Cesare Bordi

Gastric carcinoids and neuroendocrine carcinomas : Pathogenesis, pathology, and behavior

Abstract. The goal of this study was to provide information of prognostic value for gastric endocrine tumors. A total of 205 gastric endocrine tumors have been studied: 193 well differentiated tumors [2 gastrin cell tumors, 191 enterochromaffin-like (ECL) cell tumors] and 12 poorly differentiated carcinomas. Subtyping of ECL cell tumors (carcinoids) resulted in 152 associated with chronic atrophic gastritis (CAG) (type 1); 12 associated with hypertrophic gastropathy (HG) due to Zollinger-Ellison syndrome with multiple endocrine neoplasia type I (type 2), and 27 with no specific association (type 3, sporadic). Type 1 cases occurred most often in female (108 of 152), elderly (mean 63 years) patients, with no tumor-related death at an overall mean follow-up of 53 months. The 12 type 2 cases were equally distributed between the sexes (six of each), with a mean age of 45 years; there was one tumor-related death (49 months after diagnosis) and an overall mean survival of 84 months. Type 3 cases were mostly in men (20 of 27), with a mean age of 55 years; there were seven tumor-related deaths at a mean follow-up of 28 months. Poorly differentiated neuroendocrine carcinomas were observed in elderly patients (mean 63 years, range 41–76 years) of both sexes, with nine tumor-related deaths and a mean survival of 7 months. It was concluded that correct clinicopathologic subtyping may predict the clinical behavior of gastric endocrine tumors.

ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: Prognostic evaluation by pathological analysis

BACKGROUND & AIMS Gastric endocrine tumors show a wide spectrum of clinical behavior, and prognostic assessement of individual tumors is difficult. The aims of this work were to identify predictors of tumor malignancy and patient outcome and to provide a rationale for treatment guidelines. METHODS Gastric endocrine tumors (86 enterochromaffin-like cell carcinoids and 16 poorly differentiated carcinomas) were investigated for 15 clinicopathologic variables and for expression of Ki67, P53, and BCL-2 proteins. Data were analyzed by univariate and multivariate statistics for evidence of tumor malignancy and patient survival. RESULTS Histological grades 2 and 3, size >/=3 cm, 9 or more mitoses, or >/=300 Ki67-positive cells per 10 high-power fields identified 26 of 33 (79%) malignant (metastatic or deeply invasive) tumors, and size <1 cm and/or growth restricted to the mucosa characterized 46 of 69 (67%) tumors with benign behavior during a median follow-up of 39 months. Malignancy-predictive models were developed using angioinvasion, size, clinicopathologic type, mitotic index, and Ki67 index. The same variables, in addition to deep gastric wall invasion and histological grade, predicted patient outcome. CONCLUSIONS Criteria for the assessment of malignancy risk and patient outcome were developed for the different tumors, providing a basis for treatment guidelines.

Histopathological Classification of Nonantral Gastric Endocrine Growths in Man

Recently, the gastric endocrine system has been recognized as the origin of benign and malignant tumors in pernicious anemia. It has also been found that the gastric endocrine cells respond to permanent elevation of serum gastrin levels induced by changes in acid secretion in response to surgical procedures, drug therapy and age. Therefore, a definition of nonantral gastric endocrine hyperplasia (simple or diffuse, linear or chain-forming, micronodular, adenomatoid), dysplasia (enlarging or fusing micronodules, microinvasion, nodular growth) and neoplasia (intramucosal carcinoid, invasive carcinoid) is presented. The individual entities are illustrated, together with the literature discussed and the techniques for their identification presented.

The "normal" endocrine cell of the gut: changing concepts and new evidences.

Abstract: The endocrine cells of the gut are a highly specialized mucosal cell subpopulation. Within the gastrointestinal tract at least 14 different cell types produce a wide range of hormones with a specific regional distribution. The gut endocrine cells belong to the diffuse endocrine system. These cells present two regulated pathways of secretion characterized by large dense core vesicles (LDCV) and synaptic‐like microvesicles (SLMV). Gut endocrine cells are recognized by the expression of several “general” markers, including the LDCV marker chromogranin A and the SLMV marker synaptophysin, in addition to the cytosolic markers neuron‐specific enolase and protein gene product 9.5. The expression of different hormones identifies specific cell types. The gut endocrine cells are reputed to be terminally differentiated and incapable of proliferation. However, some data suggest that the number of gut endocrine cells may adapt in response to tissue‐specific physiological stimuli. Gut endocrine cell differentiation appears to follow a “constitutive” tissue‐specific pathway, which may be disrupted and investigated by genetic manipulation in mice. It is suggested that endocrine cell homeostasis is maintained by the entry of new endocrine‐committed cells along the differentiation pathway and that such intermediate cells may be sensitive to physiological stimuli as well as transforming agents.

