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Review
HPV infections and oesophageal cancer
  1. K J Syrjänen
  1. Correspondence to:
 Professor K Syrjänen, Unità di Citoistopatologia, Laboratorio di Epidemiologia e Biostatistica, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Roma, Italy;
 kasyrjan{at}libero.it

Abstract

The first reports suggesting an involvement of human papillomavirus (HPV) in the development of both benign and malignant squamous cell tumours of the oesophagus date back to 1982. Since then, a substantial amount of literature has accumulated on this subject, summarised in this review. To date, 239 oesophageal squamous cell papillomas have been analysed in 29 separate studies using different HPV detection methods, with HPV being detected in 51 (21.3%) cases. Many more squamous cell carcinomas have been analysed: of the 1485 squamous cell carcinomas analysed by in situ hybridisation, 22.9% were positive for HPV DNA, as were 15.2% of the 2020 cases tested by the polymerase chain reaction. In addition, evidence derived from large scale serological studies, animal experiments, and in vitro studies is discussed in the light of the highly variable geographical incidence rates of oesophageal carcinoma worldwide. It may be that the (multifactorial) aetiology of oesophageal cancer differs greatly between those geographical areas with a low risk and those with a high risk for this disease. Oncogenic HPV types seem to play an important causal role, particularly in high risk areas.

  • human papillomavirus
  • oesophagus
  • cancer
  • precancer
  • aetiology
  • BPV 4, bovine papillomavirus 4
  • CI, confidence interval
  • DBH, dot blot hybridisation
  • HPV, human papillomavirus
  • IHC, immunohistochemistry
  • ISH, in situ hybridisation
  • OR, odds ratio
  • PCR, polymerase chain reaction
  • SBH, Southern blot hybridisation
  • SCC, squamous cell carcinoma
  • SCP, squamous cell papilloma
  • VLP, virus-like particle

https://doi.org/10.1136/jcp.55.10.721

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    The association of human papillomavirus (HPV) infections and squamous cell precancer lesions of the uterine cervix has been established since the late 1970s.1 Oncogenic HPV types are regarded as the most important aetiological factor of cervical squamous cell carcinoma.2–4 The early 1980s witnessed the rapid expansion of HPV research from the genital tract to cover the other squamous cell epithelia, thus widening the scope of HPV associated human tumours.1,2 The squamous cell lining of the oral mucosa is in direct continuity with the oesophagus, and the first descriptions on HPV lesions in the oral mucosa5 were slightly preceded by reports suggesting that this virus might be involved in the development of both benign6 and malignant7 squamous cell lesions of the oesophagus also. These early observations were based on the discovery of morphological similarities between HPV induced lesions in the genital tract (condyloma) and squamous cell tumours (papillomas and carcinomas) of the oesophageal mucosa.6–8 These findings were soon substantiated by the demonstration of HPV structural proteins in these lesions using immunohistochemistry (IHC).8

    Following these pioneering observations, HPV research has resulted in a rapidly expanding literature on both benign and malignant oesophageal lesions in different geographical regions.9–13 The evidence accumulated during the past 20 years is strongly suggestive of a causal role for HPV in oesophageal carcinogenesis and will be reviewed here.10,14–17 This discussion is strictly limited to reviewing the data on HPV only, and does not cover the other potential aetiological agents or the intriguing global epidemiology of this disease.9,10 In addition, because HPV has only been implicated in the aetiology of squamous cell carcinoma (SCC) of the oesophagus, the discussion will be restricted to this malignancy only.

    SCC OF THE OESOPHAGUS

    One of the most intriguing features of oesophageal SCC is the wide variation in the disease incidence in different geographical regions of the world.18 In most countries, the incidence rates are around 2.5 to 5.0/100 000 for men and 1.5 to 2.5 for women. However, in distinct areas the incidence rates are remarkably higher, varying up to 500 fold from one area to another.9,10,18,19 Numerous epidemiological studies have identified the high risk countries for oesophageal cancer, namely: the People’s Republic of China, Singapore, Iran, former USSR, Puerto Rico, Chile, Brazil, Switzerland, France, and South Africa. Among these high risk countries, the highest incidence rates have been reported in the northern parts of China, the Caspian littoral of Iran, and the Transkei area of South Africa, reaching up to 246/100 000.9,10,18,19

    RISK FACTORS

    The reasons for these major regional variations in the incidence of this disease are poorly understood.9,10,19,20 Compelling epidemiological and experimental data suggest that some chemicals (such as nitrosamines, mycotoxins, cigarette smoke, excessive alcohol intake, opium abuse), nutritional deficiencies (for example, deficiencies of vitamins A, B, C, and trace elements), and physical factors (such as coarse and hot food) are associated with the development of this malignancy.9,10,19,20 An aetiological role of certain microorganisms has been implicated (direct carcinogens or promoters).9,10,21,22 Fungal contamination of foodstuffs may produce nitrosamines and/or their precursors, in addition to mycotoxins, which are mutagenic and carcinogenic both in vitro and in vivo. Bacteria may be implicated by producing carcinogenic chemicals and increasing cell proliferation while stimulating the inflammatory process. In addition to HPV, herpes simplex virus, cytomegalovirus, and Epstein-Barr virus have been shown to infect the oesophageal epithelium, but so far no firm evidence for a role in oesophageal carcinogenesis has been provided.1,2,9,10,14–16,19,20,23

    EVIDENCE FOR HPV INVOLVEMENT

    I was the first to suggest the association of HPV with both benign and malignant squamous cell lesions of the oesophagus,6,7 opening up a new area of HPV research. The evidence for the involvement of HPV in oesophageal carcinogenesis has been provided by several distinct lines of research, namely: (1) the involvement of HPV in benign squamous cell tumours (papillomas); (2) evidence from animal studies (malignant transformation of oesophageal papillomavirus lesions in cattle); (3) the detection of HPV in oesophageal cancer and its precursor lesions by morphological IHC and DNA methods; (4) seroepidemiological evidence (HPV antibodies in patients with cancer); and (5) in vitro studies (transformation of oesophageal epithelial cells by oncogenic HPV types). This evidence has been discussed in a recent textbook,2 and this review will provide an update to this discussion.

    Evidence for HPV involvement in benign oesophageal papillomas

    One line of evidence for the causal role of a suspected aetiological agent in any malignancy is the involvement of the same agent in benign lesions: squamous cell papilloma (SCP) in this case. Following my first report,6 a large series of studies have reported the presence of HPV DNA in benign SCPs of the oesophagus.6,24–51

    To date, 29 studies have been published, with a total of 239 cases having been analysed by different HPV detection methods, including morphology, IHC, dot blot hybridisation (DBH), in situ hybridisation (ISH), Southern blot hybridisation (SBH), and the polymerase chain reaction (PCR). In total, HPV has detected in 51 cases (21.3%). The role of HPV in benign oesophageal SCPs still remains contradictory. There is a tendency towards higher detection rates when using PCR, although even then a wide variation (from 0% to 100%) in the figures is evident. However, this is not unusual when looking at the published data on HPV detection rates at other mucosal sites.2 Because of the rarity of oesophageal SCPs, the number of published cases is still too small to draw definite conclusions on the role of HPV in the aetiology of oesophageal papillomas. As with some other mucosal sites, it may be that benign lesions with different aetiologies and pathogenesis exist in the oesophagus.2,14,15,23

