Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in pancreatic endocrine tumors.

Coexpression of transforming growth factor alpha (TGF-alpha) and its receptor epidermal growth factor receptor (EGFR) is known to be associated with aggressive biologic behavior and adverse clinical outcome in a variety of tumors, including pancreatic adenocarcinomas. However, very little information is currently available as to whether this is true of pancreatic endocrine tumors (PETs) as well. Thirty-five PETs were retrospectively studied for immunohistochemical expression of TGF-alpha, the intracellular and extracellular domains of EGFR, and various hormonal secretory products. Proliferative activity was additionally studied (in 20 cases only) using the MIB-1 antibody. Thirty-one (89%) of 35 tumors were reactive for 1 or more of the peptide hormones tested; 22 (63%) tumors were positive for TGF-alpha; and 23 (65%) were positive for the intracellular and/or extracellular domain of EGFR. Based on their TGF-alpha and EGFR expression, these tumors could be classified into 4 groups. Of the 10 tumors in group I (positive for TGF-alpha and the complete EGFR molecule), 3 were malignant, 6 were >2 cm in diameter, 5 were functional, and 1 had a proliferative index of >40%. The 12 tumors in group II (positive for TGF-alpha but negative for the intracellular and/or extracellular domain of EGFR) included 4 malignant tumors, 4 PETs >2 cm in diameter, 8 functional, and 1 with a proliferative index of >40%. The 7 PETs in group III (positive for the intracellular/extracellular domain of EGFR alone) included 3 malignant tumors, 3 PETs >2 cm in diameter, and 3 functional tumors. The 6 tumors in group IV (completely negative for both TGF-alpha and EGFR) included 4 malignant tumors, 3 PETs >2 cm in diameter, and 4 functional lesions. Therefore, immunohistochemical expression of TGF-alpha and EGFR, either alone or in concert, shows no correlation with size, functional status, secretory profile, or biologic behavior and hence cannot be used as a marker of malignancy in this group of tumors.

Cellular composition and anatomic distribution in nonfunctioning pancreatic endocrine tumors: immunohistochemical study of 30 cases.

OBJECTIVE: To investigate the cytological pattern and distribution in nonfunctioning pancreatic endocrine tumors. METHODS: Using labeled streptavidin-biotin (LSAB), immunohistochemical staining for insulin, glucagon, somatostatin, pancreatic polypeptide and gastrin was performed on 30 nonfunctioning pancreatic endocrine tumors from 30 patients. The cellular composition and anatomic distribution in these tumors were analyzed. RESULTS: Of 30 tumor tissues, 22 (73.3%) were found to contain cells immunoreactive to 1-4 kinds of peptide hormones; 17 (56.7%) showed positive staining for more than one peptide and up to 4 peptides; and 8 (26.7%) showed negative immunoreaction to all antiserum applied. No tumor was found to contain immunoreactive gastrin. Among 17 multihormonal tumors, 4 contained 2 kinds of peptide hormones, 8 had 3 kinds, and 5 harbored 4 kinds of peptide hormones. In addition, the difference in the number and type of positive endocrine cells between the tumors arising from the head of the pancreas and those arising from the body and tail of the pancreas were statistically significant (P < 0.05). CONCLUSIONS: Immunohistochemically, the high positive rate to peptide hormones suggests that the nonfunctioning pancreatic endocrine tumors are actually not nonfunctioning; they are asymptomatic pancreatic endocrine tumors. Moreover, an uneven distribution of positive endocrine cells in the nonfunctioning pancreas endocrine tumors within the pancreas was identified.

The gastroenteropancreatic endocrine system and related tumors.

Up to 16 types of endocrine cells have been characterized morphologically (and most of them also functionally) in the gastroenteropancreatic area. Four main groups of pancreatic endocrine tumors (with several subtypes) have been identified: islet cell, ectopic, nonfunctioning, and poorly differentiated tumors. A detailed classification system that combines cytologic and clinicopathologic patterns has been developed for the study of 132 pancreatic tumors. Among a large series (more than 120 cases) of endocrine tumors arising in the gastrointestinal tract, serotonin-producing argentaffin carcinoids have been separated from hindgut trabecular carcinoids, producing glucagon- and pancreatic polypeptide-related peptides, paragangliomas, somatostatin cell tumors, gastrinomas, and argyrophil ECL cell carcinoids. The clinicopathologic profile of the various pancreatic and gastrointestinal tumor entities has been delineated and involvement in the multiple endocrine neoplasia syndrome has been analyzed in detail.

