Francesco Paolo Pilato

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.

Quantitative electron microscopy of endocrine cells in oxyntic mucosa of normal human stomach

SummaryAn ultrastructural morphometric study of the endocrine cells of the oxyntic mucosa of the stomach in gastric biopsies collected from five male and five female healthy volunteers aged 19–31 was performed. No sex-related differences were disclosed. Endocrine cells accounted for 1.2±0.4% of the epithelial volume and 0.9±0.4% of the mucosal volume, i.e., including the lamina propria. After classification of the specific endocrine cell types according to the ultrastructural morphology of secretory granules, the volume densities of ECL, P and D cells (30±9%, 24±7%, and 22±4% of the entire endocrine cell mass, respectively) were higher than those of other endocrine cell types. In particular, EC cells contributed less than 10% and X cells represented a very low proportion of the total cells. Non-granulated profiles of cells which in all other respects appeared to be endocrine were also found with a volume density of 8±4%. D cells were distinguished by the high fraction of cytoplasm occupied by secretory granules (31±5%). Subdivision of the whole mucosa into four horizontal segments revealed the endocrine cells to be mostly distributed in the three lower, with virtually no endocrine cells in the superficial segment. The quantitative ultrastructural analysis of the endocrine cell population of the normal human oxyntic mucosa provided by this study may allow a better evaluation of physiological and pharmacological variations of the endocrine cell population.

Composite carcinoid-adenocarcinoma of the stomach associated with multiple gastric carcinoids and nonantral gastric atrophy

A case of multiple gastric carcinoids and nonantral atrophic gastritis in which the larger tumor was a composite carcinoid‐adenocarcinoma is presented. The two components of the composite tumor immunohistochemically showed clear‐cut diverging functional differentiations although the available evidence supported a common histogenesis from the metaplastic intestinal epithelium of the gastric mucosa. The carcinoid tissue of the composite tumor, which showed “atypical” features, also differed from the other, pure carcinoids, in which the histologic appearance was “typical.” Total gastrectomy performed 1 month after the original gastric resection with antrectomy disclosed regressive changes in the endocrine cell proliferations of the gastric stump consistent with the withdrawal of a stimulating effect of the antral gastrin.

Argyrophil Cell Hyperplasia of Fundic Mucosa in Patients with Chronic Atrophic Gastritis

Eighteen cases of severe hyperplasia of fundic argyrophil cells observed during routine histologic examination of endoscopic gastric biopsy specimens from unselected patients with upper gastro-intestinal symptomatology were investigated. All patients, except one, were female with a mean age of 57 years. Atrophic gastritis of fundic mucosa with severe hypo- or achlorhydria was present in all cases. Hypergastrinaemia (of antral origin) was found in 15 subjects in which circulating gastrin levels were determined. Pernicious anaemia was seen in 1 patient. At light microscopy, the hyperplastic fundic cells were stained by the Grimelius and the Sevier-Munger silver methods and, in approximately 30% of cases, by lead-haematoxylin. In addition, these cells reacted with anti chromogranin antibodies. In 8 of 9 patients studied by electron-microscopy, enterochromaffin-like (ECL) cells were found to be the more frequent cell type. D1 cells prevailed in 1 case and were rare in the others. The frequency of P cells was intermediate between that of ECL cells and that of D1 cells. In conclusion, our observations indicate that: argyrophil cell hyperplasia of atrophic fundic mucosa is prevalently found in women with hypergastrinaemia, and the hyperplastic process involves mostly the ECL type of gastric endocrine cells. It is noteworthy that similar associations have been shown to be present in patients affected by fundic carcinoid tumours and atrophic gastritis.

Comparative study of seven neuroendocrine markers in pancreatic endocrine tumours

A comparative immunocytochemical investigation was performed on a series of 59 pancreatic endocrine tumours using a panel of seven markers for neuroendocrine neoplasms: neurone specific enolase (NSE), PGP 9.5, chromogranin A (CgA), PHE5, prealbumin (Pa), HISL-19, and alpha-subunit of human chorionic gonadotropin (α-HCG). Most markers can be separated into two groups characterized by an identical immunoreactive cellular compartment and substantial overlapping in the immunohistochemical results. The first group comprises soluble cytoplasmic proteins such as NSE and PGP 9.5 and is characterized by a diffuse, homogeneous staining of the cell cytoplasm that is not related to the type of hormone produced or the degree of cell differentiation. The second group includes antigens located in the cell secretory granules such as CgA, PHE5, Pa and HISL-19 and is characterized by a heterogenous, often polarized cell staining. The latter markers strongly react with benign glucagonomas and PP-omas and, in contrast with those of the former group, are stricly neuroendocrine-specific. However, they often are less effective in staining insulinomas and malignant tumours. An additional, distinctive and useful characteristic of the HISL-19 antibody was its ability to label the Golgi complex also in tumours with absent granular staining. Finally, α-HCG was found in 9 of 16 malignant tumours (mostly glucagonomas and insulinomas) and in 4 of 43 benign neoplasms (all insulinomas). The latter finding is not in accordance with the reputed specificity of the α-HCG expression by pancreatic endocrine tumours as a marker for tumour malignancy.

Carcinoid (ECL Cell) Tumor of the Oxyntic Mucosa of the Stomach: A Hormone-Dependent Neoplasm?

