initiation of sexual
encounters at an earlier age have been associated with
HPV-related oropharyngeal malignancies and could simi-
larly be one of the risk factors for OCs in which HPV is
isolated [10-13].
Some reports have also suggested a transplacental
mode of transmission of HPV from infected mothers to
their babies in utero as well as during passage of the in-
fant through the birth canal. [14] This is supported by
findings of genital tract HPV types 6, 11, 16 and 18
(usually found in the genital tract), in oesophageal tissue
of newborns [15].
1.3. Oesophageal Squamous Cell Carcinoma
Of the main histologic subtypes of OC, OSCC accounts
for the majority of oesophageal malignancies worldwide
and is the predominant fo rm of OC diagnosed in African
and Asian countries [16,17].
The main aetiologic factors for OSCC are discussed
below. The onset and progress of oesophageal cancer is
insidious with few early symptoms, resulting in advanced
disease at time of diagnosis for many patients. Endo-
scopy and barium swallow are the mainstay of OSCC
diagnosis, with follow up endosonography and chest and
abdominal computer tomography scans used for staging
[18]. Dysphagia, odynophagia, dyspnoea, significant wei-
ght loss and other symptoms and clinical signs related to
disseminated disease are generally reported and observed
in patients with advanced OSCC. Prognosis is often poor
and the five-year survival rate in most cases, is less than
10% [18].
1.4. Epidemiology of Oesophageal Cancer—How
China Compares to the Rest of the Globe
OC is the eighth most common malignancy worldwide
with an incidence of an estimated 500,000 new cases
annually [6]. Approximately half of the world’s OC cases
occur in China where a reported annual incidence of
250,000 cases makes OC the nation’s second most com-
mon malignancy, after lung cancer [19,20]. OC has a
poor prognosis as it is usually d iagnosed late, with a five
year survival of less than 5% [21]. In 2008, oesophageal
malignancy was responsible for 406,000 deaths globally,
making it the sixth highest cause of cancer-related deaths
[22] while in China, with an an nual mortality of 150,0 00,
it is the fourth leading cause of death from malignancy
[23,24]. It is the second most common cause of can-
cer-related death in Chinese males [25]. Figure 1 depicts
the age-standardized mortality rates per 100,000 for oe-
sophageal cancer in China, from 1990-1992. The most
recent survey on oesophageal cancer incidence and mor-
tality in China was carried out from 1998 to 2002 (Table
1). From the 30 cities and counties included, Ci County
in Hebei Province had the highest incidence and mortal-
ity rates in age-standardized calculations for both men
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence
Copyright © 2013 SciRes. AID
Figure 1. Estimated oesophageal cancer incidence per 100,000 in China, 1990-1992.
and women.
1.5. Epidemiology of OSCC in China
OSCC is predominantly a disease of developing nations
and is the principal histologic type of OC in the Central
Asian OC belt, which includes high-incidence countries
such as China [26]. The average incidence rate for OC in
the Chinese population is 13 per 100,000 [19] with OS CC
representing more than 99% of all OC cases in China
[27]. The variation in geographic incidence of OSCC
internationally as well as within the same country, is well
documented [28,29]. The major endemic regions within
China are the northern Jiangsu province and the Linxian
and Anyang counties in the eastern province of Henan
[19,30], with mortality rates as high as 161/100,000 for
males and 103/100,000 for females, in Linxian [31]. Sig-
nificant differences in the incidence of OSCC also exist
between regions of the same province in China, an in-
triguing and unexplained phenomenon. For instance,
counties within the province of Hebei in the north of
China, have reported incidence rates varying from 1.4 to
118.2 per 100,000 [32].
The broad range of incidence rates both regionally and
globally has been ascribed to the complex, multifactorial
aetiology of OSCC. In developed countries, tobacco use
and excessive alcohol consumption are thought to be the
two most important causative factors, responsible for
90% of OSCC cases [7,33-35]. However, in developing
nations such as China, only a small percentage of OSCC
cases can be attributed to alcohol and smoking [7,34,35].
In these high incidence areas, opium abuse, nutritional
deficiencies [36,37], ingestion of hot food and beverages
[38,39], exposure to nitrosamines, industrial chemicals,
and certain viruses [40-45] such as HPV have also been
1.6. Evidence for Involvement of HPV in OSCC
n 1982, the carcinogenic potential of HPV in OC was
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence
Table 1. Incidence and mortality rates for oesophageal cancer in China, 1998-20021 (data sourced from Li 2007) [47].
