Insulin, Somatostatin, Vasoactive Intestinal Polypeptide, Gastrin, Glucagon, Pancreatic Polypeptide
Pancreatic endocrine tumors have been associated with several distinct clinical syndromes, such as hypoglycemia, glucagonoma syndrome, Zollinger-Ellison syndrome and WDHA (watery diarrhea, hypokalemia and achlorhydria) syndrome (Mukai et al, 1982). Routine histological examination usually fails to predict the behavior and endocrine manifestations of these neoplasms (Creutzfeldt, 1980). Immunohistochemistry permits the specific demonstration of various pancreatic hormones in tissue sections.
Sources/Clones
Insulin
Accurate (K36AC10), Axcel/Accurate (polyclonal), Biodesign (MAb 1, E2-E3, polyclonal), Biogenesis (E6E5, D4B8, IN05, C7C9, polyclonal), Biogenex (AE9D6, polyclonal), Caltag Laboratories (polyclonal), Cymbus Bioscience (MAB1), Dako (polyclonal), EY Labs, Fitzgerald (M91284, M91285, M322212, M322213, polyclonal), Immunotech Inc/Immunotech SA (E2E3), Novocastra (polyclonal), Research Diagnostics (MAB 1), Sanbio/Monosan (N-05, polyclonal), Sigma (K36AC10) and Zymed (Z005, Z006, polyclonal).
Somatostatin
Accurate (YC7, BM17), Axcel/Accurate (polyclonal), Biogenesis (170.3, polyclonal), Biogenex (polyclonal), Caltag Laboratories (polyclonal), Dako (polyclonal), Fitzgerald (polyclonal), Novocastra (polyclonal), Pharmingen (YC7), Sanbio/Monosan (polyclonal) and Zymed (polyclonal).
Vasoactive Intestinal Polypeptide
(VIP): Accurate, Biodesign (polyclonal), Biogenesis (VIP-001), Biogenex (polyclonal), Immunotech (103.10), Serotec and Zymed (polyclonal).
Gastrin
Axcel/Accurate (polyclonal), Biodesign (polyclonal), Biogenesis (polyclonal), Biogenex (polyclonal), Caltag Laboratories (polyclonal), Dako (polyclonal), Fitzgerald (M28046, M28047, polyclonal), Immunotech (4C7A1), Novocastra, Sanbio/Monosan (polyclonal) and Zymed (polyclonal).
Glucagon
Accurate/Sigma (K79bB10), Axcel/Accurate (polyclonal), Biodesign (polyclonal), Biogenesis (polyclonal), Biogenex (polyclonal), Caltag Laboratories (polyclonal), Dako (polyclonal), Fitzgerald (polyclonal), Immunotech (polyclonal), Sanbio/Monosan (polyclonal) and Zymed (polyclonal).
Pancreatic Polypeptide (PP):
Axcel/Accurate (polyclonal), Becton Dickinson, Biodesign (polyclonal), Biogenesis (polyclonal), Biogenex (polyclonal), Dako (polyclonal), Eli Lilly (polyclonal) and Zymed (polyclonal).
Fixation/Preparation
These antibodies are applicable to formalin-fixed, paraffin-embedded tissue as well as frozen sections. No pretreatment or antigen unmasking is necessary for any of the antibodies.
Background
The antigens used as immunogens to raise rabbit antibodies against the pancreatic hormones were as follows: insulin - porcine pancreatic insulin; somatostatin - synthetic peptide somatostatin - 14;VIP follows: insulin - porcine pancreatic insulin; somatostatin - synthetic peptide somatostatin - 14;VIP natural porcine VIP, conjugated to glutaraldehyde as carrier protein; gastrin - synthetic human gastrin-17 non-sulfated form(I) conjugated to bovine serum albumin; glucagon - porcine glucagon. Although there are at least eight different cell types identified in the pancreatic islets (Dayal and O'Brian, 1981), only the resident four major cell types (A, B, D and PP cells) and G and VIP cells (in neoplastic conditions) will be considered here. In the normal adult islet, insulin-containing B cells account for 60-80 % of endocrine cells (Erlandsen et al, 1976) and occupy the central portion of the islets. Glucagon-containing A cells constitute 20-30% and somatostatin-containing D cells, 5-11%. A and D cells are mostly present in the periphery of the islets and are also scattered within the islets along capillaries. Physiologically, glucagon increases hepatic glucose production and opposes hepatic glucose storage; insulin increases peripheral glucose uptake and opposes glucagon-mediated hepatic glucose production. Hence, the delicate balance of these two hormones maintains blood glucose homeotasis. Somatostatin has inhibitory actions on both A and B cells through a ''paracrine" effect, thereby regulating the balance of A- and B-cell functions. PP cells are the least numerous and are present both within and outside the islets. The function of pancreatic polypeptide has not been fully understood. PP cells have a variable distribution in the pancreas, with PP cell-rich islets being occasionally present in the posterior lobe of the pancreatic head. Hence, caution should be exercised when evaluating hyperplastic changes of PP cells (Mukai, 1983).