In 1969 Rubin1 described a proliferation of endocrine cells in the atrophic oxyntic (or fundic) mucosa of patients with pernicious anemia (PA). Shortly thereafter, Solcia et al.2 also noted hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG), even in the absence of PA, and, in addition, they reported a case of severe proliferation of the same cells in a patient with Zollinger—Ellison syndrome (ZES). These findings were confirmed in our laboratory,3,4 and we observed that hypergastrinemia is the common feature of the two otherwise opposite pathologic conditions of the oxyntic mucosa of the stomach. Considering the trophic effects of gastrin, therefore, we proposed that hypergastrinemia is responsible for the hyperplastic response of endocrine cells of the oxyntic mucosa in both CAG and ZES.4 The subsequent study of single cases of fundic carcinoid tumors extended this hypothesis by linking hypergastrinemia to the development of neoplasms from the same endocrine cell population.5,6

Ultrastructural characterization of fundic endocrine cell hyperplasia associated with atrophic gastritis and hypergastrinaemia

Clinical and experimental evidence indicates that carcinoid tumours of the stomach fundic mucosa represent another example of hormone-dependent neoplasm, gastrin being the hormone involved in tumour induction. In this context hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG) and hypergastrinaemia is regarded as the most frequent preneoplastic lesion. However, the cell type involved in this hyperplasia has not been clarified. To elucidate this problem fundic endocrine cells were characterized ultrastructurally in 9 patients from which endoscopic gastric biopsies were obtained. ECL cells were the most frequent cell type in 8 cases, in 4 of which they were more numerous than all other cell types taken together. D1 cells were the most frequent type in one case while they were inconspicuous in the other cases. P cells were found with a frequency in each case intermediate between that of ECL cells and that of D1 cells. These results indicate that fundic endocrine cell hyperplasia occurring in hypergastrinaemic CAG is in most cases cytologically similar to that found in other hypergastrinemic conditions, in which the gastrin-dependent ECL cells were already found to prevail. They also explain why fundic carcinoids arising in CAG are mostly composed of ECL cells. The relation between ECL, D1 and P cells, if any, remains obscure.

Expression of glycoprotein hormone alpha-subunit by endocrine cells of the oxyntic mucosa is associated with hypergastrinemia

Previous studies have shown that hyperplastic endocrine cells of the oxyntic mucosa in patients with atrophic gastritis may express immunoreactivity for the alpha-subunit of human chorionic gonadotropin (alpha-HCG, common to all glycoprotein hormones). Since this endocrine proliferation is regarded as dependent on the trophic effect of the concomitant hypergastrinemia, the relation between immunohistochemical expression of alpha-HCG by oxyntic endocrine cells and serum levels of gastrin were investigated. The study was performed on endoscopic gastric biopsies of the oxyntic mucosa from 49 patients subdivided into the following groups: A) with histologically normal mucosa and normogastrinemia (22 cases), B) with atrophic gastritis and normogastrinemia (12 cases), C) with normal mucosa and hypergastrinemia (Zollinger-Ellison syndrome, retained antrum) (7 cases) and D) with atrophic gastritis and hypergastrinemia (with or without pernicious anemia) (8 cases). The alpha-HCG immunoreactive cells were found in all hypergastrinemic patients (groups C and D), regardless of the concomitant pathological condition of the mucosa. These cells accounted for 7.8% to 44.7% of the number of Grimelius argyrophil cells in consecutive serial sections. In contrast, alpha-HCG-containing cells were exceptional or absent in most normogastrinemic patients. Their number was sizable in only two cases of group A and three cases of group B, where it ranged from 2.5% to 14.8% of the number of argyrophil cells. It was concluded that expression of alpha-HCG is another feature of oxyntic endocrine cells associated with hypergastrinemia in addition to those previously recognized such as development of hyperplasia and/or carcinoid tumors.

Nonrandom expression of polypeptide hormones in pancreatic endocrine tumors. An immunohistochemical study in a case of multiple islet cell neoplasia

One hundred four endocrine tumors found in the body and tail of the pancreas of a patient with the Zollinger‐Ellison syndrome (ZES) and multiple endocrine neoplasia (MEN‐I) were investigated by immunohistochemistry for insulin, glucagon, somatostatin, pancreatic polypeptide (PP), and gastrin. The results for each tumor were scored into six grades according to the frequency of immunoreactive cells. Pancreatic polypeptide, glucagon, insulin, and somatostatin were demonstrated in 96, 80, 62, and 42 tumors, respectively. When only the higher scores of cell frequency (3–5) were considered, PP and glucagon (accounting for 71 and 49 tumors, respectively) differed markedly from insulin (two tumors) and somatostatin (0). The frequency of PP‐immunoreactive cells was higher in tumors of large size whereas that of glucagon cells was higher in the smaller neoplasms. No significant associations of the tumoral hormonal expressions were found with the type of histologic structure (trabecular versus gyriform), the occurrence of stromal fibrosis, and the intrapancreatic location of the neoplasms, except for a higher number of somatostatin cells in fibrotic tumors. Gastrin‐immunoreactive cells never were found in the tumors in spite of the concomitant hypergastrinemia. In conclusion, the nonrandom expression of the hormonal phenotype by the neoplastic islet cells, as shown by the immunohistochemical, semiquantitative analysis of a large number of tumors, suggests that in our MEN‐I patient the genetically determined neoplasms also are affected by other mechanisms, possibly nongenetic.

Three months of octreotide treatment decreases gastric acid secretion and argyrophil cell density in patients with Zollinger-Ellison syndrome and antral G-cell hyperfunction

Methods: The effects of three months of treatment with octreotide on gastric acid hypersecretion induced by hypergastrinaemia were investigated in patients with Zollinger‐Ellison syndrome (n= 5) or antral G‐cell hyperfunction (n= 4). Gastric acid secretion, fasting plasma gastrin concentrations and clinical findings were examined, and a morphometrical analysis of oxyntic endocrine cells was performed.