Male Female Male Female
Beijing North 5.8 2.5 4.2 1.9
Tianjin North East 5.5 2.2 4.6 1.9
Ci County, Hebei Province North 122.3 77.8 107.8 57.2
Sha County, Fujian Province South East 92.3 52.8 81.1 46.3
Yangcheng Count y, Shanxi Province North East 119.7 69.3 95.4 49.6
Dalian, Liaoning Pr ovince North 6.5 1.4 6.3 1.0
Anshan, Liaoning Province North 6.7 1.7 5.3 1.6
Harbin, Heilongjiang Province North 7.4 1.3 5.7 0.9
Shanghai East 6.5 2.1 5.6 1.7
Haimen, Jiangsu Province East 11.3 4.2 10.4 3.8
Qidong, Jiangsu Province East 6.3 2.5 5.8 2.1
Huaian, Jiangsu Province East 85.1 62.6 58.5 41.3
Yangzhong, Jiangs u Province East 67.7 62.5 57 .5 47.5
Hangzhou, Zhejiang Province East 6.8 1.4 4.3 1.2
Jiaxing, Zhejiang Province East 9.9 3.0 10.1 2.2
Jiashan County, Zh ejiang Province East 14.7 3.6 13.4 3.2
Haining, Zhejiang Province East 11.4 3.1 9.7 2.8
Changle, Fujian Provinc e South East 12.9 4.1 11.0 3.5
Linqu County, S h a nd o ng Province East 16.5 3.1 1 5 .1 3.3
Feicheng, Shandong Province East 61.7 27.8 55.1 25.3
Linzhou, Henan Provinc e East 74.5 51.8 63.7 37.2
Wuhan, Hubei Province Central 8.6 2.7 7.1 2.1
Guangzhou, Guangdong Province South East 7.0 1.4 6.0 0.9
Shenzhen, Guangdong Province South East 38.7 21.1 6.6 3.1
Sihui, Guangdong Province South East 6.0 1.7 6.7 1.8
Zhongshan, Gu a n g d on g P rovince South East 12.6 1.4 9.5 1.0
Fusui County, Guan gxi Province South 3.3 0.7 3.6 0.6
Yanting County, Si chuan Province West 99.5 58.9 83.4 48.7
Gejiu, Yunnan Province South 0.5 0.0 NS NS
Wuwei, Gansu Province North West 53.4 21.8 NS NS
NS—not specified.
first postulated by Syrjänen following the observation of
HPV-related histological changes in OSCC tissue sam-
ples, identical to those seen in condylomas [46]. Subse-
quent investigations to assess a possible HPV-OSCC link,
including experiments in animal models, serological, in
vitro, and morphologic studies, have been well-docu-
mented [1,29]. Hypothesised modes of transmission of
1Rates are all age-standardized by Chinese standard population.
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence 21
HPV in OSCC and mechanisms of oncogenesis based on
a cervical cancer model, have also been previously sum-
marized [28].
The most convincing studies have demonstrated the
presence of HPV DNA sequences in OSCC tissue using
techniques varying from Southern Blot to polymerase
chain reaction (PCR), in situ hybridization (ISH) and
immunohistochemistry (IHC). To date, the largest num-
ber of studies investigating the role of HPV in OSCC
have been carried out in China, with some of these stud-
ies being published only in the Chinese language litera-
ture. To the best of our knowledge there have been no
previous reports on this topic, which assess papers from
both the English and Chinese language. We aim to re-
view all studies conducted in China, in English and Chi-
nese, with a view to informing prevention of OSCC in
China through the use of prophylactic HPV vaccines,
should an aetiological link to HPV be confirmed.
2.1. Search Strategy
English and Chinese language papers included in this
review were identified by searching the CNKI database
as well as Medline, Embase and PubMed. Search terms
included “human papillomavirus”, “HPV”, “oesophageal
cancer”, “squamous cell carcinoma” and “China”. In ad-
dition, reference lists of retrieved articles were reviewed
and hand searches of key journals including Annals of
Oncology, Lancet Oncology, Anticancer Research, Gas-
troenterology, International Journal of Cancer, BMC
Cancer, Diseases of the Esophagus, World Journal of
Gastroenterology, Cancer Epidemiology Biomarkers &
Prevention and Journal of Clinical Pathology, were con-
ducted to source any articles which were not electroni-
cally indexed. There were no limitations to date of pub-
lication for either English or Chinese language studies
and papers were sourced from the date when the data-
bases started until February 2012.
2.2. Data Extraction
Articles met the selection criteria if they investigated the
presence of HPV DNA in OSCC tissue in a Chinese co-
hort. All study types which included case series, cross-
sectional and case-control studies, were accepted. Papers
were searched and data were extracted by one author
(SSL). All studies which met our search criteria were
tabulated in chronological order (Table 2).
For each paper, data extraction included: 1) the year in
which the study w as conducted; 2) the geogra phic region
of China from which subjects were recruited (Tables 2
and 3, Figure 2); 3) the testing methodology; 4) HPV
types detected; 5) number of HPV positive OSCC sam-
ples compared to total number of OSCC samples tested;
6) if applicable, number of HPV positive controls com-
pared to total number of control specimens tested; 7) the
type of study; and 8) specimen retrieval method.
Recording of the specimen retrieval method is in-
tended to assess whether HPV detection rates differ be-
tween deep and superficial OSCC test specimens, the
sample retrieval method was recorded for all studies.
Deep tissue was classified as surgical resections, diag-
nostic biopsies and formalin fixed and paraffin embedded
samples; while superficial specimens included cell brush-
ings and balloon cytology samples (Table 2).