Although the presence of gastrin in D-cells has been disputed, recent studies indicate that gastrin is not present in normal adult islets (Dayal and O'Brian, 1981). VIP has been localized in human islets but the exact cellular origin has not been fully understood (Said, 1980).
In the gastroduodenal segment gastrin has been immunolocalized to the G cells of the gastric antrum, whilst somatostatin has been found in endocrine cells and nerves of the intestinal wall digestive mucosa.
Applications
Endocrine tumors of the gastrointestinal tract and pancreas may demonstrate a wide variety of histomorphological patterns:
solid (nodular solid nests with peripheral invading cords)
solid and glandular (with focal glandular formation)
gyriform (trabecular or ribbon-like structures forming an anastomosing pattern)
glandular (tubular or acinar structures) (Mukai et al, 1982).
With the availability of antibodies to the secretory products, specific designation of these neoplasms has led to terms such as insulinoma, glucagonoma, gastrinoma, somatostatinoma and VIPoma. However, small tumors found incidentally at autopsy may be clinically silent and do not necessarily cause clinical symptoms. Further, many pancreatic endocrine tumors are multihormonal (Mukai et al, 1982). Hence, Rosai prefers the designation `pancreatic endocrine tumor' followed by the description of the hormone(s) demonstrated in situ (e.g. insulin-producing) whenever this can be ascertained. Pancreatic endocrine tumors, which do not cause clinically apparent endocrine syndromes, are usually labeled as non-functioning tumors. However, with the acceptance of hormone production as a sign of function, the number of non-functioning tumors decrease with application of immunohistochemical staining procedures using antibodies to specific hormones.
In general, most insulin-producing tumors associated with hypoglycemia are benign. Conversely, endocrinologically active gastrin-producing tumors, glucagon producing tumors, VIP-producing tumors and somatostatin-producing tumors are often malignant. However, there are no definite morphologic criteria to predict hormonal activity or behavior. Metastases are the only sign of malignancy.
Therefore, all pancreatic endocrine tumors should be regarded as potentially malignant, even though metastases may not be apparent at the time of initial surgery (Mukai, 1983).
The common clinical syndromes and their causative hormones are as follows:
hypoglycemia (insulin)
Zollinger-Ellison syndrome (gastrin).
glucagonoma syndrome (glucagon).
WDHA syndrome (Verner-Morrison syndrome) (vasoactive intestinal pancreatic polypeptide)
somatostatinoma syndrome (somatostatin).
The first two syndromes are relatively frequent but the remaining three are either infrequent or rare (Larsson, 1978). Occasionally, pancreatic endocrine tumors fail to demonstrate immunoreaction in the presence of clinical syndromes. Explanations for this aberrant phenomenon include abnormal peptides (although biologically active) which may not react with specific antihormone antibodies, fixation artifact or alternatively rapid turnover in tumor cells resulting in only minute amounts being stored (Mukai et al, 1982).
Tumors from some patients with WDHA syndrome have been found to secrete PP (Lundqvist et al, 1978). PP also appears to be the most commonly found in hormone silent/non-functioning tumors (Mukai et al, 1982). Whilst the physiologic function of PP is not yet fully understood, PP cells are nevertheless a component often demonstrated in multihormonal tumors (Larsson, 1978). The frequency of multihormone production by islet cells tumors has been stated as being as high as 50% (Owyang and Go, 1980). These tumors usually cause only one clinical syndrome and a combination of syndromes is extremely rare. In fact, the predominant cell type in a tumor does not necessarily cause the corresponding syndrome (Larsson et al, 1975). Any combination of cell types is possible in pancreatic endocrine tumors, the most striking example being the high frequency of PP cells in tumors secreting VIP and causing the WDHA syndrome (Schwartz, 1979). The most likely explanation for the common presence of several cell types in pancreatic endocrine tumors is that they derive from a multipotential stem cell which may differentiate in various directions (Mukai et al, 1982).
