Chromogranin (CgA) has been shown to be an excellent marker for neuroendocrine tumours. There are now three commercial assays on the market. We wanted to compare the usefulness of the different kits in a clinical situation. We have thus measured CgA in 77 patients and compared the results from the different methods. CgA was measured with three different commercial kits according to the recommendations from the manufacturers (CGA-RIA CT; CIS bio international, Gif-sur-Yvette cedex, France, DAKO Chromogranin A ELISA kit; DAKO A/S, Glostrup, Denmark and CgA; EuroDiagnostica, Malmo, Sweden). The sensitivity and specificity differed between the different kits. The CIS kit showed a sensitivity of 67% and a specificity of 96%. The sensitivity and specificity were both 85% for the DAKO kit and 93% and 88% respectively for the EuroDiagnostica assay. We have concluded that CgA is an important tumour marker for all neuroendocrine tumours. However, different analytical properties of the respective kits give different performances, a fact that must be taken into consideration when comparing results from different clinical studies. A recognised international standard for CgA would be a step on the way to harmonisation, but antibody selection and construction of the assays will probably still influence the results.
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M Stridsberg, B Eriksson, K Oberg, and ET Janson
M Stridsberg, K Öberg, Q Li, U Engström, and G Lundqvist
Chromogranins and/or secretogranins constitute a family of water-soluble acidic glycoproteins that are present in almost all endocrine, neuroendocrine and neuronal tissue. Antibodies against chromogranins have been widely used for immunohistochemical staining of endocrine tissue and tumours of neuroendocrine origin. Furthermore, measurements of circulating chromogranin A have been used as a reliable marker for neuroendocrine tumour growth. In this study, we describe the development of specific antibodies against chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin. The antibodies were used for immunohistochemical staining of normal and neoplastic neuroendocrine tissue and development of reliable radioimmunoassays for chromogranin A, chromogranin B, chromogranin C and pancreastatin. In 44 patients with carcinoid tumours, 17 patients with sporadic endocrine pancreatic tumours and 11 patients with endocrine pancreatic tumours and the multiple endocrine neoplasia 1 syndrome, plasma measurements revealed elevated chromogranin A levels in 99%, elevated chromogranin B in 88%, elevated chromogranin C in 6% and elevated pancreastatin in 46% of the patients. Urinary measurements revealed elevated levels in 39%, 15%, 14% and 33% of the patients respectively. Gel permeation chromatography of plasma and urine showed that circulating chromogranin A, and immunoreactive fragments of chromogranin A, had a higher molecular weight distribution than the chromogranin A fragments excreted to the urine. Furthermore, it was noted that most of the patients excreting chromogranin A fragments to the urine had previously been treated with streptozotocin, a cytotoxic agent known to induce renal tubular dysfunction. The antibodies raised proved useful for immunohistochemical staining and visualised endocrine cells in pancreatic islets, adrenal medulla and the small intestine as well as in endocrine pancreatic tumours, pheochromocytoma and midgut carcinoid tumours. In conclusion, the antibodies raised were useful for both immunohistochemical staining of normal tissue and endocrine tumours as well as development of specific radioimmunoassays for plasma measurements of the different chromogranins. Furthermore, we show that plasma measurements of chromogranin A and B were superior to measurements of chromogranin C and pancreastatin and plasma measurements of the different chromogranins were more reliable as markers for tumour growth than the corresponding urine measurements.
Journal of Endocrinology (1995) 144, 49–59
M. Stridsberg, U. Hellman, E. Wilander, G. Lundqvist, K. Hellsing, and K. Öberg
Chromogranin A is a well-known protein constituent in granules of neuroendocrine cells. It is also known that plasma levels of chromogranin A increase considerably in patients with neuroendocrine tumours and thus chromogranin A is used as a marker for these tumours. In the present study, we have shown that fragments of chromogranin A are excreted into the urine in some patients with carcinoid tumours. The chromogranin A molecule appeared in the urine N-terminally cleaved at amino acid positions 116 and 210, which are previously reported cleavage sites of the molecule. The fragments identified were mainly of about 35 kDa in size. The unprocessed chromogranin A molecule was not excreted in the urine. Five out of 40 patients excreting the fragments had slight tubular dysfunction in the kidneys. We also showed that these renally excreted split products of chromogranin A were immunogenic and could be used for production of antibodies against chromogranin A. These antibodies were used both for immunocytochemistry and for the development of a specific and sensitive radioimmunoassay for chromogranin A and its fragments. Measurements of plasma chromogranin A by radioimmunoassay appeared to be a better marker for tumour growth than were measurements of chromogranin A in the urine.
Journal of Endocrinology (1993) 139, 329–337
JL Cunningham, Lopez-Egido JR, ET Janson, B Eriksson, K Oberg, and AE Gobl
A potential upregulation of receptor type protein tyrosine phosphatase IA-2 (ICA512) expression was detected by differential display and investigated in midgut carcinoid tumours. Normal intestine tissue and tumour tissue from 13 midgut carcinoid patients were studied by in situ hybridisation using an IA-2 ribonucleotide probe and confocal microscopy using specific IA-2 antibodies. Previously, it had been shown that IA-2 is located in the secretory granules of virtually all neuroendocrine cells. However, we found that IA-2 was not detectable in resting normal enterochromaffin (EC) cells of the small intestine, while high expression of IA-2 mRNA and protein was confirmed in both primary and metastatic carcinoid tissue. This difference in expression was not observed with chromogranin A or serotonin, two secretory granule hormones known to be expressed in EC cells, indicating that IA-2 was seemingly not necessary for the basal production and packaging of these hormones. When comparing patients receiving biotherapy before operation with untreated patients, we found expression of IA-2 to be lower in tumours from patients that had been treated with a combination of alpha-interferon and the somatostatin analogue, octreotide. There was no correlation between IA-2 expression and proliferation rates as measured by immunohistochemistry with antibodies against the Ki 67 antigen. Furthermore, we show that IA-2 is co-localised with serotonin in carcinoid tumours as well as in the pancreatic tumour cell line, BON1, which is interesting as serotonin secretion rate is presumably higher in tumour cells than in resting EC cells. Taken together, these findings may indicate a role for IA-2 in the later stages of the regulated secretory process.