The pathology of the gastrointestinal endocrine system.

Among endocrine tumors occurring in the gastrointestinal tract, midgut argentaffin EC cell carcinoids, gastric argyrophil ECL cell carcinoids, duodenal gastrin cell tumors, and rectal trabecular L cell carcinoids (in order of decreasing frequency) are those occurring more frequently. Together, they account for more than 80% of such tumors. Duodenal somatostatin cell tumors, gangliocytic paragangliomas, and differentiated neuroendocrine carcinomas are also well-defined tumor entities. The carcinoid syndrome, either classical, with intermittent flushing, hypotension, and diarrhea, or atypical, with persistent histamine-type red flushing, bronchospasm, and no diarrhea, and Zollinger-Ellison syndrome, with severe peptide ulcer disease, are the only hyperfunctional syndromes consistently found in association with these tumors. The carcinoid syndrome occurs in about 10% of gastrointestinal carcinoids, usually in their advanced, metastatic stage. The Zollinger-Ellison syndrome occurs in association with about 40% of intestinal gastrin cell tumors, including small intramural growths. Tumor prognosis depends on the mode and site of presentation, histology, cell type(s), size, level of invasion, metastases (especially distant metastases), and associated clinical syndrome or background disease. Hormones, trophic factors, inherited genetic traits, somatic mutations, and some chronic inflammatory processes are pathogenetically important in a large proportion of cases.

The foveolar cell component of gastric cancer.

M1, a mucin antigen, and cathepsin E, an aspartic proteinase, are both expressed in normal gastric superficial-foveolar epithelial cells. In this study, we determined by immunohistochemical staining the prevalence of these antigens in 316 gastric cancers representative of the main histologic types and stages of the disease. M1 was expressed in 201 cases (64%) and cathepsin E was expressed in 235 cases (75%) of the 313 cases investigated. Both antigens were expressed more commonly in diffuse and mixed cancers than in glandular tumors. M1 was found in 64 of 83 (77%) diffuse cancers and in 48 of 59 (81%) mixed cancers, but in only 74 of 146 (51%) glandular cancers. For cathepsin E, the prevalence was 93% in diffuse cancer, 81% in mixed cancer, and 71% in the 143 glandular cancers examined. Among 25 mucoid tumors, 15 (60%) expressed M1 but only eight (32%) expressed cathepsin E. Overall, 262 (84%) of the tumors expressed at least one of these antigens and of these, 173 (66%) expressed both antigens. No significant difference in the prevalence of M1 or cathepsin E was found between early and advanced cancer or between metastatic and nonmetastatic cancer. The two markers differed in their intracellular localization. In superficial-foveolar cells, M1 immunostaining was concentrated in secretory granules, Golgi complex, and luminal mucous, whereas cathepsin E was found in the endoplasmic reticulum. Moreover, cathepsin E, but not M1, was found in the enterocytes of duodenal villi and, occasionally, in mucopeptic cells. Parallel histochemical and ultrastructural investigations confirmed the occurrence in gastric cancer of foveolar-type cells, manifested by periodic acid-Schiff- and/or alcian blue-reactive mucous granules having a punctate substructure. We conclude that superficial-foveolar cell differentiation is common in gastric cancer and is a major component of this type of tumor. However, pure foveolar cell differentiation is rare. Rather, most gastric cancers consist of cells exhibiting features of foveolar, intestinal, and mucopeptic cell lines.

Effects of the angiotensin converting enzyme inhibitor enalapril on bacterial translocation after thermal injury and bacterial challenge.

