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We herein report the case of a 76-year-old female patient who had undergone gastrectomy for advanced gastric cancer (histologically tubular adenocarcinoma)before 5 months, presenting with abdominal skin tumor. A skin biopsy revealed tubular adenocarcinoma. Positron emission tomography-computed tomographic scanning detected right breast tumor. A partial mastectomy of the right breast and local resection of abdominal skin tumor were performed and both tumors depicted similar histology of tubular adenocarcinoma in routine pathological examination. Immunohistochemically, positive for CDX2 and MUC5AC in previously resected gastric cancer and skin tumor tissues, whereas negative for both antigens in breast cancer. Thus, the final pathological diagnosis demonstrated skin metastasis originating from gastric cancer and primary breast cancer(invasive ductal carcinoma)histologically mimicking gastric cancer. We emphasize difficulties in diagnosis of this situation and that immunohistochemistry is helpful to distinguish primary breast cancer from gastric cancer metastasizing to the breast.

Gastric neoplasia of the fundic gland (chief cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/β-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/β-catenin signal-associated gene methylation in GNCCP, we performed β-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear β-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear β-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear β-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background/aims: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG., Methods: We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs)., Results: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS., Conclusion: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG., (© 2017 S. Karger AG, Basel.)

Background: Gastric adenocarcinoma with enteroblastic differentiation (GAED) has been recognized as a variant of alpha-fetoprotein (AFP)-producing gastric carcinoma, although its clinicopathologic and immunohistochemical features have not been fully elucidated., Methods: To elucidate the clinicopathologic and immunohistochemical features of GAED, we analyzed 29 cases of GAED, including ten early and 19 advanced lesions, and compared these cases with 100 cases of conventional gastric adenocarcinoma (CGA). Immunohistochemistry for AFP, glypican 3, SALL4, and p53 was performed, and the phenotypic expression of the tumors was evaluated by immunostaining with antibodies against MUC5AC, MUC6, MUC2, CD10, and caudal-type homeobox 2 (CDX2)., Results: Lymphatic and venous invasion was more frequent in GAED (76 and 72 %) than in CGA (41 and 31 %; P ≤ 0.001). Lymph node metastasis was more frequently observed in GAED (69 %) than in CGA (38 %; P = 0.005), as were synchronous or metachronous liver metastases (GAED, 31 %; CGA, 6 %; P ≤ 0.001). Immunohistochemically, all GAED were positive for at least one of three enteroblastic linage markers (AFP, glypican 3, and SALL4). Glypican 3 was the most sensitive marker (83 %) for GAED, followed by SALL4 (72 %) and AFP (45 %), whereas no CGA was positive. Furthermore, the rate of positive p53 staining was 59 % in GAED. Regarding the mucin phenotype, CD10 and CDX2 were diffusely or focally expressed in all GAED cases. Invasive areas with hepatoid or enteroblastic differentiation were negative for CD10 and CDX2., Conclusions: Clinicopathologic features of GAED differ from those of CGA. GAED shows aggressive biological behavior, and is characteristically immunoreactive to AFP, glypican 3, or SALL4.

Frequent activation of the Wnt/β-catenin signaling pathway has recently been demonstrated in gastric adenocarcinoma/neoplasia of chief cell predominant type (GA-CCP/GN-CCP) with submucosal involvement. In this study, we examined the activation status of the Wnt/β-catenin signaling pathway in GN-CCP without submucosal involvement, which is referred to as gastric dysplasia-CCP (GD-CCP). We also examined β-catenin expression and the mutation spectrum of PPP2R1A and Wnt pathway genes in 11 cases of GD-CCP, 25 cases of gastric polyps of fundic gland type (GPs-FG), and 21 cases of GPs-FG with dysplasia (GP-FGD). β-catenin nuclear staining was observed in 3 cases of GD-CCP, none of GPs-FG, and 6 cases of GPs-FGD. Mutations in Wnt pathway genes, including PPP2R1A, were observed in 4 cases of GDs-CCP, 10 cases of GPs-FG, and 7 cases of GPs-FGD. Two of these seven GPs-FGD cases showed β-catenin nuclear staining. However, none of the 4 GD-CCP cases with mutations or the 10 GPs-FG cases with mutations showed β-catenin nuclear staining. PPP2R1A mutations were observed in 1 GD-CCP case and 1 GPs-FGD case. Although the mutation spectra of the Wnt pathway genes in GD-CCP and GP-FG differed, based on the absence of β-catenin nuclear staining despite the genetic alterations, GD-CCP is more similar to GP-FG than to GN-CCP, which shows β-catenin nuclear staining and submucosal involvement. Activation of the Wnt/β-catenin signaling by the β-catenin nuclear transition may be required during progression from GD-CCP to GN-CCP. Furthermore, this is the first report describing PPP2R1A mutations in gastric fundic gland-associated neoplasms.

