Comparative features of esophageal and gastric adenocarcinomas: recent changes in type and frequency

One hundred sixty consecutive cases of esophageal and gastric carcinoma were reviewed to evaluate the impression of recent changes in their types and characteristics. Esophageal adenocarcinomas accounted for 34 per cent of all esophageal cancers and 60 per cent of tumors confined to the lower third of the esophagus; all but one were associated with Barrett's epithelium. Among the gastric cancers, previous observations of an increased prevalence of neoplasms confined to the cardia were extended. Proximal adenocarcinomas (arising from the esophagus, gastroesophageal junction, and cardia) constituted 34 per cent of all adenocarcinomas in this series and appeared to be a distinctive group with common features. Compared with other gastric cancers, the proximal carcinomas were associated with a lower mean age (65 years), higher male-to-female ratio (3.3:1), greater frequency of hiatal hernia (40 per cent), greater incidence of smoking and alcohol use, and lower prevalence of tumors composed predominantly of signet ring cells. Thus, proximal adenocarcinomas may form a specific category etiologically different from distal gastric cancers.     

Comparative immunohistochemical investigation of markers for malignant histiocytes

The presence of lysozyme, alpha 1-antitrypsin (AT), alpha 1-antichymotrypsin (ACT), and cytoplasmic receptors for peanut and soy bean agglutinin and for concanavalin A (PNA, SBA, and ConA, respectively) was investigated in formalin-fixed, paraffin-embedded material from 16 cases of malignant histiocytosis. The tumors in these cases did not show phenotypic characteristics of T or B cells. Lysozyme and AT especially were found less frequently in tumor cells from malignant histiocytosis than in normal histiocytes, whereas ACT and binding sites for the lectins were maintained during malignancy. Specimens from 44 per cent of the cases were positive for lysozyme, 56 per cent for AT, 82 per cent for ACT, 88 per cent for PNA receptors, 94 per cent for SBA receptors, and 100 per cent for ConA receptors. Tumor cells from B- and T-cell lymphomas were negative for these markers. Plasma cells, granulocytes, and fibroblasts sometimes bound ConA, but not PNA or SBA. The cases of malignant histiocytosis were subdivided into three groups on the basis of grade of differentiation. The tumor cells from the cases in group 1 showed the highest degree of differentiation, those from group 2 an intermediate degree, and those from group 3 the lowest degree. Mitotic activity was present mainly in groups 1 and 2. Lysozyme was present most frequently in groups 1 and 3 and in cases with the least mitotic activity. Expression of AT was decreased in groups 2 and 3. The presence of phagocytosis, which is not obligatory for the diagnosis, was always correlated with ACT staining. The presence of binding sites for these lectins can be considered a useful marker for malignant histiocytes.     

FIBROBLAST GROWTH FACTOR 1 AND FIBROBLAST GROWTH FACTOR 2 IMMUNOREACTIVITY IN GASTROINTESTINAL TUMOURS

Acidic and basic fibroblast growth factors (FGF-1 and FGF-2) are mitogenic polypeptides that may play a role in autocrine and paracrine growth control of malignant tumours. We have examined the expression of FGF-1 and FGF-2 in a series of 41 colorectal tumours (24 adenomas, 17 adenocarcinomas) and 50 gastric adenocarcinomas (23 intestinal, 27 diffuse), using immunohistochemistry. Whereas the FGF-1 distribution was cytoplasmic, FGF-2 was restricted to the nuclei of the epithelial cells. FGF-1 immunoreactivity was detected in all samples (100 per cent), whereas FGF-2 immunoreactivity was seen in 17 adenomas (71 per cent), 13 colorectal carcinomas (76 per cent), and 29 gastric carcinomas (58 per cent). Compared with the normal mucosa, FGF-1 was overexpressed in 42 per cent of colorectal adenomas, 76 per cent of colorectal cancers, and 54 per cent of gastric cancers. Conversely, FGF-2 expression was reduced in 16 (66 per cent), 8 (47 per cent), and 40 (80 per cent) adenomas and colorectal and gastric samples, respectively. We found a significant correlation only between reduced FGF-2 and gastric tumour grade. These data indicate that FGF-1 overexpression occurs in a large proportion of human colorectal and gastric cancers. This may play a role in the progression of these tumours. The topographic variation in FGF-2 expression between normal (nuclear) and tumour (cytoplasmic) cells implies a corresponding functional change that may in turn facilitate tumour growth. © 1997 by John Wiley & Sons, Ltd.     