    Evidence from animal studies

    Substantial evidence for the involvement of papillomavirus in oesophageal carcinogenesis has been obtained from studies on cattle, particularly in the Scottish Highlands, which is a high incidence area for upper alimentary tract papillomas and carcinomas.52–56 Persistent and widespread papillomatosis and carcinomas can be experimentally reproduced with bovine papillomavirus 4 (BPV 4) infection in these animals.55,56 Field studies in this region have revealed that up to 96% of the cancer bearing animals have concomitant papillomas, and 40% showed more than 15 papillomas in the alimentary tract. In many instances, the progression from benign papillomas to carcinomas could be clearly identified.52,56

    The ingestion of bracken fern is the crucial factor in the malignant conversion of these papillomas. Bracken fern contains carcinogenic agents (radiomimets) and immunosuppressants (such as azathioprine).55 High copy numbers of BPV 4 DNA sequences are regularly detected in both naturally occurring or experimentally induced papillomas. However, no viral DNA or viral antigens are present in naturally occurring or experimental cancers, indicating that the viral genomes are not required for the maintenance of the malignant state.52–59

    Thus, these animal experiments suggest that: (1) BPV 4 may execute one of the early events in cell transformation, and its genetic information may not be required for malignant progression; (2) immunosuppression caused by the ingestion of bracken fern allows the spread and the persistence of BPV induced papillomas; and (3) the bracken fern supplies cocarcinogens and carcinogens, leading to cell transformation and progression to malignancy.

    Morphological similarities to established HPV lesions

    In 1982, I examined a series of 60 oesophageal SCCs, and found epithelial changes fulfilling the criteria of both exophytic, inverted, and flat HPV lesions in 24 of 60 patients.7 For the first time, the possibility was raised that HPV could be the agent responsible for the development of oesophageal SCC. This preliminary report was soon confirmed by other studies (table 1).60–64

    View this table:
    Table 1

    Detection of human papillomavirus (HPV) in oesophageal squamous cell carcinomas

    Expression of HPV structural proteins

    In 1986 Hille et al were the first to use IHC for the demonstration of HPV antigens in oesophageal SCCs, and they found antigen expression in seven of their 70 patients.60 IHC was soon replaced by different DNA hybridisation methods, and the number of purely IHC studies remained limited (table 1).29,60,65–67 In total, 182 cases were analysed by IHC and HPV antigen expression was shown in 23 cases (12.6%).

    DETECTION OF HPV DNA IN OESOPHAGEAL CARCINOMAS

    Table 1 summarises the detection of HPV in oesophageal carcinomas using different hybridisation techniques and PCR.

    Filter in situ hybridisation

    During the late 1980s filter in situ hybridisation (then abbreviated as FISH) was widely used to detect HPV DNA in various mucosal samples, particularly those of the genital tract. This technique was shown to have a low sensitivity and poor specificity, making it obsolete in the early 1990s. In total, this technique was used to analyse 129 carcinomas, and showed HPV DNA in 67 cases (51.9%), which is considerably higher than that shown using any other detection technique (as a result of the high false positive rate).2,68–70

    DBH and SBH

    There are only two studies using the DBH technique.71,72 Divergent results were reported; no HPV DNA was detected in the 37 cases analysed from Hong Kong,71 whereas 42% of cases were positive in a series collected from France.72 This last figure is consistent with the results from Chinese patients examined by means of SBH (table 1)73–76

    In situ hybridisation

    Until now, 13 studies have been published on the detection of HPV in oesophageal carcinomas using ISH.11,46,63,72,77–84 The numbers of patients in these studies have been relatively small, except for the study reported by Chang et al, which comprised 363 cases,78 and another by the same authors, which comprised a total of 700 patients from the high incidence area of China (table 1).11 In this last study, 117 of the 700 SCCs (16.9%) were HPV DNA positive, with HPV types 6, 11, 16, 18, and 30 accounting for 39.8% of the positivity. The involvement of other (possibly novel?) HPV types in a considerable proportion of the remaining positive lesions has been suggested. Indeed, several novel types have been demonstrated recently by means of PCR and sequencing.49,113

    In total, ISH has been used to study 1485 oesophageal SCCs, and HPV DNA has been found in 22.9% (341 of 1485) of these patients. HPV-16 was the most frequent HPV type detected. With regard to geographical regions, the HPV detection rate is much higher in lesions from the high risk areas than in those from Europe. This supports the view that oesophageal carcinoma might have a different aetiology in the low and high risk areas, as discussed in recent reviews.9,10,14,15,19,23,105,106,109

    Polymerase chain reaction

    By 1998, 28 PCR studies had been reported, comprising a total number of 1183 oesophageal carcinomas.23,74–76,85–107 These studies are discussed in detail elsewhere.10 HPV DNA was found in 15.6% of the cases (185 of 1183). Since then, several other studies have been published, as summarised in table 1. By March 2002, 837 additional cases had been analysed, 123 of which were HPV positive.12,15,49,51,84,108–112,114–118

    The detection rates of HPV DNA in oesophageal cancer samples with PCR are subject to a wide variation, as has also been noted in studies with other lesions. The detection of HPV has varied from 0% to 60–70% (table 1). There seems to be a common denominator for the low and high detection rates; namely, the geographical distribution of the material. Accordingly, almost all of the studies where HPV DNA could not be amplified in the tumours were carried out in low risk countries in Europe or in the USA. In contrast, the detection rates of HPV DNA in oesophageal carcinomas derived from the high risk areas (such as China, South Africa, Japan, and Alaska) are significantly higher, and only two studies that included Japanese patients reported no evidence of HPV.95,111

    Surprisingly, the overall detection rate of HPV DNA (15.2%; 308 of 2020) is less than that found with ISH (22.9%), and significantly less than that reported with SB (40–50%) and FISH (51.9%) (table 1). The reasons for these divergent results may be purely technical (as a result of errors in the interpretation of the data) and, perhaps most importantly, may reflect the diversity of these lesions in different geographical regions. However, PCR should be regarded as the most sensitive HPV detection method, and the higher detection rate with hybridisation methods might indicate a cross hybridisation of HPV probes with human DNA or DNA from other microorganisms.1–3

    HPV DNA IN OESOPHAGEAL PRECANCER LESIONS

    There is little doubt in that oesophageal SCC develops through distinct precursor lesions known as dysplasia and carcinoma in situ.119,120 In the high risk areas of China, mass screening programmes have been established to detect cancer precursors by using balloon cytology.19,74,121,122 However, these precancer lesions have not been systematically studied for the involvement of HPV until recently.9–13,69,122–124

    According to our experience, such dysplastic lesions frequently accompany invasive SCCs, and present with HPV suggestive cellular changes, such as koilocytes.10 HPV DNA was recently detected in cytological brushings of the oesophagus in a substantial proportion (17%) of human immunodeficiency virus infected patients without clinically detectable lesions,125 although it was not found in oesophageal acalasia lesions.126 In our series of 700 SCCs from China, of which 117 (16.9%) were HPV DNA positive,11 HPV signals were detected in the surrounding hyperplastic and dysplastic epithelia in 5.6% of patients, and in the resection margins of 0.2% cases, figures that agree with another recent report.118 The presence of HPV in the adjacent normal and dysplastic epithelium fits in with the “condemned mucosa” concept, recently proposed to explain the pathogenesis of multifocal HPV induced carcinogenesis in the genital tract and in the upper aerodigestive tract,127 including oesophageal SCC.10,124

    SEROLOGICAL EVIDENCE

    Virus-like particles (VLPs) have been used to detect HPV antibodies in the sera of patients with oesophageal SCC,128–131 in both low risk and high risk areas for this disease. In the study from Finland, based on a serum bank of 39 268 samples, IgG antibodies against HPV-16 VLPs were measured.128 Of the cases, eight of 39 were HPV-16 seropositive as compared with two of 78 matched controls (p < 0.001; odds ratio (OR), 14.6; 95% confidence interval (CI), 1.8 to 117). For a low risk country for this disease, this high OR clearly suggests a significantly increased risk for this malignancy among HPV-16 seropositive subjects. Data are very similar from Norway, where an increased risk of oesophageal cancer among HPV-16 seropositive subjects was of the same order of magnitude (OR, 6.6; 95% CI, 1.1 to 71).129 However, such an increased risk could not be confirmed in a study from Sweden, where the age and sex adjusted ORs for SCC were 1.0 (95% CI, 0.5 to 2.0) for HPV-16 seropositive patients and 0.5 (95% CI, 0.2 to 1.1) for HPV-18 seropositive patients.131 The reasons for these discrepant results in these three low risk neighbouring countries remain unclear at the moment.