Antibodies to pancreatic hormones may also be applied to the diagnosis of islet cell hyperplasia seen in the non-neoplastic pancreas of patients with islet cell tumors (Larsson, 1977) and primary G-cell hyperplasia (gastrin producing) in the antrum of the stomach. The latter is clinically indistinguishable from Zollinger-Ellison syndrome due to gastrinoma (Lewin et al, 1984). The demonstration of an increase in number and size of the B cell mass in the ductuloinsular complexes in neonatal hyperinsulinemic hypoglycemia is another application of pancreatic hormone immunohistochemistry (Jaffe et al, 1980).
Duodenal (periampullary) somatostatin-rich carcinoid tumors (psammomatous somatostatinoma) need to be distinguished from adenocarcinoma, because the prognosis is better in the former even though lymph node metastases may occur with carcinoids (Chetty et al, 1993). Other neuroendocrine tumors of the duodenum that require immunohistochemistry for their recognition include gastrinomas (most common), gangliocytic paraganglioma (Hamid et al, 1986),
serotonin/calcitonin/pancreatic polypeptide- producing tumors and poorly differentiated neuroendocrine carcinomas. A characteristic feature of MEN-associated gastrinoma is their frequent multicentricity (Pipeleers-Marichal et al, 1990).
Gastrointestinal carcinoid tumors have also benefited from the development of immunohistochemical technology: gastrin, VIP, PP and glucagon have been demonstrated (apart from serotonin in cases of carcinoid syndrome). In children, WDHA syndromes have been reported in association with VIP-secreting ganglioneuromas and ganglioneuroblastomas (Long et al, 1981).
Comments
Immunohistochemistry has contributed extensively to the understanding of the morphofunctional relationship of pancreatic (and related) endocrine tumors. Apart from the cellular localization of secretory products in these tumors, prediction of biological behavior has also been possible. Positive control tissues for this panel of pancreatic hormones include: normal pancreas (insulin, glucagon, somatostatin and PP), gastric antrum (gastrin) and colon (VIP).
References
•Chetty R, Silvester AC, Pitson GA 1993 Duodenal (periampullary) somatostatin-rich carcinoid in a patient with type 1 neurofibromatosis. Pathology 25: 354-355.
•Creutzfeldt, W 1980 Endocrine tumors of the pancreas: clinical chemical and morphological findings. In: Fitzgerald PJ, Morrison ABC (eds) The pancreas. Baltimore: Williams and Wilkins Baltimore pp 208-230.
•Fitzgerald PJ, Morrison ABC (eds) The pancreas. Baltimore: Williams and Wilkins Baltimore pp 208-230.
•Dayal Y, O'Brian DS 1981 The pathology of the pancreatic endocrine cells. In: DeLellis RA (ed) Diagnostic Immunohistochemistry. New York: Masson pp 111-135.
•Erlandsen SL, Hegre OD, Parsons JA, McEvoy RC, Elde RP 1976 Pancreatic islet cell hormones: distribution of cell types in the islet and evidence for the presence of somatostatin and gastrin within the D-cell. Journal of Histochemistry and Cytochemistry 24:883.
•Hamid QA, Bishop AE, Rode J et al 1986 Duodenal gangliocytic paraganglioma: a study of 10 cases with immunocytochemical neuroendocrine markers. Human Pathology 17: 1151-1157.
•Jaffe RM, Hashida Y, Yunis EJ 1980 Pancreatic pathology in hyperinsulinaemic hypoglycaemia of infancy. Laboratory Investigation 42: 356-365.
•Larsson L-I 1977 Two distinct types of islet abnormalities associated with endocrine pancreatic tumours. Virchows Archives Pathologic Anatomy 376: 209-219.
