The prevalence of ESPs is generally estimated at less than 0.1% [6
], except for three Italian studies (prevalence: 0.12%, 0.45% and 0.35%) [15
]. In our study, the prevalence of ESPs was 0.20%, and the endoscopic analysis from four different hospitals in Japan showed similar prevalence of ESPs (0.15 to 0.3%, average 0.23%; unpublished data). These figures are higher than those previously reported from Europe (Table ). The majority of the patients in our study was middle-aged (average 59.2 years), similar to the age of the populations in previously published studies. On the other hand, most of reports from western countries indicated male predominance and high prevalence in the lower third esophagus [5
], whereas, the male/female ratio was 1/1.57 and more than half of the ESPs (52.6%) occurred in the middle esophagus in our study. Mosca et al.
also reported the geographic difference of ESPs from a comparative analysis between Italy and other western countries based on the literature [15
]. Mosca et al.
and our results suggest that there might be considerable differences in the geographic distribution of ESPs due to environmental agents functioning as etiological factors.
Summary of published studies including more than five esophageal squamous papilloma cases
Chronic esophageal inflammation secondary to GERDs including RE and hiatal hernia has been suggested as an etiological factor of ESPs [7
]. The prevalence of Japanese patients with RE has recently been increasing (about 15%), but severe RE is still not common in Japan [10
]. The patients with chronic gastritis, which has a quite higher prevalence in Japan than in western countries, showed reduced gastric acid secretion [1
]. We consider the low prevalence of ESPs in the lower esophagus to be one of the characteristic features of Japanese ESP patients and to be due to low prevalence of severe RE, which is caused by chronic gastritis with reduced gastric acid secretion. In support of this consideration, the prevalence of severe RE was also low in Italy [14
], and all three studies which showed findings similar to those of our study, that is, a high prevalence of ESPs, female dominant sex distribution and high prevalence in the middle esophagus, were from Italy (Table ) [15
Although no pathological studies of the proliferative activity of ESPs have been reported, the proliferative activity of ESPs was found to be higher than that of the non-neoplastic squamous epithelium (less than 10%) [11
]. The finding that the majority of MIB-1 positive nuclei were located in the basal and parabasal epithelial cells in the tumors suggests that the ESPs continued to preserve the proliferative orientation of non-neoplastic squamous epithelium. Moreover, the tumor MIB-1 index was significantly associated with inflammation and affected patients’ proportion of RE. These results indicate that inflammation due to GERDs has an important influence on tumor cell proliferation and may act as an etiological factor of ESPs. As for severely inflamed ESPs located in the upper to middle esophagus, other environmental irritation factors such as smoking, alcohol consumption and GERD-related chronic ear-nose-throat disorders, may play a role in tumorigenesis.
To what extent HPV infection contributes as an etiological factor of ESPs is still controversial. While the prevalence of HPV-positive ESPs was 10.5% in our study, differences in detection methods have resulted in variations in published results ranging from 0% to 64% (Table ) [4
]. The PCR method which we used in this study is more sensitive than in situ
hybridization and immunohistochemical methods. Moreover, the PCR assay using consensus primers for a portion of the E6–7 open reading frame is more reliable than the ones using the E1 and L1 region primers, because it is less likely to produce false-negative results [9
]. Although HPV genotypes 6 and 11 are major subtypes in ESPs [4
], only one study with a sufficient number of cases and a few case reports have reported the detection of cancer-associated HPV subtypes [16
]. Koilocytosis, which is a histological finding indicating virus infection, was also found in cases in which the PCR method could not detect HPV infection. This seems to indicate that either koilocytosis in some cases is not related to virus infection [12
], or that we still cannot exclude the infection of other HPV subtypes [12
]. The latter point is supported by the fact that so far the full genomic sequences of 85 HPV genotypes have been identified, and that more than 120 putative novel types have been partially characterized [32
All the HPV-positive cases were female and their tumor was located in the middle esophagus, and none of the female patients with HPV-positive ESPs were associated with dysplasia or squamous cell carcinoma of the genital tract. The mean age of the HPV-positive cases was younger than that of HPV-negative cases. The past literature also reported similar results in that the middle esophagus was the most common location of the tumor of HPV-positive ESP cases, and that such patients were relatively younger than HPV-negative ESP cases [16
]. Our results and the literature might indicate that the middle esophagus represents a favorable environment for HPV infection.
In conclusion, we investigated three aspects of 38 ESPs in 35 Japanese patients, clinical, histopathological and virological. From the geographic point of view, there is no English report studying Japanese ESP patients with comparison of findings from western countries. We posit that the characteristics of ESPs in Japanese patients are relatively high prevalence (0.20%), female dominance and high frequency of location in the middle esophagus. We attribute the dominant middle esophagus distribution (the equivalent of low prevalence in the lower esophagus) to high prevalence of chronic gastritis in Japan, which brings in low prevalence of severe RE. Also similar with previous studies, HPV-positive ESPs cases showed female predominance, relatively young age and high prevalence of location in the middle esophagus. The high prevalence of ESPs seems to indicate that other etiological factors than RE may contribute more to ESP tumorigenesis in Japan. This is the first report in English of a study of Japanese ESP patients based on a sufficient number of cases to provide meaningful results.