The Chinese literature was also searched for the most
recent epidemiological data on oesophageal cancer inci-
dence and mortality and a summary of the results ob-
tained from the source [47] are presented in Table 1. In
addition, authors of this review, based at the Beijing
Cancer Institute & Hospital Chinese Academy of Medi-
cal Sciences (CICAMS), generated a map (Figure 1) of
oesophageal cancer mortality using data collected by
CICAMS from 1990-19 92, on 10% of the Chinese popu-
lation. Based on OC mortality data collected for various
counties in China, predicted mortality rates have been
projected for surrounding regions (Figure 1 ).
2.3. Analysis of Case-Control and
Cross-Sectional Studies
The case-control study design allows the investigator to
estimate the odds of an outcome, such as OSCC, occur-
ring when exposure to a potential risk factor such as
HPV, has taken place. It is particularly useful as an initial
study to determine causality, if a link between the expo-
sure and outcome of interest, has not been previously
established [48]. The case-control methodology is both
time and cost-effective when investigating diseases with
long latency periods, such as OSCC, because the disease
state already exists at the start of the investigation [48].
Furthermore, case-control study design allows the simul-
taneous assessment of multiple risk factors, which is
useful in diseases such as OSCC, which have a multifac-
torial aetiology [49]. Thus case-control studies are the
most practical study design for examining the research
question of whether HPV is an aetiological factor in
This review defines cases as patients with OSCC and
controls as healthy subjects from whom macroscopically
normal oesophageal biopsy samples have been obtained.
Papers which identify paraoesophageal tissue from OC
patients, as controls, were not acknowledged in the con-
trol column of Table 2 and were not classified as case-
control studies in Table 4, as there is a significant possi-
bility of cross-contamination and spread of HPV from
the tumour into adjacent tissue, resulting in false-positive
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence
Copyright © 2013 SciRes. AID
Table 2. Identified studies of HPV in OSCC in China in English and Chinese language literature2.
Year of
publication City/
province Region of
china Detection
method HPV types
detected Method of oscc
specimen retrieval
No.of hpv positive
oscc samples/total
tested (% hpv
No. of positive
tested (% hpv
Type of
study Ref
1989 henan east ihc ag ns 6/ 31 (19) n/a case series[51]
1990 linxian, henan east hb - surgical specimen 25/51 (49) n/a case series[102]
1990 linxian, henan east fish 11, 16, 18surgical specimen 53/80 (66) n/a case series[10 2]
1990 linxian, henan east ish 6, 11, 16, 18surgical specimen 22/51 (43) n/ a case series[102]
19913 chengdu, sichuan south west sb 16 surgical specimen 12/24 (50) n/a case s eries[103]
1992 linxian, henan east pcr 6, 11, 16, 18surgical specimen 25/51 (49) n/a c ase series[15]
1992 linxian, henan east sb 11, 16, 18, 30surgical specimen 8/20 (40) n/a case series[15]
19933 fujian south east pcr cp ffpe 24/40 (60) n/a case series[56]
1993 linxian, henan east ish 6, 11, 16,
18, 30 surgical specimen 85/363 (23) n/a case series[108]
1994 fuzhou, fujian south east pcr 6, 16 surgical specimen 24/40 (60) n/a case series[57]
19953 linxian, henan east sb, pcr 16, 18 surgical specimen 0/35 (0) n/a case series[53]
1996c zhengzhou, henan east ish 6, 11, 16, 18ffpe 22/40 (55) n/a case series[104]
1996 beijing north pcr 6, 16, 18 surgical specimen 3/70 (4) n/a case series[77]
1996c sichuan south wes t sb, pcr 16, 18 ff pe 37/103 (36) n/a case series[60]
1997 sichuan south west pcr 16, 18 surgical specimen 32/152 ( 21) n/a case series[25]
1997 ns north ish
spectrum surgical specimen 3/36 (8) n/a case series[105]
1999 anyang, henan east pcr cp
diagnostic biopsies
(3/70), surgical
specimens (7/23),
scrapings (10/24)
20/117 (17) n/a case series[59]
1999 ns ns pcr
6, 9, 18, 20,
24, 51, 52, 57surgical specimen 10/29 (34) n/ a case series[62]
shaanxi & gansu
& sichuan &
shanxi &
central &
north west &
west & north
pcr 11, 16 surgical specime n ns/22 (ns) n/a case series[95]
2000 linxian, henan east pcr cp surgical specimen 18/101 (17) n/a case series[123]
2000 linxian, henan east ish 6, 11, 16,
18, 30, 53surgical specimen 117/700 (17) n/a case series[82]
20003 shaanxi central ihc e6 ffpe 44/60 (73) 24/56 (43) case control[101]
2000 beijing north pcr cp surgical specimen ns/37 (ns) n/a case series[94]