•Larsson L-I 1978 Classification of pancreatic endocrine tumors. Scandinavian Journal of Gastroenterology 14(suppl 53): 15-18.
•Larsson L-I, Grimelius L, H anson R et al 1975 Mixed endocrine pancreatic tumors producing several peptide hormones. American Journal of Pathology 79:271-284.
•Lewin KJ, Ulich T, Walsh JH 1984 Primary gastrin cell hyperplasia of the gastric antrum. American Journal of Surgical Pathology 8: 821-832.
•Long RG, Bryant MG, Mitchell SJ et al 1981 Clinicopathological study of pancreatic and ganglioneuroblastoma tumors secreting vasoactive intestinal polypeptide (vipomas). British Medical Journal 282: 1767-1771.
•Lundqvist G, Krause U, Larsson L-I et al 1978 A pancreatic-polypeptide-producing tumour associated with the WDHA syndrome. Scandinavian Journal of Gastroenterology 13:715-718.
•Mukai K 1983 Functional pathology of pancreatic islets: immunocytochemical exploration. Pathology Annual 2: 87-107.
•Mukai K, Greider MH, Grotting JC, Rosai J 1982 Retrospective study of 77 pancreatic endocrine tumors using the immunoperoxidase method. American Journal of Surgical Pathology 6: 387-399.
•Owyang C, Go VL 1980. Multiple hormone-secreting tumors of the gastrointestinal tract. In:Glass GBJ (ed) Gastrointestinal hormones. New York: Raven Press pp 741-748.
•Pipeleers-Marichal M, Somers G, Willems G et al 1990 Gastrinomas in the duodenum of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. New England Journal of Medicine 322: 723-727.
•Said SI 1980 Vasoactive intestinal peptide (VIP): isolation, distribution, biological actions, structure-function relationships, and possible functions. In: Glass GBJ (ed) Gastrointestinal hormones New York: Raven Press pp 245-273.
•Schwartz TW 1979 Pancreatic-polypeptide (PP) and endocrine tumours of the pancreas. Scandinavian Journal of Gastroenterology 14 (suppl 53): 93-100.
Bibliografia
Manual of diagnostic antibodies for immunohistology / Anthony S.-Y. Leong, Kumarasen Cooper, F. Joel W.-M. Leong.
Pancreatic endocrine tumors have been associated with several distinct clinical syndromes, such as hypoglycemia, glucagonoma syndrome, Zollinger-Ellison syndrome and WDHA (watery diarrhea, hypokalemia and achlorhydria) syndrome (Mukai et al, 1982). Routine histological examination usually fails to predict the behavior and endocrine manifestations of these neoplasms (Creutzfeldt, 1980). Immunohistochemistry permits the specific demonstration of various pancreatic hormones in tissue sections.
Sources/Clones
Insulin
Accurate (K36AC10), Axcel/Accurate (polyclonal), Biodesign (MAb 1, E2-E3, polyclonal), Biogenesis (E6E5, D4B8, IN05, C7C9, polyclonal), Biogenex (AE9D6, polyclonal), Caltag Laboratories (polyclonal), Cymbus Bioscience (MAB1), Dako (polyclonal), EY Labs, Fitzgerald (M91284, M91285, M322212, M322213, polyclonal), Immunotech Inc/Immunotech SA (E2E3), Novocastra (polyclonal), Research Diagnostics (MAB 1), Sanbio/Monosan (N-05, polyclonal), Sigma (K36AC10) and Zymed (Z005, Z006, polyclonal).
Somatostatin
Accurate (YC7, BM17), Axcel/Accurate (polyclonal), Biogenesis (170.3, polyclonal), Biogenex (polyclonal), Caltag Laboratories (polyclonal), Dako (polyclonal), Fitzgerald (polyclonal), Novocastra (polyclonal), Pharmingen (YC7), Sanbio/Monosan (polyclonal) and Zymed (polyclonal).
Vasoactive Intestinal Polypeptide
(VIP): Accurate, Biodesign (polyclonal), Biogenesis (VIP-001), Biogenex (polyclonal), Immunotech (103.10), Serotec and Zymed (polyclonal).
Gastrin
Axcel/Accurate (polyclonal), Biodesign (polyclonal), Biogenesis (polyclonal), Biogenex (polyclonal), Caltag Laboratories (polyclonal), Dako (polyclonal), Fitzgerald (M28046, M28047, polyclonal), Immunotech (4C7A1), Novocastra, Sanbio/Monosan (polyclonal) and Zymed (polyclonal).