Gastric carcinoids and their precursor lesions. A histologic and immunohistochemical study of 23 cases

A histologic and immunohistochemical study was carried out in 23 unselected nonantral gastric carcinoids and their precursor lesions classified according to Solcia et al. None of the patients showed Zollinger‐Ellison syndrome. Two variants of carcinoids showing distinctive pathologic and pathogenetic characteristics were identified on the basis of presence or absence of associated chronic atrophic gastritis type A (A‐CAG). Chronic atrophic gastritis type A was found in 19 cases showing either single or multiple neoplasms, tumor extension limited to the mucosa or submucosa, consistent endocrine cell precursor changes in extratumoral mucosa, and consistent hypergastrinemia and/or G cell hyperplasia. Associated precursor lesions were only hyperplastic in all but two cases with single carcinoids whereas they were also dysplastic in all but one case with multiple carcinoids. The four tumors arising in nonatrophic mucosa were all single, more aggressive, and not associated with extratumoral endocrine cell proliferations or with signs of gastrin hypersecretion. Tumor cells were diffusely immunoreactive for chromogranin A and synaptophysin but usually negative for chromogranin B or HISL‐19. Scattered serotonin cells were found in ten carcinoids. They were more frequent in infiltrating than in intramucosal tumors as were the less represented pancreatic polypeptide cells whereas the reverse was found for alpha‐subunit‐containing cells. These results are of relevance for tumor pathogenesis and may provide the rationale for a less aggressive therapeutic approach in the patients.

A Prospective Study of Gastric Carcinoids and Enterochromaffin-Like Cell Changes in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: Identification of Risk Factors

CONTEXT Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. OBJECTIVES Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. SETTING AND PATIENTS Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. INTERVENTIONS AND OUTCOME MEASURES Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. RESULTS ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. CONCLUSIONS Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.

Atrophic Body Gastritis: Distinct Features Associated with Helicobacter pylori Infection

Usually, atrophic body gastritis has been considered an autoimmune disease characterized by the presence of parietal cell antibodies. Previous investigations into the role of Helicobacter pylori infection have obtained conflicting results. The aim of this study was to investigate the prevalence and role of H. pylori in a prospectively investigated population of patients with corpus‐predominant atrophic gastritis.

Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I

In recent classifications of gastric endocrine tumors, tumors arising in patients with multiple endocrine neoplasia type 1 (MEN-1) are regarded to be regulated by the concomitant hypergastrinemia resulting from to pancreatic or, most commonly, duodenal gastrinomas and to have a benign behavior. In this article, we report on two cases of MEN-1 gastric neuroendocrine tumors having a fatal course. Case 1 was a young male with hyperparathyroidism and Zollinger-Ellison syndrome and with florid development of multiple gastric carcinoids and multiple duodenal gastrinomas. Metastases occurred in the liver, of exclusive gastric origin, in periduodenal lymph nodes, of exclusive duodenal origin, and in perigastric lymph nodes, of mixed origin. The patient died 48 months after diagnosis. Case 2 was an adult female patient with hyperparathyroidism, adrenocortical disorders, and gastric tumors but no hypergastrinemia. The patient died 3 months after tumor diagnosis. At autopsy, the stomach showed multiple benign carcinoids and two independent neuroendocrine carcinomas not reported before in MEN-1 and massively metastatizing to lymph nodes, liver, and peritoneum. Multiple islet cell tumors mostly producing pancreatic polypeptide were found, whereas gastrinomas were seen in neither the pancreas nor the duodenum. Allelic losses at the MEN-1 gene locus in chromosome 11q13, the mechanism responsible for tumor development in MEN-1 syndrome, were demonstrated in the carcinoid tumors of case 1 and in the neuroendocrine carcinoma of case 2. We conclude that gastric neuroendocrine tumors in patients with MEN-1 may have a poor outcome, they have the same genetic mechanism as MEN-1 tumors in other organs, and they may be independent of the trophic effect of hypergastrinemia.

Two-thirds of Atrophic Body Gastritis Patients Have Evidence of Helicobacter pylori Infection

Helicobacter pylori is involved in the induction of atrophic body gastritis (ABG). During the progression of atrophic gastritis the disappearance of H. pylori has been documented and in time serology is the only sign that indicates a previous infection. It has been shown that a positive serology, in ABG patients without histological evidence of infection, indicates an active H. pylori infection.

Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis

Background and aimsColorectal cancer (CRC) ranks as the fourth most frequently diagnosed cancer worldwide. CRCs that arise proximally or distally to the splenic flexure show differences in epidemiologic incidence, morphology, and molecular alterations, suggesting the existence of two categories of CRC based on the site of origin. The aim of the present work is to investigate the histological and molecular differences between CRCs located proximally and distally to the splenic flexure, and their potential involvement in tumor prognosis and therapeutic strategies.MethodsWe evaluated 120 patients affected by sporadic CRC for clinicopathologic features, microsatellite instability (MSI), loss of heterozygosity (LOH) of chromosomes 18q, 8p, and 4p; they were also investigated for hMlh1, hMsh2, Fhit, p27, and Cox-2 immunostaining.ResultsThe mucinous histotype was more frequent in the proximal than in the distal CRCs (p<0.004). The frequency of MSI phenotype was higher in proximal than in distal tumors (p<0.001); moreover, reduced or absent hMlh1, Fhit, p27 immunohistochemical expressions were more frequent in proximal than in distal tumors (p<0.001 and 0.01 for p27). In contrast, the frequency of LOH in 18q was higher in distal than in proximal tumors (p=0.002). No significant differences were observed between proximal and distal tumors in the frequency of LOH in 8p and altered expression of hMsh2 and p53 protein.ConclusionThese different features may reflect different genetic pathways of carcinogenesis and support the hypothesis of a different mechanism of cancer development between the proximal and the distal colon, with potential implications in the therapeutic approach.