20013 anyang, henan east is-pcr, ish l1, e6, e7 surgical specimen 18/30 (60) n/a case series[71]
anyang &
east pcr, ish 16 ball cytology 2/2 (100) 50/112 (44) cross
sectional [65]
2001 linxian, henan east p cr cp ball cytology 2/32 (6) 4/57 (7) case control[72]
2002 anyang, henan east pcr, ish 16, 18 ball cytology 39/62 (63) 17/36 (47) case control[64]
2002 eastern guandong south east pcr cp surgical specimen 115/176 (66) n/a case series[73]
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence 23
20033 ns ns pcr cp surgical specimen28/40 (70) n/a case series[78]
20033 cixian, hebei north pcr, ihc cp surgical specimen28/152 (18) n/a case series[68]
2003 anyang & shanxi east & north
east p cr,ihc,ish 16 surgical specimen31/48 (65) n/a case series[80]
hong kong &
sichuan &
linxian &
shantou &
south &
south west &
east & south
east & central
pcr 16, 18 surgical specimen43/319 (13) n/ a case series[76]
2004 hong kong &
sichuan & linxian south & west
& east pcr 16, 18 surgical specimen18/87 (21) n/a case series[75]
2004 xinjiang north west pcr 16 surgical specimen55/104 (53) n/a case series[69]
20043 beijing north ihc e6, e7 ffpe 15/18, 16/18
(83, 89) n/a case series[100]
20043 guandong south east ihc, pcr 16 ffpe 14/30 (47) 7/60 (12) case control[83]
20053 anyang & beijing east & north ish 16 ffpe 86/11 9 ( 7 2) n/a case series[106]
2005 anyang, henan east pcr 16, 18 surgical specimen207/265 (78) 203/357 (57) case control[55]
20053 jiangsu east pcr, hb ns cell brushing 23/60 (38) 11 / 6 0 (18) case control[85]
2006 shantou south east ish 16, 18 surgical specimen24/60 (40) n/a case series[111]
2006 henan & hubei east & central ish, ihc 16, 18 surgical specimenns/82 (ns) ns unk [107]
2006 linxian, henan east ish - ball cytology 0/4 (0) 61/475 (13) cross
sectional [52]
20073 shanghai east ish 16 sur gical specimen59/90 2/20 case control[110]
20073 xinjiang nor th west pcr 18, 31, 45ffpe ns/316 (ns) n/a case series[96]
2007 anyang, henan east pcr 16 surgical specimen97/161 (60) n/a case series[81]
20073 sichuan south west pcr 16 surgical specimen43/112 (38) n/a case series[67]
2007 anyang, henan east pcr 16, 31, 51,
56, 53, 73surgical specimen1 1 /100 (11) n/a case series[58]
2007 gansu &
shandong north west &
east pcr, sb 16, 18 surgical specimen19/59 (32) n/a case series[74]
20073 anyang &
zhengzhou, henan east pcr, hb 16 surgical specimen54/110 (49 ) 7/45 (16) case control[87]
20083 linzhou, henan east pcr 16, 18 surgical specimen29/31 (94) n/a case series[63]
2008 xinjiang north west pcr
6, 11, 16, 18,
31, 52, 66surgical specimen20/67 (30) n/a case series[70]
20083 xinjiang north west pcr 16 ffpe 58/150 (39) 4/40 (10) case c o n trol[84]
20083 chongqing central pcr 16, 18 surgical specimen43/112 (38) n/a case series[88]
20093 guando ng &
henan south east &
east pcr 16, 18, 45,
33, 58, 59,
73, 31, 56surgical specimen0/140 (0) n/a case series[54]
20093 henan east pcr 16 surgical specimen37/44 (84) n/a case series[97]
20093 hebei north pcr 16, 18 surgical specimen37/42 (88) n/a case series[79]
20093 xinjiang north west pcr 16 ffpe 23/63 (37) 21/126 (17) case control[66]
20093 xinjiang north west pcr 16, e6 surgical specimen26/82 (32) n/a case series[91]
2010 shantou south east pcr 16, 18, 58surgic al specime n35/70 (50) 20/60 (33) case control[99]
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence
Copyright © 2013 SciRes. AID
2010 henan east pcr 16 surgic al specimen8/17 (47) n/a case series[98]
2010 xinjiang &
anyang &
north west &
east & south
east pcr 6, 16, 18, 26,
45, 56, 57, 58ns 160/347 (55) n/a case series[124]
2010 linxian, henan east pcr 89, 16, 31surgical specimen3/267 (1) n/a case series[61]
2010 shaanxi central pcr 16 surgical specimen35/69 (51) 2/32 (6) case control[89]
2010c xinjiang north west pcr 16, e6 ffpe (biopsy) 46/100 (46) 22/100 (22) case control[86]
2011 changhua, taiwan south east pcr, ish 6, 11, 16, 18surgical specimen2/31 (6) n/a case series[93]
2011c jiangsu east ish 16, 18 ffpe 40/72 (56) 7/48 (15) case control[109]
2011c linzhou, henan east pcr 16 diagnostic biopsy 18/18 (100) n/a case series[92]
Ag—HPV Antigens; CP—consensus primers; GP—general primers; HB—histological biopsy; IHC—immunohistochemistry; ISH—in situ hybridization;
PCR—Polymerase chain reaction; SB—southern blot hybridization; FFPE—formalin fixed and paraffin embedded; N/A—Not applicable as study did not
include controls; ND—Not Determined; UNK—Unknown d ue to insufficient information for determining study type; NS—not specified.