Burn injury and sepsis produce acute gastrointestinal derangements that may predispose patients to bacterial translocation. We studied the effects of enalapril, an angiotensin converting enzyme inhibitor (ACEI), on gastrointestinal anatomic alterations, bacterial translocation, and related mortality during gut-derived sepsis in burned mice that had received a prior bacterial challenge. BALB/c mice (n = 111) were treated with enalapril 10 or 1 mg/kg body weight or sterile saline as control twice daily for 3 days. They were then gavaged with 10(a)111 in radiolabeled or unlabeled Escherichia coli and given a 20% total body surface area (TBSA) burn injury. Animals gavaged with unlabeled bacteria were observed for survival (n = 60). Survival was significantly higher in the group receiving enalapril 10 mg/Kg compared with control (75% vs. 10%). Mice treated with enalapril maintained small intestine weight, measured 4 h postburn, and ileal mucosal height was preserved, whereas burned untreated animals lost intestinal weight and mucosal height. Bacterial translocation was decreased in mice treated with enalapril, but killing was unaffected. This study suggests that treatment with enalapril positively affects the outcome in gut-derived sepsis by ameliorating gastrointestinal structural and functional damage and decreasing bacterial translocation.

Widespread expression of intestinal markers in gastric carcinoma: a light and electron microscopic study using BD-5 monoclonal antibody.

BD-5 monoclonal antibody reacted with tumour cells in 262 of 316 cases of gastric cancers, including 121 of 134 early, 141 of 182 advanced tumours (p less than 0.01), and 113 of 146 glandular, 72 of 83 diffuse, 22 of 25 mucoid, and 55 of 59 mixed tumours. No difference in reactivity was observed between metastatic and non-metastatic advanced tumours. Immunocytochemical techniques applied to light and electron microscopical specimens of colorectal mucosa and gastric cancer showed that BD-5 immunoreactive material occurred in the Golgi complex, in small clear, to dense cored, cytoplasmic vesicles, and in the glycocalix of the luminal and lateral membranes of normal and neoplastic cells in the glands, as well as in the peripheral membrane of dispersed neoplastic cells. Mucin granules stored in the cytoplasm of goblet cells were unreactive or poorly reactive. Ultrastructural features consistent with colorectal type differentiation were observed in many reactive tumours. Unreactive tumours showing ultrastructural patterns consistent with intestinal differentiation, especially of small bowel type, were also observed. Signs of intestinal differentiation, including BD-5 immunoreactivity, often occur in gastric cancer, irrespective of histological type and stage of disease.

The role of histological investigation in prognostic evaluation of advanced gastric cancer. Analysis of histological structure and molecular changes compared with invasive pattern and stage.

The relative contribution of tumour histology or molecular changes, compared with invasion pattern or stage, to prognostic assessment of gastric cancer was investigated in a series of 185 advanced (T2 to T4, stage IB to IV) cancers that had undergone intentionally curative surgery at Varese General Hospital. Survival analysis of the histological types considered in commonly used classifications, such as Lauren, Kubo, the World Health Organization (WHO) and related classifications, allowed separation of a small high-grade (Hg, 12 cases) group of adenosquamous, anaplastic and small cell endocrine carcinomas from a large cohesive group (C, 86 glandular or solid cancers) and from another large (87 cases) group of tumours with dissociated cells [29 diffuse (D) and 58 mixed (M) tumours]. Univariate and multivariate analysis showed the independent prognostic value of this C/M+D/Hg classification approach, which proved superior to other classifications and to cell dissociation at the growing front or angio, lympho and neuro-invasion. Expression of sialyl Lewis(c), the DUPAN-2 antigen, proved to be an independent predictor of worse survival among tumours beyond stage I, showing an exclusively or predominantly cohesive structure. Microsatellite instability (MSI) predicted favourable survival in purely cohesive tumours of intermediate (II) stage, especially of solid/medullary and lymphoid stroma/lympho-epithelioma-like structure, among which two distinct tumour subsets were characterised, one MSI-positive and the other Epstein-Barr virus positive. T2NOM0 (stage IB) tumours showed mostly favourable survival independently from histological type, invasive pattern, DUPAN-2 or MSI status. It is concluded that an appropriate histological evaluation, coupled with sialylated glycoproteins histochemistry and, for stage-II tumours, MSI tests may contribute significantly to prognostic assessment of tumours beyond stage I. However, the stage itself, with special reference to lymph-node metastases and invasion level beyond subserosa, remains the most important prognostic clue for gastric cancer.

Neoplastic cells containing lysozyme in gastric carcinomas.

