Undifferentiated-type Gastric Cancer Research Articles

Effect of Helicobacter pylori infection on malignancy of undifferentiated-type gastric cancer

BackgroundAlthough almost all cases of gastric cancer are caused by Helicobacter pylori (HP) infection, there are some rare exceptions. Furthermore, the clinicopathological characteristics of gastric cancer may differ depending on HP infection status. This study aimed to determine the clinicopathological characteristics of undifferentiated-type gastric cancer (UD-GC) according to HP status.MethodsThe study involved 83 patients with UD-GC who were selected from 1559 patients with gastric cancer who underwent endoscopic resection at our hospital and whose HP infection status was confirmed. Clinicopathological characteristics were evaluated according to HP status (eradicated, n = 28; infected, n = 32; not infected, n = 23).ResultsIn patients without HP infection, UD-GCs were < 20 mm and intramucosal with no vascular invasion. In patients with eradicated HP, there was no correlation between development of UD-GC and time since eradication. Nine of twelve patients with a tumor detected ≥ 5 years after eradication had undergone yearly endoscopy. Submucosal invasion was observed in two of four patients and lymphovascular invasion in three of four patients whose UD-GC was detected ≥ 10 years after eradication. There was no significant between-group difference in the frequency of lesions with invasion into the submucosal layer or deeper (14.3%, 10.5%, and 0% in the UD-E, UD-I, and UD-U groups, respectively).ConclusionThe clinicopathological characteristics of UD-GC were similar between HP-infected patients and HP-eradicated patients. Three of four patients with eradicated HP whose UD-GC developed ≥ 10 years after eradication were not eligible for endoscopic treatment and required additional surgery resection. In contrast, UD-GC was curable by endoscopic resection in all patients without HP infection.

Impact of the Interval between Previous Endoscopic Exam and Diagnosis on the Mortality and Treatment Modality of Undifferentiated-Type Gastric Cancer.

PurposeThe impact of the interval between previous endoscopy and diagnosis on the treatment modality or mortality of undifferentiated (UD)-type gastric cancer is unclear. This study aimed to investigate the effect of endoscopic screening interval on the stage, cancer-related mortality, and treatment methods of UD-type gastric cancer.Materials and MethodsWe reviewed the medical records of newly diagnosed patients with UD gastric cancer in 2013, in whom the interval between previous endoscopy and diagnosis could be determined. The patients were classified into different groups according to the period from the previous endoscopy to diagnosis (<12 months, 12–23 months, 24–35 months, ≥36 months, and no history of endoscopy), and the outcomes were compared between the groups. In addition, patients who underwent endoscopic and surgical treatment were reclassified based on the final treatment results.ResultsThe number of enrolled patients was 440, with males representing 64.1% of the study population; 11.8% of the participants reported that they had undergone endoscopy for the first time in their cancer diagnosis. The percentage of stage I cancer at diagnosis significantly decreased as the interval from the previous endoscopy to diagnosis increased (65.4%, 63.2%, 64.2%, 45.9%, and 35.2% for intervals of <12 months, 12–23 months, 24–35 months, ≥36 months, and no previous endoscopy, respectively, P<0.01). Cancer-related mortality was significantly lower for a 3-year interval of endoscopy (P<0.001).ConclusionsA 3-year interval of endoscopic screening reduces gastric-cancer-related mortality, particularly in cases of UD histology.

Risk factors of lymph node metastasis after non-curative endoscopic resection of undifferentiated-type early gastric cancer.

This study aimed to investigate risk factors for lymph node (LN) or distant metastasis after non-curative endoscopic resection (ER) of undifferentiated-type early gastric cancer (EGC). Of 1124 patients who underwent ER for undifferentiated-type gastric cancer at 18 tertiary hospitals across six geographic areas in Korea between 2005 and 2014, 634 with non-curative ER beyond the expanded criteria were retrospectively enrolled. According to the treatment after ER, patients were divided into additional surgery (n = 270) and follow-up (n = 364) groups. The median follow-up duration was 59months for recurrence and 84months for mortality. LN metastasis was found in 6.7% (18/270) of patients at surgery. Ulcer [odds ratio (OR) 3.83; 95% confidence interval (CI) 1.21-12.13; p = 0.022] and submucosal invasion (OR 10.35; 95% CI 1.35-79.48; p = 0.025) were independent risk factors. In the follow-up group, seven patients (1.9%) developed LN or distant recurrence. Ulcer [hazard ratio (HR) 7.60; 95% CI 1.39-35.74; p = 0.018], LVI (HR 6.80; 95% CI 1.07-42.99; p = 0.042), and positive vertical margin (HR 6.71; 95% CI 1.28-35.19; p = 0.024) were independent risk factors. In the overall cohort, LN metastasis rates were 9.6% in patients with two or more risk factors and 1.2% in those with no or one risk factor. LVI, ulcer, submucosal invasion, and positive vertical margin are independently associated with LN or distant metastasis after non-curative ER of undifferentiated-type EGC. Surgical resection is strongly recommended for patients with two or more risk factors.

