[Flow-cytometric study of familial paragangliomas of the carotid body]. / Studio citofluorimetrico di paragangliomi familiari del corpo carotideo.

Paragangliomas of the carotid body with an autosomal dominant genetic transmission have been described in a familial presentation in 7-10% of all the cases observed. In less than 10% malignancy is confirmed by secondary metastatic localization rather than by typical histological features of malignant diseases, such as vascular or perineural invasion, nuclear pleomorphism, mitotic activity. The purpose of the study is to present a familial group of paragangliomas of the carotid boy and a flow cytometric analysis of tumor content DNA and to discuss the prognostic value of the results. The paragangliomas of these related patients (father and daughter) are diploid, without regional lymph node or distant metastases; clinical and cytometric findings support a good prognosis even if an accurate follow up of such neuroendocrine tumors is nonetheless mandatory. Considering data in Literature, the Authors also propose a prognostic classification of paragangliomas as follows: noninvasive (capsulated, without vascular or perineural infiltration, diploid); locally invasive (histological signs such as vascular or perineural infiltration, nuclear pleomorphism, abnormal mitoses etc, diploid); potentially malignant (histological signs, non-diploid, expression of few antigens) and malignant (regional or distant metastases).

[Morphology and histogenesis of paraganglioma]. / Morfologiia i gistogenez paragangliomy.

Histological and ultrastructural studies were performed to examine 6 paragangliomas of various sites: carotid glomus, aortic body, sympathetic chain, and stomach. Five of the tumors in question had a histological structure typical of a paraganglioma. The gastric tumor was distinguished by being similar to a pheochromocytoma. With regard to the degree of infiltrative growth, the paragangliomas of the sympathetic chain and stomach were regarded as malignant. The ultrastructures of the paragangliomas examined were found to be of the same type. In all the neoplasms, tumor cells had signs of neuroendocrine and neurogenous differentiations that were characteristic of the ultrastructural organization of postganglionic neurons in the autonomic nervous system. The neurogenous differentiation was evidenced by cytoplasmic portions that are structurally similar to rough-surface endoplasmic reticulum, which is pertaining to Nissl's bodies; neurofilaments that form concentric structures containing neuroendocrine granules such as fibrous or Pick's bodies; intracytoplasmic cilia; specialized cytoplasmic processes of two types: axons and dendrites; partially reduced intercellular contacts, such as axosomatic and axodendritic synapses; sustentacular cells (sustenocytes). In the neoplasms evaluated as malignant, the neurogenous differential signs were more pronounced by reducing the number of neurosecretory granules, which might, apparently, serve as an ultrastructural criterion for establishing the degree of paraganglioma malignancy.

[Oncocytic paraganglioma of the carotid body]. / Onkozytäres Paragangliom des Karotiskörpers.

One case of benign oncocytic paraganglioma which had originated from the non-chromaffin cells of the carotid body in a woman, 66 years of age, is described in this paper. The microscopic pattern of the tumor consisted mainly of large, round, eosinophilic cells arranged in solid nests and sheets. Pale rather than eosinophilic cells of polygonal shape were predominant in the peripheral areas. Ultrastructural analysis revealed the presence of three cell types: oncocytes, cells with electron-dense granules, 150 to 200 nm in size, and transitional forms between these two. Possible development of oncocytes from APUD cells is discussed.

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.

Paragangliomas of the head and neck: ultrastructural and immunohistochemical analysis.

Eighteen head and neck paragangliomas were studied by light microscopy and light microscopic immunohistochemistry by the peroxidase technique for the presence of NSE (neuron-specific enolase), serotonin, and a battery of neuropeptides. Seven of these tumors were also studied by electron microscopy. All 18 cases demonstrated immunostaining for NSE; 10 of the 11 carotid body tumors had immunostaining for multiple hormones. Considering all 18 cases, the most frequently demonstrated hormonal substances were in order: serotonin, leu-enkephalin, gastrin, substance P, vasoactive intestinal polypeptide (VIP), somatostatin, bombesin, calcitonin, and alpha MSH. In several tumors, adjacent-step sections stained for different hormonal substances strongly suggested reactivity for more than one hormone in given tumor cells. By electron microscopy, all 7 cases studied displayed considerable heterogeneity of the neurosecretory granules with respect to size, shape, and electron density. This demonstrated that branchiomeric paragangliomas are capable of producing a spectrum of neuropeptides in addition to their known amine content. The presence of immunoreactive serotonin in most of these neoplasms was confirmed. In addition to these findings, neurofibrils within the substance of carotid body paragangliomas demonstrated immunoreactivity for somatostatin and a gastrinlike neuropeptide. The significance of the neuropeptides in these neoplasms and their possible presence and role in normal and hyperplastic paraganglia remain to be defined.

