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PubMed1985

[Polyfunctional endometrial adenocarcinoma producing melatonin, noradrenaline and chorionic gonadotropin].

Highly differentiated endometrial adenocarcinoma is described in which the cells of the APUD-system (apudocytes) producing melatonin, noradrenaline and chorionic gonadotropin are detected histochemically and immunohistochemically. The disturbance of lipid metabolism in the patient is attributed to the hyperproduction of noradrenaline and melatonin exerting a mobilizing effect on lipid metabolism.

Adenocarcinoma↗
PubMedDate not supplied

[Neurocristopathies : embryology, physiology, and pathology of the neural crest derivatives (author's transl)].

The authors review various of the derivatives of the neural crest, consider their relationship with the APUD System, and deduce the physiopathological consequences applicable to these cells, whose only similarity lies in their common embryologic origin. They propose a system of classification of interrelated pathological conditions that these cells may show, an detail clinical information as well as the mode of genetic transmission of the principal neurocristopathic syndroms.

APUD Cells↗
PubMed1991

Solitary neuroendocrine cells and neuroepithelial bodies in the lower airways of embryonic, fetal, and postnatal sheep.

The sheep pulmonary intraepithelial APUD system was studied by histochemical, immunocytochemical, and electron microscopy techniques during different periods of lung development: embryonic, fetal (pseudoglandular, canalicular, and alveolar), and postnatal. The cells of the ovine pulmonary intraepithelial APUD system were found randomly distributed throughout the conducting and respiratory or undifferentiated airways. They appeared as isolated cells (solitary neuroendocrine cells) or in groups (neuroepithelial bodies). These cells were argyrophilic and immunoreactive for neuron-specific enolase but were not argentaffin. Ultrastructurally they were characterized by a basal position in the respiratory epithelium and by the presence of neurosecretory granules (dense-core vesicles) ranging between 65 and 230 nm of diametre. Quantitative studies showed that single neuroendocrine cells were more numerous in distal conducting airways and at fetal stages. The earliest identifiable argyrophilic and NSE-immunoreactive neuroendocrine cells in sheep airways appeared at gestational week 5, close to the term of the embryonic period.

APUD Cells↗
PubMed1981

The APUD system and its apudomas.

As sensitive radioimmunoassays for the detection of polypeptide hormones are developed, the exciting discovery of a diffusely distributed system of interrelated endocrine cells has begun a new era of endocrinology. This system, although anatomically disassociated, is bound together by a number of common features such as its biosynthetic mechanism, histochemical and ultrastructural features, and embryologic origin (Table I). The most prominent feature, however, is their biosynthetic pathways for hormone production, from which the acronym APUD has been derived. These are the capacity for Amine Precursor Uptake such as DOPA and then subsequent Decarboxylation, resulting in the synthesis of bioactive amines or polypeptide hormones. Hyperplasias or neoplasms of these cells are defined as apudomas. In the last ten years a great deal of research has rapidly altered the original concepts of this system, especially in terms of its embryologic origin, physiologic interrelationships, classification, as well as the addition of many new APUD cell members. These will be reviewed, and the origin, diagnosis, and treatment of each recognized apudoma will be synthesized in light of its membership within the APUD system.

APUD Cells↗
PubMed1999

[Changes in the APUD system of the large intestine as a risk factor for colorectal cancer].

A common population of endocrine cells, apudocytes producing serotonin, melatonin, vaso-intestinal peptides and mast cells were examined on unaffected mucous membranes of 27 colorectal cancer patients. Light and electron microscopy, immunohistochemical and morphometric methods were used. A marked decrease in total number of apudocytes, hypoplasia of cells producing serotonin, melatonin, vaso-intestinal peptides were revealed at early stages of cancer irrespective of the tumor structure. Mast cells in premetastatic period outnumbered those after emergence of metastases. The results obtained may serve as additional criteria of early colorectal cancer diagnosis.

APUD Cells↗
PubMed1981

Endocrine-related biochemistry in the spectrum of human lung carcinoma.

