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Histogenesis of cardiac carcinomas compared to distal gastric carcinomas.

 

  

Dr. A. Driessen

Department of Pathology - University Hospital Maastricht - The Netherlands

Messina
15 giugno 2001

 

Epidemiological data:

 Gastric cancer is one of the most common malignancies in the world: it is the second cause of cancer mortality worldwide [1]. Epidemiological studies however have shown that the incidence rates of gastric cancer are declining in U.S.A. and Western-Europe [2, 3]. This evolution is predominantly due to a decreasing incidence of antral cancer, although some studies have shown that diffuse tumours of the corpus have also been declined in frequency [4]. Synchronous with the decline of distal gastric cancer, the incidence rates of cardiac cancer  have dramatically increased in U.S.A., up to 4 – 5 % annually [5, 6]. However the increasing trend for cardiac adenocarcinomas varied in function of the age: below 65 years the prevalence of this type of carcinoma increased with 20 %, whereas above the age of 65 years the increase was 60 % [7]. In parallel with the increase of cardiac adenocarcinomas, the incidence of oesophageal adenocarcinomas is rising at an alarming rate as a result of which the incidence of oesophageal adenocarcinoma is higher than the incidence of oesophageal squamous carcinoma in the U.S.A. [7]. In contrast to distal gastric cancer, where there is no gender predominance, cancers of the cardia predominantly affect white males; a feature which also is observed in oesophageal adenocarcinomas  [7,8]. Compared to distal gastric cancer, cardiac cancer has an even worse prognosis. This bad prognosis is related to the advanced stage of disease at the time of presentation: T1 lesions are significantly less commonly diagnosed in the cardia than in distal gastric cancer [9]. Moreover a higher incidence of regional lymph nodes and hepatic metastases is found in association with this type of cancer [10]. The different evolution in incidence rate as well the differences in clinical features suggest that distal gastric cancer and cardiac cancer are two distinct entities.

Distal gastric cancer – Histogenesis:
According to the classification of Lauren, gastric adenocarcinomas are classified in intestinal type and diffuse type of adenocarcinomas, based on the glandular architecture and the cell adhesion between tumour cells. Besides their different morphology, both types of gastric cancer have different epidemiological characteristics [11]. The classification of Mulligan recognizes a third type of carcinoma, namely the pylorocardiac gland cell type [12]. This type, which arises at the cardia or the antrum,  is characterized by its papillary growth pattern and clear cell appearance.  Around 20 % of the antral and cardiac adenocarcinomas belong to this type of cancer.

According to Correa gastric carcinogenesis is a multistage model, in which the development of the intestinal type of gastric cancer begins with the induction of a chronic inflammation. This inflammatory process, which is strongly related to a Helicobacter pylori infection, leads to the development of atrophy and intestinal metaplasia. Due to the chronic inflammation damage will occur to the genome of cell, resulting in dysplasia and finally in to an invasive neoplastic process or carcinoma. This sequence is not only determined by the presence of Helicobacter pylori, but is also dependent on the characteristics of the host and other environmental factors [13]. Until the discovery of Helicobacter pylori in 1983 by Marshall et al., the role of these environmental factors have been considered to be very important [14]. Multivariate analysis, performed in the study of Hansson et al., has shown that low fruit intake, smoking, high alcohol and coffee consumption increase the risk for gastric cancer (OR 1.7-10.5) [15]. Antioxidants, such as vitamin C, reduces the risk for gastric cancer by approximately one half [16]. 

Nowadays there is no doubt that the risk for gastric cancer is influenced primarily by the presence of Helicobacter pylori. Hence the World Health Organization’s International Agency for Research on Cancer has classified this micro-organism as a group I or definite carcinogen (IARC) [17]. In a meta-analysis performed on the pooled data of the three most important prospective studies, Helicobacter pylori infection gives an almost nine-fold increased risk of cancer [18]. This risk is dependent on the age of acquisition of a Helicobacter pylori infection as in young adults the relative risk is nine times higher than in elderly people [19].  Besides the age, microbial virulence factors as well as the host response to the organism will determine the outcome of the colonization. Type 1 strains, which are cagA- and vacA-positive strains, are more virulent strains, inducing a more pronounced inflammatory response and an increased risk for distal gastric cancer, in particular intestinal type of cancer [20-22].