    In Shaanxi Province, China, a high risk area for oesophageal cancer,130 90 patients with tumours and 121 cancer free matched control subjects were analysed for the presence of HPV-16 specific antibodies using VLP as the antigen. With the HPV-16 seropositivity cut off value similar to that used in cervical cancer studies, 24% of the patients and only 7% of the controls were seropositive (OR, 4.5; 95% CI, 1.8 to 11.9). OR increased with increasing HPV-16 seroreactivity. Thus, the serological results correlate with the HPV DNA detection data in the balloon cytology samples from the screening population,69,122 suggesting that HPV-16 infection is an important risk factor for oesophageal carcinoma in this high risk area for the disease 9,10,19,130

    IN VITRO STUDIES

    During the 1990s, the loss of function of the p53 tumour suppressor gene by mutation or interaction with the E6 protein of the oncogenic HPV types was established as a frequent event in oesophageal SCC.132,133 The presence of p53 mutations in HPV positive SCCs suggests that HPV and p53 mutation are not mutually exclusive events.93,133 The interactions between HPV-16 E7 and the retinoblastoma protein in clinical samples have not been studied systematically.2,10 Similar results have been reported in HPV positive oesophageal cancer cell lines,134 where different types of p53 mutations were a frequent occurrence. Interestingly, p53 seems to be mutated even in early precancer lesions, at least in the high risk area of China,135 although p53 mutations are exceptional in benign SCPs.136 The presence of frequent mutations of the p53 gene in both HPV positive and HPV negative carcinomas suggests an important role for environmental carcinogens in oesophageal carcinogenesis.20,93,104,132,133,135–140

    Recently, several HPV-16 and HPV-18 positive cells lines from oesophageal SCCs have been established,92 and have been used to study HPV replication.141 HPV-16 and HPV-18 genomes were independently transiently transfected into HCE-4 and HCE-7 cell lines with and without E1 and E2 genes under the control of heterologous promoters. These cell lines supported viral replication, and heterologous E1 and E2 were not required for HPV replication, suggesting that specific host nuclear factors in oesophageal squamous epithelial cells may support HPV replication.141 Malignant transformation of human embryonic epithelial cells was induced in vitro by HPV-18 E6/E7 in synergy with TPA, and these cells were subsequently grown as an established SHEE (synergically infected human embryonic oesophageal cells) cell line.142 Three different passages of this cell line were used to study cytogenesis, telomere and telomerase, and the c-myc, ras, bcl-2, and p53 genes. The results revealed that changes of chromosomes, telomere length, telomerase activity, and the expression of certain genes occurred as a dynamic progressive process, suggesting that they are important events in the immortalisation of HPV infected oesophageal epithelial cells.140 Immortal cell lines have been recently produced by the transduction of HPV-16 E6/E7 into primary culture of human oesophageal keratinocytes, using a recombinant adenovirus.143 Oesophageal keratinocytes with an extended lifespan have upregulated telomerase activity and have acquired serum resistant growth. The high efficiency of E6/E7 induction by adenovirus vector also revealed the M1 and M2 stages of keratinocyte immortalisation. In vitro experiments will probably shed more light on the complex process of oesophageal carcinogenesis in the near future.

    CONCLUSIONS

    The possible mechanisms of HPV associated carcinogenesis in the oesophagus have been discussed in more detail recently.2,9,10 Despite the accumulating evidence on the presence of the HPV genome in cancer samples, and the malignant transformation of oesophageal epithelial cells by the oncogenic HPV types, several questions need to be answered before the causal role of HPV in oesophageal carcinogenesis can be as firmly established as in cervical cancer.2–4 However, because of the limits of space only a brief account of some key issues is possible in this context.

    One of the prerequisites for the development of cervical cancer seems to be persistent infection by the oncogenic HPV types.2–4 Such persistent HPV infections probably occur in the oesophagus also, as has been suggested by the detection of HPV DNA in normal oesophageal epithelium and in cancer precursor lesions.11,118,124–127 So far, however, no prospective follow up studies of such HPV positive lesions or normal oesophageal mucosa harbouring HPV are available, to establish whether such persistent HPV infections are associated with an increased risk of cancer.

    There is no reason to doubt that oesophageal cancer develops secondary to multiple genetic events. Infections with microorganisms cause an acute and/or chronic inflammatory process, thereby increasing cell proliferation,144 and produce carcinogens or promotors that act directly on oesophageal epithelial cells.19,144 Of importance in this context is the chronic (non-reflux related) oesophagitis described as the most frequent finding in high risk populations for oesophageal SCC in Iran and China, and presumed to be a precursor lesion of this disease.9,10,19 The extracts of several fungi isolated from foodstuffs in these high risk areas have been shown to have mutagenic and carcinogenic effects by both in vitro and in vivo studies.10,19 In oesophageal carcinogenesis, some of the factors may be important in the initiation of the neoplastic process, whereas others may act in the promotion and progression of the lesions. In addition to chemical agents, nutritional deficiencies, and physical factors, the current data suggest that HPV may play an important role in the aetiology of oesophageal SCC.1–3,10,145,146

    At this point, it is too early to speculate upon the detailed molecular mechanisms whereby HPV is involved in the development of malignant transformation in the oesophagus.141–143,147 The experimental data accumulated so far suggest that similar mechanisms to those detected in cervical carcinogenesis are also involved in the oesophagus.2–4,9,10,14–17 The analogy with BPV 4 induced carcinogenesis in cattle cannot be ruled out, with regard to synergistic actions between HPV and chemical carcinogens present in foodstuffs, particularly in high incidence areas of the disease,2,9,10 although the papilloma–carcinoma sequence in the human oesophagus is not firmly documented. The occurrence of p53 mutations in oesophageal carcinomas is a frequent phenomenon, both in HPV negative and HPV positive lesions,83,132,133,147 but much less attention has been paid to the interactions of HPV E7 and the retinoblastoma protein so far. In the cervix, it is clear that both E6 and E7 crucially interfere with cell cycle regulation, and the role of E7 might be even more important.2–4 Analysis of the expression of these viral oncogenes should be the major focus of HPV research in oesophageal carcinogenesis.

