The DNA ploidy patterns in early gastric cancers as a criterion for surgery

A study of the ploidy patterns in gastric cancer has been conducted, focusing on 20 cases diagnosed prior to surgery as early stage gastric cancers. The gastric cancer in 10 cases was confined to the submucosa, where as in the other 10, the gastric cancer had invaded the muscle propria. The DNA ploidy patterns were classified as follows: Type D, Type A1 and Type A2. Even with gastric cancers of less than 2 cm, the likelihood that those with Type A1, and Type A2 patterns would spread into the lymph node was high (A1, 43% and A2, 67%), suggesting that careful consideration should be given to limiting the intended surgery. With gastric cancers of the Type D pattern, however, the incidence of a lymph node metastasis was low. These results are felt to be important factors when considering the extent of surgery.     

Differentiation of growth patterns of early gastric carcinoma determined by cytophotometric DNA analysis

Cell nuclear DNA content was microspectrophotometrically measured in 60 cases of early and six of advanced gastric carcinoma. DNA distribution pattern was classified into Types I, II and III, according to the degree of dispersion on the DNA histogram. Five of 6 cases of the advanced carcinomas were Type III. In early carcinoma, the majority of Super (superficially spreading) type were Type II, while all of Pen A (expansively penetrating growth) type were Type III. In Pen B (infiltratively penetrating growth) type, six of ten cases were Type II and the other four were Type III. Thus, there was a distinct difference in the DNA pattern between Super and Pen Types, i.e., the DNA analysis reflected these growth types. Since about 20% of those with small mucosal carcinomas, not classifiable into the Super or the Pen types presented Type III, the cytophotometric DNA analysis should be useful in the detection of Pen A like carcinoma, in its early stage. The development from early to advanced carcinoma was discussed in terms of the similarity of the DNA histogram patterns.     

An immunohistological study of gastric cancer--with special reference to the expression of carbohydrate antigens and nuclear DNA ploidy patterns

The expression of carbohydrate antigens specific to Span-1, CA 19.9, and SLEX in cancer tissues and nuclear DNA ploidy patterns were studied from tissue specimens of lesions excised from 137 patients with gastric cancer. The frequency of detection of each antigen was augmented with advanced invasion depth and progress in regional lymph node metastasis. In the cases which were positive for all three kinds of antigens, lymph node metastasis and lymphatic or venous invasion were detected with significantly higher frequencies than in the negative cases. The DNA histograms showed a DNA ploidy pattern of Type Ia or Ib in the cases negative for these antigens and a non-diploid or aneuploid pattern of Type II or III in many of the positive cases. These findings suggest that an immunohistological study of gastric cancer using monoclonal antibodies, combined with a nuclear DNA ploidy analysis, might be useful for understanding malignancy of the tumour.     

Prognostic value of S-phase fraction and DNA ploidy studied with in vivo administration of bromodeoxyuridine on human gastric cancers

The authors studied the prognostic values of DNA ploidy pattern and proliferative activity with in vivo administration of bromodeoxyuridine in human gastric cancers. Fresh specimens surgically removed from 117 patients with gastric cancer were investigated by flow cytometric study using a monoclonal antibody to bromodeoxyuridine. DNA ploidy patterns were classified into four types according to the bivariate BrdUrd/DNA distribution: D1, tumors with single diploid population; D2, tumors which showed mosaic of diploid and aneuploid population; A1, tumors with single aneuploid population; and A2, several aneuploid populations without diploid population. The numbers of cases of each ploidy pattern were as follows: D1, 36 cases (30.8%); D2, 38 cases (32.5%); A1, 15 cases (12.8%); and A2, 27 cases (23.1%). DNA ploidy pattern and S-phase fraction (SPF) showed no relation with clinicopathologic findings, except for type A2. In type A2, lymph node metastasis and lymphatic vessel invasion were observed more often than type D1. The SPF calculated from the bivariate BrdUrd/DNA distribution was higher in aneuploidy (D2, A1, and A2) than in diploidy (D1) (P less than 0.01). Also, A2 exhibited a higher SPF than A1 (P less than 0.01). Furthermore, SPF correlated with DNA index significantly (P less than 0.01). Patients who showed aneuploid tumors, DNA ploidy type A2, or SPF of more than 10% survived 3 years less than those with diploid tumors, DNA ploidy type D1, or SPF of less than 10%, respectively (P less than 0.05). By analyzing with the Cox's proportional hazard's model, it is revealed that DNA ploidy and SPF are one of the independent factors of prognostic significance. The results indicated that the patients with aneuploid tumors or highly proliferative tumors had a poor prognosis and that DNA ploidy pattern and SPF were useful prognostic factors for gastric cancers.     