Figure 2. Representation of the number of HPV-OSCC studies carried out in various provinces in China.
HPV detection rates. We identified 14 case control stud-
ies and a further 2 cross-sectional studies (Table 4) in- vestigating OSCC tissue compared to oesophageal tissue
from healthy controls, for the presence of HPV DNA in
2Control subjects in this paper are defined as individuals who do not have a diagnosis of OSCC. Therefore studies which have determined controls to
be biopsies of macroscopically normal oesophageal tissue adjacent to the primary tumour, have been discounted;
3Chinese language papers. The remaining papers are in English.
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence 25
Table 3. HPV Detection Rate by Region in China, based on
64 identified studies from the English and Chinese Litera-
North 154/447 (34)
North West 228/566 (40)
South East 300/643 (47)
South West 124/391 (32)
South 16/123 (13)
East 1173/3415 (34)
Central 132/298 (44)
Regions 38/69 (55)
China (Total) 2165/5952 (36)
the Chinese population . Epi Info 3.5.3 [50] wa s used to
calculate odds ratios (OR) with 95% confid ence intervals,
for the association of HPV with OSCC, by cross-tabu-
lating the summary data presented in the papers for
case-control and cross-sectional studies. P-values for the
significance of the ORs were calculated from chi-squared
test. Only two of the identified studies presented calcula-
tions of ORs. Few studies adjusted for confounding fac-
tors and our calculation of unadjusted odds ratios for the
association of HPV with OSCC from the summary data
provided in the papers, must therefore be interpreted in
this context.
3. Results
The first study looking for an aetiological link between
HPV and OSCC in China was carried out in 1989 using
immunohistochemistry (IHC) [51]. In total, 64 studies
Table 4. Case-Control and Cross-Sectional Studies Examining HPV DNA in OSCC in China, from English and Chinese lan-
guage literature4.
2000 Shaanxi (Centr a l) IHC E6 44/60 (73) 24/56 (43) 3.67 (1.57 - 8.65) 0.0009 [101]
2001 Shangzhua ng - Anyang
& Tangmiao - Neihuang
(East) PCR, ISH 16 2/2 (100) 50/112 (44) Incalculabl e 0.1192 [65]
2001 Linxian, Henan (East) PCR CP 2/32 (6) 4/57 (7) 0.88 (0.1 - 6.13) 0.8898 [72]
2002 Anyang, Henan (East) PCR, ISH 16,18 39/62 (63) 17/36 (47) 1.90 (0.76 - 4.75 ) 0.1305 [64]
2004 Guandong (SE) IHC, PCR 16 14/30 (47) 7/60 (12) 6.63 (2.04 - 22.23) 0.0002 [83]
2005 Anyang, Henan (East) PCR 16,18 207/265 (78) 203/357 (57) 2.71 (1.86 - 3.94) <0.0001[55]
2005 Ji an g su (East) PCR, HB NS 23/60 (38) 11/60 (18) 2.77 (1.12 - 6.97) 0.0151 [85]
2006 Linxian, Henan (East) ISH Nil 0/4 (0) 61/475 (13) 0.00 (0 - 10.6 8) 0.4429 [52]
2007 Anyang &
Zhengzhou, Henan
(East) PCR, HB 16 54/110 (49) 7/45 (16) 5.23 (2.02 - 14.12) 0.0001 [87]
2007 Shanghai (East) ISH 16 59/90 (66) 2/20 (10) 17.13 (3.46 - 114 .6) <0.0001[11 0]
2008 Xinjiang (NW) PCR 16 58/150 (39) 4/40 (10) 5.67 (1.8 - 19.87) 0.0006 [84]
20096 Xinjiang (NW) PCR 16 23/63 (37) 21/126 (17) 2.88 (1.36 - 6.11) 0.0023 [66]
2010 Shaanxi (Central) PCR 16 35/69 (51) 2/32 (6) 15.44 (3.20 - 101.46) <0.0001[89]
2010 Shantou (SE) PCR 16,18,58 35/70 (50) 20/60 (33) 2.00 (0.92 - 4.35) 0.0552 [99]
20107 Xinjiang (NW) PCR 16, E6 46/100 (46) 22/100 (22) 3.02 (1.56 - 5.86) 0.0003 [86]
2011 Jian gs u (East) ISH 16,18 40/72 (56) 7/48 (15) 7.32 (2.69 - 20. 7 1) <0.0001[109]
Total 681/1239 (55) 478/1684(28)
CP—consensus primers; HCII—Hybrid Capture 2; IHC—immunohistochemistry; ISH—in situ hybridization; LR—Low-risk HPV types; HR—High risk HPV
pes; PCR—Polymerase chain reaction. ty
4Table excludes studies which did not report t he number of HPV positive OSCC samples from the tota l tested.
