Biomedical subjects

E Wilander

Publications and source records attributed to E Wilander.

At least 19 recordsLinked to original sources

PubMed1992

A chromogranin peptide is co-stored with insulin in the human pancreatic islet B-cell granules.

The immunoreaction of a rabbit chromogranin A and B antiserum was studied in normal human pancreatic islets. By examination of consecutive light microscopical sections, it was revealed that, at high antiserum concentrations (1:2000 or less), the whole islet area was heavily labelled, although the peripheral glucagon (A)-cells were the most intense in their immunoreaction. At low antiserum concentrations (1:4000 or more) the A-cells still showed the same intense labelling reaction, but the central B-cells were weakly labelled. Electron microscopically, reactivity towards the chromogranin A and B antiserum and the monoclonal insulin antibodies was present in the same central electron-dense core of the B-cell secretory granules, as demonstrated after application of the immunogold technique at different antibody dilutions. In the A-cells, the chromogranin immunoreactivity was concentrated at the peripheral mantle of the secretory granules. The D-cell granules showed a weak immunolabelling. Examination of human islets with the monoclonal chromogranin A antibody LK2H10 revealed immunogold labelling only in the peripheral mantle of the A-cell granules, while the B-cell granules were unlabelled. The present results show that a chromogranin peptide is co-stored with insulin the in normal human B-cell secretory granules. Although the exact composition of this B-cell chromogranin is unknown, it is not identical to that of the chromogranin A present in the A-cell granules.

Adult↗

PubMed1992

Chromogranin A immunoreactivity compared with argyrophilia, calcitonin immunoreactivity, and amyloid as tumour markers in the histopathological diagnosis of medullary (C-cell) thyroid carcinoma.

Applying the WHO criteria for the histopathological diagnosis of medullary thyroid carcinoma (MTC)--as well as the criterion that a significant amount of argyrophil cells, amyloid deposits, or calcitonin (CT) immunoreactive cells shall be present--122 cases were identified from the files of the Swedish Cancer Registry. Both non-occult (n = 110) and "occult" (less than 1 cm in diameter) (n = 12) MTCs were included. Both primary tumours (n = 91) and metastatic lesions (n = 31) were investigated. The specimens available were all only conventionally formalin-fixed and paraffin-embedded. The presence of neoplastic cells immunoreactive with antisera against chromogranin A (Chr A) was compared with that of the other three MTC markers. Chr A immunoreactive cells were present in practically all the cases. Similar results were obtained when the argyrophil reaction alone and CT immunoreactivity alone were used as markers. When two of the three MTC markers were combined, it was found that virtually everyone of the 122 tumours could be identified as a MTC. In contrast, the presence of amyloid deposits was found to be a less constant MTC marker; whereas 94% of the primary tumours had amyloid deposits, they were present in only approximately 70% and 60% of the metastatic and "occult" tumours respectively. No differences in the staining reaction patterns were found between familial (n = 18) and the sporadic (n = 104) types of MTC.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloid↗

PubMed1992

A study of biological behavior based on the expression of a proliferating antigen in neuroendocrine tumors of the digestive system.

The expression of a proliferating antigen by Ki-67 immunohistochemistry was evaluated in 32 gastrointestinal carcinoids and in 5 pancreatic islet cell tumors. In the tissue sections the number of labelled nuclei was calculated per tumor area. The tumors were classified as low proliferating (less than 0.3 labelled cells/mm2), medium proliferating (0.3-1 labelled cells/mm2), and high proliferating (greater than 1 labelled cell/mm2). In 26 tumors obtained from patients receiving antitumor therapy (alpha-interferon) the proliferative activity was decreased. In treated midgut carcinoids the proliferative activity in metastatic tissue was significantly reduced (p less than 0.05). Though not statistically significant, primary midgut carcinoids collected from untreated patients displayed a lower proliferative activity than liver metastases. A survival analysis revealed that patients with tumors displaying low proliferative activity had a better survival than those with high proliferative activity (p less than 0.05). Single cell cytofluorometric DNA analyses showed regular diploid stem cell lines in the majority of tumors from untreated patients (9/11 cases). No correlation was found between the calculated proliferative activity and the DNA profile. The obtained results indicate that the expression of a proliferation antigen by Ki-67 immunohistochemistry can be used to evaluate the biological behavior of neuroendocrine tumors of the digestive system and predict survival.