Cytophotometric DNA analysis of gastric carcinoma--relationship between DNA ploidy and lymph node metastasis

Two hundred forty-four cases of gastric carcinoma were subjected to cytophotometric DNA analysis. DNA distribution patterns were roughly classified into low and high ploidies. The ratio of high ploidy was 55.7% (44/79) in the positive group of lymph node metastasis, which was significantly higher than 31.5% (52/165) in the negative group (P less than 0.01). The incidence of lymph node metastasis increased rapidly in the high ploidy cases with the progression of carcinoma, while it increased slowly in the low ploidy cases. DNA ploidy was well correlated with lymph node metastasis, and the mode of metastasis seemed to be different between the low and high ploidy groups.     

Heterogeneity in gastric carcinoma with special reference to DNA content and mitotic activity: histopathologic differentiation.

DNA ploidy and mitotic activity were microspectrophotometrically investigated in 46 patients with gastric carcinoma. Measurements of DNA content and mitotic index (M.I.) were examined in the mucosal, submucosal, muscularis propria, and serosal layers of tumors, respectively. The frequency of cells with values exceeding hexaploid chromosome (6c) and mitotic counting analysis revealed a significant higher value in serosa, compared with findings in the mucosa. This tendency was not evident in cases of a differentiated type adenocarcinoma but was noted in those with the undifferentiated type. There were 37 tumors (80.0%) with the same DNA distribution patterns in every layer of the stomach (homogeneous DNA ploidy). Heterogeneity of DNA ploidy was observed in nine tumors (20.0%). Carcinoma with a heterogeneous DNA ploidy manifested a significantly higher incidence of metastasis to the lymph nodes than did those with homogeneous type. Characteristically, there was venous permeation preponderance in the differentiated type and peritoneal dissemination preponderance in the undifferentiated type. This evidence of DNA heterogeneity in gastric carcinoma tissues suggests a possible correlation with the metastatic behavior.     

Study of c-erbB-2 protein and epidermal growth factor receptor expression and DNA ploidy pattern in colorectal carcinoma

Correlation of c-erbB-2 protein (n = 44), epidermal growth factor receptor (EGFR) (n = 41) expression, and DNA ploidy pattern (n = 42) with clinical outcomes of human colorectal cancers was studied. Using monoclonal antibodies against c-erbB-2 protein and EGFR, an immunohis-tochemical study of the expression of c-erbB-2 protein and EGFR in frozen tissue sections from the lesion was performed. There was no significant correlation between the expression of c-erbB-2 protein and clinicopatho-logical findings such as, tumor size, histological type, depth of invasion, lymph node metastasis, lymphatic vessel invasion, or venous invasion. However, the incidence of c-erbB-2 protein expression in Dukes D was significantly higher (9/10, 90%) than that in Dukes A to C (16/34, 47.1%). Similar tendency was also observed in the expression of EGFR. Aneuploid case was observed in 12 of observed 25 (48%) cases without lymph node metastasis, while it was observed in 16 of 17 cases (94.1%) with lymph node metastasis and there was significant association between DNA ploidy pattern and lymph node metastasis (P< 0.01) and most of the cases (17/20, 85%) were aneuploidy in Dukes C and D. The results above suggest that the expression of c-erbB-2 protein or EGFR was associated with distant metastasis, while on the other hand DNA ploidy pattern was correlated with lymph node metastasis. © 1993 Wiley-Liss, Inc.     