Gastric adenocarcinoma of the fundic gland type (GAFG) is a rare variant of gastric tumor. We have recently reported the frequent accumulation of β-catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in CTNNB1/AXINs/APC, leading to the constitutive activation of the Wnt/β-catenin pathway. However, the mechanisms of Wnt signaling activation in the remaining cases are unknown. Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt/β-catenin pathway or the ERK1/2 MAPK pathway. Therefore, we analyzed the mutations in GNAS (exons 8 and 9) and in KRAS (exon 2) in 26 GAFGs. Immunohistochemistry revealed nuclear β-catenin expression in 22 of 26 GAFGs, and 10 (38.5%) of 26 cases harbored at least 1 mutation in CTNNB1/AXINs/APC. Activating mutations in GNAS were found in 5 (19.2%) of 26 GAFGs, all of which harbored R201C mutations. Activating mutations in KRAS were found in 2 (7.7%) of 26 GAFGs, and both of these also contained GNAS activating mutations. Four of 5 cases with GNAS mutation showed nuclear β-catenin expression, and presence of GNAS mutation was associated with β-catenin nuclear expression (P = .01). Furthermore, 3 of these 4 cases did not harbor mutations in CTNNB1, APC, or AXINs, suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively. These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt/β-catenin signaling pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gastric neoplasia of chief cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar cells mimicking chief cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in addition to nuclear β-catenin immunolabeling and direct sequencing of members of the Wnt/β-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear β-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear β-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/β-catenin pathway., (© 2013.)

Gastrointestinal stromal tumors feature a wide spectrum of biologic behavior, ranging from benign to extremely malignant. To determine the role of p16(INK4a) alteration in progression of gastrointestinal stromal tumors of the stomach, we have investigated protein expression and gene methylation in correlation with clinicopathologic factors and survival. In addition to immunohistochemical analysis of p16(INK4a) in a series of 95 cases, real-time quantitative methylation specific polymerase chain reaction for p16(INK4a) and immunostaining for cyclin D1, cyclin E, pRb, DP-1, E2F-1, and Ki-67 were also evaluated in randomly selected samples. The p16(INK4a) labeling indices ranged from 0% to 74% (median, 21%), demonstrating a significant inverse correlation with size (P = .046). On univariate (P = .003) and multivariate (P = .067) analyses, loss of p16(INK4a) expression increased the likelihood of a poor tumor-related survival. In addition, size (P = .036) and the mitotic index (P = .005) had independent prognostic influence. The p16(INK4a) methylation index, which ranged from 0% to 100% (median, 17%), was significantly higher in larger tumors (P < .001) and in high-risk category lesions (P = .001) and inversely correlated with protein expression. Hierarchical cluster analysis based on expression of p16(INK4a) network members identified 2 clusters in 27 randomly selected tumor samples, containing 11 and 16 tumors each. Former cluster samples demonstrated higher risk category (P = .022), higher p16(INK4a) methylation (P < .001), and more reduced pRb expression (P < .018). In addition, p16(INK4a) network members clustered into 2 groups: (1) showing down-regulated p16(INK4a) protein and up-regulating of both cyclin D1 and DP-1 and (2) down-regulated pRb and up-regulated E2F-1. We conclude that p16(INK4a) alteration has an important role in progression of gastrointestinal stromal tumors of the stomach. Furthermore, the study provides a possible link between regulation of p16(INK4a) network members and gastrointestinal stromal tumors., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Objectives: The p16(INK4a) (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas., Methods: Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases., Results: Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P = 0.009). Cyclin D1 (P = 0.042) and CDK4 (P = 0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P = 0.022). The patients with p16+/pRb-/cyclin D1-/CDK4- or p16-/pRb+/cyclin D1-/CDK4- tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors., Conclusions: The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis.

