Endocrine tumors of the duodenum and upper jejunum. A study of 33 cases with clinico-pathological characteristics and hormone content.

Thirty duodenal and three upper-jejunal endocrine tumors are reported. Clinical manifestations included: a) the Zollinger-Ellison syndrome (10 cases); b) peptic ulcer disease in which hypergastrinemia was not documented (3 cases); c) cholestasis or cholelithiasis (4 cases); d) abdominal pain (4 cases); e) gastro-intestinal bleeding (1 case); f) celiac sprue (1 case). Ten further tumors were discovered incidentally, at autopsy or in pathological specimens after gastrectomy or duodenopan-createctomy. Histological pattern was trabecular in 19 cases, insular in 2 and mixed in ten cases. Two cases were typical ganglioneuromatous paragangliomas. All tumors were examined immunohistochemically. Twelve tumors contained gastrin, four somatostatin, six both of these peptides, one serotonin, two both gastrin and serotonin, and two tumors contained gastrin, serotonin and somatostatin. Ganglioneuromatous paragangliomas combined somatostatin and/or pancreatic polypeptide containing endocrine cells with protein-S100-positive Schwann cells. In four tumors no peptide or amine was demonstrated. Gastrin cell tumors (63.6% of our cases), both functionally active (gastrinomas) and clinically silent, predominated in the proximal duodenum, while somatostatin cell tumors (15.1%) and paragangliomas were mostly found in the periampullary region. Two tumors were classified as malignant on the basis of lymph node metastases, and both were jejunal gastrinomas associated with Zollinger-Ellison syndrome. Two somatostatin cell tumors had manifestations of von Recklinghausen's disease.

Malignant paraganglioma of the posterior mediastinum. A case report and review of the literature.

A case of malignant paraganglioma arising from the posterior mediastinum and presenting with a chest wall metastasis is reported with immunocytochemical and ultrastructural documentation. The pathobiologic features of this rare disease are reassessed with a review of the literature. Cytoarchitectural features do not provide reliable information regarding malignant potential. However, evidence of local invasiveness at surgical exploration and/or lack of initial surgical control are likely to be associated with synchronous or metachronous metastatic disease. Although there are clinicopathologic differences warranting distinction between benign paragangliomas arising in the anterior and posterior mediastinal compartments, there is no apparent pathobiologic difference with regard to the malignant group.

[Gangliocytic paraganglioma of the duodenum. Case report with immunocytochemical characterization]. / Das gangliozytische Paragangliom des Duodenums. Fallbericht mit immunzytochemischer Charakterisierung.

Described in this paper are histological, electron-microscopic, and immunocytochemical findings recorded from a duodenal gangliocytic paraganglioma in a 21-year old man. The sessile polypoid tumor consisted of epithelial cells, neuroid spindle cells, and gangliocytic elements. Neurosecretory granules were detected by electron-microscopy in the epithelial cells. The neuroid spindle cells exhibited the ultrastructural feature of Schwann cells. The tumor was immunocytochemically characterized by the S-100-reactivity of the spindle cells and numerous PP-reactive epithelial cells. Gangliocytic paragangliomas of the duodenum are of benign behaviour and should be removed by local excision.

A review of the histology, ultrastructure, immunohistology, and molecular biology of extra-adrenal paragangliomas.

This review summarizes our understanding of extra-adrenal paragangliomas, a subject that has evolved considerably during the past several years. Our object was to review the anatomical, histologic, and biological features of normal and neoplastic glands, with emphasis on immunohistologic studies, and briefly discuss the potential application of nucleic acid hybridization. Since it is difficult to predict clinical outcome for patients with paragangliomas, we have emphasized the differences between benign and malignant paragangliomas, concentrating on recent results obtained using immunohistologic techniques. These studies have emphasized the critical importance of the identification, by immunohistologic means, of two distinct cell populations, chief cells (type I) and sustentacular cells (type II). The relationship between these two cell populations, stable in normal glands and benign tumors, is progressively lost in tumors of increasing degrees of malignancy, sustentacular cells being absent from the most progressively metastasizing paragangliomas.

Gangliocytic paraganglioma.

A study of gangliocytic paragangliomas (GPs) of the gastrointestinal tract from 51 patients showed characteristic microscopic features: epithelioid cells with an endocrine growth pattern, spindle cells, and ganglion cells. Forty-nine tumors were located in the duodenum, 1 in the jejunum, and 1 in the pylorus. Twenty-one patients were female, 28 male, and for two the sex was unknown. The average age at presentation was 54 years (range, 23-83). No patient had a recurrence. No neuroendocrine syndrome was found in any patient or patient's family. Immunohistochemical stains in 33 cases yielded the following (proportion positive): S-100 protein 94%, synaptophysin 94%, neuron-specific enolase 94%, pancreatic polypeptide 88%, somatostatin 75%, chromogranin 72%, neurofilament protein 64%, keratin 52%, leu-enkephalin 48%, serotonin (one case), and gastrin (one case). Antisera usually stained one or two of the three major cell types. Pancreatic-type tissue was identified in or near 28 tumors, including the pyloric and jejunal lesions and two in the distal duodenum. The authors conclude that GP is benign; is not associated with endocrine syndromes; contains autonomic, neural, and endocrine cell types; and is related to pancreatic development.