    Take home messages

    • Oesophageal squamous cell carcinoma has a highly divergent geographical distribution, with up to 500 fold variations between low and high risk areas

    • Epidemiological and experimental data suggest that some chemicals, nutritional deficiencies, physical factors, and infectious agents are associated with the development of this malignancy

    • Evidence for the involvement of human papillomavirus (HPV) in oesophageal carcinogenesis has been provided by several distinct lines of research: (1) HPV involvement in benign squamous cell tumours (papillomas); (2) evidence from animal studies (malignant transformation of oesophageal papillomavirus lesions in cattle); (3) the detection of HPV in oesophageal cancer and its precursor lesions by morphological immunohistochemistry and DNA methods; (4) seroepidemiological evidence (anti-HPV antibodies in patients with cancer); and (5) in vitro studies (transformation of oesophageal epithelial cells by oncogenic HPV types)

    • HPV detection rates in oesophageal carcinomas are highly variable in different geographical areas of the world, being significantly higher in high risk areas than in low risk regions. Of the several thousands of carcinomas analysed, HPV detection rates are 23% using in situ hybridisation and 15% by the polymerase chain reaction

    • The experimental data accumulated so far suggest that similar mechanisms to those that occur in cervical carcinogenesis are also involved in the oesophagus—both the E6 and E7 oncogenes interfere with cell cycle regulation—and analysis of the expression of these viral oncogenes should be the major focus of HPV research in oesophageal carcinogenesis

    • It may be that the aetiology of oesophageal cancer differs greatly between those geographical areas with a low risk and those with a high risk for this disease. This would be the most feasible explanation for the highly divergent detection rates of HPV in oesophageal carcinomas from these different geographical areas

    It may be that the aetiology of oesophageal cancer varies greatly between those geographical areas with a low risk and those with a high risk for this disease.1,2,10 This would be the most feasible explanation for the highly divergent detection rates of HPV in oesophageal carcinomas from these different areas, as discussed earlier. This divergent prevalence of HPV in oesophageal carcinomas in different geographical areas also makes it extremely difficult to speculate on the proportion of oesophageal carcinomas that are associated with HPV. An approximate estimate could be obtained by using the average HPV prevalence rate (15.2%) reported by the studies using PCR (table 1) and the current number of incident cases, 412 00018: approximately 62 000 cases annually. This figure is certainly biased by the unbalanced global distribution of the disease (341 000 of the cases being detected in the developing countries) and the highly divergent HPV prevalence rates in the different global regions, making any such estimation merely speculative.