Glucagon
Accurate/Sigma (K79bB10), Axcel/Accurate (polyclonal), Biodesign (polyclonal), Biogenesis (polyclonal), Biogenex (polyclonal), Caltag Laboratories (polyclonal), Dako (polyclonal), Fitzgerald (polyclonal), Immunotech (polyclonal), Sanbio/Monosan (polyclonal) and Zymed (polyclonal).
Pancreatic Polypeptide (PP):
Axcel/Accurate (polyclonal), Becton Dickinson, Biodesign (polyclonal), Biogenesis (polyclonal), Biogenex (polyclonal), Dako (polyclonal), Eli Lilly (polyclonal) and Zymed (polyclonal).
Fixation/Preparation
These antibodies are applicable to formalin-fixed, paraffin-embedded tissue as well as frozen sections. No pretreatment or antigen unmasking is necessary for any of the antibodies.
Background
The antigens used as immunogens to raise rabbit antibodies against the pancreatic hormones were as follows: insulin - porcine pancreatic insulin; somatostatin - synthetic peptide somatostatin - 14;VIP follows: insulin - porcine pancreatic insulin; somatostatin - synthetic peptide somatostatin - 14;VIP natural porcine VIP, conjugated to glutaraldehyde as carrier protein; gastrin - synthetic human gastrin-17 non-sulfated form(I) conjugated to bovine serum albumin; glucagon - porcine glucagon. Although there are at least eight different cell types identified in the pancreatic islets (Dayal and O'Brian, 1981), only the resident four major cell types (A, B, D and PP cells) and G and VIP cells (in neoplastic conditions) will be considered here. In the normal adult islet, insulin-containing B cells account for 60-80 % of endocrine cells (Erlandsen et al, 1976) and occupy the central portion of the islets. Glucagon-containing A cells constitute 20-30% and somatostatin-containing D cells, 5-11%. A and D cells are mostly present in the periphery of the islets and are also scattered within the islets along capillaries. Physiologically, glucagon increases hepatic glucose production and opposes hepatic glucose storage; insulin increases peripheral glucose uptake and opposes glucagon-mediated hepatic glucose production. Hence, the delicate balance of these two hormones maintains blood glucose homeotasis. Somatostatin has inhibitory actions on both A and B cells through a ''paracrine" effect, thereby regulating the balance of A- and B-cell functions. PP cells are the least numerous and are present both within and outside the islets. The function of pancreatic polypeptide has not been fully understood. PP cells have a variable distribution in the pancreas, with PP cell-rich islets being occasionally present in the posterior lobe of the pancreatic head. Hence, caution should be exercised when evaluating hyperplastic changes of PP cells (Mukai, 1983).
Although the presence of gastrin in D-cells has been disputed, recent studies indicate that gastrin is not present in normal adult islets (Dayal and O'Brian, 1981). VIP has been localized in human islets but the exact cellular origin has not been fully understood (Said, 1980).
In the gastroduodenal segment gastrin has been immunolocalized to the G cells of the gastric antrum, whilst somatostatin has been found in endocrine cells and nerves of the intestinal wall digestive mucosa.
Applications
Endocrine tumors of the gastrointestinal tract and pancreas may demonstrate a wide variety of histomorphological patterns:
solid (nodular solid nests with peripheral invading cords)
solid and glandular (with focal glandular formation)
gyriform (trabecular or ribbon-like structures forming an anastomosing pattern)
glandular (tubular or acinar structures) (Mukai et al, 1982).
With the availability of antibodies to the secretory products, specific designation of these neoplasms has led to terms such as insulinoma, glucagonoma, gastrinoma, somatostatinoma and VIPoma. However, small tumors found incidentally at autopsy may be clinically silent and do not necessarily cause clinical symptoms. Further, many pancreatic endocrine tumors are multihormonal (Mukai et al, 1982). Hence, Rosai prefers the designation `pancreatic endocrine tumor' followed by the description of the hormone(s) demonstrated in situ (e.g. insulin-producing) whenever this can be ascertained. Pancreatic endocrine tumors, which do not cause clinically apparent endocrine syndromes, are usually labeled as non-functioning tumors. However, with the acceptance of hormone production as a sign of function, the number of non-functioning tumors decrease with application of immunohistochemical staining procedures using antibodies to specific hormones.