Duodenal gangliocytic paraganglioma with lymph node metastasis in a 17-year-old boy.

A case of duodenal gangliocytic paraganglioma (DGP) in a 17-year-old boy is presented. In this case a lymph node in the peripancreatic region was involved by a metastatic tumor. A review of the literature on DGP indicates that this case represents the youngest patient and is the second case of DGP with metastasis. Immunohistochemical staining for neuron-specific enolase (NSE), neurofilament (NF), pancreatic polypeptide, and somatostatin showed positive results for epithelioid and ganglion-like cells, whereas spindle cells showed immunoreactivities for S-100 protein, NSE, and NF. The histogenesis of DGP is discussed.

[An autopsied case of malignant paraganglioma of the posterior thoracic cavity].

An autopsied case of a malignant paraganglioma of the posterior thoracic cavity is reported. A 68-year-old man had complained of chest discomfort, and serial examinations revealed a functioning paraganglioma with bone metastasis. After death a pathological examination revealed that the tumors consisted of alveolarly arranged cells and well developed capillary vessels. Numerous neurosecretory granules were observed on viewing by electron microscopy. An immunohistochemical examination showed that most of the tumor cells were positive for NSE, while only a few cells were positive for the S-100 protein. These results indicate that a paraganglioma originating from the aortic sympathetic paraganglia had similar features of a carcinoid and a neuroblastoma.

Malignant primary pulmonary paraganglioma.

The histological, immunocytochemical, and electron microscopic findings in a case of malignant primary pulmonary paraganglioma are reported. The existence of this rare tumour is evidence for the presence of pulmonary chemoreceptors.

Duodenal gangliocytic paraganglioma. Report of a case and review of the literature.

A case of gangliocytic paraganglioma (GP) of the ampulla of Vater is reported and the literature reviewed, with special attention to immunohistochemical studies. The present case, which occurred in a 56-year-old woman, shows the typical histological admixture of epithelioid, ganglion and spindle cells. Immunohistochemistry reveals strong reactivity for synaptophysin, Leu-7, somatostatin, S-100 protein and vimentin. A few ganglion cells are reactive for neurofilaments. Chromogranin A, myelin basic protein, desmin and cytokeratin are absent. Immunohistochemical data from literature regarding the cytoskeletal composition of GPs are not unequivocal: cytokeratin and neurofilament positivity is reported by some authors and denied by others. More uniformity is reported concerning the peptides produced by GPs: somatostatin and pancreatic polypeptide are the most frequently found antigens, followed by serotonin. General neuroendocrine markers like neuron specific enolase and protein gene product 9.5 are always positive, whereas chromogranins are rarely found. S-100 protein is always positive in the spindle cell component. Our data are in keeping with those previously reported and add the diffuse positivity for the Leu-7 antigen and the positivity of ganglion cells for synaptophysin. The nature of the tumour is still a matter of debate and it is difficult to agree with either of the proposed hypotheses--hamartoma/choristoma versus true neoplasm. However the recent reports of the occasional malignant evolution of GPs may support their true neoplastic nature.

Melanotic paraganglioma of the orbit: a case report.

A paraganglioma of the orbit in a 21-year-old woman is presented, containing oculo-cutaneous melanin in many tumor cells, occasionally adjacent to neurosecretory granules, and in macrophages. This tumor expands the list of neuroectodermal tumors with potential melaninization.

Paraganglioma of the cauda equina: an ultrastructural and immunohistochemical study of two cases.

The ultrastructural and immunohistochemical features of 2 paragangliomas arising in the cauda equina are described. In both cases the tumor cells were arranged in small nests or cords and contained characteristic neurosecretory granules, lamellar stacks of rough endoplasmic reticulum (RER), and some well-developed Golgi apparatuses in their cytoplasm. The cells varied in electron density; the darker cells, occasionally resembling sustentacular cells, were probably dehydrated light cells because they contained a few neurosecretory granules. Sustentacular cells were difficult to identify by electron microscopy, but irregularly distributed S-100 protein and glial fibrillary acidic protein (GFAP) were found in these cells by immunostaining. Many tumor cells contained abundant neurofilaments. Curiously, a few cytokeratin-positive cells were found in 1 case. On microscopic examination, a small area of ganglioneuroma was found associated with the paraganglioma in 1 case. Ganglionic differentiation was concluded to be frequent in paragangliomas of the cauda equina region as in duodenal paragangliomas.

