Early and late gastric cancer arising in the remnant stomach after distal gastrectomy

AIM: Following distal gastrectomy, carcinogenesis has been suggested to result from gastroduodenal reflux. In this study, surgical cases of gastric cancer arising after distal gastrectomy were analyzed clinico-pathologically and the possible link to reflux examined. PATIENTS: Thirty-two patients (24 males, 8 females; mean age, 68.7 years; age range, 33-84 years) with gastric cancer arising in the remnant stomach after gastrectomy (also known as gastric stump cancer) were included in this study. Patients were divided into two groups on the basis of the initial diagnosis (benign or malignant) prompting surgery, and distal gastrectomy reconstruction method (Billroth I or II). RESULTS: The interval between distal gastrectomy and detection of cancer in the remnant stomach of patients treated initially for a benign gastric condition vs. malignancy was 360+/-33.04 and 63+/-19.16 months (median+/-SE), respectively (p<0.0001). However, the benign and malignant groups did not differ significantly in the clinicopathological analysis of their stump cancers. All 10 patients in whom gastric cancer was diagnosed within five years of initial surgery had initially been surgically treated for malignancy. The interval between surgery and detection of gastric cancer in the Billroth I and Billroth II groups was 84+/-26.67 and 276+/-44.26 months (median+/-SE), respectively (p<0.01). In the remnant stomach, cancer tended to occur near the site of gastrojejunostomy in the Billroth II group (p=0.05). Helicobacter pylori infection was only detected histologically in four patients who had undergone Billroth I reconstructions after distal gastrectomy for malignancy. CONCLUSION: After distal gastrectomy, careful periodic endoscopic examination for microcarcinoma is required in patients, particularly in those who undergo surgery for malignancy, to maximize detection of gastric cancer.     

Microsatellite instability in patients with gastric remnant cancer

Background. About 2% of patients who undergo partial distal gastrectomy for gastroduodenal diseases develop gastric remnant cancer 10 to 30 years after the gastrectomy. It is important in clinical practice to determine a molecular marker to identify patients susceptible to gastric remnant cancer. Methods. We investigated nine gastric remnant cancers (from nine individuals who had gastrectomies for primary gastric cancer or gastroduodenal ulcer) for microsatellite instability (MSI) at six loci, using the polymerase chain reaction (PCR). A control group of ten patients with sporadic gastric cancers in the upper third of the stomach was also similarly analyzed. Results. MSI was demonstrated in eight of nine cancers from the individuals who had had primary gastric cancer or gastroduodenal ulcer (88.9%) compared with two of ten cancers from the individuals with sporadic gastric cancer in the upper third of the stomach (20%). Conclusion. These results suggest that one or more MSI is associated with remnant gastric cancer after gastrectomy. Received on Sept. 6, 1999; accepted on Dec. 20, 1999     

Incidence of metachronous gastric cancer in the remnant stomach after synchronous multiple cancer surgery

Background

In the preoperative evaluation for gastric cancer, high-resolution endoscopic technologies allow us to detect small accessory lesions. However, it is not known if the gastric remnant after partial gastrectomy for synchronous multiple gastric cancers has a greater risk for metachronous cancer. The purpose of this study was to determine the incidence of metachronous cancer in this patient subset compared with that after solitary cancer surgery.

Methods

Data on a consecutive series of 1,281 patients gastrectomized for early gastric cancer from 1991 to 2007 were analyzed retrospectively. The 715 gastric remnants after distal gastrectomy were periodically surveyed by endoscopic examination in Shikoku Cancer Center. Among those surveyed cases, 642 patients were pathologically diagnosed with solitary lesion (SO group) and 73 patients with synchronous multiple lesions (MU group) at the time of the initial surgery.

Results

In the follow-up period, 15 patients in the SO group and 3 patients in the MU group were diagnosed as having metachronous cancer in the gastric remnant. The cumulative 4-year incidence rate was 1.9 % in the SO group and 5.5 % in the MU group. The difference did not reach the significant level by the log-rank test.