Characterization of Helicobacter pylori-Naïve Early Gastric Cancers

Aim: Helicobacter pylori-naïve gastric cancers(GCs) have not been well documented. We aimed to characterize early H. pylori-naïve GCs. Subjects and Methods: Of 666 patients with GC resected by endoscopic submucosal dissection, H. pylori-naïve patients were extracted according to the definition: no H. pylori eradication history, negative for serum H. pylori-antibody and current H. pylori-infection tests, and no gastric atrophy by pepsinogen (PG) test, endoscopy, and histology. Results: It was found that 16 GCs were H. pylori-naïve, and classified into undifferentiated and differentiated type adenocarcinoma. All 9 undifferentiated type GCs were pale, depressed, mucosal pure signet ring cell adenocarcinoma except one of them and 7 differentiated type GCs were classified into 3 fundic gland type GCs and 4 foveolar type GCs. All fundic gland type GCs positive for PG-1 were cardia small submucosal tumor (SMT)-like protrusions with dilated vessels on the surface. All 4 foveolar type GCs were composed of dysplastic clear cells resembling foveolar epithelium, negative for PG-1 but positive for mucin 6 (MUC6) and MUC5AC. Endoscopically, all were laterally spreading elevations with papillary or villous surface. Conclusions: H. pylori-naïve GCs were infrequent at 2.5%, and classified into 3 types: a small pale depression of signet ring cell adenocarcinoma, a small SMT-like protrusion of fundic gland type GC, and a large laterally spreading elevation of foveolar type GC.

Research progress of the clinically uncommon gastric carcinoma

Gastric cancer is one of the most important diseases that endangers people's health. Beside gastric adenocarcinoma, gastric carcinoma also includes the following types: adenosquamous carcinoma, squamous carcinoma, gastric neuroendocrine tumor, gastric hepatoid adenocarcinoma, AFP-producing gastric cancer, EBV-associated gastric cancer, lymphoepithelioma-like carcinoma, undifferentiated-type gastric cancer, gastric carcinosarcoma and so on. The adenosquamous carcinoma, squamous carcinoma of stomach, gastric hepatoid adenocarcinoma, AFP-producing gastric cancer and gastric carcinosarcoma mainly occurred in old men, while the linitisplastica gastric cancer was common in young women. It refers to the gastric cancers that are clinically rare and have lower incidence, unique histological and pathological features, however, without obviously clinical manifestations. The clinically uncommon gastric cancers are easy to be misdiagnosed or missed, and further to miss the optimal opportunity for treatment due to the unclearly specific pathogenesis and disease progression. With the development of studies on the clinically uncommon gastric carcinoma, although people have a further knowledge of its pathologic features, methods of diagnosis and treatment, the diagnosis and treatment standards for the clinically uncommon gastric cancer has not yet been established and unified. The therapeutic principle of the clinically uncommon gastric cancers is also the radical surgery, radiotherapy and chemotherapy as the main comprehensive treatment supplemented by individualized treatment. With lucubrating the pathogenesis of them, specific diagnostic methods and treatment measures are new hope for improving the diagnosis and treatment of the clinically uncommon gastric cancers. So, the further researches on the clinically uncommon gastric cancers and exploring their etiology, pathogenesis, histological and pathological features have important significance to their diagnosis and treatment. This article makes a summary of the clinically uncommon gastric cancers with the aspects of epidemiology, histology, pathology, diagnosis, treatment, to provide reference to clinical diagnosis and scientific studies.