The association of hormonal syndrome and APUD (amine precursor uptake, decarboxylase) features with small cell carcinoma of the lung (SCC) has suggested that SCC has a separate cell origin from other major forms of lung cancer. Recently, however, both SCC and non-SCC lung cancers have been found to contain small polypeptide hormones and APUD enzymes. The present study quantitates, in 50 samples of human lung cancer tissue, relationships among the 4 major types of lung cancer and endocrine-related properties. Among 4 parameters measured (dopa decarboxylase, histaminase, beta-endorphin, and calcitonin), no single marker clearly separated SCC from non-SCC lung cancer. The high activity of dopa decarboxylase (the "D" in "APUD") best separated SCC from non-SCC, but significant overlap existed even for this critical APUD property. In fact, 2 adenocarcinomas had among the highest concentrations of dopa decarboxylase, histaminase, and calcitonin of any tumor tissue studied. The simultaneous appearance of high levels of 2 or more markers favored SCC. This was quantitated by deriving an index unit based upon the product of the values for the 4 markers in each lesion. This index separated all SCC from all non-SCC lung carcinomas, with the exception of the above 2 adenocarcinomas. Endocrine-related properties thus occur throughout the spectrum of human lung cancer. Biochemical differences between the major histopathological types are quantitative rather than qualitative and probably reflect the fact that the major forms of lung cancer represent a continuum of differentiation within a common cell lineage which includes both SCC and non-SCC lung tumors.

APUD Cells↗
PubMed1981

Comparative histochemistry as a springboard for the discovery of biogenic amines and active peptides in molluscan tissues and amphibian skin.

Histochemistry has been the springboard for the identification in molluscan tissues (hypobranchial body and salivary glands) and amphibian skin of a number of biogenic amines, choline esters and active peptides. Among the biogenic amines 5-HT and related indolealkylamines, octopamine, tyramine and several histamines are to be listed; among the choline esters murexine, dihydromurexine, senecioylcholine and acryloylcholine; among the peptides an array of compounds belonging to at least ten different peptide families. 5-HT, octopamine, tyramine and histamine are present, together with representatives of some peptide families in the posterior salivary glands of octopods, the hypobranchial body of prosobranchiate molluscs and the amphibian skin. This points to the possible occurrence in the above structures of cells belonging to the Pearse's APUD series, intended in its broadest sense. Immunocytochemical studies and even ultrastructural studies on amine and peptide storing cells in molluscan tissues and amphibian skin are virtually lacking. This is certainly a gap that deserves to be filled, considering that these studies may help in elucidating problems of general relevance in invertebrates and vertebrates.

Amphibian Proteins↗
PubMed1986

Immunohistochemical demonstration of HNK-1-defined antigen in gynecologic tumors with argyrophilia.

Gynecologic tumors with argyrophilia were tested immunohistochemically for reactivity with monoclonal antibody HNK-1, which detects normal and neoplastic cells derived from the neuroectodermal and the amine-precursor-uptake and decarboxylation (APUD) systems. The tumors included six small cell carcinomas and four adenocarcinomas of the cervix; 23 adenocarcinomas of the endometrium (13 with type I and 10 with type II argyrophil cells); and 11 mucinous tumors (three benign, three borderline, and five malignant), eight endometrioid carcinomas (four with type I and four with type II argyrophil cells), and two carcinoid tumors (one insular and one strumal) of the ovary. HNK-1 reactive cells were found in almost every category of tumor: in four small cell carcinomas and two adenocarcinomas of the cervix; 11 adenocarcinomas of the endometrium (eight with type I and three with type II argyrophil cells); and four mucinous (two benign and two borderline), two endometrioid (one with type I and one with type II argyrophil cells), and two carcinoid tumors of the ovary. These cells corresponded to at least some of the type I argyrophil cells in endometrial and ovarian endometrioid carcinomas and to similar cells in mucinous and carcinoid tumors of the ovary and small cell carcinoma and adenocarcinoma of the cervix. However, the remaining type I and similar argyrophil cells and almost all type II argyrophil cells were HNK-1 negative, and some of the nonargyrophil tumor cells were HNK-1 positive. Although the significance of such discrepancies in reactivity with HNK-1 antibody remains unknown, the present results suggest that some of the gynecologic tumors with argyrophilia are related to APUDomas.