Conclusions

The incidence of metachronous cancer is higher after multiple cancer surgery; however, the difference is not statistically significant.     

Gastric stump cancer after distal gastrectomy for benign gastric ulcer in a population-based study

The risk of cancer in the gastric remnant after distal gastrectomy for benign ulcer disease has been assessed mainly in studies of small sample size, selected series and limited follow-up time. This was a population-based cohort study of patients who had undergone distal gastrectomy for benign ulcer disease in 1964-2008 in Sweden. Data for follow-up for cancer and censoring for death were obtained from nationwide registries of Cancer and Population, respectively. The number of observed cancer cases in the gastrectomy cohort was divided by the expected number, calculated from the cancer incidence of the Swedish population of corresponding age, sex and calendar year. Relative risks were presented as standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). The distal gastrectomy cohort included 18,912 patients and 323,676 person-years at risk. The observed total number of gastric stump cancers (n = 140) was not higher than expected (SIR 0.84, 95% CI 0.71-0.99). There was no increased SIR with latency periods shorter than 30 years; increase was seen only among patients who had undergone gastric resection over 30 years earlier (SIR 2.29, 95% CI 1.38-3.57). Sex, age, ulcer location and type of surgical reconstruction were not associated with any considerable differences in SIR. In conclusion, this large population-based study revealed an increased risk of cancer in the gastric remnant only 30 years or longer after gastric resection for benign disease, whereas other factors did not influence this risk.     

Surgically treated Cronkhite-Canada syndrome associated with gastric cancer

Cronkhite-Canada syndrome is generally accepted to be a benign disorder, with 374 reported cases to the present. Worldwide, there have been 18 previously reported cases of Cronkhite-Canada syndrome associated with gastric cancer. In this report we describe a case of a 52-year-old man with the clinical features of Cronkhite-Canada syndrome combined with gastric cancer. Although the gastric tumor was located at the antrum of the stomach, we performed a total gastrectomy because of the edematous swelling and high risk of malignancy in the remnant stomach. As Cronkhite-Canada syndrome may be a premalignant condition for gastric cancer, as well as for colorectal cancer, we suggest periodic examination of the stomach, colon, and rectum for patients with Cronkhite-Canada syndrome. Received: July 24, 2000 / Accepted: September 18, 2000     

The endoscopic evaluation of gastritis,gastric remnant residue,and the incidence of secondary cancer after pylorus-preserving and transverse gastrectomies

Background Pylorus-preserving gastrectomy (PPG) and transverse gastrectomy (TrG) have been accepted as function-preserving procedures for node-negative early gastric cancer. It is believed that a better quality of life is guaranteed after PPG or TrG compared to that after distal subtotal gastrectomy (DSG) with Billroth type-I reconstruction. However, objective evaluations of the gastric remnant following gastrectomy have not been widely reported, and the real advantages and disadvantages of PPG or TrG over DSG remain unclear. Moreover, the risk of secondary cancer after PPG or TrG is uncertain.Methods Between 1991 and 2000, 834 DSGs were carried out in our institute for preoperatively diagnosed patients with early gastric cancer. The degree of residual gastritis and the amount of diet residue in the gastric remnant were evaluated by annual gastrointestinal endoscopic investigations prospectively for 72 patients after PPG, 95 patients after TrG, and 60 patients after DSG. These analyses were performed using the RGB classification (residue, gastritis, bile). The incidence of disease greater than or equal to grade 2 was calculated, and the time trends of the incidence for each procedure were also studied for 3 years after gastrectomy. In addition, secondary cancer cases in the gastric remnant mucosa were checked for each procedure during this period, and the incidence of secondary cancer after each operation was calculated.Results The incidence of gastritis, of grade 2 or more, found in the gastric remnant was significantly lower after PPG (1.4%) and TrG (2.1%) than after DSG (43.3%). However, the incidence of moderate or greater residue in the gastric remnant, grade 2 or more, was significantly higher after PPG (45.8%) and TrG (40.0%) than after DSG (11.7%). The analysis of time trends of gastritis and diet residue reflected the significant advantage or disadvantage for each procedure 1 year after surgery. The analysis also included these factors without consideration of elapsed time following surgery. Two patients after PPG (2.8%) and three patients after TrG (3.2%) developed secondary cancer in the gastric remnant. No DSG-treated patient showed new cancer genesis in the remaining stomach.Conclusion PPG and TrG have the advantage over DSG in preventing postoperative gastritis in the gastric remnant. On the other hand, moderate or greater diet residue in the gastric remnant is more common after PPG or TrG than after DSG. For the risk of carcinogenesis in the remnant gastric mucosa, we could not conclude that there was any apparent difference between these range-limited gastrectomies and conventional DSG. Further study is necessary to determine the significant advantages and disadvantages of using PPG or TrG.     