DNA ploidy is closely linked to tumor invasion, lymph node metastasis, and prognosis in clinical gastric cancer

DNA ploidy microspectrophotometrically determined in 254 patients with gastric carcinoma was investigated from the standpoint of tumor invasion, lymph node metastasis, and prognosis. DNA distribution patterns were grouped into low and high ploidies. The 24.0% frequency in the high ploidy group, at the mucosal stage, increased in proportion to invasion into the deeper layers. There was a high incidence of lymph node metastasis in the high ploidy group, compared with the low ploidy group, in case of invasion beyond the mucosa. Widespread nodal involvement was frequent in the high ploidy group. The 5-year survival rate was 73.7% in patients of high ploidy, with a statistical difference compared to the 90.6% in those of low ploidy (P less than 0.01). In the multivariate analysis of 226 patients undergoing curative surgery, the DNA ploidy proved to be a major independent prognostic factor. These findings indicate a close correlation among DNA ploidy, tumor invasion and nodal involvement, and the significant clinical value of DNA analysis for predicting the prognosis in patients with gastric carcinoma.     

Correlation of DNA ploidy and proliferative activity in human gastric cancer

Analysis of DNA ploidy patterns was performed on 129 cases of primary gastric cancer and the results were correlated with histologic findings and in vivo bromodeoxyuridine (BrdU) labeling. Forty-nine cases were diploid (38%) and 80 cases were aneuploid (62%). There was no correlation between DNA ploidy and histologic type. In aneuploid tumors, incidence of lymphatic invasion, lymph node metastasis, and rate of advanced cases were significantly higher than those in diploid tumors. During the follow-up period of 5 to 10 years, 23 of 40 patients (55%) with aneuploid tumors died of disease within 3 to 120 months. Only 13 of 36 patients (36%) with diploid tumors died of disease. The BrdU labeling indices (BrdU LI) ranged from 2.8% to 26.7%, with a mean of 10.4%. There was no correlation between BrdU LI and histologic type or stage. The mean BrdU LI of early cancers was 8.1%. The mean BrdU LI of advanced cancers was 11.9%. The BrdU LI of cancers with lymphatic invasion or lymph node metastasis was higher than those without them. The mean BrdU LI of diploid cancers was 6.0%. The mean BrdU LI of aneuploid cancers was 11.9%. There was a good correlation between BrdU LI and DNA ploidy patterns. These results indicate that DNA ploidy patterns and BrdU LI may possibly be useful prognostic markers for gastric cancers.     

Therapeutic strategy for patients with pN0 gastric carcinoma

BACKGROUND AND OBJECTIVES: The prognosis for patients with pN0 gastric cancer is moderately hopeful (expected 5-year survival: 80%). However, the relevant prognostic factors and most appropriate surveillance protocol have not been identified. METHODS: We investigated 733 gastric cancer patients without lymph node metastasis for prognostic factors by uni- and multi-variate analysis and by documenting causes of death and recurrence patterns. RESULTS: Univariate analysis revealed that age, tumor location, macroscopic appearance, tumor diameter, invasion depth, lymphatic invasion, and venous invasion affected prognosis. Multivariate analysis showed that age (> or = 60 years), ill-defined macroscopic appearance, and undifferentiated histological type independently reduced survival rates. Age (> or = 60 years) and undifferentiated histological type adversely influenced prognosis in 507 early gastric cancer patients whereas ill-defined macroscopic appearance adversely affected prognosis in 226 advanced cancer patients. Recurrence patterns in these patients were similar to those produced by lymph node metastasis. The predominant recurrence pattern was peritoneal dissemination, observed 2-3 years post-resection. CONCLUSIONS: This study identified adverse prognostic factors in pN0 gastric cancer patients. Randomized controlled studies of adjuvant chemotherapy are necessary to assess whether such therapy is beneficial for patients with adverse prognostic factors.     