A case of gastric carcinoma mostly composed of cells with histological, immunohistochemical and ultrastructural features of Paneth cells prompted a comparative investigation of the occurrence of similar cells in gastric, colorectal and mammary carcinomas. Cells containing lysozyme were demonstrated by the immunoperoxidase-PAP technique in 34.9% of 83 gastric carcinomas. They were found in 38% of intestinal-type and in 30% of diffuse-type tumours. Paneth-type granules were demonstrated ultrastructurally in 4 of 7 carcinomas in which lysozyme had been demonstrated immunohistochemically. No lysozyme was demonstrated in a series of 30 breast carcinomas and in only 1 of 27 cases of colorectal neoplasm. The possibility of using lysozyme as a marker for some carcinomas of gastric origin is considered.

Primary malignant duodenal tumours: a point of view and a proposal of classification.

To date, malignant duodenal tumours have remained obscure subject-matter although they were first described in the eighteenth century. Recent development in technology and in anatomohistopathology makes it necessary to review the duodenal tumours classification, especially in relation to the progressive development of stromal and neuroendocrine forms. In the literature, precise epidemiological data are not reported and, as regards some duodenal tumours, simply do not exist. Series are generally either surgical, anatomopathological or gastroenterological. Hospital centres need to establish a collaboration which gathers new observed cases to avoid the dispersion of case series. Thus, a European Register will be established to report the real incidence by analyzing the specific differential elements.

Duodenal gastric metaplasia, gastric anatomic-functional correlations (parietal cell mass and hydrochloric acid secretion) and Helicobacter pylori. Any differences between chronic autonomous non-specific duodenitis ("non active") and duodenal ulcer?

BACKGROUND AND METHODS: Aim of the present experience was to carry out a study on a dyspeptic population in order to verify the role of Helicobacter Pylori (HP), duodenal gastric metaplasia (GM), hydrochloric acid secretion in the genesis of chronic autonomous non-specific duodenitis (ANSD). A comparison with duodenal ulcer (DU) was effected. RESULTS: Histology showed the presence of ANSD in 24.6% of dyspeptic population. GM was present in 15.1% of ANSD, in 12.8% of dyspepsia without ANSD and in 78.1% of DU. HP in duodenum was present in 12.1% of ANSD, in 10.8% of cases of dyspepsia and in 75% of DU. Concerning parietal cell mass and acid secretion in ANSD and in dyspepsia was found a prevalence of normoparietalism with normochlorhydria, while in DU was found a prevalence of hyperparietalism with hyperchlorhydria. This study shows that the role of HP has not a well defined etiologic weight in ANSD. CONCLUSIONS: The observations of the present experience, which differentiate ANSD and DU, lead to exclude a pathogenetic relation between ANSD and DU.

Helicobacter pylori influence on gastric acid secretion in duodenal ulcer patients diagnosed for the first time.

BACKGROUND: Many experiences have hypothesised that Helicobacter pylori induced hypergastrinemia could lead to an increase of the parietal cell mass and, consequently, of acid secretion. METHODS: The parietal cell mass and maximal acid output have been studied in patients with duodenal ulcer diagnosed for the first time, not due to drugs assumption. In particular, it has been evaluated the parietal cell mass and the acid secretion subdividing duodenal ulcer patients in relation to gastrinemia values (hypergastrinemia and normogastrinemia). RESULTS: The parietal cell mass and the maximal acid output remain high independently of Helicobacter pylori presence. About 60% of the subjects in the Helicobacter pylori positive group show gastrinemia values higher than the average: neither did the study reveal in this group any variations in the parietal cell mass and acid secretion. CONCLUSIONS: It emerges from the results that the mild chronic hypergastrinemia in Helicobacter pylori positive duodenal ulcer is not important enough to induce an increase in parietal cell mass and acid secretion. Therefore, Helicobacter pylori eradication is important in relapse prevention of duodenal ulcer, but not for its repercussions on the gastric secretion.

p53 and Ki-67 expression in epithelial gastric dysplasia and in gastric cancer.