[Immunohistochemical detection of growth hormone-releasing factor (GRF) in neuroendocrine tumors]. / Immunhistochemischer Nachweis des Growth hormone-releasing factor (GRF) in neuroendokrinen Tumoren.

We examined formalin-fixed, paraffin-embedded human tumors (42) from autopsies and surgical specimens for the presence of human pancreatic GRF-40 using the unlabeled antibody peroxidase-antiperoxidase method to assess the prevalence of tumors containing GRF, to define their primary sites and cellular derivations, and to correlate clinical and pathological features. Two paragangliomas, 1 pancreatic endocrine tumor, 1 bronchial carcinoid and 1 ganglioneuroma were immunoreactive for GRF. Of the GRF-containing tumors, only one bronchial carcinoid and one paraganglioma were associated with acromegaly.

Decreased expression of neuropeptides in malignant paragangliomas: an immunohistochemical study.

Paraffin-embedded sections of 99 human adrenal and extraadrenal paragangliomas were analyzed by the indirect immunoperoxidase technique for the presence of neuron-specific enolase (NSE) and 10 neuropeptides. Each showed diffuse staining for NSE. Most tumors were positive for [Leu5]-enkephalin (76 per cent), [Met5]-enkephalin (75 per cent), somatostatin (67 per cent), and pancreatic polypeptide (51 per cent), followed by vasoactive intestinal polypeptide (VIP) (43 per cent), substance P (31 per cent), ACTH (28 per cent), calcitonin (23 per cent), bombesin (15 per cent), and neurotensin (12 per cent). The neuropeptides paralleled to a large extent those normally found in the sympathetic nervous system. Clinically malignant paragangliomas (n = 25) with proven regional or distant metastases expressed considerably fewer neuropeptides, although the spectrum of those seen remained similar. Malignant paragangliomas contained an average of two neuropeptides per tumor, in contrast to five for the benign tumors (P less than 0.05). Logistic regression analysis of staining results revealed that the paucity of enkephalins, somatostatin, pancreatic polypeptide, and VIP along with the patient's sex was predictive of clinical malignancy. Our results show a definite relationship between expression of neuropeptides and the biologic behavior of these paragangliomas.

Gangliocytic paraganglioma of the duodenum: case report.

A case of gangliocytic paraganglioma of the second portion of the duodenal loop is presented. The tumor was polypoid and, histologically, composed of mature ganglion cells, spindle cells and epithelial-like cells. Immunocytochemical examination demonstrated the presence of neurofilament 200 K and S-100 protein only in the first two types of cells; all the cells were positive for neuron-specific enolase. The reaction for cytokeratin was negative in all neoplastic components. According to morphologic and immunocytochemical findings, we suggest a hamartomatous nature of this entity.

Gangliocytic paraganglioma associated with duodenal adenocarcinoma. Case report with immunohistochemical evaluation.

We present the first reported case (to our knowledge) of duodenal gangliocytic paraganglioma (GPG) to be associated with an underlying invasive adenocarcinoma. The patient, a 71-year-old man, presented with epigastric tenderness and was found to have metastatic adenocarcinoma in two regional lymph nodes. Immunohistochemical evaluation of the GPG demonstrated positive staining for gastrin, glial-fibrillary acidic protein, glucagon, neuron-specific enolase, pancreatic polypeptide, S100 protein, somatostatin, and substance P. The clinical, pathologic, and immunohistochemical features of GPG are discussed, with a review of the literature.

[Malignant paraganglioma of the duodenum. Immunohistochemical and ultrastructural study of a case]. / Le paragangliome malin du duodénum. Etude immunohistochimique et ultrastructurale d'un cas.

Paragangliomas of the duodenum are rare. Only 40 cases, most of them corresponding to benign tumours, have been published. In this study, we report a malignant paraganglioma of the duodenum with lymph node metastasis occurring in a 73 year old woman. The essential clinical manifestations which brought the patient to surgery were abdominal pain, melaena and anemia. The surgical specimen was investigated histologically, immunohistochemically and ultrastructurally. The tumour was composed of three types of cells: epithelial, gangliocytic and spindle shaped mesenchymal cells. The first contained ultrastructurally intracytoplasmic granules bound with double membranes; they stained with monoclonal antibodies against chromogranin. Gangliocytic cells stained with monoclonal N.S.E. antibodies and the spindle cells stained with S 100 protein. The spindle cells displayed ultrastructurally glial cell characteristics, containing micro-filaments of glial type. These immunological and ultrastructural features argued in favor of the neuroendocrine cell origin of this paraganglioma.