    REFERENCES

    1. ↵
      Syrjänen K, Gissmann L, Koss LG, eds. Papillomaviruses and human disease. Berlin: Springer Verlag, 1987.
    2. ↵
      Syrjänen K, Syrjänen S. Papillomavirus infections in human pathology. New York: Wiley & Sons, 2000.
    3. ↵
      IARC Monographs on the evaluation of carcinogenic risks to humans. Papillomaviruses, Vol. 64. Lyon: IARC, 1995.
    4. ↵
      Bosch XF, Lorincz A, Muñoz N, et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol2002;55:244–65.
      OpenUrlAbstract/FREE Full Text
    5. ↵
      Syrjänen SM. Papillomavirus infections in the oral cavity. In: Syrjänen K, Gissmann L, Koss LG, eds. Papillomaviruses and human disease. Berlin: Springer Verlag, 1987:104–137.
    6. ↵
      Syrjänen K, Pyrhönen S, Aukee S, et al. Squamous cell papilloma of the esophagus: a tumour probably caused by human papilloma virus (HPV). Diagn Histopathol1982;5:291–6.
      OpenUrlPubMedWeb of Science
    7. ↵
      Syrjänen KJ. Histological changes identical to those of condylomatous lesions found in esophageal squamous cell carcinomas. Arch Geschwulstforsch1982;52:283–92.
      OpenUrlPubMedWeb of Science
    8. ↵
      Kashima H, Mounts P. Tumors of the head and neck, larynx, lung and esophagus and their possible relation to HPV. In: Syrjänen K, Gissmann L, Koss LG, eds. Papillomaviruses and human disease. Berlin: Springer Verlag, 1987:138–57.
    9. ↵
      Syrjänen K, Chang F, Syrjänen S. Infectious agents as etiological factors in esophageal carcinogenesis. In: Tahara E, Sugimachi K, Oohara T. eds. Recent advances in gastroenterological carcinogenesis I. Bologna: Monduzzi Editore, 1996:29–43.
    10. ↵
      Syrjänen K. HPV infections of the oesophagus. In: Syrjänen K, Syrjänen S. Papillomavirus infections in human pathology. New York: J Wiley & Sons, 2000:413–28.
    11. ↵
      Chang F, Syrjänen S, Shen Q, et al. Detection of HPV DNA in oesophageal squamous cell carcinoma from the high-incidence area of Linxian, China. Scand J Gastroenterol2000;35:123–30.
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      Chang F, Syrjanen S, Shen Q, et al. Evaluation of HPV, CMV, HSV and EBV in esophageal squamous cell carcinomas from a high-incidence area of China. Anticancer Res2000;20:3935–40.
      OpenUrlPubMedWeb of Science
    13. ↵
      Tripodi S, Chang F, Syrjänen S, et al. Quantitative image analysis of oesophageal squamous cell carcinoma from the high-incidence area of China, with special reference to tumour progression and papillomavirus (HPV) involvement. Anticancer Res2000;20:3855–62.
      OpenUrlPubMedWeb of Science
    14. ↵
      Sur M, Cooper K. The role of the human papilloma virus in esophageal cancer. Pathology1998;30:348–54.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      Poljak M, Cerar A, Seme K. Human papillomavirus infection in esophageal carcinomas: a study of 121 lesions using multiple broad-spectrum polymerase chain reactions and literature review. Hum Pathol1998;29:266–71.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      Tandi Matsha MS, Erasmus R, Kafuko AB, et al. Human papillomavirus associated with oesophageal cancer. J Clin Pathol2002;55:587–90.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      zur Hausen H. Yohei Ito memorial lecture: papillomaviruses in human cancers. Leukemia1999;13:1–5.
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide, Version 1.0. IARC Cancer Base No. 5. Lyon: IARC Press, 2001.
    19. ↵
      Chang F, Syrjänen SM, Wang L, et al. Infectious agents in the etiology of esophageal cancer. Gastroenterology1992;103:1336–48.
      OpenUrlPubMedWeb of Science
    20. ↵
      Franceschi S, Munoz N, Bosch XF, et al. Human papillomavirus and cancers of the upper aerodigestive tract: a review of epidemiological and experimental evidence. Cancer Epidemiol Biomarkers Prev1996;5:567–75.
      OpenUrlAbstract
    21. ↵
      Ribeiro U, Posner MC, Safatle-Ribeiro AV, et al. Risk factors for squamous cell carcinoma of the oesophagus. Br J Surg1996;83:1174–85.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      Baehr PH, McDonald GB. Esophageal infections: risk factors, presentation, diagnosis, and treatment. Gastroenterology1994;106:509–32.
      OpenUrlPubMedWeb of Science
    23. ↵
      Benamouzig R, Jullian E, Pompidou A, et al. Are human papillomaviruses involved in esophageal carcinogenesis? Head and Neck Cancer Advances and Basic Research1996;114:391–5.
    24. ↵
      Winkler B, Capo V, Reumann W, et al. Human papillomavirus infection of the esophagus. A clinicopathologic study with demonstration of papillomavirus antigen by the immunoperoxidase technique. Cancer1985;55:149–55.
      OpenUrlCrossRefPubMedWeb of Science
    25. Lesec G, Gogusev J, Fermaud H, et al. Presence d’un antigene viral de groupe papilloma dans un condylome aesophagien chez i’homme. Gastroenterol Clin Biol1985;9:165–8.
      OpenUrl
    26. De Borges RJ, Acevedo F, Miralles E, et al. Squamous papilloma of the esophagus diagnosed by cytology. Report of a case with concurrent occult epidermoid carcinoma. Acta Cytol1986;30:487–90.
      OpenUrlPubMedWeb of Science
    27. Fekete F, Chazouilleres O, Ganthier V, et al. A case of esophageal papillomatosis in adults. Gastroenterol Clin Biol1988;12:66–70.
      OpenUrlPubMedWeb of Science
    28. Valerdiz S, Vazquez JJ, Munoz M. Papillomas of the esophagus: presentation of 5 cases and review of the literature. Rev Esp Enferm Apar Dig1989;75:259–61.
      OpenUrlPubMedWeb of Science
    29. ↵
      van Cutsem E, Geboes K, Visser L, et al. Squamous papillomatosis of the oesophagus with malignant degeneration and demonstration of the human papilloma virus. Eur J Gastroenterol Hepatol1991;3:561–6.
    30. Hörding M, Hörding U, Daugaard S, et al. Human papilloma virus type 11 in a fatal case of esophageal and bronchial papillomatosis. Scand J Infect Dis1989;21:229–31.
      OpenUrlPubMedWeb of Science
    31. Chang F, Janatuinen E, Pikkarainen P, et al. Esophageal squamous cell papillomas. Failure to detect human papillomavirus DNA by in situ hybridization and polymerase chain reaction. Scand J Gastroenterol1991;26:535–45.
      OpenUrlPubMedWeb of Science
    32. Fontolliet C, Hurlimann J, Monnier P, et al. Is papilloma of the esophagus a preneoplastic lesion? Study of 33 cases. Schweiz Med Wochenschr1991;121:754–7.
      OpenUrlPubMedWeb of Science
    33. Janson JA, Baillie J, Pollock M. Endoscopic removal of esophageal condylomata acuminatum containing human papilloma virus. Gastrointest Endosc1991;37:367–70.
      OpenUrlPubMedWeb of Science
    34. Politoske EJ. Squamous papilloma of the esophagus associated with the human papillomavirus. Gastroenterology1992;102:668–73.
      OpenUrlPubMedWeb of Science
    35. Odze R, Antonioli D, Shocket D, et al. Esophageal squamous papillomas. A clinicopathologic study of 38 lesions and analysis for human papillomavirus by the polymerase chain reaction. Am J Surg Pathol1993;17:803–12.
      OpenUrlCrossRefPubMedWeb of Science
    36. Carr NJ, Bratthauer GL, Lichy JH, et al. Squamous cell papillomas of the esophagus: a study of 23 lesions for human papillomavirus by in situ hybridization and the polymerase chain reaction. Hum Pathol1994;25:536–40.
      OpenUrlCrossRefPubMedWeb of Science
    37. Poljak M, Cerar A. Detection of human papilloma virus type-6 DNA in an esophageal squamous cell papilloma. Eur J Clin Microbiol Infect Dis1994;13:188–9.
      OpenUrlCrossRefPubMedWeb of Science
    38. Al-Sohaibani MO, Al-Rashed RS. Squamous papilloma of the esophagus: a clinicopathologic study of 10 cases and review of the literature. Ann Saudi Med1995;15:140–2.
      OpenUrlPubMedWeb of Science