A case report of prostate cancer metastasis to the stomach resembling undifferentiated-type early gastric cancer

BackgroundOccurrence of metastatic cancer to the stomach is rare, particularly in patients with prostate cancer. Gastric metastasis generally presents as a solitary and submucosal lesion with a central depression.Case presentationWe describe a case of gastric metastasis arising from prostate cancer, which is almost indistinguishable from the undifferentiated-type gastric cancer. A definitive diagnosis was not made until endoscopic resection. On performing both conventional and magnifying endoscopies, the lesion appeared to be slightly depressed and discolored area and it could not be distinguished from undifferentiated early gastric cancer. Biopsy from the lesion was negative for immunohistochemical staining of prostate-specific antigen, a sensitive and specific marker for prostate cancer. Thus, false initial diagnosis of an early primary gastric cancer was made and endoscopic submucosal dissection was performed. Pathological findings from the resected specimen aroused suspicion of a metastatic lesion. Consequently, immunostaining was performed. The lesion was positive for prostate-specific acid phosphatase and negative for prostate-specific antigen, cytokeratin 7, and cytokeratin 20. Accordingly, the final diagnosis was a metastatic gastric lesion originating from prostate cancer.ConclusionIn this patient, the definitive diagnosis as a metastatic lesion was difficult due to its unusual endoscopic appearance and the negative stain for prostate-specific antigen. We postulate that both of these are consequences of hormonal therapy against prostate cancer.

A case of undifferentiated-type mucosal gastric cancer with multiple lymph node metastases fulfilling the curative criteria for endoscopic resection according to routine pathological analysis.

BackgroundEndoscopic resection is accepted as the standard treatment for early mucosal gastric cancer, and its indications have recently been expanded while its long-term outcomes are still unclear. Herein, we present a didactic case of undifferentiated-type mucosal gastric cancer fulfilling the expanded indication and curative criteria for endoscopic submucosal dissection (ESD), having synchronous multiple lymph node metastases.Case presentationA 40-year-old woman was found to have a Helicobacter pylori infection at a standard health check with no abdominal symptoms. She received an upper gastrointestinal endoscopy and found to have an undifferentiated-type mucosal gastric cancer with the size of 15 mm in diameter without ulceration, which fulfilled the expanded indication for ESD. According to patient’s preference, we performed laparoscopy-assisted distal gastrectomy with D1+ lymph node dissection, and routine pathological analysis revealed a predominantly signet ring cell carcinoma limited to the mucosa without ulceration or any vessel involvement; on the other hand, 15 lymph node metastases were detected. Then, we added deep sectioning of the whole tumoral area at a thickness of 20 μm and immunohistochemical analyses. As the result, an isolated lymphatic capillary involvement of the extremely superficial submucosa was identified in a single histological section, and pathological diagnosis was corrected to ly1. She received postoperative adjuvant chemotherapy with an S-1 oral agent and had no recurrence under strict surveillance for 1 year postoperatively.ConclusionsWhen we perform ESD for undifferentiated-type gastric cancer, deep sectioning of the whole tumoral area into thin slices and immunohistochemical staining using D2-40 should be practically considered.

Sa1382 Differences in Titer and Seropositivity Rates of CagA Antibody Among Patients With Differentiated-Type Gastric Cancer, Undifferentiated-Type Gastric Cancer, or Peptic Ulcer

Sa1382 Differences in Titer and Seropositivity Rates of CagA Antibody Among Patients With Differentiated-Type Gastric Cancer, Undifferentiated-Type Gastric Cancer, or Peptic Ulcer

Clinicopathological Significance and Prognostic Value of Lactate Dehydrogenase A Expression in Gastric Cancer Patients

IntroductionLDH-A, the enzyme responsible for transforming pyruvate into lactate, has been demonstrated to be up-regulated in many types of cancer and to give rise to more aggressive behavior by regulating proliferation and anti-apoptosis. However, its expression in gastric cancer (GC) has not been characterized thoroughly. The purpose of this study was to clarify the expression and potential impact of LDH-A in GC.MethodsWe examined LDH-A expression by immunohistochemistry on GC tissue microarray (TMA) and using Western blot on fresh GC tissues and cell lines. Prognostic value and correlation with other clinicopathologic factors were evaluated. We transfected siRNA into GC cells against LDH-A. LDH-A was analyzed by Western blotting and real-time RT-PCR. Cell growth was evaluated in vitro and in vivo. Lactate and ATP production by cells were determined.ResultsThere was significantly higher LDH-A expression in carcinoma than in non-neoplastic mucosa (NNM). There was a positive correlation of LDH-A expression with age, histological type and Lymph node metastases. Survival analysis demonstrated that high expression of LDH-A in GC was associated with lower overall survival (OS). When stratified by Lauren grade and histological classification, significance appeared in diffuse type and undifferentiated type GC. In multivariate analysis, the LDH-A expression in GC was an independent prognostic risk factor for OS (hazard ratio = 1.829, 95%CI 1.375–2.433,P<0.0001). Specific siRNA against LDH-A in GC cell line retarded cell growth both in vitro and in mouse models. LDH-A knockdown also reduced lactate and ATP production in GC cells.ConclusionsOur study indicated the oncogenic role of LDH-A in GC. LDH-A expression is an independent prognostic risk factor in GC patients and up-regulated expression of LDH-A could be predictive of poor outcomes in diffuse type and undifferentiated type GC. Our results suggested that LDH-A might be a potential therapeutic target in gastric cancer.