Adenoma, Islet Cell↗

PubMed1992

Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1.

In multiple endocrine neoplasia type 1 (MEN-1), benign enlargement of the adrenal cortex has been found in about one third of necropsy cases. To elucidate the clinical and genetic characteristics of the MEN-1 adrenal lesion, we have investigated 33 MEN-1 patients. Twelve individuals (37%) demonstrated adrenal enlargement, which was bilateral in 7 of them. Histopathology revealed diffuse and nodular cortical hyperplasia, adenomas, and a single case of adrenocortical carcinoma. The apparently benign adrenal enlargements were not associated with presently ascertainable biochemical disturbances in the hypothalamic-pituitary-adrenocortical axis, and they were without radiological signs of progression during follow-up. The individual developing unilateral adrenocortical carcinoma showed rapid adrenal expansion, feminization, and an abnormal urinary steroid profile after 4 yr of observation for bilateral minor adrenal enlargements. Pancreatic endocrine tumors were significantly overrepresented and present in all MEN-1 individuals with adrenal involvement. In agreement with findings in sporadic cases, the MEN-1 adrenocortical carcinoma genome showed loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and 11q. The benign adrenal lesions retained heterozygosity for the MEN-1 locus at chromosome 11 q 13. Despite its prevalence and malignant potential, the pituitary-independent adrenocortical proliferation does not appear to be a primary lesion in MEN-1, but might represent a secondary phenomenon, perhaps related to the pancreatic endocrine tumor.

Adrenal Cortex↗

PubMed1992

Islet amyloid polypeptide-producing pancreatic islet cell tumor. A clinical and biochemical characterization.

Islet amyloid peptide (IAPP) or amylin is a recently discovered polypeptide without settled physiology in man. We present a patient with an endocrine pancreatic tumor secreting huge amounts of IAPP-like immunoreactivity (20,000 mol/l) and a concomitant development of diabetes mellitus. The release of insulin and pancreatic polypeptide (PP) was totally absent after an oral glucose load and a mixed meal, respectively. Tumor secretion of IAPP-like immunoreactivity seemed to be influenced by cholinergic mechanisms and by nutrients. The observed effects on insulin and PP secretion by high circulating levels of IAPP-like immunoreactivity may be of beneficial value for further studies of the physiology of IAPP in man.

Adenoma, Islet Cell↗

PubMed1991

Trends in thyroid cancer incidence in Sweden, 1958-1981, by histopathologic type.

Time trends in the incidence of malignant neoplasms of the thyroid were examined for Sweden for the period 1958-81, 5,838 cases being studied. Autopsy-diagnosed cases were excluded. Mean annual changes in the age-standardized rates over this period were 1.9% and 1.2% for women and men, respectively, for all thyroid carcinomas combined; 4.9% and 2.1% for papillary carcinoma; 0.9% and 2.1% for follicular carcinoma; and -1.0% and -2.1% for anaplastic carcinoma. Age, period and cohort models were fitted. There was a progressive increase in papillary cancer incidence for cohorts born since 1919. This increase cannot be satisfactorily explained as an artefact of trends in classification, and probably reflects a real increase in incidence. A less marked increase was seen for follicular cancer, and there was a decline for cohorts born since 1939. While the risk of papillary and anaplastic carcinoma was lower in iodine-deficient areas, follicular cancer risk was twice as high in these areas, for men only. There was a steady decline of anaplastic cancer in both sexes after 1965, largely attributable to a decline in cohorts born since 1924.