    39. Ferrari AP, Lanzoni VP, Kondo M, et al. Esophageal squamous cell papilloma. Report of 3 cases. Diagnostic aspects. Rev Assoc Med Bras1995;41:266–70.
    40. Poljak M, Orlowska J, Cerar A. Human papillomavirus infection in esophageal squamous cell papillomas: a study of 29 lesions. Anticancer Res1995;15:965–9.
      OpenUrlPubMedWeb of Science
    41. van Cutsem E, Snoeck R, Van Ranst M, et al. Successful treatment of a squamous papilloma of the hypopharynx-esophagus by local injections of (S)-1-(3-hydroxy-2-p hosphonylmethoxypropyl) cytosine. J Med Virol1995;45:230–5.
      OpenUrlCrossRefPubMedWeb of Science
    42. Yamada Y, Ninomiya M, Kato T, et al. Human papillomavirus type 16-positive esophageal papilloma at an endoscopic injection sclerotherapy site. Gastroenterology1995;108:550–3.
      OpenUrlCrossRefPubMedWeb of Science
    43. Mastour M, Lefebre A, Dambron P, et al. Papillome oesophagien hemorragique associe a la prise d’anti-inflammatoires non steroidiens. Gastroenterol Clin Biol1996;20:406–7.
      OpenUrlPubMedWeb of Science
    44. Sandvik AK, Aase S, Kveberg KH, et al. Papillomatosis of the esophagus. J Clin Gastroenterol1996;22:35–7.
      OpenUrlCrossRefPubMedWeb of Science
    45. Van den Borre K, Rutgeerts L, Ghillebert G, et al. Squameuze slokdarmpapillomen. Ned Tijdschr Geneeskd1996;140:987–90.
      OpenUrlPubMed
    46. ↵
      Woo YJ, Yoon HK. In situ hybridization study on human papillomavirus DNA expression in benign and malignant squamous lesions of the esophagus. J Korean Med Sci1996;11:467–73.
      OpenUrlPubMed
    47. Ratoosh SL, Glombicki AP, Lockhart SG, et al. Mastication of verruca vulgaris associated with esophageal papilloma: HPV-45 sequences detected in oral and cutaneous tissues. J Am Acad Dermatol1997;36:853–7.
      OpenUrlCrossRefPubMedWeb of Science
    48. Ravakhah K, Midamba F, West BC. Esophageal papillomatosis from human papilloma virus proven by polymerase chain reaction. Am J Med Sci1998;316:285–8.
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      Lavergne D, de Villiers EM. Papillomavirus in esophageal papillomas and carcinomas. Int J Cancer1999;80:681–4.
      OpenUrlCrossRefPubMedWeb of Science
    50. ↵
      Talamini G, Capelli P, Zamboni G, et al. Alcohol, smoking and papillomavirus infection as risk factors for esophageal squamous-cell papilloma and esophageal squamous-cell carcinoma in Italy. Int J Cancer2000;86:874–78.
      OpenUrlCrossRefPubMedWeb of Science
    51. ↵
      Mosca S, Manes G, Monaco R, et al. Squamous papilloma of the esophagus: long-term follow up. J Gastroenterol Hepatol2001;16:857–61.
      OpenUrlCrossRefPubMedWeb of Science
    52. ↵
      Jarrett WFH, NcNeil PE, Grimshaw TR, et al. High incidence area of cattle cancer with a possible interaction between an environmental carcinogen and a papillomavirus. Nature1978;274:215–17.
      OpenUrlCrossRefPubMed
    53. Campo MS, Moar MH, Jarrett WFH, et al. A new papillomavirus associated with alimentary cancer in cattle. Nature1980;280:180–2.
      OpenUrlCrossRef
    54. Campo MS, McCaffery RE, Doherty I, et al. The Harvey ras 1 gene is activated in papillomavirus-associated carcinomas of the upper alimentary canal in cattle. Oncogene1990;5:303–8.
      OpenUrlPubMedWeb of Science
    55. ↵
      Campo MS. Papillomas and cancer in cattle. Cancer Surv1987;6:39–54.
      OpenUrlPubMedWeb of Science
    56. ↵
      Jarrett WFH. Environmental carcinogens and papillomaviruses in the pathogenesis of cancer. Proc R Soc Lond B Biol Sci1987;231:1–11.
      OpenUrlPubMed
    57. Gaukroger J, Bradley A, O’Neil B, et al. Induction of virus-producing tumors in athymic nude mice by bovine papillomavirus type 4. Vet Rec1989;125:391–2.
      OpenUrlAbstract
    58. Gaukroger J, Chandrachud L, Jarrett WFH, et al. Malignant transformation of a papilloma induced by bovine papillomavirus type 4 in the nude mouse renal capsule. J Gen Virol1991;72:1165–8.
      OpenUrlAbstract/FREE Full Text
    59. ↵
      Anderson RA, Scobie L, O’Neil BW, et al. Viral proteins of bovine papillomavirus type 4 during the development of alimentary canal tumours. Vet J1997;154:69–78.
      OpenUrlCrossRefPubMedWeb of Science
    60. ↵
      Hille JJ, Margolius KA, Markowitz S, et al. Human papillomavirus infection related to oesophageal carcinoma in black South Africans. A preliminary study. S Afr Med J1986;69:417–20.
      OpenUrlPubMedWeb of Science
    61. ↵
      Hale MJ, Liptz TR, Paterson AC. Association between human papillomavirus and carcinoma of the oesophagus in South African blacks. A histochemical and immunohistochemical study. S Afr Med J1989;76:329–30.
      OpenUrlPubMedWeb of Science
    62. ↵
      Matos M, Golindano C, Guirola E, et al. Esophageal lesions caused by human papillomaviruses (HPV). G E N1990;44:377–84.
      OpenUrlPubMed
    63. ↵
      Chang F, Syrjänen S, Shen Q, et al. Human papillomavirus (HPV) DNA in esophageal precancer lesions and squamous cell carcinomas from China. Int J Cancer1990;45:21–5.
      OpenUrlCrossRefPubMedWeb of Science
    64. ↵
      Goldsmith MF. Papillomavirus invades esophagus, incidence seems to be increasing. JAMA1984;251:2185–7.
      OpenUrlCrossRefPubMed
    65. ↵
      Mori M, Shimono R, Inoue T, et al. Papillomavirus and esophageal cancer in the Japanese and Chinese. Gastroenterology1989;84:1126–7.
      OpenUrl
    66. ↵
      Nakamura T, Ide H, EguchiI R, et al. Expression of p53 protein related to human papillomavirus and DNA ploidy in superficial esophageal carcinoma. Surg Today1995;25:591–7.
      OpenUrlCrossRefPubMedWeb of Science
    67. ↵
      Kuwano H, Sumiyoshi K, Sonoda K, et al. Pathogenesis of esophageal squamous cell carcinoma with lymphoid stroma. Hepatogastroenterology2001;48:458–61.
      OpenUrlPubMed
    68. ↵
      Kulski J, Demeter T, Sterret GF, et al. Human papillomavirus DNA in esophageal carcinoma. Lancet1986;ii:683–4.
      OpenUrl
    69. ↵
      Chang F, Shen Q, Zhou J, et al. Detection of human papillomavirus DNA in cytologic specimens derived from esophageal precancer lesions and cancer. Scand J Gastroenterol1990;25:383–8.
      OpenUrlPubMedWeb of Science
    70. ↵
      Kulski JK, Demeter T, Mutavdzic S, et al. Survey of histologic specimens of human cancer for human papillomavirus types 6/11/16/18 by filter in situ hybridization. Am J Clin Pathol1990;94:566–70.
      OpenUrlPubMedWeb of Science
    71. ↵
      Loke SL, Ma L, Wong M, et al. Human papillomavirus in oesophageal squamous cell carcinoma. J Clin Pathol1990;43:909–12.
      OpenUrlAbstract/FREE Full Text
    72. ↵
      Benamouzig R, Pigot F, Quiroga G, et al. Human papillomavirus infection in esophageal squamous cell carcinoma in Western countries. Int J Cancer1992;50:549–52.
      OpenUrlPubMedWeb of Science
    73. ↵
      Li Y, Huang G, Xiao H, et al. The status of human papillomavirus 16 DNA in the tissues of human esophagus carcinoma. Hua Hsi I Ko Ta Hsueh Hsueh Pao1991;22:157–60.
    74. ↵
      Chang F, Syrjänen S, Shen Q, et al. Human papillomavirus (HPV) involvement in esophageal precancer lesions and squamous cell carcinomas as evidenced by microscopy and different DNA techniques. Scand J Gastroenterol1992;27:553–63.
      OpenUrlPubMedWeb of Science
    75. ↵
      Lu S, Luo F, Li H. Detection of human papilloma virus in esophageal squamous cell carcinoma and adjacent tissue specimens in Linxian. Zhonghua Zhong Liu Za Zhi1995;17:321–4.
      OpenUrlPubMed
    76. ↵
      He D, Tsao SW, Bu H. Human papillomavirus infection and esophageal squamous cell carcinoma. Zhonghua Bing Li Xue Za Zhi1996;25:351–4.
      OpenUrlPubMed
    77. ↵
      Ashworth MT, McDicken IW, Southern SA, et al. Human papillomavirus in squamous cell carcinoma of the oesophagus associated with tylosis. J Clin Pathol1993;46:573–5.