An analysis of the DNA ploidy patterns of gastric cancer

This article deals with DNA measurements by fluorometry of nuclei in 33 freshly obtained specimens and in 109 fixed specimens of gastric cancer in Japanese patients. Histograms of the DNA measurements can be classified into four types (Ia, Ib, II, III). The nuclear DNA patterns had definite, if not significant, correlations with clinical and histologic parameters. For example, 88.2% of the cases classified as Type III were advanced stage disease, whereas early stage cases were predominant in Type Ia. Type II and III were frequently found in hepatic, peritoneal, and lymph node metastasis. The rate of occurrence of polyploid cells was significantly higher in the group with hepatic or lymph node metastasis than in the other group without metastasis. The results of this study show that fluorometric measurement of nuclear DNA is considered one method of determining the biological activity of gastric cancer cells.     

DNA ploidy is associated with growth potential in gastric carcinoma

To correlate growth potential with DNA ploidy 109 patients with early gastric carcinoma and 132 patients with advanced gastric carcinoma were studied. Early gastric carcinomas were classified by growth potential into the small mucosal type, the superficially spreading (super) type, or the expansively penetrating (Pen A)/infiltratively penetrating (Pen B) types. Advanced gastric carcinomas were classified into funnel, column, or mountain types, each of which was divided further into expanding and infiltrative types. Cell nuclear DNA content was measured by microspectrophotometric study and classified as either low or high ploidy according to the degree of dispersion on the DNA histogram. Super type early and funnel type advanced carcinomas, characterized by superficially spreading growth, were more likely to have low DNA ploidy. In contrast, Pen A type early and column-expanding type advanced carcinomas, characterized by expansively penetrating growth, were more likely to have high DNA ploidy.     

High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer

(Cancer Sci 2010; 101: 639–645) Gastric cancers show high frequency of DNA aneuploidy, a phenotype of chromosomal instability. It is suggested that the abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. We studied the mechanism by assessing the expression of BUBR1 in gastric cancer. The DNA ploidy patterns of 116 gastric cancer samples obtained from the Department of Surgery and Science at Kyushu University Hospital were analyzed. Of those, DNA aneuploidy was seen in 70 (60.3%) cases of gastric cancer. The expression of BUBR1 was studied by immunohistochemistry in 181 gastric cancer samples and by real‐time RT‐PCR in several gastric cancer cell lines. Ninety‐one (50.3%) cases had high expression of BUBR1 and those cases correlated significantly with DNA aneuploidy (P < 0.05). Also high expression of BUBR1 cases had significant correlation with deep invasion, lymph node metastasis, liver metastasis, and poor prognosis. In gastric cancer cell lines, high expression of BUBR1 had a significant relationship with DNA aneuploidy (P < 0.05). Then, gastric cancer cell lines MKN‐28 and SNU‐1 were transfected with full‐length BUBR1 to observe the significance of the change in BUBR1 expression. Enforced expression of BUBR1 resulted in changes to the ploidy pattern and high Ki‐67 expression. Collectively, our clinical and in vitro data indicate that high expression of BUBR1 may be one of causative factors for the induction of DNA aneuploidy and progression of gastric cancer.     