Lysozyme in human gastric carcinoma: a retrospective immunohistochemical study

A total of 171 gastric carcinomas comprising 69 advanced cancers and 102 early cancers were examined immunohistochemically for lysozyme. Tumour cells containing lysozyme were detected in 65 cases or 38% of the 171 gastric cancer cases. The incidence of these cells did not differ remarkably by histological type and infiltrative growth of gastric carcinoma. Of the foregoing 65 cases, two well-differentiated adenocarcinomas and three signet ring cell carcinomas had numerous lysozyme-containing tumour cells, 13 had many argentaffin or argyrophil cells, and 40 had various amounts of several types of mucin. In addition, tumour cells containing both lysozyme and mucin could be identified. No correlation could be observed between lysozyme immunoreactivity in the tumour cells and cellular infiltration of granulocytes or macrophages around the tumour. The lysozyme appeared to be produced by tumour cells. The two year survival rates indicate a tendency for advanced gastric cancers containing lysozyme to have a poor prognosis.     

大肠肿瘤p53基因表达及其临床病理意义

应用免疫组织化学Ｓ－Ｐ法检测了１０６例良，恶性大肠组织中抑癌基因ｐ５３基因表达民政部结果发现；正常大肠粘膜及非肿瘤性息肉均阴性；腺癌中１８．１８％ｐ５３阳性，但均为弱阳性，局灶型，而腺癌组织中４２．１１ｐ５３阳性，其中７５％为强阳性或阳性；癌组织中ｐ５３阳性表达与大肠癌的分化、组织学类型、侵范围是淋巴结转移等因素有关，低分化腺癌及粘液癌阳性率较高，ｐ５３阳性及强阳性者更易于侵出肌层及发生淋巴结转移     

Localization of CEA,HCG, Lysozyme,alpha-1-antitrypsin,and alpha-1-antichymotrypsin in gastric cancer and prognosis

Summary Carcinoembryonic antigen (CEA),-human chorionic gonadotropin (HCG), alpha-1-antichymotrypsin (ACT), alpha-1-antitrypsin (AAT) and Lysozyme (LYS) were traced by immunoperoxidase staining in gastric carcinomas. The immunohistological results were evaluated in relation to histological types (WHO and Laurén), stage of disease, grade and survival time. CEA was demonstrated in 96% of the tumours, HCG in 34%, ACT in 78%, AAT in 42%, and LYS in 71%. Comparing the staining patterns of the antigens and the intensity of staining some differences were notable. Except for signet-ring cell carcinomas, all of which were intensively positive, CEA expression decreased significantly with loss of differentiation. This observation was not seen with the other marker substances. None of the tested markers was characteristic for one particular histological type, nor could they be correlated with the tumour stage or grade. The marker positivity of CEA, ACT and LYS was not related to survival time. For HCG only, a correlation between tissue expression and a restricted survival time was established. Patients with AAT positive carcinomas had a significantly better survival probability.     

EXPRESSION OF CRIPTO IN HUMAN GALL BLADDER LESIONS

The expression of cripto, a member of the epidermal growth factor (EGF) family, was examined by immunohistochemistry in benign lesions and carcinomas of the gall bladder. Cripto expression was detected in 6 (67 per cent) of 9 hyperplasias, 4 (58 per cent) of 7 adenomas, and 89 (68 per cent) of 132 adenocarcinomas of the gall bladder. The degree of cripto expression was not correlated with depth of tumour invasion, tumour stage or patient prognosis. The incidence of cases with cripto expression was significantly higher in papillary and well-differentiated adenocarcinomas (positive 73 per cent; strongly positive 38 per cent) than in moderately and poorly differentiated adenocarcinomas (positive 54 per cent; strongly positive 17 per cent) ( P <0·05). These results suggest that cripto expression may not relate to progression in gall bladder carcinomas, but may be associated with tumour differentiation.     

GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker

OBJECTIVE:

To analyze glucose transporter 1 expression patterns in malignant tumors of various cell types and evaluate their diagnostic value by immunohistochemistry.

INTRODUCTION:

Glucose is the major source of energy for cells, and glucose transporter 1 is the most common glucose transporter in humans. Glucose transporter 1 is aberrantly expressed in several tumor types. Studies have implicated glucose transporter 1 expression as a prognostic and diagnostic marker in tumors, primarily in conjunction with positron emission tomography scan data.