Age Factors↗

PubMed1991

Oncoprotein immunoreactivity in human endocrine tumours.

Abnormally expressed oncogenes are implicated in neoplastic transformation. We have investigated a series of endocrine tumours using immunocytochemistry as a first screening tool to detect oncogene expression. Paraffin sections of 44 pulmonary small cell carcinomas, 15 pulmonary atypical carcinoids, 12 bronchial carcinoids, 28 medullary thyroid carcinomas, 27 phaeochromocytomas, and 17 insulinomas were immunostained with antibodies to c-erbB-2, c-myc, L-myc, and N-myc. Diffuse immunoreactivity was detectable for c-erbB-2 in 8 out of 44 (18 per cent) pulmonary small cell carcinomas, 3 out of 15 (20 per cent) pulmonary atypical carcinoids, and 6 out of 27 (22 per cent) phaeochromocytomas; for c-myc in 18 out of 44 (41 per cent) pulmonary small cell carcinomas and 5 out of 15 (33 per cent) pulmonary atypical carcinoids; for N-myc in 6 out of 28 (21 per cent) medullary thyroid carcinomas; and for L-myc in 4 out of 27 (15 per cent) phaeochromocytomas. There was considerable intratumoral and intertumoral heterogeneity and, in each tumour group, no relationship was found between tumour pattern, mitotic index, and oncoprotein immunoreactivity. These results suggest that oncogene products are present in a proportion of endocrine tumours, and that specific oncoproteins seem to be related to tumour type but not to other histopathological findings. Thus, oncoprotein detection may be a useful tool for identifying subsets of endocrine tumours that are not otherwise recognizable morphologically.

Endocrine System Diseases↗

PubMed1991

In situ hybridization study of chromogranin A and B mRNA in carcinoid tumors.

The distribution of the mRNAs for chromogranin A and B was analyzed by in situ hybridization with 35S-labeled oligonucleotide probes in formalin-fixed paraffin-embedded carcinoid tumor tissues. All the 15 mid-gut carcinoid tumors examined contained both mRNAs for chromogranin A and B at high level in tumor cells. Sixteen of 18 bronchial carcinoid tumors but only 2 of 5 rectal carcinoid tumors expressed one or both species of chromogranin mRNAs. The same tendency was seen with the argyrophil reaction according to Grimelius where most of the mid-gut tumor cells were uniformly stained, while considerable variation in reactivity was seen in some of the bronchial and rectal carcinoid tumor cells. The sequential sections were stained with a monoclonal antibody against chromogranin A and a polyclonal antiserum which reacts with both chromogranins. The expression of the mRNA for chromogranin A on the carcinoid tumors was almost concordant with that of chromogranin B as well as with the chromogranin A protein, whereas almost all tumors stained positively with the polyclonal antibodies. Analyses of mRNA expression of chromogranin A before and after interferon therapy on 4 patients with mid-gut carcinoids indicated an inhibition at pre-translational level. In conclusion, the mRNAs for chromogranin A and B are good markers for the carcinoid tumors, especially of mid-gut origin. Fore-gut, mid-gut and rectal carcinoid tumors are different in their endocrine properties regarding the expression of the chromogranins.

Biomarkers, Tumor↗

PubMed1991

Histochemical and immunohistochemical morphology of carcinoid heart disease.

Histochemical and immunohistochemical investigations were performed on tissue obtained from the right heart side in three patients subjected to valve, replacement operations because of severe carcinoid heart disease. Extensive fibrotic changes were present on the endocardium of the right atrium, the papillary muscles of the tricuspid valve and the leaflets of the tricuspid and pulmonic valves of all patients. The main constituent of the lesions was a stroma with abundant acid mucopolysaccharides and collagen but devoid of stainable elastic components. The lesions were in some areas sharply delineated from the normal endocardium, but often also extended into the endocardium and myocardium. Small to medium sized vessels were demonstrated histochemically in the lesions and confirmed by positive immunoreaction against endothelial and smooth muscle cells. The moderate number of mesenchymal cells within the lesions had immunoreactivity consistent with muscle cells which seemed to have a very low proliferating activity. The histochemical and immunohistochemical techniques used confirmed some earlier observations in carcinoid heart disease but also rendered new information contradicting previous findings. The infiltrative nature of the carcinoid plaque gives a new dimension to the carcinoid heart disease. The etiology still remains obscure and well known growth factors for connective tissue such as platelet derived growth factor (PDGF) do not seem to be directly involved in the process.