Relationship of p53 and Helicobacter pylori to clinicopathological features of human remnant stomach cancer after gastric surgery for primary gastric cancer.

The purpose of this study was to evaluate the biological features of gastric cancer of the remnant stomach (RSC). Twenty-one patients underwent resection of the remnant stomach for RSC and were divided into two groups: the RSCB group consisted of 11 patients who underwent distal gastrectomy for benign disease and the RSCM group consisted of 10 patients who underwent gastrectomy for primary gastric cancer. The interval between primary surgery and the appearance of gastric cancer in the remnant stomach was significantly shorter in the RSCM group than in the RSCB group. Invasion of adjacent organs was more frequent in the RSCM group than in the RSCB group and the Ki-67 labeling index of the tumors was significantly higher in the former group. Furthermore, p53 overexpression by tumors was almost twice as common in the RSCM group as in the RSCB group. Although there was no significant difference of the H. pylori positivity between the two groups, the rate for both groups was higher than reported in previous studies. Mutation of p53 may play an important role in the high proliferative activity of tumors in the RSCM group and H. pylori infection may be closely related to carcinogenesis in patients with RSC.     

Occurrence of non-gastric cancer in the digestive tract after remote partial gastrectomy: analysis of an Amsterdam cohort

If peptic ulcer surgery favors the formation of carcinogenic N-nitroso compounds in the gastric remnant, an increased risk of cancer at sites in the gastrointestinal tract distant from the stomach might be predicted. To estimate the risk of carcinomas in the digestive tract, other than the stomach, occurring after partial gastrectomy, we analyzed an Amsterdam cohort of 2,633 post-gastrectomy patients operated on for benign disease between 1931 and 1960. Mortality in the study population was compared with the general Dutch population through person-year analysis. An excess mortality of biliary tract cancer (O/E:2.64; CL:1.32-4.72; p less than 0.01) and pancreatic cancer (O/E:1.65; CL:1.06-2.44; p less than 0.05) was found in males more than 5 years after surgery; females showed only an increased risk of pancreatic cancer in the first 5 years postoperatively (O/E:15.33; CL:1.85-55.43; p less than 0.01), probably due to misdiagnosis. All other non-gastric sites of the digestive tract carried no increased risk for cancer. In males, mortality due to colorectal cancer more than 5 years post-operatively was significantly decreased (O/E:0.58; CL 0.34-0.92; p less than 0.01). The excess mortality of biliary-tract and pancreatic cancer in males, which increases with the duration of post-operative interval, is consistent with a dose-response phenomenon. This study therefore supports the hypothesis that carcinogens are not only locally activated in the gastric remnant, but are hepatically excreted and initiate cancer in the biliary tree and pancreatic duct. Further exploration of this mechanism of carcinogenesis is warranted, since it may also explain the pathogenesis of pancreatic and biliary cancers in patients without gastrectomy.     

