[show abstract][hide abstract] ABSTRACT: The role of Wnt pathway in digestive endocrine tumours is debated. The aim of this work is to investigate key players in Wnt pathway by a multimodal approach. Sixty cases (49 well-differentiated and 11 poorly differentiated) were investigated for methylation of adenomatous polyposis coli (APC) and E-cadherin promoters, the loss of heterozygosity (LOH) at APC locus and beta-catenin and E-cadherin expression by immunohistochemistry. Tumours showing altered beta-catenin localization were tested for beta-catenin and APC mutations. APC promoter methylation was restricted to gastroduodenal tumours (21 out of 59, 36%), prevalent in poorly differentiated carcinomas (P=0.042) and correlating with aggressive features (high histology grade, P<0.02; tumour death, P=0.026; high fractional allelic loss, P=0.002, in turn correlating with short survival, P=0.017). LOH at APC locus was found in 14 out of 53 cases (26%, 10 gastroduodenal and 4 colorectal), prevalent in poorly differentiated carcinomas (P=0.002) and correlating with histology grade (P=0.012). beta-catenin abnormal expression was found in 41 out of 54 cases (76%), with nuclear staining correlating with APC alteration (P=0.047) and short survival (P=0.006). APC, but not beta-catenin, gene mutations were found (7 out of 35 tumours), 4 of which in the midgut. E-cadherin promoter methylation was rarely detected (2 out of 52 cases), with cytoplasmic expression in 18 out of 43 cases (42%), not correlating with any clinico-pathological feature. In conclusion, Wnt pathway alterations, as represented by abnormal beta-catenin localization, are common events in digestive endocrine tumours, but only nuclear expression correlates with tumour aggressiveness. Though with different alteration mechanisms according to anatomical site, APC plays a major role in Wnt pathway activation and in determining the high chromosomal instability observed in aggressive endocrine carcinomas.
Endocrine Related Cancer 12/2008; 15(4):1013-24. · 5.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers.
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.
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.
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.
[show abstract][hide abstract] ABSTRACT: Two cases of gastric tumors showing mixed composition of endocrine cell clusters and exocrine glands and originally diagnosed as mixed neoplasms are described. In both cases, the exocrine glandular component was restricted to the upper third of the neoplasms being consistently absent in areas of muscular wall invasion and, in case 2, in nodal metastases. These glands were in close anatomical contiguity with the glands of the overlying gastric mucosa or, in case 1, apparently derived from deep pouch-like invaginations of the mucosa. They showed either lack of dysplasia (case 1) or mild dysplasia (case 2) with a Ki67 proliferation index consistently lower than that of the intramucosal glands. The intratumoral glands presented intestinal metaplastic features confirmed by intense Cdx2 immunostaining that, conversely, was absent in the endocrine component of the tumors. The latter showed intense vesicular monoamine transporter 2 immunoreactivity consistent with its origin from the enterochromaffin-like cells of the gastric oxyntic mucosa. On the basis of these findings, it is proposed that the exocrine glands do not represent a true neoplastic component of the tumors. Although mucosal entrapment by the tumor cannot be ruled out, they more likely reflect a hitherto unrecognized mechanism of mucosal colonization of gastric endocrine tumors.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2008; 452(2):169-74. · 2.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: In contrast with the large amount of data generated from endocrine tumors of the pancreas, sparse and mostly unconfirmed data are available on the criteria for the assessment of malignancy risk and patient outcome in endocrine tumors of the gastrointestinal tract. In these conditions the 2000 WHO classification with its standardized scheme of pathologic report constitutes a framework facilitating the assessment of tumor malignancy and has been regarded as useful for clinical purposes, providing the basis for proper management of the patients and for the design of treatment protocols. The classification is based on a combination of pathological and clinical features with parameters specific for each organ in which the endocrine tumors originate. Three main categories, one further subdivided into two subgroups, are considered: (1) well-differentiated endocrine tumors, further subdivided into tumors with benign and with uncertain behavior; (2) well-differentiated endocrine carcinomas, low grade; and (3) poorly differentiated endocrine carcinomas, high grade. In this review the differential tumor characteristics between the different categories are summarized. Moreover, the relevance of additional features with respect to tumor prognostication, chiefly the Ki-67 proliferation index and malignancy-associated genetic changes, is discussed with emphasis on the discrepancies emerging between tumors of foregut and of midgut origin.
[show abstract][hide abstract] ABSTRACT: Carcinoid tumours arising in the presacral region are extremely rare and they are usually benign. We report the case of a 37-year-old black man with a clinically malignant carcinoid tumour (well differentiated endocrine carcinoma) occurring in a sacrococcygeal teratoma and already metastasised to pelvic nodes, liver and bone at the time of the initial diagnosis. Such an aggressive behaviour of the presacral carcinoid tumours has never been described. The derivation of these tumours from hindgut rests with reference to embryological development of the tailgut cysts is discussed.
Digestive and Liver Disease 05/2005; 37(4):278-81. · 3.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of the present study was to evaluate the extent of the ventricular epicardial fat and its relationship with the underlying myocardium, neither of which is still completely understood.
A total of 117 autoptic human hearts was subdivided into four groups: normals (N), ischemics (I), hypertrophics (H) and hypertrophic-ischemics (HI). In each heart, the ventricular myocardial and epicardial fat weights were measured. On the basis of these data, the epicardial fat percentage within the ventricles was calculated.
The left, right and total ventricular fat weights were greater in H and HI than in N and I (P<.05, P<.05, P<.01, respectively). No differences were detected in the epicardial fat weights in comparing H versus HI and N versus I. Moreover, the fat percentage in each ventricle did not vary between the four groups. However, if compared with the right ventricle, the left ventricle showed an epicardial fat percentage consistently lower (P<.0001). In nonhypertrophied hearts (N and I), the body mass index and the total epicardial fat weight were correlated (P<.05), whereas in hypertrophied hearts (H and HI), they were not.
A constant fat-muscle ratio exists in each ventricle, which is not influenced by ischemia or hypertrophy. Accordingly, during the hypertrophic process, the ventricular fat and the underlying myocardium show a parallel and correlated increase in their masses.