Can an intramucosal undifferentiated-type gastric cancer become a candidate for endoscopic submucosal resection?

Can an intramucosal undifferentiated-type gastric cancer become a candidate for endoscopic submucosal resection?

Early gastric cancer shows different associations with adipose tissue volume depending on histological type

Visceral obesity is known to be a risk factor for diabetes and cardiovascular disease. Cancer of the gastric cardia has been shown to have a close association with obesity in Western countries. In order to examine the possible relationship between fat volume and the development of gastric cancer (GC), we quantified visceral and subcutaneous fat areas of computed tomography (CT) images of patients with early GC. A total of 210 patients who underwent endoscopic resection or surgical gastrectomy and whose disease was pathologically diagnosed as early GC were investigated for total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) with Fat Scan software, using a CT slice at the umbilical level, and the relationships of these findings with clinical and pathological data were analyzed. The same analysis was performed in 147 patients with early colorectal cancer (CRC). TFA, VFA, and SFA values in GC patients were not significantly different from the values in CRC patients. These values did not differ with the location of the GC. However, patients with undifferentiated-type GC had significantly smaller VFAs and SFAs than those with differentiated-type GC. Among the patients with undifferentiated GC, TFA and SFA values in the patients with submucosal cancer were significantly smaller than those in the patients with mucosal cancer. GC has different associations with adipose tissue volume according to its histological type. As compared with differentiated GC, lower adipose tissue volume may be a preferential environment for the development and progression of undifferentiated GC.

Hedgehog signaling pathway is a possible therapeutic target for gastric cancer

It has been shown that the hedgehog (Hh) signaling pathway is activated in gastric cancer. To investigate the viability of the Hh pathway as a therapeutic target, we analyzed activation of the Hh pathway in gastric cancer. Surgically resected gastric carcinoma specimens and lymph nodes were analyzed immunohistochemically. We used the percentage of cancer cells with nuclear translocation of Gli1 as a marker of Hh pathway activation. Nuclear localization of Gli1 was higher in 28 undifferentiated-type tumors than in 30 differentiated-type tumors. Eighteen of the fifty-eight cancer specimens consisted of a mixture of a histologically predominant part and a small area with different histology. In these 18 tumors, the percentage of cells showing nuclear staining of Gli1 was higher in the undifferentiated-type part than in the differentiated-type part. Nuclear staining of Gli1 in primary tumors was positively correlated with lymph node metastasis. The Gli1 nuclear staining percentage of metastatic lymph nodes correlated closely with that of each primary carcinoma. Cyclopamine, a Hh pathway inhibitor, suppressed the growth of gastric cancer cells in vitro. The Hh pathway may be a useful therapeutic target for such as undifferentiated-type gastric cancer with lymph node metastasis.

Candidate regions of tumor suppressor locus on chromosome 9q31.1 in gastric cancer.

Loss of heterozygosity (LOH) is an important event of tumorigenesis. In gastric cancer, we found a novel region of LOH in chromosome 9q having about 800 kb deletions at 9q31.1. The microsatellite marker D9S938 in that region exhibiting the highest LOH frequency, 56.5%. In addition, the LOH at 9q31.1 did not show any relationship to either histologic types or stages of gastric cancers, and several genes were predicted in the remaining allele by in silico methods. These data suggest that the deletion at 9q31.1 would be common in both differentiated-type and undifferentiated-type gastric cancers. Furthermore, this deletion was found in the primary tumors of early-stage gastric cancer, indicating that loss of function of predicted genes appears to be associated with the tumorigenesis of gastric cancer.