      OpenUrlAbstract/FREE Full Text
    78. ↵
      Chang F, Syrjänen S, Shen Q, et al. Screening for human papillomavirus infections in esophageal squamous cell carcinomas by in situ hybridization. Cancer1993;72:2525–30.
      OpenUrlCrossRefPubMedWeb of Science
    79. ↵
      van Rensburg EJV, Venter EH, Simson IW. Human papillomavirus DNA in aerodigestive squamous carcinomas demonstrated by means of in situ hybridization. S Afr Med J1993;83:516–18.
      OpenUrlPubMedWeb of Science
    80. ↵
      Furihata M, Ohtsuki Y, Ogoshi S, et al. Prognostic significance of human papillomavirus genomes (type 16, 18) and aberrant expression of p53 protein in human esophageal cancer. Int J Cancer1993;54:226–30.
      OpenUrlPubMedWeb of Science
    81. ↵
      Ono H, Takahashi A, Ogoshi S, et al. Relationship between h-ras p21 product and p53 protein or high-risk human papillomaviruses in esophageal cancer from Kochi, Japan. Am J Gastroenterol1994;89:646–7.
      OpenUrlPubMedWeb of Science
    82. ↵
      Cooper K, Taylor L, Govind S. Human papillomavirus DNA in oesophageal carcinomas in South Africa. J Pathol1995;175:273–7.
      OpenUrlCrossRefPubMedWeb of Science
    83. ↵
      Chang F, Syrjanen S, Wang L, et al. p53 overexpression and human papillomavirus (HPV) infection in oesophageal squamous cell carcinomas derived from a high-incidence area in China. Anticancer Res1997;17:709–15
      OpenUrlPubMedWeb of Science
    84. ↵
      Takahashi A, Ogoshi S, Ono H, et al. High-risk human papillomavirus infection and overexpression of p53 protein in squamous cell carcinoma of the esophagus from Japan. Dis Esophagus1998;11:162–7.
      OpenUrlPubMed
    85. ↵
      Kiyabu MT, Shibata D, Arnheim N, et al. Detection of human papillomavirus in formalin-fixed, invasive squamous cell carcinoma using polymerase chain reaction. Am J Surg Pathol1989;13:221–4.
      OpenUrlPubMedWeb of Science
    86. ↵
      Williamson AL, Jaskiesicz K, Gunning A. The detection of human papillomavirus in oesophageal lesions. Anticancer Res1991;11:263–5.
      OpenUrlPubMedWeb of Science
    87. ↵
      Kim WH, Song SY, Kang JK, et al. Detection of human papillomavirus DNA from esophageal cancer tissue using polymerase chain reaction [abstract]. Gastroenterology1991;100:A1272.
      OpenUrl
    88. ↵
      Toh Y, Kuwano H, Tanaka S, et al. Detection of human papillomavirus DNA in esophageal carcinoma in Japan by polymerase chain reaction. Cancer1992;70:2234–8.
      OpenUrlCrossRefPubMedWeb of Science
    89. ↵
      Poljak M, Cerar A. Human papillomavirus type 16 DNA in oesophageal squamous cell carcinoma. Anticancer Res1993;13:2113–16.
      OpenUrlPubMedWeb of Science
    90. ↵
      Chen B, Yin H, Dhurandhar N. Detection of human papillomavirus DNA in esophageal squamous cell carcinomas by the polymerase chain reaction using general consensus primers. Hum Pathol1994;25:920–3.
      OpenUrlCrossRefPubMedWeb of Science
    91. ↵
      Lewensohn-Fuchs I, Munck-Wikland E, Berke Z, et al. Involvement of aberrant p53 expression and human papillomavirus in carcinoma of the head, neck and esophagus. Anticancer Res1994;14:1281–5.
      OpenUrlPubMedWeb of Science
    92. ↵
      Togawa K, Jaskiewicz K, Takahashi H, et al. Human papillomavirus DNA sequences in esophagus squamous cell carcinoma. Gastroenterology1994;107:128–36.
      OpenUrlPubMedWeb of Science
    93. ↵
      Cooper K. p53 mutations in human papillomavirus-associated oesophageal squamous cell carcinoma. Br J Cancer1995;72:1337.
      OpenUrlPubMedWeb of Science
    94. ↵
      Benamouzig R, Jullian E, Chang FJ, et al. Absence of human papillomavirus DNA detected by polymerase chain reaction in French patients with esophageal carcinoma. Gastroenterology1995;109:1876–81.
      OpenUrlCrossRefPubMedWeb of Science
    95. ↵
      Akutsu N, Shirasawa H, Nakano K, et al. Rare association of human papillomavirus DNA with esophageal cancer in Japan. J Infect Dis1995;171:425–8.
      OpenUrlAbstract/FREE Full Text
    96. ↵
      Sugimachi K, Sumiyoshi K, Nozoe T, et al. Carcinogenesis and histogenesis of esophageal carcinoma. Cancer1995;75:1440–5.
      OpenUrlCrossRefPubMedWeb of Science
    97. ↵
      Shibagaki I, Tanaka H, Shimada Y, et al. p53 mutation, murine double minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in esophageal squamous cell carcinoma. Clin Cancer Res1995;1:769–73.
      OpenUrlAbstract
    98. ↵
      Smits HL, Tjong-A-Hung SP, ter Schegget J, et al. Absence of human papillomavirus DNA from esophageal carcinoma as determined by multiple broad spectrum polymerase chain reactions. J Med Virol1995;46:213–15.
      OpenUrlPubMedWeb of Science
    99. ↵
      Fidalgo PO, Cravo ML, Chaves PP, et al. High prevalence of human papillomavirus in squamous cell carcinoma and matched normal esophageal mucosa: assessment by polymerase chain reaction. Cancer1995;76:1522–8.
      OpenUrlCrossRefPubMedWeb of Science
    100. ↵
      Suzuk L, Noffsinger AE, Hui YZ, et al. Detection of human papillomavirus in esophageal squamous cell carcinoma. Cancer1996;78:704–10.
      OpenUrlCrossRefPubMedWeb of Science
    101. ↵
      West AB, Soloway GN, Lizarraga G, et al. Type 73 human papillomavirus in esophageal squamous cell carcinoma: a novel association. Cancer1996;77:2440–4.
      OpenUrlCrossRefPubMedWeb of Science
    102. ↵
      He D, Zhang D-K, Lam K-Y, et al. Prevalence of HPV infection in esophageal squamous cell carcinoma in Chinese patients and its relationship to the p53 gene mutation. Int J Cancer1997;72:959–64.
      OpenUrlCrossRefPubMedWeb of Science
    103. ↵
      Kok TC, Nooter K, Tjong-A-Hung SP, et al. No evidence of known types of human papillomavirus in squamous cell cancer of the oesophagus in a low-risk area. Eur J Cancer1997;33:1865–8.
    104. ↵
      Lam KY, He D, Ma L, et al. Presence of human papillomavirus in esophageal squamous cell carcinomas in Hong Kong Chinese and its relationship with p53 gene mutation. Hum Pathol1997;28:657–63.
      OpenUrlCrossRefPubMedWeb of Science
    105. ↵
      Miller BA, Davidson M, Myerson D, et al. Human papillomavirus type 16 DNA in esophageal carcinomas from Alaska natives. Int J Cancer1997;71:218–22.
      OpenUrlCrossRefPubMedWeb of Science
    106. ↵
      Mizobuchi S, Sakamoto H, Tachimori Y, et al. Absence of human papillomavirus-16 and -18 DNA and Epstein-Barr virus DNA in esophageal squamous cell carcinoma. Jpn J Clin Oncol1997;27:1–5.
      OpenUrlAbstract/FREE Full Text
    107. ↵
      Morgan RJ, Perry ACF, Newcomb PV, et al. Human papillomavirus and oesophageal squamous cell carcinoma in the UK. Eur J Surg Oncol1997;23:513–17.
      OpenUrlCrossRefPubMedWeb of Science
    108. ↵
      Paz IB, Cook N, Odom-Maryon T, et al. Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer’s tonsillar ring. Cancer1997;79:595–604.
      OpenUrlCrossRefPubMedWeb of Science
    109. ↵
      Rugge M, Bovo D, Busatto G, et al. p53 alterations but no human papillomavirus infection in preinvasive and advanced squamous esophageal cancer in Italy. Cancer Epidemiol Biomarker Prev1997;6:171–6.
      OpenUrlAbstract
    110. ↵
      Turner JR, Shen LH, Crum CP, et al. Low prevalence of human papillomavirus infection in esophageal squamous cell carcinomas from North America: analysis by a highly sensitive and specific polymerase chain reaction-based approach. Hum Pathol1997;28:174–8.
      OpenUrlCrossRefPubMedWeb of Science
    111. ↵
      Saegusa M, Hashimura M, Takano Y, et al. Absence of human papillomavirus genomic sequences detected by the polymerase chain reaction in oesophageal and gastric carcinomas in Japan. Mol Pathol1997;50:101–4.
      OpenUrlAbstract/FREE Full Text
    112. ↵