Combined resection of invaded organs in patients with T4 gastric carcinoma

Background. To understand the efficacy of gastrectomy combined with the resection of other organs and to refine the indications for this type of surgery, the records of 156 patients with carcinoma of the stomach directly invading adjacent organs or structures (T4 gastric carcinoma) were analyzed retrospectively. Methods. The patients were divided into three groups, as follows: in group A, curative resection was performed by the combined resection of invaded organs or structures; in group B, although combined resection was performed, curative resection could not be performed because of the extent of lymph node metastasis, liver metastasis, and/or peritoneal metastasis; in group C, combined resection was not performed. Results. In patients with peritoneal or liver metastasis, there was no significant difference in prognosis among the three groups. In patients without peritoneal and liver metastasis, the prognosis of group A was significantly better than that of group B or group C, irrespective of the extent of lymph node metastasis or the number of invaded organs. In these group A patients, the 5-year survival rates of those with localized tumors and no lymph node metastasis, those with localized tumors and lymph node metastasis, those with infiltrating tumors and no lymph node metastasis, and those with infiltrating tumors and lymph node metastasis were 100%, 56.2%, 57.1%, and 13.6%, respectively. Conclusions. Combined resection of involved organs should be carried out with curative intent in patients with localized gastric cancer or infiltrating gastric cancer without lymph node metastasis. Received: July 16, 2001 / Accepted: October 18, 2001     

胃癌细胞增殖活性与脉管转移及预后关系的探讨

目的探讨胃癌细胞溴化脱氧脲嘧啶核苷（BrdUrd）标记指数（LI）、G2／M期细胞比率（G2／MPF）、DNA含量与胃癌淋巴管侵袭、淋巴结转移、静脉侵袭及预后之间的关系。方法用BrdUrd／DNA双参数流式细胞术（FCM）检测60例胃癌新鲜标本。碘化丙啶（PI）用于检测细胞DNA的荧光探针,抗BrdUrd单克隆抗体用于掺入DNA中的BrdUrd探针。荧光标记的羊抗鼠抗体用于第二抗体。用体外标记BrdUrd法检测S期比率,同时检测DNA倍体和G2／MPF。结果淋巴管侵袭阳性者BrdUrd LI和G2／MPF均明显高于阴性者（P〈0．01）,二者5年生存率差异有统计学意义（P〈0．01）。淋巴结转移阳性者BrdUrd LI和G2／MPF较阴性者明显增高（P〈0．01）,二者5年生存率差异有统计学意义（P〈0．01）。异倍体癌淋巴结转移阳性者明显增高（P〈0．05）,二倍体癌的5年生存率较异倍体癌明显增高（P〈0．05）。淋巴结多数转移者（〉5个）的BrdUrd LI较无转移者（P〈0．01）和少数转移者（1～4个）明显增高（P〈0．05）,G2／MPF较无转移者明显增高（P〈0．01）;淋巴结少数转移者较无转移者的G2／MPF明显增高（P〈0．05）,淋巴无结转移、少数转移和多数转移者之间比较,其5年生存率差异有统计学意义（P〈0．01）;异倍体癌淋巴结多数转移者明显增高（P〈0．01）。静脉侵袭阳性的G2／MPF较阴性者明显增高（P〈0．01）。结论胃癌细胞BrdUrd LI、G2／MPF、DNA含量和脉管侵袭与胃癌预后有一定的关系。     

Comparison of DNA content in gastric cancer cells between primary lesions and lymph node metastases

Cytophotomtric DNA contents of tumor cells in primary lesions and the corresponding metastatic lymph nodes were compared in 61 cases of gastric cancer to determine whether the DNA content remains stable during lymph node metastasis. The DNA distribution patterns were grouped into three types, according to the proportion of aneuploid cell population. Changes in DNA patterns between primary and metastatic lesions were evident in 36 of 61 patients (59.0%); in the remaining 25 (41.0%), the same DNA distribution patterns were noted for both lesions. In 33 of these 36, DNA pattern in the primary carcinoma was transformed into a more narrowly scattered one in the metastatic lesion of the lymph node. Mean and modal values and the frequency of cells over tetraploid (4c) or hexaploid (6c) were significantly higher in the primary lesion compared with findings in the metastatic lesions. This reduction in DNA content in the metastatic lesions was a more frequent occurrence in differentiated (18 of 23) than in undifferentiated adenocarcinoma (15 of 35) (P less than 0.01). Therefore, in primary lesions with a widely scattered DNA ploidy, the tumor cells with a smaller DNA ploidy frequently metastasized to lymph nodes, particularly in cases of a differentiated carcinoma. Such observations may be pertinent in future designing of treatment protocols.     