A Case of undifferentiated type gastric mucosal cancer, type IIc, with lymph node metastasis

A 50-year-old woman who was pointed out an abnormality by gastric mass survey in November 1999, visited our center and received upper GI endoscopy. Endoscopic examination revealed a slightly discolored and depressed lesion with tapering of the fold in the greater curvature of the middle body. The pathological diagnosis was undifferentiated type gastric cancer. Gastrointestinal radiologic examination showed an irregular depressed lesion with tapering of the fold in the greater curvature of the middle body. We diagnosed undifferentiated type gastric mucosal cancer, so subtotal gastrectomy was performed. The lesion was 25×18mm in size and histopathological examination revealed the signet-ring cell carcinoma, partly showing adenocarcinoma microtubulare, limited to the mucosal membrane and lymphatic permeation was slightly suspected. Lymphnode metastasis was recognized in microscopic findings. In conclusion, it seems that the treatment for like this case requires circumspection because there is a possibility that only partial resection is not enough.

Detection of thioredoxin in gastric cancer: association with histological type.

Thioredoxin (TRX) is a redox-active protein with multiple intra- and extracellular functions. This protein exists ubiquitously in all life forms, from primitive living cells, such as Escherichia coli and yeast, to higher mammals. Recently, augmentation of the expression and transcription level of TRX has been reported in tumors of various organs. In this study, we examined the expression of TRX in gastric cancer with respect to its histological type and depth of invasion. The association with cell proliferation was also studied. Results of histochemical analysis of surgical specimens as well as cytochemical analysis and Northern blot analysis of gastric cancer cell lines indicated that TRX is predominantly expressed in undifferentiated type gastric cancer rather than in the differentiated type. Neither the depth of tumor invasion nor cell proliferation significantly determined the staining intensity for TRX.

Amplification of growth factor receptor genes and DNA ploidy pattern in the progression of gastric cancer.

To study the background of oncogene amplification in gastric cancers, we examined the correlation between occurrence of oncogene amplification and DNA ploidy pattern. In 57 primary gastric cancers, amplifications of c-erbB, c-erbB-2, c-met and K-sam genes were investigated by Southern blot analysis, and the DNA ploidy pattern was determined by static cytofluorometry and by flow cytometry. Oncogene amplification was detected in 11 cancers, 10 of which were advanced gastric cancers and 1 was an early differentiated type. The amplification of c-erbB-2 and K-sam genes was found exclusively in differentiated- and undifferentiated-type cancers, respectively. Of the 11 cancers, 5 were DNA-diploid and 6 were DNA-aneuploid. All the 11 tumours with oncogene amplification contained polyploid cell populations (polyploidy), whereas none of the tumours without polyploidy showed oncogene amplification. In differentiated-type cancers the incidence of polyploidy was high in both early and advanced stages, while in undifferentiated-type cancers it was low in early stages but significantly higher in advanced stages. It was shown that amplification of growth factor receptor genes is closely related to the presence of polyploidy, irrespective of any different stemline DNA-ploidy mode. The time-course of oncogene amplification and kinds of genes amplified may differ between differentiated- and undifferentiated-type gastric cancers.

Reproductive Life History as Gastric Cancer Risk for Females : Case-Control Study

The purpose of this study was to investigate whether the reproductive life history, including hormonal environment, was a risk factor for gastric cancer in females by age groups or by histological subgroups. A case-control study with incident cases accompanied by individually matched one or two controls was carried out, using self administered questionnaire which included personal profile, smoking and drinking habits, dietary habits, past history of disease and reproductive life history. Analysis was made for 116 females cases and matched 144 controls separately by two histological type subgroups (differentiated and undifferentiated type) and by two age groups (young and older), using proportional hazard model to obtain relative risks with 95% C.I. For the undiffer- entiated gastric cancer in female under 40 years of age, mean of cumulative estradiol concentration (CEC) during all pregnant period and mean pregnant period per pregnancy revealed increased relative risk (R.R.) of 7.7 (95% C.I.: 1.41-41.75) (for each 1 ng/ml) and 3.1 (95% C.I.: 1.01-9.55) (for each 10 weeks), respectively. In the same group, 4 bowls or more rice consumption per day and drinking showed significant protective effect (R.R.: 0.20, 95% C.I.: 0.04-0.90 and R.R.: 0.23, 95% C.I.: 0.07-0.70, respectively). For differentiated gastric cancer in both age groups and undifferentiated one in older female, these factors stated above have no striking effect for gastric cancer occurrence. For differentiated type, several dietary habits were suggested to be risk factors for gastric cancer, although they were not statistically significant. On the other hand, for undifferentiated type, this tendency was not observed. This study suggests that etiologic factors for gastric cancer might be differed between histological types, and that undifferentiated type gastric cancer in young female with pregnancy has some etiological relation with reproductive histories. J Epidemiol, 1995; 5 : 177-185.