A 41-year-old woman presented to the Department of Obstetrics and Gynecology of our hospital because of abdominal distension and irregular genital bleeding. Computed tomography and ultrasonography of the abdomen revealed bilateral ovarian tumors, massive ascites, and bilateral pleural effusion. Type IV advanced gastric cancer was diagnosed on upper gastrointestinal endoscopy. The patient was admitted to our department. She received 3 courses of combination chemotherapy with methotrexate, 5-fluorouracil, and low-dose cisplatin. Pleural effusion and ascites disappeared. Surgery (total gastrectomy, resection of the tail of the pancreas, lymph-node dissection, total hysterectomy, and adnexectomy) was performed, and the patient was discharged. Chemotherapy was repeated after surgery. Lymph-node metastasis recurred 1 year 8 months after the start of chemotherapy. Treatment was switched to irinotecan plus cisplatin, and the lymph nodes shrank. After 9 months, 3 courses of TS-1 were administered. Two years 10 months after starting chemotherapy, abdominal and low back pain developed. Bone scintigraphy revealed bone metastasis. Lymph node swelling was present. The patient responded to radiotherapy with chemotherapy (cisplatin plus 5-fluorouracil). Subsequently, abdominal computed tomography showed lymph-node swelling, multiple metastases to the liver, ascites, and a right pleural effusion. She was readmitted to the hospital and received intraperitoneal chemotherapy with cisplatin. Her condition deteriorated, and she died. The patient survived for about 3 years 4 months after the start of treatment. Chemotherapy with methotrexate, 5-fluorouracil, and low-dose cisplatin may thus be an effective therapeutic option in patients who have advanced gastric cancer with peritoneal dissemination.

Background: Argon plasma coagulation (APC) is a noncontact technique for tissue coagulation. APC has been used to treat early gastric cancer in patients who cannot undergo EMR or open surgery, but a standard procedure for APC is lacking., Objective: Our objectives were to assess the clinical usefulness of APC in patients with early gastric cancer., Design: This was a small, retrospective pilot study., Setting: All patients were treated at the Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Japan., Methods: We studied 40 patients with early gastric cancer in whom both EMR and open surgery were contraindicated. The macroscopic tumor type was superficial elevated in 11 patients, superficial depressed in 27, and superficial elevated plus superficial depressed in two. The histologic classification was intestinal type in 37 patients and diffuse type in 3., Intervention: From January 1998 through March 1999, all patients received one session of APC. From April 1999 through August 2001, all patients received two sessions of APC. From September 2001 through March 2002, an additional session of APC was given only to patients who had large protruding lesions, depressed lesions 2 cm or greater in diameter, or submucosal invasion., Main Outcome Measurements: The main outcome measurements were residual tumor or recurrence of early gastric cancer., Results: Intestinal-type intramucosal carcinoma disappeared after one or two sessions of APC. Submucosal and diffuse-type tumors had a high risk of residual tumor cells because of inadequate treatment after one session of APC. However, such lesions were locally controlled by follow-up APC., Limitations: This was a small, retrospective pilot study. Confirmation of long-term outcome is required., Conclusions: Small early gastric carcinomas can be successfully treated by a single session of APC. Larger protruding-type lesions and submucosal tumors are likely to require two sessions of APC.