BACKGROUND: The aim of this study was to examine p53 and Ki-67 expression in relation to high grade dysplasia (HGD) clinical behaviour. METHODS: A retrospective, cross sectional study was conducted on mucosal biopsies from the stomach of 38 consecutive cases of HGD (25 males, average age: 57.5). The studied samples are represented by gastric biopsies obtained in course of gastroscopy for dyspepsia (at least 8 biopsies). HGD diagnosis was done by experienced pathologists (MC, DG) according to Goldstein's criteria. There were 12 non-dysplastic controls (7 males, average age: 49.4). The immunohistochemical study has been led with the utilization of a p53-antibody. For the cell proliferation assay, the sections were incubated with the MM1 monoclonal antibody. The clinical outcome subdivision of HGD was effected using the criteria of Rugge et al. For the classification of gastric cancer (GC): UICC TNM. RESULTS: p53 positivity has been evidenced in 65.5% of cases, while hyperproliferation in 100% of cases. That independently of the clinical behaviour. CONCLUSIONS: p53 positivity has been found only in part of the HGD cases and moreover a number of HGD with low or absent p53 scores has been found associated with high proliferation indices independently of the clinical evolution. This dissociation of cell kinetics and p53 expression suggests that other genetic events contributing to unregulate cell proliferation may occur in these lesions.

[Changes in hormonal and biochemical parameters in gastric adenocarcinoma]. / Modificazioni di parametri ormonali e biochimici nell'adenocarcinoma gastrico.

In 51 patients with gastric adenocarcinoma the fasting blood concentrations of hCG, beta hCG, alpha subunits, ADH, calcitonin, enteroglucagon, gastrin, GH, melatonin, somatostatin, estradiol, CEA and pepsinogen I in the peripheral vein were estimated by radioimmunoassay at the time of diagnosis and, in those who underwent surgery, 7 days after the operation, to determine the incidence of the modifications of the above mentioned substances' blood levels and the existence of possible markers. In presence of increases of the examined parameters greater than 50%, considering M +/- 2 SD of 10 control subjects as normal range, the tumours were examined immunohistochemically. In patients with gastric adenocarcinoma, in comparison with normal subjects, we found significant higher blood levels of hCG alpha subunits, gastrin and CEA and lower of melatonin, pepsinogen I and GH. The immunohistological results demonstrated CEA in both examined cases, alpha subunits in 2 of 6 (respectively in dysplasic areas and in surrounding non neoplastic mucosa) and enteroglucagon in 1 of 3 (dysplasic areas). Our results indicate that none of the parameters we examined, because of their non-specificity or of the low incidence of their modifications, can be considered a marker of gastric adenocarcinoma.

Histopathology, cytology and cytochemistry of pheochromocytomas and paragangliomas including chemodectomas.

The results of histopathological, histochemical and ultrastructural investigations on pheochromocytomas and paragangliomas have been reported. These results allowed the functional identification of the cell types composing many of such tumours. Moreover, comparison of these data with clinico-pathologic findings outlined the advantages and limits of cytologic studies for understanding the natural history of pheochromocytomas and paragangliomas and improving our diagnostic and prognostic criteria.

Characterization of four main cell types in gastric cancer: foveolar, mucopeptic, intestinal columnar and goblet cells. An histopathologic, histochemical and ultrastructural study of "early" and "advanced" tumours.

Gastrectomy specimens of 148 gastric cancers, 40 of them being intramucosal or microinvasive, 27 penetrating the submucosa and 81 invading the muscularis propria, with or without involvement of the serosa and perigastric tissues, have been investigated with conventional histopathologic techniques, mucin histochemistry and electron microscopy to characterize the various lines of tumour cell differentiation and to correlate these with the histologic patterns of tumour growth. More or less differentiated intestinal columnar, intestinal goblet, gastric foveolar or mucopeptic cells were recognized in most tumours, of glandular, diffuse or mucoid type. Although simultaneous expression of more than one cell type into the same tumour occurred very frequently, intestinal columnar cells were more prominent in tubular adenocarcinomas, goblet cells (especially of colorectal type) in mucoid cancers, mucopeptic cells in diffuse cancers of invasive desmoplastic type and foveolar cells in diffuse cancers of intramucosal signet-ring cell type. In general, an increased tendency to foveolar cell differentiation and a reduced tendency to mucopeptic differentiation has been found in intramucosal cancers as compared to invasive cancers. It is concluded that the type of tumour cell differentiation, which might have some influence on the natural history of gastric cancer, is better related with more defined tumour subtypes than with the usually recognized glandular or diffuse patterns.

