Gastroenterostoma after Billroth antrectomy as a premalignant condition

Abstract

Gastric stump carcinoma (GSC) following remote gastric surgery is widely recognized as a separate entity within the group of various types of gastric cancer. Gastrectomy is a well established risk factor for the development of GSC at a long time after the initial surgery. Both exo- as well as endogenous factors appear to be involved in the etiopathogenesis of GSC, such as achlorhydria, hypergastrinemia and biliary reflux, Epstein-Barr virus and Helicobacter pylori infection, atrophic gastritis, and also some polymorphisms in interleukin-1β and maybe cyclo-oxygenase-2. This review summarizes the literature of GSC, with special reference to reliable early diagnostics. In particular, dysplasia can be considered as a dependable morphological marker. Therefore, close endoscopic surveillance with multiple biopsies of the gastroenterostomy is recommended. Screening starting at 15 years after the initial ulcer surgery can detect tumors at a curable stage. This approach can be of special interest in Eastern European countries, where surgery for benign gastroduodenal ulcers has remained a practice for a much longer time than in Western Europe, and therefore GSC is found with higher frequency.

Key Words: Gastric stump cancer, Gastrectomy, Risk factors, Endoscopic surveillance

INTRODUCTION

The first partial gastrectomy with gastroduodenostomy was performed by Billroth in 1881 and was followed by the first gastrojejunostomy 3 years later. Both procedures became known as Billroth I and II, respectively[1]. Although the famous Viennese surgeon Theodor Billroth is credited for the first gastric resection, known as the Billroth I procedure, the less well-known Ludwik Rydygier from Poland, performed and described the procedure several months earlier[2]. Particularly in Europe, the Billroth II resection became the most popular treatment for peptic ulcer disease until the mid 1970s[3]. Since then, a significant decrease of peptic ulcer surgery was seen due to the introduction of H2-receptor antagonists[4], and later the proton pump inhibitors[5]. In the early 1980s, the discovery of Helicobacter pylori (H. pylori)[6] as the main cause of peptic ulcer disease further diminished the role of surgery in the treatment of this disease[7-12]. Surgical treatment for uncomplicated peptic ulcer disease became rare, but operations for complications of peptic ulcer disease such as perforation, bleeding or gastric outlet obstruction are still regularly performed. The rise of the use of nonsteroidal anti-inflammatory drugs explains part of this occurrence[13-16]. In Eastern Europe, the prevalence of surgery for benign gastroduodenal ulcers remained higher for a longer time than in Western Europe. In Poland for example, several thousand complicated as well as chronic peptic ulcer patients were still operated upon[17-20], and there, the introduction of of antisecretory drugs occurred in the late 1980s[21]. Nevertheless, complications of peptic ulcer surgery will presumably become less important there as a public health problem[22].

HISTOPATHOLOGY

Billroth antrectomy and its various modifications remove the part where the ulcer is located and that contains the gastrin-producing antral mucosa responsible for the stimulation of acid production through the oxyntic mucosa. It also induces biliary reflux, felt to be beneficial for healing due to its alkaline contents. The majority of patients with peptic ulcer disease will have an antrum-predominant H. pylori gastritis[23,24], The biliary reflux creates a microenvironment that is not suitable for H. pylori and it will eradicate the microorganisms from the anastomosis after surgery. The microscopy of the anastomosis will therefore change from the chronic active H. pylori gastritis picture into that of the typical reflux gastritis. The most important features of reflux gastritis are foveolar hyperplasia, congestion, paucity of inflammatory infiltrate, reactive epithelial change and smooth muscle fiber proliferation. These changes are already apparent shortly after surgery; less so when a Roux-en-Y conversion is carried out to avoid reflux[25,26]. The picture is therefore directly related to the reflux of bile, as is the eradication of H. pylori from the anastomosis.