5Unadjusted ORs calculated using Epi Info 3.5.3, from summary data presented in the papers. As adjustments for confounding factors have not been
carried out in most studies, it is important to in terpret these ORs with caution. Only two studies calculate d ORs as highlighted below.
6OR calculated by authors of study: 2.67 ( 1.38 - 5.17); P < 0.05.
7OR calculated by authors of study: 3.020; P < 0.001.
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence
have been conducted in China to date, which include a
total of 6409 OSCC samples as summarised in Table 2.
Of these, 36 were in the English language and 29 were in
Chinese. Of the 64 studies investigating the role of HPV
in OSCC in China, a majority of 47 were case series,
with 14 case-control studies, 2 cross-sectional studies
and 1 report of indeterminable study design (Table 2).
From all studies conducted in the Chinese population,
2166/5953 (36%) of all OSCC tissue and 478/1684 (28%)
of all healthy control tissu e, tested positive for HPV ( Ta-
ble 2).
3.1. Regions of China
To date, the Chinese population has contributed the lar-
gest number of OSCC specimens for HPV analysis, com-
pared to any other country [28]. Henan province in East
China is the site of over 50% of all na tional studies (Fig-
ure 2). Of all OSCC samples tested in this high incidence
area, 34% yielded positive HPV results (Table 3). Other
high-incidence areas within China from the north-west,
south-east, and the central regions have reported even
higher rates of HPV DNA detection in OSCC tissue,
ranging from 40% - 47 % (Table 3).
3.2. Testing Methods
As summarized in Table 2, a variety of techniques have
been used in these studies to detect HPV. The detection
rate of HPV in OSCC tissue varied from 0 to 100%. Only
three studies did not detect HPV in any of the OSCC
samples tested [52-54]. Forty-nine of 64 studies utilized
PCR with HPV detection rates varying widely from 0% -
100% [15,25,53-99]. PCR yield ed a HPV positive rate in
37% of all OSCC tissue tested using this method. Ap-
proximately one quarter of all OSCC specimens were
analysed by ISH, with HPV detected in 30% of these
samples. Six studies have used IHC to test OSCC tissues
samples with HPV detection rates varying from 18% -
89% [51,68,80,83,100,101]. One study reported a 66%
HPV detection rate usi ng filter in situ hybridisation (FISH)
[102], five studies used southern blot hybridization [15,
53,60,74,103] and a further three studies examined his-
tological biopsies of oesophageal lesions [85,87,102].
Sixteen studies used ISH with percentage of OSCC
tissues testing positive fo r HPV, varying from 0% - 72%
[52,64,65,71,80,82,93,102,104-111]. ISH was the meth-
odology used in the largest study to be carried out on this
topic, analyzing a total of 700 OSCC samples from the
Henan Province, with an HPV detection rate of 17% [82].
High-risk HPV types 16 and 18 were the most commonly
detected genotypes in this study, as well as in all other
investigations from the Chinese cohort.
3.3. Site of Specimen Retrieval
We also examined studies for any potential relationship
between HPV detection rates and whether OSCC test
specimens were superficial cell scrapings or deep tissue
biopsies. Of the 60 studies which had sufficient informa-
tion for analysis, one tested both superficial and deep
oesophageal tissue specimens, 54 tested only deep tissue
and the remaining 5 tested superficial specimens (Table
2). We found that 76/184 (41%) of superficial OSCC
samples and 1990/5607 (35%) of deep OSCC tissue
samples tested positive for HPV DNA.
3.4. Results of Case-Control and Cross-Sectional
As highlighted in Table 4, we identified 14 case-control
studies and 2 cross-sectional studies which investigate
the association of HPV DNA in OSCC tissue compared
to normal control tissue in the Chinese population. From
these studies, 681/1239 (55%) of all OSCC samples and
478/1684 (28%) of all healthy control tissue tested posi-
tive for HPV. Only two of these studies calculated an
odds ratio in the published papers [66,86]. Table 4 pre-
sents these results as well as our unadjusted, crude odds
ratios which were calcula ted using Epi Info 3.5.3 (CDC)
[50]. Our analysis demonstrates that 11/16 studies had
statistically significant odds ratios which support a po-
tential HPV-OSCC link. The largest stud y, carried out in
the high incidence County of Anyang in Henan Province
[55], reported 207/265 (78%) OSCC tissues testing posi-
tive for HPV DNA against 203/357 (57%) controls and
had an unadjusted odds ratio of 2.71 (p-value < 0.0001).
4. Discussion
Our findings of a statistically significant association of
HPV with OSCC in 11/16 case-control and cross-sec-
tional Chinese studies, suggest that HPV may be a poten-
tial aetiological factor in OSCC, in the Chinese popula-
tion. However, as our unadjusted ORs have been calcu-
lated from summary data in papers, many of which have
not adjusted for important confounding factors, it is im-
portant to interpret our results accordingly.