Mixed endocrine-exocrine tumors of the gastrointestinal tract.

Mixed endocrine-exocrine tumors of the gastrointestinal tract are rare neoplasms, which have been reported in the literature mainly as case reports and have been designated with a various and rather confusing terminology. In this review, on the basis of personally studied cases and of the analysis of cases reported in the literature, we have tried to identify types of mixed endocrine-exocrine tumors showing different clinicopathologic and biological characteristics. We have also tried to group the different clinicopathologic entities in prognostic classes which include: benign, low-grade, intermediate grade, and high-grade malignant mixed endocrine-exocrine tumors. The criteria for identifying the various types of mixed endocrine-exocrine tumors are extensively discussed.

Cathepsin E in antigen-presenting Langerhans and interdigitating reticulum cells. Its possible role in antigen processing.

A specific rabbit anti-human cathepsin E serum detected this aspartic proteinase in Langerhans cells of the skin, in interdigitating reticulum cells of lymph nodes and spleen and in histiocytosis X cells, but not in macrophages. Immunoblotting of tissue extracts confirmed the presence of cathepsin E in skin and lymph nodes. Electron immunocytochemistry with the protein A gold technique localized cathepsin E in the endoplasmic reticulum and in endosomal vesicles of both interdigitating and Langerhans cells, likely involving Birbeck bodies. A role of endosomal cathepsin E in antigen processing is suggested.

Stimulated gastrinemia, parietal cell mass and stimulated acid secretion in autonomous chronic gastritis: Helicobacter pylori influence.

BACKGROUND/AIMS: In the present experience, an evaluation has been carried out of stimulated gastrinemia, parietal cell mass, and acid secretion in the course of a paradigmatic condition, such as autonomous chronic gastritis, in order to reveal possible changes induced by the presence of Helicobacter Pylori (HP). MATERIALS AND METHODS: We evaluated 153 patients with chronic gastritis of the antrum and/or body fundus, in different combinations not associated with peptic pathology. RESULTS: In the group of subjects with antral superficial chronic gastritis associated with normal body-fundic mucosa or with body-fundic superficial chronic gastritis, about 40% of the subjects in the HP positive group show gastrinemia values which are higher than the norm. The evaluation of parietal cell and stimulated acid secretion yielded no differences between the HP positive and HP negative groups: it emerges that these parameters vary exclusively according to the histologic state of the body-fundic mucosa. In the patients group with hypergastrinemia, the study has revealed no variations in parietal cell mass and acid secretion. CONCLUSION: Evidently the increase in gastrinemia in these subjects was not important enough to induce an increase in parietal cell mass and acid secretion. It emerges how the presence of HP does not imply substantial changes on the gastric cyto-functional parameters: these variations depend mainly on the histologic state of the gastric mucosa.

Gastric cyto-secretory correlations in peptic ulcer.

BACKGROUND/AIMS: Maximal acid output, parietal cell mass, serum pepsinogen A (PGA) and total peptic activity (TPA) in gastric juice were studied and compared in duodenal ulcer and in different gastric ulcer sites. METHODOLOGY: 152 peptic ulcer patients were studied. 64 cases of gastric ulcer (GU) were subdivided according to Johnsons's classification and compared with 88 duodenal ulcer (DU) patients diagnosed for the first time. 40 normal subjects were studied as controls. RESULTS: Duodenal ulcer is characterized by normo-hyperparietalism, normo-hyperchloridria and an increase in peptic activity. In cases of GU, such correlation is not only conditioned by the topographic seat of the ulcer, but by the histological condition of the gastric mucosa too. Body GU is characterized by hypoparietalism, hypochloridria, hyper-PGA and hyper-TPA. Pre-pyloric GU is characterized by normo-hyperparietalism, normo-hyperchloridria, hyper-PGA and hyper-TPA. In GU the cyto-secretory behavior is characterized by the histology of the body mucosa with prevalence of preatrophic-atrophic gastritis in case of body GU and prevalence of superficial gastritis in case of GU type II and III. CONCLUSIONS: The results confirm the anatomic-functional analogy between DU and type II and III GU. If considered from the functional point of view, these conditions differ considerably from those that are characteristic of type I GU (as they closely follow the chronic gastritis pattern).