In general, most insulin-producing tumors associated with hypoglycemia are benign. Conversely, endocrinologically active gastrin-producing tumors, glucagon producing tumors, VIP-producing tumors and somatostatin-producing tumors are often malignant. However, there are no definite morphologic criteria to predict hormonal activity or behavior. Metastases are the only sign of malignancy.
Therefore, all pancreatic endocrine tumors should be regarded as potentially malignant, even though metastases may not be apparent at the time of initial surgery (Mukai, 1983).
The common clinical syndromes and their causative hormones are as follows:
hypoglycemia (insulin)
Zollinger-Ellison syndrome (gastrin).
glucagonoma syndrome (glucagon).
WDHA syndrome (Verner-Morrison syndrome) (vasoactive intestinal pancreatic polypeptide)
somatostatinoma syndrome (somatostatin).
The first two syndromes are relatively frequent but the remaining three are either infrequent or rare (Larsson, 1978). Occasionally, pancreatic endocrine tumors fail to demonstrate immunoreaction in the presence of clinical syndromes. Explanations for this aberrant phenomenon include abnormal peptides (although biologically active) which may not react with specific antihormone antibodies, fixation artifact or alternatively rapid turnover in tumor cells resulting in only minute amounts being stored (Mukai et al, 1982).
Tumors from some patients with WDHA syndrome have been found to secrete PP (Lundqvist et al, 1978). PP also appears to be the most commonly found in hormone silent/non-functioning tumors (Mukai et al, 1982). Whilst the physiologic function of PP is not yet fully understood, PP cells are nevertheless a component often demonstrated in multihormonal tumors (Larsson, 1978). The frequency of multihormone production by islet cells tumors has been stated as being as high as 50% (Owyang and Go, 1980). These tumors usually cause only one clinical syndrome and a combination of syndromes is extremely rare. In fact, the predominant cell type in a tumor does not necessarily cause the corresponding syndrome (Larsson et al, 1975). Any combination of cell types is possible in pancreatic endocrine tumors, the most striking example being the high frequency of PP cells in tumors secreting VIP and causing the WDHA syndrome (Schwartz, 1979). The most likely explanation for the common presence of several cell types in pancreatic endocrine tumors is that they derive from a multipotential stem cell which may differentiate in various directions (Mukai et al, 1982).
Antibodies to pancreatic hormones may also be applied to the diagnosis of islet cell hyperplasia seen in the non-neoplastic pancreas of patients with islet cell tumors (Larsson, 1977) and primary G-cell hyperplasia (gastrin producing) in the antrum of the stomach. The latter is clinically indistinguishable from Zollinger-Ellison syndrome due to gastrinoma (Lewin et al, 1984). The demonstration of an increase in number and size of the B cell mass in the ductuloinsular complexes in neonatal hyperinsulinemic hypoglycemia is another application of pancreatic hormone immunohistochemistry (Jaffe et al, 1980).
Duodenal (periampullary) somatostatin-rich carcinoid tumors (psammomatous somatostatinoma) need to be distinguished from adenocarcinoma, because the prognosis is better in the former even though lymph node metastases may occur with carcinoids (Chetty et al, 1993). Other neuroendocrine tumors of the duodenum that require immunohistochemistry for their recognition include gastrinomas (most common), gangliocytic paraganglioma (Hamid et al, 1986),
serotonin/calcitonin/pancreatic polypeptide- producing tumors and poorly differentiated neuroendocrine carcinomas. A characteristic feature of MEN-associated gastrinoma is their frequent multicentricity (Pipeleers-Marichal et al, 1990).
Gastrointestinal carcinoid tumors have also benefited from the development of immunohistochemical technology: gastrin, VIP, PP and glucagon have been demonstrated (apart from serotonin in cases of carcinoid syndrome). In children, WDHA syndromes have been reported in association with VIP-secreting ganglioneuromas and ganglioneuroblastomas (Long et al, 1981).