METHODS:

Immunohistochemistry for glucose transporter 1 was performed in tissue microarray slides, comprising 1955 samples of malignant neoplasm from different cell types.

RESULTS:

Sarcomas, lymphomas, melanomas and hepatoblastomas did not express glucose transporter 1. Forty-seven per cent of prostate adenocarcinomas were positive, as were 29% of thyroid, 10% of gastric and 5% of breast adenocarcinomas. Thirty-six per cent of squamous cell carcinomas of the head and neck were positive, as were 42% of uterine cervix squamous cell carcinomas. Glioblastomas and retinoblastomas showed membranous glucose transporter 1 staining in 18.6% and 9.4% of all cases, respectively. Squamous cell carcinomas displayed membranous expression, whereas adenocarcinomas showed cytoplasmic glucose transporter 1 expression.

CONCLUSION:

Glucose transporter 1 showed variable expression in various tumor types. Its absence in sarcomas, melanomas, hepatoblastomas and lymphomas suggests that other glucose transporters mediate the glycolytic pathway in these tumors. The data suggest that glucose transporter 1 is a valuable immunohistochemical marker that can be used to identify patients for evaluation by positron emission tomography scan. The function of cytoplasmic glucose transporter 1 in adenocarcinomas must be further examined.     

Expression of vascular endothelial growth factor in human gastric carcinomas

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a secreted protein which may play a pivotal role in tumor-associated microvascular angiogenesis and hyperpermeability. The expression of mRNA for VEGF was examined in eight gastric carcinoma cell lines and 30 gastric carcinoma tissues as well as corresponding normal mucosa. All the cell lines expressed VEGF mRNA at various levels that correlated well with the amounts of VEGF secreted into the condition medium. The expression of VEGF mRNA by TMK-1 cells was increased by the treatment of epidermal growth factor (EGF) or interleukin-1α (IL-1α), whereas it was decreased by the treatment of interferon-β (IFN-β). In gastric carcinoma tissues, the level of VEGF mRNA in primary tumors was higher than that in the corresponding normal mucosas in six (46%) of 13 well-differentiated adenocarcinomas and in two (12%) of 17 poorly differentiated adenocarcinomas, respectively. Vessel counts in well-differentiated adenocarcinomas had a tendency to be higher than those in poorly differentiated adenocarcinomas. In well-differentiated adenocarcinomas, the levels of VEGF mRNA expression tended to be higher in carcinomas of advanced stage than in early stage carcinomas. Both in situ mRNA hybridization and immunohistochemistry demonstrated the presence of VEGF expression within the tumor cells. These results suggest that VEGF may confer angiogenesis and progression of human gastric carcinomas, especially of the well-differentiated type.     

Expression of alpha-1-antichymotrypsin in prostate carcinoma.

Prostate specific antigen (PSA) is a glycoprotein with the enzymatic activity of serine protease, the gene which is encoded in the human glandular kallikrein gene locus. Catalytically active PSA released into serum may be inactivated by a complex formation with alpha 1ACT (ACT) and alpha 2MG (MG), two major protease inhibitors. The serum complex-to-total PSA ratio can be used as a marker for the differentiation between prostate carcinoma (PCa) and a benign lesion because of a significant elevation of PSA binding to ACT in PCa. Apparently higher immunohistochemical expressions of PSA and ACT have been reported in PCa of low Gleason scores when compared with benign lesions. The fact that only normal secretory epitheliums are capable of producing ACT was recently proved by immunohistochemical and in situ hybridization methods. Our immunohistochemical study of ACT showed a tendency toward stronger expression in high Gleason grade PCa than in low Gleason grade Pca. Prostate intraepithelial neoplasia (PIN), as well as BPH, seldom react to ACT. Expression of ACT in normal ducts or acini was influenced by their location. In a normal prostate, expression of ACT was predominantly in secretory epithelial cells, with a minority of basal cells and rarely in the interdigitating neuroendocrine cells. Whereas the potency of ACT production in epithelial cells almost always appeared to be suppressed under normal conditions, it was noted that a strong expression of ACT was apparent in the normal ducts or acini near a high grade carcinoma with a weak reaction to ACT. ACT expression is much more enhanced in high grade carcinomas and in the residual normal acini adjacent to carcinomas of low ACT expression, presumably representing scale down the elevated PSA.     

Molecular characterization of undifferentiated-type gastric carcinoma

As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.     