The risk for gastric cancer is also dependent on the topography of the chronic inflammation. Populations with a predominant antral gastritis have a lower risk than those with a pangastritis [23]. The explanation for this phenomenon is the atrophy of the corpus, induced by the chronic Helicobacter pylori related inflammation, resulting in a hypochlorydia or achlorydia. Due to the high pH the stomach will be colonized by other bacteria, producing carcinogenic products, namely N-nitroso compounds. The carcinogenic effect of these products has been confirmed in animal models [24]. Several cohort studies have shown that the annual incidence of atrophic gastritis is 1 up to 3 % [25, 26].  In parallel with the development of atrophy, the gastric foveolar epithelium will be replaced by another well-differentiated intestinal-type epithelium. This phenomenon, named intestinal metaplasia, may however occur independently of the process of atrophy. The annual incidence of intestinal metaplasia in association with an atrophic gastritis is around 7 % per year [26]. Atrophy as well as intestinal metaplasia are both precancerous lesions, associated with an increased risk for an intestinal type of distal gastric cancer. Whereas according to Sipponen et al. the gastric cancer risk increases up to 18-fold in the presence of atrophic gastritis, the odds-ratio for gastric cancer is 3.8 in the presence of type III intestinal metaplasia in a population from Slovenia  [27, 28].  Other studies however could not confirm that this subtype of intestinal metaplasia, also named type IIb or colonic-type of intestinal metaplasia, is associated with an increased risk for gastric cancer. In these studies the presence of type III intestinal metaplasia was related to the age of the patients, as it was more prevalent in elderly patients [29].

This well-established sequence of events holds through for the intestinal type of cancer only. The histogenesis of diffuse type carcinoma is less well understood. According to the hypothesis of Sipponen et al. this type of cancer originates from a non-atrophic chronic gastritis [30]. Other studies propose that a normal mucosa or dysplastic non-metaplastic structures or hyperplastic foveolar structures are the origin of this tumour [31-33].

Proximal gastric cancer – Histogenesis :

 In contrast to the numerous data, concerning the etiopathogenesis of distal gastric cancer, the histogenesis of cardiac adenocarcinomas is less clear. The development of cardiac carcinoma is presumably also a stepwise organized process, in which environmental factors are involved [34]. These environmental factors are similar to those in case of distal gastric cancer, be it that the relationship between smoking and the risk for cardiac cancer is stronger [35-37]. Similar to the development of distal gastric cancer, the histogenesis of cardiac cancer begins with a chronic inflammation of the cardia, which gives rise to the presence of intestinal metaplasia. Conflicting data however have been published concerning the etiopathogenesis of carditis. Several studies identified a relationship between carditis and gastroesophageal reflux. In these studies carditis is considered to be a better histological marker for gastroesophageal reflux disease than reflux oesophagitis [38, 39]. In contrast other studies considered carditis as an extension of a Helicobacter pylori related pangastritis to the most proximal part of the stomach [40, 41]. The prevalence of Helicobacter pylori in carditis varies between 10.9 % and 95 % [39, 41]. Although Genta et al. showed that the prevalence of Helicobacter pylori in the cardia is similar to the antrum, the meta-analysis of Huang et al. could not confirm that the presence of these micro-organisms increases the risk for cardiac cancer [19, 42].  Moreover the study of Chown et al. has shown that colonization with the more virulent strains, namely CagA+ strains, is associated with a reduced risk for cardiac cancer [43]. In the study of Voutilainen et al. however carditis was related to Helicobacter pylori as well as gastroesophageal reflux, be it that the association with Helicobacter pylori was more obvious [44].