Antigens, Neoplasm↗
PubMed1986

Regulatory peptides of the gastrointestinal and respiratory tracts.

The gastrointestinal and respiratory tracts contain numerous regulatory peptides produced by and released from specialised epithelial cells and the organ innervation. This complex system of endocrine cells and nerves is generally called "the diffuse neuroendocrine system". Markers are now available which permit the visualisation of the diffuse neuroendocrine system or its individual components. These include antibodies to neuron-specific enolase, chromogranin, neurofilament triplet proteins, the brain protein S100 and antibodies to a variety of regulatory peptides. Peptides present in the gut and lung innervation include: vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), galanin, substance P, calcitonin gene-related peptide (CGRP), neuropeptide tyrosine (NPY), somatostatin and cholecystokinin (the latter two are also localised to endocrine cells of the gut). Bombesin-immunoreactivity is found in nerves in the gut and in endocrine cells of the foetal/neonatal lung. Neuropeptides of the gut and lung originate either from local neurons (e.g. VIP, PHI, galanin) or extrinsic neurons localised in sensory ganglia (e.g. substance P and CGRP) or the sympathetic chain (e.g. NPY). Recent studies point to the involvement of regulatory peptides in diseases of the gut and lung. These, together with detailed distribution studies, provide supportive data on the putative role of the peptides in the control of normal bowel and respiratory functions. The gastrointestinal and respiratory tracts were within the systems investigated by Feyrter during his original observations on the existence of specialised epithelial cells with a putative regulatory function (Feyrter, 1938). These "endocrine/paracrine" cells were found to be scattered in epithelial organs throughout the body. In fact, endocrine cells of the respiratory tract are frequently referred to as "Feyrter's cells". The term "regulatory peptides" was introduced as a generic term (Polak and Bloom, 1983) after the finding that active peptides are produced both by cells of the diffuse endocrine or APUD (amine precursor uptake and decarboxylation) system (Pearse, 1983) and autonomic/sensory nerves. These peptides are released into the circulation from endocrine cells or locally from nerve terminals or paracrine cells. The concept of "gut/brain" peptides was dispelled after the findings that the respiratory tract was provided abundantly with numerous active peptides produced by and released from mucosal endocrine cells and/or the innervation.

Animals↗
PubMed1993

A phase II trial of carboplatin in patients with advanced APUD tumors.

BACKGROUND: Chemotherapy remains inadequate for patients with carcinoid tumors, islet cell tumors, and medullary carcinomas of the thyroid. Carboplatin has shown activity in oat cell carcinoma of the lung, another tumor of neuroectodermal origin. METHODS: Forty-two patients with advanced APUD tumors (20 carcinoid tumors, 9 islet cell carcinomas, 5 medullary carcinomas of the thyroid, and 9 neuroendocrine tumors of unknown primary site) were treated with carboplatin in a Phase II study. RESULTS: Carboplatin was inactive in carcinoid and islet cell tumors, with 0 of 20 and 0 of 9 patients responding, respectively. Of the 41 total patients evaluable for response, only 2 (5%) achieved a partial response. Both of these responding patients had neuroendocrine tumors of unknown primary site. No complete responses were seen. Toxicities were those previously noted with carboplatin, with myelosuppression, particularly thrombocytopenia, being dose limiting. CONCLUSIONS: Carboplatin is inactive in carcinoid tumors and did not show evidence of activity in islet cell tumors. Further investigations are needed to identify active agents in the treatment of neuroendocrine malignancies.

Adenoma, Islet Cell↗
PubMed1991

Substance P- and neuron-specific enolase-like immunoreactivity of rodent Leydig cells in tissue section and cell culture.

Comparative immunocytochemical studies concerning the presence of a neurotransmitter (substance P), and a marker of neuroendocrine cells (neuron-specific enolase), in the Leydig cells of 3 mammalian species (golden hamster, guinea pig, and rat) were carried out on tissue sections and cell cultures. Substance P(SP)-like immunoreactivity (-LI) was found to be present in both fetal and adult generation of Leydig cells in hamster and guinea pig, while neuron-specific enolase (NSE)-LI was detected in Leydig cells of the 3 species at all stages studied: fetal, neonatal and adult. In primary cultures of Leydig cells isolated from adult hamster testes, SP- and NSE-LI was also established. This result was considered as an indirect evidence for the synthesis of the substances under study by the steroidogenic cells of the testis. A comparison of these results with data obtained in vivo suggests that Leydig cells may be related to the APUD- or the diffuse neuroendocrine system.