      Khurshid A, Kazuya N, Hanae I, et al. Infection of human papillomavirus (HPV) and Epstein-Barr virus (EBV) and p53 expression in human esophageal carcinoma. J Pak Med Assoc1998;48:138–42.
      OpenUrlPubMed
    113. ↵
      de Villiers EM, Lavergne D, Chang F, et al. An interlaboratory study to determine the presence of human papillomavirus DNA in esophageal carcinoma from China. Int J Cancer1999;81:225–8.
      OpenUrlCrossRefPubMedWeb of Science
    114. ↵
      Kawaguchi H, Ohno S, Araki K, et al. p53 polymorphism in human papillomavirus-associated esophageal cancer. Cancer Res2000;60:2753–5.
      OpenUrlAbstract/FREE Full Text
    115. ↵
      Lambot MA, Haot J, Peny MO, et al. Evaluation of the role of human papillomavirus in oesophageal squamous cell carcinoma in Belgium. Acta Gastroenterol Belg2000;63:154–6.
      OpenUrlPubMed
    116. ↵
      Peixoto-Guimaraes D, Hsin Lu S, Snijders P, et al. Absence of association between HPV DNA, TP53 codon 72 polymorphism, and risk of oesophageal cancer in a high-risk area of China. Cancer Lett2001;162:231–5.
      OpenUrlCrossRefPubMedWeb of Science
    117. ↵
      Sobti RC, Kochar J, Singh K, et al. Telomerase activation and incidence of HPV in human gastrointestinal tumors in North Indian population. Mol Cell Biochem2001;217:51–6.
      OpenUrlCrossRefPubMedWeb of Science
    118. ↵
      Astori G, Merluzzi S, Arzese A, et al. Detection of human papillomavirus DNA and p53 gene mutations in esophageal cancer samples and adjacent normal mucosa. Digestion2001;64:9–14.
      OpenUrlCrossRefPubMedWeb of Science
    119. ↵
      Ushigome S, Spjut HJ, Noon GP. Extensive dysplasia and carcinoma in situ of esophageal epithelium. Cancer1967;20:1023–32.
      OpenUrlCrossRefPubMedWeb of Science
    120. ↵
      Nagamatsu M, Mori M, Kuwano H, et al. Serial histologic investigation of squamous epithelial dysplasia associated with carcinoma of the esophagus. Cancer1992;69:1094–8.
      OpenUrlPubMedWeb of Science
    121. ↵
      Roth MJ, Liu S-F, Dawsey SM, et al. Cytologic detection of esophageal squamous cell carcinoma and precursor lesions using balloon and sponge samplers in asymptomatic adults in Linxian, China. Cancer1997;80:2047–59.
      OpenUrlCrossRefPubMedWeb of Science
    122. ↵
      Li T, Lu ZM, Chen KN, et al. Human papillomavirus type 16 is an important infectious factor in the high incidence of esophageal cancer in Anyang area of China. Carcinogenesis2001;22:929–34.
      OpenUrlAbstract/FREE Full Text
    123. Jacob JH, Riviere A, Mandard AM, et al. Prevalence survey of precancerous lesions of the oesophagus in a high-risk population for oesophageal cancer in France. Eur J Cancer Prev1993;2:53–9.
      OpenUrlPubMed
    124. ↵
      Cintorino M, Tripodi SA, Santopietro R, et al. Cytokeratin expression in oesophageal squamous cell carcinoma: a study of 354 cases from the high-incidence area of Linxian, China. Anticancer Res2001;21:4195–201.
      OpenUrlPubMedWeb of Science
    125. ↵
      Trottier AM, Coutlee F, Leduc R, et al. Human immunodeficiency virus infection is a major risk factor for detection of human papillomavirus DNA in esophageal brushings. Clin Infect Dis1997;24:565–9.
      OpenUrlAbstract/FREE Full Text
    126. ↵
      Birgisson S, Galinski MS, Goldblum JR, et al. Achalasia is not associated with measles or known herpes and human papilloma viruses. Dig Dis Sci1997;42:300–6.
      OpenUrlCrossRefPubMedWeb of Science
    127. ↵
      Pillai MR, Nair MK. Development of a condemned mucosa syndrome and pathogenesis of human papillomavirus-associated upper aerodigestive tract and uterine cervical tumors. Exp Mol Pathol2000;69:233–41.
      OpenUrlCrossRefPubMedWeb of Science
    128. ↵
      Dillner J, Knekt P, Schiller JT, et al. Prospective seroepidemiological evidence that human papillomavirus type 16 infection is a risk factor for oesophageal squamous cell carcinoma. BMJ1996;311:1346.
      OpenUrlFREE Full Text
    129. ↵
      Han C, Qiao G, Hubbert NL, et al. Serologic association between human papillomavirus type 16 infection and esophageal cancer in Shaanxi Province, China. J Natl Cancer Inst1996;88:1467–71.
      OpenUrlAbstract/FREE Full Text
    130. ↵
      Björge T, Hakulinen T, Engeland A, et al. A prospective, seroepidemiological study of the role of human papillomavirus in esophageal cancer in Norway. Cancer Res1997;57:3989–92.
      OpenUrlAbstract/FREE Full Text
    131. ↵
      Lagergren J, Wang Z, Bergström R, et al. Human papillomavirus infection and esophageal cancer: a nationwide seroepidemiologic case-control study in Sweden. J Natl Cancer Inst1999;91:156–62.
      OpenUrlAbstract/FREE Full Text
    132. ↵
      Chang F, Syrjänen S, Tervahauta A, et al. Frequent mutations of p53 gene in oesophageal squamous cell carcinomas with and without human papillomavirus (HPV) involvement suggest the dominant role of environmental carcinogens in oesophageal carcinogenesis. Br J Cancer1994;70:346–51.
      OpenUrlPubMedWeb of Science
    133. ↵
      Chang F, Syrjänen S, Syrjänen K. Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol1995;13:1009–22.
      OpenUrlAbstract
    134. ↵
      Reiss M, Brash DE, Munoz-Antonia T, et al. Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines. Oncol Res1992;4:349–57.
      OpenUrlPubMedWeb of Science
    135. ↵
      Gao H, Wang L-D, Zhou Q, et al. p53 tumor suppressor gene mutation is early esophageal precancerous lesions and carcinoma among high-risk populations in Henan, China. Cancer Res1994;54:4242–6.
      OpenUrl
    136. ↵
      Poljak M, Cerar A, Orlowska J. p53 protein expression in esophageal squamous cell papillomas: a study of 36 lesions. Scand J Gastroenterol1996;31:10–13.
      OpenUrlPubMedWeb of Science
    137. Galloway DA, Daling JR. Is the evidence implicating human papillomavirus type 16 in esophageal cancer hard to swallow? J Natl Cancer Inst1996;88:1421–3.
    138. Montesano R, Hollstein M, Hainaut P. Molecular etiopathogenesis of esophageal cancers. Ann Ist Super Sanita1996;32:73–84.
      OpenUrlPubMed
    139. Montesano R, Hollstein M, Hainaut P. Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review. Int J Cancer1996;69:225–35.
      OpenUrlCrossRefPubMedWeb of Science
    140. ↵
      Shen ZY, Xu LY, Chen XH, et al. The genetic events of HPV-immortalized esophageal epithelium cells. Int J Mol Med2001;8:537–42.
      OpenUrlPubMed
    141. ↵
      Togawa K, Rustgi AK. Human papillomavirus-16 and -18 replication in esophagus squamous cancer cell lines does not require heterologous E1 and E2 proteins. J Med Virol1995;45:435–8.
      OpenUrlPubMedWeb of Science
    142. ↵
      Shen Z, Cen S, Shen J, et al. Study of immortalization and malignant transformation of human embryonic esophageal epithelial cells induced by HPV18 E6E7. J Cancer Res Clin Oncol2000;126:589–94.
      OpenUrlCrossRefPubMedWeb of Science
    143. ↵
      Sashiyama H, Shino Y, Kawamata Y, et al. Immortalization of human esophageal keratinocytes by E6 and E7 of human papillomavirus type 16. Int J Oncol2001;19:97–103.
      OpenUrlPubMedWeb of Science
    144. ↵
      Ribeiro U, Posner MC, Safatle-Ribeiro AV, et al. Risk factors for squamous cell carcinoma of the oesophagus. Br J Surg1996;83:1174–85.
    145. ↵
      Benamouzig R, Jullian E. Role of human papillomavirus in oesophageal carcinogenesis. Ann Pathol1994;14:307–10.
      OpenUrlPubMedWeb of Science
    146. ↵
      Meltzer SJ. The molecular biology of esophageal carcinoma. Recent Results Cancer Res1996;142:1–8.
      OpenUrlPubMed
    147. ↵
      Chang F, Syrjänen S, Kurvinen K, et al. The p53 tumor-suppressor gene as a common cellular target in human carcinogenesis. Am J Gastroenterol1993;88:174–86.
      OpenUrlPubMedWeb of Science