Our results showed a significant relationship between PPK and ESCC. The relationship is particularly high for ESCC cases with family history of esophageal cancer. As presented in Table , the proportion of PPK is higher in the ESCC group (70.7%) compared with the control group (28.1%) with OR = 6.2 (95%CI = 2.9–13.3). The proportion of PPK is strikingly high in cases with positive family history (92.3%).
The association of PPK with ESCC was firstly reported by Clarke and McConnel in one family in 1954 [16
]. Then, this association was confirmed by Howel-Evans et al [10
]. In their study of two related Liverpool families, esophageal carcinoma occurred in 18 of 48 tylotic family members, but only in one of 87 non-tylotic members. Later, Ellis et al. reviewed these two related families and portrayed a single family containing 345 individuals, 92 were diagnosed as having focal PPK of which 32 died, 21 of esophageal cancer [17
]. In this pedigree, there was no oesophageal cancer in family members who were unaffected by PPK. It was calculated that a PPK sufferer in this pedigree had a 92% probability of dying from oesophageal cancer by age of 70 [17
]. Subsequently, a large midwestern American pedigree containing 125 affected individuals with an identical pattern of PPK was described, in which the skin disorder was associated with oesophageal and other cancer [11
]. In American pedigree, there were 19 reported malignancies in members with PPK, eight of which were esophageal or oral squamous cell carcinomas. The life time risk of developing oesophageal cancer for an affected member of this family was calculated to be 40% by age 70. Maillefer and Greydanus reported that late-onset PPK lesions (Type A) have a significant association with ESCC, while early onset PPK lesions (Type B) have no such association [18
We suggest that, the underlying reason of the significant association between ESCC and PPK in our study is a hereditary predisposition which causes both PPK lesions and ESCC. While there is evidence that late onset PPK might be a paraneoplastic finding for some other types of cancer [19
], our observations do not confirm such explanation for the association between PPK and ESCC. In these studies [19
], PPK lesions were found to be paraneoplastic findings because these lesions were regressed and disappeared if the cancer was treated and response was achieved. In our study, we observed some cases that, there was no change regarding the PPK lesions after esophageal cancer symptoms regressed and disappeared following surgery and primary curative chemoradiotherapy. Although we do not have reliable data on the onset of PPK lesions in most ESCC patients, a few of them exactly remembered that PPK lesions occurred 15–20 years before ESCC symptoms. Maillefer and Greydanus reported that the onset of type A tylosis occur between the ages of 5–15 years, while the onset of esophageal cancer occur no less than the age of 29 years. Therefore, we suggest that PPK lesions do not develop as a result of ESCC development; rather, ESCC and PPK develop on the same hereditary background.
PPK may also be caused by environmental reasons and lifestyle [22
]. Although we did not matched the two groups for the occupation, we controlled the effects of age, gender and living place (urban / rural). Eighty-eight percent of both groups consisted of men living in rural areas and women in rural and urban areas. Another survey conducted in Van region showed that almost all women (98%) in Van were housewives [23
]; thus, we may suggest that women in the case and control groups have similar lifestyles. Almost all men who live in rural areas work in farming and breeding; so, they have also very similar lifestyles both in the case and control groups. Thus, we assume that there is no considerable lifestyle difference between cases and controls.
The proportion of PPK among the ESCC cases without family history (62.5%) was also significantly higher than that of controls (28.1%); and the odds ratio was 4.3 (95%CI = 1.9–9.8). In other words, presence of PPK can make up risk for ESCC in future even if family history of ESCC is not present. To explain this result, we need to look at the genetic background of PPK and ESCC. The suspected gene for PPK and ESCC couldn't be isolated exactly until now. However, the locus for focal PPK in association with ESCC has been mapped on chromosome 17q25. This gene region frequently undergoes to deletion in hereditary as well as in sporadic ESCC cases [24
]. The loss of heterozygosity on 17q25 was detected in 71% and 69% of sporadic ESCC cases. Therefore, it was proven that this chromosomal region is also commonly affected in sporadic ESCC cases. The reason why we observed PPK also in ESCC cases without family history may depend on the affected same gene locus.
Even though the lowest proportion of PPK in our study was in the control group, it is still a considerably high proportion (28.1%) compared to some other studies. In their review on PPK, Maillefer and Greydanus described PPK as a rare syndrome [18
]. The prevalence of PPK in a region of Sweden, where PPK is frequently observed, has been reported to be 0.3–0.55% by two studies [26
]. We may consider the high proportion of PPK in our control group as a sign of high PPK prevalence in Van region. One reason of this high prevalence may be work styles that involve a lot of standing/walking which is highly prevalent in both the rural and urban areas in Van region. Another reason may be the genetic characteristics of the people. We noted above that all of our ESCC cases and controls were people whose places of birth were Van region. Due to a series of social and economical reasons, people living in this region frequently migrate to other regions of Turkey; but there is almost no migration from other regions of Turkey to Van region. Traditionally, most of the marriages in the local communities happen between relatives, and a part of these marriages happen between cousins. Consequently, the region has a homogeneous genetic population to a degree and therefore, hereditary syndromes can be frequently observed in the local community as in hereditary PPK cases. These characteristics, perhaps, made Van region a suitable place to observe such association between ESCC and PPK.
The study contains some limitations that should be noted. Firstly, sizes of the case and control groups are not large. This could lead to a type II error if there was not a big difference between the proportions in the case and control groups. In our study, the small group sizes did not lead to insignificant results, but this caused some large confidence intervals as seen in table . Secondly, our data on the association between PPK and ESCC is based on a matched case control design; rather than longitudinal. This limits the extent to which conclusions about causality can be drawn. Thirdly, we did not investigate the genetic inheritance of the PPK in relatives of ESCC patients and controls; thus, we are not able to discuss the existence of a dominant inheritance pattern for PPK. This point should be a focus of future research.