Animals↗
PubMed1982

Mucus-producing medullary cell carcinoma of the thyroid gland.

A case of medullary carcinoma of the thyroid with the presence of mucus-secreting (goblet) cells was reported. Ultrastructurally, the tumor was composed of two types of cells, one with neurosecretory granules and the other with mucus granules. The secretion of calcitonin and mucus was demonstrated by histochemical methods. The presence of two cell populations in this tumor casts doubts on the "APUD" concept, which proposes a neuroectodermal origin for parafollicular (C) cells of the thyroid gland. The significance of this tumor with regard to the histogenesis of the cells involved, is discussed.

Adult↗
PubMed2004

[Merkel cell carcinoma of the head and neck].

Merkel cell carcinoma (MCC) is a skin cancer arising from neurosecretory cells which take part in APUD system. In most cases it is locally growing tumor with significant tendency to local recurrences after surgery. The authors have described four cases MCC localised on the skin of the middle angle of the eye, lower eyelid, auricle and cheek, without nodal metastases. All patients have been surgery treated, in two cases reconstructive surgery was performed. Radiotherapy followed surgery was used for two patients. The authors have reported 5-year survival rate in 2 cases, 2-year disease-free rate and 18 month in other cases.

Aged↗
PubMed1982

A new antimitochondria antibody (anti-M6) in iproniazid-induced hepatitis.

A new immunofluorescence pattern of non-organ- and non-species-specific antibody has been observed in occasional sera. Variations of the fluorescence were found in different species. Recognition of the new pattern was particularly characteristic in rat organs (liver: the hepatocytes showed intense roughly granular fluorescence evenly distributed in the cytoplasm; kidney: the bright fluorescence of the first portion of the proximal tubules contrasted with the negative aspect of the other portions of the tubules; stomach: only some cells probably corresponding to the APUD system were positive; pancreas: fluorescence was limited to the islets of Langherhans). The positivity in the ellipsoid region of the rods and cones of the eye and the absorption on different liver organelles showed that this aspect corresponded to the mitochondria. We propose to name this pattern 'antimitochondria antibody number 6' or 'anti-M6'. High titres of anti-M6 were found in four patients suffering from iproniazid-induced hepatitis. A decrease in the titre was obtained after stopping the treatment. The now exceptional use of iproniazid and the rare occurrence of anti-M6 suggest a link between these two phenomena.

Adult↗
PubMed1980

Relationship of metastatic medullary thyroid carcinoma to calcitonin content of pheochromocytomas: an immunohistochemical study.

Immunoperoxidase studies have been utilized to investigate further the previously reported presence of immunoassayable calcitonin in pheochromocytoma tissue from some patients with MEN II syndromes. We have been able to demonstrate calcitonin in pheochromocytoma tissue only in two patients with MEN II syndromes in whom the pheochromocytomas contained metastatic medullary thyroid carcinoma. In both cases, the calcitonin was present only in the medullary carcinoma. We have not been able to demonstrate immunoreactive calcitonin in normal adrenal glands or in pheochromocytomas of other patients with and without MEN syndromes. Adrenal medullary cells and thyroid C cells are both of neural crest origin and both possess APUD characteristics. The presence of calcitonin in medullary thyroid carcinoma cells and not in pheochromocytes has important implications with regard to cellular differentiation and peptide hormone production.

Adrenal Gland Neoplasms↗
PubMed1995

Evaluation of somatostatin as a plasma tumor marker in medullary thyroid carcinoma.