Aged↗

PubMed1991

Islet amyloid polypeptide (IAPP). A short review.

The islet amyloid polypeptide (IAPP) was originally identified by chemical analysis of the amyloid component in a human pancreatic islet cell tumor. It consists of 37 amino acids and displays about 50% homology with the neuropeptide calcitonin gene-related peptide (CGRP). In the pancreatic islets the IAPP is confined to the beta-cells, co-stored with insulin in the secretory granules and apparently co-secreted with insulin on glucose stimulation. In beta-cell depletion states such as streptozotocin diabetes in animals and in human type I diabetes mellitus both the IAPP and the insulin levels display reduction or are even absent. Within the mature IAPP molecule the amino acid sequence 23-29 shows considerable amino acid heterogenicity among various mammalian species. The amino acid composition of human IAPP in this specific region promotes the development of pancreatic islet amyloidosis, a phenomenon related to the ability to develop type II diabetes in that particular species. However, as type II diabetes is an inherited disease affecting a subpopulation of humans, not only the gene coding mature IAPP, but also one or several other hereditary factors of unknown origin are needed for the disease to develop. We have established a radioimmunoassay for plasma measurements of IAPP. During screening investigations of a large material of endocrine tumors we found a patient with extremely elevated plasma levels of IAPP, about 20,000 pmol/l. Immunohistochemical investigations confirmed the IAPP content and also revealed amyloid deposits. While performing an oral glucose tolerance test insulin levels remained unchanged whereas there was an increase in the glucose and IAPP levels. It is thus concluded that IAPP can be used as a tumor marker in pancreatic islet cell tumors and that high plasma levels of IAPP can inhibit glucose stimulated insulin secretion.

Animals↗

PubMed1991

Diagnostic criteria of classical carcinoids.

The classical (mid-gut) carcinoids of the intestinal tract display a characteristic light microscopic morphology. However, sometimes intestinal tumours are seen resembling carcinoids and differential diagnostic difficulties arise. In the present study silver stains and immunoreactivities to chromogranin A + B, cytokeratins and epithelial membrane antigen (EMA) were evaluated as diagnostic adjuncts in six classical carcinoids and six intestinal carcinomas with carcinoid-like features. All classical carcinoids were argentaffin and argyrophil and contained a majority cell population with chromogranin immunoreactivity while only one carcinoid-like carcinoma was chromogranin-immunoreactive and the stained cells in that case represented a minority of the tumour cell population. The cytokeratins were shown to be non-discriminatory. However, EMA expression occurred in five intestinal carcinomas and in the majority of the tumour cells of four of these cases, while only one classical carcinoid displayed a few EMA positive cells. Thus, silver stains in combination with chromogranin A + B and EMA appears to be of value to discriminate between classical carcinoids and carcinoid-like intestinal carcinomas. Further when intestinal carcinoids and carcinoid-like carcinomas are diagnosed with the aid of various tumour markers both qualitative and quantitative considerations must be made.

Carcinoid Tumor↗

PubMed1990

Effects of interferon on tumor tissue content in liver metastases of human carcinoid tumors.