Efficacy of Helicobacter pylori eradication on the chronic mucosal inflammation of the remnant stomach after distal gastrectomy for early gastric cancer

Although eradication of Helicobacter pylori (Hp) after early gastric carcinoma has been recommended, very limited studies have been reported and the method differs from standard therapy. Here, we attempted the eradication of Hp in the remnant stomach after surgery for primary gastric cancer with the standardized method. We examined efficacy and the safeness of the treatment. Thirty-three H. pylori-positive patients after distal gastrectomy were treated with proton pump inhibitor (PPI)-based triple therapies. After eradication, endoscopic and histological changes were classified on the basis of the Updated Sydney System. The eradication rate in the remnant stomach was 90.9% (30 out of 33 cases) after triple therapy. Temporal minor side effects were notified in 3 cases. After eradication, the remnant stomach showed significant decreases in inflammation- and activity-scores. Moreover, significant improvement in glandular atrophy to normal mucosa was found. In conclusion, PPI-based standard therapy is just as effective for Hp eradication in the remnant stomach than it is in the non-operative stomach. Eradication therapy could be performed safely and resulted in a significant improvement in inflammation and atrophy of the mucosal layer in the remnant stomach after early gastric cancer surgery.     

Clinicopathological Characteristics of Synchronous Multiple Gastric Cancers in Chinese： An Analysis of 44 Cases

Objective: To investigate the clinicopathologic characteristics of the primary synchronous multiple gastric cancers (SMGC) in Chinese.Methods: Clinicopathologic data of patients with histologically confirmed gastric cancer who received surgical operations in our department between 1993 and 2002 were retrospectively collected and analyzed. Clinicopathologic characteristics including gender, age, tumor location, differentiation and staging between patients with SMGC and those with solitary gastric cancer (SGC) were compared. Synchronous multiple and solitary gastric cancers were diagnosed and classified based on radiography upper endoscopy and histology. All the cases were followed up after the operation and 5-year survival rate between the two groups was compared.Results: A total of 871 patients with gastric cancer were included. Synchronous multiple gastric cancers were found in 44 (5.1%) of these cases. More of the diagnose in the early stage to SMGC than to SGC. SMGC were more likely to be located at the lower third stomach and of a low grade differentiation, compared to SGC. However, there were no significant differences in the rates of lymph node metastasis and lymphatic vessel invasion between multiple and solitary gastric cancers. In addition, the 5-year survival rate did not difference between the two groups.Conclusion: The whole stomach should be detected carefully to avoid missing out the multiple gastric cancers. Concerning the treatment of multiple gastric cancer, the sufficient extent of the stomach wall resection was necessary, and the extent of lymphadenectomy was supposed to follow the operation for the solitary gastric cancer according to the staging of the cancer lesions.     

Multiple duodenal carcinomas associated with multiple gastric cancers

Because of the rarity of primary duodenal cancer, the coexistence of this disease with gastric cancer is very rare. The case presented herein suffered from two carcinomas of the duodenum and six gastric cancers. The patient was 71-year-old man who underwent subtotal gastrectomy and pancreatoduodenectomy. Pathologic studies showed that all of the gastric and one of the duodenal cancers were limited to the mucosal layer and that the other duodenal tumor invaded to the pancreas. Several cases of double cancers in the duodenum and the stomach have been reported in Japan, and this is first of multiple carcinomas of the duodenum associated with multiple gastric cancers.     

Promoting effect of partial gastrectomy on carcinogenesis in the remnant stomach of rats after oral administration of N-methyl-N'-nitro-N-nitrosoguanidine

The promoting effect of partial gastrectomy in the development of cancer in the remnant stomach was examined in rats after oral administration of N-methyl-N'-nitro-N-nitrosoguanidine, using various surgical approaches. The incidence with which cancer developed in the remnant stomach following gastrectomy was lower than the incidence of gastric cancer in the entire glandular stomach. The incidence of cancer in the remnant stomach following Billroth II procedure according to Mayo's method, was higher than the incidence of cancer with other reconstructive methods as well as the corresponding area in the nonresected groups. There was a correlation between the incidence of cancer and the total bile acid concentration in the remnant stomach.     