In the 16 studies in China which have tested control
subjects for HPV [52,55,64-66,72,83-87,89,99,101,109,
110], a number of controls have tested positive for HPV,
including two studies in which HPV was isolated from a
greater percentage of controls than cases [52,72]. Inter-
estingly, both of these studies were carried out in Linxian
within Henan province, a region which has one of the
highest incidence rates of OC in the world [30]. Fidalgo
et al. also reported 100% of controls testing positive for
HPV DNA in a Portuguese cohort [112]. This trend may
be suggestive of an early role fo r HPV in the aetiology of
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence 27
OSCC, in which normal oesophageal mucosa infected by
HPV may undergo malignant transformation following
expression of the E6/E7 viral oncogenes [77].
We found that HPV types 16 and 18 are the most com-
monly detected genotypes within oesophageal tissue in
China. However, it is also important to note that a ma-
jority of studies to date test only for the main oncogenic
genotypes of HPV, namely types 16 and 18, thereby
raising the possibility that less common HPV types are
missed in the testing process. Nevertheless, some HPV
types, which have not previously been isolated from oe-
sophageal tissue, have been described in some studies
which have tested for a broader range of HPV types. Of
note are types 30, 53, 56, 66, 73 and 89 in the Chinese
cohort (Table 2). In particular, Chang et al., reported 8
out of 85 HPV-positive OSCC samples with HPV 30
[108]. As HPV 30 has only previously been identified in
two genital condylomas [113], and one malignant laryn-
geal lesion, the finding of this HPV genotype in eight
OSCC samples has led to proposals that HPV 30 may
have a proclivity to infect oesophageal mucosa [108].
This review underscores the highly variable results of
HPV detection in OSCC, between different regions of
China, for which diverse testing methodology may be a
contributing factor. It is difficult to draw conclusions on
which testing methods yield the highest and lowest rates
of HPV detection since certain techniques such as FISH,
SB and HB have been employed in very few studies and
PCR which has been used in 76% of studies has also
shown variable results between studies.
While general trends have reported higher HPV DNA
detection rates in OSCC tissue from high incidence
OSCC regions, the results of our review did not demon-
strate this pattern. Thirty-four percent of all OSCC sam-
ples, sourced predominantly from the highest OSCC in-
cidence region of Henan Province in eastern China, were
positive for HPV DNA. However, we found that other
high-incidence areas within China from the north-west-
ern counties in Xinjiang, to Guandong in the south-east,
Hebei in the north and the central Province of Shaanxi
have reported even higher rates of HPV DNA detection
in OSCC tissue. Of note is a study carried out by Ko shiol
where only 3/267 OSCC samples tested using PCR, were
positive for HPV [61]. This is one of the largest studies
to be carried out and th eir result is particu larly interestin g
as it has been conducted in Linxian, Henan province [30].
This result is not in keeping with the generally observed
trends of high HPV detection rates in high-risk OSCC
populations. Furthermore, the three studies in China which
did not isolate HPV from OSCC, also recruited subjects
residing in Henan province [52-54].
A recent study by Furrer et al. reported higher rates of
HPV DNA detection in superficial oral scrapes compared
to deep tissue biopsies from patients with oral cancer, in
an Argentinian cohort [114]. They suggest that th e site of
specimen sampling is important in obtaining an accurate
epidemiological picture on the HPV link to carcinogene-
sis. This hypothesis may be extended to oesophageal
cancer and we therefore aimed to examine whether the
location from which the oesophageal specimen was taken
in OSCC patients, i.e. superficial scrapings or deep tissue
biopsy, may have any correlation with HPV detection
rate. We found that 35 % of deep tissue biopsies and 41%
of superficial scrapings from OSCC patients were HPV
positive. This finding is consistent with results reported
by Furrer et al.
With the growing evidence that the spectrum of HPV-
related malignancies may spread beyond cancers of the
anogenital tract [1], the global health burden attributable
to HPV continues to increase. As a result, there has been
increasing pressure to make the HPV vaccines more
widely available for males, thereby immunizing entire
cohorts against the effects of this virus. If HPV plays a
significant role in the aetiology of OSCC, the introduc-
tion of prophylactic HPV vaccines could have a public
health impact in a nation such as China where OC is one
of the leading causes of malignancy-related mortality.
In many developed countries public health funding for
the prophylactic HPV vaccines is available for girls and
young women prior to their sexual debut [115]. However,
in China, there are currently no national programs for
cervical cancer screening and a majority of women have
never been screened. Consequently, at present, the pro-
phylactic HPV vaccines have not been licensed for dis-
tribution in China.