Comments
Immunohistochemistry has contributed extensively to the understanding of the morphofunctional relationship of pancreatic (and related) endocrine tumors. Apart from the cellular localization of secretory products in these tumors, prediction of biological behavior has also been possible. Positive control tissues for this panel of pancreatic hormones include: normal pancreas (insulin, glucagon, somatostatin and PP), gastric antrum (gastrin) and colon (VIP).
References
•Chetty R, Silvester AC, Pitson GA 1993 Duodenal (periampullary) somatostatin-rich carcinoid in a patient with type 1 neurofibromatosis. Pathology 25: 354-355.
•Creutzfeldt, W 1980 Endocrine tumors of the pancreas: clinical chemical and morphological findings. In: Fitzgerald PJ, Morrison ABC (eds) The pancreas. Baltimore: Williams and Wilkins Baltimore pp 208-230.
•Fitzgerald PJ, Morrison ABC (eds) The pancreas. Baltimore: Williams and Wilkins Baltimore pp 208-230.
•Dayal Y, O'Brian DS 1981 The pathology of the pancreatic endocrine cells. In: DeLellis RA (ed) Diagnostic Immunohistochemistry. New York: Masson pp 111-135.
•Erlandsen SL, Hegre OD, Parsons JA, McEvoy RC, Elde RP 1976 Pancreatic islet cell hormones: distribution of cell types in the islet and evidence for the presence of somatostatin and gastrin within the D-cell. Journal of Histochemistry and Cytochemistry 24:883.
•Hamid QA, Bishop AE, Rode J et al 1986 Duodenal gangliocytic paraganglioma: a study of 10 cases with immunocytochemical neuroendocrine markers. Human Pathology 17: 1151-1157.
•Jaffe RM, Hashida Y, Yunis EJ 1980 Pancreatic pathology in hyperinsulinaemic hypoglycaemia of infancy. Laboratory Investigation 42: 356-365.
•Larsson L-I 1977 Two distinct types of islet abnormalities associated with endocrine pancreatic tumours. Virchows Archives Pathologic Anatomy 376: 209-219.
•Larsson L-I 1978 Classification of pancreatic endocrine tumors. Scandinavian Journal of Gastroenterology 14(suppl 53): 15-18.
•Larsson L-I, Grimelius L, H anson R et al 1975 Mixed endocrine pancreatic tumors producing several peptide hormones. American Journal of Pathology 79:271-284.
•Lewin KJ, Ulich T, Walsh JH 1984 Primary gastrin cell hyperplasia of the gastric antrum. American Journal of Surgical Pathology 8: 821-832.
•Long RG, Bryant MG, Mitchell SJ et al 1981 Clinicopathological study of pancreatic and ganglioneuroblastoma tumors secreting vasoactive intestinal polypeptide (vipomas). British Medical Journal 282: 1767-1771.
•Lundqvist G, Krause U, Larsson L-I et al 1978 A pancreatic-polypeptide-producing tumour associated with the WDHA syndrome. Scandinavian Journal of Gastroenterology 13:715-718.
•Mukai K 1983 Functional pathology of pancreatic islets: immunocytochemical exploration. Pathology Annual 2: 87-107.
•Mukai K, Greider MH, Grotting JC, Rosai J 1982 Retrospective study of 77 pancreatic endocrine tumors using the immunoperoxidase method. American Journal of Surgical Pathology 6: 387-399.
•Owyang C, Go VL 1980. Multiple hormone-secreting tumors of the gastrointestinal tract. In:Glass GBJ (ed) Gastrointestinal hormones. New York: Raven Press pp 741-748.
•Pipeleers-Marichal M, Somers G, Willems G et al 1990 Gastrinomas in the duodenum of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. New England Journal of Medicine 322: 723-727.
•Said SI 1980 Vasoactive intestinal peptide (VIP): isolation, distribution, biological actions, structure-function relationships, and possible functions. In: Glass GBJ (ed) Gastrointestinal hormones New York: Raven Press pp 245-273.
•Schwartz TW 1979 Pancreatic-polypeptide (PP) and endocrine tumours of the pancreas. Scandinavian Journal of Gastroenterology 14 (suppl 53): 93-100.
Bibliografia
Manual of diagnostic antibodies for immunohistology / Anthony S.-Y. Leong, Kumarasen Cooper, F. Joel W.-M. Leong.