Background/aims: Helicobacter pylori (Hp) infection has been suggested to be a risk factor for gastric carcinogenesis. The aims of this study were to clarify differences in clinicopathological features, tumor cell kinetics and p53 expression between early gastric cancers developing within and at a distance from Hp actively infected mucosa and those away from the infected area., Methodology: A total of 91 consecutive patients who were diagnosed as having early gastric carcinoma were enrolled in this study. Phenol red solution and urea were sprayed over the surgically resected stomachs (the PR test). Tumors included in and away from positive (red color) areas on PR testing were considered as infected and non-infected cases, respectively, and compared for Ki67 (proliferative activity), ssDNA (apoptotic activity) and p53 immunoreactivity., Results: The average age of the infected cases (n=46) was 9 years younger than that for their non-infected counterparts (n=45; P<0.0001). Depressed macroscopic and diffuse histologic types were more prevalent in the infected cases (P<0.05 and P<0.001, respectively). In neither intestinal nor diffuse histologic types were any significant differences in Ki67, ssDNA or p53 immunoreactivity apparent between the infected and non-infected cases., Conclusions: Cases of early gastric cancer developing within and at a distance from Hp infected mucosa are clinicopathologically different although the presence of bacteria in the surrounding mucosa does not appear to affect tumor cell kinetics or p53 expression.

Background: The efficacy and limitations of preoperative endoscopic clipping for determining the resection line in patients with early gastric cancer remain unclear., Materials and Methods: Subjects comprised 100 patients with early gastric cancer (33 females, 67 males; mean age, 60.5 years; range, 33-84 years) who underwent pre-operative endoscopic clipping for lesions located in the middle or upper corpus of the stomach. The results of endoscopic clipping for a selection of appropriate surgical procedures were investigated., Results: Distal gastrectomy was performed in 94 patients, the mean length between the lesion and proximal surgical margin of the resected stomach being 28.9 +/- 18.0 mm (mean +/- SD). The surgical margin was eventually free of tumor in all patients. In 5 patients, clips were considered to be placed inadequately, and all 5 tumors were macroscopically depressed or flat and > 40 mm in size., Conclusion: Pre-operative endoscopic clipping represents a safe and reliable procedure to determine the resection line for tumors located in the middle or upper corpus of the stomach for treatment of early gastric cancer. During surgical resection, frozen section examination of the proximal cut end is recommended for patients with tumors that are macroscopically depressed or flat and > 40 mm in size, or that display a macroscopically unclear proximal margin.

Background and Study Aims: Gastric carcinoid tumors are a rare disease. Previously, total gastrectomy was regarded as the treatment of choice. However, differences in biological malignancy have recently led to the increased use of endoscopic mucosal resection (EMR) for treatment. We studied the outcome of EMR in patients with gastric carcinoids who were treated at our hospital and discuss the indications for endoscopic treatment., Patients and Methods: Between 1986 and 1999 we carried out gastric mucosal resection in five patients with gastric carcinoid tumors. The procedure used for EMR was either strip biopsy or endoscopic aspiration mucosectomy., Results: The carcinoid tumors measured 10 mm or less in four of the five patients. Two patients had type A gastritis, and all had hypergastrinemia. There was no evidence of recurrence during follow-up (range 6 - 66 months; mean 32.6 months)., Conclusion: EMR is useful in the management of type 1 gastric carcinoids as classified by Rindi (hypergastrinemia; tumor diameter of 10 mm or less).

In order to investigate cell kinetics and cell cycle regulator protein expression with reference to the growth pattern of early gastric carcinomas (EGCs), we evaluated a total of 240 EGCs with submucosal invasion clinicopathologically and 106 submucosal invasive lesions immunohistochemically. The incidence of lymph node metastasis was relatively high (36.4%) in the superficially spreading growth (SUP) type tumors whereas the penetrating growth (PEN) type had a low incidence (5.7%, P < 0.001) and correlated with submucosal tumor size. Ki67 labeling was lower in submucosal areas of the SUP-type tumors (median, 37.3%) than the PEN-type tumors (51.0%, P < 0.001). ssDNA labeling in the lamina propria, indicative of apoptotic activity, was higher in the SUP-type tumors (0.55%) than in PEN-type (0.30%, P < 0.01) lesions. The expression of cell cycle regulator p21WAF1/CIP1 was lower in the SUP-type tumors (lamina propria 15.6%, submucosa 2.6%) than in PEN-type tumors (lamina propria 26.5%, submucosa 4.4%, P < 0.05-0.001). In conclusion, differences in cell kinetics and p21WAF1/CIP1 expression might influence the growth pattern of EGCs. The SUP-type EGC, characterized by high apoptotic in the lamina propria and low proliferative activities in the submucosa, is associated with frequent lymph node metastasis, suggesting a strong correlation between tumor size in the submucosa and metastatic potential.