In 21 patients ultrasound-guided cutting biopsies, from carcinoid metastases of the liver, were taken before and after therapy with alpha-interferon. Each biopsy was examined under light microscopy and the amount of tumor tissue and connective tissue was quantified and then correlated to objective response to interferon therapy. A significant reduction of the amount of tumor tissue, in spite of unaltered metastatic size and a corresponding increase in connective tissue, was seen after interferon therapy. A more pronounced reduction of tumor tissue occurred after long-term interferon therapy. A positive correlation between objective therapy response and tumor tissue reduction was also present. Patients responding poorly, or not at all, to therapy did not show any significant decrease in tumor tissue. Since treatment with immune response modifiers is expected to increase in the near future, it is important to choose the right investigations for therapy monitoring, and since all patients in this investigation had unchanged tumor size on repeated radiological examinations, it is obvious that microscopic examination of core biopsies is a better method for evaluating effects of long-term therapy than tumor size measurement with radiological techniques. Further, the results may indicate that interferon exerts a cytotoxic effect on carcinoid tumor cells in vivo.

Adult↗

PubMed1990

Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors.

A prospective study was performed on 84 patients with neuroendocrine pancreatic tumors. Fifty-nine (70%) had malignant tumors and received causal medical treatment. Streptozotocin in combination with 5-fluorouracil or doxorubicin was used as first-line treatment and produced overall objective responses in 20 of 44 (45%) patients with a median duration of response of 27.5 months. Thirty-two patients who failed on chemotherapy subsequently received interferon treatment and 20 (63%) responded objectively with a median duration of 20.5 months. Octreotide, third-line treatment in 14 patients, produced objective responses in four patients (28%) (median duration of response, 16 months). The median survival from diagnosis in malignant cases was 6.7 years. Even if none of the current medical therapies are curative for patients with malignant endocrine pancreatic tumors, a prolonged survival would be observed during the last decade. Since the age at diagnosis has not been dramatically reduced despite improvements in diagnostic methods, the prolonged survival might be attributed to causal medical treatment.

Adolescent↗

PubMed1990

Silver stains for identification of neuroendocrine cells. A study of the chemical background.

The chemical background of silver stains used for visualization and characterization of peripheral neuroendocrine cells in the gastrointestinal tract and pancreas, and of their corresponding tumours, was studied in tissue sections and by a dot-blot technique. Sequential staining of pancreatic islets with an immunohistochemical procedure and silver staining of the same tissue section revealed that chromogranin A immunostained cells also displayed an argyrophil reaction with the Grimelius method, but no argentaffin reaction with the Masson technique. Accordingly, purified chromogranin A (15 micrograms or less) treated in formalin and applied to nitrocellulose did not show any argentaffin reaction but displayed a dose-related argyrophil reaction. Equal quantities of other polypeptide components did not give rise to any silver reaction. Further dot-blot studies showed that the tryptophan and tyrosine metabolites, dopamine, norepinephrine, 5-hydroxytryptamine and 5-hydroxinodole caused strongly argentaffin and argyrophil reactions while epinephrine, 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophan gave only the former reaction. Among other chemical components studied, only guanine displayed weak silver staining. The results indicate that the reaction products between aldehydes and the granular content of biogenic amines synthesized from tryptophan and tyrosine display an argentaffin reaction and that the granular chromogranin A caused an argyrophil but no argentaffin reaction.

Animals↗

PubMed1990

Bronchial carcinoids with S-100 positive sustentacular cells. A comparative study with gastrointestinal carcinoids, pheochromocytomas and paragangliomas.