In the long run, other microscopic features are encountered in the operated stomach[27]. Loss of parietal cells with the subsequent disappearance of the chief cells introduces an accelerated mucosal atrophy that is caused by the lack of the trophic hormone gastrin and the vagotomy that is mostly done simultaneously. The specialized glandular mucosa is replaced by intestinal metaplasia and pseudopyloric metaplasia[28-31]. Atrophy of the gastric mucosa may lead to vitamin B12 deficiency. At the site of the anastomosis, the glands often become cystically dilated, and sometimes these cystically dilated glands herniate through the muscularis mucosae. This provides a nodular aspect to the anastomosis and gives rise to a microscopic picture known as gastritis polyposis cystica or gastritis cystica profunda[32-34]. Erosions may occur as a result of compromised vasculature due to the surgery, but in the case of persistent ulceration after surgery, Zollinger-Ellison-like syndrome or a retained antrum needs consideration and these conditions are accompanied by high gastrin levels. The retained antrum is caused by resection that is too limited and G-cell hyperplasia in the stretch of antral mucosa left behind[35,36].

Xanthelasmas, also known as gastric xanthomas or gastric lipid islands, are aggregates of foamy macrophages filled with lipids that can be seen in the stomach and more often after partial gastrectomy[37,38]. At endoscopy, they appear as grossly visible whitish nodules or plaques, well circumscribed, with a size varying from 1 to 10 mm in diameter[39,40]. They typically occur along the lesser curve[41], the so-called “magenstrasse” where generally reflux is most severe. It is felt that these aggregates phagocytose remnants of cellular debris after degradation due to chemical injury, and they are harmless. Their importance lies in the fact that these should not be confused with signet ring cell carcinoma, because the microscopy of xanthelasma can resemble signet ring cells. Special stains for mucin or immunohistochemistry for cytokeratins versus histiocytic macrophages makes this differentiation easy[42,43]. Xanthelasmas occur more frequently in stomachs harboring other pathological changes such as chronic gastritis, atrophic gastritis and intestinal metaplasia[39,44]. The significance of these lesions remains unknown.

PREMALIGNANT CONDITION

The stump of the stomach after remote gastric resection because of benign ulcer disease is a well-defined premalignant condition. Many studies in the past have confirmed that, after remote partial gastrectomy, there is an increased risk for stomach cancer[3,45-49]. GSC is defined as a malignancy of the stomach occurring > 5 years after initial partial gastrectomy, to confusion with cancer recurrence after initial misdiagnosis. The risk for stump cancer is remarkable because most of these patients suffer from peptic ulcer disease prior to surgery. The relation between peptic ulcer disease and gastric cancer is not fully understood. Gastric cancer and peptic ulcer disease are inversely associated and they are accompanied by distinct patterns of acid secretion[50]; by contrast, gastric ulcers, non-peptic gastric ulcers, and gastric cancer partly share pathophysiological features[51-53]. The part of the stomach that is at the highest risk for gastric cancer is removed by surgery. Nevertheless, with an increasing postoperative interval, there is a steadily increasing risk for stomach cancer in the gastric remnant. After more than 15-20 years postoperatively, the risk is higher than can be expected for an age- and sex-matched general population, and it rapidly increases thereafter[45,48,54]. In line with the increased risk for stomach cancer, the post-gastrectomy stomach also harbors dysplasia relatively frequently[29,55,56]. The dysplasia is typically encountered around the gastric anastomosis, and similarly the cancers are almost exclusively found there. Both the dysplasia and the cancers can be multifocal and extensive mapping of the mucosa with endoscopic biopsies is warranted. Unlike primary gastric cancer, which is frequently resectable (resectability rate in Poland: 66%), gastric stump carcinoma once detected because of symptoms is virtually unresectable in the majority of patients In view of the increased risk, surveillance of post-gastrectomy patients has been advocated and it can indeed detect cancer at an early and operable stage[57]. Whether or not large-scale screening would be indicated is however questionable. In a screening program carried out in Amsterdam among > 500 patients > 15 years postoperatively, 10 cancers were found; six of which turned out to be early cancers[56]. Mortality of stomach cancer among these screened individuals was, however, only marginally different from that among the patients who did not participate in the screening program, after an observation period of 10 years. Moreover, a similar difference in mortality was observed in lung cancer, suggestive of selection bias among the screened patients[58].