Recent studies have explored the possibility of using endoscopic mucosal resection (EMR) to treat lesions with a relative indication for endoscopic therapy. We used EMR to manage poorly differentiated adenocarcinoma, a relative indication for endoscopic treatment, in a patient who requested such treatment and refused surgical intervention. We describe our experience with this patient, who died of tumor recurrence 4 years after the EMR. This case describes the problems of using EMR for the treatment of poorly differentiated adenocarcinoma.

Background: Endoscopic mucosal resection is an established treatment option for early stage gastric cancer. However, several problems with endoscopic mucosal resection remain to be solved, such as appropriate treatment for recurrence and incomplete tumor resection. The outcome for patients undergoing endoscopic aspiration mucosectomy (endoscopic mucosal resection) by a modification of the cap-fitted technique was evaluated retrospectively to determine factors associated with complete resection and tumor recurrence., Methods: Endoscopic mucosal resection was performed in 106 patients with early stage gastric cancers up to 20 mm in diameter that were well or moderately differentiated adenocarcinoma. All were superficial lesions without ulceration, distinct signs of submucosal invasion, or a poorly demarcated border. En bloc (tumors <10 mm in diameter) or piecemeal (tumors 10-20 mm in diameter) resection was performed. Follow-up endoscopy was performed at 2, 6, 12, 18, and 24 months and thereafter once per year. Outcome and factors associated with complete resection and tumor recurrence were assessed retrospectively., Results: Sixty-eight patients (64%) underwent en bloc resection and 38 (36%) piecemeal resection. The mean longest dimension (SD) of the resected lesions was significantly greater after piecemeal resection (12.3 [4.0] mm) than after en bloc resection (7.6 [4.0] mm; p < 0.01). In patients with tumors completely resected, there was no recurrence after either en bloc or piecemeal resection. Six of 8 patients found to have submucosal invasion after endoscopic mucosal resection underwent surgery. Patients with incompletely resected intramucosal lesions underwent additional endoscopic treatment. Cancer recurred in 3 patients (2.8%), all of whom had lesions measuring more than 15 mm in diameter., Conclusions: Endoscopic mucosal resection is safe and useful for the management of early stage gastric cancer. Further improvement in outcome requires more accurate preoperative diagnosis and postoperative histopathologic evaluation. Patients with incompletely resected lesions should undergo aggressive additional treatment.

To investigate tumorigenesis in the gastric hyperplastic polyp (HP), we evaluated 19 HPs with and 50 HPs without dysplasia (including carcinoma in situ), as compared with normal mucosa and fundic gland polyps. Helicobacter pylori density was highest in HPs without dysplasia. Apoptotic activity and Ki-67 and p53 expression also were higher in dysplasia in HPs than in normal mucosa, fundic gland polyps, or HPs themselves. The p21WAF1/CIP1 and cyclin D1 levels, in contrast, were highest in HPs. In HPs without dysplasia, size was correlated positively with the degree of stromal inflammation and with p53 and cyclin D1 expression. p53 and c-Ki-ras mutations were detected in 41% (8/19) and 5% (1/19) of dysplasia (including carcinoma in situ) in HPs. Our results demonstrate that the HP enlarges with enhanced cell turnover and overexpression of p53, p21WAF1/CIP1, and cyclin D1, associated with H pylori-related inflammation, and that p53 but not c-Ki-ras mutations may have an important role in dysplastic change in HPs.