Early carcinoma of the gastric remnant: pathological features relating to the interval between the initial and second surgery

Twenty cases of early carcinoma of the gastric remnant have been treated at our hospital and examined clinico-pathologically. In 11 cases, the interval after the initial gastrectomy, due to the gastric carcinoma, was done was short compared with length of the interval of 9 cases after a gastrectomy for a benign gastric disease. There were two types of gastric remnant carcinomas in cases in which the interval extended 10 years. The first type developed at the site of the gastro-intestinal anastomosis, especially when the anastomosis was found to be joined by the Billroth II method, and the carcinoma was associated with a gastritis cystica polyposa (GCP). The other type showed a polypoid appearance except for the stomal site.     

Does remnant gastric cancer really differ from primary gastric cancer? A systematic review of the literature by the Task Force of Japanese Gastric Cancer Association

Remnant gastric cancer, most frequently defined as cancer detected in the remnant stomach after distal gastrectomy for benign disease and those cases after surgery of gastric cancer at least 5 years after the primary surgery, is often reported as a tumor with poor prognosis. The Task Force of Japanese Gastric Cancer Association for Research Promotion evaluated the clinical impact of remnant gastric cancer by systematically reviewing publications focusing on molecular carcinogenesis, lymph node status, patient survival, and surgical complications. A systematic literature search was performed using PubMed/MEDLINE with the keywords “remnant,” “stomach,” and “cancer,” revealing 1154 relevant reports published up to the end of December 2014. The mean interval between the initial surgery and the diagnosis of remnant gastric cancer ranged from 10 to 30 years. The incidence of lymph node metastases at the splenic hilum for remnant gastric cancer is not significantly higher than that for primary proximal gastric cancer. Lymph node involvement in the jejunal mesentery is a phenomenon peculiar to remnant gastric cancer after Billroth II reconstruction. Prognosis and postoperative morbidity and mortality rates seem to be comparable to those for primary proximal gastric cancer. The crude 5-year mortality for remnant gastric cancer was 1.08 times higher than that for primary proximal gastric cancer, but this difference was not statistically significant. In conclusion, although no prospective cohort study has yet evaluated the clinical significance of remnant gastric cancer, our literature review suggests that remnant gastric cancer does not adversely affect patient prognosis and postoperative course.     

Diffuse submucosal cysts of the stomach associated with gastric cancer: contribution of Helicobacter pylori infections

Diffuse submucosal cysts (DSCs) in the stomach are often associated with gastric cancer and a high occurrence of multiple gastric cancers. We studied the clinicopathological features of four early gastric cancer patients with DSCs in the submucosal layer of the stomach. All patients had early gastric cancers with gastritis and erosion in the gastric mucosa, and were positive for Helicobacter pylori (H. pylori). Based on a review of the reported cases, we found that a very high proportion (>94%) of DSCs are associated with infection by H. pylori. Although DSCs have previously been considered to be paracancerous lesions of gastric cancer, we speculate that DSCs might be post-inflammatory changes following infection by H. pylori, which may result in the high incidence of gastric cancer development.     

同时性多发性胃癌的诊疗进展

同时性多发性胃癌是指胃内不同部位同时出现2个及以上的独立肿瘤，是一种较为少见的胃癌类型，约占胃癌总发病率的6%~14%。目前，多发性胃癌分为单克隆起源及多克隆起源多发性胃癌，部分肿瘤存在遗传易感性和错配修复基因突变。多发性胃癌多见于老年男性，好发于近端胃，早期胃癌多见，与单发性胃癌相比，其脉管癌栓、分化及淋巴结转移情况等临床病理特征方面均无显著性差异。根据分期及发病位置不同，多发性胃癌患者可行内镜下局部切除、部分胃切除和全胃切除等治疗方法。对于存在遗传易感性的多发性胃癌患者，是否需行扩大性胃切除术则需进一步探讨。      