In our multicenter study, performed on a study-population of oesophageal (n = 133, mean age 63 yrs, M/F-ratio = 6), cardiac (n = 109, mean age = 64 yrs, M/F-ratio = 3.95) and distal gastric cancer (n = 100, mean age 68 yrs, M/F-ratio = 1.4), we have observed a significant difference in chronic gastritis in corpus biopsies. Whereas the prevalence of chronic inflammation in oesophageal adenocarcinomas is 36 %, a significant higher prevalence of chronic gastritis is observed in association with cardiac adenocarcinomas (56 %) (p < 0.01), be it that this is still significantly lower than in case of distal gastric cancer (88 %) (p < 10-6). In our study the presence of chronic gastritis is Helicobacter pylori-related with a prevalence of respectively 23 %, 33 % and 73 % in oesophageal, cardiac and distal gastric cancer [45, 46].

Intestinal metaplasia, which prevalence at the normal squamocolumnar junction varies between 9 and 31 %, is related to Helicobacter pylori or gastroesophageal reflux [41, 43, 47, 48]. Several studies have indicated that Barrett’s oesophagus, which is due to gastroesophageal reflux, may be the precursor of cardiac adenocarcinomas. In these studies the prevalence of Barrett’s oesophagus, which is mostly a short segment Barrett,  is around 42% [46, 47]. This observation however could not be confirmed in other studies [51, 52].

In literature conflicting data have been published concerning the histogenesis of cardiac carcinomas, which may either be related to a Helicobacter pylori infection or gastroesophageal reflux. Epidemiological as well as histological data suggest that cardiac adenocarcinomas may be related to either distal gastric cancer or oesophageal cancer. The lack of clarity in the current data may possibly be due to the different definitions of cardiac adenocarcinomas, applied in the literature [53-55].  Molecular data, concerning the histogenesis of cardiac carcinomas, are limited and do not solve this problem. 

Microsatellite instability, which results from the inactivation of mismatch repair genes and occurs in around 30 % of the gastric cancer, is more prevalent in cardiac adenocarcinomas according to the study of Lin et al. [56]. This observation however could not be confirmed in the study of Keller et al. [57]. Flow cytometric analysis has shown that cardiac adenocarcinomas appear to have the highest DNA aneuploidy rate of nearly 100 %, compared to distal gastric tumours [58]. During the inflammatory response polymorphonuclears produce free oxygen radicals, which may damage the DNA of cell. As a result the function of tumour suppressor genes or proto-oncogenes may become disturbed. The p53 gene, situated on the short arm of chromosome 17, is a tumour suppressor gene, which encodes a protein, playing a essential role cell cycle regulation and tumour suppression [59]. The prevalence of p53 gene mutations, which is mostly situated in the exons 5 to 8, varies in function of the gastric cancer subsite and the phenotype. p53 mutations are more frequent in cardiac cancers (54 %) than distal gastric cancers (25 %), and are more frequently associated with intestinal type gastric cancer [60]. Whereas the study of Strickler et al. shows a comparable number of p53 mutations in cardiac as well as distal gastric cancer, other studies showed that these mutations are as common as in oesophageal carcinomas [61-63]. Comparative genomic hybridisation has shown that chromosome 5q (DCC), 17 p (p53) and 18q (APC) loci are important in the carcinogenesis of  oesophageal, cardiac as well as distal gastric cancer. However molecular analysis does not show consistent differences in function of the localisation of the tumour. Comparative genomic hybridisation of oesophageal and cardiac adenocarcinomas reveals identical genetic patterns in these two groups with few exceptions [64, 65]. Similar genetic abnormalities may be found in distal cancer, be it that the prevalence of these can vary [66].   

Conclusions:

 Based on the current, sometimes contradictory, scientific data it is not possible to classify cardiac carcinomas definitively as being either of oesophageal or gastric origin. As already mentioned, these conflicting results in the studies are possibly due to the different definitions of the cardiac adenocarcinomas applied [53-55]. Therefore a clear definition of a cardiac adenocarcinoma has to be defined in order that the population of cardiac tumours will be more homogenous. Recently a commentary on ‘an uniform use of the TNM-classification’ is published, in which advices are given concerning the classification of gastroesophageal tumours as being of oesophageal or gastric origin [67]. 

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A cura di: Unità di Chirurgia Endoscopica - Ospedale Piemonte - Messina

© 2001