Demonstration of S-100 protein in sustentacular cells of phaeochromocytomas and paragangliomas.

Eighteen phaeochromocytomas, including both sporadic and familial cases, four cervical paragangliomas, two jugular paragangliomas, and one abdominal paraganglioma were examined immunohistochemically for the presence of S-100 protein. Positive staining in cells morphologically similar to the sustentacular cells of normal paraganglia and adrenal medulla were found in all paragangliomas and in the benign and aggressively growing phaeochromocytomas. In the two malignant tumours no positive reaction was demonstrated. In one tumour the sustentacular cells were shown to contain glial fibrillary acidic protein further supporting their Schwann cell relationship. The number of S-100 positive cells varied considerably. They demonstrated a spindle celled or elongated configuration with long slender processes. The nature of the sustentacular cell proliferation, neoplastic versus reactive, is discussed.

Expression of neurofilament triplet proteins in human neural tumors. An immunohistochemical study of paraganglioma, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma.

Intermediate filaments which are specific to neural cells, ie, neurofilaments, consist of three subcomponents--68, 150, and 200 kd. Thirty human neural tumors were examined for the presence of these three subcomponents by means of their monospecific antisera. All 8 paragangliomas contained cells that were positive for the 68-kd component, but only 5 of them had cells positive for the 150-kd and 200-kd components. All 4 ganglioneuromas and 11 ganglioneuroblastomas contained cells that reacted with antibodies to all three components. All 7 neuroblastomas had cells reacting with antibody to 68 kd, but only 3 of them had cells that reacted with antibodies to 150 kd and 200 kd. In each case, the number of positive cells depended on the antibody used. The largest number reacting with antibody to 68 kd and the smallest with antibody to 200 kd. Furthermore, it was possible to detect tumor cells in which the 68-kd subcomponent existed by itself, but no tumor cells in which the 150-kd or 200-kd subcomponent existed alone could be detected. These results seem to indicate that antibody to the 68-kd component is sufficiently discriminating to be applied diagnostically.

Cardiac paragangliomas. A clinicopathologic and immunohistochemical study of four cases.

Cardiac paragangliomas are extremely rare neoplasms. Four surgically resected tumors were examined by immunohistochemistry and electron microscopy. The patients ranged in age from 18 to 36 years. All patients had hypertension and elevated urine catecholamine levels. Three tumors were located on the posterior left atrium, and one tumor was located in the interventricular groove at the aortic root. The tumors ranged in size from 5 to 7 cm, and they displayed a prominent Zellballen pattern without significant necrosis or mitosis. The tumors were mostly unencapsulated and infiltrated adjacent cardiac tissue in two cases. Immunoperoxidase staining showed that all tumors were positive for chromogranin and neuron-specific enolase. Three tumors were positive for methionine enkephalin. Positive staining for S-100 protein was seen in the sustentacular cells of all tumors but was negative in chromaffin cells. All tumors were negative for insulin, glucagon, gastrin, vasoactive intestinal polypeptide, somatostatin, adrenocorticotropic hormone, calcitonin, serotonin, pancreatic polypeptide, and rat atrial peptide. Ultrastructural studies of all four tumors showed moderate numbers of predominantly norepinephrine-type granules and a few epinephrine-type granules. These results show that cardiac paragangliomas are commonly found in close proximity to the left atrium and have immunohistochemical and ultrastructural features similar to other paragangliomas.

Neuroendocrine markers in paragangliomas of the head and neck.

Eighteen paragangliomas of the head and neck (11 carotid body tumors, four glomus tympanicum tumors, three glomus jugulare tumors) were studied retrospectively. Tissue from each of these tumors was immunostained for the presence of serotonin, a variety of neuropeptide hormones, and the enzyme neuron-specific enolase (NSE). Seven tumors were studied by electron microscopy. The clinical and laboratory records were reviewed for evidence of endocrine activity or metabolic imbalance. All tumors displayed diffuse and intense immunostaining for NSE. In addition, a wide variety of hormonal substances could be identified. Those most frequently demonstrated were serotonin and leu-enkephalin. Ten of the 11 carotid body tumors demonstrated immunoreactivity for multiple hormones. By electron microscopy all tumors contained a heterogeneous population of membrane-bound neurosecretory granules. None of these tumors was associated with a clinically apparent endocrine syndrome. We conclude that paragangliomas of the head and neck are neuroendocrine tumors that are capable of synthesizing a variety of hormonal substances. These hormonal substances rarely elicit a clinically apparent endocrine or metabolic imbalance. All of the tumors demonstrated immunostaining for NSE. Future studies on serum levels of NSE may provide useful diagnostic and follow-up data.