ETIOLOGY

It is thought that after partial gastrectomy, an environment is created that is favorable for the development of cancer. Patients enter an accelerated neoplastic process due to the altered microenvironment. The stump carcinomas evolve as the end result of a series of mutagenic cell transformations, leading to stepwise tumor progression from atrophic gastritis with metaplasia via dysplasia to invasive carcinoma. During tumor progression an increased proliferation and expansion of the proliferative compartment towards the luminal surface is observed. This is accompanied by an increasing concomitant chance of mutations, because the proliferating cells are particularly vulnerable to mutation. Biliary reflux, achlorhydria, atrophic gastritis and formation of N-nitroso compounds are considered factors that contribute to carcinogenesis in the gastric stump[3,59,60]. It has been shown that the changes in the quantity of the nitrate-reducing bacteria and in the N-nitrosamine concentration depend on the type of surgical intervention performed. The highest content of nitrate-reducing bacteria and the N-nitrosamine concentration were found in the gastric juice of patients after Billroth II antrectomy, and the lowest values after highly selective vagotomy[61].

Epstein-Barr virus (EBV) positivity by RNA in situ hybridization is seen more often in carcinomas in the gastric remnant than in the intact stomach[62]. In contrast, H. pylori is less frequently observed[63]. Interestingly, there is an inverse relationship between positivity for EBV and positive immunohistochemistry for TP53; also loss of heterozygosity of 17p at the locus of TP53 is less frequently observed in EBV-positive stump carcinomas[64]. It has been reported that the EBV-encoded EBNA-5 protein can form a complex with TP53 and retinoblastoma proteins, and it is conceivable that this may lead to accelerated degradation of either one of these proteins[65].

Endogenous factors may also play a role. The interleukin (IL)-1β 31T>C polymorphism is associated with higher gastric cancer risk. This allele confers hypoacidity to the oxyntic mucosa of the H. pylori-infected intact stomach and it thereby induces a corpus-predominant inflammatory gastritis[66,67]. The IL-1β-31T>C polymorphism is also associated with GSC (Table 1 and Figure 1)[68]. Apparently, the relatively few peptic ulcer disease patients carrying this genotype are at particularly high risk for the development of stomach cancer, after operation. Surgery has a similar effect as pharmacologically induced acid suppression; a fact that is known to lead from an antrum- to a corpus-predominant inflammatory picture in the gastric mucosa.

Table 1 IL-1β-31T>C genotype in gastric stump cancer and in conventional gastric cancer n (%).

Genotype of IL-1β-31T>C1	Gastric stumpcancer	Conventional gastriccancer
CC	8/30 (27)	21/96 (22)
TC	19/30 (63)	36/96 (37)
TT	3/30 (10)	39/96 (41)
Presence of C allele	90	59

¹All percentages rounded to the nearest digit. IL: Interleukin.

Figure 1 An example of the sequence analysis of the T/T, C/T and C/C interleukin-1β-polymorphism.

Cyclo-oxygenase (COX)-2 expression is increased in gastric stump cancer and the 765 G allele of COX-2 is associated with higher gastric cancer risk (Table 2 and Figure 2)[69]. There is however no direct relationship between expression of COX-2 and the -765 C>G polymorphism in gastric stump cancer. This finding contrasts with observations in the duodenum of familial adenomatous polyposis patients, in whom this polymorphism is associated with increased COX-2 expression in the normal mucosa[70].

Table 2 Prevalence of -765G>C COX-2 genotype n (%).

COX-2 -765 genotype1	Gastric stump cancer	Conventional gastric cancer	Early-onset gastric cancer	Controls
GG	23/30 (77)	73/96 (76)	80/115 (70)	59 (59)
GC	5/30 (17)	19/96 (20)	33/115 (29)	32 (32)
CC	2/30 (7)	4/96 (4)	2/115 (2)	9 (9)
Presence of C allele	23	24	30	41

¹All percentages rounded to the nearest digit.

Figure 2 An example of cyclo-oxygenase-2 immunohistochemistry. A: Cyclo-oxygenase (COX)-2 low staining; B: COX-2 high staining.

CONCLUSION

Partial gastrectomy for benign peptic ulcer disease is a well-established premalignant condition. With increasing postoperative interval since the initial surgery, the risk steadily increases and after more than 15-20 years postoperatively, gastric cancer risk is higher than that of age and sex-matched controls with intact stomachs. The surgery itself and the resulting biliary reflux seem responsible for the risk. Endogenous factors such as polymorphisms in IL-1β and COX-2 may contribute. EBV infection is more prevalent than in the intact stomach, and H. pylori infection less frequent. EBV may interact with the TP53 gene. Stump cancer is preceded by well-defined preinvasive precursor lesions, most notably dysplasia. Dysplasia can be considered a dependable morphological marker, amenable for early detection by endoscopic surveillance.