Fourty-six bronchial carcinoids, twelve tumourlets and twenty areas of neuroendocrine cell dysplasia (NED) were immunohistochemically evaluated for various neuroendocrine markers, S-100 protein (S-100), myelin basic protein, intermediate filaments, actin, Leu-7 and several neurohormonal polypeptides. Eighteen of the bronchial carcinoids (39.1%) showed a biphasic cell pattern, with abundant stellate-shaped S-100 positive cells (SC). SC were not reactive for chromogranin A, myelin basic protein, cytokeratins, neurofilaments, glial fibrillary acidic protein or actin, and were only occasionally weakly positive for vimentin. SC were not detected in the tumourlets nor in the NED observed. For comparison a group of other neuroendocrine tumours (11 gastrointestinal carcinoids, 4 pheochromocytomas and 4 paragangliomas) were immunostained for S-100, chromogranin A and actin. SC similar to the ones detected in the bronchial carcinoids could be detected in appendiceal carcinoids, paragangliomas and in two out of four pheochromocytomas. Our present data are in keeping with a Schwannian/sustentacular nature of SC rather than that of a histiocytic or myoepithelial nature. We suggest that SC-rich bronchial carcinoids are biphasic tumours, which could be designed "paraganglioid" bronchial carcinoids. The relationship between SC-rich bronchial carcinoids and tumourlets/NED is a matter of further investigation: SC-rich bronchial carcinoids may either differentiate in a biphasic pattern during tumoural growth or may not be histogenetically related to tumourlets.

Adrenal Gland Neoplasms↗

PubMed1990

The enterochromaffin cells in the mouse gastrointestinal tract after streptozotocin treatment.

Effects of 5 weeks streptozotocin treatment on the mouse gastrointestinal tract were studied with special emphasis on enterochromaffin (EC) cells. In the streptozotocin-treated animals the frequency of EC cells was reduced in the antral area and in the small intestine, but increased in the colon. The length of the intestinal tract and the mucosal thickness were increased in these animals. Possible mechanisms underlying these abnormalities of the EC cell system are discussed.

Animals↗

PubMed1990

Neuroendocrine pancreatic tumours: clinical presentation, biochemical and histopathological findings in 84 patients.

A prospective study has been performed on 84 patients with endocrine pancreatic tumours evaluated at the Medical Department in Uppsala. Available information concerning the patients' presenting symptoms, age at diagnosis, clinical syndrome, tumour location, location of metastases, diagnostic radiology, biochemical and histopathological findings has been analysed. Our results indicate that most patients initially show rather vague and non-specific symptoms, with dyspepsia and pain being the most frequent presenting features. The median delay between appearance of the first symptom and diagnosis was 2 years; the delay was 35 months in sporadic cases and 14.5 months in familial cases. In spite of improvements in diagnostic methods, the median age at diagnosis (53 years) has not been reduced, and most patients are encountered when the tumour has reached an advanced stage. There is a need for a method of screening patients with still uncharacteristic abdominal symptoms for a neuroendocrine tumour. The presence of elevated levels of plasma chromogranin in all patients with a proven tumour suggests that such possibilities exist, and the use of this biochemical marker in the future might reduce the age at diagnosis and thus improve the likelihood of cure and survival of patients with endocrine pancreatic tumours.

Adenoma, Islet Cell↗

PubMed1990

A polyclonal antiserum against chromogranin A and B--a new sensitive marker for neuroendocrine tumours.

Chromogranins A, B, and C, proteins that are co-stored and co-released with peptides and amines, have been identified in a variety of neuroendocrine tissues, both normal and neoplastic. We examined the secretion of chromogranin A and chromogranin A + B by hormone-producing tumours in patients with endocrine pancreatic tumours, carcinoid tumours, pheochromocytomas, and small cell lung cancer. The radioimmunoassay determining the plasma concentrations of chromogranin A + B showed a greater sensitivity than that determining chromogranin A alone. All patients with endocrine pancreatic tumours, carcinoids, and pheochromocytomas had increased levels of chromogranin A + B, whereas a small number of the patients (5/18 with endocrine pancreatic tumours and 1/3 with pheochromocytomas) had normal levels of chromogranin A. Also in immunocytochemical stainings, our polyclonal antiserum detecting both chromogranin A and B showed a greater sensitivity than other available antisera against chromogranin A, B and C. We have demonstrated that a polyclonal antiserum against a mixture of chromogranin A and B might be a more sensitive marker than chromogranin A alone for diagnosing neuroendocrine tumours. This is not surprising, since both chromogranins are widely distributed in neuroendocrine cells.

Amino Acids↗