Aims: To investigate the histogenetic relationship between gastric epithelial neoplasms we studied differences in expression of mucin carbohydrate antigens and mucin core protein, in normal and metaplastic gastric mucosa, and in gastric adenomas and superficial adenocarcinomas., Methods and Results: We generated four monoclonal antibodies, including HGM72/75 against human gastric mucin and HCM14/21 against human colonic mucin, and investigated immunoreactivities of these antibodies and MUC2 protein expression in normal and metaplastic gastric mucosa, adenomas (15 samples) and superficial adenocarcinomas (intestinal-type, 77; diffuse-type, 59 samples). HGM72 reacted with mucous neck cells of the fundic glands and with pyloric glandular cells whereas HGM75 stained foveolar cells and metaplastic goblet cells. Weak binding of HCM14/21 and strong staining with MUC2 were found in metaplastic goblet cells. Binding of HGM75, HCM14, MUC2, but not HGM72 was high in adenomas. An equivalent staining with HGM72 and HGM75 with low expression of MUC2 and HCM14 was shown in intestinal-type carcinomas while the diffuse-type demonstrated more strong reactivity with HGM75 than with HGM72, MUC2 and HCM14. Little binding of HCM21 was observed in any specimens., Conclusions: This study demonstrates that adenomas predominantly have a intestinal phenotype, but both types of adenocarcinomas retain some cells with a gastric phenotype during the early steps of neoplastic development.

To cast light on tumorigenesis in the remnant stomach after distal gastrectomy for peptic ulcer or gastric cancer, 45 cases in gastroduodenostomy (Billroth I, 17 cases) and gastrojejunostomy (Billroth II, 28 cases) groups were compared for a series of parameters. Cancers in Billroth II were significantly more predominant in the anastomosis area and more frequently associated with Epstein-Barr virus infection. Active gastritis, accelerated epithelial cell turnover (as assessed by measurements of apoptosis and cell proliferation), DNA damage, and foveolar cell hyperplasia were all greater in anastomotic areas after Billroth II than in proximal areas after Billroth II or either area after Billroth I. K-ras mutations were rare, but Epstein-Barr virus infection in cancers was seen frequently in anastomosis cases. In conclusion, active gastritis, possibly induced by enterogastric reflux, is linked to tumorigenesis in anastomosis sites in Billroth II cases.

G1 cyclins and cyclin-dependent kinase (CDK) complexes play important roles in G1 cell cycle transition, and their overexpression is implicated for neoplasia. The p27 protein (p27) negatively regulates G1 progression by binding to G1 cyclins/CDK complexes and inhibits their activity, resulting in inhibition of entry to the cell cycle. We investigated overexpression of cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin E (CCNE), CDK2, and CDK4, in addition to p27, in 260 gastric cancer cases on the basis of Western blots, reverse transcriptase-polymerase chain reaction Southern blots, and immunohistochemistry to clarify the roles of these proteins in tumor progression and prognosis. Examination of 20 cases of fresh cancer and matched normal tissues demonstrated a clear tendency for increased mRNA synthesis to be more frequent than expected from protein levels, and a direct correlation between p27 protein and mRNA was not found. Immunohistochemistry demonstrated 21. 5%, 34.2%, 30.4%, 44.2%, and 48.0% positivity for CCND1, CCND2, CCNE, CDK2, and CDK4, respectively, in the 260 gastric cancer cases. Overexpression of CCND2 and CDK4 significantly correlated with tumor progression. Moreover, CCND2 cytoplasmic staining (26.2%) appeared to be strictly linked with progression, whereas nuclear staining (7. 8%) demonstrated an inverse correlation. Survival curves showed CCND2 (especially cytoplasmic staining) and CDK4 positivity to be associated with a poor prognosis and CCNE positivity with a better prognosis. Tumors with high p27 labeling indices (LIs) were well differentiated, with low levels of invasion and lymph node metastasis. p27-negative cases (37.3%) demonstrated a poor prognosis. Multivariate analysis revealed positivity for CCND2 and negativity for p27 to be independent prognostic factors. There were no direct links among CCND2, CCNE, CDK4, and p27. The results indicate that CCND2 cytoplasmic localization might reflect an important physiological role in tumor progression, whereas CCNE overexpression correlates with differentiation and a good prognosis, possibly because of accumulation of inactive forms of CCNE-CDK2 complexes. Loss of p27 caused by degradation activity may affect tumor cell growth in the presence of an altered extracellular matrix, facilitating metastasis. Cell-cycle-regulatory proteins appear to work independently.