Treatment of Multiple Early Gastric Cancer

To investigate the treatment of multiple early gastric cancer,82 cases were compared with 829 single early gastric cancers.Univariate analyses with respect to eight clinicopathologicalfactors-age, sex, family history of gastric cancer, macroscopicappearance, histologic type, depth of tumor invasion, tumorlocation, and lymph node metastasis-were performed. Age, malesex, elevated and differentiated-type tumors, frequent occurrencein the lower third, and mucosal cancers were correlated significantlywith multiple early gastric cancer. However, there was no significantdifference in the frequency of node involvement. Multiple earlygastric cancer, limited to the mucosal layer, was not associatedwith node involvement. Therefore, endoscopic mucosal resectionmay be feasible for the treatment of multiple early gastriccancer when there is no evidence of submucosal invasion in anyof the lesions and none exceed 2.0 cm in diameter. Upon examinationof the long-term results for patients with multiple early gastriccancer, two (3.0%, 2/66) had died of recurrence due to hematogenousspread, and one (1.9%, 1/52) had developed cancer of the remnantstomach. Other primary malignancies were observed in 12 patients(18.2%, 12/66). In particular, lung cancer was the major neoplasmoccurring after gastrectomy. These results suggest the importanceof systemic surveillance for the detection of other malignanciesas well as cancer of the remnant stomach and recurrence aftergastrectomy for multiple early gastric cancer.     

Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway

Cancer found in the post-operative remnant stomach includes both newly developed cancer after surgery for benign-disease (PRC) and metachronous multiple cancer (MRC). Differences in the carcinogenic pathway between PRC and MRC have been suspected from clinical studies. However, no study has demonstrated the difference in molecular alteration between these diseases. P16 is inactivated predominantly by epigenetic change, rather than genetic alteration. We analyzed the methylation status and protein expression of the p16 gene in cancers of the remnant stomach. Eleven lesions of PRC, 24 lesions of MRC and corresponding non-cancerous tissue, as well as 13 primary gastric cancer (PC) lesions were examined. DNA was extracted by the micro-dissection method from paraffin-embedded surgical specimens. The methylation status of the promoter CpG island of the p16 gene was examined by using a methylation-specific polymerase chain reaction technique. To detect protein expression, immunohistochemical staining was employed. p16 promoter hypermethylation was observed more often in remnant gastric cancer than in PC. A significantly more frequent hypermethylation in the p16 gene was found in PRC (64%) than in MRC (21%) or PC (23%). Moreover, a significant correlation was found between p16 promoter hypermethylation and diminishment of protein expression in cancers of the remnant stomach. Silencing of the p16 gene by methylation of its promoter CpG island was suggested as a unique molecular mechanism in the carcinogenesis of PRC compared with MRC or PC.     

Simple pathological examination technique for detection of cancer located at the surgical margin of the stomach

Background

The technique for examining surgical resection margins described in the Japanese Classification of Gastric Carcinoma is based on the examination of continuous infiltration by the primary tumor, and discontinuous lesions such as multiple cancers are not examined. However, examining lesions—particularly cancers—at the resection margins is important for the prevention of cancers in the remaining stomach that result from cancer remnants (remnant gastric cancer).

Methods

The clinical usefulness of a simple pathological examination technique for detecting cancer located at the surgical margin of the stomach was studied. A specimen 5–8 mm wide was resected from the surgical cut margin along the entire circumference of the stomach. When the pathological margin was positive for cancer, the surgical margin was also examined, and cases that were positive for cancer were regarded as marginally positive.

Results

Of the 1,498 patients with early gastric cancer who were examined using this method, 17 (1.1 %) were marginally positive for multiple cancers, and 8 of these 17 patients (57 %) had microcancers <5 mm in diameter.

Conclusion

This method is simple and useful for detecting cancer involving the surgical margin, which occurs at a rate of 1.1 %, making it possible to prevent remnant gastric cancer by reoperation.