Interaction between transforming growth factor-alpha and c-Ha-ras p21 in progression of human gastric carcinoma

The expression of TGF alpha and c-Ha-ras p21 was studied immunohistochemically in a total of 174 gastric carcinomas, comprising 27 early carcinomas and 147 advanced carcinomas. TGF alpha-immunoreactivity was detected in 7 (25.9%) of the 27 early carcinomas and in 110 (74.8%) of the 147 advanced carcinomas, the incidence being significantly different between the two (P less than 0.01). Out of the 67 c-Ha-ras p21 positive carcinomas, 59 (88.1%) showed TGF alpha-immunoreactivity synchronously. A significant positive correlation was observed between the grade of TGF alpha and incidence of c-Ha-ras p21-immunoreactivity in tumor cells (P less than 0.01). Furthermore, a good correlation was demonstrated between synchronous expression of TGF alpha and c-Ha-ras p21 and depth of tumor invasion (P less than 0.01). The incidence of synchronous expression of TGF alpha and c-Ha-ras p21 in metastatic tumors was significantly higher than that in primary tumors showing no lymphatic metastasis (P less than 0.01). Patients with carcinomas showing synchronous expression of TGF alpha and c-Ha-ras p21 had an extremely poorer prognosis than those without TGF alpha and c-Ha-ras p21. These results indicate that the synchronous expression of TGF alpha and c-Ha-ras p21 plays an important role in high malignancy of gastric carcinomas.     

Disturbed expression of the apoptosis regulators XIAP, XAF1, and Smac/DIABLO in gastric adenocarcinomas.

Dysregulation of apoptosis plays an important role in carcinogenesis and tumor progression. Whereas x-linked inhibitor of apoptosis (XIAP) is a potent inhibitor of apoptosis, its antagonists second mitochondria-derived activator of caspases/direct IAP binding protein with low PI (Smac/DIABLO), and XIAP-associated factor 1 (XAF1) promote apoptosis. To explore the relevance of XIAP, Smac/DIABLO, and XAF1 for carcinogenesis and tumor progression, we analyzed 46 primary gastric adenocarcinomas and non-neoplastic gastric mucosa samples by quantitative real-time polymerase chain reaction. XIAP, Smac/DIABLO, and XAF1 expression was found in all non-neoplastic gastric mucosa samples and all adenocarcinomas. XIAP expression levels did not change between non-neoplastic gastric mucosa and adenocarcinomas or between carcinomas of early and advanced stages. Although Smac/DIABLO expression was significantly (P=0.01) higher in carcinomas, the ratio of XIAP to Smac/DIABLO expression remained stable between non-neoplastic mucosa and carcinomas. XAF1 expression had the tendency to decrease from non-neoplastic mucosa to advanced adenocarcinomas. Importantly, the ratio of XIAP to XAF1 expression significantly (P=0.03) increased from non-neoplastic mucosa to adenocarcinomas and the increase was even higher in carcinomas of advanced stage (P=0.01). Moreover, expression of the XAF1 splice variants differing in the zinc-finger domain essential for XIAP-binding was analyzed and revealed a significant higher (P=0.03) variant-2/variant-1 ratio in advanced carcinomas. In conclusion, an increased expression ratio of XIAP to XAF1 in combination with a disturbed expression of the XAF1 splice variants could be shown in gastric adenocarcinomas. These marked imbalances probably result in an impaired ability for XAF1 to antagonize the effects of XIAP thereby contributing to apoptosis-resistance and generating an important growth advantage.     

Application of the crypt isolation technique to the flow cytometric analysis of DNA content in gastric carcinoma

An inevitable limitation of conventional flow cytometric analysis of gastric cancer DNA content is that the preparations of tumor cell nuclei are contaminated with stromal cell nuclei. Using the crypt isolation technique, we separated tumor tissues from stromal tissues and analyzed the DNA content in samples of pure gastric cancer cells (64 intestinal-type and 46 diffuse-type) by flow cytometry. Morphologically, crypts from well-differentiated and moderately differentiated adenocarcinomas usually showed large tube-like or sheet structures, whereas tumor tissues isolated from poorly differentiated adenocarcinomas usually exhibited small tumor cell clumps or clusters of varying sizes. Tumor ploidy was divided into diploid, aneuploid, and multiploid subgroups. Aneuploidy and multiploidy were observed in 12% (13 of 110) and 64% (71 of 110) of gastric cancers, respectively. A high frequency of DNA aneuploidy or multiploidy was associated with intestinal-type tumors, but not with any of the other clinicopathologic variables tested. In contrast, high S-phase fraction values demonstrated a close association with tumors with abnormal ploidy, advanced stage, intestinal type, and late TNM stage. Our results suggest that S-phase fraction may be a more useful indicator of aggressive behavior in gastric cancers than DNA aneuploidy. To our knowledge, the present study is the first to report flow cytometric DNA content in a large number of gastric cancer samples obtained using the crypt isolation technique.     