Background: Several techniques are available for the endoscopic treatment of gastric intramucosal cancers, but their advantages and disadvantages have not been adequately evaluated. We compared the therapeutic usefulness of endoscopic aspiration mucosectomy with that of strip biopsy., Methods: Between May 1995 and May 1997, we performed strip biopsy (May 1995 through February 1996) or endoscopic aspiration mucosectomy (March 1996 through May 1997) in a consecutive series of patients with intestinal-type intramucosal cancer. Parameters of assessment included the following: size of removed specimens, en bloc resection rate, time required for resection, duration of hospitalization, and complications., Results: Forty-nine patients with gastric intramucosal cancers underwent endoscopic aspiration mucosectomy and 44 underwent strip biopsy. The two groups were similar with respect to age, gender, and lesion macroscopic appearance, size, and site. The mean longest diameter of the resected specimens was significantly greater with endoscopic aspiration mucosectomy (20.3 +/- 3.4 mm) than with strip biopsy (15. 8 +/- 4.4 mm) (p < 0.001). The rate of en bloc resection (resection of an entire lesion in one procedure) was significantly higher with endoscopic aspiration mucosectomy (61.2%, 30 of 49) than with strip biopsy (36.4%, 16 of 44) (p < 0.05). The number of specimens obtained by piecemeal resection was slightly, but not significantly, higher with strip biopsy (2.4 +/- 1.7) than with endoscopic aspiration mucosectomy (2.0 +/- 1.7). The time required for treatment was similar for each procedure. The duration of hospitalization was significantly shorter with endoscopic aspiration mucosectomy (12.8 +/- 5.3 days) than with strip biopsy (15.9 +/- 74 days) (p < 0.05). As for complications, the rate of bleeding was 20. 5% (9 of 44) with strip biopsy and 10.2% (5 of 49) with endoscopic aspiration mucosectomy; bleeding was controlled in all cases by treatment with a heater probe., Conclusions: Endoscopic resection of large gastric intramucosal tumors is easier with endoscopic aspiration mucosectomy compared with strip biopsy. Endoscopic aspiration mucosectomy is a useful procedure for en bloc resection.

We report a rare case of gastritis cystica profunda (GCP) accompanied by carcinoma that developed in a 51-year-old Japanese man without antecedent gastric surgery. The polypoid tumor was located in the upper body of the resected stomach. Histologically, it was characterized by herniation of surface epithelium and cystic glands in the submucosa, muscularis propria, and subserosa. Marked chronic atrophic gastritis was found throughout the stomach, and dysplastic epithelia and a few adenocarcinoma cells were found in the deeper parts of the GCP. The Ki-67, p53, and p21WAF1/CIP1 labeling indices for the deeper part of the GCP were higher than those for the superficial parts or the surrounding mucosa, suggesting that both epithelial cell proliferation and p53-dependent p21WAF1/CIP1 expression in DNA-damaged cells, which might be associated with gastritis, are enhanced in line with penetration of glands. The underlying mechanisms might be linked in a chain of factors leading to malignancy.

Objectives: To assess cell proliferation and analyze oncogenetic abnormalities in cases of juvenile polyposis of the stomach (JPs), with or without coexisting tumors., Methods: The Ki-67 labeling indices (KLI) were compared for juvenile polyps and coexisting tumors in three cases of JPs along with values for gastritis, foveolar epithelial hyperplastic polyps, adenomas, and carcinomas. Expression of p53, Bcl-2, and c-ErbB-2 in tumors was examined immunohistochemically, and a search for c-Ki-ras mutations was made by DNA direct sequencing., Results: The KLI for JPs did not significantly differ between cases, being consistently lower than the values for both hyperplastic polyps and gastritis. The KLI for the papillary tumors and a signet ring cell carcinoma found in association with JPs tended to be lower than those for their conventional counterparts. P53, but not Bcl-2 and c-ErbB-2, was focally expressed in the papillary tumors, whereas all three were absent in the signet ring cell carcinoma, in the JPs. No c-Ki-ras mutations were detected in the papillary tumors., Conclusions: The cell proliferation of JPs is relatively low and the polyps can be considered hamartomatous. However, neoplastic change clearly can occur in association with a relative increase in proliferative activity being observed in coexisting tumors. Low cellular proliferative activity and absence of oncogenetic abnormalities in tumors of JPs, compared with their conventional counterpart tumors, suggest that pathways of tumorigenesis and genetic alteration in JPs may be different from those in their conventional counterparts.