Somatostatin (SRIF) immunoreactivity has been frequently reported in tumor tissues of cell types, belonging to the APUD system, including medullary thyroid carcinoma (MTC). However, the value of SRIF as a plasma tumor marker for MTC is controversial. We have measured SRIF plasma levels in 35 patients with different stages of MTC to evaluate the use of SRIF as a plasma tumor marker compared to the current "gold standard" calcitonin (CT). The median SRIF value in healthy controls was 36.5 pg/mL, the upper limit of normal was defined at the controls. The median value was 28 pg/mL (p = 0.37, Mann-Whitney U test). Five patients in the control group and three in the MTC group had SRIF levels that exceed the 95th percentile. SRIF and CT levels correlated only weakly (0.38), as determined by the Spearman rank order correlation test. Pentagastrin stimulation led to a diagnostic increase in SRIF levels in only one of five MTC patients. During selective venous catheterization, diagnostic gradients for CT, allowing tumor localization, could be demonstrated, whereas measurement of SRIF levels did not aid in tumor detection. Although SRIF immunostaining may be valuable as an additional marker in the histochemical diagnosis of MTC, SRIF has no value as a plasma tumor marker in the diagnosis of this disease.

Adult↗
PubMed1993

The Leydig cell of the human testis--a new member of the diffuse neuroendocrine system.

A number of marker substances for neuronal and neuroendocrine cells have been demonstrated in the cytoplasm of the interstitial Leydig cells of human testes using basic immunocytochemical methods and some of their modifications. We were able to reveal immunoreactivity for enzymes involved in the synthesis of the catecholamines dopamine and noradrenaline (tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine-beta-hydroxylase), for the indolamine 5-hydroxytryptamine (serotonin), as well as for a number of well-known neuronal markers such as the neurofilament protein 200, synaptophysin, chromogranin A + B, the neural cell-adhesion molecule (N-CAM), the microtubule-associated protein (MAP-2), and the calcium-binding proteins: S-100, calbindin and parvalbumin. Immunoreactivity for these substances was found in the majority of the interstitial cells although differences in the staining intensity among the individual Leydig cells and among Leydig cells from different patients were observed. At the electron-microscopic level the Leydig cell cytoplasm was seen to contain microtubules, intermediate- and microfilaments as well as clear (40-60 nm) and dense-core (100-300 nm) vesicles, providing a morphological correlate for some of the immunocytochemical results. Although individual marker substances are not absolutely specific for nerve and neuroendocrine cells, the results obtained, together with the already established neuron-specific enolase-, substance P-, methionine-enkephalin- and proopiomelanocortin (POMC)-derived peptide-like immunoreactivity, provide strong evidence for the neuroendocrine (paraneuronal, APUD-like) nature of the Leydig cells of the human testis.

Adult↗
PubMed1996

Neuroendocrine differentiation in prostatic malignancy.

BACKGROUND: The prostatic neuroendocrine cell is a regulatory cell that produces serotonin and peptide hormones. This cell is part of a more widely dispersed diffuse neuroendocrine regulatory system known as the APUD system. Focal neuroendocrine differentiation is seen in virtually all prostate carcinomas to one degree or another. Specific malignancies that are purely neuroendocrine include small cell carcinoma and carcinoid/carcinoid-like tumors. A variety of studies suggest a possible prognostic significance of neuroendocrine differentiation in prostate carcinoma. METHODS: The literature on the prostatic neuroendocrine cell and neuroendocrine differentiation in prostate carcinoma is reviewed. RESULTS: Based on analogy with other better studied elements of the diffuse neuroendocrine regulatory system or APUD system, as well as the morphology and specific products produced by neuroendocrine cells, it is likely that they play an important regulatory role in the prostate. Neuroendocrine differentiation may be of prognostic significance in prostate carcinoma. Mechanisms are not well characterized at this point, but the known growth factor activity of the neuroendocrine cell products, an increase in proliferation in cells surrounding neuroendocrine cells, and a lack of androgen receptor expression in neuroendocrine cells, suggest mechanisms by which they may be of prognostic significance. CONCLUSIONS: Neuroendocrine differentiation in prostate carcinoma may be of prognostic significance, but better methods to define neuroendocrine, differentiation are necessary. The therapeutic implications of neuroendocrine differentiation in prostate carcinoma may be of significance and need to be explored further.

APUD Cells↗