Host defense factors, tumor aggressiveness, and prognosis associated with carcinomas of the breast

Analysis of disease-free survival rates in 405 women with operable breast cancers was undertaken in a five-year retrospective study; tumor aggressiveness and host defense factors ( HDF ) were evaluated by a histologic method. Tumors were classified as slightly, moderately, or highly aggressive carcinomas by a scoring method that takes into account several histologic features. The presence of absence of HDF was determined by nodal sinus histiocytosis in the regional axillary lymph nodes and by stromal mononuclear reaction in the primary tumor. Overall, women with positive HDF had better cumulative five-year survival rates (76 per cent) than women with negative HDF (49 per cent). The combination of highly aggressive tumors, metastatic lymph nodes, and negative HDF was associated with extremely poor five-year survival rates (1 per cent) compared with those observed for women with aggressive tumors, nodal metastases, and positive HDF (30 percent), P less than 0.001. In this group, patients with four or fewer metastatic nodes showed a recurrence rate of 28 per cent; however, if five or more nodes were involved, the recurrence rate was 93 per cent. This pattern in disease-free survival rates related to HDF was not found in slightly or moderately aggressive tumors with or without metastases or in aggressive tumors without metastases. In addition, there was no relation between the number of metastatic nodes and survival in patients with slightly or moderately aggressive tumors or with aggressive tumors and negative HDF . It is concluded that HDF influence survival only in aggressive tumors with metastases and that the inherent aggressiveness of the tumor is the main factor that determines prognosis.     

Clinical correlations of alpha2,6-sialyltransferase expression in colorectal cancer patients

We have previously demonstrated a link between alpha2,6-Sialyltransferase (alpha2,6-ST; E.C. 2.4.99.1) expression and differentiation of colon tumors. So far, information is not available relative to the expression of alpha2,6-ST in tumors and the survival of patients with colorectal cancer. We have examined the expression of alpha2,6-ST in a variety of colorectal adenocarcinomas (n = 46) at different stages of differentiation (G1 to G3) by immunoperoxidase assay using monoclonal antibody (MAb) 6B9. Clinical outcome of the patients in a 5-year follow-up study has been correlated with the expression of alpha2,6-ST in tumors surgically removed from the same patients. No significant difference in the alpha2,6-ST expression was noted when age, sex, and tumor locations (colon, rectum) were included as parameters. However, 52% of the moderate (G2) and well-differentiated (G1) adenocarcinomas showed stronger alpha2,6-ST expression compared with poorly differentiated (G3) adenocarcinomas. Notably, absence to moderate levels of tumor alpha2,6-ST expression was correlated with 100% survival in patients with stage I and II tumors compared with 64% survival in patients with strong tumor alpha2,6-ST expression (p < 0.01). These studies suggest a negative correlation between the expression of alpha2,6-ST in tumors and a good clinical outcome in colorectal cancer patients.     

Expression of hepatocyte nuclear factor 4 alpha in primary ovarian mucinous tumors

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a member of the nuclear receptor superfamily and is expressed in several endodermal tissues. The aim of the present study was to examine the expression of HNF4 alpha on ovarian epithelial tumors with immunocytochemistry and immunohistochemistry using mAbs recognizing P1 and P2 promoter-driven HNF4 alpha. Ovarian mucinous adenoma, mucinous tumors of borderline malignancy, and mucinous adenocarcinoma had positive nuclear staining for HNF4 alpha (41/45, 91%). One-third (34%) of mucinous tumors had P1-positive staining and most had P1/P2-positive staining (93%). MUC2- and MUC5AC-positive staining was observed in 34% and 95% of mucinous tumors, respectively. The histological subtype of these mucinous tumors was not correlated with HNF4 alpha expression. On cytology it was found that cancer cells in the ascites from ovarian mucinous adenocarcinomas were HNF4 alpha positive, but tumor cells in ascites from other types of ovarian carcinomas were negative for HNF4 alpha. Thus, HNF4 alpha is demonstrated to be a useful marker for histological and cytological diagnosis of ovarian mucinous tumors.