Population-based surveys of Chinese women have
been carried out recently to identify potential difficulties
in the implementation of a prophylactic vaccination pro-
gram in China [116,117]. One of the largest obstacles is
the price of the vaccination, should government funding
be insufficient to cover costs [116,117]. Prophylactic
HPV vaccines are to date the most expensive vaccine
developed with a retail price of US $120 per dose of
Gardasil® (US $360 for the complete course) excluding
administrative costs [118]. Other problems include rural
habitation with poor access to health services, cultural
and religious barriers, personal attitudes and beliefs as
well as limited knowledge of HPV and vaccination [116,
117]. However, the introduction of the Hepatitis B vac-
cine (HBV) to protect against hepatocellular carcinoma
(HCC) in China may provide a template upon which the
prophylactic HPV vaccination program can be modeled
[117]. The first national HBV program was instigated in
Taiwan in 1984 [119]. Over a 10 year period from 1984
to 1994, follow-up studies in ch ild ren und er the ag e of 15,
demonstrated a reduction in HBsAg prevalence rates
Copyright © 2013 SciRes. AID
The Relationship between Human Papillomavirus and Oesophageal Squamous Cell Carcinoma in
China—A Review of the Evidence
from 9·8% to 1.3% [120]. A recent cross-sectional sero-
prevalence study by Chang et al. also reported a statisti-
cally significant reduction in incidence of HCC in a co-
hort of vaccinated children aged 6-19 years, compared to
a comparable unvaccinated group [119].
From the results of this review, we determine that
HPV DNA was found in over one third of OSCC tissue
samples, compared to cervical cancer where HPV is re-
sponsible for the pathogenesis of 100% of lesions. Thus
the impact of prophylactic vaccination would be consid-
erably higher in cervical cancers than in OSCC, if a link
exists. However, it is important to clarify any HPV-
OSCC association as even a 20% - 30% rate of HPV in-
fection as a causal co-factor would be significantly im-
pacted by vaccination, particularly in a geographically
targeted vaccination program.
5. Conclusions
We found that 36% of all OSCC samples and 28% of all
healthy control samples tested from the Chinese popula-
tion were positive for HPV DNA and the majority (11/16)
of case-control and cross-sectional studies found a statis-
tically significant association between HPV and OSCC.
The findings of this review are in line with the hy-
pothesis that HPV detection rates are higher in superfi-
cial oesophageal cancer samples compared deep tissue
specimens [114]. It may therefore be important to con-
sider depth of tissue biopsy when interpreting epidemi-
ological studies assessing HPV aetiology in malignancy.
Research carried out over the last 30 years has neither
precluded nor established HPV as an aetiological factor
in OSCC. The difficulty in determining a link may be
due to several factors including 1) the poor methodolo-
gical design and generally smaller sample sizes in a ma-
jority of studies. Only few case-contro l studies have ever
been done, with the vast majority of studies on the sub-
ject being case-series, which are unable to adequately
address the question of aetiology or risk factors. The fact
that none of the identified case-control studies included
statistical measures of association, even when data were
collected to enable these measures, indicates the problem
of poor study design; 2) the utilization of many different
HPV detection methods with varying specificity and sen-
sitivity ranges i.e. PCR with either general or consensus
primers which identify different HPV genotypes, histo-
logical biopsy (HB), IHC, ISH, FISH, general primer
(GP), consensus primer (CP), serological testing, hybrid
capture; 3) inter-laboratory deviation on similar testing
methodology; 4) utilization of various types of specimens
i.e. balloon cell samples, OSCC tissue from resections or
biopsies which may be either fresh or archival; 5) varia-
tion within tissue samples examined; 6) differences in
histopathological classification and tissue storage i.e.
Iodine staining, paraffin samples; 7) the presence of po-
tential co-factors (e.g. smoking, opium abuse, nutritional
deficiencies, ingestion of nitrosamines and exposure to
other industrial chemicals) which may be more important
depending on geographical location, could act synergis-
tically with HPV to promote infection of oesophageal
tissue; 8) the possible “hit and run” mechanism proposed
by Campo and modeled on observations of bovine papil-
lomavirus type 4 (BPV-4) infection of bovine oesophag-
eal tissue [121]; 9) genetic polymorphisms facilitating
malignant transformation [122].
Despite the many factors which could be responsible
for the high variability of results reported, it remains that
an equal potential for inconsistency with similar vari-
ables existed in investigations carried ou t to establish the
role of HPV in cervical and other HPV-related cancers,
which have yielded more convincing results. Therefore,
it may be inferred that if a link does exist between HPV
and OSCC, it may be weaker than in other HPV-related
cancer, or geographically varied and related to other co-
factors [52].
A meta-analysis of existing case-control studies as
well as further large-scale case-control studies with ade-
quate statistical power are required to more meanin gfully
address whether a causal relationship between HPV and
OSCC exists. The introduction of the prophylactic HPV
vaccines has made it even more important to definitively
determine the answer to this research question, particu-
larly for countries such as China, where there is a sig-
nificant cancer burden from oesophageal malignancy.
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BPV: Bovine papillomavirus
CICAMS: Cancer Institute & Hospital Chinese Academy
of Medical Sciences
CDC: Centre for Disease Control
CNKI: Chinese National Knowledge Infrastructure
CP: Consensus primer
FISH: Filter in situ hybridisation
GP: General primer
HCC: Hepatocellular carcinoma
HB: Histological biopsy
HPV: Human papillomavirus
IHC: Imm unoh i s t ochemistry
ISH: In situ hybridisation
IARC: International Agency on Research on Cancer
OC: Oesophageal cancer
OSCC: Oesophageal squamous cell carcinoma
PCR: Polymerase chain reaction