An ultrastructural cytochemical stain specific for neuroendocrine neoplasms.

Previous work from our laboratory has indicated that the uranaffin reaction, when run under specific conditions, will stain neurosecretory granules. In this ultrastructural cytochemical study, we analyzed the granule-staining properties of 13 normal, 10 abnormal (non-neoplastic), and 138 neoplastic tissues in an attempt to evaluate the specificity of the uranaffin reaction for diagnostic purposes when compared with routinely processed specimens. For the uranaffin reaction, previously fixed tissue stored in buffer was rinsed with 0.9% NaCl and reacted with a 4% aqueous solution of uranyl acetate (pH 3.9) for 48 hours. After three NaCl rinses, the tissue was dehydrated and processed for electron microscopy. The granules of normal or non-neoplastic neuroendocrine cells that stained positively with the uranaffin reaction included pancreatic islet cells, thyroid C cells, adrenal medullary cells, parathyroid chief cells, and the neuroendocrine cells of the intestine. All 42 neuroendocrine neoplasms studied possessed abundant uranaffin-positive granules and included carcinoids, oat cell carcinomas, islet cell neoplasms, medullary carcinomas of the thyroid, pheochromocytomas, carotid body paragangliomas, a pituitary adenoma, Merkel cell carcinomas, parathyroid adenomas, and a neuroblastoma. All 96 control neoplasms that were not classified as neuroendocrine in nature were negative for neurosecretory granules when studied with the uranaffin reaction and included 13 neoplasms derived from endocrine glands, 57 neoplasms from secretory epithelium, 10 of hematopoietic origin, and 16 miscellaneous neoplasms. It was determined that the uranaffin reaction is a useful ultrastructural cytochemical marker for neuroendocrine granules and helped distinguish these cytoplasmic organelles from ultrastructurally similar granules derived from non-neuroendocrine cells.

Malignant catecholamine-secreting carotid body paraganglioma.

The second known case of a malignant catecholamine-secreting (DA)-secreting carotid body paraganglioma is presented. Dopamine synthesis and secretion can be increased in malignant tumors derived from neural crest cells. Whether this is true, in addition, for extra-adrenal paragangliomas is not yet clear. Malignant paragangliomas of the carotid body and larynx, although rare, frequently have been accompanied by increased catecholamine secretion. Malignant catecholamine-secreting carotid body paragangliomas are best treated by composite resection (internal carotid artery and neck dissection), with special attention being given to measures preventing severe hypertension and arrhythmias in the perioperative period.

Functional carotid paragangliomas. Biochemical, ultrastructural, and histochemical correlation with clinical symptoms.

To our knowledge, this study is the first to correlate the results of biochemical, electron microscopic (EM), and histochemical analyses of tissues from functional paragangliomas of the upper carotid area with a patient's clinical symptoms. The tumor tissues from our two patients contained epinephrine, norepinephrine, and dopamine. Neurosecretory granules were identified in both tumors by EM and by the Grimelius silver stain. The patient with the most severe symptoms exhibited evidence of higher circulating levels of catecholamines by biochemical, EM, and histochemical analyses.

Metastatic carotid body paraganglioma in von Hippel-Lindau disease. An electron microscopic study.

Pulmonary metastases from a carotid body paraganglioma developed in a patient with von Hippel-Lindau disease. On electron microscopic examination, these metastases consisted solely of chief cells that contained membrane-bound, dense-core granules and formed numerous cytoplasmic processes. These data support the hypothesis that the chief cell is the sole neoplastic cell in paragangliomas. Finally, to our knowledge, this clinical association of a malignant carotid body paraganglioma and pheochromocytoma in von Hippel-Lindau disease is unique.

[Investigations on the ultrastructural cytology of branchiomeric paragangliomas (author's transl)]. / Untersuchungen zur ultrastrukturellen Zytologie branchiomerer Paragangliome.