Low incidence of hereditary nonpolyposis colorectal cancer syndrome in a selected area of the Lombardy Cancer Registry.

AIMS AND BACKGROUND: Epidemiological investigations on the frequency of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are few and have shown a variable worldwide incidence ranging from 1% to 7% of all colorectal cancers (CRCs). In Italy, relevant differences have been observed: 2.8-3% of all CRCs in northern regions and less than 1% in southern regions. The aim of the present study was to investigate the HNPCC incidence in a selected area of northern Italy belonging to the Lombardy Cancer Registry. METHODS AND STUDY DESIGN: We analyzed 197 consecutive patients with newly diagnosed CRCs, histologically verified, and resident in two areas of the Lombardy Cancer Registry. For each case, genetic counseling with at least three generations pedigree reconstruction, HNPCC classification according to Amsterdam criteria, molecular analysis for microsatellite instability and immunohistochemistry for hMLH1 and hMSH2 were performed. RESULTS: A very low frequency (0.5%) of HNPCC fulfilling the Amsterdam criteria was found in comparison to the other Italian areas. Such an incidence seems to be due to actual population differences and reflects a genetic heterogeneity. CONCLUSIONS: The data underline the importance of a precise knowledge of actual HNPCC incidence in different populations in order to optimize effectiveness and efficiency of screening programs for the disease.

[The parietal cell mass and acid secretion: Helicobacter pylori does not induce changes in the course of a duodenal ulcer]. / Massa cellulare parietale e secrezione acida: l'Helicobacter pylori non induce modificazioni in corso di ulcera duodenale.

Some studies have postulated that Helicobacter pylori (HP) itself might be responsible for hypergastrinemia and acid secretion in duodenal ulcer (DU). In each DU patient parietal cell mass (expressed by a parietal index) and stimulated acid secretion (expressed by maximal acid output) were evaluated. The study has been conducted grouping DU patients in relation to HP infection in antral mucosa. HP infection does not modify parietal cell mass and stimulated acid secretion. Therefore, mild chronic hypergastrinemia induced by HP infection is not sufficient to justify any increase of parietal index and acid secretion. In fact, parietal cells and acid secretion remain higher in DU subjects independently from HP infection.

[Helicobacter pylori, chronic gastritis and precancerous gastric manifestations]. / Helicobacter pylori, gastrite cronica e manifestazioni precancerose gastriche.

Helicobacter Pylori (HP) has been noticed in about 80% of cases of superficial chronic gastritis. In about 75% of HP positive biopsies degenerative lesions of superficial gastric epithelium, represented by irregularities of the superficial profile, micropapillar-transformation and erosions have been observed. Furthermore, it is possible the observation, in areas of high bacterial colonization, of vacuoles which are the result of a direct action of HP strains producing vacuolating cythotoxin. In correspondence with the glandular necks active inflammation is present in about 90% of cases. Hp is responsible, by means of direct cytotoxicity and inflammatory cell aggression, of most superficial gastritis, it may help the evolution towards atrophic gastritis and may superimpose on an already noted gastritis situation, promoting their inflammatory exacerbation. The presence of HP infection decreases with the increase histological damage: superficial gastritis (SG) 89%, atrophic gastritis (AG) 58%, intestinal metaplasia (IM) 51% and dysplasia (D) 47%. The founding of the bacterium in conditions such as AG or in surrounding zones IM or D is the demonstration of a possible role of the bacterium in the development of the phases subsequent to AG or of phenomena like IM and D, and not confined to the already verified passage SG/AG. The continuous rearrangement in correspondence with the glandular necks induced by active inflammation HP induced and the subsequent hyperproliferation may help mytotic error, giving rise to metaplastic or dysplastic cellular lines. Therefore, HP in the progression towards IM and D should act as promoter by means of the increase of cellular kinetics.