Retrospective study of 77 pancreatic endocrine tumors using the immunoperoxidase method.

Immunocytochemical stains for various pancreatic hormones were performed on 77 pancreatic endocrine tumors from 59 patients [17 with hypoglycemia, three with glucagonoma syndrome, 18 were Zollinger-Ellison syndrome, six with WDHA (watery, diarrhea, hypokalemia, and achlorhydria) syndrome and 15 without endocrine symptoms]. In all tumors that caused either hypoglycemia or glucagonoma syndrome, insulin and glucagon were respectively identified. On the other hand, only 10 tumors from 18 patients with Zollinger-Ellison syndrome were positive for gastrin, and only four of six patients with WDHA syndrome had a vasoactive intestinal peptides-positive tumor. Ten of 15 clinically silent tumors contained hormone-producing cells but without a consistent pattern. Ten neoplasms were negative for all hormones tested. Twenty-six tumors showed positively for more than one hormone and usually one cell type predominated. Four patients had multiple tumors which showed variation in the architecture and cellular composition. The tumors were classified into three major histopathologic groups: solid, gyriform, and glandular. The correlation between the pattern of growth and the hormonal production was generally poor. However, a pure gyriform pattern was often associated with insulin production, and glandular differentiation was commonly seen in tumors associated with Zollinger-Ellison syndrome. This study demonstrates the reliability of the immunocytochemical method for the specific identification of cell types in pancreatic endocrine tumors.

Islet cell tumors of the pancreas: clinico-biochemical correlations.

Islet cell tumors produce a spectrum of syndromes. Intensive investigations of these tumors have enhanced our understanding of cellular origin, physiology and biochemistry of the islet hormones. Biochemical studies on the hormones are helpful in the diagnosis and treatment planning of the islet tumors. For example, insulinoma and glucagonoma can be diagnosed more readily by demonstration of proinsulin and proglucagon-like components, respectively, in the blood. Similarly, measurement of vasoactive intestinal polypeptide is not only useful in the diagnosis, but also in the follow-up of patients with pancreatic cholera syndrome. This mini-review examines these and other clinico-biochemical correlates seen in islet tumors.

Morphology and immunohistochemically-defined endocrine function of pancreatic islet cell tumours.

Thirty pancreatic islet cell tumours were histologically classified and analysed for their possible peptide hormone content using the immunohistoperoxidase method. Seven tumours contained insulin, six tumours contained gastrin and eight tumours contained glucagon. One tumour contained all three hormones. In the insulin and gastrin-containing tumours, the cells were usually arranged in solid nests of cells, with tubular and acinar formations in about half the cases. In the glucagon-containing tumours the cells were mainly arranged in anastomosing ribbons consisting of one of two layers of small cells. Most of the hormone-containing tumours were argyrophilic using Grimelius' silver reaction. All but one of the glucagon-containing tumours were incidental findings at autopsy. About half of the other tumours had metastasized. It is concluded that a relation exists between the histological pattern of growth and immunohistochemically defined endocrine function of pancreatic islet cell tumours.

Endocrine pancreatic tumors.

The pathology and cell biology of endocrine pancreatic tumors are reviewed. It is probable that all these tumors are "functioning" in the sense that they elaborate hormones that cause more or less conspicuous clinical syndromes. Identification of such secretory products is essential for an optimal diagnosis, localization, treatment, and follow-up. Recent data indicate that endocrine pancreatic tumors evolve from progenitor cells of ducts. This histogenetic mechanism may explain the occurrence not only of mixed or multihormonal tumors but also of tumors producing hormones that are absent from the adult human pancreas. In addition to their clinically apparent effects, many endocrine pancreatic tumors affect the surrounding endocrine pancreas in a characteristic way. The mechanisms behind and the potential diagnostic usefulness of these changes are discussed.