Prognostic significance of DNA content with special reference to age in gastric cancer

The authors studied 93 patients who had undergone curative resection for advanced gastric cancer to assess the prognostic significance of DNA ploidy in relation to patient age. The cancers were classified as low and high-ploidy carcinomas and the patients were grouped by age (22-44 years, 45-64 years, 65-79 years). The incidence of high ploidy cancers increased with age. The 5-year survival rate increased with patient age in the low ploidy group whereas it decreased with patient age in the high ploidy group. There was a statistically significant difference (P less than 0.05) in the 5-year survival between our oldest patients with low (100%) and high ploidy (25.7%) gastric cancer. High ploidy cancers manifested a higher incidence of vessel invasion and lymph node metastasis. Our findings indicate that analysis of the DNA distribution pattern in gastric carcinoma is of prognostic value especially in older patients.     

Characteristics of gastric carcinoma invading the muscularis propria

BACKGROUND: Although gastric carcinomas invading the muscularis propria (mp) are classified among advanced-stage cancers in Japan, postoperative survival has been reported to approximate that in early gastric carcinoma. Characteristics of gastric carcinomas invading the mp, therefore, were compared to carcinomas invading only the mucosa (m) or submucosa (sm), and to those invading the subserosa (ss) or serosa (se). METHODS: We retrospectively compared clinicopathologic findings, prognosis, and cause of death in patients with gastric carcinoma invading mp to those showing the other levels of invasion. RESULTS: Patients with carcinomas invading the mp had larger tumors and more frequent lymph node and hematogenous metastases than those with carcinomas invading only m or sm. Yet they had smaller tumors and less frequent lymph node or peritoneal metastasis than those with carcinomas invading ss or se. Postoperative survival with tumors invading the mp was intermediate between that with carcinoma invading only m or sm and that with subserosal or serosal invasion. Causes of death with tumors invading muscularis were similar to those with carcinomas invading only m or sm. CONCLUSIONS: Characteristics of gastric carcinoma invading the mp are intermediate between those of early and advanced carcinoma.     

早期胃癌的淋巴结转移规律及预后分析

目的 分析早期胃癌的临床病理特征与预后之间的关系及早期胃癌的淋巴结转移规律.方法 对1994年1月～2005年10月手术治疗并有完整资料的255例早期胃癌的临床病理学资料进行回顾性分析.结果 255例患者的总5年生存率为91.4%.单因素分析显示,肿瘤浸润深度、脉管瘤栓和区域淋巴结转移与患者术后生存率有关;而性别、年龄...     

层黏连蛋白及其受体在胃癌中的表达及其与侵袭和转移的关系

目的 :探讨层黏连蛋白 (LN)和LN受体 (LN R)的表达与胃癌侵袭和转移的关系。方法 :应用免疫组织化学S P法检测 68例胃癌组织中LN和LN R的表达。结果 :LN在有淋巴结转移组中阳性表达率明显低于无转移组 ,P <0 0 1;LN在其他各组中的表达差异无统计学意义 ,P >0 0 5 ;LN R的阳性表达率有随肿瘤分化水平的降低、浸润深度的增加而增高 ,P <0 0 1;淋巴结转移组中的LN R表达明显高于无淋巴结转移组 ,P <0 0 0 1。结论 :LN的低表达与肿瘤的转移有关 ,LN R的高表达与肿瘤分化、侵袭和转移的关系十分密切。LN和LN R可作为胃癌进展的重要生物学指标之一。