The paragangliomas of the jugular and carotid bodies are growth processes which show varying histological and cytological patterns. The real nature of these lesions is still a matter of discussion. In this study 6 jugular and 3 carotid body tumours were investigated using the electron microscope. The main components were irregular cells with short and long cytoplasmic processes closely packed and mostly arranged in complexes. The ultrastructural cytology of the jugular and carotid bodies showed no striking differences. The great majority of the cells exhibits a clear similarity to the cells of normal paraganglia, especially to chief cells of carotid bodies (type I cells). But there were some modifications in the cellular structure including the abnormal structure of mitochondria and a greater variation in the morphology of the dense cored granules. The cytoplasm was dominated by differing populations of mitochondria comprising such of the crista type and such showing tubulus-like structures with a dense matrix and very often intramitochondrial bodies. The characteristic feature was the occurrence of randomly distributed dense cored granules measuring 700-800 A in diameter. These granules display a homogeneous electron dense or moderately dense somewhat granular core which is separated from limiting membrane by a clear electron lucent halo. A further population of granules was of a greater dimension (3,000-4,000 A) revealing an oval or cigar-like shape. In contrast to the former type the homogeneous dense cores of these granules showed a smooth contour and the lucent halo was very narrow. In general, singular exocytotic phenomena could be supposed. More frequently, however, signs of granulolysis were encountered. Free ribosomes, arranged often as polysomes, sparse, disorderly distributed microfilaments of 60-80 A diameter, few 240 A-microtubules and some lysosomal structures are also observed. Usually the cell clusters abutted directly upon the vascular connective tissue. In other cases cytoplasmic processes are intercalated resembling sustentacular cells. Fenestrated capillaries known to be typical for the paraganglionic tissues were only seldom detected. In the interstitial tissue typical collagen fibres are found showing a periodicity of 600-700 A, but occasionally fibres with a periodicity of about 1,200 A could be seen resembling fibrous-long-spacing collagen. Synaptic junctions and nerves or axons were always lacking.

Malignant carotid body paraganglioma: light and electron microscopic study of the tumor and its metastases.

A right carotid body paraganglioma (CBP) was removed from a 30-year-old female after finding metastases to cervical lymph nodes. The tumor and its metastases were studied by light and electron microscopy to determine the neoplastic cell type. Light microscopy confirmed the presence of chief cells but was inadequate alone to exclude sustentacular cells. By electron microscopy, only chief cells were found in both the primary and secondary tumors. This is the first report of an ultrastructural study of a metastasis from a malignant CBP. From our observation, we suggest that CBP be defined as a proliferation of chief and sustentacular cells. Electron microscopy is essential to determine the cell types present and thereby help classify the lesion as a tumor or hyperplasia of the carotid body.

[A case of multiple chemodectoma: clinical and electron microscopical studies]. / Ein Fall des multiplen Chemodektoms. --Klinische und elektronenmikroskopische Untersuchungen--.

We observed electronmicroscopically and clinically a case of multiple chemodectoma, which has occurred from glomus caroticum sinistra and glomus jugularis sinistra of a 18 year old boy. The diagnosis was especially made by an angiography of the left common carotid artery and by a retrograde venography of the left internal jugular vein. Electronmicroscopically two kinds of tumor cells in this chemodectoma were identified. These cytoplasmas showed cored neurosecretory granules measured 125 to 250 A in diameter markedly increasing in number. Moreover in the island of the tumor cells of the carotid body tumor we happened to observe the nerve ending.

Vagal body tumor (nonchromaffin paraganglioma, chemodectoma, and carotid body-like tumor) with cervical node metastasis and familial association: ultrastructural study and review.

A case of a vagal body tumor with a solitary cervical node metastasis is described. There was a remarkable familial association: a biopsy-proven paraganglioma occurred in two members of the patient's family and there was a strong clinical suspicion of a paraganglioma in two others. In a review of the literature, eight patients with metastasizing vagal body tumors and eight patients in whom the vagal body tumor was a component of multicentric presentation of paragangliomas were found. Only one other patient in whom there was a familial occurrence involving a vagal body tumor has been reported. Ultrastructural study of the cervical node metastasis revealed the presence of light and dark chief cells containing scanty, membrane-bound, densecore, neurosecretory-type granules. Atypical granules were noted in a few of the dark cells. Nerve fibers, synaptic vesicles, and sustentacular cells, such as occur in normal paraganglionic tissue, were not observed in this tumor.